miladalsh/processed_scinews_dataset · Datasets at Hugging Face

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The extracellular matrix protects biofilm cells by reducing diffusion of antimicrobials. Tobramycin is an antibiotic used extensively to treat P. aeruginosa biofilms, but it is sequestered in the biofilm periphery by the extracellular negative charge matrix and loses its efficacy significantly. Dispersal of the biofilm extracellular matrix with enzymes such as DNase I is another promising therapy that enhances antibiotic diffusion into the biofilm. Here, we combine the charge neutralization of tobramycin provided by dextran-based single-chain polymer nanoparticles (SCPNs) together with DNase I to break the biofilm matrix. Our study demonstrates that the SCPNs improve the activity of tobramycin and DNase I by neutralizing the ionic interactions that keep this antibiotic in the biofilm periphery. Moreover, the detailed effects and interactions of nanoformulations with extracellular matrix components were revealed through time-lapse imaging of the P. aeruginosa biofilms by laser scanning confocal microscopy with specific labeling of the different biofilm components. Introduction Antibiotics are the principal therapy against acute bacterial infections. However, when a bacterial community attaches to a surface and grows as a biofilm, the resulting infections become chronic, and antibiotics are much less effective 1 . Bacteria form biofilms by building an extracellular matrix, which creates a physical and chemical barrier that is the leading cause of antibiotic inefficiency. This extracellular biofilm matrix comprises polysaccharides, lipids, proteins, and extracellular DNA (eDNA) 2 . Pseudomonas aeruginosa is a bacterium that usually forms biofilms in lungs affected by cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Apart from being the primary cause of morbidity and mortality for these illnesses 3 , P. aeruginosa is usually involved in chronic wound infections 4 and is the leading cause of microbial keratitis 5 . Pseudomonas biofilms are a public health concern 6 as the leading cause of nosocomial infections 7 , such as ventilator-associated pneumonia 8 and catheter-associated urinary tract infections 9 . Moreover, P. aeruginosa is frequently associated with other bacteria, and these coinfections worsen the outcome of the disease 6 , 10 . eDNA is a key part of the P. aeruginosa extracellular biofilm matrix, as it promotes bacterial adhesion on the surface in the early stages, maintains its structural stability in mature biofilms 11 , 12 , 13 and increases the viscosity of sputum in CF patients 14 . eDNA was thought to be only a residual material of bacterial lysis until it was reported that the enzyme deoxyribonuclease (DNase I) inhibits biofilm formation and dissolves established biofilms 15 . Currently, this enzyme (commercially available by Genentech with the name of Pulmozyme) is used to treat CF patients via aerosol administration, and it aids mucus clearance by reducing the viscosity and improving antibiotic chemotherapy 16 . When a pulmonary infection of P. aeruginosa becomes chronic and forms a biofilm, it frequently converts to a mucoid phenotype by overproducing the anionic polysaccharide alginate in the extracellular matrix 17 . Alginate protects bacteria from the immune system by inhibiting the complement system and reducing phagocytosis by neutrophils and macrophages. Together with eDNA, this negatively charged polysaccharide binds to a positively charged antibiotic, thus diminishing antibiotic diffusion throughout the biofilm 18 , 19 , 20 . Drug nanocarriers can be used to effectively overcome these barriers and transport the drug to the site of interest. Nanoparticles protect the antimicrobial agent from degradation or deactivation, prevent interactions between the drug and biofilm extracellular polymeric substances (EPS), and release the antibiotic locally and in a controlled manner to enhance antimicrobial activity. Rational design of nanocarriers for pulmonary administration is key to reaching the biofilm resulting from a lung infection and delivering the cargo to the site of infection. Previous studies have demonstrated that to cross the mucus layer surrounding the infection, the size and surface charge of the delivery system are critical. Nanoparticles smaller than 500 nm in diameter and neutral or negatively charged are considered the best candidates 21 , 22 , 23 , 24 . However, for treatment of P. aeruginosa biofilms, it has been shown that the diffusion rate is size-dependent, and a nanosystem size below 100 nm is crucial 25 . Moreover, the mobility and diffusion rate of negatively charged nanoparticles are higher than those of positively charged nanoparticles, since the latter are retained by the anionic eDNA in the EPS 26 via electrostatic interactions. The most studied polymeric nanoparticles are based on chitosan and poly(lactic- co -glycolic acid) (PLGA), among others. The biocompatibility, degradability, and antimicrobial nature of chitosan make it a promising vector, but its hydrophobicity, which promotes aggregation under biological conditions, hinders its use. On the other hand, PLGA nanoparticles have the disadvantage of generating acidic degradation products and exhibiting low encapsulation efficiencies. Nevertheless, it is worth mentioning that PLGA loaded with ciprofloxacin/DNase I and colistin considerably reduced biofilm formation 27 , 28 . However, in both cases, the relatively small amount of antibiotic encapsulated, i.e., not higher than 1 wt%, indicates the need for administration of a very high concentration of the nanoformulation dose, which might jeopardize nebulization and rule out clinical use as a therapy for chronically infected patients. Recently, single-chain polymer nanoparticles (SCPNs) based on dextran natural polysaccharides have been used to carry antimicrobial peptides to fight infections from antimicrobial-resistant bacteria 29 . SCPNs 30 , 31 , 32 , 33 , 34 , 35 are obtained by collapsing a single polymer chain to form small nanoparticles with sizes generally reported to be below 20 nm, which are comparable to those of proteins and viruses. Functionalization can be readily modulated during or after production. Dextran-based SCPNs have shown ideal characteristics for use as nanocarriers in imaging and immunotherapy, as they are size-controlled, biocompatible, biodegradable, and water-dispersible 36 , 37 . Due to their small hydrodynamic sizes, homogenous lung distribution was observed by SPECT-CT after intratracheal administration using a Penn Century Microsprayer ® aerosolizer, indicating that these SCPNs are suitable nanocarriers for lung administration 29 , 37 , 38 , 39 . In this work, SCPNs were used to carry tobramycin via electrostatic interactions, which", "role": "user" }, { "content": "Persistent lung infections, chronic wounds, and health care-associated infections are typically much more difficult to treat than other types of bacterial infections. This is because they are often caused by biofilms, that is, colonies of microbes—mainly bacteria— that grow together in a self-produced matrix that protects and isolate them from the external environment. Now, a new triple-acting antibiotic agent has managed to break through the biofilm extracellular matrix and eliminate more than 50% of the pathogens in one shot, according to a study published in the journal npj Biofilms and Microbiomes. The study was led by Eduard Torrents, lecturer at the Department of Genetics, Microbiology and Statistics of the Faculty of Biology and head of the group on Bacterial Infections: Antimicrobial Therapy of the Institute for Bioengineering of Catalonia (IBEC). This extracellular matrix exacerbates antibiotic resistance, one of the biggest threats to global health, according to the World Health Organization (WHO), since killing the bacteria inside the film is up to a thousand times harder. Biofilm infections are therefore the most important nonspecific mechanism of antimicrobial resistance. Attacking these microbes using only antibiotics is not enough. There is a need for tools that break down the extracellular matrix to access and kill the bacteria inside. The first author of this study, which has achieved this milestone, is Núria Blanco-Cabra, postdoctoral researcher of the group led by Eduard Torrents at the UB and IBEC. The study was carried out together with scientists from CIDETEC (Basque Country). A triple-acting drug combination The study focused on the bacteria Pseudomonas areuginosa, a pathogen that often grows in biofilms in the lungs of those patients with cystic fibrosis or chronic obstructive pulmonary disease (COPD), causing persistent infections. \"We grew biofilm cultures in vitro, using a technique that resembles to the way in which they exist and grow in nature,\" added Torrents. In clinical practice, these infections are usually treated with an antibiotic called tobramycin. However, its effectiveness is limited by its inability to penetrate the film. This happens because tobramycin, which is positively charged, is neutralized by the extracellular matrix (with a negative charge). The researchers loaded the antibiotic into negatively charged nanoparticle carriers. This could neutralize the positive charge before the drug reached the biofilm, which enabled it to break the extracellular matrix and kill the bacteria inside. What is more important, these carriers—built by dextran-based single chain nanoparticles—were able to transport up to 40% of the weight of the antibiotic. \"Many of the previously studied nanotransporters have only been able to sustain a small load of the target compound, which has prevented their clinical use. We managed to overcome this obstacle,\" says Torrents. The antibiotic-loaded nanocarriers were also coated in an enzyme called DNase I. One of the compounds that holds bacteria biofilms together is structural DNA found throughout the extracellular matrix. DNase I can break down this \"glue,\" causing the matrix to loosen, and allowing the antibiotic to penetrate the biofilm even further. \"By combining an antibiotic with a couple of agents that break the biofilm up, we have created a drug that is more powerful than the antibiotic alone which kills the bacteria that lives inside the film,\" notes Eduard Torrents, principal researcher of the study. Using microscopy images, the researchers found that the new agent had not only dissolved the structural DNA in the extracellular matrix, but also that it was acting on and killing the bacteria inside. With just a single application, they reduced the bacterial biomass by more than half. \"Having achieved such significant biofilm clearance with a single dose of our agent, we predicted that a full course of antibiotics could significantly reduce the burden of these infections, which are extremely difficult to treat.\" In future clinical uses, this agent could be administered in multiple doses, as is standard practice with antibiotics. The next step is to work on the clinical validation of this system. Its commercialization would represent a decisive advance in the treatment of biofilm infections, the global economic cost of which currently amounts to 4 billion dollars a year. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The extracellular matrix protects biofilm cells by reducing diffusion of antimicrobials. Tobramycin is an antibiotic used extensively to treat P. aeruginosa biofilms, but it is sequestered in the biofilm periphery by the extracellular negative charge matrix and loses its efficacy significantly. Dispersal of the biofilm extracellular matrix with enzymes such as DNase I is another promising therapy that enhances antibiotic diffusion into the biofilm. Here, we combine the charge neutralization of tobramycin provided by dextran-based single-chain polymer nanoparticles (SCPNs) together with DNase I to break the biofilm matrix. Our study demonstrates that the SCPNs improve the activity of tobramycin and DNase I by neutralizing the ionic interactions that keep this antibiotic in the biofilm periphery. Moreover, the detailed effects and interactions of nanoformulations with extracellular matrix components were revealed through time-lapse imaging of the P. aeruginosa biofilms by laser scanning confocal microscopy with specific labeling of the different biofilm components. Introduction Antibiotics are the principal therapy against acute bacterial infections. However, when a bacterial community attaches to a surface and grows as a biofilm, the resulting infections become chronic, and antibiotics are much less effective 1 . Bacteria form biofilms by building an extracellular matrix, which creates a physical and chemical barrier that is the leading cause of antibiotic inefficiency. This extracellular biofilm matrix comprises polysaccharides, lipids, proteins, and extracellular DNA (eDNA) 2 . Pseudomonas aeruginosa is a bacterium that usually forms biofilms in lungs affected by cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Apart from being the primary cause of morbidity and mortality for these illnesses 3 , P. aeruginosa is usually involved in chronic wound infections 4 and is the leading cause of microbial keratitis 5 . Pseudomonas biofilms are a public health concern 6 as the leading cause of nosocomial infections 7 , such as ventilator-associated pneumonia 8 and catheter-associated urinary tract infections 9 . Moreover, P. aeruginosa is frequently associated with other bacteria, and these coinfections worsen the outcome of the disease 6 , 10 . eDNA is a key part of the P. aeruginosa extracellular biofilm matrix, as it promotes bacterial adhesion on the surface in the early stages, maintains its structural stability in mature biofilms 11 , 12 , 13 and increases the viscosity of sputum in CF patients 14 . eDNA was thought to be only a residual material of bacterial lysis until it was reported that the enzyme deoxyribonuclease (DNase I) inhibits biofilm formation and dissolves established biofilms 15 . Currently, this enzyme (commercially available by Genentech with the name of Pulmozyme) is used to treat CF patients via aerosol administration, and it aids mucus clearance by reducing the viscosity and improving antibiotic chemotherapy 16 . When a pulmonary infection of P. aeruginosa becomes chronic and forms a biofilm, it frequently converts to a mucoid phenotype by overproducing the anionic polysaccharide alginate in the extracellular matrix 17 . Alginate protects bacteria from the immune system by inhibiting the complement system and reducing phagocytosis by neutrophils and macrophages. Together with eDNA, this negatively charged polysaccharide binds to a positively charged antibiotic, thus diminishing antibiotic diffusion throughout the biofilm 18 , 19 , 20 . Drug nanocarriers can be used to effectively overcome these barriers and transport the drug to the site of interest. Nanoparticles protect the antimicrobial agent from degradation or deactivation, prevent interactions between the drug and biofilm extracellular polymeric substances (EPS), and release the antibiotic locally and in a controlled manner to enhance antimicrobial activity. Rational design of nanocarriers for pulmonary administration is key to reaching the biofilm resulting from a lung infection and delivering the cargo to the site of infection. Previous studies have demonstrated that to cross the mucus layer surrounding the infection, the size and surface charge of the delivery system are critical. Nanoparticles smaller than 500 nm in diameter and neutral or negatively charged are considered the best candidates 21 , 22 , 23 , 24 . However, for treatment of P. aeruginosa biofilms, it has been shown that the diffusion rate is size-dependent, and a nanosystem size below 100 nm is crucial 25 . Moreover, the mobility and diffusion rate of negatively charged nanoparticles are higher than those of positively charged nanoparticles, since the latter are retained by the anionic eDNA in the EPS 26 via electrostatic interactions. The most studied polymeric nanoparticles are based on chitosan and poly(lactic- co -glycolic acid) (PLGA), among others. The biocompatibility, degradability, and antimicrobial nature of chitosan make it a promising vector, but its hydrophobicity, which promotes aggregation under biological conditions, hinders its use. On the other hand, PLGA nanoparticles have the disadvantage of generating acidic degradation products and exhibiting low encapsulation efficiencies. Nevertheless, it is worth mentioning that PLGA loaded with ciprofloxacin/DNase I and colistin considerably reduced biofilm formation 27 , 28 . However, in both cases, the relatively small amount of antibiotic encapsulated, i.e., not higher than 1 wt%, indicates the need for administration of a very high concentration of the nanoformulation dose, which might jeopardize nebulization and rule out clinical use as a therapy for chronically infected patients. Recently, single-chain polymer nanoparticles (SCPNs) based on dextran natural polysaccharides have been used to carry antimicrobial peptides to fight infections from antimicrobial-resistant bacteria 29 . SCPNs 30 , 31 , 32 , 33 , 34 , 35 are obtained by collapsing a single polymer chain to form small nanoparticles with sizes generally reported to be below 20 nm, which are comparable to those of proteins and viruses. Functionalization can be readily modulated during or after production. Dextran-based SCPNs have shown ideal characteristics for use as nanocarriers in imaging and immunotherapy, as they are size-controlled, biocompatible, biodegradable, and water-dispersible 36 , 37 . Due to their small hydrodynamic sizes, homogenous lung distribution was observed by SPECT-CT after intratracheal administration using a Penn Century Microsprayer ® aerosolizer, indicating that these SCPNs are suitable nanocarriers for lung administration 29 , 37 , 38 , 39 . In this work, SCPNs were used to carry tobramycin via electrostatic interactions, which<|im_end|> <|im_start|>assistant Persistent lung infections, chronic wounds, and health care-associated infections are typically much more difficult to treat than other types of bacterial infections. This is because they are often caused by biofilms, that is, colonies of microbes—mainly bacteria— that grow together in a self-produced matrix that protects and isolate them from the external environment. Now, a new triple-acting antibiotic agent has managed to break through the biofilm extracellular matrix and eliminate more than 50% of the pathogens in one shot, according to a study published in the journal npj Biofilms and Microbiomes. The study was led by Eduard Torrents, lecturer at the Department of Genetics, Microbiology and Statistics of the Faculty of Biology and head of the group on Bacterial Infections: Antimicrobial Therapy of the Institute for Bioengineering of Catalonia (IBEC). This extracellular matrix exacerbates antibiotic resistance, one of the biggest threats to global health, according to the World Health Organization (WHO), since killing the bacteria inside the film is up to a thousand times harder. Biofilm infections are therefore the most important nonspecific mechanism of antimicrobial resistance. Attacking these microbes using only antibiotics is not enough. There is a need for tools that break down the extracellular matrix to access and kill the bacteria inside. The first author of this study, which has achieved this milestone, is Núria Blanco-Cabra, postdoctoral researcher of the group led by Eduard Torrents at the UB and IBEC. The study was carried out together with scientists from CIDETEC (Basque Country). A triple-acting drug combination The study focused on the bacteria Pseudomonas areuginosa, a pathogen that often grows in biofilms in the lungs of those patients with cystic fibrosis or chronic obstructive pulmonary disease (COPD), causing persistent infections. "We grew biofilm cultures in vitro, using a technique that resembles to the way in which they exist and grow in nature," added Torrents. In clinical practice, these infections are usually treated with an antibiotic called tobramycin. However, its effectiveness is limited by its inability to penetrate the film. This happens because tobramycin, which is positively charged, is neutralized by the extracellular matrix (with a negative charge). The researchers loaded the antibiotic into negatively charged nanoparticle carriers. This could neutralize the positive charge before the drug reached the biofilm, which enabled it to break the extracellular matrix and kill the bacteria inside. What is more important, these carriers—built by dextran-based single chain nanoparticles—were able to transport up to 40% of the weight of the antibiotic. "Many of the previously studied nanotransporters have only been able to sustain a small load of the target compound, which has prevented their clinical use. We managed to overcome this obstacle," says Torrents. The antibiotic-loaded nanocarriers were also coated in an enzyme called DNase I. One of the compounds that holds bacteria biofilms together is structural DNA found throughout the extracellular matrix. DNase I can break down this "glue," causing the matrix to loosen, and allowing the antibiotic to penetrate the biofilm even further. "By combining an antibiotic with a couple of agents that break the biofilm up, we have created a drug that is more powerful than the antibiotic alone which kills the bacteria that lives inside the film," notes Eduard Torrents, principal researcher of the study. Using microscopy images, the researchers found that the new agent had not only dissolved the structural DNA in the extracellular matrix, but also that it was acting on and killing the bacteria inside. With just a single application, they reduced the bacterial biomass by more than half. "Having achieved such significant biofilm clearance with a single dose of our agent, we predicted that a full course of antibiotics could significantly reduce the burden of these infections, which are extremely difficult to treat." In future clinical uses, this agent could be administered in multiple doses, as is standard practice with antibiotics. The next step is to work on the clinical validation of this system. Its commercialization would represent a decisive advance in the treatment of biofilm infections, the global economic cost of which currently amounts to 4 billion dollars a year. <|im_end|>

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2,314

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Previous research has linked sedentary behaviour (SB) to adverse physical health outcomes in adults and youth. Although evidence for the relationship between SB and mental health outcomes (e.g., depression) is emerging, little is known regarding risk of anxiety. Methods A systematic search for original research investigating the association between SB and risk of anxiety was performed using numerous electronic databases. A total of nine observational studies (seven cross-sectional and two longitudinal) were identified. Methodological quality of studies was assessed and a best-evidence synthesis was conducted. Results One cross-sectional study demonstrated a strong methodological quality, five cross-sectional studies demonstrated a moderate methodological quality and three studies (two cross-sectional one longitudinal) received a weak methodological quality rating. Overall, there was moderate evidence for a positive relationship between total SB and anxiety risk as well as for a positive relationship between sitting time and anxiety risk. There was inconsistent evidence for the relationship between screen time, television viewing time, computer use, and anxiety risk. Conclusion Limited evidence is available on the association between SB and risk of anxiety. However, our findings suggest a positive association (i.e. anxiety risk increases as SB time increases) may exist (particularly between sitting time and risk of anxiety). Further high-quality longitudinal/interventional research is needed to confirm findings and determine the direction of these relationships. Peer Review reports Background Sedentary behaviour (i.e. activities which require minimal body movement resulting in low energy expenditure similar to resting level [1.0 to 1.5 metabolic equivalent (METs)] [ 1 ]) includes behaviours such as sitting for a range of purposes (e.g. work, travel), and screen-based activities such as computer use, electronic gaming, and television viewing. Time spent in sedentary behaviour has emerged as a potentially important indicator of health in adult populations [ 2 ], independent of achieving sufficient physical activity. Among the general adult population some evidence suggests sedentary behaviour is associated with increased risk of developing various chronic diseases (e.g. overweight and obesity [ 3 ], cardiovascular disease [ 4 ], osteoporosis [ 5 ], type two diabetes [ 3 ], and various cancers [ 6 ]). However, reviews of prospective studies suggest that there is yet insufficient or no evidence to conclude relationships between sedentary behaviour and certain health outcomes (e.g. adulthood weight gain, cardiovascular disease risk, and some cancers) [ 7 , 8 ]. A range of health consequences of sedentary behaviour in children and adolescents have also been identified (e.g. unfavourable body composition, decreased fitness, lowered scores for self-esteem, and pro-social behaviour and decreased academic achievement [ 9 ], sleep problems, musculoskeletal pain, depression, and poor psychological well-being [ 10 ]). However, like that of the adult literature, reviews of prospective studies in young people suggest that there still remains insufficient evidence to conclude associations between sedentary behaviour and some health indicators (e.g. body weight, blood pressure, bone mass) [ 11 ]. The association between sedentary behaviour and mental health issues such as depression [ 12 , 13 ] and self-esteem [ 14 ] have been explored within some population groups (e.g., women, adolescents), and on the balance it has been suggested that a positive relationship exists between most sedentary behaviours and depression [ 12 ] and self-esteem [ 9 ]. However little is known regarding the relationship between sedentary behaviour and other mental illnesses such as anxiety. Anxiety is a mental illness that affects approximately 14 % of Australians adults [ 15 ] and 15 % of 16–24 year olds [ 16 ], with global estimates indicating anxiety to affect over 27 million people [ 17 ]. Anxiety is characterised by excessive and persistent (yet often unrealistic) worry which can inhibit one’s ability to carry out activities of daily living [ 18 ]. Physiological symptoms can include: pounding heart; difficulty breathing; upset stomach; muscle tension; sweating; and, feeling faint, or shaky [ 18 ]. The illness has been shown to be linked to other serious diseases such as increased risk of cardiovascular disease and cancer [ 19 ] with estimates that anxiety and depression together contribute to 10 % of the total burden of disease in Australian women [ 20 ]. Considering anxiety has such a large impact on society (e.g. healthcare costs, quality of life, and life expectancy) and is highly prevalent across the life span, it is important to understand the behavioural factors that may be linked to it. It has been hypothesised that sedentary behaviour may lead to anxiety through biological pathways. For example, engaging in screen-based entertainment, such as video gaming, has been shown to increase the arousal of the central nervous system (CNS) [ 21 ], which could potentially lead to increased levels of anxiety. Additionally, screen-based sedentary behaviours have been linked to disrupted sleeping patterns which may also cause elevated levels of anxiety [ 22 ]. Given the plausibility of these short-term effects of sedentary behaviours on mood (i.e. distraction, CNS arousal, sleep), it is likely that the cumulative effects of these behaviours may further result in longer-term impacts on anxiety risk. Alternatively, the link between sedentary behaviour and anxiety could be explained by poor metabolic health. For example, research has shown sedentary behaviour to be linked to an increased risk of type 2 diabetes [ 3 ], a disease which is subsequently associated with poor mental health [ 23 ]. On the other hand, it could be hypothesised that those with mental illness (e.g. anxiety) tend to engage in sedentary behaviour more than those without the illness. Although research has indicated an inverse association between physical activity and anxiety may exist [ 24 – 26 ], currently the evidence regarding the association between sedentary behaviour and anxiety is unclear. Thus, the aim of this systematic review is to investigate the association between sedentary behaviour and risk of anxiety across the lifespan. Methods Search strategy A structured electronic search (employing PRISMA reporting guidelines) of publication years from 1990 (through November 2014) was conducted, since the 1990’s saw an increase in sedentary behaviour levels of the population with the widespread", "role": "user" }, { "content": "Low energy activities that involve sitting down are associated with an increased risk of anxiety, according to research published in the open access journal BMC Public Health. These activities, which include watching TV, working at a computer or playing electronic games, are called sedentary behavior. Further understanding of these behaviors and how they may be linked to anxiety could help in developing strategies to deal with this mental health problem. Many studies have shown that sedentary behavior is associated with physical health problems like obesity, heart disease, type 2 diabetes and osteoporosis. However, there has been little research into the link between sedentary behavior and mental health. This is the first systematic review to examine the relationship between anxiety and sedentary behavior. Anxiety is a mental health illness that affects more than 27 million people worldwide. It is a debilitating illness that can result in people worrying excessively and can prevent people carrying out their daily life. It can also result in physical symptoms, which amongst others includes pounding heartbeat, difficulty breathing, tense muscles, and headaches. Megan Teychenne, lead researcher and lecturer at Deakin University's Centre for Physical Activity and Nutrition Research (C-PAN) in Australia, said: \"Anecdotally - we are seeing an increase in anxiety symptoms in our modern society, which seems to parallel the increase in sedentary behavior. Thus, we were interested to see whether these two factors were in fact linked. Also, since research has shown positive associations between sedentary behavior and depressive symptoms, this was another foundation for further investigating the link between sedentary behavior and anxiety symptoms.\" C-PAN researchers analyzed the results of nine studies that specifically examined the association between sedentary behavior and anxiety. The studies varied in what they classified as sedentary behavior from television viewing/computer use to total sitting time, which included sitting while watching television, sitting while on transport and work-related sitting. Two of the studies included children/adolescents while the remaining seven included adults. It was found in five of the nine studies that an increase in sedentary behavior was associated with an increased risk of anxiety. In four of the studies it was found that total sitting time was associated with increased risk of anxiety. The evidence about screen time (TV and computer use) was less strong but one study did find that 36% of high school students that had more than 2 hours of screen time were more like to experience anxiety compared to those who had less than 2 hours. The C-PAN team suggests the link between sedentary behavior and anxiety could be due to disturbances in sleep patterns, social withdrawal theory and poor metabolic health. Social withdrawal theory proposes that prolonged sedentary behavior, such as television viewing, can lead to withdrawal from social relationships, which has been linked to increased anxiety. As most of the studies included in this systematic-review were cross-sectional the researchers say more follow-up work studies are required to confirm whether or not anxiety is caused by sedentary behavior. Megan Teychenne said: \"It is important that we understand the behavioral factors that may be linked to anxiety - in order to be able to develop evidence-based strategies in preventing/managing this illness. Our research showed that evidence is available to suggest a positive association between sitting time and anxiety symptoms - however, the direction of this relationship still needs to be determined through longitudinal and interventional studies.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Previous research has linked sedentary behaviour (SB) to adverse physical health outcomes in adults and youth. Although evidence for the relationship between SB and mental health outcomes (e.g., depression) is emerging, little is known regarding risk of anxiety. Methods A systematic search for original research investigating the association between SB and risk of anxiety was performed using numerous electronic databases. A total of nine observational studies (seven cross-sectional and two longitudinal) were identified. Methodological quality of studies was assessed and a best-evidence synthesis was conducted. Results One cross-sectional study demonstrated a strong methodological quality, five cross-sectional studies demonstrated a moderate methodological quality and three studies (two cross-sectional one longitudinal) received a weak methodological quality rating. Overall, there was moderate evidence for a positive relationship between total SB and anxiety risk as well as for a positive relationship between sitting time and anxiety risk. There was inconsistent evidence for the relationship between screen time, television viewing time, computer use, and anxiety risk. Conclusion Limited evidence is available on the association between SB and risk of anxiety. However, our findings suggest a positive association (i.e. anxiety risk increases as SB time increases) may exist (particularly between sitting time and risk of anxiety). Further high-quality longitudinal/interventional research is needed to confirm findings and determine the direction of these relationships. Peer Review reports Background Sedentary behaviour (i.e. activities which require minimal body movement resulting in low energy expenditure similar to resting level [1.0 to 1.5 metabolic equivalent (METs)] [ 1 ]) includes behaviours such as sitting for a range of purposes (e.g. work, travel), and screen-based activities such as computer use, electronic gaming, and television viewing. Time spent in sedentary behaviour has emerged as a potentially important indicator of health in adult populations [ 2 ], independent of achieving sufficient physical activity. Among the general adult population some evidence suggests sedentary behaviour is associated with increased risk of developing various chronic diseases (e.g. overweight and obesity [ 3 ], cardiovascular disease [ 4 ], osteoporosis [ 5 ], type two diabetes [ 3 ], and various cancers [ 6 ]). However, reviews of prospective studies suggest that there is yet insufficient or no evidence to conclude relationships between sedentary behaviour and certain health outcomes (e.g. adulthood weight gain, cardiovascular disease risk, and some cancers) [ 7 , 8 ]. A range of health consequences of sedentary behaviour in children and adolescents have also been identified (e.g. unfavourable body composition, decreased fitness, lowered scores for self-esteem, and pro-social behaviour and decreased academic achievement [ 9 ], sleep problems, musculoskeletal pain, depression, and poor psychological well-being [ 10 ]). However, like that of the adult literature, reviews of prospective studies in young people suggest that there still remains insufficient evidence to conclude associations between sedentary behaviour and some health indicators (e.g. body weight, blood pressure, bone mass) [ 11 ]. The association between sedentary behaviour and mental health issues such as depression [ 12 , 13 ] and self-esteem [ 14 ] have been explored within some population groups (e.g., women, adolescents), and on the balance it has been suggested that a positive relationship exists between most sedentary behaviours and depression [ 12 ] and self-esteem [ 9 ]. However little is known regarding the relationship between sedentary behaviour and other mental illnesses such as anxiety. Anxiety is a mental illness that affects approximately 14 % of Australians adults [ 15 ] and 15 % of 16–24 year olds [ 16 ], with global estimates indicating anxiety to affect over 27 million people [ 17 ]. Anxiety is characterised by excessive and persistent (yet often unrealistic) worry which can inhibit one’s ability to carry out activities of daily living [ 18 ]. Physiological symptoms can include: pounding heart; difficulty breathing; upset stomach; muscle tension; sweating; and, feeling faint, or shaky [ 18 ]. The illness has been shown to be linked to other serious diseases such as increased risk of cardiovascular disease and cancer [ 19 ] with estimates that anxiety and depression together contribute to 10 % of the total burden of disease in Australian women [ 20 ]. Considering anxiety has such a large impact on society (e.g. healthcare costs, quality of life, and life expectancy) and is highly prevalent across the life span, it is important to understand the behavioural factors that may be linked to it. It has been hypothesised that sedentary behaviour may lead to anxiety through biological pathways. For example, engaging in screen-based entertainment, such as video gaming, has been shown to increase the arousal of the central nervous system (CNS) [ 21 ], which could potentially lead to increased levels of anxiety. Additionally, screen-based sedentary behaviours have been linked to disrupted sleeping patterns which may also cause elevated levels of anxiety [ 22 ]. Given the plausibility of these short-term effects of sedentary behaviours on mood (i.e. distraction, CNS arousal, sleep), it is likely that the cumulative effects of these behaviours may further result in longer-term impacts on anxiety risk. Alternatively, the link between sedentary behaviour and anxiety could be explained by poor metabolic health. For example, research has shown sedentary behaviour to be linked to an increased risk of type 2 diabetes [ 3 ], a disease which is subsequently associated with poor mental health [ 23 ]. On the other hand, it could be hypothesised that those with mental illness (e.g. anxiety) tend to engage in sedentary behaviour more than those without the illness. Although research has indicated an inverse association between physical activity and anxiety may exist [ 24 – 26 ], currently the evidence regarding the association between sedentary behaviour and anxiety is unclear. Thus, the aim of this systematic review is to investigate the association between sedentary behaviour and risk of anxiety across the lifespan. Methods Search strategy A structured electronic search (employing PRISMA reporting guidelines) of publication years from 1990 (through November 2014) was conducted, since the 1990’s saw an increase in sedentary behaviour levels of the population with the widespread<|im_end|> <|im_start|>assistant Low energy activities that involve sitting down are associated with an increased risk of anxiety, according to research published in the open access journal BMC Public Health. These activities, which include watching TV, working at a computer or playing electronic games, are called sedentary behavior. Further understanding of these behaviors and how they may be linked to anxiety could help in developing strategies to deal with this mental health problem. Many studies have shown that sedentary behavior is associated with physical health problems like obesity, heart disease, type 2 diabetes and osteoporosis. However, there has been little research into the link between sedentary behavior and mental health. This is the first systematic review to examine the relationship between anxiety and sedentary behavior. Anxiety is a mental health illness that affects more than 27 million people worldwide. It is a debilitating illness that can result in people worrying excessively and can prevent people carrying out their daily life. It can also result in physical symptoms, which amongst others includes pounding heartbeat, difficulty breathing, tense muscles, and headaches. Megan Teychenne, lead researcher and lecturer at Deakin University's Centre for Physical Activity and Nutrition Research (C-PAN) in Australia, said: "Anecdotally - we are seeing an increase in anxiety symptoms in our modern society, which seems to parallel the increase in sedentary behavior. Thus, we were interested to see whether these two factors were in fact linked. Also, since research has shown positive associations between sedentary behavior and depressive symptoms, this was another foundation for further investigating the link between sedentary behavior and anxiety symptoms." C-PAN researchers analyzed the results of nine studies that specifically examined the association between sedentary behavior and anxiety. The studies varied in what they classified as sedentary behavior from television viewing/computer use to total sitting time, which included sitting while watching television, sitting while on transport and work-related sitting. Two of the studies included children/adolescents while the remaining seven included adults. It was found in five of the nine studies that an increase in sedentary behavior was associated with an increased risk of anxiety. In four of the studies it was found that total sitting time was associated with increased risk of anxiety. The evidence about screen time (TV and computer use) was less strong but one study did find that 36% of high school students that had more than 2 hours of screen time were more like to experience anxiety compared to those who had less than 2 hours. The C-PAN team suggests the link between sedentary behavior and anxiety could be due to disturbances in sleep patterns, social withdrawal theory and poor metabolic health. Social withdrawal theory proposes that prolonged sedentary behavior, such as television viewing, can lead to withdrawal from social relationships, which has been linked to increased anxiety. As most of the studies included in this systematic-review were cross-sectional the researchers say more follow-up work studies are required to confirm whether or not anxiety is caused by sedentary behavior. Megan Teychenne said: "It is important that we understand the behavioral factors that may be linked to anxiety - in order to be able to develop evidence-based strategies in preventing/managing this illness. Our research showed that evidence is available to suggest a positive association between sitting time and anxiety symptoms - however, the direction of this relationship still needs to be determined through longitudinal and interventional studies." <|im_end|>

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1,985

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Pyroclastic density currents (PDCs) are the most lethal volcanic process on Earth. Forecasting their inundation area is essential to mitigate their risk, but existing models are limited by our poor understanding of their dynamics. Here, we explore the role of evolving grain-size distribution in controlling the runout of the most common PDCs, known as block-and-ash flows (BAFs). Through a combination of theory, analysis of deposits and experiments of natural mixtures, we show that rapid changes of the grain-size distribution transported in BAFs result in the reduction of pore volume (compaction) within the first kilometres of their runout. We then use a multiphase flow model to show how the compressibility of granular mixtures leads to fragmentation-induced fluidisation (FIF) and excess pore-fluid pressure in BAFs. This process dominates the first ~2 km of their runout, where the effective friction coefficient is progressively reduced. Beyond that distance, transport is modulated by diffusion of the excess pore pressure. Fragmentation-induced fluidisation provides a physical basis to explain the decades-long use of low effective friction coefficients used in depth-averaged simulations required to match observed flow inundation. Introduction Fatalities from volcanic eruptions in the past decades have been largely related to pyroclastic density currents (PDCs) 1 . The most common PDCs are known as block-and-ash flows 2 , 3 , 4 (BAFs), which form by gravitational collapse of a hot lava dome 5 , 6 lava lakes or flows 7 or perched pyroclastic debris 8 , and have been the deadliest volcanic processes in the past century 1 , 9 . Observations and depositional evidence suggest these flows are characterised by a concentrated basal avalanche (underflow) overlain by a dilute turbulent ash-cloud (ash-cloud surge) 10 , 11 , 12 , 13 . Nevertheless, key properties of these layers remain obscured, particularly in the concentrated underflow that dominates the mass and momentum budget of these flows 14 . The extreme mobility of BAFs defies our understanding of the dynamics of granular flows and prevents effective risk mitigation 15 . Their long runouts are particularly confounding as they initiate with relatively low energy compared to PDCs fed by column collapse 16 , 17 , 18 . Considerable efforts by hazard practitioners and numerical modellers have been made to forecast the propagation of PDCs by using depth-averaged models on 3D topography 10 , 15 , 19 , 20 , 21 , 22 , 23 , 24 , 25 . These studies suggest the existence of a mechanism that reduces the effective friction of the volcanic mixtures that are otherwise highly frictional when static (angle of repose of ~30–35° 26 ). Lowering the effective friction could be achieved through the generation of elevated-pore pressure 26 , 27 , 28 , 29 , which makes the mixture fluid-like (fluidised). However, the source of the fluidisation mechanism in BAFs remains elusive because, unlike column collapse PDC, they do not form by impact of a column collapse or rapid-sedimentation, and are coarse (permeable) mixtures in proximal reaches 30 . For example, the 2018 Fuego dome-less BAFs that originated from the collapse (>70% volume 31 ) of existing “perched” proximal tephra, lava, and spatter were some of the most mobile and deadly events of the past century 8 , 32 , and yet cannot be explained by our existing knowledge of auto-fluidisation 26 , 33 . The evolving grain-size distribution (GSD) of block-and-ash flows may provide such a mechanism. In column collapse PDCs, secondary fragmentation, or comminution, has led to measurable rounding differences and is linked to enhanced runout distances 34 , 35 , 36 , 37 . BAF deposits start as a mixture dominated by blocks (>64 mm) and transform into a blend of blocks immersed in fines-rich (<4 mm) matrix (Fig. 1a ). However, the feedback between the rapid evolution of the GSD in BAFs prior to proximal deposition, evolving permeability (i.e. abundance of fines and porosity 38 , 39 , 40 ), and the subsequent role of the interstitial gas modifying the effective friction of the mixture has never been studied. Fig. 1: Block-and-ash flow deposits at Merapi volcano. a Outcrop of the block-and-ash flow deposit from the June 14, 2006, event at Merapi volcano at 2.8 km from source. Each yellow bar is 1 m long. b Proximal, medial and distal grain-size distributions of samples collected at Merapi for all three BAFs of June 14, 2006 (blue), October 26, 2010 (grey) and November 5, 2010 (red) (Φ = −log2( d [mm]). Note that samples in the “proximal” region were collected close to the proximal/media transition. c Sorting and mean grain-size parameters for all samples plotted with distance. The runout of each event is indicated on the top with vertical arrows. d Number of particles with diameter > d as a function of particle size for all samples of the three BAF events at Merapi. The two black reference dashed lines illustrate the difference in slope between power-law distributions with fractal dimension of 2.9 and 3.4 46 , which are typical bounds of the slope measured in other PDC deposit samples around the world. The power-law exponent D is plotted against distance for all samples. The greyed box represents the range of D exponents measured in other PDC deposits. Full size image In this work, we introduce the mechanism of fragmentation-induced fluidisation (FIF), in which gas-particle coupling in an evolving permeable mixture generates elevated pore pressure in the granular mixture. As demonstrated in experimental studies, the permeability and pore-pressure diffusion timescales are controlled by the polydispersity. A key component of the fragmentation-induced fluidisation process is a reduction in the void space through the production of fine particles via cascading fragmentation. As a simple thought experiment, one would expect that this reduction in void space due to fragmentation would increase the pore pressure at the same time as reducing permeability and the ability of the flow to expel trapped gas. To better understand how such a process plays a role in the formation and propagation of BAFs and explain their high mobility,", "role": "user" }, { "content": "The discovery of the driving force behind the world's deadliest volcanic events could help improve forecasting of their devastating effects, new research suggests. The findings reveal the mechanism that enables dense, scorching avalanches of a mixture of rock, ash and gases ejected during volcanic eruptions—called pyroclastic flows—to travel at up to 100 miles per hour. Better predicting the path of pyroclastic flows—which can reach temperatures of 600°C—could help prevent injuries and deaths following volcanic eruptions, researchers say. More than 600 million people around the world live in regions that could be hit by pyroclastic flows. The pyroclastic flow triggered by the eruption of Mount Vesuvius in 79 AD is one of the most famous examples of these lethal events. While scientists have long been aware of the immense dangers they pose, the underlying mechanism that enables them to travel at such high speed and long distances—up to 12 miles—had remained unknown. Fluid-like behavior Now, a team led by an Edinburgh researcher has revealed the science behind so-called block-and-ash flows, the most common and destructive type of pyroclastic flow. Their work is published in the journal Nature Communications. They identified a mechanism that greatly reduces the friction of the dense volcanic mixtures, enabling them to travel at high speed. The process—called fragmentation-induced fluidization—causes the base layer of pyroclastic flows to exhibit fluid-like behavior. This effect is triggered by rapidly compacting the mixture, and raising the pressure between fine particles after large blocks have disintegrated into powder. This enhanced fluidity, coupled with the large amounts—often millions of tons—of volcanic material, is the reason pyroclastic flows can travel far at high speeds as dense avalanches, destroying everything in their path, the team says. Density changes The researchers conducted a comprehensive analysis by examining pyroclastic flow deposits from previous eruptions at Mount Merapi in Java, Indonesia, in 2006 and 2010. They also carried out laboratory experiments and ran computer simulations to investigate the impact of density changes within pyroclastic flows and the ability of their granular mixtures to become fluid-like. \"The discovery of the fragmentation-induced fluidization process is hugely significant, as it enables us to develop more reliable numerical models that can accurately evaluate pyroclastic flow hazards around both current and potentially future active volcanoes. Our findings not only reveal a fundamental geoscience principle but also urges us to reconsider the focus of our field-based studies. This work lays the foundation for a multitude of investigations that my research group at University of Edinburgh will undertake, ultimately refining and reshaping our understanding of volcanic hazards,\" says Dr. Eric Breard, School of GeoSciences. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Pyroclastic density currents (PDCs) are the most lethal volcanic process on Earth. Forecasting their inundation area is essential to mitigate their risk, but existing models are limited by our poor understanding of their dynamics. Here, we explore the role of evolving grain-size distribution in controlling the runout of the most common PDCs, known as block-and-ash flows (BAFs). Through a combination of theory, analysis of deposits and experiments of natural mixtures, we show that rapid changes of the grain-size distribution transported in BAFs result in the reduction of pore volume (compaction) within the first kilometres of their runout. We then use a multiphase flow model to show how the compressibility of granular mixtures leads to fragmentation-induced fluidisation (FIF) and excess pore-fluid pressure in BAFs. This process dominates the first ~2 km of their runout, where the effective friction coefficient is progressively reduced. Beyond that distance, transport is modulated by diffusion of the excess pore pressure. Fragmentation-induced fluidisation provides a physical basis to explain the decades-long use of low effective friction coefficients used in depth-averaged simulations required to match observed flow inundation. Introduction Fatalities from volcanic eruptions in the past decades have been largely related to pyroclastic density currents (PDCs) 1 . The most common PDCs are known as block-and-ash flows 2 , 3 , 4 (BAFs), which form by gravitational collapse of a hot lava dome 5 , 6 lava lakes or flows 7 or perched pyroclastic debris 8 , and have been the deadliest volcanic processes in the past century 1 , 9 . Observations and depositional evidence suggest these flows are characterised by a concentrated basal avalanche (underflow) overlain by a dilute turbulent ash-cloud (ash-cloud surge) 10 , 11 , 12 , 13 . Nevertheless, key properties of these layers remain obscured, particularly in the concentrated underflow that dominates the mass and momentum budget of these flows 14 . The extreme mobility of BAFs defies our understanding of the dynamics of granular flows and prevents effective risk mitigation 15 . Their long runouts are particularly confounding as they initiate with relatively low energy compared to PDCs fed by column collapse 16 , 17 , 18 . Considerable efforts by hazard practitioners and numerical modellers have been made to forecast the propagation of PDCs by using depth-averaged models on 3D topography 10 , 15 , 19 , 20 , 21 , 22 , 23 , 24 , 25 . These studies suggest the existence of a mechanism that reduces the effective friction of the volcanic mixtures that are otherwise highly frictional when static (angle of repose of ~30–35° 26 ). Lowering the effective friction could be achieved through the generation of elevated-pore pressure 26 , 27 , 28 , 29 , which makes the mixture fluid-like (fluidised). However, the source of the fluidisation mechanism in BAFs remains elusive because, unlike column collapse PDC, they do not form by impact of a column collapse or rapid-sedimentation, and are coarse (permeable) mixtures in proximal reaches 30 . For example, the 2018 Fuego dome-less BAFs that originated from the collapse (>70% volume 31 ) of existing “perched” proximal tephra, lava, and spatter were some of the most mobile and deadly events of the past century 8 , 32 , and yet cannot be explained by our existing knowledge of auto-fluidisation 26 , 33 . The evolving grain-size distribution (GSD) of block-and-ash flows may provide such a mechanism. In column collapse PDCs, secondary fragmentation, or comminution, has led to measurable rounding differences and is linked to enhanced runout distances 34 , 35 , 36 , 37 . BAF deposits start as a mixture dominated by blocks (>64 mm) and transform into a blend of blocks immersed in fines-rich (<4 mm) matrix (Fig. 1a ). However, the feedback between the rapid evolution of the GSD in BAFs prior to proximal deposition, evolving permeability (i.e. abundance of fines and porosity 38 , 39 , 40 ), and the subsequent role of the interstitial gas modifying the effective friction of the mixture has never been studied. Fig. 1: Block-and-ash flow deposits at Merapi volcano. a Outcrop of the block-and-ash flow deposit from the June 14, 2006, event at Merapi volcano at 2.8 km from source. Each yellow bar is 1 m long. b Proximal, medial and distal grain-size distributions of samples collected at Merapi for all three BAFs of June 14, 2006 (blue), October 26, 2010 (grey) and November 5, 2010 (red) (Φ = −log2( d [mm]). Note that samples in the “proximal” region were collected close to the proximal/media transition. c Sorting and mean grain-size parameters for all samples plotted with distance. The runout of each event is indicated on the top with vertical arrows. d Number of particles with diameter > d as a function of particle size for all samples of the three BAF events at Merapi. The two black reference dashed lines illustrate the difference in slope between power-law distributions with fractal dimension of 2.9 and 3.4 46 , which are typical bounds of the slope measured in other PDC deposit samples around the world. The power-law exponent D is plotted against distance for all samples. The greyed box represents the range of D exponents measured in other PDC deposits. Full size image In this work, we introduce the mechanism of fragmentation-induced fluidisation (FIF), in which gas-particle coupling in an evolving permeable mixture generates elevated pore pressure in the granular mixture. As demonstrated in experimental studies, the permeability and pore-pressure diffusion timescales are controlled by the polydispersity. A key component of the fragmentation-induced fluidisation process is a reduction in the void space through the production of fine particles via cascading fragmentation. As a simple thought experiment, one would expect that this reduction in void space due to fragmentation would increase the pore pressure at the same time as reducing permeability and the ability of the flow to expel trapped gas. To better understand how such a process plays a role in the formation and propagation of BAFs and explain their high mobility,<|im_end|> <|im_start|>assistant The discovery of the driving force behind the world's deadliest volcanic events could help improve forecasting of their devastating effects, new research suggests. The findings reveal the mechanism that enables dense, scorching avalanches of a mixture of rock, ash and gases ejected during volcanic eruptions—called pyroclastic flows—to travel at up to 100 miles per hour. Better predicting the path of pyroclastic flows—which can reach temperatures of 600°C—could help prevent injuries and deaths following volcanic eruptions, researchers say. More than 600 million people around the world live in regions that could be hit by pyroclastic flows. The pyroclastic flow triggered by the eruption of Mount Vesuvius in 79 AD is one of the most famous examples of these lethal events. While scientists have long been aware of the immense dangers they pose, the underlying mechanism that enables them to travel at such high speed and long distances—up to 12 miles—had remained unknown. Fluid-like behavior Now, a team led by an Edinburgh researcher has revealed the science behind so-called block-and-ash flows, the most common and destructive type of pyroclastic flow. Their work is published in the journal Nature Communications. They identified a mechanism that greatly reduces the friction of the dense volcanic mixtures, enabling them to travel at high speed. The process—called fragmentation-induced fluidization—causes the base layer of pyroclastic flows to exhibit fluid-like behavior. This effect is triggered by rapidly compacting the mixture, and raising the pressure between fine particles after large blocks have disintegrated into powder. This enhanced fluidity, coupled with the large amounts—often millions of tons—of volcanic material, is the reason pyroclastic flows can travel far at high speeds as dense avalanches, destroying everything in their path, the team says. Density changes The researchers conducted a comprehensive analysis by examining pyroclastic flow deposits from previous eruptions at Mount Merapi in Java, Indonesia, in 2006 and 2010. They also carried out laboratory experiments and ran computer simulations to investigate the impact of density changes within pyroclastic flows and the ability of their granular mixtures to become fluid-like. "The discovery of the fragmentation-induced fluidization process is hugely significant, as it enables us to develop more reliable numerical models that can accurately evaluate pyroclastic flow hazards around both current and potentially future active volcanoes. Our findings not only reveal a fundamental geoscience principle but also urges us to reconsider the focus of our field-based studies. This work lays the foundation for a multitude of investigations that my research group at University of Edinburgh will undertake, ultimately refining and reshaping our understanding of volcanic hazards," says Dr. Eric Breard, School of GeoSciences. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract With DNA genomes reaching 2.5 Mb packed in particles of bacterium-like shape and dimension, the first two Acanthamoeba-infecting pandoraviruses remained up to now the most complex viruses since their discovery in 2013. Our isolation of three new strains from distant locations and environments is now used to perform the first comparative genomics analysis of the emerging worldwide-distributed Pandoraviridae family. Thorough annotation of the genomes combining transcriptomic, proteomic, and bioinformatic analyses reveals many non-coding transcripts and significantly reduces the former set of predicted protein-coding genes. Here we show that the pandoraviruses exhibit an open pan-genome, the enormous size of which is not adequately explained by gene duplications or horizontal transfers. As most of the strain-specific genes have no extant homolog and exhibit statistical features comparable to intergenic regions, we suggest that de novo gene creation could contribute to the evolution of the giant pandoravirus genomes. Introduction For 10 years after the serendipitous discovery of the first giant virus (i.e., easily visible by light microscopy) Acanthamoeba polyphaga Mimivirus 1 , 2 , environmental sampling in search of other Acanthamoeba-infecting viruses only succeeded in the isolation of additional members of the Mimiviridae family 3 , 4 . Then, when we returned in 2013 to the Chilean coastal area from where we previously isolated Megavirus chilensis 3 , we isolated the even bigger Pandoravirus salinus 5 . Its unique characteristics suggested the existence of a different family of giant viruses infecting Acanthamoeba. The worldwide distribution of this predicted virus family, the proposed Pandoraviridae , was quickly hinted by our subsequent isolation of Pandoravirus dulcis more than 15 000 km away, in a freshwater pond near Melbourne, Australia 5 . We also spotted pandoravirus-like particles in an article reporting micrographs of Acanthamoeba infected by an unidentified “endosymbiont” 6 , the genome sequence of which has recently become available as that of the German isolate Pandoravirus inopinatum 7 . Here we describe three new members of the proposed Pandoraviridae family that were isolated from different environments and distant locations: Pandoravirus quercus , isolated from ground soil in Marseille (France); Pandoravirus neocaledonia , isolated from the brackish water of a mangrove near Noumea airport (New Caledonia); and Pandoravirus macleodensis , isolated from a freshwater pond near Melbourne (Australia), only 700 m away from where we previously isolated P. dulcis . Following the characterization of their replication cycles in Acanthamoeba castellanii by light and electron microscopy, we analyzed the five pandoravirus strains available in our laboratory through combined genomic, transcriptomic, and proteomic approaches. We then used these data (together with the genome sequence of P. inopinatum ) in a comparative manner to build a global picture of the emerging family and refine the genome annotation of each individual strain. While the number of encoded proteins has been revised downward, we unraveled hundreds of previously unpredicted genes associated to non-coding transcripts. From the comparison of the six representatives at our disposal, the Pandoraviridae family appears quite diverse in terms of gene content, consistent with a family for which many members are still to be isolated. A large fraction of the pan-genome codes for proteins without homologs in cells or other viruses, raising the question of their origin. The purified virions are made of more than 200 different proteins, about half of which are shared by all tested strains in well-correlated relative abundances. This large core proteome is consistent with the highly similar early infection stages exhibited by the different isolates. Results Environmental sampling and isolation of pandoravirus strains We used the same isolation protocol that led to the discovery of P. salinus and P. dulcis 5 . It consists in mixing the sampled material with cultures of Acanthamoeba adapted to antibiotic concentrations high enough to inhibit the growth of other environmental microorganisms (especially bacteria and fungi). Samples were taken randomly from humid environments susceptible to harbor Acanthamoeba cells. This led to the isolation of three new pandoravirus strains: P. quercus ; P. neocaledonia ; and P. macleodensis (Table 1 , see Methods). They exhibit adequate divergence to start assessing the conserved features and the variability of the emerging Pandoraviridae family. When appropriate, our analyses also include data from P. inopinatum , isolated in a German laboratory from a patient with an Acanthamoeba keratitis 7 . Table 1 Data on the pandoravirus isolates used in this work Full size table Study of the replication cycles and virion ultrastructures Starting from purified particles inoculated into A. castellanii cultures, we analyzed the infectious cycle of each isolate using both light and transmission electron microscopy (ultrathin section). As previously observed for P. salinus and P. dulcis , the replication cycles of these new pandoraviruses were found to last an average of 12 h 5 (8 h for the fastest P. neocaledonia ). The infectious process is the same for all viruses, beginning with the internalization of individual particles by Acanthamoeba cells. Following the opening of their apical pore, the particles (“pandoravirions”) transfer their translucent content to the cytoplasm through the fusion of the virion internal membrane with that of the phagosome. The early stage of the infection is remarkably similar for all isolates. While we previously reported that the cell nucleus was fully disrupted during the late stage of the infectious cycle 5 , the thorough observation of the new strains revealed neo-synthetized particles in the cytoplasm of cells still exhibiting nucleus-like compartments in which the nucleolus was no longer recognizable (Supplementary Fig. 1 ). Eight hours post infection, mature virions became visible in vacuoles and are released through exocytosis (Supplementary Movie ). For all isolates, the replicative cycle ends with the cells lysis and the release of about a hundred particles (Fig. 1 ). Fig. 1 The new pandoravirus isolates. a Overproduction by an A. castellanii cell of Pandoravirus macleodensis virions from the environmental sample prior cell lysis. Environmental bacteria can be seen in the culture medium together with P. macleodensis virions. (scale bar is 10 µm). b TEM image of an ultrathin section of A. castellanii cell during the early", "role": "user" }, { "content": "Three new members have been isolated and added to the Pandoravirus family by researchers at the Structural and Genomic Information Laboratory (CNRS/Aix-Marseille Université), working with partners at the Large Scale Biology Laboratory (CEA/Inserm/Université Grenoble-Alpes) and at CEA-Genoscope. This strange family of viruses, with their giant genomes and many genes with no known equivalents, surprised the scientists when they were discovered a few years ago. In the 11 June 2018 edition of Nature Communications, researchers offer an explanation: Pandoviruses appear to be factories for new genes—and therefore new functions. From freaks of nature to evolutionary innovators, giant viruses continue to shake branches on the tree of life. In 2013, the discovery of two giant viruses unlike anything seen before blurred the line between the viral and cellular world. Pandoraviruses are as big as bacteria, and contain genomes that are more complex than those found in some eukaryotic organisms. Their strange amphora shape and enormous, atypical genome led scientists to wonder where they came from. The same team has since isolated three new members of the family in Marseille, continental France, Nouméa, New Caledonia, and Melbourne, Australia. With another virus found in Germany, the team compared those six known cases using different approaches. Analyses showed that despite having very similar shapes and functions, these viruses only share half of their genes coding for proteins. Usually, however, members of the same family have more genes in common. Furthermore, these new members are notable for the gigantic size of pandoravirus genomes, their diversity and the large proportion of orphan genes they contain: most of these viruses have large number of orphan genes, i.e. genes which encode proteins that have no equivalent in other living organisms (this was already the case for the two previously discovered pandoraviruses). This unexplained characteristic is at the heart of many a debate over the origin of viruses. What most surprised researchers was that the orphan genes differed from one pandoravirus to another, making it less likely that they were inherited from a common ancestor. Bioinformatic analysis showed that these orphan genes exhibit features very similar to those of non-coding (or intergenic) regions in the pandoravirus genome. Findings indicate the only possible explanation is that the genes may originate spontaneously and randomly in intergenic regions. In this scenario, genes \"appear\" in different locations from one strain to another, thus explaining their unique nature. If confirmed, this groundbreaking hypothesis would make these giant viruses craftsmen of genetic creativity—a central, but still poorly explained component of any understanding of the source of life and its evolution. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract With DNA genomes reaching 2.5 Mb packed in particles of bacterium-like shape and dimension, the first two Acanthamoeba-infecting pandoraviruses remained up to now the most complex viruses since their discovery in 2013. Our isolation of three new strains from distant locations and environments is now used to perform the first comparative genomics analysis of the emerging worldwide-distributed Pandoraviridae family. Thorough annotation of the genomes combining transcriptomic, proteomic, and bioinformatic analyses reveals many non-coding transcripts and significantly reduces the former set of predicted protein-coding genes. Here we show that the pandoraviruses exhibit an open pan-genome, the enormous size of which is not adequately explained by gene duplications or horizontal transfers. As most of the strain-specific genes have no extant homolog and exhibit statistical features comparable to intergenic regions, we suggest that de novo gene creation could contribute to the evolution of the giant pandoravirus genomes. Introduction For 10 years after the serendipitous discovery of the first giant virus (i.e., easily visible by light microscopy) Acanthamoeba polyphaga Mimivirus 1 , 2 , environmental sampling in search of other Acanthamoeba-infecting viruses only succeeded in the isolation of additional members of the Mimiviridae family 3 , 4 . Then, when we returned in 2013 to the Chilean coastal area from where we previously isolated Megavirus chilensis 3 , we isolated the even bigger Pandoravirus salinus 5 . Its unique characteristics suggested the existence of a different family of giant viruses infecting Acanthamoeba. The worldwide distribution of this predicted virus family, the proposed Pandoraviridae , was quickly hinted by our subsequent isolation of Pandoravirus dulcis more than 15 000 km away, in a freshwater pond near Melbourne, Australia 5 . We also spotted pandoravirus-like particles in an article reporting micrographs of Acanthamoeba infected by an unidentified “endosymbiont” 6 , the genome sequence of which has recently become available as that of the German isolate Pandoravirus inopinatum 7 . Here we describe three new members of the proposed Pandoraviridae family that were isolated from different environments and distant locations: Pandoravirus quercus , isolated from ground soil in Marseille (France); Pandoravirus neocaledonia , isolated from the brackish water of a mangrove near Noumea airport (New Caledonia); and Pandoravirus macleodensis , isolated from a freshwater pond near Melbourne (Australia), only 700 m away from where we previously isolated P. dulcis . Following the characterization of their replication cycles in Acanthamoeba castellanii by light and electron microscopy, we analyzed the five pandoravirus strains available in our laboratory through combined genomic, transcriptomic, and proteomic approaches. We then used these data (together with the genome sequence of P. inopinatum ) in a comparative manner to build a global picture of the emerging family and refine the genome annotation of each individual strain. While the number of encoded proteins has been revised downward, we unraveled hundreds of previously unpredicted genes associated to non-coding transcripts. From the comparison of the six representatives at our disposal, the Pandoraviridae family appears quite diverse in terms of gene content, consistent with a family for which many members are still to be isolated. A large fraction of the pan-genome codes for proteins without homologs in cells or other viruses, raising the question of their origin. The purified virions are made of more than 200 different proteins, about half of which are shared by all tested strains in well-correlated relative abundances. This large core proteome is consistent with the highly similar early infection stages exhibited by the different isolates. Results Environmental sampling and isolation of pandoravirus strains We used the same isolation protocol that led to the discovery of P. salinus and P. dulcis 5 . It consists in mixing the sampled material with cultures of Acanthamoeba adapted to antibiotic concentrations high enough to inhibit the growth of other environmental microorganisms (especially bacteria and fungi). Samples were taken randomly from humid environments susceptible to harbor Acanthamoeba cells. This led to the isolation of three new pandoravirus strains: P. quercus ; P. neocaledonia ; and P. macleodensis (Table 1 , see Methods). They exhibit adequate divergence to start assessing the conserved features and the variability of the emerging Pandoraviridae family. When appropriate, our analyses also include data from P. inopinatum , isolated in a German laboratory from a patient with an Acanthamoeba keratitis 7 . Table 1 Data on the pandoravirus isolates used in this work Full size table Study of the replication cycles and virion ultrastructures Starting from purified particles inoculated into A. castellanii cultures, we analyzed the infectious cycle of each isolate using both light and transmission electron microscopy (ultrathin section). As previously observed for P. salinus and P. dulcis , the replication cycles of these new pandoraviruses were found to last an average of 12 h 5 (8 h for the fastest P. neocaledonia ). The infectious process is the same for all viruses, beginning with the internalization of individual particles by Acanthamoeba cells. Following the opening of their apical pore, the particles (“pandoravirions”) transfer their translucent content to the cytoplasm through the fusion of the virion internal membrane with that of the phagosome. The early stage of the infection is remarkably similar for all isolates. While we previously reported that the cell nucleus was fully disrupted during the late stage of the infectious cycle 5 , the thorough observation of the new strains revealed neo-synthetized particles in the cytoplasm of cells still exhibiting nucleus-like compartments in which the nucleolus was no longer recognizable (Supplementary Fig. 1 ). Eight hours post infection, mature virions became visible in vacuoles and are released through exocytosis (Supplementary Movie ). For all isolates, the replicative cycle ends with the cells lysis and the release of about a hundred particles (Fig. 1 ). Fig. 1 The new pandoravirus isolates. a Overproduction by an A. castellanii cell of Pandoravirus macleodensis virions from the environmental sample prior cell lysis. Environmental bacteria can be seen in the culture medium together with P. macleodensis virions. (scale bar is 10 µm). b TEM image of an ultrathin section of A. castellanii cell during the early<|im_end|> <|im_start|>assistant Three new members have been isolated and added to the Pandoravirus family by researchers at the Structural and Genomic Information Laboratory (CNRS/Aix-Marseille Université), working with partners at the Large Scale Biology Laboratory (CEA/Inserm/Université Grenoble-Alpes) and at CEA-Genoscope. This strange family of viruses, with their giant genomes and many genes with no known equivalents, surprised the scientists when they were discovered a few years ago. In the 11 June 2018 edition of Nature Communications, researchers offer an explanation: Pandoviruses appear to be factories for new genes—and therefore new functions. From freaks of nature to evolutionary innovators, giant viruses continue to shake branches on the tree of life. In 2013, the discovery of two giant viruses unlike anything seen before blurred the line between the viral and cellular world. Pandoraviruses are as big as bacteria, and contain genomes that are more complex than those found in some eukaryotic organisms. Their strange amphora shape and enormous, atypical genome led scientists to wonder where they came from. The same team has since isolated three new members of the family in Marseille, continental France, Nouméa, New Caledonia, and Melbourne, Australia. With another virus found in Germany, the team compared those six known cases using different approaches. Analyses showed that despite having very similar shapes and functions, these viruses only share half of their genes coding for proteins. Usually, however, members of the same family have more genes in common. Furthermore, these new members are notable for the gigantic size of pandoravirus genomes, their diversity and the large proportion of orphan genes they contain: most of these viruses have large number of orphan genes, i.e. genes which encode proteins that have no equivalent in other living organisms (this was already the case for the two previously discovered pandoraviruses). This unexplained characteristic is at the heart of many a debate over the origin of viruses. What most surprised researchers was that the orphan genes differed from one pandoravirus to another, making it less likely that they were inherited from a common ancestor. Bioinformatic analysis showed that these orphan genes exhibit features very similar to those of non-coding (or intergenic) regions in the pandoravirus genome. Findings indicate the only possible explanation is that the genes may originate spontaneously and randomly in intergenic regions. In this scenario, genes "appear" in different locations from one strain to another, thus explaining their unique nature. If confirmed, this groundbreaking hypothesis would make these giant viruses craftsmen of genetic creativity—a central, but still poorly explained component of any understanding of the source of life and its evolution. <|im_end|>

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1,972

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Dravet syndrome is a catastrophic pediatric epilepsy with severe intellectual disability, impaired social development and persistent drug-resistant seizures. One of its primary monogenic causes are mutations in Na v 1.1 ( SCN1A ), a voltage-gated sodium channel. Here we characterize zebrafish Na v 1.1 ( scn1Lab ) mutants originally identified in a chemical mutagenesis screen. Mutants exhibit spontaneous abnormal electrographic activity, hyperactivity and convulsive behaviours. Although scn1Lab expression is reduced, microarray analysis is remarkable for the small fraction of differentially expressed genes (~3%) and lack of compensatory expression changes in other scn subunits. Ketogenic diet, diazepam, valproate, potassium bromide and stiripentol attenuate mutant seizure activity; seven other antiepileptic drugs have no effect. A phenotype-based screen of 320 compounds identifies a US Food and Drug Administration-approved compound (clemizole) that inhibits convulsive behaviours and electrographic seizures. This approach represents a new direction in modelling pediatric epilepsy and could be used to identify novel therapeutics for any monogenic epilepsy disorder. Introduction Epilepsy can be acquired as a result of an insult to the brain or genetic mutation. Among the genetic epilepsies, more than 650 variants have been identified in the SCN1A gene 1 , 2 . Missense or frame-shift mutations in this gene are associated with generalized epilepsy with febrile seizures plus 3 as well as a more severe disorder known as Dravet syndrome (DS). Children with DS initially exhibit normal development but often experience febrile seizure episodes within the first year of life, with eventual progression to severe spontaneous recurrent seizures, intellectual disability, ataxia and psychomotor dysfunction. Seizures are inadequately managed using available antiepileptic drugs (AEDs) and these children are poor candidates for neurosurgical resection 4 . In mammalian brain, there are four main subtypes of voltage-gated sodium channel α-subunits: Na V 1.1, Na V 1.2, Na V 1.3 and Na V 1.6, encoded for by the genes SCN1A , SCN2A , SCN3A and SCN8A , respectively. Opening of these channels produces a sodium conductance and rapid cell membrane depolarization, for example, features integral to action potential initiation 5 . In mice, Na v 1.1 is widely expressed in the central nervous system (CNS), including the axon initial segment of parvalbumin-positive hippocampal interneurons and excitatory principal cells 6 , 7 . Heterozygous deletion of Na v 1.1 in mice leads to a reduction in the firing capability of acutely dissociated fast-spiking interneurons 8 . Mice with global or interneuron-specific heterozygous deletion of Na v 1.1 exhibit temperature-induced and spontaneous seizures, mild ataxia, autism-like behaviours and premature death 8 , 9 , 10 . Knock-in mouse carrying a premature stop codon in domain III of the Na v 1.1 channel also exhibit a decrement in spike amplitude during prolonged interneuron firing and increased sensitivity to temperature-induced seizures 11 . Generation and characterization of valid animal models is critical to efforts to understand the pathophysiology of DS, and to aid in the identification of novel therapies. Although considerable attention has focused on modelling SCN1A mutations in mice, these animals have proven to be difficult to breed, and epilepsy phenotypes are strongly influenced by the background strain genetics. Induced pluripotent stem cells can be generated from DS patients, but individual neurons do not recapitulate the network environment necessary for in-vivo seizure generation. Danio rerio (zebrafish), a simple vertebrate species, provide an alternative model system with significant advantages for genetic manipulation, cost-efficient breeding and in-vivo drug discovery 12 , 13 , 14 . Ideally, an animal model should be based on a known genetic cause of the disease ( SCN1A mutation), accurately recapitulate key features of the disease (epilepsy), and respond, or not, to therapies commonly used in patients with the disease (pharmacological validation). If successful, such a model could inform our understanding of the disease process and catalyse explorations towards new therapies. In zebrafish, the voltage-gated sodium channel family consists of four sets of duplicated genes: scn1Laa and scn1Lab , scn4aa and scn4ab , scn5Laa and scn5Lab , and scn8aa and scn8ab (ref. 15 ). The zebrafish scn1Lab gene shares a 77% identity with human SCN1A and is expressed in the CNS. A homozygous zebrafish mutant for this gene (originally termed didy s552 ) was discovered in a chemical mutagenesis screen using the optokinetic response as an assay 16 . These types of screens are based on inducing random point mutations using the alkylating agent N- ethyl -N- nitrosourea; the resulting mutations are typically loss-of-function and recessive. Although this is a homozygous mutation, scn1Lab zebrafish mutants are relevant for the autosomal dominant human DS given the genome duplication in zebrafish and the presence of an additional Na v 1.1 homologue ( scn1Laa ). In this paper, we characterized scn1Lab mutants at the molecular and behavioural level, demonstrated that mutants exhibit spontaneous drug-resistant seizures and then used them in a novel high-throughput screening programme to identify compounds that ameliorate the epilepsy phenotype. A phenotype-based screen identified clemizole, an US Food and Drug Administration (FDA)-approved compound, as an effective inhibitor of spontaneous convulsive behaviours and electrographic seizures in these mutants. Results Developmental scn1Lab expression and characterization Zebrafish with a mutation in domain III of a voltage-gated sodium channel were identified by Dr Herwig Baier during a chemical mutagenesis screen 16 . We backcrossed original scn1Lab mutants onto the Tupfel long background for seven to ten generations and confirmed a methionine (M) to arginine (R) mutation in our colony ( Fig. 1a ). Reverse-transcriptase and quantitative (q) PCR revealed a decrease in mRNA expression for scn1Lab in mutant larvae at 3, 5 and 7 days post fertilization (dpf; Fig. 1b ); antibodies recognizing this protein in zebrafish are not available. As expected 15 , scn1Lab is prominently expressed during early stages of larval development ( Fig. 1b ) and specifically in the CNS at 3 dpf ( Fig. 1d,e ). Whole-mount in situ hybridization revealed diffuse but prominent expression in the brain regions corresponding to the forebrain (telencephalon), optic tectum and cerebellum. A similar expression pattern was observed for scn1Laa at 3 dpf. At 5 and 7", "role": "user" }, { "content": "According to new research on epilepsy, zebrafish have certainly earned their stripes. Results of a study in Nature Communications suggest that zebrafish carrying a specific mutation may help researchers discover treatments for Dravet syndrome (DS), a severe form of pediatric epilepsy that results in drug-resistant seizures and developmental delays. Scott C. Baraban, Ph.D., and his colleagues at the University of California, San Francisco (UCSF), carefully assessed whether the mutated zebrafish could serve as a model for DS, and then developed a new screening method to quickly identify potential treatments for DS using these fish. This study was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health and builds on pioneering epilepsy zebrafish models first described by the Baraban laboratory in 2005. Dravet syndrome is commonly caused by a mutation in the Scn1a gene, which encodes for Nav1.1, a specific sodium ion channel found in the brain. Sodium ion channels are critical for communication between brain cells and proper brain functioning. The researchers found that the zebrafish that were engineered to have the Scn1a mutation that causes DS in humans exhibited some of the same characteristics, such as spontaneous seizures, commonly seen in children with DS. Unprovoked seizure activity in the mutant fish resulted in hyperactivity and whole-body convulsions associated with very fast swimming. These types of behaviors are not seen in normal healthy zebrafish. \"We were also surprised at how similar the mutant zebrafish drug profile was to that of Dravet patients,\" said Dr. Baraban. \"Antiepileptic drugs shown to have some benefits in patients (such as benzodiazepines or stiripentol) also exhibited some antiepileptic activity in these mutants. Conversely, many of the antiepileptic drugs that do not reduce seizures in these patients showed no effect in the mutant zebrafish.\" In this study, the researchers developed a fast and automated drug screen to quickly test the effectiveness of various compounds in mutant zebrafish. The researchers tracked behavior and measured brain activity in the mutant zebrafish to determine if the compounds had an impact on seizures. \"Scn1a mutants seize often, so it is relatively easy to monitor their seizure behavior at baseline and then again after a drug application,\" said Dr. Baraban. \"Using zebrafish placed individually in a 96-part petri dish we can accurately quantify this seizure behavior. In this way, we can test almost 100 fish at one time and quickly determine whether a drug candidate has any effect on these spontaneous seizures.\" In the first such application of this approach, UCSF researchers screened 320 compounds and found that clemizole was most effective in inhibiting seizure activity. Clemizole is approved by the U.S. Food and Drug Administration and has a safe toxicology profile. \"This finding was completely unexpected. Based on what is currently known about clemizole, we did not predict that it would have antiepileptic effects,\" said Dr. Baraban. These findings suggest that Scn1a mutant zebrafish may serve as a good model of DS and that the drug screen may be effective in quickly identifying novel therapies for epilepsy. Dr. Baraban also noted that someday these experiments can be \"personalized,\" by looking at mutated zebrafish that use genetic information from individual patients. This research was funded by the Exceptional, Unconventional Research Enabling Knowledge Acceleration (EUREKA) program at NIH that supports innovative research with the potential for big impact in biomedical science. \"The goal of the EUREKA program is to provide a means to test high-risk ideas to see if they are worth pursuing further. These kinds of ideas often come from left field and are very creative. Since they are so unique, however, there may not be any existing preliminary data to support the hypothesis or demonstrate feasibility. EUREKA grants provide an opportunity to gather this information,\" said Brandy Fureman, Ph.D., program director at NINDS. This particular study was chosen in response to a request by NINDS to help spur novel research on epilepsy. \"This research was selected for a EUREKA grant because it proposed a well-designed, inventive model of genetic epilepsy that could accelerate the pace of drug-screening for this devastating form of pediatric epilepsy\" said Dr. Fureman. Dr. Fureman noted that these findings not only describe a novel model of Dravet syndrome, but the positive results with an unexpected FDA-approved drug may lead to new therapeutic avenues. \"There is more work to be done, but I am very pleased to see these initial results. These kinds of new directions are exactly what we hoped to stimulate with the EUREKA program,\" she said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Dravet syndrome is a catastrophic pediatric epilepsy with severe intellectual disability, impaired social development and persistent drug-resistant seizures. One of its primary monogenic causes are mutations in Na v 1.1 ( SCN1A ), a voltage-gated sodium channel. Here we characterize zebrafish Na v 1.1 ( scn1Lab ) mutants originally identified in a chemical mutagenesis screen. Mutants exhibit spontaneous abnormal electrographic activity, hyperactivity and convulsive behaviours. Although scn1Lab expression is reduced, microarray analysis is remarkable for the small fraction of differentially expressed genes (~3%) and lack of compensatory expression changes in other scn subunits. Ketogenic diet, diazepam, valproate, potassium bromide and stiripentol attenuate mutant seizure activity; seven other antiepileptic drugs have no effect. A phenotype-based screen of 320 compounds identifies a US Food and Drug Administration-approved compound (clemizole) that inhibits convulsive behaviours and electrographic seizures. This approach represents a new direction in modelling pediatric epilepsy and could be used to identify novel therapeutics for any monogenic epilepsy disorder. Introduction Epilepsy can be acquired as a result of an insult to the brain or genetic mutation. Among the genetic epilepsies, more than 650 variants have been identified in the SCN1A gene 1 , 2 . Missense or frame-shift mutations in this gene are associated with generalized epilepsy with febrile seizures plus 3 as well as a more severe disorder known as Dravet syndrome (DS). Children with DS initially exhibit normal development but often experience febrile seizure episodes within the first year of life, with eventual progression to severe spontaneous recurrent seizures, intellectual disability, ataxia and psychomotor dysfunction. Seizures are inadequately managed using available antiepileptic drugs (AEDs) and these children are poor candidates for neurosurgical resection 4 . In mammalian brain, there are four main subtypes of voltage-gated sodium channel α-subunits: Na V 1.1, Na V 1.2, Na V 1.3 and Na V 1.6, encoded for by the genes SCN1A , SCN2A , SCN3A and SCN8A , respectively. Opening of these channels produces a sodium conductance and rapid cell membrane depolarization, for example, features integral to action potential initiation 5 . In mice, Na v 1.1 is widely expressed in the central nervous system (CNS), including the axon initial segment of parvalbumin-positive hippocampal interneurons and excitatory principal cells 6 , 7 . Heterozygous deletion of Na v 1.1 in mice leads to a reduction in the firing capability of acutely dissociated fast-spiking interneurons 8 . Mice with global or interneuron-specific heterozygous deletion of Na v 1.1 exhibit temperature-induced and spontaneous seizures, mild ataxia, autism-like behaviours and premature death 8 , 9 , 10 . Knock-in mouse carrying a premature stop codon in domain III of the Na v 1.1 channel also exhibit a decrement in spike amplitude during prolonged interneuron firing and increased sensitivity to temperature-induced seizures 11 . Generation and characterization of valid animal models is critical to efforts to understand the pathophysiology of DS, and to aid in the identification of novel therapies. Although considerable attention has focused on modelling SCN1A mutations in mice, these animals have proven to be difficult to breed, and epilepsy phenotypes are strongly influenced by the background strain genetics. Induced pluripotent stem cells can be generated from DS patients, but individual neurons do not recapitulate the network environment necessary for in-vivo seizure generation. Danio rerio (zebrafish), a simple vertebrate species, provide an alternative model system with significant advantages for genetic manipulation, cost-efficient breeding and in-vivo drug discovery 12 , 13 , 14 . Ideally, an animal model should be based on a known genetic cause of the disease ( SCN1A mutation), accurately recapitulate key features of the disease (epilepsy), and respond, or not, to therapies commonly used in patients with the disease (pharmacological validation). If successful, such a model could inform our understanding of the disease process and catalyse explorations towards new therapies. In zebrafish, the voltage-gated sodium channel family consists of four sets of duplicated genes: scn1Laa and scn1Lab , scn4aa and scn4ab , scn5Laa and scn5Lab , and scn8aa and scn8ab (ref. 15 ). The zebrafish scn1Lab gene shares a 77% identity with human SCN1A and is expressed in the CNS. A homozygous zebrafish mutant for this gene (originally termed didy s552 ) was discovered in a chemical mutagenesis screen using the optokinetic response as an assay 16 . These types of screens are based on inducing random point mutations using the alkylating agent N- ethyl -N- nitrosourea; the resulting mutations are typically loss-of-function and recessive. Although this is a homozygous mutation, scn1Lab zebrafish mutants are relevant for the autosomal dominant human DS given the genome duplication in zebrafish and the presence of an additional Na v 1.1 homologue ( scn1Laa ). In this paper, we characterized scn1Lab mutants at the molecular and behavioural level, demonstrated that mutants exhibit spontaneous drug-resistant seizures and then used them in a novel high-throughput screening programme to identify compounds that ameliorate the epilepsy phenotype. A phenotype-based screen identified clemizole, an US Food and Drug Administration (FDA)-approved compound, as an effective inhibitor of spontaneous convulsive behaviours and electrographic seizures in these mutants. Results Developmental scn1Lab expression and characterization Zebrafish with a mutation in domain III of a voltage-gated sodium channel were identified by Dr Herwig Baier during a chemical mutagenesis screen 16 . We backcrossed original scn1Lab mutants onto the Tupfel long background for seven to ten generations and confirmed a methionine (M) to arginine (R) mutation in our colony ( Fig. 1a ). Reverse-transcriptase and quantitative (q) PCR revealed a decrease in mRNA expression for scn1Lab in mutant larvae at 3, 5 and 7 days post fertilization (dpf; Fig. 1b ); antibodies recognizing this protein in zebrafish are not available. As expected 15 , scn1Lab is prominently expressed during early stages of larval development ( Fig. 1b ) and specifically in the CNS at 3 dpf ( Fig. 1d,e ). Whole-mount in situ hybridization revealed diffuse but prominent expression in the brain regions corresponding to the forebrain (telencephalon), optic tectum and cerebellum. A similar expression pattern was observed for scn1Laa at 3 dpf. At 5 and 7<|im_end|> <|im_start|>assistant According to new research on epilepsy, zebrafish have certainly earned their stripes. Results of a study in Nature Communications suggest that zebrafish carrying a specific mutation may help researchers discover treatments for Dravet syndrome (DS), a severe form of pediatric epilepsy that results in drug-resistant seizures and developmental delays. Scott C. Baraban, Ph.D., and his colleagues at the University of California, San Francisco (UCSF), carefully assessed whether the mutated zebrafish could serve as a model for DS, and then developed a new screening method to quickly identify potential treatments for DS using these fish. This study was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health and builds on pioneering epilepsy zebrafish models first described by the Baraban laboratory in 2005. Dravet syndrome is commonly caused by a mutation in the Scn1a gene, which encodes for Nav1.1, a specific sodium ion channel found in the brain. Sodium ion channels are critical for communication between brain cells and proper brain functioning. The researchers found that the zebrafish that were engineered to have the Scn1a mutation that causes DS in humans exhibited some of the same characteristics, such as spontaneous seizures, commonly seen in children with DS. Unprovoked seizure activity in the mutant fish resulted in hyperactivity and whole-body convulsions associated with very fast swimming. These types of behaviors are not seen in normal healthy zebrafish. "We were also surprised at how similar the mutant zebrafish drug profile was to that of Dravet patients," said Dr. Baraban. "Antiepileptic drugs shown to have some benefits in patients (such as benzodiazepines or stiripentol) also exhibited some antiepileptic activity in these mutants. Conversely, many of the antiepileptic drugs that do not reduce seizures in these patients showed no effect in the mutant zebrafish." In this study, the researchers developed a fast and automated drug screen to quickly test the effectiveness of various compounds in mutant zebrafish. The researchers tracked behavior and measured brain activity in the mutant zebrafish to determine if the compounds had an impact on seizures. "Scn1a mutants seize often, so it is relatively easy to monitor their seizure behavior at baseline and then again after a drug application," said Dr. Baraban. "Using zebrafish placed individually in a 96-part petri dish we can accurately quantify this seizure behavior. In this way, we can test almost 100 fish at one time and quickly determine whether a drug candidate has any effect on these spontaneous seizures." In the first such application of this approach, UCSF researchers screened 320 compounds and found that clemizole was most effective in inhibiting seizure activity. Clemizole is approved by the U.S. Food and Drug Administration and has a safe toxicology profile. "This finding was completely unexpected. Based on what is currently known about clemizole, we did not predict that it would have antiepileptic effects," said Dr. Baraban. These findings suggest that Scn1a mutant zebrafish may serve as a good model of DS and that the drug screen may be effective in quickly identifying novel therapies for epilepsy. Dr. Baraban also noted that someday these experiments can be "personalized," by looking at mutated zebrafish that use genetic information from individual patients. This research was funded by the Exceptional, Unconventional Research Enabling Knowledge Acceleration (EUREKA) program at NIH that supports innovative research with the potential for big impact in biomedical science. "The goal of the EUREKA program is to provide a means to test high-risk ideas to see if they are worth pursuing further. These kinds of ideas often come from left field and are very creative. Since they are so unique, however, there may not be any existing preliminary data to support the hypothesis or demonstrate feasibility. EUREKA grants provide an opportunity to gather this information," said Brandy Fureman, Ph.D., program director at NINDS. This particular study was chosen in response to a request by NINDS to help spur novel research on epilepsy. "This research was selected for a EUREKA grant because it proposed a well-designed, inventive model of genetic epilepsy that could accelerate the pace of drug-screening for this devastating form of pediatric epilepsy" said Dr. Fureman. Dr. Fureman noted that these findings not only describe a novel model of Dravet syndrome, but the positive results with an unexpected FDA-approved drug may lead to new therapeutic avenues. "There is more work to be done, but I am very pleased to see these initial results. These kinds of new directions are exactly what we hoped to stimulate with the EUREKA program," she said. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Face memory, including the ability to recall a person’s name, is of major importance in social contexts. Like many other memory functions, it may rely on sleep. We investigated whether targeted memory reactivation during sleep could improve associative and perceptual aspects of face memory. Participants studied 80 face-name pairs, and then a subset of spoken names with associated background music was presented unobtrusively during a daytime nap. This manipulation preferentially improved name recall and face recognition for those reactivated face-name pairs, as modulated by two factors related to sleep quality; memory benefits were positively correlated with the duration of stage N3 sleep (slow-wave sleep) and negatively correlated with measures of sleep disruption. We conclude that (a) reactivation of specific face-name memories during sleep can strengthen these associations and the constituent memories, and that (b) the effectiveness of this reactivation depends on uninterrupted N3 sleep. Introduction We often rely on face recognition and name recall—such as when we notice friends from a distance and call to them by their names. Most people are extraordinarily adept at recognizing the faces of individuals, even those they’ve met just once. Yet, there are also times when we fail to recognize someone—and it can be embarrassing when we forget a name that we should have remembered. What determines which memories continue to be enduringly available and which are forgotten? Given that the human brain is remarkably active during sleep, researchers have asserted that neural events during sleep may function to stabilize and strengthen recently acquired memories 1 , 2 , 3 , 4 . The delineation of these neural events and their specific ramifications for memory has become increasingly central to memory research and the science of learning. A prevalent view is that memories can benefit due to spontaneous replay during sleep 5 , 6 , 7 , 8 . In recent years, Targeted Memory Reactivation (TMR) has emerged as a useful tool for investigating this process 9 . In the TMR procedure, information that people learn is associated with a sound or smell during learning. Researchers then present the same sensory cue, while people sleep, without waking them. After sleep, people remember information associated with the cue stimulus better than other information that was equally well-learned, a frequently reported finding confirmed in a recent meta-analysis 10 . Moreover, the notion that TMR benefits memory through reactivation is supported by neuronal evidence of hippocampal place cell replay engaged following the presentation of learning-related sounds during sleep 11 . In addition to functioning as a powerful research tool, TMR offers the potential to enhance memory with a simple, noninvasive intervention during sleep, which may be useful in many scenarios. Because learning face-name associations is an important and widely relevant form of memory, we asked whether TMR could enhance this type of learning. We developed a procedure whereby participants learned about people ostensibly in either a Japanese History class or a Latin-American History class. Learning was accompanied by a background music track, either traditional Japanese music or traditional Latin-American music, respectively. Each classroom had 40 pupils. To learn the names of these pupils, participants viewed each face adjacent to the corresponding written name, while also hearing the spoken name. Recall training, feedback, and visualization practice served to solidify this learning. Next, we assessed both face recognition and name recall. Then, during a period of sleep, some of the spoken names and associated background music were softly presented. After awakening, participants were exposed to additional faces and names, potentially interfering with the original learning. Finally, we assessed memory again. Figure 1 shows the experimental procedure schematically, and additional details are provided in METHODS. Fig. 1: Experimental procedure overview. Stages of the protocol are illustrated at the top (with mean beginning and ending times). Details of the learning and testing procedures are listed below. Full size image This experimental design thus makes it possible to determine the extent to which face memory can be selectively improved by reactivation during sleep. Such results, along with analyses of relationships between memory change and characteristics of slow-wave sleep, could have implications for understanding the physiological mechanisms that generally enable memory reactivation during sleep to be effective. Results The influence of TMR on memory varied with duration of stage N3 sleep Memory testing demonstrated effective learning of faces and associated names. On the name recall test, participants correctly recalled a mean of 74.04 (SD = 4.83) names before sleep and 75.00 (SD = 4.03) names after sleep (in each case from a total of 80 face-name associations). When requested, hints were provided in the form of up to three starting letters. Across all 80 names in the test, participants requested a mean of 0.77 (SD = 0.69) hint letters per name before sleep and 0.80 (SD = 0.75) after sleep. On the presleep recognition test, participants successfully recognized 97% (SD = 3%) of the identical old faces and 92% (SD = 7%) of the old faces that were rotated from their original view. For new faces, 74% (SD = 24%) were endorsed correctly as new faces. Postsleep recognition scores were similar (97%, 91%, and 85% correct for old, rotated, and new, SDs = 4%, 9%, 15%, respectively). To examine the effect of TMR, we first computed the change in the number of names successfully recalled across sleep. This value, Δrecall, did not differ significantly between the cued class, designated class C , and the uncued class, designated class U [mean Δrecall 0.75 and 0.21, SDs = 2.03 and 1.70, respectively; t (23) = 0.93, p = 0.36]. In initial planned comparisons, we analyzed the cueing effect on Δrecall (defined as the difference between class-C Δrecall and class-U Δrecall) in relation to several sleep measures: total sleep duration, N2 duration, N3 duration, and REM duration. As shown in Fig. 2a , the size of the cuing effect on Δrecall was correlated with the duration of stage N3 sleep [ χ² (1 , N = 24) = 5.18, p = 0.02]. This cueing effect", "role": "user" }, { "content": "For those who rarely forget a face, but struggle with names, the remedy for boosting learning may as near as your pillow. New research by Northwestern University is the first to document the effect reactivating memory during sleep has on face-name learning. The researchers found that people's name recall improved significantly when memories of newly learned face-name associations were reactivated while they were napping. Key to this improvement was uninterrupted deep sleep. \"It's a new and exciting finding about sleep, because it tells us that the way information is reactivated during sleep to improve memory storage is linked with high-quality sleep,\" said lead author Nathan Whitmore, a Ph.D. candidate in the Interdepartmental Neuroscience Program at Northwestern. The paper, \"Targeted memory reactivation of face-name learning depends on ample and undisturbed slow-wave sleep,\" will publish Jan. 12 in the Nature partner journal npj: Science of Learning. The paper's senior author is Ken Paller, professor of psychology and director of the Cognitive Neuroscience Program at Weinberg College of Arts and Sciences at Northwestern. The paper was also co-authored by Adrianna Bassard, Ph.D. candidate in psychology at Northwestern. The research team found that for study participants with EEG measures (a recording of electrical activity of the brain picked up by electrodes on the scalp) that indicated disrupted sleep, the memory reactivation didn't help and may even be detrimental. But in those with uninterrupted sleep during the specific times of sound presentations, the reactivation led to a relative improvement averaging just over 1.5 more names recalled. The study was conducted on 24 participants, aged 18-31 years old, who were asked to memorize the faces and names of 40 pupils from a hypothetical Latin American history class and another 40 from a Japanese history class. When each face was shown again, they were asked to produce the name that went with it. After the learning exercise, participants took a nap while the researchers carefully monitored brain activity using EEG measurements. When participants reached the N3 \"deep sleep\" state, some of the names were softly played on a speaker with music that was associated with one of the classes. When participants woke up, they were retested on recognizing the faces and recalling the name that went with each face. The researchers say the finding on the relationship between sleep disruption and memory accuracy is noteworthy for several reasons. \"We already know that some sleep disorders like apnea can impair memory,\" said Whitmore. \"Our research suggests a potential explanation for this—frequent sleep interruptions at night might be degrading memory.\" The lab is in the midst of a follow-up study to reactivate memories and deliberately disrupt sleep in order to learn more about the relevant brain mechanisms. \"This new line of research will let us address many interesting questions—like whether sleep disruption is always harmful or whether it could be used to weaken unwanted memories,\" said Paller, who also holds the James Padilla Chair in Arts & Sciences at Northwestern. \"At any rate, we are increasingly finding good reasons to value high-quality sleep.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Face memory, including the ability to recall a person’s name, is of major importance in social contexts. Like many other memory functions, it may rely on sleep. We investigated whether targeted memory reactivation during sleep could improve associative and perceptual aspects of face memory. Participants studied 80 face-name pairs, and then a subset of spoken names with associated background music was presented unobtrusively during a daytime nap. This manipulation preferentially improved name recall and face recognition for those reactivated face-name pairs, as modulated by two factors related to sleep quality; memory benefits were positively correlated with the duration of stage N3 sleep (slow-wave sleep) and negatively correlated with measures of sleep disruption. We conclude that (a) reactivation of specific face-name memories during sleep can strengthen these associations and the constituent memories, and that (b) the effectiveness of this reactivation depends on uninterrupted N3 sleep. Introduction We often rely on face recognition and name recall—such as when we notice friends from a distance and call to them by their names. Most people are extraordinarily adept at recognizing the faces of individuals, even those they’ve met just once. Yet, there are also times when we fail to recognize someone—and it can be embarrassing when we forget a name that we should have remembered. What determines which memories continue to be enduringly available and which are forgotten? Given that the human brain is remarkably active during sleep, researchers have asserted that neural events during sleep may function to stabilize and strengthen recently acquired memories 1 , 2 , 3 , 4 . The delineation of these neural events and their specific ramifications for memory has become increasingly central to memory research and the science of learning. A prevalent view is that memories can benefit due to spontaneous replay during sleep 5 , 6 , 7 , 8 . In recent years, Targeted Memory Reactivation (TMR) has emerged as a useful tool for investigating this process 9 . In the TMR procedure, information that people learn is associated with a sound or smell during learning. Researchers then present the same sensory cue, while people sleep, without waking them. After sleep, people remember information associated with the cue stimulus better than other information that was equally well-learned, a frequently reported finding confirmed in a recent meta-analysis 10 . Moreover, the notion that TMR benefits memory through reactivation is supported by neuronal evidence of hippocampal place cell replay engaged following the presentation of learning-related sounds during sleep 11 . In addition to functioning as a powerful research tool, TMR offers the potential to enhance memory with a simple, noninvasive intervention during sleep, which may be useful in many scenarios. Because learning face-name associations is an important and widely relevant form of memory, we asked whether TMR could enhance this type of learning. We developed a procedure whereby participants learned about people ostensibly in either a Japanese History class or a Latin-American History class. Learning was accompanied by a background music track, either traditional Japanese music or traditional Latin-American music, respectively. Each classroom had 40 pupils. To learn the names of these pupils, participants viewed each face adjacent to the corresponding written name, while also hearing the spoken name. Recall training, feedback, and visualization practice served to solidify this learning. Next, we assessed both face recognition and name recall. Then, during a period of sleep, some of the spoken names and associated background music were softly presented. After awakening, participants were exposed to additional faces and names, potentially interfering with the original learning. Finally, we assessed memory again. Figure 1 shows the experimental procedure schematically, and additional details are provided in METHODS. Fig. 1: Experimental procedure overview. Stages of the protocol are illustrated at the top (with mean beginning and ending times). Details of the learning and testing procedures are listed below. Full size image This experimental design thus makes it possible to determine the extent to which face memory can be selectively improved by reactivation during sleep. Such results, along with analyses of relationships between memory change and characteristics of slow-wave sleep, could have implications for understanding the physiological mechanisms that generally enable memory reactivation during sleep to be effective. Results The influence of TMR on memory varied with duration of stage N3 sleep Memory testing demonstrated effective learning of faces and associated names. On the name recall test, participants correctly recalled a mean of 74.04 (SD = 4.83) names before sleep and 75.00 (SD = 4.03) names after sleep (in each case from a total of 80 face-name associations). When requested, hints were provided in the form of up to three starting letters. Across all 80 names in the test, participants requested a mean of 0.77 (SD = 0.69) hint letters per name before sleep and 0.80 (SD = 0.75) after sleep. On the presleep recognition test, participants successfully recognized 97% (SD = 3%) of the identical old faces and 92% (SD = 7%) of the old faces that were rotated from their original view. For new faces, 74% (SD = 24%) were endorsed correctly as new faces. Postsleep recognition scores were similar (97%, 91%, and 85% correct for old, rotated, and new, SDs = 4%, 9%, 15%, respectively). To examine the effect of TMR, we first computed the change in the number of names successfully recalled across sleep. This value, Δrecall, did not differ significantly between the cued class, designated class C , and the uncued class, designated class U [mean Δrecall 0.75 and 0.21, SDs = 2.03 and 1.70, respectively; t (23) = 0.93, p = 0.36]. In initial planned comparisons, we analyzed the cueing effect on Δrecall (defined as the difference between class-C Δrecall and class-U Δrecall) in relation to several sleep measures: total sleep duration, N2 duration, N3 duration, and REM duration. As shown in Fig. 2a , the size of the cuing effect on Δrecall was correlated with the duration of stage N3 sleep [ χ² (1 , N = 24) = 5.18, p = 0.02]. This cueing effect<|im_end|> <|im_start|>assistant For those who rarely forget a face, but struggle with names, the remedy for boosting learning may as near as your pillow. New research by Northwestern University is the first to document the effect reactivating memory during sleep has on face-name learning. The researchers found that people's name recall improved significantly when memories of newly learned face-name associations were reactivated while they were napping. Key to this improvement was uninterrupted deep sleep. "It's a new and exciting finding about sleep, because it tells us that the way information is reactivated during sleep to improve memory storage is linked with high-quality sleep," said lead author Nathan Whitmore, a Ph.D. candidate in the Interdepartmental Neuroscience Program at Northwestern. The paper, "Targeted memory reactivation of face-name learning depends on ample and undisturbed slow-wave sleep," will publish Jan. 12 in the Nature partner journal npj: Science of Learning. The paper's senior author is Ken Paller, professor of psychology and director of the Cognitive Neuroscience Program at Weinberg College of Arts and Sciences at Northwestern. The paper was also co-authored by Adrianna Bassard, Ph.D. candidate in psychology at Northwestern. The research team found that for study participants with EEG measures (a recording of electrical activity of the brain picked up by electrodes on the scalp) that indicated disrupted sleep, the memory reactivation didn't help and may even be detrimental. But in those with uninterrupted sleep during the specific times of sound presentations, the reactivation led to a relative improvement averaging just over 1.5 more names recalled. The study was conducted on 24 participants, aged 18-31 years old, who were asked to memorize the faces and names of 40 pupils from a hypothetical Latin American history class and another 40 from a Japanese history class. When each face was shown again, they were asked to produce the name that went with it. After the learning exercise, participants took a nap while the researchers carefully monitored brain activity using EEG measurements. When participants reached the N3 "deep sleep" state, some of the names were softly played on a speaker with music that was associated with one of the classes. When participants woke up, they were retested on recognizing the faces and recalling the name that went with each face. The researchers say the finding on the relationship between sleep disruption and memory accuracy is noteworthy for several reasons. "We already know that some sleep disorders like apnea can impair memory," said Whitmore. "Our research suggests a potential explanation for this—frequent sleep interruptions at night might be degrading memory." The lab is in the midst of a follow-up study to reactivate memories and deliberately disrupt sleep in order to learn more about the relevant brain mechanisms. "This new line of research will let us address many interesting questions—like whether sleep disruption is always harmful or whether it could be used to weaken unwanted memories," said Paller, who also holds the James Padilla Chair in Arts & Sciences at Northwestern. "At any rate, we are increasingly finding good reasons to value high-quality sleep." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Time-calibrated phylogenies of extant species (referred to here as ‘extant timetrees’) are widely used for estimating diversification dynamics 1 . However, there has been considerable debate surrounding the reliability of these inferences 2 , 3 , 4 , 5 and, to date, this critical question remains unresolved. Here we clarify the precise information that can be extracted from extant timetrees under the generalized birth–death model, which underlies most existing methods of estimation. We prove that, for any diversification scenario, there exists an infinite number of alternative diversification scenarios that are equally likely to have generated any given extant timetree. These ‘congruent’ scenarios cannot possibly be distinguished using extant timetrees alone, even in the presence of infinite data. Importantly, congruent diversification scenarios can exhibit markedly different and yet similarly plausible dynamics, which suggests that many previous studies may have over-interpreted phylogenetic evidence. We introduce identifiable and easily interpretable variables that contain all available information about past diversification dynamics, and demonstrate that these can be estimated from extant timetrees. We suggest that measuring and modelling these identifiable variables offers a more robust way to study historical diversification dynamics. Our findings also make it clear that palaeontological data will continue to be crucial for answering some macroevolutionary questions. Main A central challenge in evolutionary biology is to reconstruct rates of speciation and extinction over time 5 . Unfortunately, the majority of taxa that have ever lived have not left much trace in the fossil record, and the primary source of information on their past diversification dynamics therefore comes from extant timetrees. Many methods have been developed for extracting this information; most methods fit variants of a birth–death process 1 , 6 . Despite the popularity of these methods, which collectively have been used in thousands of studies 7 , 8 , 9 , their reliability has been called into question by comparisons with fossil-based estimates 1 , 3 , 5 , 6 , 10 . The reasoning behind these critiques is that there may be insufficient information in extant timetrees to fully reconstruct historical diversification dynamics. However, this critical issue has remained unresolved; it is unknown precisely what information on speciation and extinction rates is contained in extant timetrees. Here we present a definite answer to this question for the general stochastic birth–death process with homogeneous (that is, lineage-independent) rates, in which speciation (‘birth’) rates ( λ ) and extinction (‘death’) rates ( μ ) can vary over time, that underlies the majority of existing methods for reconstructing diversification dynamics from phylogenies 1 . We mathematically show that, for any given candidate birth–death model, there exists an infinite number of alternative birth–death models that can explain any extant timetree equally as well as can the candidate model. These alternative models may appear to be similarly plausible and yet exhibit markedly different features, such as different trends through time in both λ and μ . This severe ambiguity persists for arbitrarily large trees and cannot be resolved even with an infinite amount of data; it is thus impossible to design asymptotically consistent estimators for λ and μ . Using simulated and real timetrees as examples, we demonstrate how failing to recognize this issue can seriously mislead our inferences about past diversification dynamics. We present appropriately modified variables that are asymptotically identifiable and that contain all available information on historical diversification dynamics. Lineages through time An important feature of extant timetrees is the lineages-through-time curve (LTT), which counts the number of lineages at each time in the past that are represented by at least one sampled extant descending species in the tree. The likelihood of a tree under a given birth–death model, the LLT of the tree and the LTT that would be expected under the model are linked as follows. Any given combination of (potentially time-dependent) speciation and extinction rates ( λ and μ , respectively) and the probability that an extant species will be included in the tree (‘sampling fraction’) ( ρ ) can be used to define a deterministic diversification process, in which the number of lineages through time no longer varies stochastically but instead according to a set of differential equations 6 , 11 ( Supplementary Information section S.1 ). Given a number of extant sampled species ( M o ), the LTT predicted by these differential equations (the deterministic LTT (dLTT)) corresponds to the LTT that is expected for trees generated by the original stochastic model 1 , 11 . The likelihood of a tree under a given birth–death model can be written purely in terms of the LTT of the tree and the dLTT of the model (see Supplementary Information section S.1.2 and ref. 12 for derivations). This means that any two models with the same dLTT (conditioned on M o ) yield identical likelihoods for the tree. We therefore call two models ‘congruent’ if they have the same dLTT for any given M o . Any two models are either congruent or non-congruent, regardless of any particular data considered ( Supplementary Information section S.1 ). The probability distribution of tree sizes generated by a model, when conditioned on the age of the stem or crown, is identical among congruent models ( Supplementary Information section S.1.7 ). Hence, congruent models have equal probabilities of generating any given timetree, analogous to how congruent geometric objects exhibit similar properties (discussion in Supplementary Information section S.1.8 ). Although the mathematical relationship between the dLTT of a model and its likelihood has been known 12 , its implications for macroevolutionary inference have remained unexamined and—as we show below—severely underestimated. The breadth of congruent model sets When seen as a random variable, extant timetrees have the same probability distribution under any two congruent models. Therefore, in the absence of further information, congruent models cannot possibly be distinguished solely on the basis of extant timetrees—neither through the likelihood nor any other test statistic. For any birth–death model, this leads to four important unresolved questions: how many alternative congruent models there are, how different these", "role": "user" }, { "content": "When species under a taxonomic umbrella have faced forks in the road, leading to extinction or adaptation, the path taken has been difficult to follow. In a newly published paper, two scientists argue that long-used approaches for reconstructing these paths are deeply flawed. While paleontological evidence provides insights on how and why patterns of biodiversity have changed over geological time, fossil finds for many types of organisms are too scant to say anything, said University of Oregon biologist Stilianos Louca, lead author of a paper placed online April 15 ahead of print in the journal Nature. An alternative approach, he noted, relies on using identifiable changes in an organism's genetic makeup, but the signal in this type of data can be misleading. \"Our finding casts serious doubts over literally thousands of studies that use phylogenetic trees of extant data to reconstruct the diversification history of taxa, especially for those taxa where fossils are rare, or that found correlations between environmental factors such as changing global temperatures and species extinction rates,\" said Louca, who is a member of the UO's Institute of Ecology and Evolution. In their paper, Louca and Matthew W. Pennell, an evolutionary biologist at the University of British Columbia in Vancouver, also offer a way forward—a mathematical model that introduces alternative variables to characterize long-term evolutionary scenarios that can be accurately identified from phylogenetic data. \"I have been working with these traditional types of models for a decade now,\" Pennell said. \"I am one of the lead developers of a popular software package for estimating diversification rates from phylogenetic trees. And, as such, I thought I had a really good sense of how these models worked. I was wrong.\" In their paper, the researchers note that long-used methods extract information about evolution from still-living organisms, using variants of a mathematical birth-death process. These, however, cannot possibly extract information about both speciation and extinction rates, especially for a majority of taxa, such as bacteria, that have left no fossil record. The paleontological approach estimates the number of species that have appeared and disappeared in various intervals based on discovered fossils and their estimated minimum and maximum ages. In the phylogenetic approach, information is extracted from evolutionary relationships between existing species, using mostly genetic data, and structured in phylogenetic trees known as timetrees. This is often done by finding a speciation/extinction scenario that would have been the most likely to generate a given phylogenetic tree. \"While an impressive suite of computational methods has been developed over the past decades for extracting whatever information is left, until now we lacked a good understanding of exactly what information is left in these trees, and what information is forever lost,\" Louca said. Louca and Pennell's mathematically driven approach clarifies precisely what information can be extracted from extant timetrees under the generalized birth-death model. The researchers introduce new identifiable and easily interpretable variables that contain all available information about past diversification dynamics and how they can be estimated. \"We suggest that measuring and modeling these identifiable variables offers a more robust way to study historical diversification dynamics,\" they write in the paper. \"Our findings also make clear that paleontological data will continue to be crucial for answering some macroevolutionary questions.\" \"The future depends on synthesizing information from datasets of both molecules and fossils,\" Pennell said. The researchers emphasize that their results do not invalidate the theory of evolution itself, they just put constraints on what type of information can possibly be extracted from genetic data to reconstruct evolution's path. The pair's paper will appear in the April 23 print issue of Nature. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Time-calibrated phylogenies of extant species (referred to here as ‘extant timetrees’) are widely used for estimating diversification dynamics 1 . However, there has been considerable debate surrounding the reliability of these inferences 2 , 3 , 4 , 5 and, to date, this critical question remains unresolved. Here we clarify the precise information that can be extracted from extant timetrees under the generalized birth–death model, which underlies most existing methods of estimation. We prove that, for any diversification scenario, there exists an infinite number of alternative diversification scenarios that are equally likely to have generated any given extant timetree. These ‘congruent’ scenarios cannot possibly be distinguished using extant timetrees alone, even in the presence of infinite data. Importantly, congruent diversification scenarios can exhibit markedly different and yet similarly plausible dynamics, which suggests that many previous studies may have over-interpreted phylogenetic evidence. We introduce identifiable and easily interpretable variables that contain all available information about past diversification dynamics, and demonstrate that these can be estimated from extant timetrees. We suggest that measuring and modelling these identifiable variables offers a more robust way to study historical diversification dynamics. Our findings also make it clear that palaeontological data will continue to be crucial for answering some macroevolutionary questions. Main A central challenge in evolutionary biology is to reconstruct rates of speciation and extinction over time 5 . Unfortunately, the majority of taxa that have ever lived have not left much trace in the fossil record, and the primary source of information on their past diversification dynamics therefore comes from extant timetrees. Many methods have been developed for extracting this information; most methods fit variants of a birth–death process 1 , 6 . Despite the popularity of these methods, which collectively have been used in thousands of studies 7 , 8 , 9 , their reliability has been called into question by comparisons with fossil-based estimates 1 , 3 , 5 , 6 , 10 . The reasoning behind these critiques is that there may be insufficient information in extant timetrees to fully reconstruct historical diversification dynamics. However, this critical issue has remained unresolved; it is unknown precisely what information on speciation and extinction rates is contained in extant timetrees. Here we present a definite answer to this question for the general stochastic birth–death process with homogeneous (that is, lineage-independent) rates, in which speciation (‘birth’) rates ( λ ) and extinction (‘death’) rates ( μ ) can vary over time, that underlies the majority of existing methods for reconstructing diversification dynamics from phylogenies 1 . We mathematically show that, for any given candidate birth–death model, there exists an infinite number of alternative birth–death models that can explain any extant timetree equally as well as can the candidate model. These alternative models may appear to be similarly plausible and yet exhibit markedly different features, such as different trends through time in both λ and μ . This severe ambiguity persists for arbitrarily large trees and cannot be resolved even with an infinite amount of data; it is thus impossible to design asymptotically consistent estimators for λ and μ . Using simulated and real timetrees as examples, we demonstrate how failing to recognize this issue can seriously mislead our inferences about past diversification dynamics. We present appropriately modified variables that are asymptotically identifiable and that contain all available information on historical diversification dynamics. Lineages through time An important feature of extant timetrees is the lineages-through-time curve (LTT), which counts the number of lineages at each time in the past that are represented by at least one sampled extant descending species in the tree. The likelihood of a tree under a given birth–death model, the LLT of the tree and the LTT that would be expected under the model are linked as follows. Any given combination of (potentially time-dependent) speciation and extinction rates ( λ and μ , respectively) and the probability that an extant species will be included in the tree (‘sampling fraction’) ( ρ ) can be used to define a deterministic diversification process, in which the number of lineages through time no longer varies stochastically but instead according to a set of differential equations 6 , 11 ( Supplementary Information section S.1 ). Given a number of extant sampled species ( M o ), the LTT predicted by these differential equations (the deterministic LTT (dLTT)) corresponds to the LTT that is expected for trees generated by the original stochastic model 1 , 11 . The likelihood of a tree under a given birth–death model can be written purely in terms of the LTT of the tree and the dLTT of the model (see Supplementary Information section S.1.2 and ref. 12 for derivations). This means that any two models with the same dLTT (conditioned on M o ) yield identical likelihoods for the tree. We therefore call two models ‘congruent’ if they have the same dLTT for any given M o . Any two models are either congruent or non-congruent, regardless of any particular data considered ( Supplementary Information section S.1 ). The probability distribution of tree sizes generated by a model, when conditioned on the age of the stem or crown, is identical among congruent models ( Supplementary Information section S.1.7 ). Hence, congruent models have equal probabilities of generating any given timetree, analogous to how congruent geometric objects exhibit similar properties (discussion in Supplementary Information section S.1.8 ). Although the mathematical relationship between the dLTT of a model and its likelihood has been known 12 , its implications for macroevolutionary inference have remained unexamined and—as we show below—severely underestimated. The breadth of congruent model sets When seen as a random variable, extant timetrees have the same probability distribution under any two congruent models. Therefore, in the absence of further information, congruent models cannot possibly be distinguished solely on the basis of extant timetrees—neither through the likelihood nor any other test statistic. For any birth–death model, this leads to four important unresolved questions: how many alternative congruent models there are, how different these<|im_end|> <|im_start|>assistant When species under a taxonomic umbrella have faced forks in the road, leading to extinction or adaptation, the path taken has been difficult to follow. In a newly published paper, two scientists argue that long-used approaches for reconstructing these paths are deeply flawed. While paleontological evidence provides insights on how and why patterns of biodiversity have changed over geological time, fossil finds for many types of organisms are too scant to say anything, said University of Oregon biologist Stilianos Louca, lead author of a paper placed online April 15 ahead of print in the journal Nature. An alternative approach, he noted, relies on using identifiable changes in an organism's genetic makeup, but the signal in this type of data can be misleading. "Our finding casts serious doubts over literally thousands of studies that use phylogenetic trees of extant data to reconstruct the diversification history of taxa, especially for those taxa where fossils are rare, or that found correlations between environmental factors such as changing global temperatures and species extinction rates," said Louca, who is a member of the UO's Institute of Ecology and Evolution. In their paper, Louca and Matthew W. Pennell, an evolutionary biologist at the University of British Columbia in Vancouver, also offer a way forward—a mathematical model that introduces alternative variables to characterize long-term evolutionary scenarios that can be accurately identified from phylogenetic data. "I have been working with these traditional types of models for a decade now," Pennell said. "I am one of the lead developers of a popular software package for estimating diversification rates from phylogenetic trees. And, as such, I thought I had a really good sense of how these models worked. I was wrong." In their paper, the researchers note that long-used methods extract information about evolution from still-living organisms, using variants of a mathematical birth-death process. These, however, cannot possibly extract information about both speciation and extinction rates, especially for a majority of taxa, such as bacteria, that have left no fossil record. The paleontological approach estimates the number of species that have appeared and disappeared in various intervals based on discovered fossils and their estimated minimum and maximum ages. In the phylogenetic approach, information is extracted from evolutionary relationships between existing species, using mostly genetic data, and structured in phylogenetic trees known as timetrees. This is often done by finding a speciation/extinction scenario that would have been the most likely to generate a given phylogenetic tree. "While an impressive suite of computational methods has been developed over the past decades for extracting whatever information is left, until now we lacked a good understanding of exactly what information is left in these trees, and what information is forever lost," Louca said. Louca and Pennell's mathematically driven approach clarifies precisely what information can be extracted from extant timetrees under the generalized birth-death model. The researchers introduce new identifiable and easily interpretable variables that contain all available information about past diversification dynamics and how they can be estimated. "We suggest that measuring and modeling these identifiable variables offers a more robust way to study historical diversification dynamics," they write in the paper. "Our findings also make clear that paleontological data will continue to be crucial for answering some macroevolutionary questions." "The future depends on synthesizing information from datasets of both molecules and fossils," Pennell said. The researchers emphasize that their results do not invalidate the theory of evolution itself, they just put constraints on what type of information can possibly be extracted from genetic data to reconstruct evolution's path. The pair's paper will appear in the April 23 print issue of Nature. <|im_end|>

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2,072

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Studies on the effects of global marine plastic pollution have largely focused on physiological responses of few organism groups (e.g., corals, fishes). Here, we report the first observation of polymer nanoparticles being incorporated into the calcite skeleton of a large benthic foraminifera (LBF), a significant contributor to global carbonate production. While previous work on LBF has documented selectivity in feeding behaviour and a high degree of specialization regarding skeletal formation, in this study, abundant cases of nanoplastic encrustation into the calcite tests were observed. Nanoplastic incorporation was associated with formation of new chambers, in conjunction with rapid nanoplastic ingestion and subsequent incomplete egestion. Microalgae presence in nanoplastic treatments significantly increased the initial feeding response after 1 day, but regardless of microalgae presence, nanoplastic ingestion was similar after 6 weeks of chronic exposure. While ~ 40% of ingesting LBF expelled all nanoplastics from their cytoplasm, nanoplastics were still attached to the test surface and subsequently encrusted by calcite. These findings highlight the need for further investigation regarding plastic pollution impacts on calcifying organisms, e.g., the function of LBF as potential plastic sinks and alterations in structural integrity of LBF tests that will likely have larger ecosystem-level impacts on sediment production. Introduction Plastic pollution was first reported in the 1970s 1 and has since then been documented in all marine habitats 2 . Microplastic particles (1 µm to 5 mm in size), in particular, are considered potential hazards to ecosystems, through ingestion by marine biota 3 , 4 , permeation of trophic levels 5 , 6 and as vectors for pollution (e.g., toxic waste, heavy metals, pathogens) 7 , 8 , 9 . Subsequently, nanoplastics (≤ 1 μm 10 ) have become an area of concern as these are even more prone to passive ingestion 11 . One of the largely unknown impacts of micro- and nanoplastics is their potential to affect protective skeletal structures of marine calcifying organisms. Only recently, skeletal encrustation of microplastics in scleractinian corals was observed 12 , 13 . One group of important carbonate producers is that of the photosymbiotic large benthic foraminifera 14 (LBF), which exhibit a mixotrophic lifestyle similar to scleractinian corals, and host a wide range of endosymbiotic algae (e.g., diatoms, dinoflagellates, red algae) 15 . Calcareous foraminifera are generally categorized as hyaline or porcelaneous, depending on their test structure 16 , 17 . These unicellular organisms contribute to about 5% of the worldwide shallow water carbonate production 18 , 19 with locally much higher densities 19 . Due to vast numbers and high turnover in coastal ecosystems, LBF contribute greatly to shoreline and island formation and stabilization 14 . Additionally, the ability to evolve rapidly and fill ecological niches makes these organisms a valuable tool for paleoenvironmental interpretations and environmental monitoring 20 , 21 . Previous studies on plastic impacts on foraminifera have shown the ingestion of plastic particles in varied size ranges (0.5 μm to 6 μm in diameter) with species-specific selectivity towards certain sizes 22 , 23 , and an active feeding preference of biofilm-coated microplastics was observed in the LBF Amphistegina gibbosa 24 . Stress reactions (i.e., accumulation of neutral lipids and enhanced reactive oxygen species production) were observed in Ammonia parkinsonia by the uptake of nanoplastic particles 25 . The incorporation of microplastics into the agglutinated tests of Textularia bocki has been documented, accompanied by oxidative stress and protein aggregation in the exposed foraminifera 23 . However, leachates from seawater-soaked polypropylene (typically containing bisphenol A, octylphenol and nonylphenol) 26 were reported to have no significant effect on locomotion or metabolism of Haynesina germanica 27 . Here, we document the effects of nanoplastics exposure (≤ 1 µm particles) on the LBF Amphistegina ( A. gibbosa and A. lobifera ) that offer insights into organismal ingestion and egestion mechanisms of nanoplastic. Amphistegina spp. are hyaline LBF that grow by forming new test chambers through biologically mediated mineralization. Formation of new test chambers in these organisms is initiated through a cytoplasmic extrusion of the LBF, providing the shape for the newly forming chamber and a thin primary organic layer as the base for CaCO 3 precipitation 28 , 29 . During a secondary calcification stage, the chamber wall thickening, the majority of CaCO 3 is precipitated 30 . Like other photosymbiotic LBF, Amphistegina spp. (referred to as Amphistegina hereafter) exhibit a facultative heterotrophic mode, acquiring nutrients through both symbiont autotrophy and heterotrophic feeding 31 , 32 , 33 , 34 . As heterotrophic feeding is vital for the growth of these organisms 31 , organismal ingestion and egestion mechanisms of nanoplastics were assessed in food choices of: (1) nanoplastic particles only (fluorescent functionalized polystyrene; ‘nanoplastic-only treatment’), (2) a mixture of Nannochloropsis microalgae and nanoplastic particles (‘mixed treatment’), and (3) microalgae only (‘control treatment’). The size of nanoplastic particles and microalgae (~ 1 μm) was chosen to correspond to the size of microalgae naturally occurring in the marine environment, to minimize potential bias to size. Nanoplastic incorporation into skeletal structure of LBF This study documents the first known instance of nanoplastic incorporation into the skeleton of a calcifying organism (Fig. 1 ). Ingestion responses were documented with fluorescence microscopy after 1-day and 6-week exposure to nanoplastic and egestion after an additional 2-week recovery (Fig. 2 ). Subsequently, skeletal incorporation was investigated using Scanning Electron Microscopy (SEM). At the test surface of newly formed chambers, nanoplastic particles appear to be encrusted by calcite, primarily observed close to ornamental spikes at the aperture (Fig. 1 a). Encrusted nanoplastic particles formed dome-like structures often in accumulations of larger aggregates (> 5 particles) observed in various degrees of encrustation (Fig. 1 c–e). As the LBF aperture is an area of active food uptake, the incorporation of nanoplastic into the test likely occurred in conjunction with ingestion and incomplete egestion processes. While previous studies of foraminifera 22 , 23 , 25 have observed the uptake of nanoplastic particles, egestion of foreign particles is largely unknown. Following the 2-week recovery period, the percentage of LBF containing nanoplastic significantly", "role": "user" }, { "content": "Single-celled organisms with calcareous shells, called foraminifera, contribute significantly to the formation of sand deposited on beaches, islands and coastal areas. Researchers at the Leibniz Centre for Tropical Marine Research (ZMT) have now found for the first time that foraminifera can take up tiny plastic particles and incorporate them into their calcareous shells. The results were published in Scientific Reports and Limnology and Oceanography Letters. Gleaming white tropical beaches are coveted destinations for many recreation-seekers. But how do we perceive such beaches if we have to fear that they consist to a not inconsiderable extent of micro- and nanoplastics—invisible to our eyes? Tropical beaches are mainly formed by calcifying marine animals such as corals, mussels and snails. The fact that corals incorporate microplastics into their calcareous skeleton has already been proven in studies. In some regions of the world, however, such as Indonesia, the Philippines and Australia, many beaches consist largely of the calcareous shells of foraminifera. These are single-celled organisms, a few millimeters in size and with a protective calcareous shell, that can be found in warm, shallow coastal areas worldwide. Are tiny plastic particles, as they are produced from our plastic waste by friction, salt, bacteria or UV light everywhere in the ocean, also found in foraminifera? This was the question of a team of marine researchers at the ZMT. Since foraminifera are found in oceans worldwide, their shells forming not only beach sand but also large parts of the sediment on the seafloor and solidifying the structure of coral reefs, it is important to understand how the single-celled organisms deal with small plastic particles. \"Foraminifera feed on, among other things, microalgae or organic material particles they find on the seafloor. Micro- and nanoplastic particles have similar sizes and could easily be mistaken for potential food,\" explains Marlena Joppien, first author of the studies. In a series of experiments, the ZMT team exposed several hundred foraminifera to seawater tanks for several weeks. They fed them partly with tiny micro- or nanoplastic particles, partly with natural food particles or a mixture of both. They observed that while the foraminifera preferred the natural food, when both were available at the same time, they frequently ate plastic pieces. Using a fluorescence microscope, the researchers were able to observe a large number of yellow glowing nanoplastic particles in the foraminifera. Although some of the unicellular organisms rejected the plastic after the feeding experiments, about half of the foraminifera retained the plastic load inside the cell. Then, after eight weeks, a scanning electron microscope with 80,000x magnification revealed that many of the single-celled organisms had already encrusted the plastic particles with a layer of calcium carbonate and were apparently in the process of incorporating them into their shell. \"So if the plastic particles are small enough, the foraminifera will take them in as food,\" reports Marleen Stuhr, co-author of the studies. \"For the environment, this could have advantages and disadvantages. For example, the trillions of foraminifera on the seafloor could be a sink for nanoplastics, a system that removes plastic from the ocean.\" One problem the researcher sees, however, is potential impacts on the health of the foraminifera. On beaches and in shallow marine areas, the shells of foraminifera are often deposited at high densities of more than 1 kg per m2. However, if the protozoa interchange plastic particles with their natural food and incorporate them into their calcareous shells, their fitness, shell formation and stability could be disrupted—with consequences for their population as a whole. This, in turn, could have a long-term impact on coasts and islands, which are already suffering greatly under the weight of sea-level rise and erosion from increasingly frequent and powerful storm surges. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Studies on the effects of global marine plastic pollution have largely focused on physiological responses of few organism groups (e.g., corals, fishes). Here, we report the first observation of polymer nanoparticles being incorporated into the calcite skeleton of a large benthic foraminifera (LBF), a significant contributor to global carbonate production. While previous work on LBF has documented selectivity in feeding behaviour and a high degree of specialization regarding skeletal formation, in this study, abundant cases of nanoplastic encrustation into the calcite tests were observed. Nanoplastic incorporation was associated with formation of new chambers, in conjunction with rapid nanoplastic ingestion and subsequent incomplete egestion. Microalgae presence in nanoplastic treatments significantly increased the initial feeding response after 1 day, but regardless of microalgae presence, nanoplastic ingestion was similar after 6 weeks of chronic exposure. While ~ 40% of ingesting LBF expelled all nanoplastics from their cytoplasm, nanoplastics were still attached to the test surface and subsequently encrusted by calcite. These findings highlight the need for further investigation regarding plastic pollution impacts on calcifying organisms, e.g., the function of LBF as potential plastic sinks and alterations in structural integrity of LBF tests that will likely have larger ecosystem-level impacts on sediment production. Introduction Plastic pollution was first reported in the 1970s 1 and has since then been documented in all marine habitats 2 . Microplastic particles (1 µm to 5 mm in size), in particular, are considered potential hazards to ecosystems, through ingestion by marine biota 3 , 4 , permeation of trophic levels 5 , 6 and as vectors for pollution (e.g., toxic waste, heavy metals, pathogens) 7 , 8 , 9 . Subsequently, nanoplastics (≤ 1 μm 10 ) have become an area of concern as these are even more prone to passive ingestion 11 . One of the largely unknown impacts of micro- and nanoplastics is their potential to affect protective skeletal structures of marine calcifying organisms. Only recently, skeletal encrustation of microplastics in scleractinian corals was observed 12 , 13 . One group of important carbonate producers is that of the photosymbiotic large benthic foraminifera 14 (LBF), which exhibit a mixotrophic lifestyle similar to scleractinian corals, and host a wide range of endosymbiotic algae (e.g., diatoms, dinoflagellates, red algae) 15 . Calcareous foraminifera are generally categorized as hyaline or porcelaneous, depending on their test structure 16 , 17 . These unicellular organisms contribute to about 5% of the worldwide shallow water carbonate production 18 , 19 with locally much higher densities 19 . Due to vast numbers and high turnover in coastal ecosystems, LBF contribute greatly to shoreline and island formation and stabilization 14 . Additionally, the ability to evolve rapidly and fill ecological niches makes these organisms a valuable tool for paleoenvironmental interpretations and environmental monitoring 20 , 21 . Previous studies on plastic impacts on foraminifera have shown the ingestion of plastic particles in varied size ranges (0.5 μm to 6 μm in diameter) with species-specific selectivity towards certain sizes 22 , 23 , and an active feeding preference of biofilm-coated microplastics was observed in the LBF Amphistegina gibbosa 24 . Stress reactions (i.e., accumulation of neutral lipids and enhanced reactive oxygen species production) were observed in Ammonia parkinsonia by the uptake of nanoplastic particles 25 . The incorporation of microplastics into the agglutinated tests of Textularia bocki has been documented, accompanied by oxidative stress and protein aggregation in the exposed foraminifera 23 . However, leachates from seawater-soaked polypropylene (typically containing bisphenol A, octylphenol and nonylphenol) 26 were reported to have no significant effect on locomotion or metabolism of Haynesina germanica 27 . Here, we document the effects of nanoplastics exposure (≤ 1 µm particles) on the LBF Amphistegina ( A. gibbosa and A. lobifera ) that offer insights into organismal ingestion and egestion mechanisms of nanoplastic. Amphistegina spp. are hyaline LBF that grow by forming new test chambers through biologically mediated mineralization. Formation of new test chambers in these organisms is initiated through a cytoplasmic extrusion of the LBF, providing the shape for the newly forming chamber and a thin primary organic layer as the base for CaCO 3 precipitation 28 , 29 . During a secondary calcification stage, the chamber wall thickening, the majority of CaCO 3 is precipitated 30 . Like other photosymbiotic LBF, Amphistegina spp. (referred to as Amphistegina hereafter) exhibit a facultative heterotrophic mode, acquiring nutrients through both symbiont autotrophy and heterotrophic feeding 31 , 32 , 33 , 34 . As heterotrophic feeding is vital for the growth of these organisms 31 , organismal ingestion and egestion mechanisms of nanoplastics were assessed in food choices of: (1) nanoplastic particles only (fluorescent functionalized polystyrene; ‘nanoplastic-only treatment’), (2) a mixture of Nannochloropsis microalgae and nanoplastic particles (‘mixed treatment’), and (3) microalgae only (‘control treatment’). The size of nanoplastic particles and microalgae (~ 1 μm) was chosen to correspond to the size of microalgae naturally occurring in the marine environment, to minimize potential bias to size. Nanoplastic incorporation into skeletal structure of LBF This study documents the first known instance of nanoplastic incorporation into the skeleton of a calcifying organism (Fig. 1 ). Ingestion responses were documented with fluorescence microscopy after 1-day and 6-week exposure to nanoplastic and egestion after an additional 2-week recovery (Fig. 2 ). Subsequently, skeletal incorporation was investigated using Scanning Electron Microscopy (SEM). At the test surface of newly formed chambers, nanoplastic particles appear to be encrusted by calcite, primarily observed close to ornamental spikes at the aperture (Fig. 1 a). Encrusted nanoplastic particles formed dome-like structures often in accumulations of larger aggregates (> 5 particles) observed in various degrees of encrustation (Fig. 1 c–e). As the LBF aperture is an area of active food uptake, the incorporation of nanoplastic into the test likely occurred in conjunction with ingestion and incomplete egestion processes. While previous studies of foraminifera 22 , 23 , 25 have observed the uptake of nanoplastic particles, egestion of foreign particles is largely unknown. Following the 2-week recovery period, the percentage of LBF containing nanoplastic significantly<|im_end|> <|im_start|>assistant Single-celled organisms with calcareous shells, called foraminifera, contribute significantly to the formation of sand deposited on beaches, islands and coastal areas. Researchers at the Leibniz Centre for Tropical Marine Research (ZMT) have now found for the first time that foraminifera can take up tiny plastic particles and incorporate them into their calcareous shells. The results were published in Scientific Reports and Limnology and Oceanography Letters. Gleaming white tropical beaches are coveted destinations for many recreation-seekers. But how do we perceive such beaches if we have to fear that they consist to a not inconsiderable extent of micro- and nanoplastics—invisible to our eyes? Tropical beaches are mainly formed by calcifying marine animals such as corals, mussels and snails. The fact that corals incorporate microplastics into their calcareous skeleton has already been proven in studies. In some regions of the world, however, such as Indonesia, the Philippines and Australia, many beaches consist largely of the calcareous shells of foraminifera. These are single-celled organisms, a few millimeters in size and with a protective calcareous shell, that can be found in warm, shallow coastal areas worldwide. Are tiny plastic particles, as they are produced from our plastic waste by friction, salt, bacteria or UV light everywhere in the ocean, also found in foraminifera? This was the question of a team of marine researchers at the ZMT. Since foraminifera are found in oceans worldwide, their shells forming not only beach sand but also large parts of the sediment on the seafloor and solidifying the structure of coral reefs, it is important to understand how the single-celled organisms deal with small plastic particles. "Foraminifera feed on, among other things, microalgae or organic material particles they find on the seafloor. Micro- and nanoplastic particles have similar sizes and could easily be mistaken for potential food," explains Marlena Joppien, first author of the studies. In a series of experiments, the ZMT team exposed several hundred foraminifera to seawater tanks for several weeks. They fed them partly with tiny micro- or nanoplastic particles, partly with natural food particles or a mixture of both. They observed that while the foraminifera preferred the natural food, when both were available at the same time, they frequently ate plastic pieces. Using a fluorescence microscope, the researchers were able to observe a large number of yellow glowing nanoplastic particles in the foraminifera. Although some of the unicellular organisms rejected the plastic after the feeding experiments, about half of the foraminifera retained the plastic load inside the cell. Then, after eight weeks, a scanning electron microscope with 80,000x magnification revealed that many of the single-celled organisms had already encrusted the plastic particles with a layer of calcium carbonate and were apparently in the process of incorporating them into their shell. "So if the plastic particles are small enough, the foraminifera will take them in as food," reports Marleen Stuhr, co-author of the studies. "For the environment, this could have advantages and disadvantages. For example, the trillions of foraminifera on the seafloor could be a sink for nanoplastics, a system that removes plastic from the ocean." One problem the researcher sees, however, is potential impacts on the health of the foraminifera. On beaches and in shallow marine areas, the shells of foraminifera are often deposited at high densities of more than 1 kg per m2. However, if the protozoa interchange plastic particles with their natural food and incorporate them into their calcareous shells, their fitness, shell formation and stability could be disrupted—with consequences for their population as a whole. This, in turn, could have a long-term impact on coasts and islands, which are already suffering greatly under the weight of sea-level rise and erosion from increasingly frequent and powerful storm surges. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Resolving the electronic structure of a single atom within a molecule is of fundamental importance for understanding and predicting chemical and physical properties of functional molecules such as molecular catalysts. However, the observation of the orbital signature of an individual atom is challenging. We report here the direct identification of two adjacent transition-metal atoms, Fe and Co, within phthalocyanine molecules using high-resolution noncontact atomic force microscopy (HR-AFM). HR-AFM imaging reveals that the Co atom is brighter and presents four distinct lobes on the horizontal plane whereas the Fe atom displays a “square” morphology. Pico-force spectroscopy measurements show a larger repulsion force of about 5 pN on the tip exerted by Co in comparison to Fe. Our combined experimental and theoretical results demonstrate that both the distinguishable features in AFM images and the variation in the measured forces arise from Co’s higher electron orbital occupation above the molecular plane. The ability to directly observe orbital signatures using HR-AFM should provide a promising approach to characterizing the electronic structure of an individual atom in a molecular species and to understand mechanisms of certain chemical reactions. Introduction Real-space experimental observation of localized electron orbital signatures for individual atoms within complex systems can elucidate how atoms interact with each other and provide critical information on the dissociation and formation of chemical bonds needed for identifying reaction pathways. However, the direct measurement of the electronic structure of a single atom or a chemical bond is challenging. Several experimental methods have enabled probing of molecular orbital distributions under certain conditions, including angle-resolved photoemission spectroscopy 1 , 2 , high harmonic interferometry 3 , and photoionization microscopy 4 . In real space, orbital-related information can be obtained with scanning tunneling microscopy (STM) 5 , 6 , 7 , 8 , 9 , 10 , which images the spatially resolved local density of states near the Fermi level 11 . In addition, HR-AFM with molecularly functionalized tips has been used for quantitative structural measurements on organic molecules with spectacular atomic resolution 12 , 13 . Bond order 14 , 15 and heteroatom 16 , 17 discrimination, and even real-space imaging of individual atoms 18 , 19 and intermolecular bonds have been reported 20 , 21 . These experimental advances have been accompanied by the innovation of new algorithms and an exponential increase of computer processing power, which provides an avenue for solutions of the electronic structure of complicated molecular systems using density functional theory (DFT) 22 , 23 -based methods. These solutions offer accurate simulations of atomic force imaging and the possibility of utilizing HR-AFM to directly probe the electronic structure of atoms at the orbital level. Here, we center on single transition-metal atoms, Fe and Co, within Fe-phthalocyanine (FePc) and Co-phthalocyanine (CoPc) on Cu(111) surfaces using a qPlus type nc-AFM with a CO-functionalized tip. In constant-height AFM images, the Co atom appears brighter with four distinct lobes on the horizontal plane while the Fe appears to have a nearly “square” shape. In pico-force spectroscopy measurements, distinct force-distance curves and a difference of about 5 pN at the minimum point were observed on the Fe and Co centers of FePc and CoPc. These differences can be ascribed to the different \${d}_{{xz}}\$ , \${d}_{{yz}}\$ and \${d}_{{z}^{2}}\$ orbital occupations of the Fe and Co centers. Our DFT-based AFM simulations further show that for both Fe and Co, changes in the occupation of the \${d}_{{z}^{2}}\$ orbitals lead to different images and interaction forces in AFM measurements. Our results demonstrate that electronic orbital signatures can be revealed by real-space HR-AFM imaging and spectroscopy. Results and discussion STM topography of Fe/CoPc on Cu(111) surface A large-scale STM topographic image of the sample surface shows the overall metal phthalocyanine (MPc) distribution on a Cu(111) substrate after depositing FePc and CoPc molecules sequentially (Fig. 1a ). Both MPcs have a coverage of less than 10% of one monolayer. The cross-shape of FePc and CoPc molecules are clearly evident. Figure 1b, c shows schematic side and top views of the relaxed FePc molecule adsorbed on a Cu(111) substrate where the Fe atom is at a bridge site 24 . Fig. 1: STM topography and schematic views of the adsorption geometry. a Low-magnification STM image of FePc and CoPc molecules using a CO tip ( V = 100 mV, I = 30 pA). Schematic side ( b ) and top ( c ) views of the relaxed FePc molecule adsorbed on a Cu(111) substrate. The red dashed curve in b indicates the calculated bent adsorption geometry. \${h}_{M-{Cu}}\$ is the MPc adsorption height and is defined as the distance between the metal atom within the Pc and the surface of the Cu substrate. \${h}_{{Fe}-{Cu}}\$ = 261.4 pm, \${h}_{{Co}-{Cu}}\$ = 248.8 pm. Blue: Fe, yellow: C, pink: N, white: H, dark purple: Cu. Full size image HR-AFM characterization and analysis In Fig. 2a , we present a HR-AFM image showing the sub-molecular structure of the FePc and CoPc molecules. The image was taken using a CO-functionalized tip operated in a constant-height scanning mode (see Supplementary Fig. 2 for images taken at larger tip heights and the corresponding DFT-calculated 3D electron density maps). For both FePc and CoPc, the internal features of the carbon heterocyclic skeleton can be resolved, as well as the central metal atoms. For both MPc molecules, the peripheral carbon rings are slightly brighter than the internal carbon-carbon bonds. This indicates that the molecular plane bends upward 25 as illustrated by the red dashed curve in our calculated structure (Fig. 1b ). We find that, FePc and CoPc can be distinguished by comparing details in the metal centers, as highlighted by two white dashed circles for the pair on the left: (1) Co appears brighter than Fe; (2) Co shows a more pronounced extension of the four lobes along the Co-N bonds while the Fe atom displays a more square-like shape with a wider dimension. Similar features are also observed for the FePc and CoPc pair on the right. We apply a glow-edges filter to these", "role": "user" }, { "content": "No one will ever be able to see a purely mathematical construct such as a perfect sphere. But now, scientists using supercomputer simulations and atomic resolution microscopes have imaged the signatures of electron orbitals, which are defined by mathematical equations of quantum mechanics and predict where an atom's electron is most likely to be. Scientists at UT Austin, Princeton University, and ExxonMobil have directly observed the signatures of electron orbitals in two different transition-metal atoms, iron (Fe) and cobalt (Co) present in metal-phthalocyanines. Those signatures are apparent in the forces measured by atomic force microscopes, which often reflect the underlying orbitals and can be so interpreted. Their study was published in March 2023 as an Editors' Highlight in the journal Nature Communications. \"Our collaborators at Princeton University found that despite Fe and Co being adjacent atoms on the periodic table, which implies similarity, the corresponding force spectra and their measured images show reproducible experimental differences,\" said study co-author James R. Chelikowsky, the W.A. \"Tex\" Moncrief, Jr. Chair of Computational Materials and professor in the Departments of Physics, Chemical Engineering, and Chemistry in the College of Natural Sciences at UT Austin. Chelikowsky also serves as the director of the Center for Computational Materials at the Oden Institute for Computational Engineering and Sciences. Without a theoretical analysis, the Princeton scientists could not determine the source of the differences they spotted using high-resolution non-contact atomic force microscopy (HR-AFM) and spectroscopy that measured molecular-scale forces on the order of piconewtons (pN), one-trillionth of a Newton. \"When we first observed the experimental images, our initial reaction was to marvel at how experiment could capture such subtle differences. These are very small forces,\" Chelikowsky added. \"By directly observing the signatures of electron orbitals using techniques such as atomic force microscopy, we can gain a better understanding of the behavior of individual atoms and molecules, and potentially even how to design and engineer new materials with specific properties. This is especially important in fields such as materials science, nanotechnology, and catalysis,\" Chelikowsky said. The required electronic structure calculations are based on density functional theory (DFT), which starts from basic quantum mechanical equations and serves as a practical approach for predicting the behavior of materials. \"Our main contribution is that we validated through our real-space DFT calculations that the observed experimental differences primarily stem from the different electronic configurations in 3d electrons of Fe and Co near the Fermi level, the highest energy state an electron can occupy in the atom,\" said study co-first author Dingxin Fan, a former graduate student working with Chelikowsky. Fan is now a postdoctoral research associate at the Princeton Materials Institute. The DFT calculations included the copper substrate for the Fe and Co atoms, adding a few hundred atoms to the mix and calling for intense computation, for which they were awarded an allocation on the Stampede2 supercomputer at the Texas Advanced Computing Center (TACC). \"In terms of our model, at a certain height, we moved the carbon monoxide tip of the AFM over the sample and computed the quantum forces at every single grid point in real space,\" Fan said. \"This entails hundreds of different computations. The built-in software packages on TACC's Stampede2 helped us to perform data analysis much more easily. For example, the Visual Molecular Dynamics software expedites an analysis of our computational results.\" \"Stampede2 has provided excellent computational power and storage capacity to support various research projects we have,\" Chelikowsky added. By demonstrating that the electron orbital signatures are indeed observable using AFM, the scientists assert that this new knowledge can extend the applicability of AFM into different areas. What's more, their study, used an inert molecular probe tip to approach another molecule and accurately measured the interactions between the two molecules. This allowed the science team to study specific surface chemical reactions. For example, suppose that a catalyst can accelerate a certain chemical reaction, but it is unknown which molecular site is responsible for the catalysis. In this case, an AFM tip prepared with the reactant molecule can be used to measure the interactions at different sites, ultimately determining the chemically active site or sites. Moreover, since the orbital level information can be obtained, scientists can gain a much deeper understanding of what will happen when a chemical reaction occurs. As a result, other scientists could design more efficient catalysts based on this information. Said Chelikowsky: \"Supercomputers, in many ways, allow us to control how atoms interact without having to go into the lab. Such work can guide the discovery of new materials without a laborious 'trial and error' procedure.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Resolving the electronic structure of a single atom within a molecule is of fundamental importance for understanding and predicting chemical and physical properties of functional molecules such as molecular catalysts. However, the observation of the orbital signature of an individual atom is challenging. We report here the direct identification of two adjacent transition-metal atoms, Fe and Co, within phthalocyanine molecules using high-resolution noncontact atomic force microscopy (HR-AFM). HR-AFM imaging reveals that the Co atom is brighter and presents four distinct lobes on the horizontal plane whereas the Fe atom displays a “square” morphology. Pico-force spectroscopy measurements show a larger repulsion force of about 5 pN on the tip exerted by Co in comparison to Fe. Our combined experimental and theoretical results demonstrate that both the distinguishable features in AFM images and the variation in the measured forces arise from Co’s higher electron orbital occupation above the molecular plane. The ability to directly observe orbital signatures using HR-AFM should provide a promising approach to characterizing the electronic structure of an individual atom in a molecular species and to understand mechanisms of certain chemical reactions. Introduction Real-space experimental observation of localized electron orbital signatures for individual atoms within complex systems can elucidate how atoms interact with each other and provide critical information on the dissociation and formation of chemical bonds needed for identifying reaction pathways. However, the direct measurement of the electronic structure of a single atom or a chemical bond is challenging. Several experimental methods have enabled probing of molecular orbital distributions under certain conditions, including angle-resolved photoemission spectroscopy 1 , 2 , high harmonic interferometry 3 , and photoionization microscopy 4 . In real space, orbital-related information can be obtained with scanning tunneling microscopy (STM) 5 , 6 , 7 , 8 , 9 , 10 , which images the spatially resolved local density of states near the Fermi level 11 . In addition, HR-AFM with molecularly functionalized tips has been used for quantitative structural measurements on organic molecules with spectacular atomic resolution 12 , 13 . Bond order 14 , 15 and heteroatom 16 , 17 discrimination, and even real-space imaging of individual atoms 18 , 19 and intermolecular bonds have been reported 20 , 21 . These experimental advances have been accompanied by the innovation of new algorithms and an exponential increase of computer processing power, which provides an avenue for solutions of the electronic structure of complicated molecular systems using density functional theory (DFT) 22 , 23 -based methods. These solutions offer accurate simulations of atomic force imaging and the possibility of utilizing HR-AFM to directly probe the electronic structure of atoms at the orbital level. Here, we center on single transition-metal atoms, Fe and Co, within Fe-phthalocyanine (FePc) and Co-phthalocyanine (CoPc) on Cu(111) surfaces using a qPlus type nc-AFM with a CO-functionalized tip. In constant-height AFM images, the Co atom appears brighter with four distinct lobes on the horizontal plane while the Fe appears to have a nearly “square” shape. In pico-force spectroscopy measurements, distinct force-distance curves and a difference of about 5 pN at the minimum point were observed on the Fe and Co centers of FePc and CoPc. These differences can be ascribed to the different ${d}_{{xz}}$ , ${d}_{{yz}}$ and ${d}_{{z}^{2}}$ orbital occupations of the Fe and Co centers. Our DFT-based AFM simulations further show that for both Fe and Co, changes in the occupation of the ${d}_{{z}^{2}}$ orbitals lead to different images and interaction forces in AFM measurements. Our results demonstrate that electronic orbital signatures can be revealed by real-space HR-AFM imaging and spectroscopy. Results and discussion STM topography of Fe/CoPc on Cu(111) surface A large-scale STM topographic image of the sample surface shows the overall metal phthalocyanine (MPc) distribution on a Cu(111) substrate after depositing FePc and CoPc molecules sequentially (Fig. 1a ). Both MPcs have a coverage of less than 10% of one monolayer. The cross-shape of FePc and CoPc molecules are clearly evident. Figure 1b, c shows schematic side and top views of the relaxed FePc molecule adsorbed on a Cu(111) substrate where the Fe atom is at a bridge site 24 . Fig. 1: STM topography and schematic views of the adsorption geometry. a Low-magnification STM image of FePc and CoPc molecules using a CO tip ( V = 100 mV, I = 30 pA). Schematic side ( b ) and top ( c ) views of the relaxed FePc molecule adsorbed on a Cu(111) substrate. The red dashed curve in b indicates the calculated bent adsorption geometry. ${h}_{M-{Cu}}$ is the MPc adsorption height and is defined as the distance between the metal atom within the Pc and the surface of the Cu substrate. ${h}_{{Fe}-{Cu}}$ = 261.4 pm, ${h}_{{Co}-{Cu}}$ = 248.8 pm. Blue: Fe, yellow: C, pink: N, white: H, dark purple: Cu. Full size image HR-AFM characterization and analysis In Fig. 2a , we present a HR-AFM image showing the sub-molecular structure of the FePc and CoPc molecules. The image was taken using a CO-functionalized tip operated in a constant-height scanning mode (see Supplementary Fig. 2 for images taken at larger tip heights and the corresponding DFT-calculated 3D electron density maps). For both FePc and CoPc, the internal features of the carbon heterocyclic skeleton can be resolved, as well as the central metal atoms. For both MPc molecules, the peripheral carbon rings are slightly brighter than the internal carbon-carbon bonds. This indicates that the molecular plane bends upward 25 as illustrated by the red dashed curve in our calculated structure (Fig. 1b ). We find that, FePc and CoPc can be distinguished by comparing details in the metal centers, as highlighted by two white dashed circles for the pair on the left: (1) Co appears brighter than Fe; (2) Co shows a more pronounced extension of the four lobes along the Co-N bonds while the Fe atom displays a more square-like shape with a wider dimension. Similar features are also observed for the FePc and CoPc pair on the right. We apply a glow-edges filter to these<|im_end|> <|im_start|>assistant No one will ever be able to see a purely mathematical construct such as a perfect sphere. But now, scientists using supercomputer simulations and atomic resolution microscopes have imaged the signatures of electron orbitals, which are defined by mathematical equations of quantum mechanics and predict where an atom's electron is most likely to be. Scientists at UT Austin, Princeton University, and ExxonMobil have directly observed the signatures of electron orbitals in two different transition-metal atoms, iron (Fe) and cobalt (Co) present in metal-phthalocyanines. Those signatures are apparent in the forces measured by atomic force microscopes, which often reflect the underlying orbitals and can be so interpreted. Their study was published in March 2023 as an Editors' Highlight in the journal Nature Communications. "Our collaborators at Princeton University found that despite Fe and Co being adjacent atoms on the periodic table, which implies similarity, the corresponding force spectra and their measured images show reproducible experimental differences," said study co-author James R. Chelikowsky, the W.A. "Tex" Moncrief, Jr. Chair of Computational Materials and professor in the Departments of Physics, Chemical Engineering, and Chemistry in the College of Natural Sciences at UT Austin. Chelikowsky also serves as the director of the Center for Computational Materials at the Oden Institute for Computational Engineering and Sciences. Without a theoretical analysis, the Princeton scientists could not determine the source of the differences they spotted using high-resolution non-contact atomic force microscopy (HR-AFM) and spectroscopy that measured molecular-scale forces on the order of piconewtons (pN), one-trillionth of a Newton. "When we first observed the experimental images, our initial reaction was to marvel at how experiment could capture such subtle differences. These are very small forces," Chelikowsky added. "By directly observing the signatures of electron orbitals using techniques such as atomic force microscopy, we can gain a better understanding of the behavior of individual atoms and molecules, and potentially even how to design and engineer new materials with specific properties. This is especially important in fields such as materials science, nanotechnology, and catalysis," Chelikowsky said. The required electronic structure calculations are based on density functional theory (DFT), which starts from basic quantum mechanical equations and serves as a practical approach for predicting the behavior of materials. "Our main contribution is that we validated through our real-space DFT calculations that the observed experimental differences primarily stem from the different electronic configurations in 3d electrons of Fe and Co near the Fermi level, the highest energy state an electron can occupy in the atom," said study co-first author Dingxin Fan, a former graduate student working with Chelikowsky. Fan is now a postdoctoral research associate at the Princeton Materials Institute. The DFT calculations included the copper substrate for the Fe and Co atoms, adding a few hundred atoms to the mix and calling for intense computation, for which they were awarded an allocation on the Stampede2 supercomputer at the Texas Advanced Computing Center (TACC). "In terms of our model, at a certain height, we moved the carbon monoxide tip of the AFM over the sample and computed the quantum forces at every single grid point in real space," Fan said. "This entails hundreds of different computations. The built-in software packages on TACC's Stampede2 helped us to perform data analysis much more easily. For example, the Visual Molecular Dynamics software expedites an analysis of our computational results." "Stampede2 has provided excellent computational power and storage capacity to support various research projects we have," Chelikowsky added. By demonstrating that the electron orbital signatures are indeed observable using AFM, the scientists assert that this new knowledge can extend the applicability of AFM into different areas. What's more, their study, used an inert molecular probe tip to approach another molecule and accurately measured the interactions between the two molecules. This allowed the science team to study specific surface chemical reactions. For example, suppose that a catalyst can accelerate a certain chemical reaction, but it is unknown which molecular site is responsible for the catalysis. In this case, an AFM tip prepared with the reactant molecule can be used to measure the interactions at different sites, ultimately determining the chemically active site or sites. Moreover, since the orbital level information can be obtained, scientists can gain a much deeper understanding of what will happen when a chemical reaction occurs. As a result, other scientists could design more efficient catalysts based on this information. Said Chelikowsky: "Supercomputers, in many ways, allow us to control how atoms interact without having to go into the lab. Such work can guide the discovery of new materials without a laborious 'trial and error' procedure." <|im_end|>

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2,405

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract A longstanding goal in cellular mechanobiology has been to link dynamic biomolecular processes underpinning disease or morphogenesis to spatio-temporal changes in nanoscale mechanical properties such as viscoelasticity, surface tension and adhesion. This requires the development of quantitative mechanical microscopy methods with high spatio-temporal resolution within a single cell. The Atomic Force Microscope (AFM) can map the heterogeneous mechanical properties of cells with high spatial resolution, however, the image acquisition time is 1–2 orders of magnitude longer than that required to study dynamic cellular processes. We present a technique that allows commercial AFM systems to map quantitatively the dynamically changing viscoelastic properties of live eukaryotic cells at widely separated frequencies over large areas (several 10’s of microns) with spatial resolution equal to amplitude-modulation (AM-AFM) and with image acquisition times (tens of seconds) approaching those of speckle fluorescence methods. This represents a ~20 fold improvement in nanomechanical imaging throughput compared to AM-AFM and is fully compatible with emerging high speed AFM systems. This method is used to study the spatio-temporal mechanical response of MDA-MB-231 breast carcinoma cells to the inhibition of Syk protein tyrosine kinase giving insight into the signaling pathways by which Syk negatively regulates motility of highly invasive cancer cells. Introduction Mechano-chemical heterogeneity is a hallmark of living eukaryotic cells: the cell membrane is highly heterogeneous 1 , 2 , cell-cell and cell-extracellular matrix interactions are spatially localized through adhesion complexes 3 , 4 , cell motility requires asymmetric force generation 5 , subcellular organelles are discretely distributed within a cell 6 and the cytoskeleton non-uniformly reinforces the cell’s rigidity 7 . These heterogeneities change dynamically with cell migration, morphogenesis, or by response to drugs 8 , 9 , 10 . Thus, there is a growing interest in technologies that are capable of mapping mechano-chemical heterogeneities within living cells with high spatio-temporal resolution. Achieving high-speed mapping of nanomechanical properties of whole live eukaryotic cells (elastic modulus <100 kPa), over large areas (~50 × 50 μm 2 ) and with significant range of topographies (cell height ~1–10 μm) has been a long standing challenge in AFM. This is due to the softness of live eukaryotic cells, which reduces the sensitivity of dynamic AFM observables such as amplitude and phase and also because of the large height variations of live cells, which requires a high Z-piezo positioning range to track. Recent advances in AFM such as peak force tapping 11 , 12 and multi-harmonic AFM 13 , 14 , 15 , have significantly improved material property mapping speeds on live cells compared to the conventional force-volume method. However, the acquisition time for a high resolution material property map over an entire eukaryotic cell remains >~10 minutes, which is insufficient for studying dynamic processes in cell biology 16 . Parallel developments in high speed scanning using high bandwidth electronics, scanners and microcantilevers have imaged the topography of moderately stiff samples 17 , 18 , 19 , 20 , 21 (elastic modulus >10 MPa) or the peripheral/flat areas of eukaryotic cells 22 , 23 without mapping nanomechanical properties. Here we present a method by which commercial AFM systems with directly excited cantilevers (magnetic, Lorentz force, or photothermal excitation) can be operated using a new cantilever deflection feedback scheme that boosts by at least one order of magnitude the speed of imaging whole live eukaryotic cells in solution as compared to AM-AFM. The method is fully compatible with emerging high speed AFM systems 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 . Recent advances in high speed AFM systems suggest that high speed scanning in specialized AFM systems using deflection feedback is possible 26 . Thus, the approach described in the present work should, in principle, be compatible with high speed AFM systems also. We conclude that; (a) the use of cantilever mean deflection as feedback signal instead of amplitude can boost by 1 order of magnitude the speed of nanomechanical mapping using resonant cantilevers over live cells in culture media. (b) The observables acquired from directly excited cantilevers scanning over cells with mean deflection feedback can be easily converted to quantitative local mechanical properties using advanced continuum mechanics models. (c) The method can be extended to multi-frequency approaches, for example by simultaneous excitation of the two fundamental eigenmodes of the cantilever and the observables can be used to map the viscoelastic response of cells at two widely space frequencies confirming that classical viscoelastic frequency dependence is present. (d) These advances permit, for the first time, the observation of nanomechanical spatio-temporal response of the cortical actin cytoskeleton including the formation and movement of lateral actin bands characteristic of the retrograde actin flow machinery rapidly formed by inhibiting Syk expression in MDA-MB-231 breast cancer cells. Taken together, these findings suggest that the method allows the study of time varying heterogeneous physical properties of live cells during dynamic processes over large areas that was not heretofore possible. Results Dynamic AFM design for fast imaging of live cells Boosting the scanning speed of dynamic AFM on live cells requires the appropriate choice of feedback channel. We first tested the sensitivities dA 0 /dZ and dA 1 /dZ on a live cell of the cantilever mean deflection A 0 and first harmonic amplitude A 1 (the traditional feedback channel). A Lorentz force excited soft microcantilever (calibrated stiffness k cant = 0.08 N/m, resonance frequency ω dr = 8 kHz) is made to approach and press down on the surface of a live rat fibroblast cell in culture medium. As shown in Fig. 1 , dA 0 /dZ is ~12, ~3 and ~2 times larger than dA 1 /dZ on the nuclear region, cell periphery and the gelatin-coated dish, respectively. The low sensitivity of A 1 on a live cell stems from two effects: (i) the small repulsive force gradients on a live cell which only perturb slightly the resonance frequency of the freely vibrating microcantilever and (ii) the low Q factor which ensures that small force gradients do not", "role": "user" }, { "content": "Researchers who developed a high-speed form of atomic force microscopy have shown how to image the physical properties of live breast cancer cells, for the first time revealing details about how deactivation of a key protein may lead to metastasis. The new findings also are providing evidence for the mechanisms involved in a cell's response to anti-cancer drugs, said Arvind Raman, Purdue University's Robert V. Adams Professor of Mechanical Engineering. In atomic force microscopy (AFM), a tiny vibrating probe called a cantilever passes over a material, precisely characterizing its topography and physical properties. However, before now the procedure has been too slow to record some quickly changing biological processes in action. \"Before this advance you could see only the before and after, but not what happened in between, the dynamics of the event,\" Raman said. \"There is evidence based on this work and our previous findings that there might be a mechanical signature to drug resistance.\" Advanced models allow researchers to convert AFM data into properties about the cell's internal scaffolding, called the cortical actin cytoskeleton, including the motion of fibers called actin. Findings are detailed in a paper appearing Monday (June 29) in the research journal Scientific Reports, the open access journal of the Nature Publishing Group. The researchers used the technique to study breast cancer cells, probing a key enzyme called spleen tyrosine kinase, or Syk. Kinases cause phosphorylation of proteins, a biochemical process that can alter enzymes and plays a significant role in a wide range of cellular processes. \"So if you turn the kinase off, proteins will get dephosphorylated and then changes could occur,\" said Robert L. Geahlen, Distinguished Professor of Medicinal Chemistry at Purdue. \"We were able to show the turn off of this kinase very rapidly alters the physical properties of the cell. So it's undoubtedly due to the phosphorylation events that are having immediate effects on cytoskeletal proteins.\" The paper was authored by former doctoral student Alexander X. Cartagena-Rivera, now a postdoctoral fellow at the National Institutes of Health's National Institute on Deafness and Other Communication Disorders (NIDCD); Purdue postdoctoral research associate Wen-Horng Wang; Geahlen; and Raman. The researchers studied breast cancer cells exposed to a chemical \"inhibitor\" that blocks the functioning of Syk, leaving the cells free to metastasize. Because of the new higher-speed AFM, the researchers for the first time have been able to observe what happens when the inhibitor is added. After adding the inhibitor, actin bands propagate across the cell, causing the cell to change shape. \"This takes about 10 minutes, which is quite fast compared to many biological processes,\" Raman said. The images can be taken at a speed of about 50 seconds per frame. \"Before we did this it would take roughly 15 to 20 minutes to take one frame, which is too slow to observe this transition process,\" he said. Bands of actin were shown to move in a sweeping motion across the cell. \"You think of actin as a scaffolding, but it's a dynamic scaffolding,\" Raman said. \"We can see bands of actin that are going around and changing the physical properties during the transition, which was not understood before.\" When Syk is missing or deactivated, breast cancer cells undergo a process called EMT, or epithelial-mesenchymal transition, causing them to become highly motile and to undergo metastasis. \"If this kinase is in the cells, the cells cannot metastasize, so we've been trying to figure out what the mechanisms are by which you have to get rid of this kinase in order to become highly motile and metastatic,\" said Geahlen, who is affiliated with the Purdue Center for Cancer Research. \"And that's one of the reasons we were looking at this particular type of cancer cell with this particular form of Syk in it.\" One goal of the research is to correlate physical properties of cells with tumor suppression and the action of the kinase on the cell. The advance in AFM technology was accomplished by two innovations: as the cantilever scans a cell it bends differently depending on the properties of the material being scanned. A laser measures this \"deflection,\" and models convert the data to reveal information about the material's composition. Previous applications of AFM microscopy to study live cells provided feedback on the amplitude and frequency of the vibrating cantilever, but not the deflection. However, that approach takes too long to provide images of the quickly changing processes inside living cells. Providing feedback on the deflection instead has now been shown to increase the imaging speed 10-fold, making the method practical for studying cellular processes. The other innovation is a technique that enables the cantilever to vibrate at two frequencies simultaneously. \"In one scan we can map the local physical properties of the cell, and we can do it fast enough that we compile maps of the changing cell,\" Raman said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract A longstanding goal in cellular mechanobiology has been to link dynamic biomolecular processes underpinning disease or morphogenesis to spatio-temporal changes in nanoscale mechanical properties such as viscoelasticity, surface tension and adhesion. This requires the development of quantitative mechanical microscopy methods with high spatio-temporal resolution within a single cell. The Atomic Force Microscope (AFM) can map the heterogeneous mechanical properties of cells with high spatial resolution, however, the image acquisition time is 1–2 orders of magnitude longer than that required to study dynamic cellular processes. We present a technique that allows commercial AFM systems to map quantitatively the dynamically changing viscoelastic properties of live eukaryotic cells at widely separated frequencies over large areas (several 10’s of microns) with spatial resolution equal to amplitude-modulation (AM-AFM) and with image acquisition times (tens of seconds) approaching those of speckle fluorescence methods. This represents a ~20 fold improvement in nanomechanical imaging throughput compared to AM-AFM and is fully compatible with emerging high speed AFM systems. This method is used to study the spatio-temporal mechanical response of MDA-MB-231 breast carcinoma cells to the inhibition of Syk protein tyrosine kinase giving insight into the signaling pathways by which Syk negatively regulates motility of highly invasive cancer cells. Introduction Mechano-chemical heterogeneity is a hallmark of living eukaryotic cells: the cell membrane is highly heterogeneous 1 , 2 , cell-cell and cell-extracellular matrix interactions are spatially localized through adhesion complexes 3 , 4 , cell motility requires asymmetric force generation 5 , subcellular organelles are discretely distributed within a cell 6 and the cytoskeleton non-uniformly reinforces the cell’s rigidity 7 . These heterogeneities change dynamically with cell migration, morphogenesis, or by response to drugs 8 , 9 , 10 . Thus, there is a growing interest in technologies that are capable of mapping mechano-chemical heterogeneities within living cells with high spatio-temporal resolution. Achieving high-speed mapping of nanomechanical properties of whole live eukaryotic cells (elastic modulus <100 kPa), over large areas (~50 × 50 μm 2 ) and with significant range of topographies (cell height ~1–10 μm) has been a long standing challenge in AFM. This is due to the softness of live eukaryotic cells, which reduces the sensitivity of dynamic AFM observables such as amplitude and phase and also because of the large height variations of live cells, which requires a high Z-piezo positioning range to track. Recent advances in AFM such as peak force tapping 11 , 12 and multi-harmonic AFM 13 , 14 , 15 , have significantly improved material property mapping speeds on live cells compared to the conventional force-volume method. However, the acquisition time for a high resolution material property map over an entire eukaryotic cell remains >~10 minutes, which is insufficient for studying dynamic processes in cell biology 16 . Parallel developments in high speed scanning using high bandwidth electronics, scanners and microcantilevers have imaged the topography of moderately stiff samples 17 , 18 , 19 , 20 , 21 (elastic modulus >10 MPa) or the peripheral/flat areas of eukaryotic cells 22 , 23 without mapping nanomechanical properties. Here we present a method by which commercial AFM systems with directly excited cantilevers (magnetic, Lorentz force, or photothermal excitation) can be operated using a new cantilever deflection feedback scheme that boosts by at least one order of magnitude the speed of imaging whole live eukaryotic cells in solution as compared to AM-AFM. The method is fully compatible with emerging high speed AFM systems 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 . Recent advances in high speed AFM systems suggest that high speed scanning in specialized AFM systems using deflection feedback is possible 26 . Thus, the approach described in the present work should, in principle, be compatible with high speed AFM systems also. We conclude that; (a) the use of cantilever mean deflection as feedback signal instead of amplitude can boost by 1 order of magnitude the speed of nanomechanical mapping using resonant cantilevers over live cells in culture media. (b) The observables acquired from directly excited cantilevers scanning over cells with mean deflection feedback can be easily converted to quantitative local mechanical properties using advanced continuum mechanics models. (c) The method can be extended to multi-frequency approaches, for example by simultaneous excitation of the two fundamental eigenmodes of the cantilever and the observables can be used to map the viscoelastic response of cells at two widely space frequencies confirming that classical viscoelastic frequency dependence is present. (d) These advances permit, for the first time, the observation of nanomechanical spatio-temporal response of the cortical actin cytoskeleton including the formation and movement of lateral actin bands characteristic of the retrograde actin flow machinery rapidly formed by inhibiting Syk expression in MDA-MB-231 breast cancer cells. Taken together, these findings suggest that the method allows the study of time varying heterogeneous physical properties of live cells during dynamic processes over large areas that was not heretofore possible. Results Dynamic AFM design for fast imaging of live cells Boosting the scanning speed of dynamic AFM on live cells requires the appropriate choice of feedback channel. We first tested the sensitivities dA 0 /dZ and dA 1 /dZ on a live cell of the cantilever mean deflection A 0 and first harmonic amplitude A 1 (the traditional feedback channel). A Lorentz force excited soft microcantilever (calibrated stiffness k cant = 0.08 N/m, resonance frequency ω dr = 8 kHz) is made to approach and press down on the surface of a live rat fibroblast cell in culture medium. As shown in Fig. 1 , dA 0 /dZ is ~12, ~3 and ~2 times larger than dA 1 /dZ on the nuclear region, cell periphery and the gelatin-coated dish, respectively. The low sensitivity of A 1 on a live cell stems from two effects: (i) the small repulsive force gradients on a live cell which only perturb slightly the resonance frequency of the freely vibrating microcantilever and (ii) the low Q factor which ensures that small force gradients do not<|im_end|> <|im_start|>assistant Researchers who developed a high-speed form of atomic force microscopy have shown how to image the physical properties of live breast cancer cells, for the first time revealing details about how deactivation of a key protein may lead to metastasis. The new findings also are providing evidence for the mechanisms involved in a cell's response to anti-cancer drugs, said Arvind Raman, Purdue University's Robert V. Adams Professor of Mechanical Engineering. In atomic force microscopy (AFM), a tiny vibrating probe called a cantilever passes over a material, precisely characterizing its topography and physical properties. However, before now the procedure has been too slow to record some quickly changing biological processes in action. "Before this advance you could see only the before and after, but not what happened in between, the dynamics of the event," Raman said. "There is evidence based on this work and our previous findings that there might be a mechanical signature to drug resistance." Advanced models allow researchers to convert AFM data into properties about the cell's internal scaffolding, called the cortical actin cytoskeleton, including the motion of fibers called actin. Findings are detailed in a paper appearing Monday (June 29) in the research journal Scientific Reports, the open access journal of the Nature Publishing Group. The researchers used the technique to study breast cancer cells, probing a key enzyme called spleen tyrosine kinase, or Syk. Kinases cause phosphorylation of proteins, a biochemical process that can alter enzymes and plays a significant role in a wide range of cellular processes. "So if you turn the kinase off, proteins will get dephosphorylated and then changes could occur," said Robert L. Geahlen, Distinguished Professor of Medicinal Chemistry at Purdue. "We were able to show the turn off of this kinase very rapidly alters the physical properties of the cell. So it's undoubtedly due to the phosphorylation events that are having immediate effects on cytoskeletal proteins." The paper was authored by former doctoral student Alexander X. Cartagena-Rivera, now a postdoctoral fellow at the National Institutes of Health's National Institute on Deafness and Other Communication Disorders (NIDCD); Purdue postdoctoral research associate Wen-Horng Wang; Geahlen; and Raman. The researchers studied breast cancer cells exposed to a chemical "inhibitor" that blocks the functioning of Syk, leaving the cells free to metastasize. Because of the new higher-speed AFM, the researchers for the first time have been able to observe what happens when the inhibitor is added. After adding the inhibitor, actin bands propagate across the cell, causing the cell to change shape. "This takes about 10 minutes, which is quite fast compared to many biological processes," Raman said. The images can be taken at a speed of about 50 seconds per frame. "Before we did this it would take roughly 15 to 20 minutes to take one frame, which is too slow to observe this transition process," he said. Bands of actin were shown to move in a sweeping motion across the cell. "You think of actin as a scaffolding, but it's a dynamic scaffolding," Raman said. "We can see bands of actin that are going around and changing the physical properties during the transition, which was not understood before." When Syk is missing or deactivated, breast cancer cells undergo a process called EMT, or epithelial-mesenchymal transition, causing them to become highly motile and to undergo metastasis. "If this kinase is in the cells, the cells cannot metastasize, so we've been trying to figure out what the mechanisms are by which you have to get rid of this kinase in order to become highly motile and metastatic," said Geahlen, who is affiliated with the Purdue Center for Cancer Research. "And that's one of the reasons we were looking at this particular type of cancer cell with this particular form of Syk in it." One goal of the research is to correlate physical properties of cells with tumor suppression and the action of the kinase on the cell. The advance in AFM technology was accomplished by two innovations: as the cantilever scans a cell it bends differently depending on the properties of the material being scanned. A laser measures this "deflection," and models convert the data to reveal information about the material's composition. Previous applications of AFM microscopy to study live cells provided feedback on the amplitude and frequency of the vibrating cantilever, but not the deflection. However, that approach takes too long to provide images of the quickly changing processes inside living cells. Providing feedback on the deflection instead has now been shown to increase the imaging speed 10-fold, making the method practical for studying cellular processes. The other innovation is a technique that enables the cantilever to vibrate at two frequencies simultaneously. "In one scan we can map the local physical properties of the cell, and we can do it fast enough that we compile maps of the changing cell," Raman said. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In this study we investigated the role of the circadian mechanism on cognition-relevant brain regions and neurobiological impairments associated with heart failure (HF), using murine models. We found that the circadian mechanism is an important regulator of healthy cognitive system neurobiology. Normal Clock ∆19/∆19 mice had neurons with smaller apical dendrite trees in the medial prefrontal cortex (mPFC), and hippocampus, showed impaired visual-spatial memory, and exhibited lower cerebrovascular myogenic tone, versus wild types (WT). We then used the left anterior descending coronary artery ligation model to investigate adaptations in response to HF. Intriguingly, adaptations to neuron morphology, memory, and cerebrovascular tone occurred in differing magnitude and direction between Clock ∆19/∆19 and WT mice, ultimately converging in HF. To investigate this dichotomous response, we performed microarrays and found genes crucial for growth and stress pathways that were altered in Clock ∆19/∆19 mPFC and hippocampus. Thus these data demonstrate for the first time that (i) the circadian mechanism plays a role in neuron morphology and function; (ii) there are changes in neuron morphology and function in HF; (iii) CLOCK influences neurobiological gene adaptations to HF at a cellular level. These findings have clinical relevance as patients with HF often present with concurrent neurocognitive impairments. There is no cure for HF, and new understanding is needed to reduce morbidity and improve the quality of life for HF patients. Introduction Ischemic heart disease leading to myocardial infarction (MI, heart attack) and heart failure (HF) is a leading cause of morbidity and mortality worldwide 1 . Cognitive impairment, depression or brain changes are frequently observed in patients with HF 2 , 3 , 4 . Here we investigated a role for the circadian mechanism in neurocognitive impairments in HF, using murine models. In support of this approach, recent experimental and clinical studies show that the circadian mechanism is important for cardiovascular physiology. It underlies daily rhythms in heart rate 5 , blood pressure 6 , and organizing of the cardiac genome 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , proteome 15 , 16 , 17 , contractility and metabolism (reviewed in 11 , 18 , 19 , 20 ). Moreover, we and others have shown that the circadian mechanism contributes to remodeling in ischemic heart disease and HF 9 , 12 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 . However, how the circadian mechanism affects the neurobiological adaptations in HF is not known, in large part because studies have focused only on the heart and have not investigated what happens concurrently in the brain. The circadian system coordinates our physiology with the diurnal environment – mammals are awake in the day or at night (reviewed in 33 , 34 ). Briefly, the system is hierarchically orchestrated; time-setting light cues (Zeitgebers, ZT) are received by the master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN then communicates via neural and hormonal outputs to all other regions of the brain and body to set time. At a molecular level, the circadian mechanism is comprised of a 24-hour transcription and translation loop present in virtually all our cells. CLOCK is a key component of the circadian mechanism and relative abundance over the 24-hour daily cycles drives the positive and negative arms of the circadian mechanism 35 , 36 . In doing so, CLOCK regulates daily patterns of genes and proteins in the normal heart, and cardiac remodeling in heart disease (e.g. 10 , 16 , 21 , 22 , 37 ). However, whether CLOCK also has an effect on the brain in response to HF is largely unknown. Here we investigate the role of the circadian mechanism on normal neurobiology using Clock ∆19/∆19 mice, and how the circadian mechanism contributes to neurobiological adaptations within cognition-relevant brain regions in HF. We use the clinically relevant murine left anterior descending coronary artery ligation (MI) model, to simulate the possible effects on the evolution of HF in humans 23 , 24 . We demonstrate that Clock ∆19/∆19 mice have neurons with smaller apical dendrite trees within layer 2/3 of the medial prefrontal cortex (mPFC) and CA1 region of the hippocampus, and deficits in visual-spatial memory, compared with wild type (WT) mice. Interestingly, in response to HF, the Clock ∆19/∆19 mice exhibit reduced cardiac remodelling and better outcomes. Moreover, the Clock ∆19/∆19 mice show differences in the magnitude and direction of their neurobiological responses, as compared to WTs. However, despite different neurobiological adaptations, they result in similar end outcomes in terms of neuron morphology, memory, and cerebrovascular tone in HF. To investigate the mechanisms underlying this dichotomous response, we examined gene expression at baseline, MI and HF in the mPFC and hippocampus in Clock ∆19/∆19 vs. WT mice. We found differential activation of genes important for neural growth, cytoskeleton, signalling and metabolism. Collectively these data reveal that CLOCK is an important regulator of healthy cognitive system neurobiology, and adaptations in neuron morphology and function in HF. Importantly, there is no cure for HF, and neurocognitive impairments frequently coincide in patients with HF. Elucidating a role for the circadian mechanism in the neurobiology of the cognitive system can lead to new strategies to reduce morbidity and improve the quality of life of patients with HF. Results Characterization of circadian Clock ∆19/∆19 vs. WT models We postulated that the circadian mechanism influences neurobiology in the brain’s cognitive systems. To test this, we focused on the circadian factor CLOCK, as it is a canonical part of the circadian mechanism, and relatively well characterized in experimental heart disease models. Clock ∆19/∆19 mice were genotyped and phenotyped using conventional approaches. The Clock ∆19/∆19 mutation extends the circadian period from ~23.9 hours in WT mice to ~27.6 hours in Clock ∆19/∆19 mice. Figure 1a shows representative wheel running actigraphy for Clock ∆19/∆19 (left) and WT (middle) mice under a diurnal 12 hour light: 12 hour dark (LD) cycle and", "role": "user" }, { "content": "Heart failure patients often have trouble with thinking and depression. A new study by University of Guelph researchers explains why and points to ways to prevent and treat both heart and brain maladies through the emerging field of circadian medicine. Published recently in Nature's Scientific Reports, the study is the first to reveal how cognition and mood in mice are regulated by the body clock and how pertinent brain regions are impaired in heart failure, said Tami Martino, a professor in U of G's Department of Biomedical Sciences and director of the Centre for Cardiovascular Investigations. \"Neurosurgeons always look in the brain; cardiologists always look in the heart. This new study looked at both,\" said Martino, whose work in the emerging field of circadian medicine is supported by funding from the Canadian Institutes of Health Research. She recently received a Mid-Career Investigator Award from the Heart and Stroke Foundation of Canada. Coronary heart disease, the most common cause of heart failure, causes one in three deaths in Canada, according to the Heart and Stroke Foundation. Human patients with heart failure often have neurological conditions such as cognitive impairment and depression, said Martino. She worked on the study with master's student Austin Duong and Ph.D. student Cristine Reitz—both co-first authors—and neuroscientists including U of G psychology professor Boyer Winters and biomedical sciences professor Craig Bailey. Martino suspected the heart-brain connection involved the circadian mechanism molecule, called \"clock.\" Circadian rhythms in humans and other organisms follow Earth's 24-hour cycle of light and darkness, signalling when to sleep and when to be awake. Martino's earlier research showed how disrupting circadian rhythms—as with shift workers, jet-lagged travellers and patients disturbed in intensive-care units—can trigger changes that worsen heart disease and impair overall health and well-being. For this new study, the researchers compared normal mice with mice carrying a mutation in their circadian mechanism (called \"clock mice\"). They found that the mutation affected the structure of neurons in brain areas important for cognition and mood. Working with University of Toronto colleagues, the team also found differences in clock regulation of blood vessels in the brains of the clock mice. After inducing heart failure in mice to simulate human heart failure, they used microarray profiling to identify key genes in the brain that were altered in neural growth, stress and metabolism pathways. The results show that the circadian mechanism influences neural effects of heart failure, said Martino. Pointing out that no cure exists for the heart condition, she said understanding how the circadian mechanism works in the brain may lead to new strategies to improve patients' quality of life. Patients recovering from heart attacks often experience disturbed circadian rhythms from light, noise and interactions with hospital staff at night. \"Maintaining circadian rhythms especially for patients with heart disease could lead to better health outcomes.\" More generally, the findings point to potential health benefits for people in general. Avoiding shift work for people with underlying heart conditions or sleep disorders, reducing light at night or avoiding social jet lag (going to bed late and waking up later than usual on weekends) could all help reduce neurobiological impairments. Those problems—and potential solutions—involve not just hearts but brains, she said. \"If we're not yet able to cure heart failure, we should at least be focusing on how we can improve quality of life for patients.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In this study we investigated the role of the circadian mechanism on cognition-relevant brain regions and neurobiological impairments associated with heart failure (HF), using murine models. We found that the circadian mechanism is an important regulator of healthy cognitive system neurobiology. Normal Clock ∆19/∆19 mice had neurons with smaller apical dendrite trees in the medial prefrontal cortex (mPFC), and hippocampus, showed impaired visual-spatial memory, and exhibited lower cerebrovascular myogenic tone, versus wild types (WT). We then used the left anterior descending coronary artery ligation model to investigate adaptations in response to HF. Intriguingly, adaptations to neuron morphology, memory, and cerebrovascular tone occurred in differing magnitude and direction between Clock ∆19/∆19 and WT mice, ultimately converging in HF. To investigate this dichotomous response, we performed microarrays and found genes crucial for growth and stress pathways that were altered in Clock ∆19/∆19 mPFC and hippocampus. Thus these data demonstrate for the first time that (i) the circadian mechanism plays a role in neuron morphology and function; (ii) there are changes in neuron morphology and function in HF; (iii) CLOCK influences neurobiological gene adaptations to HF at a cellular level. These findings have clinical relevance as patients with HF often present with concurrent neurocognitive impairments. There is no cure for HF, and new understanding is needed to reduce morbidity and improve the quality of life for HF patients. Introduction Ischemic heart disease leading to myocardial infarction (MI, heart attack) and heart failure (HF) is a leading cause of morbidity and mortality worldwide 1 . Cognitive impairment, depression or brain changes are frequently observed in patients with HF 2 , 3 , 4 . Here we investigated a role for the circadian mechanism in neurocognitive impairments in HF, using murine models. In support of this approach, recent experimental and clinical studies show that the circadian mechanism is important for cardiovascular physiology. It underlies daily rhythms in heart rate 5 , blood pressure 6 , and organizing of the cardiac genome 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , proteome 15 , 16 , 17 , contractility and metabolism (reviewed in 11 , 18 , 19 , 20 ). Moreover, we and others have shown that the circadian mechanism contributes to remodeling in ischemic heart disease and HF 9 , 12 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 . However, how the circadian mechanism affects the neurobiological adaptations in HF is not known, in large part because studies have focused only on the heart and have not investigated what happens concurrently in the brain. The circadian system coordinates our physiology with the diurnal environment – mammals are awake in the day or at night (reviewed in 33 , 34 ). Briefly, the system is hierarchically orchestrated; time-setting light cues (Zeitgebers, ZT) are received by the master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN then communicates via neural and hormonal outputs to all other regions of the brain and body to set time. At a molecular level, the circadian mechanism is comprised of a 24-hour transcription and translation loop present in virtually all our cells. CLOCK is a key component of the circadian mechanism and relative abundance over the 24-hour daily cycles drives the positive and negative arms of the circadian mechanism 35 , 36 . In doing so, CLOCK regulates daily patterns of genes and proteins in the normal heart, and cardiac remodeling in heart disease (e.g. 10 , 16 , 21 , 22 , 37 ). However, whether CLOCK also has an effect on the brain in response to HF is largely unknown. Here we investigate the role of the circadian mechanism on normal neurobiology using Clock ∆19/∆19 mice, and how the circadian mechanism contributes to neurobiological adaptations within cognition-relevant brain regions in HF. We use the clinically relevant murine left anterior descending coronary artery ligation (MI) model, to simulate the possible effects on the evolution of HF in humans 23 , 24 . We demonstrate that Clock ∆19/∆19 mice have neurons with smaller apical dendrite trees within layer 2/3 of the medial prefrontal cortex (mPFC) and CA1 region of the hippocampus, and deficits in visual-spatial memory, compared with wild type (WT) mice. Interestingly, in response to HF, the Clock ∆19/∆19 mice exhibit reduced cardiac remodelling and better outcomes. Moreover, the Clock ∆19/∆19 mice show differences in the magnitude and direction of their neurobiological responses, as compared to WTs. However, despite different neurobiological adaptations, they result in similar end outcomes in terms of neuron morphology, memory, and cerebrovascular tone in HF. To investigate the mechanisms underlying this dichotomous response, we examined gene expression at baseline, MI and HF in the mPFC and hippocampus in Clock ∆19/∆19 vs. WT mice. We found differential activation of genes important for neural growth, cytoskeleton, signalling and metabolism. Collectively these data reveal that CLOCK is an important regulator of healthy cognitive system neurobiology, and adaptations in neuron morphology and function in HF. Importantly, there is no cure for HF, and neurocognitive impairments frequently coincide in patients with HF. Elucidating a role for the circadian mechanism in the neurobiology of the cognitive system can lead to new strategies to reduce morbidity and improve the quality of life of patients with HF. Results Characterization of circadian Clock ∆19/∆19 vs. WT models We postulated that the circadian mechanism influences neurobiology in the brain’s cognitive systems. To test this, we focused on the circadian factor CLOCK, as it is a canonical part of the circadian mechanism, and relatively well characterized in experimental heart disease models. Clock ∆19/∆19 mice were genotyped and phenotyped using conventional approaches. The Clock ∆19/∆19 mutation extends the circadian period from ~23.9 hours in WT mice to ~27.6 hours in Clock ∆19/∆19 mice. Figure 1a shows representative wheel running actigraphy for Clock ∆19/∆19 (left) and WT (middle) mice under a diurnal 12 hour light: 12 hour dark (LD) cycle and<|im_end|> <|im_start|>assistant Heart failure patients often have trouble with thinking and depression. A new study by University of Guelph researchers explains why and points to ways to prevent and treat both heart and brain maladies through the emerging field of circadian medicine. Published recently in Nature's Scientific Reports, the study is the first to reveal how cognition and mood in mice are regulated by the body clock and how pertinent brain regions are impaired in heart failure, said Tami Martino, a professor in U of G's Department of Biomedical Sciences and director of the Centre for Cardiovascular Investigations. "Neurosurgeons always look in the brain; cardiologists always look in the heart. This new study looked at both," said Martino, whose work in the emerging field of circadian medicine is supported by funding from the Canadian Institutes of Health Research. She recently received a Mid-Career Investigator Award from the Heart and Stroke Foundation of Canada. Coronary heart disease, the most common cause of heart failure, causes one in three deaths in Canada, according to the Heart and Stroke Foundation. Human patients with heart failure often have neurological conditions such as cognitive impairment and depression, said Martino. She worked on the study with master's student Austin Duong and Ph.D. student Cristine Reitz—both co-first authors—and neuroscientists including U of G psychology professor Boyer Winters and biomedical sciences professor Craig Bailey. Martino suspected the heart-brain connection involved the circadian mechanism molecule, called "clock." Circadian rhythms in humans and other organisms follow Earth's 24-hour cycle of light and darkness, signalling when to sleep and when to be awake. Martino's earlier research showed how disrupting circadian rhythms—as with shift workers, jet-lagged travellers and patients disturbed in intensive-care units—can trigger changes that worsen heart disease and impair overall health and well-being. For this new study, the researchers compared normal mice with mice carrying a mutation in their circadian mechanism (called "clock mice"). They found that the mutation affected the structure of neurons in brain areas important for cognition and mood. Working with University of Toronto colleagues, the team also found differences in clock regulation of blood vessels in the brains of the clock mice. After inducing heart failure in mice to simulate human heart failure, they used microarray profiling to identify key genes in the brain that were altered in neural growth, stress and metabolism pathways. The results show that the circadian mechanism influences neural effects of heart failure, said Martino. Pointing out that no cure exists for the heart condition, she said understanding how the circadian mechanism works in the brain may lead to new strategies to improve patients' quality of life. Patients recovering from heart attacks often experience disturbed circadian rhythms from light, noise and interactions with hospital staff at night. "Maintaining circadian rhythms especially for patients with heart disease could lead to better health outcomes." More generally, the findings point to potential health benefits for people in general. Avoiding shift work for people with underlying heart conditions or sleep disorders, reducing light at night or avoiding social jet lag (going to bed late and waking up later than usual on weekends) could all help reduce neurobiological impairments. Those problems—and potential solutions—involve not just hearts but brains, she said. "If we're not yet able to cure heart failure, we should at least be focusing on how we can improve quality of life for patients." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Poor growth during infancy and childhood is a characteristic feature of cystic fibrosis (CF). However, the impact of CF on intrauterine growth is unclear. We studied the effect of CF on birth weight in Denmark and Wales, and assessed whether any associations are due to differences in gestational age at birth. Methods We conducted national registry linkage studies in two countries, using data for 2.2 million singletons born in Denmark (between 1980 and 2010) and Wales (between 1998 and 2015). We used hospital inpatient and outpatient data to identify 852 children with CF. Using causal mediation methods, we estimated the direct and indirect (via gestational age) effect of CF on birth weight after adjustment for sex, parity and socioeconomic background. We tested the robustness of our results by adjusting for additional factors such as maternal smoking during pregnancy in subpopulations where these data were available. Results Babies with CF were more likely to be born preterm and with low birth weight than babies with no CF (12.7% vs 5% and 9.4% vs 5.8% preterm; 11.9% vs 4.2% and 11% vs 5.4% low birth weight in Denmark and Wales, respectively). Using causal mediation methods, the total effect of CF on birth weight was estimated to be −178.8 g (95% CI −225.43 to −134.47 g) in the Danish population and −210.08 g (95% CI −281.97 to −141.5 g) in the Welsh population. About 40% of this effect of CF on birth weight was mediated through gestational age. Conclusions CF significantly impacts on intrauterine growth and leads to lower birth weight in babies with CF, which is only partially explained by shorter gestation. cystic fibrosis clinical epidemiology This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: . googletag.cmd.push(function() { googletag.display(\"dfp-ad-mpu\"); }); Statistics from Altmetric.com See more details Picked up by 12 news outlets Blogged by 1 Tweeted by 18 On 2 Facebook pages Reddited by 1 46 readers on Mendeley Linked Articles Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. ?xml version=\"1.0\" encoding=\"UTF-8\" ? Request permissions cystic fibrosis clinical epidemiology Key messages What is the key question? Does having cystic fibrosis (CF) impact on birth weight and gestational age at birth? What is the bottom line? CF has a large effect on birth weight, similar to the impact of maternal smoking during pregnancy, and is only partially explained by shorter gestation, indicating that having CF impacts directly on intrauterine growth. Why read on? Using record-linked data for 2.2 million babies in two countries and modern methods of causal mediation analysis, we show that babies with CF are born about 200 g lighter than babies with no CF, and only around 40% of this effect is explained by reduced gestational age. Introduction Cystic fibrosis (CF) impacts negatively on the growth of children. Suboptimal growth is associated with worse lung function and increased risk of premature death in people with CF. 1–5 Around the time of diagnosis, children with CF are on average lighter than non CF children 6 and a number of small studies have suggested that babies with CF may be born lighter than the non-CF population. 1 7–14 A higher prevalence of preterm birth in babies with CF has been suggested as a possible reason, 7 13 whereas other studies have suggested that even in babies born at term, those with CF are lighter than those without CF 1 raising the possibility of prenatal and genetic influences on growth. A limitation of these studies has been that they have not been population-based, and have only captured small samples of children with CF from specific regions or seen at individual care centres. In children with CF, as in the general population, those from socially disadvantaged backgrounds are smaller and lighter compared with children from more affluent families, and have worse health outcomes and survival. In children with CF these associations are evident at diagnosis, and they appear to track forward influencing subsequent outcomes. 15 The socioeconomic differences in early growth in children with CF may be a consequence of social differences in birth weight in children with CF, as well as differential weight loss by socioeconomic status in children with CF prior to diagnosis in those that are not diagnosed by new-born screening. In this study, we aimed to clarify the association of CF with preterm birth and birth weight, and establish whether these associations vary by childhood socioeconomic conditions (SECs), at population level in Denmark and Wales. We further aimed to assess whether any differences in birth weight observed were due to differences in gestational age between babies with CF and babies with no CF, or whether there are separate biological processes linked to CF that lead to reduced birth weight. Methods Study design, setting, data sources and participants We undertook a population-level linkage study of all singleton children born in Denmark between 1980 and 2010 and in Wales between 1998 and 2015. In Denmark, we accessed the data from the Danish Medical Birth Register 16 linked to the Danish National Patient Register (DNPR) 17 and to data on highest obtained educational level in Statistics Denmark for all children and their parents. Linkage was based on the Central Person Registry Number. In Wales, we analysed data from the Secure Anonymised Information Linkage databank. 18 19 We accessed the National Community of Child Health (NCCH) Database and used Anonymised Linkage Fields to link to the Congenital Anomaly Register and Information Service (CARIS), Patient Episode Database for Wales (PEDW), Welsh Longitudinal General", "role": "user" }, { "content": "New research, published in Thorax, funded by the Cystic Fibrosis Trust has shown that babies with cystic fibrosis (CF) are born weighing less than babies without the condition, even allowing that they are more likely to be born prematurely. The research, conducted by CF-EpiNet—a Cystic Fibrosis Trust Strategic Research Centre (SRC) of which the University of Liverpool is a member—has shown that having CF results in lower average birth weight, revealing the need for further research into how CF affects the development of babies in the womb. Findings The research team compared babies born with and without CF using data on 2.2?million babies in Denmark and Wales. This research, published in July in Thorax, a world-leading respiratory medicine journal, indicates that, while babies with CF are often born prematurely, this only accounts for around 40% of the effect on birth weight. This means that the CF mutation could also have an effect on the way babies develop within the womb. These results may be the first step to understanding and improving the health of babies with CF before they are born. The findings further show that babies born to disadvantaged families are likely to have a lower weight at birth, regardless of whether or not they have cystic fibrosis. This indicates that the socio-economic inequalities in outcomes that occur in CF may start in the intrauterine period. CF-EpiNet The CF-EpiNet SRC allows researchers to use and enhance the data within the Trust's UK CF Registry to tell us more about what happens when you live with cystic fibrosis. This study has used databases for Wales and Denmark to begin investigating the effects of socio-economic deprivation on outcomes in CF. These databases contain anonymous information from the whole population across these countries. Importance? Poor nutrition and slow growth are common features in babies with CF, and both can have an impact on the lung function and survival of those babies in the future. Rebecca Cosgriff, Registry Lead, said: \"Currently, we do not know how birthweight affects future health. The next stage of the research will be to link the databases used in this study with the UK CF Registry. This will add in more CF-specific information and may give further insight. \"A direct result of this study could be that birthweight is added to the data collected by the UK CF Registry from people with CF (or their guardians, if under 18) who choose to share it. By investigating the possible link between factors that cause low birthweight and adult health outcomes, we hope to be able to find ways to address these inequalities and give parents of babies with CF hope for a brighter future.\" Impact similar to smoking Professor David Taylor-Robinson, Co-Principal Investigator, University of Liverpool, said: \"Our study shows the importance of data linkage for child health. Using datasets linked across different sources we could look at over two million children in two countries to show that CF has a large effect on birth weight, similar to the impact of maternal smoking during pregnancy. \"The results show that having CF impacts directly on intrauterine growth. More research is needed to understand the biological mechanisms for this, and to assess how birthweight predicts survival for people with CF. From a clinical perspective it is important to optimise support for children with CF right from the start of life \" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Poor growth during infancy and childhood is a characteristic feature of cystic fibrosis (CF). However, the impact of CF on intrauterine growth is unclear. We studied the effect of CF on birth weight in Denmark and Wales, and assessed whether any associations are due to differences in gestational age at birth. Methods We conducted national registry linkage studies in two countries, using data for 2.2 million singletons born in Denmark (between 1980 and 2010) and Wales (between 1998 and 2015). We used hospital inpatient and outpatient data to identify 852 children with CF. Using causal mediation methods, we estimated the direct and indirect (via gestational age) effect of CF on birth weight after adjustment for sex, parity and socioeconomic background. We tested the robustness of our results by adjusting for additional factors such as maternal smoking during pregnancy in subpopulations where these data were available. Results Babies with CF were more likely to be born preterm and with low birth weight than babies with no CF (12.7% vs 5% and 9.4% vs 5.8% preterm; 11.9% vs 4.2% and 11% vs 5.4% low birth weight in Denmark and Wales, respectively). Using causal mediation methods, the total effect of CF on birth weight was estimated to be −178.8 g (95% CI −225.43 to −134.47 g) in the Danish population and −210.08 g (95% CI −281.97 to −141.5 g) in the Welsh population. About 40% of this effect of CF on birth weight was mediated through gestational age. Conclusions CF significantly impacts on intrauterine growth and leads to lower birth weight in babies with CF, which is only partially explained by shorter gestation. cystic fibrosis clinical epidemiology This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: . googletag.cmd.push(function() { googletag.display("dfp-ad-mpu"); }); Statistics from Altmetric.com See more details Picked up by 12 news outlets Blogged by 1 Tweeted by 18 On 2 Facebook pages Reddited by 1 46 readers on Mendeley Linked Articles Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. ?xml version="1.0" encoding="UTF-8" ? Request permissions cystic fibrosis clinical epidemiology Key messages What is the key question? Does having cystic fibrosis (CF) impact on birth weight and gestational age at birth? What is the bottom line? CF has a large effect on birth weight, similar to the impact of maternal smoking during pregnancy, and is only partially explained by shorter gestation, indicating that having CF impacts directly on intrauterine growth. Why read on? Using record-linked data for 2.2 million babies in two countries and modern methods of causal mediation analysis, we show that babies with CF are born about 200 g lighter than babies with no CF, and only around 40% of this effect is explained by reduced gestational age. Introduction Cystic fibrosis (CF) impacts negatively on the growth of children. Suboptimal growth is associated with worse lung function and increased risk of premature death in people with CF. 1–5 Around the time of diagnosis, children with CF are on average lighter than non CF children 6 and a number of small studies have suggested that babies with CF may be born lighter than the non-CF population. 1 7–14 A higher prevalence of preterm birth in babies with CF has been suggested as a possible reason, 7 13 whereas other studies have suggested that even in babies born at term, those with CF are lighter than those without CF 1 raising the possibility of prenatal and genetic influences on growth. A limitation of these studies has been that they have not been population-based, and have only captured small samples of children with CF from specific regions or seen at individual care centres. In children with CF, as in the general population, those from socially disadvantaged backgrounds are smaller and lighter compared with children from more affluent families, and have worse health outcomes and survival. In children with CF these associations are evident at diagnosis, and they appear to track forward influencing subsequent outcomes. 15 The socioeconomic differences in early growth in children with CF may be a consequence of social differences in birth weight in children with CF, as well as differential weight loss by socioeconomic status in children with CF prior to diagnosis in those that are not diagnosed by new-born screening. In this study, we aimed to clarify the association of CF with preterm birth and birth weight, and establish whether these associations vary by childhood socioeconomic conditions (SECs), at population level in Denmark and Wales. We further aimed to assess whether any differences in birth weight observed were due to differences in gestational age between babies with CF and babies with no CF, or whether there are separate biological processes linked to CF that lead to reduced birth weight. Methods Study design, setting, data sources and participants We undertook a population-level linkage study of all singleton children born in Denmark between 1980 and 2010 and in Wales between 1998 and 2015. In Denmark, we accessed the data from the Danish Medical Birth Register 16 linked to the Danish National Patient Register (DNPR) 17 and to data on highest obtained educational level in Statistics Denmark for all children and their parents. Linkage was based on the Central Person Registry Number. In Wales, we analysed data from the Secure Anonymised Information Linkage databank. 18 19 We accessed the National Community of Child Health (NCCH) Database and used Anonymised Linkage Fields to link to the Congenital Anomaly Register and Information Service (CARIS), Patient Episode Database for Wales (PEDW), Welsh Longitudinal General<|im_end|> <|im_start|>assistant New research, published in Thorax, funded by the Cystic Fibrosis Trust has shown that babies with cystic fibrosis (CF) are born weighing less than babies without the condition, even allowing that they are more likely to be born prematurely. The research, conducted by CF-EpiNet—a Cystic Fibrosis Trust Strategic Research Centre (SRC) of which the University of Liverpool is a member—has shown that having CF results in lower average birth weight, revealing the need for further research into how CF affects the development of babies in the womb. Findings The research team compared babies born with and without CF using data on 2.2?million babies in Denmark and Wales. This research, published in July in Thorax, a world-leading respiratory medicine journal, indicates that, while babies with CF are often born prematurely, this only accounts for around 40% of the effect on birth weight. This means that the CF mutation could also have an effect on the way babies develop within the womb. These results may be the first step to understanding and improving the health of babies with CF before they are born. The findings further show that babies born to disadvantaged families are likely to have a lower weight at birth, regardless of whether or not they have cystic fibrosis. This indicates that the socio-economic inequalities in outcomes that occur in CF may start in the intrauterine period. CF-EpiNet The CF-EpiNet SRC allows researchers to use and enhance the data within the Trust's UK CF Registry to tell us more about what happens when you live with cystic fibrosis. This study has used databases for Wales and Denmark to begin investigating the effects of socio-economic deprivation on outcomes in CF. These databases contain anonymous information from the whole population across these countries. Importance? Poor nutrition and slow growth are common features in babies with CF, and both can have an impact on the lung function and survival of those babies in the future. Rebecca Cosgriff, Registry Lead, said: "Currently, we do not know how birthweight affects future health. The next stage of the research will be to link the databases used in this study with the UK CF Registry. This will add in more CF-specific information and may give further insight. "A direct result of this study could be that birthweight is added to the data collected by the UK CF Registry from people with CF (or their guardians, if under 18) who choose to share it. By investigating the possible link between factors that cause low birthweight and adult health outcomes, we hope to be able to find ways to address these inequalities and give parents of babies with CF hope for a brighter future." Impact similar to smoking Professor David Taylor-Robinson, Co-Principal Investigator, University of Liverpool, said: "Our study shows the importance of data linkage for child health. Using datasets linked across different sources we could look at over two million children in two countries to show that CF has a large effect on birth weight, similar to the impact of maternal smoking during pregnancy. "The results show that having CF impacts directly on intrauterine growth. More research is needed to understand the biological mechanisms for this, and to assess how birthweight predicts survival for people with CF. From a clinical perspective it is important to optimise support for children with CF right from the start of life " <|im_end|>

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2,020

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Electron transfer in respiratory chains generates the electrochemical potential that serves as energy source for the cell. Prokaryotes can use a wide range of electron donors and acceptors and may have alternative complexes performing the same catalytic reactions as the mitochondrial complexes. This is the case for the alternative complex III (ACIII), a quinol:cytochrome c /HiPIP oxidoreductase. In order to understand the catalytic mechanism of this respiratory enzyme, we determined the structure of ACIII from Rhodothermus marinus at 3.9 Å resolution by single-particle cryo-electron microscopy. ACIII presents a so-far unique structure, for which we establish the arrangement of the cofactors (four iron–sulfur clusters and six c -type hemes) and propose the location of the quinol-binding site and the presence of two putative proton pathways in the membrane. Altogether, this structure provides insights into a mechanism for energy transduction and introduces ACIII as a redox-driven proton pump. Introduction Energy is at the basis of life as all organisms depend on constant energy transduction mechanisms to grow and reproduce themselves. Electron transfer respiratory chains generate the transmembrane difference of electrochemical potential that is the energy source for ATP synthesis, solute transport, and motility. In eukaryotes, the respiratory chain is located in mitochondria and is classically viewed as a linear composition of four electron transfer complexes, known as complex I–IV. However, in many organisms respiratory chains differ in composition and organization 1 . Prokaryotes can use a wide range of electron donors and acceptors and may have alternative complexes performing essentially the same catalytic reactions as the canonical mitochondrial complexes 2 . The diversity and apparent redundancy of prokaryotic respiratory chains reflects the versatility and robustness of their organisms. The oxidation of quinol with subsequent reduction of cytochrome c seemed until 1999 to evade the paradigm of diversified respiratory chains in prokaryotes. The reaction was thought to be exclusively catalyzed by the bc 1 / b 6 f complex 2 , also known as complex III. This notion changed with the identification of alternative complex III (ACIII), a quinol:cytochrome c /high potential iron–sulfur protein (HiPIP) oxidoreductase that was identified in Rhodothermus marinus 3 . ACIII is widespread in bacteria 3 , 4 , 5 , 6 , 7 and mainly present in organisms that lack the bc 1 / b 6 f complex. Nonetheless, the genes coding for ACIII and complex III coexist in some species 1 , 8 . Their expression in these may depend on the cellular metabolic needs, as it has been reported for respiratory enzymes performing the same catalytic activity, such as complex I and NDH-2 in Escherichia coli 9 . In addition to reducing periplasmatic proteins, such as HiPIP 10 and soluble cytochrome c 11 , ACIII can directly transfer electrons from quinol to the caa 3 terminal oxidase without the intervention of any soluble electron carrier 8 . Besides the functional linkage of ACIII with the caa 3 oxygen reductase, the structural association of the two complexes into a supercomplex has also been proposed in R. marinus membranes based on biochemical and functional experiments 8 . These observations agree with the fact that gene clusters encoding ACIII are frequently followed by gene clusters encoding oxygen reductases 8 , 12 . Even though ACIII is functionally equivalent to the cytochrome bc 1 complex 3 , 4 , 13 , 14 , these two enzymes are structurally unrelated. In R. marinus , ACIII is composed of seven subunits encoded by the Act gene cluster 8 , six of which are conserved across species (ActA to ActF). ActA and ActE are cytochromes with five and one c -type hemes, respectively. The largest subunit in the complex is ActB, which is composed of two domains. These domains, designated B1 and B2, are homologous to the catalytic subunit and to the iron–sulfur protein of the members of the complex iron–sulfur molybdoenzyme (CISM) family 14 , respectively. ActC and ActF are membrane subunits and are homologous to subunit C of the polysulfide reductase protein (PsrC), also a member of the CISM family 7 , 14 . Finally, ActD and ActG are predicted to be transmembrane proteins, without redox cofactors, and seem to be present exclusively in ACIII 15 . ACIII is composed by a combination of proteins present in other respiratory complexes, which reinforces the modularity concept of energy transducing machines 12 . However, no structural characterization of this family of respiratory enzymes was performed to date. In this work, we describe a 3.9 Å cryo-EM structure of ACIII from R. marinus . Our structure shows that ACIII meets all requirements for an energy-transducing machine that couples quinol oxidation to translocation of protons across the membrane. Results Overall structure of ACIII ACIII was purified from R. marinus membranes solubilized with n -dodecyl β- d -maltoside (DDM) (Supplementary Fig. 1a ) and studied by cryo-EM. Grids showed ACIII as compact particles with a good distribution in the ice in random orientations (Supplementary Fig. 1b, d ). By 2D and 3D classification routines, two populations of particles were identified in the data set (Supplementary Fig. 1c ). The largest set, with almost 40% of the particles, produced a map at an average resolution of 3.9 Å (Supplementary Fig. 1e, f and Supplementary Fig. 2a ). At this resolution, α-helices, β-sheets, side chains for most residues, and the iron–sulfur clusters and heme groups and their protein ligands are easy to recognize (Supplementary Fig. 2 b-e). The only exception are glutamate and aspartate side chains, which are highly radiation sensitive 16 , 17 , 18 . This map was used to solve the ACIII structure (Fig. 1 and Supplementary Table 1 ). The smaller set of particles (7% of the initial data set) produced a map at 20 Å resolution that displays a large extra density and is compatible with an ACIII– caa 3 supercomplex that was previously proposed to exist 8 (Fig. 2 ). Fig. 1 Overall structure of ACIII. ACIII is composed of at least seven subunits; the peripheral subunits ActA (green), ActB (cyan),", "role": "user" }, { "content": "Energy is the basis of life, and all organisms depend on mechanisms of energy transformation for growth and reproduction. Living beings get their energy through cellular respiration. In eukaryotes, like us humans, this is done in the presence of oxygen in an organelle called the mitochondria through four protein complexes, which constitute the respiratory chain. Bacteria have more diverse protein complexes and they are able to use other compounds besides oxygen, such as sulfur and nitrogen species or iron. This diversity is what enables microorganisms to colonize environments as extreme as volcanoes, the bottom of the ocean or the inside of our bowls. In this work, ITQB NOVA researchers from Manuela Pereira Lab and Miguel Teixeira Lab with colleagues from Max Planck Institute in Germany have described a new bacterial respiratory complex from a deep see organism. The results were published today in Nature Communications, open access magazine from Nature Publishing group. Rhodothermus marinus is a thermophile collected from Azores, at Ribeira Quente Beach. It grows at 65 °C but it also needs oxygen, so it colonizes a thin layer of sea water where it finds optimal temperature and oxygen pressure. This bacterium has been studied at ITQB NOVA, at Manuela Pereira Lab and Miguel Teixeira Lab, for many years. Now, they were able to take a big advancement by obtaining a cryo-electron microscopy image of the membrane protein complex that is responsible for energy transduction in these bacteria. Cryo-electron microscopy for the high-resolution structure determination of biomolecules in solution is the technique that awarded the Nobel Chemistry Prize to Joachim Frank, Richard Henderson and Jacques Dubochet in 2017. In fact, the results now obtained gave fundamental structural information to understand how this \"molecular machine\" transforms energy into the usable ATP. (more on the Portuguese consortium that is is committed in bringing this technique to Portugal to make it more available for researchers). \"In this work we have described a new respiratory alternative complex, that is increasing the knowledge we have on the great diversity of microorganisms molecular strategies for life and reproduction\", according to Manuela Pereira, corresponding author. \"Rhodothermus marinus presents a unique structure, which provides insights into a mechanism for energy transduction and introduces ACIII as a redox-driven proton pump.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Electron transfer in respiratory chains generates the electrochemical potential that serves as energy source for the cell. Prokaryotes can use a wide range of electron donors and acceptors and may have alternative complexes performing the same catalytic reactions as the mitochondrial complexes. This is the case for the alternative complex III (ACIII), a quinol:cytochrome c /HiPIP oxidoreductase. In order to understand the catalytic mechanism of this respiratory enzyme, we determined the structure of ACIII from Rhodothermus marinus at 3.9 Å resolution by single-particle cryo-electron microscopy. ACIII presents a so-far unique structure, for which we establish the arrangement of the cofactors (four iron–sulfur clusters and six c -type hemes) and propose the location of the quinol-binding site and the presence of two putative proton pathways in the membrane. Altogether, this structure provides insights into a mechanism for energy transduction and introduces ACIII as a redox-driven proton pump. Introduction Energy is at the basis of life as all organisms depend on constant energy transduction mechanisms to grow and reproduce themselves. Electron transfer respiratory chains generate the transmembrane difference of electrochemical potential that is the energy source for ATP synthesis, solute transport, and motility. In eukaryotes, the respiratory chain is located in mitochondria and is classically viewed as a linear composition of four electron transfer complexes, known as complex I–IV. However, in many organisms respiratory chains differ in composition and organization 1 . Prokaryotes can use a wide range of electron donors and acceptors and may have alternative complexes performing essentially the same catalytic reactions as the canonical mitochondrial complexes 2 . The diversity and apparent redundancy of prokaryotic respiratory chains reflects the versatility and robustness of their organisms. The oxidation of quinol with subsequent reduction of cytochrome c seemed until 1999 to evade the paradigm of diversified respiratory chains in prokaryotes. The reaction was thought to be exclusively catalyzed by the bc 1 / b 6 f complex 2 , also known as complex III. This notion changed with the identification of alternative complex III (ACIII), a quinol:cytochrome c /high potential iron–sulfur protein (HiPIP) oxidoreductase that was identified in Rhodothermus marinus 3 . ACIII is widespread in bacteria 3 , 4 , 5 , 6 , 7 and mainly present in organisms that lack the bc 1 / b 6 f complex. Nonetheless, the genes coding for ACIII and complex III coexist in some species 1 , 8 . Their expression in these may depend on the cellular metabolic needs, as it has been reported for respiratory enzymes performing the same catalytic activity, such as complex I and NDH-2 in Escherichia coli 9 . In addition to reducing periplasmatic proteins, such as HiPIP 10 and soluble cytochrome c 11 , ACIII can directly transfer electrons from quinol to the caa 3 terminal oxidase without the intervention of any soluble electron carrier 8 . Besides the functional linkage of ACIII with the caa 3 oxygen reductase, the structural association of the two complexes into a supercomplex has also been proposed in R. marinus membranes based on biochemical and functional experiments 8 . These observations agree with the fact that gene clusters encoding ACIII are frequently followed by gene clusters encoding oxygen reductases 8 , 12 . Even though ACIII is functionally equivalent to the cytochrome bc 1 complex 3 , 4 , 13 , 14 , these two enzymes are structurally unrelated. In R. marinus , ACIII is composed of seven subunits encoded by the Act gene cluster 8 , six of which are conserved across species (ActA to ActF). ActA and ActE are cytochromes with five and one c -type hemes, respectively. The largest subunit in the complex is ActB, which is composed of two domains. These domains, designated B1 and B2, are homologous to the catalytic subunit and to the iron–sulfur protein of the members of the complex iron–sulfur molybdoenzyme (CISM) family 14 , respectively. ActC and ActF are membrane subunits and are homologous to subunit C of the polysulfide reductase protein (PsrC), also a member of the CISM family 7 , 14 . Finally, ActD and ActG are predicted to be transmembrane proteins, without redox cofactors, and seem to be present exclusively in ACIII 15 . ACIII is composed by a combination of proteins present in other respiratory complexes, which reinforces the modularity concept of energy transducing machines 12 . However, no structural characterization of this family of respiratory enzymes was performed to date. In this work, we describe a 3.9 Å cryo-EM structure of ACIII from R. marinus . Our structure shows that ACIII meets all requirements for an energy-transducing machine that couples quinol oxidation to translocation of protons across the membrane. Results Overall structure of ACIII ACIII was purified from R. marinus membranes solubilized with n -dodecyl β- d -maltoside (DDM) (Supplementary Fig. 1a ) and studied by cryo-EM. Grids showed ACIII as compact particles with a good distribution in the ice in random orientations (Supplementary Fig. 1b, d ). By 2D and 3D classification routines, two populations of particles were identified in the data set (Supplementary Fig. 1c ). The largest set, with almost 40% of the particles, produced a map at an average resolution of 3.9 Å (Supplementary Fig. 1e, f and Supplementary Fig. 2a ). At this resolution, α-helices, β-sheets, side chains for most residues, and the iron–sulfur clusters and heme groups and their protein ligands are easy to recognize (Supplementary Fig. 2 b-e). The only exception are glutamate and aspartate side chains, which are highly radiation sensitive 16 , 17 , 18 . This map was used to solve the ACIII structure (Fig. 1 and Supplementary Table 1 ). The smaller set of particles (7% of the initial data set) produced a map at 20 Å resolution that displays a large extra density and is compatible with an ACIII– caa 3 supercomplex that was previously proposed to exist 8 (Fig. 2 ). Fig. 1 Overall structure of ACIII. ACIII is composed of at least seven subunits; the peripheral subunits ActA (green), ActB (cyan),<|im_end|> <|im_start|>assistant Energy is the basis of life, and all organisms depend on mechanisms of energy transformation for growth and reproduction. Living beings get their energy through cellular respiration. In eukaryotes, like us humans, this is done in the presence of oxygen in an organelle called the mitochondria through four protein complexes, which constitute the respiratory chain. Bacteria have more diverse protein complexes and they are able to use other compounds besides oxygen, such as sulfur and nitrogen species or iron. This diversity is what enables microorganisms to colonize environments as extreme as volcanoes, the bottom of the ocean or the inside of our bowls. In this work, ITQB NOVA researchers from Manuela Pereira Lab and Miguel Teixeira Lab with colleagues from Max Planck Institute in Germany have described a new bacterial respiratory complex from a deep see organism. The results were published today in Nature Communications, open access magazine from Nature Publishing group. Rhodothermus marinus is a thermophile collected from Azores, at Ribeira Quente Beach. It grows at 65 °C but it also needs oxygen, so it colonizes a thin layer of sea water where it finds optimal temperature and oxygen pressure. This bacterium has been studied at ITQB NOVA, at Manuela Pereira Lab and Miguel Teixeira Lab, for many years. Now, they were able to take a big advancement by obtaining a cryo-electron microscopy image of the membrane protein complex that is responsible for energy transduction in these bacteria. Cryo-electron microscopy for the high-resolution structure determination of biomolecules in solution is the technique that awarded the Nobel Chemistry Prize to Joachim Frank, Richard Henderson and Jacques Dubochet in 2017. In fact, the results now obtained gave fundamental structural information to understand how this "molecular machine" transforms energy into the usable ATP. (more on the Portuguese consortium that is is committed in bringing this technique to Portugal to make it more available for researchers). "In this work we have described a new respiratory alternative complex, that is increasing the knowledge we have on the great diversity of microorganisms molecular strategies for life and reproduction", according to Manuela Pereira, corresponding author. "Rhodothermus marinus presents a unique structure, which provides insights into a mechanism for energy transduction and introduces ACIII as a redox-driven proton pump." <|im_end|>

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439, 264, 2579, 5241, 32505, 82586, 14155, 1210, 220, 128257, 198 ]

1,946

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Sleep is an essential state of decreased activity and alertness but molecular factors regulating sleep duration remain unknown. Through genome-wide association analysis in 446,118 adults of European ancestry from the UK Biobank, we identify 78 loci for self-reported habitual sleep duration ( p < 5 × 10 −8 ; 43 loci at p < 6 × 10 −9 ). Replication is observed for PAX8 , VRK2 , and FBXL12/UBL5/PIN1 loci in the CHARGE study ( n = 47,180; p < 6.3 × 10 −4 ), and 55 signals show sign-concordant effects. The 78 loci further associate with accelerometer-derived sleep duration, daytime inactivity, sleep efficiency and number of sleep bouts in secondary analysis ( n = 85,499). Loci are enriched for pathways including striatum and subpallium development, mechanosensory response, dopamine binding, synaptic neurotransmission and plasticity, among others. Genetic correlation indicates shared links with anthropometric, cognitive, metabolic, and psychiatric traits and two-sample Mendelian randomization highlights a bidirectional causal link with schizophrenia. This work provides insights into the genetic basis for inter-individual variation in sleep duration implicating multiple biological pathways. Introduction Sleep is an essential homeostatically regulated state of decreased activity and alertness conserved across animal species, and both short and long sleep duration associate with chronic disease and all-cause mortality 1 , 2 . Research in model organisms (reviewed in refs. 3 , 4 ) has delineated aspects of the neural circuitry of sleep–wake regulation 5 and molecular components including specific neurotransmitter and neuropeptide systems, intracellular signaling molecules, ion channels, circadian clock genes and metabolic and immune factors 4 , and more recently phosphorylation of synaptic proteins 6 , but their specific roles and relevance to human sleep regulation are largely unknown. Prospective epidemiologic studies suggest that both short (<6 h per night) and long (>9 h per night) habitual self-reported sleep duration associate with cognitive and psychiatric, metabolic, cardiovascular, and immunological dysfunction as well as all-cause mortality compared to sleeping 7–8 h per night 7 , 8 , 9 . Furthermore, chronic sleep deprivation in modern society may lead to increased errors and accidents 10 . Yet, whether short or long habitual sleep duration causally contributes to disease initiation or progression remains to be established. Habitual self-reported sleep duration is a complex trait with an established genetic component (twin- and family-based heritability ( h 2 ) estimates = 9–45% 11 , 12 , 13 , 14 ). Candidate gene sequencing in pedigrees and functional validation of rare, missense variants established BHLHE41 (previously DEC2 ), a repressor of CLOCK / ARNTL activity, as a causal gene 15 , 16 , supporting the role of the circadian clock in sleep regulation. Previous genome-wide association studies (GWASs), including a recent GWAS in up to 128,286 individuals, identified association of common variants at or near the PAX8 and VRK2 genes, among other signals that have not yet been replicated 13 , 14 , 17 , 18 , 19 . Here, we extend GWAS of self-reported sleep duration in UK Biobank, test for consistency of effects in independent studies of adults and children/adolescents, determine their impact on accelerometer-derived estimates, perform pathway and tissue enrichment to highlight relevant biological processes, and explore causal relationships with disease traits. Results GWAS for self-reported habitual sleep duration Among UK Biobank participants of European ancestry ( n = 446,118), mean self-reported habitual sleep duration was 7.2 h (1.1 standard deviation) per day (Supplementary Table 1 ). GWAS using 14,661,600 imputed genetic variants identified 78 loci ( P < 5 × 10 −8 ; Fig. 1a , Supplementary Data 1 , 2 , Supplementary Figure 1a ). Individual signals exert an average effect of 1.04 min (0.34 standard deviation) per allele, with the largest effect at the PAX8 locus, with an estimate of 2.44 min (0.16 standard error) per allele. The 5% of participants carrying the most sleep duration-increasing alleles self-reported 22.2 min longer sleep duration compared to the 5% carrying the fewest. The 78 loci explained 0.69% of the variance in sleep duration, and genome-wide single-nucleotide polymorphism (SNP)-based heritability was estimated at 9.8 (0.1)%. Of the 78 variants, 43 variants passed a more stringent multiple correction threshold of P < 6 × 10 −9 established by permutation testing for a related sleep trait 20 . Fig. 1 Plots for genome-wide association analysis results for sleep duration and short/long sleep. a Manhattan plot of sleep duration ( n = 446,118) and b Miami plot of short (cases n = 106,192/305,742) and long (cases n = 34,184/305,742) sleep. Plots show the −log 10 P values ( y -axis) for all genotyped and imputed single-nucleotide polymorphisms (SNPs) passing quality control in each genome-wide association study (GWAS), plotted by chromosome ( x -axis). Blue peaks represent genome-wide significant loci. Horizontal red line denotes genome-wide significance ( P = 5 × 10 −8 ) Full size image Sensitivity analyses indicated that the 78 genetic associations were largely independent of known risk factors (Supplementary Data 3 ). Effect estimates at 15/78 loci were attenuated by 15–25% upon adjustment for frequent insomnia symptoms, perhaps reflecting contribution to an insomnia sub-phenotype with physiological hyperarousal and objective short sleep duration 21 (Supplementary Data 3 ). Effect estimates at 19/78 were also slightly attenuated after adjustment of lifestyle factors. No signal attenuation was observed when accounting for body mass index (BMI) at rs9940646 at FTO , the established BMI-associated signal ( r 2 = 0.81 with rs9939609 22 and where the higher BMI allele associated with shorter sleep duration). Analysis conditioned on the lead SNPs in each genomic region identified 4 secondary association signals at the VRK2 , DAT1 (SLC6A3) , DRD2 , and MAPT loci (Supplementary Table 2 ). Effect estimates were largely consistent in GWAS excluding shift workers and those with prevalent chronic and psychiatric disorders (excluding n = 119,894 participants) (Supplementary Data 1 , 2 , Supplementary Table 3 , Supplementary Figure 1 b , 2 ). GWAS results were similar for men and women ( r g (SE) = 0.989 (0.042); P < 0.001) (Supplementary Table", "role": "user" }, { "content": "A study led by investigators from Massachusetts General Hospital (MGH) and the University of Exeter Medical School has identified 76 new gene regions associated with sleep duration. The study by a team that recently reported finding gene sites associated with insomnia risk and chronotype - the tendency to be an early riser or a 'night owl' - has been published in Nature Communications. \"While we spend about a third of our life asleep, we have little knowledge of the specific genes and pathways that regulate the amount of sleep people get,\" says Hassan Saeed Dashti, Ph.D., RD, of the MGH Center for Genomic Medicine, co-lead author of the report. \"Our study suggests that many of the genes important for sleep in animal models may also influence sleep in humans and opens the door to better understanding of the function and regulation of sleep.\" It is well understood that regularly getting adequate sleep—7 to 8 hours per night—is important to health, and both insufficient sleep—6 or fewer hours—and excessive sleep—9 hours or more—have been linked to significant health problems. Family studies have suggested that from 10 to 40 percent of variation in sleep duration may be inherited, and previous genetic studies have associated variants in two gene regions with sleep duration. The current study, the largest of its kind to address sleep duration, analyzed genetic data from more than 446,000 participants in the U.K. Biobank who self-reported the amount of sleep they typically received. That genome-wide association study (GWAS) identified 78 gene regions—including the two previously identified—as associated with sleep duration. While carrying a single gene variant influenced the average amount of sleep by only a minute, participants carrying the largest number of duration-increasing variants reported an average of 22 more minutes of sleep, compared with those with the fewest, which is comparable to other well-recognized factors that influence sleep duration. To confirm the accuracy of findings based on self-reported sleep duration, the researchers tested the 78 duration-associated variants in a subgroup of participants who had worn motion-detecting devices called accelerometers for up to a week. Not only were those gene regions supported by objective measurement of sleep duration, but this analysis was also able to associate duration-related variants with factors such as sleep efficiency, instances of waking up during the night and daytime inactivity. Only a few of the gene regions identified in this study overlap with those identified in the group's previous studies of insomnia and chronotype. The sites identified in this study showed consistent effects with a previous GWAS of more than 47,000 adults but limited consistency with another GWAS of sleep duration among more than 10,500 children and adolescents, which supports research suggesting that the genetics of sleep duration may be different in children than in adults. Since both shorter- and longer-than-average sleep duration have been associated with health problems, the team conducted separate GWASs for participants who reported short or long sleep duration. Those studies identified additional genes not identified in the larger group analysis that contributed to either longer or shorter sleep duration. The researchers also found shared genetic links between both short and long sleep duration and factors such as higher levels of body fat, depression symptoms and fewer years of schooling, implying negative effects from both too little and too much sleep. In addition, short sleep duration was genetically linked with traits such as insomnia and smoking, while long-duration variants were linked with schizophrenia, type 2 diabetes and coronary artery disease. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Sleep is an essential state of decreased activity and alertness but molecular factors regulating sleep duration remain unknown. Through genome-wide association analysis in 446,118 adults of European ancestry from the UK Biobank, we identify 78 loci for self-reported habitual sleep duration ( p < 5 × 10 −8 ; 43 loci at p < 6 × 10 −9 ). Replication is observed for PAX8 , VRK2 , and FBXL12/UBL5/PIN1 loci in the CHARGE study ( n = 47,180; p < 6.3 × 10 −4 ), and 55 signals show sign-concordant effects. The 78 loci further associate with accelerometer-derived sleep duration, daytime inactivity, sleep efficiency and number of sleep bouts in secondary analysis ( n = 85,499). Loci are enriched for pathways including striatum and subpallium development, mechanosensory response, dopamine binding, synaptic neurotransmission and plasticity, among others. Genetic correlation indicates shared links with anthropometric, cognitive, metabolic, and psychiatric traits and two-sample Mendelian randomization highlights a bidirectional causal link with schizophrenia. This work provides insights into the genetic basis for inter-individual variation in sleep duration implicating multiple biological pathways. Introduction Sleep is an essential homeostatically regulated state of decreased activity and alertness conserved across animal species, and both short and long sleep duration associate with chronic disease and all-cause mortality 1 , 2 . Research in model organisms (reviewed in refs. 3 , 4 ) has delineated aspects of the neural circuitry of sleep–wake regulation 5 and molecular components including specific neurotransmitter and neuropeptide systems, intracellular signaling molecules, ion channels, circadian clock genes and metabolic and immune factors 4 , and more recently phosphorylation of synaptic proteins 6 , but their specific roles and relevance to human sleep regulation are largely unknown. Prospective epidemiologic studies suggest that both short (<6 h per night) and long (>9 h per night) habitual self-reported sleep duration associate with cognitive and psychiatric, metabolic, cardiovascular, and immunological dysfunction as well as all-cause mortality compared to sleeping 7–8 h per night 7 , 8 , 9 . Furthermore, chronic sleep deprivation in modern society may lead to increased errors and accidents 10 . Yet, whether short or long habitual sleep duration causally contributes to disease initiation or progression remains to be established. Habitual self-reported sleep duration is a complex trait with an established genetic component (twin- and family-based heritability ( h 2 ) estimates = 9–45% 11 , 12 , 13 , 14 ). Candidate gene sequencing in pedigrees and functional validation of rare, missense variants established BHLHE41 (previously DEC2 ), a repressor of CLOCK / ARNTL activity, as a causal gene 15 , 16 , supporting the role of the circadian clock in sleep regulation. Previous genome-wide association studies (GWASs), including a recent GWAS in up to 128,286 individuals, identified association of common variants at or near the PAX8 and VRK2 genes, among other signals that have not yet been replicated 13 , 14 , 17 , 18 , 19 . Here, we extend GWAS of self-reported sleep duration in UK Biobank, test for consistency of effects in independent studies of adults and children/adolescents, determine their impact on accelerometer-derived estimates, perform pathway and tissue enrichment to highlight relevant biological processes, and explore causal relationships with disease traits. Results GWAS for self-reported habitual sleep duration Among UK Biobank participants of European ancestry ( n = 446,118), mean self-reported habitual sleep duration was 7.2 h (1.1 standard deviation) per day (Supplementary Table 1 ). GWAS using 14,661,600 imputed genetic variants identified 78 loci ( P < 5 × 10 −8 ; Fig. 1a , Supplementary Data 1 , 2 , Supplementary Figure 1a ). Individual signals exert an average effect of 1.04 min (0.34 standard deviation) per allele, with the largest effect at the PAX8 locus, with an estimate of 2.44 min (0.16 standard error) per allele. The 5% of participants carrying the most sleep duration-increasing alleles self-reported 22.2 min longer sleep duration compared to the 5% carrying the fewest. The 78 loci explained 0.69% of the variance in sleep duration, and genome-wide single-nucleotide polymorphism (SNP)-based heritability was estimated at 9.8 (0.1)%. Of the 78 variants, 43 variants passed a more stringent multiple correction threshold of P < 6 × 10 −9 established by permutation testing for a related sleep trait 20 . Fig. 1 Plots for genome-wide association analysis results for sleep duration and short/long sleep. a Manhattan plot of sleep duration ( n = 446,118) and b Miami plot of short (cases n = 106,192/305,742) and long (cases n = 34,184/305,742) sleep. Plots show the −log 10 P values ( y -axis) for all genotyped and imputed single-nucleotide polymorphisms (SNPs) passing quality control in each genome-wide association study (GWAS), plotted by chromosome ( x -axis). Blue peaks represent genome-wide significant loci. Horizontal red line denotes genome-wide significance ( P = 5 × 10 −8 ) Full size image Sensitivity analyses indicated that the 78 genetic associations were largely independent of known risk factors (Supplementary Data 3 ). Effect estimates at 15/78 loci were attenuated by 15–25% upon adjustment for frequent insomnia symptoms, perhaps reflecting contribution to an insomnia sub-phenotype with physiological hyperarousal and objective short sleep duration 21 (Supplementary Data 3 ). Effect estimates at 19/78 were also slightly attenuated after adjustment of lifestyle factors. No signal attenuation was observed when accounting for body mass index (BMI) at rs9940646 at FTO , the established BMI-associated signal ( r 2 = 0.81 with rs9939609 22 and where the higher BMI allele associated with shorter sleep duration). Analysis conditioned on the lead SNPs in each genomic region identified 4 secondary association signals at the VRK2 , DAT1 (SLC6A3) , DRD2 , and MAPT loci (Supplementary Table 2 ). Effect estimates were largely consistent in GWAS excluding shift workers and those with prevalent chronic and psychiatric disorders (excluding n = 119,894 participants) (Supplementary Data 1 , 2 , Supplementary Table 3 , Supplementary Figure 1 b , 2 ). GWAS results were similar for men and women ( r g (SE) = 0.989 (0.042); P < 0.001) (Supplementary Table<|im_end|> <|im_start|>assistant A study led by investigators from Massachusetts General Hospital (MGH) and the University of Exeter Medical School has identified 76 new gene regions associated with sleep duration. The study by a team that recently reported finding gene sites associated with insomnia risk and chronotype - the tendency to be an early riser or a 'night owl' - has been published in Nature Communications. "While we spend about a third of our life asleep, we have little knowledge of the specific genes and pathways that regulate the amount of sleep people get," says Hassan Saeed Dashti, Ph.D., RD, of the MGH Center for Genomic Medicine, co-lead author of the report. "Our study suggests that many of the genes important for sleep in animal models may also influence sleep in humans and opens the door to better understanding of the function and regulation of sleep." It is well understood that regularly getting adequate sleep—7 to 8 hours per night—is important to health, and both insufficient sleep—6 or fewer hours—and excessive sleep—9 hours or more—have been linked to significant health problems. Family studies have suggested that from 10 to 40 percent of variation in sleep duration may be inherited, and previous genetic studies have associated variants in two gene regions with sleep duration. The current study, the largest of its kind to address sleep duration, analyzed genetic data from more than 446,000 participants in the U.K. Biobank who self-reported the amount of sleep they typically received. That genome-wide association study (GWAS) identified 78 gene regions—including the two previously identified—as associated with sleep duration. While carrying a single gene variant influenced the average amount of sleep by only a minute, participants carrying the largest number of duration-increasing variants reported an average of 22 more minutes of sleep, compared with those with the fewest, which is comparable to other well-recognized factors that influence sleep duration. To confirm the accuracy of findings based on self-reported sleep duration, the researchers tested the 78 duration-associated variants in a subgroup of participants who had worn motion-detecting devices called accelerometers for up to a week. Not only were those gene regions supported by objective measurement of sleep duration, but this analysis was also able to associate duration-related variants with factors such as sleep efficiency, instances of waking up during the night and daytime inactivity. Only a few of the gene regions identified in this study overlap with those identified in the group's previous studies of insomnia and chronotype. The sites identified in this study showed consistent effects with a previous GWAS of more than 47,000 adults but limited consistency with another GWAS of sleep duration among more than 10,500 children and adolescents, which supports research suggesting that the genetics of sleep duration may be different in children than in adults. Since both shorter- and longer-than-average sleep duration have been associated with health problems, the team conducted separate GWASs for participants who reported short or long sleep duration. Those studies identified additional genes not identified in the larger group analysis that contributed to either longer or shorter sleep duration. The researchers also found shared genetic links between both short and long sleep duration and factors such as higher levels of body fat, depression symptoms and fewer years of schooling, implying negative effects from both too little and too much sleep. In addition, short sleep duration was genetically linked with traits such as insomnia and smoking, while long-duration variants were linked with schizophrenia, type 2 diabetes and coronary artery disease. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Synthesis and degradation of cellular constituents must be balanced to maintain cellular homeostasis, especially during adaptation to environmental stress. The role of autophagy in the degradation of proteins and organelles is well-characterized. However, autophagy-mediated RNA degradation in response to stress and the potential preference of specific RNAs to undergo autophagy-mediated degradation have not been examined. In this study, we demonstrate selective mRNA degradation by rapamycin-induced autophagy in yeast. Profiling of mRNAs from the vacuole reveals that subsets of mRNAs, such as those encoding amino acid biosynthesis and ribosomal proteins, are preferentially delivered to the vacuole by autophagy for degradation. We also reveal that autophagy-mediated mRNA degradation is tightly coupled with translation by ribosomes. Genome-wide ribosome profiling suggested a high correspondence between ribosome association and targeting to the vacuole. We propose that autophagy-mediated mRNA degradation is a unique and previously-unappreciated function of autophagy that affords post-transcriptional gene regulation. Introduction Autophagy is a highly conserved eukaryotic pathway that isolates cellular components for degradation and recycling in response to nutrient starvation, thereby maintaining homeostasis in nutrient-limited environments 1 , 2 . Upon autophagy induction, substrates are sequestered within a double-membrane vesicle called an autophagosome and subsequently delivered to the vacuole (yeast) or lysosome (mammals) where they are degraded by hydrolytic enzymes. Autophagy is originally thought to be nonselective (i.e., bulk), which isolates cytoplasmic material in an apparently random manner. In contrast, selective autophagy eliminates harmful proteins and superfluous, damaged organelles, such as endoplasmic reticula (ER) and mitochondria 3 . Substrates of selective autophagy, often marked for degradation by modifications such as ubiquitination, are recognized through their binding to receptors that facilitate localization to the site of autophagosome formation 4 , 5 , 6 . In addition to the clear distinction of substrate, autophagy may show the broad spectrum of protein substrate preference. Acetaldehyde dehydrogenase and tRNA ligases 7 , 8 are such examples. The mechanism underlying this preference has been still unknown. Despite the many studies of protein and organelle degradation by autophagy, RNA degradation by autophagy has not been well examined. Historically, RNA degradation by autophagy was suggested in pioneering works examining amino acid-starved rat livers by Lardeux and Mortimore 9 , 10 , 11 , 12 . More recently, our group showed that RNA delivered to vacuoles via autophagy is degraded by the T2-type RNase Rny1, and that the resulting nucleotides are further hydrolyzed to nucleosides by the vacuolar phosphatase/nucletidase Pho8 13 . The question of whether RNA degradation by autophagy occurs preferentially, however, remains unaddressed. In this study, we examine the degradation of mRNAs by rapamycin-induced autophagy in yeast. mRNA sequencing reveals that autophagy preferentially delivers a subset of mRNA species to the vacuole for Rny1-mediated degradation. We further find that the selectivity of autophagy-mediated mRNA degradation is coupled with translation by reporter gene analysis. Genome-wide ribosome profiling further demonstrates that persistent ribosomal interaction is associated with selective mRNA delivery to vacuoles. The autophagic delivery of ribosome-mRNA complexes to the vacuole depends on Atg24 sorting nexin complex, which is required for autophagic degradation of multisubunit complexes, such as the proteasome and ribosome. We provide a foundational description of autophagy-mediated RNA degradation in yeast, as well as molecular insights into the selectivity of this hitherto underappreciated pathway. Results Autophagy delivers mRNAs to the vacuole for degradation We began by identifying mRNAs species delivered to vacuoles by autophagy. As mRNA delivered to the vacuole is immediately degraded by the vacuolar ribonuclease Rny1 in wild-type (WT) cells 13 , we constructed a strain ( rny1 Δ) lacking this enzyme. To isolate vacuole-delivered mRNAs, we adopted a strategy employing a highly purified vacuolar fraction from cell lysates by flotation with ultracentrifugation (Fig. 1a ). The purity of the vacuolar fraction was confirmed by vacuole protein enrichment and the apparent absence of ER, Golgi, and nucleolar proteins (Supplementary Fig. 1a ). Fig. 1: Determination of the autophagy-dependent vacuolar transcriptome. a Schematic illustration of the experimental design. Following the induction of autophagy by 3 h rapamycin treatment, vacuoles from yeasts were purified by ultracentrifugal flotation. A strain deleted for the vacuolar nuclease Rny1, which degrades nucleic acids within the vacuole, was used. b Autophagy-dependent mRNA accumulation in the vacuole fraction. Agarose gel electrophoresis image of RNAs detected in the vacuole fraction of rapamycin-treated (3 h) cells. rRNA subtraction was performed by treating extracted RNA samples with oligonucleotides complementary to rRNAs. Representative results from three independent experiments are shown. Asterisk indicates a nonspecific band. c Meta-gene analysis for mRNA-Seq read distributions around the 5′ and 3′ ends of transcripts from whole-cell lysate (gray) or vacuole fraction (purple). The 5′ end of reads is depicted. The line and shaded area represent the median and interquartile range, respectively. d Change in mitochondrial genome-encoded mRNAs’ enrichment in vacuoles versus total cellular extracts following 3 h rapamycin treatment. Box plots show the accumulation of reads originating from nuclear and mitochondrial genomes, as determined by RNA-Seq. The median, interquartile range (IQR), and 1.5 IQR are represented by a solid line, box, and whiskers, respectively. Significance was determined by unpaired two-sided Mann-Whitney U-test. Full size image Using rapamycin to induce autophagy through TORC1 suppression 14 and the vacuole purification method described above, we examined the accumulation of RNA species in vacuoles. In addition to rRNAs, we also detected mRNAs that were clearly observed following rRNA subtraction (Fig. 1b ). Importantly, we determined that the presence of mRNAs in vacuoles depends on autophagy: mRNAs were hardly detected in atg2 Δ cells, which are completely defective for autophagy 15 . Next, we characterized the mRNAs in the vacuoles by RNA sequencing. The even distribution of vacuolar mRNA reads suggests that nontruncated, full length mRNAs are delivered to vacuoles in rny1 Δ cells (Fig. 1c ) and verifies that Rny1 is the sole vacuolar nuclease responsible for mRNA degradation 13 . In contrast to nuclear genome-encoded mRNAs, mitochondrial genome-encoded mRNAs were clearly excluded from the vacuole fraction (Fig. 1d ), suggesting only limited mitochondrial degradation under the employed conditions. Vacuolar delivery of mRNA has selectivity", "role": "user" }, { "content": "Optimal cell function requires a fine balance between the synthesis and degradation of biomolecules. Autophagy is the process by which cells degrade and recycle their own components, helping to clean up and maintain the cell's internal environment and ensure the smooth functioning of cellular processes. Autophagy is strongly induced when cells are subjected to stresses like nutrient deprivation, acting under such conditions to supply nutrients through its breakdown of unneeded cellular material. Autophagy substrates are delivered to vacuoles in yeast or lysosomes in mammals for degradation by double-membrane vesicles called \"autophagosomes.\" While autophagy was originally considered a non-selective process that isolates substrates in the cytoplasm of the cell in a random manner, studies have reported that certain cellular components, such as a subset of proteins and damaged or superfluous cell organelles, are isolated in a selective manner. In contrast to this well-established targeting of organelles and proteins by autophagy, the question of whether RNAs are subjected to autophagy and if they are selectively degraded has remained unanswered. In their latest study, which was published in Nature Communications, researchers from the Tokyo Tech and RIKEN conducted a detailed analysis of the preferential degradation by autophagy of messenger RNAs (mRNAs), which contain the information required to make cellular protein and bind ribosomes for protein synthesis. Corresponding author Prof. Yoshinori Ohsumi of the Tokyo Tech, who was awarded the 2016 Nobel Prize in Physiology or Medicine for his pioneering work in the field of autophagy, explained the group's findings, stating \"We have previously shown that RNA delivered to the vacuole via autophagy in yeast cells, where it is degraded by vacuolar nucleases. The question of whether RNA degradation by autophagy occurs preferentially, however, remains unaddressed. This difficult to address question was the starting point of this project.\" As RNAs that accumulate in the vacuole are enzymatically degraded by the nuclease Rny1, they first constructed a yeast strain lacking this enzyme. Using this strain, they were able to isolate and identify RNAs that accumulated in the vacuole. Next, they used the drug rapamycin, which is known to induce autophagy, to assess unique features of mRNA species delivered to the vacuole in Rny1-deficient cells when autophagy is induced. Critically, they discovered that autophagy-mediated mRNA delivery to vacuoles is selective, not random, in nature. The researchers then characterized the different mRNA species by conducting a broad analysis of the types of mRNAs in these cells, identifying 'vacuole-enriched' and 'vacuole-depleted' mRNAs. Interestingly, housekeeping mRNAs, such as those encoding proteins involved in amino acid biosynthesis, were most likely to be delivered to vacuoles. In contrast, mRNAs required for the synthesis of proteins with regulatory functions, such as protein kinases, were predominantly detected in the vacuole-depleted mRNA fraction. Furthermore, they demonstrated that mRNAs undergoing translation are delivered to the vacuole, which is suggested to be a translation-dependent process. Moreover, persistent ribosome-mRNA association upon rapamycin treatment was found to be a key determinant of vacuolar mRNA delivery during autophagy-mediated degradation. Dr. Makino and Prof. Ohsumi highlighted the importance of autophagy in gene regulation, remarking, \"Our findings suggest that autophagy regulates mRNA degradation at the translation step, thereby enabling a rapid and sensitive switch from ribosome-associated mRNAs to expression of mRNAs that are essential for an effective response to stress. Preferential degradation of ribosome-mRNAs by autophagy is therefore very likely to determine the fate of individual mRNAs as cells adapt to new conditions.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Synthesis and degradation of cellular constituents must be balanced to maintain cellular homeostasis, especially during adaptation to environmental stress. The role of autophagy in the degradation of proteins and organelles is well-characterized. However, autophagy-mediated RNA degradation in response to stress and the potential preference of specific RNAs to undergo autophagy-mediated degradation have not been examined. In this study, we demonstrate selective mRNA degradation by rapamycin-induced autophagy in yeast. Profiling of mRNAs from the vacuole reveals that subsets of mRNAs, such as those encoding amino acid biosynthesis and ribosomal proteins, are preferentially delivered to the vacuole by autophagy for degradation. We also reveal that autophagy-mediated mRNA degradation is tightly coupled with translation by ribosomes. Genome-wide ribosome profiling suggested a high correspondence between ribosome association and targeting to the vacuole. We propose that autophagy-mediated mRNA degradation is a unique and previously-unappreciated function of autophagy that affords post-transcriptional gene regulation. Introduction Autophagy is a highly conserved eukaryotic pathway that isolates cellular components for degradation and recycling in response to nutrient starvation, thereby maintaining homeostasis in nutrient-limited environments 1 , 2 . Upon autophagy induction, substrates are sequestered within a double-membrane vesicle called an autophagosome and subsequently delivered to the vacuole (yeast) or lysosome (mammals) where they are degraded by hydrolytic enzymes. Autophagy is originally thought to be nonselective (i.e., bulk), which isolates cytoplasmic material in an apparently random manner. In contrast, selective autophagy eliminates harmful proteins and superfluous, damaged organelles, such as endoplasmic reticula (ER) and mitochondria 3 . Substrates of selective autophagy, often marked for degradation by modifications such as ubiquitination, are recognized through their binding to receptors that facilitate localization to the site of autophagosome formation 4 , 5 , 6 . In addition to the clear distinction of substrate, autophagy may show the broad spectrum of protein substrate preference. Acetaldehyde dehydrogenase and tRNA ligases 7 , 8 are such examples. The mechanism underlying this preference has been still unknown. Despite the many studies of protein and organelle degradation by autophagy, RNA degradation by autophagy has not been well examined. Historically, RNA degradation by autophagy was suggested in pioneering works examining amino acid-starved rat livers by Lardeux and Mortimore 9 , 10 , 11 , 12 . More recently, our group showed that RNA delivered to vacuoles via autophagy is degraded by the T2-type RNase Rny1, and that the resulting nucleotides are further hydrolyzed to nucleosides by the vacuolar phosphatase/nucletidase Pho8 13 . The question of whether RNA degradation by autophagy occurs preferentially, however, remains unaddressed. In this study, we examine the degradation of mRNAs by rapamycin-induced autophagy in yeast. mRNA sequencing reveals that autophagy preferentially delivers a subset of mRNA species to the vacuole for Rny1-mediated degradation. We further find that the selectivity of autophagy-mediated mRNA degradation is coupled with translation by reporter gene analysis. Genome-wide ribosome profiling further demonstrates that persistent ribosomal interaction is associated with selective mRNA delivery to vacuoles. The autophagic delivery of ribosome-mRNA complexes to the vacuole depends on Atg24 sorting nexin complex, which is required for autophagic degradation of multisubunit complexes, such as the proteasome and ribosome. We provide a foundational description of autophagy-mediated RNA degradation in yeast, as well as molecular insights into the selectivity of this hitherto underappreciated pathway. Results Autophagy delivers mRNAs to the vacuole for degradation We began by identifying mRNAs species delivered to vacuoles by autophagy. As mRNA delivered to the vacuole is immediately degraded by the vacuolar ribonuclease Rny1 in wild-type (WT) cells 13 , we constructed a strain ( rny1 Δ) lacking this enzyme. To isolate vacuole-delivered mRNAs, we adopted a strategy employing a highly purified vacuolar fraction from cell lysates by flotation with ultracentrifugation (Fig. 1a ). The purity of the vacuolar fraction was confirmed by vacuole protein enrichment and the apparent absence of ER, Golgi, and nucleolar proteins (Supplementary Fig. 1a ). Fig. 1: Determination of the autophagy-dependent vacuolar transcriptome. a Schematic illustration of the experimental design. Following the induction of autophagy by 3 h rapamycin treatment, vacuoles from yeasts were purified by ultracentrifugal flotation. A strain deleted for the vacuolar nuclease Rny1, which degrades nucleic acids within the vacuole, was used. b Autophagy-dependent mRNA accumulation in the vacuole fraction. Agarose gel electrophoresis image of RNAs detected in the vacuole fraction of rapamycin-treated (3 h) cells. rRNA subtraction was performed by treating extracted RNA samples with oligonucleotides complementary to rRNAs. Representative results from three independent experiments are shown. Asterisk indicates a nonspecific band. c Meta-gene analysis for mRNA-Seq read distributions around the 5′ and 3′ ends of transcripts from whole-cell lysate (gray) or vacuole fraction (purple). The 5′ end of reads is depicted. The line and shaded area represent the median and interquartile range, respectively. d Change in mitochondrial genome-encoded mRNAs’ enrichment in vacuoles versus total cellular extracts following 3 h rapamycin treatment. Box plots show the accumulation of reads originating from nuclear and mitochondrial genomes, as determined by RNA-Seq. The median, interquartile range (IQR), and 1.5 IQR are represented by a solid line, box, and whiskers, respectively. Significance was determined by unpaired two-sided Mann-Whitney U-test. Full size image Using rapamycin to induce autophagy through TORC1 suppression 14 and the vacuole purification method described above, we examined the accumulation of RNA species in vacuoles. In addition to rRNAs, we also detected mRNAs that were clearly observed following rRNA subtraction (Fig. 1b ). Importantly, we determined that the presence of mRNAs in vacuoles depends on autophagy: mRNAs were hardly detected in atg2 Δ cells, which are completely defective for autophagy 15 . Next, we characterized the mRNAs in the vacuoles by RNA sequencing. The even distribution of vacuolar mRNA reads suggests that nontruncated, full length mRNAs are delivered to vacuoles in rny1 Δ cells (Fig. 1c ) and verifies that Rny1 is the sole vacuolar nuclease responsible for mRNA degradation 13 . In contrast to nuclear genome-encoded mRNAs, mitochondrial genome-encoded mRNAs were clearly excluded from the vacuole fraction (Fig. 1d ), suggesting only limited mitochondrial degradation under the employed conditions. Vacuolar delivery of mRNA has selectivity<|im_end|> <|im_start|>assistant Optimal cell function requires a fine balance between the synthesis and degradation of biomolecules. Autophagy is the process by which cells degrade and recycle their own components, helping to clean up and maintain the cell's internal environment and ensure the smooth functioning of cellular processes. Autophagy is strongly induced when cells are subjected to stresses like nutrient deprivation, acting under such conditions to supply nutrients through its breakdown of unneeded cellular material. Autophagy substrates are delivered to vacuoles in yeast or lysosomes in mammals for degradation by double-membrane vesicles called "autophagosomes." While autophagy was originally considered a non-selective process that isolates substrates in the cytoplasm of the cell in a random manner, studies have reported that certain cellular components, such as a subset of proteins and damaged or superfluous cell organelles, are isolated in a selective manner. In contrast to this well-established targeting of organelles and proteins by autophagy, the question of whether RNAs are subjected to autophagy and if they are selectively degraded has remained unanswered. In their latest study, which was published in Nature Communications, researchers from the Tokyo Tech and RIKEN conducted a detailed analysis of the preferential degradation by autophagy of messenger RNAs (mRNAs), which contain the information required to make cellular protein and bind ribosomes for protein synthesis. Corresponding author Prof. Yoshinori Ohsumi of the Tokyo Tech, who was awarded the 2016 Nobel Prize in Physiology or Medicine for his pioneering work in the field of autophagy, explained the group's findings, stating "We have previously shown that RNA delivered to the vacuole via autophagy in yeast cells, where it is degraded by vacuolar nucleases. The question of whether RNA degradation by autophagy occurs preferentially, however, remains unaddressed. This difficult to address question was the starting point of this project." As RNAs that accumulate in the vacuole are enzymatically degraded by the nuclease Rny1, they first constructed a yeast strain lacking this enzyme. Using this strain, they were able to isolate and identify RNAs that accumulated in the vacuole. Next, they used the drug rapamycin, which is known to induce autophagy, to assess unique features of mRNA species delivered to the vacuole in Rny1-deficient cells when autophagy is induced. Critically, they discovered that autophagy-mediated mRNA delivery to vacuoles is selective, not random, in nature. The researchers then characterized the different mRNA species by conducting a broad analysis of the types of mRNAs in these cells, identifying 'vacuole-enriched' and 'vacuole-depleted' mRNAs. Interestingly, housekeeping mRNAs, such as those encoding proteins involved in amino acid biosynthesis, were most likely to be delivered to vacuoles. In contrast, mRNAs required for the synthesis of proteins with regulatory functions, such as protein kinases, were predominantly detected in the vacuole-depleted mRNA fraction. Furthermore, they demonstrated that mRNAs undergoing translation are delivered to the vacuole, which is suggested to be a translation-dependent process. Moreover, persistent ribosome-mRNA association upon rapamycin treatment was found to be a key determinant of vacuolar mRNA delivery during autophagy-mediated degradation. Dr. Makino and Prof. Ohsumi highlighted the importance of autophagy in gene regulation, remarking, "Our findings suggest that autophagy regulates mRNA degradation at the translation step, thereby enabling a rapid and sensitive switch from ribosome-associated mRNAs to expression of mRNAs that are essential for an effective response to stress. Preferential degradation of ribosome-mRNAs by autophagy is therefore very likely to determine the fate of individual mRNAs as cells adapt to new conditions." <|im_end|>

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2,405

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The cannabinoid cannabidiol (CBD) is characterised in this study as a helper compound against resistant bacteria. CBD potentiates the effect of bacitracin (BAC) against Gram-positive bacteria ( Staphylococcus species, Listeria monocytogenes , and Enterococcus faecalis ) but appears ineffective against Gram-negative bacteria. CBD reduced the MIC value of BAC by at least 64-fold and the combination yielded an FIC index of 0.5 or below in most Gram-positive bacteria tested. Morphological changes in S. aureus as a result of the combination of CBD and BAC included several septa formations during cell division along with membrane irregularities. Analysis of the muropeptide composition of treated S. aureus indicated no changes in the cell wall composition. However, CBD and BAC treated bacteria did show a decreased rate of autolysis. The bacteria further showed a decreased membrane potential upon treatment with CBD; yet, they did not show any further decrease upon combination treatment. Noticeably, expression of a major cell division regulator gene, ezrA , was reduced two-fold upon combination treatment emphasising the impact of the combination on cell division. Based on these observations, the combination of CBD and BAC is suggested to be a putative novel treatment in clinical settings for treatment of infections with antibiotic resistant Gram-positive bacteria. Introduction Since the discovery of penicillin in 1928 by Sir Alexander Fleming, antibiotics have saved millions of lives from fatal infections world-wide. However, with time bacteria have developed mechanisms to escape the effects of antibiotics. The amount of antibiotics used seems to be directly related to development of antibiotic resistance. Similarly, a growing number of multi drug resistant (MDR) bacteria is a result of inadequate intentions to solve the resistance problem and increasing unmet demands for new antibacterial drugs 1 . With fewer antibiotics available to treat MDR bacterial infections, the possibility of entering a pre-antibiotic era is looming ahead. Alternative strategies are being explored and helper compounds, also known as antibiotic potentiators or resistant breakers, are attracting attention 2 . Helper compounds are non-antibiotic compounds functioning as adjuvants for antibiotics to operate in synergy through various mechanisms including efflux pump inhibition, inhibition of enzymes, and changes in membrane permeability, all of which may contribute to increasing the efficacy of a specific antibiotic 3 , 4 . Drugs found to contain helper compound properties are normally used for treatment of non-infectious diseases but may contain some degree of antibacterial activity itself 5 . Helper compounds are usually associated with side-of-action in the central and peripheral nervous system as local anaesthetics and in psychopharmaceutic practice, where they usually block membrane associated transporter activity 5 . Overuse of antibiotics is the main cause of antibiotic resistance. Therefore, by combining an antibiotic with a helper compound less antibiotic is needed in order to achieve bacterial growth inhibition or killing compared to using the antibiotic alone. This strategy may therefore decrease the likelihood of resistance development, and investigations to identify efficient helper compounds are thus important. Cannabinoids are categorised as either endogenous cannabinoids, which are cannabinoids produced by the human body, or exogenous cannabinoids, which are produced either by plants such as Cannabis sativa or synthetically. Cannabinoids act on the endocannabinoid system of the human body 6 consisting of two G-protein coupled receptors (GPCR). These are named cannabinoid type 1 and 2 (CB1 and CB2) receptors, and, depending on the specific cannabinoid, the binding results in either an agonistic or antagonistic downstream effect 7 . Besides endocannabinoids being ligands for the endocannabinoid receptors, exogenous cannabinoids are also ligands for the receptors. One of the best characterised exogenous ligands is tetrahydrocannabinol (THC). It is a partial agonist for both CB1 and CB2 receptor mediating effects such as analgesia, muscle relaxation, and antiemetic effects, but also results in negative effects such as anxiety, psychosis, and sedation. Another exogenous cannabinoid is cannabidiol (CBD), which has been observed to decrease the adverse negative effects of THC. CBD is an antagonist of both CB1 and CB2 receptor leading to anti-sedative, anti-psychotic, and anxiolytic effects 7 . However, these are not the only known effects of CBD, as it is able to cause a variety of different effects such as inhibition of cancer cell growth 8 , neuroprotection in both neuro-degenerative diseases such as Parkinson’s Disease 9 and post-ischemia 10 , and anti-inflammatory effects as in type-1 diabetes 11 . Not much is known regarding antimicrobial effects of cannabinoids and even less on the mechanism of action. Endocannabinoids and exogenous cannabinoids such as CBD have been observed to inhibit growth of bacteria 12 , 13 , 14 , yet the use of cannabidiol as an antibiotic adjuvant has not been studied so far. In the present study, we aim to characterise cannabidiol as a potential helper compound against resistant bacteria in combination with the cyclic peptide antibiotic bacitracin (BAC). BAC is a mixture of related cyclic peptides operating as a bactericidal antibiotic by interfering with the cell wall and interrupting the biosynthesis of the peptidoglycan leading to cell lysis 15 . Results The combination of CBD and BAC is effective against Gram-positive bacteria Initially, we validated the antimicrobial effect of cannabidiol (CBD) against the Gram-positive bacterium Methicillin-Resistant Staphylococcus aureus (MRSA) as previously published by Appendino and colleagues 14 but also for Enterococcus faecalis ( E. faecalis ) , Listeria monocytogenes ( L. monocytogenes ), and Methicillin-Resistant Staphylococcus epidermidis (MRSE). We found the Minimum Inhibitory Concentration (MIC) to be 4 µg/mL for S. aureus , L. monocytogenes , and the MRSE strain and 8 µg/mL for E. faecalis , indicating that Gram-positive bacteria are sensitive towards CBD (Table 1 ). Table 1 *FIC index indicates synergy when FIC index ≤ 0.5, indifference when 0.5 < FIC index < 4, and antagonism when FIC index > 4 37 . Full size table To determine whether CBD would induce a higher susceptibility of BAC in Gram-positive bacteria, MICs of BAC were determined for the four Gram-positive bacteria in the presence of CBD. Remarkably, the MIC of BAC was decreased by 8 to at least 64-fold when combined with", "role": "user" }, { "content": "Since the discovery of penicillin in 1928 by Sir Alexander Fleming, antibiotics have saved millions of lives from fatal infections world-wide. However, with time bacteria have developed mechanisms to escape the effects of antibiotics—they have become resistant. With fewer antibiotics available to treat resistant bacterial infections, the possibility of entering a pre-antibiotic era is looming ahead. Alternative strategies are being explored and helper compounds are attracting attention. Helper compounds are non-antibiotic compounds with the capability of enhancing the efficacy of antibiotics. How to boost antibiotics One such helper compound has been suspected to be cannabidiol (CBD); a cannabinoid from the cannabis plant. Now a research team from University of Southern Denmark, has published a scientific study proving the effect of CBD. Janne Kudsk Klitgaard is Principal Investigator and corresponding author. First author is Ph.D. student Claes Søndergaard Wassmann. The study is published in the journal Scientific Reports. When we combined CBD and antibiotics, we saw a more powerful effect than when treating with antibiotics alone. So, in order to kill a certain number of bacteria, we needed less antibiotics, they say. Bacteria clones spread globally In the study, CBD was used to enhance the effect of the antibiotic bacitracin against Staphylococcus aureus bacteria; a major human pathogen that frequently causes community- and hospital-acquired disease. Multidrug-resistant clones of this pathogen have spread globally. In some countries, treatment of bacterial infections with these resistant bacteria are difficult and the problem is projected to be an ever-larger problem in the future. According to the researchers, the combination of CBD and antibiotics may be a novel treatment of infections with antibiotic resistant bacteria. How do the bacteria die? Three things happened with the Staphylococcus aureus bacteria, when the researchers treated them with the combination in their study: The bacteria could no longer divide normally.The expression of certain key genes (cell division and autolysis genes) in the bacteria was lowered.The bacterial membrane became unstable. Anti-resistance must be stopped According to the researchers, overuse of antibiotics is the main cause of antibiotic resistance. If we combine an antibiotic with a helper compound, that enhances the effect of the antibiotic, we need less antibiotic to achieve the same effect. This may contribute to the development of fewer resistant bacteria, says Janne Kudsk Klitgaard. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The cannabinoid cannabidiol (CBD) is characterised in this study as a helper compound against resistant bacteria. CBD potentiates the effect of bacitracin (BAC) against Gram-positive bacteria ( Staphylococcus species, Listeria monocytogenes , and Enterococcus faecalis ) but appears ineffective against Gram-negative bacteria. CBD reduced the MIC value of BAC by at least 64-fold and the combination yielded an FIC index of 0.5 or below in most Gram-positive bacteria tested. Morphological changes in S. aureus as a result of the combination of CBD and BAC included several septa formations during cell division along with membrane irregularities. Analysis of the muropeptide composition of treated S. aureus indicated no changes in the cell wall composition. However, CBD and BAC treated bacteria did show a decreased rate of autolysis. The bacteria further showed a decreased membrane potential upon treatment with CBD; yet, they did not show any further decrease upon combination treatment. Noticeably, expression of a major cell division regulator gene, ezrA , was reduced two-fold upon combination treatment emphasising the impact of the combination on cell division. Based on these observations, the combination of CBD and BAC is suggested to be a putative novel treatment in clinical settings for treatment of infections with antibiotic resistant Gram-positive bacteria. Introduction Since the discovery of penicillin in 1928 by Sir Alexander Fleming, antibiotics have saved millions of lives from fatal infections world-wide. However, with time bacteria have developed mechanisms to escape the effects of antibiotics. The amount of antibiotics used seems to be directly related to development of antibiotic resistance. Similarly, a growing number of multi drug resistant (MDR) bacteria is a result of inadequate intentions to solve the resistance problem and increasing unmet demands for new antibacterial drugs 1 . With fewer antibiotics available to treat MDR bacterial infections, the possibility of entering a pre-antibiotic era is looming ahead. Alternative strategies are being explored and helper compounds, also known as antibiotic potentiators or resistant breakers, are attracting attention 2 . Helper compounds are non-antibiotic compounds functioning as adjuvants for antibiotics to operate in synergy through various mechanisms including efflux pump inhibition, inhibition of enzymes, and changes in membrane permeability, all of which may contribute to increasing the efficacy of a specific antibiotic 3 , 4 . Drugs found to contain helper compound properties are normally used for treatment of non-infectious diseases but may contain some degree of antibacterial activity itself 5 . Helper compounds are usually associated with side-of-action in the central and peripheral nervous system as local anaesthetics and in psychopharmaceutic practice, where they usually block membrane associated transporter activity 5 . Overuse of antibiotics is the main cause of antibiotic resistance. Therefore, by combining an antibiotic with a helper compound less antibiotic is needed in order to achieve bacterial growth inhibition or killing compared to using the antibiotic alone. This strategy may therefore decrease the likelihood of resistance development, and investigations to identify efficient helper compounds are thus important. Cannabinoids are categorised as either endogenous cannabinoids, which are cannabinoids produced by the human body, or exogenous cannabinoids, which are produced either by plants such as Cannabis sativa or synthetically. Cannabinoids act on the endocannabinoid system of the human body 6 consisting of two G-protein coupled receptors (GPCR). These are named cannabinoid type 1 and 2 (CB1 and CB2) receptors, and, depending on the specific cannabinoid, the binding results in either an agonistic or antagonistic downstream effect 7 . Besides endocannabinoids being ligands for the endocannabinoid receptors, exogenous cannabinoids are also ligands for the receptors. One of the best characterised exogenous ligands is tetrahydrocannabinol (THC). It is a partial agonist for both CB1 and CB2 receptor mediating effects such as analgesia, muscle relaxation, and antiemetic effects, but also results in negative effects such as anxiety, psychosis, and sedation. Another exogenous cannabinoid is cannabidiol (CBD), which has been observed to decrease the adverse negative effects of THC. CBD is an antagonist of both CB1 and CB2 receptor leading to anti-sedative, anti-psychotic, and anxiolytic effects 7 . However, these are not the only known effects of CBD, as it is able to cause a variety of different effects such as inhibition of cancer cell growth 8 , neuroprotection in both neuro-degenerative diseases such as Parkinson’s Disease 9 and post-ischemia 10 , and anti-inflammatory effects as in type-1 diabetes 11 . Not much is known regarding antimicrobial effects of cannabinoids and even less on the mechanism of action. Endocannabinoids and exogenous cannabinoids such as CBD have been observed to inhibit growth of bacteria 12 , 13 , 14 , yet the use of cannabidiol as an antibiotic adjuvant has not been studied so far. In the present study, we aim to characterise cannabidiol as a potential helper compound against resistant bacteria in combination with the cyclic peptide antibiotic bacitracin (BAC). BAC is a mixture of related cyclic peptides operating as a bactericidal antibiotic by interfering with the cell wall and interrupting the biosynthesis of the peptidoglycan leading to cell lysis 15 . Results The combination of CBD and BAC is effective against Gram-positive bacteria Initially, we validated the antimicrobial effect of cannabidiol (CBD) against the Gram-positive bacterium Methicillin-Resistant Staphylococcus aureus (MRSA) as previously published by Appendino and colleagues 14 but also for Enterococcus faecalis ( E. faecalis ) , Listeria monocytogenes ( L. monocytogenes ), and Methicillin-Resistant Staphylococcus epidermidis (MRSE). We found the Minimum Inhibitory Concentration (MIC) to be 4 µg/mL for S. aureus , L. monocytogenes , and the MRSE strain and 8 µg/mL for E. faecalis , indicating that Gram-positive bacteria are sensitive towards CBD (Table 1 ). Table 1 *FIC index indicates synergy when FIC index ≤ 0.5, indifference when 0.5 < FIC index < 4, and antagonism when FIC index > 4 37 . Full size table To determine whether CBD would induce a higher susceptibility of BAC in Gram-positive bacteria, MICs of BAC were determined for the four Gram-positive bacteria in the presence of CBD. Remarkably, the MIC of BAC was decreased by 8 to at least 64-fold when combined with<|im_end|> <|im_start|>assistant Since the discovery of penicillin in 1928 by Sir Alexander Fleming, antibiotics have saved millions of lives from fatal infections world-wide. However, with time bacteria have developed mechanisms to escape the effects of antibiotics—they have become resistant. With fewer antibiotics available to treat resistant bacterial infections, the possibility of entering a pre-antibiotic era is looming ahead. Alternative strategies are being explored and helper compounds are attracting attention. Helper compounds are non-antibiotic compounds with the capability of enhancing the efficacy of antibiotics. How to boost antibiotics One such helper compound has been suspected to be cannabidiol (CBD); a cannabinoid from the cannabis plant. Now a research team from University of Southern Denmark, has published a scientific study proving the effect of CBD. Janne Kudsk Klitgaard is Principal Investigator and corresponding author. First author is Ph.D. student Claes Søndergaard Wassmann. The study is published in the journal Scientific Reports. When we combined CBD and antibiotics, we saw a more powerful effect than when treating with antibiotics alone. So, in order to kill a certain number of bacteria, we needed less antibiotics, they say. Bacteria clones spread globally In the study, CBD was used to enhance the effect of the antibiotic bacitracin against Staphylococcus aureus bacteria; a major human pathogen that frequently causes community- and hospital-acquired disease. Multidrug-resistant clones of this pathogen have spread globally. In some countries, treatment of bacterial infections with these resistant bacteria are difficult and the problem is projected to be an ever-larger problem in the future. According to the researchers, the combination of CBD and antibiotics may be a novel treatment of infections with antibiotic resistant bacteria. How do the bacteria die? Three things happened with the Staphylococcus aureus bacteria, when the researchers treated them with the combination in their study: The bacteria could no longer divide normally.The expression of certain key genes (cell division and autolysis genes) in the bacteria was lowered.The bacterial membrane became unstable. Anti-resistance must be stopped According to the researchers, overuse of antibiotics is the main cause of antibiotic resistance. If we combine an antibiotic with a helper compound, that enhances the effect of the antibiotic, we need less antibiotic to achieve the same effect. This may contribute to the development of fewer resistant bacteria, says Janne Kudsk Klitgaard. <|im_end|>

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315, 17162, 31785, 24032, 11, 2795, 4448, 818, 735, 664, 4991, 29041, 275, 95589, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In order to control and eradicate epidemic cholera, we need to understand how epidemics begin, how they spread, and how they decline and eventually end. This requires extensive sampling of epidemic disease over time, alongside the background of endemic disease that may exist concurrently with the epidemic. The unique circumstances surrounding the Argentinian cholera epidemic of 1992–1998 presented an opportunity to do this. Here, we use 490 Argentinian V. cholerae genome sequences to characterise the variation within, and between, epidemic and endemic V. cholerae . We show that, during the 1992–1998 cholera epidemic, the invariant epidemic clone co-existed alongside highly diverse members of the Vibrio cholerae species in Argentina, and we contrast the clonality of epidemic V. cholerae with the background diversity of local endemic bacteria. Our findings refine and add nuance to our genomic definitions of epidemic and endemic cholera, and are of direct relevance to controlling current and future cholera epidemics. Introduction Latin America stands apart from the rest of the world in terms of its history of large-scale cholera epidemics 1 , 2 , 3 . There have been seven global cholera pandemics in recorded history, between 1819 and the present day 4 . Of these, the second pandemic (1829–1850) was the first to be seen in Latin America 5 , 6 . Between the 1830s and 1895, the region suffered from repeated cholera outbreaks, linked to global pandemics 2 through 5 (refs. 4 , 6 ). Importantly, although the sixth pandemic (1899–1923) 4 affected most of Africa and Asia, Latin America did not experience cholera epidemics during this period, and thus was free of epidemic cholera for 96 years 6 . In 1991, during the seventh pandemic (1961–present), cholera returned to Latin America. Phylogeographic data have shown that this was attributable to the simultaneous introduction of two distinct sub-lineages of a globally-circulating phylogenetic lineage of Vibrio cholerae serogroup O1 biotype El Tor, dubbed 7PET 7 , 8 , 9 . An antimicrobial-sensitive sub-lineage of 7PET (LAT-1) was introduced into Peru in January 1991 and spread rapidly across South America 7 , 10 , 11 . Concurrently, a separate and distinct drug-resistant 7PET sub-lineage (LAT-2) was introduced into Mexico 1 , 7 . The Haitian cholera epidemic in 2010 was also caused by 7PET, albeit by a third, independently-introduced sub-lineage, LAT-3 (refs. 7 , 8 , 12 ). Since Latin America had been free of cholera epidemics for 96 years, and because the major epidemics seen in the 1990s and in 2010 are attributed to the introduction of epidemic 7PET sub-lineages originating in South Asia 7 , Latin America presented a unique opportunity to understand the longitudinal evolution of pandemic V. cholerae upon its introduction into a naïve population. Argentina is an ideal setting in which to study the evolution of the pandemic clone during the 1990s because, unlike some other countries in the region, the socioeconomic position of Argentina 10 , 13 , and its preparedness for epidemics by the time cholera reached the country, are thought to have enabled the monitoring and control of the epidemic. Argentina instituted the mandatory notification of cholera cases nationwide during 1991 after cholera broke out in Peru 14 , and developed public information campaigns which resulted in a concomitant increase in the rate of diarrhoeal disease reporting 15 . This included changes to the Argentinian national diarrhoeal surveillance system, and the creation of the National Diarrhoea Network (formerly the National Cholera Network) which comprises 75 member laboratories as of 2014 (ref. 16 ). In addition, cumulative numbers of cholera cases and deaths in Argentina were reported to the World Health Organization (WHO) and the Pan American Health Organization (PAHO) ( , 17 , 18 , 19 , 20 , 21 , Fig. 1a ). Fig. 1: Geographic and temporal origin of Vibrio cholerae stored at INEI. Cholera cases were reported to WHO and PAHO throughout the epidemic period. a V. cholerae O1 and non-O1 were received by INEI from the North of Argentina. b The diameter of each circle scales with the number of isolates recorded to have originated from the indicated region. Circles are coloured by the year of receipt. Locations were inferred from the city (where recorded) or from the province which sent the isolate to INEI. These isolates were received between 1992 and 2002. c The V. cholerae O1 received were principally clinical isolates, whereas non-O1 V. cholerae were both clinical and environmental isolates. In our study, we sought to capture the genetic changes that occurred in V. cholerae O1 at the beginning and the end of the cholera epidemic ( d ), and included contemporaneous non-O1 isolates. Geographic data were unavailable for six O1 and 14 non-O1 V. cholerae ( b ); dates of isolation were not recorded for five V. cholerae ( c ). Four sequenced isolates had no date of isolation ( d ). It should be noted that the peaks in V. cholerae receipt in 1997–1998 predate Hurricane Mitch (October 1998), a natural disaster which led to the increase of cholera incidence in Central America 94 . Seven isolates from 2003 onwards that were sequenced as part of this study post-date the epidemic, and were not included in the metadata used to produce ( c ). Y-axes in ( c ) and ( d ): number of isolates received/sequenced. Publicly-available data were taken from 17 , 18 , 19 , 20 , 21 , , and , to produce ( a ). Full size image Following the beginning of the epidemic in Peru in January 1991, cholera spread to Argentina, with the first cholera cases reported in Salta province 18 , 22 , near to the border with Bolivia, on the 5th of February 1992 (refs. 11 , 18 ). Subsequently, Argentina reported cholera cases annually between 1992 and 1998 (refs. 14 , 23 , 24 , 25 ), with a total of 4,281 cases reported to WHO for this period 17 , 18 , 19 , 20 , 21 .", "role": "user" }, { "content": "The evolution of epidemic and endemic strains of the cholera-causing bacterium Vibrio cholerae in Argentina has been mapped in detail by researchers at the Wellcome Sanger Institute, the London School of Hygiene and Tropical Medicine, the University of Cambridge and the INEI-ANLIS 'Dr. Carlos G. Malbrán,' Argentina. The teams used whole genome sequencing to study the bacteria circulating during the 1991-1998 outbreak of cholera in the country. The data have influenced health policy in Argentina, where the national alert surveillance system now uses whole-genome sequencing to distinguish between pandemic and non-pandemic lineages of V. cholerae bacteria. The study is published in Nature Communications today. Cholera, caused by strains of V. cholerae bacteria, currently affects 47 countries world-wide and claims the lives of nearly 100,000 people a year. Since the 1800s, there have been seven cholera pandemics around the globe, causing millions of deaths. The current pandemic, which began in the 1960s, is caused by a single lineage of V. cholerae, called 7PET. While South and Central Latin America have largely recovered from the outbreaks that began in Haiti in 2010, the lineage continues to circulate the globe and is the cause of the world's largest cholera epidemic, ongoing in Yemen, where hundreds of thousands have been infected. In a new study, the team sequenced the genomes of a unique set of historical V. cholerae samples, held at INEI-ANLIS \"Dr. Carlos G. Malbrán\", the national reference laboratory of Argentina. By re-analyzing the past, the international team of researchers hope to understand better the future patterns of disease, and to enable rapid alerts for new introductions of pandemic lineages. Using phylogenetic analysis, they confirmed that the 1992 outbreak of cholera in Argentina was caused by one introduction of 7PET V. cholerae bacteria, originally introduced into Peru. The bacteria then evolved very little during the six years of the epidemic. This was in contrast to the diverse, multiple endemic strains of V. cholerae circulating at the same time. Previous work by the team has shown that while endemic strains can make people ill, they seem to lack the potential to spread quickly and cause an epidemic. Matthew Dorman, first author on the study from the Wellcome Sanger Institute said: \"When a 7PET pandemic strain enters into Latin America from elsewhere, it can cause massive epidemics, such as those seen in Peru in the 1990s and Haiti in 2010. If we are to control cholera epidemics efficiently, it is vital that we are able to distinguish and understand the differences between the local, endemic V. cholerae that co-exist alongside 7PET during a cholera epidemic. Our study elaborated the genomic evolutionary history of these two types together in a single country, during a decade where there were major cholera outbreaks in this region.\" The findings have been used by public health authorities in Argentina, where the national alert system has now been changed to distinguish between pandemic 7PET lineage and local V. cholerae lineages using whole-genome sequencing. Dr. Josefina Campos, senior author from INEI-ANLIS \"Dr. Carlos G. Malbrán\", Buenos Aires, Argentina said: \"Thanks to a comprehensive surveillance and reporting system, the reference laboratory in Argentina contains a snapshot of an entire epidemic. This gave us a unique opportunity to understand the detailed evolution of V. cholerae bacteria in our country. We will be able to use these data and this experience to inform how we monitor and respond to any future cholera outbreaks—bacteria that cause epidemics pose a very different risk to those that do not; this is simple information that is critical for disease control. We are the first national reporting system in the world to use genomic data to monitor cholera like this.\" Professor Nick Thomson, senior author from the Wellcome Sanger Institute and the London School of Hygiene and Tropical Medicine said: \"Detailed studies like this contribute to our growing understanding of how cholera is moving across the globe: evidence to inform improved control strategies as well as identify areas for further research. Our challenge is to better understand why such a simple bacterium continues to pose such a threat to human health, with this study we are a little step closer.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In order to control and eradicate epidemic cholera, we need to understand how epidemics begin, how they spread, and how they decline and eventually end. This requires extensive sampling of epidemic disease over time, alongside the background of endemic disease that may exist concurrently with the epidemic. The unique circumstances surrounding the Argentinian cholera epidemic of 1992–1998 presented an opportunity to do this. Here, we use 490 Argentinian V. cholerae genome sequences to characterise the variation within, and between, epidemic and endemic V. cholerae . We show that, during the 1992–1998 cholera epidemic, the invariant epidemic clone co-existed alongside highly diverse members of the Vibrio cholerae species in Argentina, and we contrast the clonality of epidemic V. cholerae with the background diversity of local endemic bacteria. Our findings refine and add nuance to our genomic definitions of epidemic and endemic cholera, and are of direct relevance to controlling current and future cholera epidemics. Introduction Latin America stands apart from the rest of the world in terms of its history of large-scale cholera epidemics 1 , 2 , 3 . There have been seven global cholera pandemics in recorded history, between 1819 and the present day 4 . Of these, the second pandemic (1829–1850) was the first to be seen in Latin America 5 , 6 . Between the 1830s and 1895, the region suffered from repeated cholera outbreaks, linked to global pandemics 2 through 5 (refs. 4 , 6 ). Importantly, although the sixth pandemic (1899–1923) 4 affected most of Africa and Asia, Latin America did not experience cholera epidemics during this period, and thus was free of epidemic cholera for 96 years 6 . In 1991, during the seventh pandemic (1961–present), cholera returned to Latin America. Phylogeographic data have shown that this was attributable to the simultaneous introduction of two distinct sub-lineages of a globally-circulating phylogenetic lineage of Vibrio cholerae serogroup O1 biotype El Tor, dubbed 7PET 7 , 8 , 9 . An antimicrobial-sensitive sub-lineage of 7PET (LAT-1) was introduced into Peru in January 1991 and spread rapidly across South America 7 , 10 , 11 . Concurrently, a separate and distinct drug-resistant 7PET sub-lineage (LAT-2) was introduced into Mexico 1 , 7 . The Haitian cholera epidemic in 2010 was also caused by 7PET, albeit by a third, independently-introduced sub-lineage, LAT-3 (refs. 7 , 8 , 12 ). Since Latin America had been free of cholera epidemics for 96 years, and because the major epidemics seen in the 1990s and in 2010 are attributed to the introduction of epidemic 7PET sub-lineages originating in South Asia 7 , Latin America presented a unique opportunity to understand the longitudinal evolution of pandemic V. cholerae upon its introduction into a naïve population. Argentina is an ideal setting in which to study the evolution of the pandemic clone during the 1990s because, unlike some other countries in the region, the socioeconomic position of Argentina 10 , 13 , and its preparedness for epidemics by the time cholera reached the country, are thought to have enabled the monitoring and control of the epidemic. Argentina instituted the mandatory notification of cholera cases nationwide during 1991 after cholera broke out in Peru 14 , and developed public information campaigns which resulted in a concomitant increase in the rate of diarrhoeal disease reporting 15 . This included changes to the Argentinian national diarrhoeal surveillance system, and the creation of the National Diarrhoea Network (formerly the National Cholera Network) which comprises 75 member laboratories as of 2014 (ref. 16 ). In addition, cumulative numbers of cholera cases and deaths in Argentina were reported to the World Health Organization (WHO) and the Pan American Health Organization (PAHO) ( , 17 , 18 , 19 , 20 , 21 , Fig. 1a ). Fig. 1: Geographic and temporal origin of Vibrio cholerae stored at INEI. Cholera cases were reported to WHO and PAHO throughout the epidemic period. a V. cholerae O1 and non-O1 were received by INEI from the North of Argentina. b The diameter of each circle scales with the number of isolates recorded to have originated from the indicated region. Circles are coloured by the year of receipt. Locations were inferred from the city (where recorded) or from the province which sent the isolate to INEI. These isolates were received between 1992 and 2002. c The V. cholerae O1 received were principally clinical isolates, whereas non-O1 V. cholerae were both clinical and environmental isolates. In our study, we sought to capture the genetic changes that occurred in V. cholerae O1 at the beginning and the end of the cholera epidemic ( d ), and included contemporaneous non-O1 isolates. Geographic data were unavailable for six O1 and 14 non-O1 V. cholerae ( b ); dates of isolation were not recorded for five V. cholerae ( c ). Four sequenced isolates had no date of isolation ( d ). It should be noted that the peaks in V. cholerae receipt in 1997–1998 predate Hurricane Mitch (October 1998), a natural disaster which led to the increase of cholera incidence in Central America 94 . Seven isolates from 2003 onwards that were sequenced as part of this study post-date the epidemic, and were not included in the metadata used to produce ( c ). Y-axes in ( c ) and ( d ): number of isolates received/sequenced. Publicly-available data were taken from 17 , 18 , 19 , 20 , 21 , , and , to produce ( a ). Full size image Following the beginning of the epidemic in Peru in January 1991, cholera spread to Argentina, with the first cholera cases reported in Salta province 18 , 22 , near to the border with Bolivia, on the 5th of February 1992 (refs. 11 , 18 ). Subsequently, Argentina reported cholera cases annually between 1992 and 1998 (refs. 14 , 23 , 24 , 25 ), with a total of 4,281 cases reported to WHO for this period 17 , 18 , 19 , 20 , 21 .<|im_end|> <|im_start|>assistant The evolution of epidemic and endemic strains of the cholera-causing bacterium Vibrio cholerae in Argentina has been mapped in detail by researchers at the Wellcome Sanger Institute, the London School of Hygiene and Tropical Medicine, the University of Cambridge and the INEI-ANLIS 'Dr. Carlos G. Malbrán,' Argentina. The teams used whole genome sequencing to study the bacteria circulating during the 1991-1998 outbreak of cholera in the country. The data have influenced health policy in Argentina, where the national alert surveillance system now uses whole-genome sequencing to distinguish between pandemic and non-pandemic lineages of V. cholerae bacteria. The study is published in Nature Communications today. Cholera, caused by strains of V. cholerae bacteria, currently affects 47 countries world-wide and claims the lives of nearly 100,000 people a year. Since the 1800s, there have been seven cholera pandemics around the globe, causing millions of deaths. The current pandemic, which began in the 1960s, is caused by a single lineage of V. cholerae, called 7PET. While South and Central Latin America have largely recovered from the outbreaks that began in Haiti in 2010, the lineage continues to circulate the globe and is the cause of the world's largest cholera epidemic, ongoing in Yemen, where hundreds of thousands have been infected. In a new study, the team sequenced the genomes of a unique set of historical V. cholerae samples, held at INEI-ANLIS "Dr. Carlos G. Malbrán", the national reference laboratory of Argentina. By re-analyzing the past, the international team of researchers hope to understand better the future patterns of disease, and to enable rapid alerts for new introductions of pandemic lineages. Using phylogenetic analysis, they confirmed that the 1992 outbreak of cholera in Argentina was caused by one introduction of 7PET V. cholerae bacteria, originally introduced into Peru. The bacteria then evolved very little during the six years of the epidemic. This was in contrast to the diverse, multiple endemic strains of V. cholerae circulating at the same time. Previous work by the team has shown that while endemic strains can make people ill, they seem to lack the potential to spread quickly and cause an epidemic. Matthew Dorman, first author on the study from the Wellcome Sanger Institute said: "When a 7PET pandemic strain enters into Latin America from elsewhere, it can cause massive epidemics, such as those seen in Peru in the 1990s and Haiti in 2010. If we are to control cholera epidemics efficiently, it is vital that we are able to distinguish and understand the differences between the local, endemic V. cholerae that co-exist alongside 7PET during a cholera epidemic. Our study elaborated the genomic evolutionary history of these two types together in a single country, during a decade where there were major cholera outbreaks in this region." The findings have been used by public health authorities in Argentina, where the national alert system has now been changed to distinguish between pandemic 7PET lineage and local V. cholerae lineages using whole-genome sequencing. Dr. Josefina Campos, senior author from INEI-ANLIS "Dr. Carlos G. Malbrán", Buenos Aires, Argentina said: "Thanks to a comprehensive surveillance and reporting system, the reference laboratory in Argentina contains a snapshot of an entire epidemic. This gave us a unique opportunity to understand the detailed evolution of V. cholerae bacteria in our country. We will be able to use these data and this experience to inform how we monitor and respond to any future cholera outbreaks—bacteria that cause epidemics pose a very different risk to those that do not; this is simple information that is critical for disease control. We are the first national reporting system in the world to use genomic data to monitor cholera like this." Professor Nick Thomson, senior author from the Wellcome Sanger Institute and the London School of Hygiene and Tropical Medicine said: "Detailed studies like this contribute to our growing understanding of how cholera is moving across the globe: evidence to inform improved control strategies as well as identify areas for further research. Our challenge is to better understand why such a simple bacterium continues to pose such a threat to human health, with this study we are a little step closer." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract We present an additive approach for the inverse design of kirigami-based mechanical metamaterials by focusing on the empty (negative) spaces instead of the solid tiles. By considering each negative space as a four-bar linkage, we identify a simple recursive relationship between adjacent linkages, yielding an efficient method for creating kirigami patterns. This allows us to solve the kirigami design problem using elementary linear algebra, with compatibility, reconfigurability and rigid-deployability encoded into an iterative procedure involving simple matrix multiplications. The resulting linear design strategy circumvents the solution of a non-convex global optimization problem and allows us to control the degrees of freedom in the deployment angle field, linkage offsets and boundary conditions. We demonstrate this by creating a large variety of rigid-deployable, compact, reconfigurable kirigami patterns. We then realize our kirigami designs physically using two simple but effective fabrication strategies with very different materials. Altogether, our additive approaches present routes for efficient mechanical metamaterial design and fabrication based on ori/kirigami art forms. Main Kirigami and origami are ancient art forms that have been rejuvenated as paradigms of a class of structural mechanical metamaterials derived from thin sheets. Kirigami works with cuts to create a globally coordinated, articulated, deployable structure that can lead to spectacular patterns in two and three dimensions, while origami works with creases to create a similar effect, although almost always in three dimensions. Both kirigami and origami can lead to complex structures that have been studied extensively in art, mathematics, science and engineering 1 , 2 . However, the research literature on these subjects has had only a few points of convergence. Indeed, both artistic and technical books on origami 3 , 4 , 5 scarcely, if ever, mention, kirigami, and vice versa 6 . From a mathematical perspective, although there are deep similarities between kirigami and origami, there are some subtle differences that require qualitatively different approaches to understand the implications of the local constraints on the global properties that result. In particular, both origami and kirigami exploit coordinated rotations of individual facets to achieve collective geometric changes of the connected structures; that is, they use piecewise deformations (with strong discontinuities along cuts/creases) to affect complex shape-shifting abilities. However, the nature of the discontinuity differs between origami and kirigami. In origami, creases are locations identified with a discontinuous geometry (slope jump), whereas in kirigami, cuts are identified with a topological discontinuity (position jump). Numerous studies have explored different kirigami-based deployable structures, with a focus that is primarily on the forward problem, that of predicting the geometric and mechanical response of given designs 7 , 8 , 9 , 10 , 11 , 12 , 13 . The solution of the inverse problem typically involves setting up a global constrained optimization problem that encodes the geometric constraints in terms of the angles and lengths of the constituent tiles 14 , 15 , 16 , 17 , 18 . Although such an approach is capable of producing patterns and mechanisms with different shape changes, the process of finding a solution to the nonlinear global constrained optimization problem for large patterns is both computationally difficult and hard to control. Inspired by biological morphogenesis driven by growing matter 19 , and its synthetic analog, additive manufacturing 20 , one is naturally led to the question of whether it is possible to simplify the design of origami/kirigami metamaterials by switching from a global optimization perspective to some locally constrained additive process. In recent work, we showed that the use of local marching rules allows for an additive origami design approach 21 , converting a difficult non-convex global optimization problem 22 into a simpler, but still nonlinear, local problem. In this Article we show that kirigami also lends itself to a simple additive approach that identifies and exploits a linear marching construction to connect local growth rules to a global form. The subtle differences in the nature of the geometric and topological constraints between origami and kirigami imply that there are qualitative differences in these marching algorithms that lead to a much simpler algorithm for kirigami, despite it being a far richer paradigm for structural material design. Furthermore, we show that we can control the flexibility of encoding contractibility, compact reconfigurability and rigid-deployability for the design of quad kirigami in any contracted or deployed space using a simple design matrix characterized by a combination of certain edge-length and angle parameters. This substantially simplifies the process of designing kirigami patterns as matrix multiplications. Our approach of decoupling the length field, angle field and the boundary node constraints allows us to systematically analyze the degrees of freedom in the design space of different types of quad kirigami tessellations. Finally, to realize these designs in practice, we describe two manufacturing approaches using additive manufacturing and casting/molding for robust kirigami structures with soft, fabric hinges. Results Additive design framework We tackle the kirigami design problem by working our way up a ladder of hierarchical complexity, beginning with the smallest building block, a single four-bar linkage representing the negative space of a unit cell of four quads, before moving on to strips of linkages and finally linkage arrays. At each level, our strategy will be to describe a geometric marching construction, the forward process, which can be cast as matrix multiplication, allowing us then to convert the marching algorithm into a flexible and intuitive design framework using linear inverse design techniques. In Fig. 1 we present an overview of the marching construction for quad kirigami design. The key idea is to identify the constraints in the negative spaces in a deployed configuration, and use them to form a design matrix that is nonlinearly dependent on the deployment angles and edge lengths. However, once the matrix is determined, the coordinates of all nodes can be obtained by a simple matrix multiplication step, yielding a linear design method for quad kirigami. Fig. 1: Marching construction for quad kirigami design. a , Geometric design of a four-bar linkage representing a negative space in an ( m + 1) × (", "role": "user" }, { "content": "Kirigami takes pop-up books to a whole new level. The Japanese paper craft involves cutting patterns in paper to transform a two-dimensional sheet into an intricate, three-dimensional structure when partially folded. In the hands of an artist, kirigami can yield remarkably detailed and delicate replicas of structures in nature, architecture, and more. Scientists and engineers have also taken inspiration from kirigami, applying principles from paper-cutting to design robotic grippers, stretchable electronics, water-harvesting sheets, and other shape-shifting materials and devices. For the most part, such inventions are products of from-scratch design. There's been no blueprint for engineers to determine the pattern of cuts that will transform a material from one desired shape to another—that is, until now. A new study in Nature Computational Science presents a general computational strategy that can solve any two-dimensional, kirigami-inspired transformation. The method can be used to determine the angle and length of cuts to make, such that a sheet can transform from one desired shape to another when pulled open and pushed back together, like an intricate, expandable lattice. With their new method, researchers designed and fabricated a number of transformable, 2D kirigami structures, including a circle that turns into a square, and a triangle that morphs into a heart. \"People have talked of the square and circle as one of the impossible problems in mathematics: You cannot turn one into the other,\" says Gary Choi, a postdoctoral instructor in applied mathematics at MIT. \"But with kirigami, we can actually turn a square shape into a circle shape.\" For engineers, the new method could be used to solve various design problems, such as how a robot can be engineered to transform from one shape to another to carry out a particular task or navigate certain spaces. There's also potential to design active materials, for instance as smart coverings for buildings and homes. \"One of the first applications we thought of was building façades,\" says Kaitlyn Becker, an assistant professor of mechanical engineering at MIT. \"This could help us to make large, kirigami-like façades that can transform their shape to control sunlight, ultraviolet radiation, and be adaptive to their environment.\" Becker and Choi are co-authors of the new study, along with Levi Dudte, a quantitative researcher at Optiver, and L. Mahadevan, a professor at Harvard University. Credit: Kaitlyn Becker/Gary Choi The space between The study grew out of the team's previous work in both kirigami and origami—the Japanese art of paper folding. \"We found there are a lot of mathematical connections in kirigami and origami,\" Choi says. \"So we wanted to come up with a mathematical formulation that can help people design a large variety of patterns.\" In 2019, the team devised an optimization approach for kirigami to find the pattern of cuts that would be required to turn one shape into another. But Choi says the approach was too computationally intensive, and it took a large amount of time to derive an optimal pattern to achieve a particular transformation. In 2021, the researchers took on a similar problem in origami and found that through a slightly different perspective, they were able to derive a more efficient strategy. Rather than planning out a pattern of individual folds (similar to kirigami's individual cuts), the team focused on growing a pattern from a simple folded seed. By working panel by panel, and establishing relationships between panels, such as how one panel would move if an adjacent panel were folded, they were able to derive a relatively efficient algorithm for planning out the design of any origami structure. The team wondered if a similar approach be applied to kirigami. In traditional kirigami, once cuts have been made in a sheet of paper, the sheet can be partially folded such that the resulting empty spaces create a three-dimensional structure. Like the panels between origami folds, could the empty spaces between cuts, and their relation to each other, yield a more efficient formula for kirigami design? This question motivated the team's new study. Math links The study focuses on two-dimensional kirigami transformations. The researchers considered a general kirigami design comprising a mosaic of interconnected quadrilateral tiles, each cut to various angles and sizes. The conceptual mosaic begins as one shape and can be pulled apart and pushed back together to form an entirely new shape. The challenge was to describe how one shape can transform into another, based on the empty spaces between tiles and how the spaces change as the tiles are pulled apart and pushed back together. \"If the tiles themselves are solid and unchangeable, then it's the empty spaces between that are an opportunity for motion,\" Becker says. The team first considered the simplest representation of empty space, in the form of a rhombus, or what they term a \"four-bar linkage.\" Each side of the rhombus represents a bar, or the edge of a solid tile. Each corner of the rhombus represents a linkage, or hinge that connects tiles. By changing the length and angle of the rhombus' edges, the team could study how the empty space in between changes. By studying progressively larger assemblages of four-bar linkages, the team identified relationships between the angle and length of bars, the shape of individual empty spaces, and the shape of the overall assemblage. They worked these relationships into a general formula, and found that it could efficiently identify the pattern of cuts—including their angle and length—that would be required to transform a two-dimensional sheet from one desired shape to another. \"Without a tool like this, I might brute force this problem in Matlab, or guess and check, but it would take me a very long time to get something that can transform from a circle to a square,\" Becker says. In simulations, the team found that the formula could indeed find a pattern of tiles that would turn a circle-shaped mosaic into a square, as well as virtually any shape into any other desired shape. Going a step further, the team developed two fabrication methods to physically realize the formula's designs. They quickly realized that a key challenge in making the transformable mosaics was in finding the right material to serve as the tile-connecting hinges. The connections needed to be strong, yet easily bendable. \"I thought, what is very strong in tension, and tear-resistant, but can have a zero bending radius, almost like a pinpoint hinge?\" Becker says. \"And the answer, it turns out, is fabric.\" The team used two methods—3D printing, and mold casting—to embed small strips of fabric into quadrilateral plastic tiles, in a way that closely connected the tiles while allowing them to bend against each other. Using these two methods, the team fabricated circle-shaped mosaics that transformed into squares, as well as simple triangle mosaics that morphed into more complex heart shapes. \"We can basically go to any two-dimensional shape,\" Choi says. \"That's guaranteed, using our mathematical formulation. Now we're looking to extend this to 3D kirigami.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract We present an additive approach for the inverse design of kirigami-based mechanical metamaterials by focusing on the empty (negative) spaces instead of the solid tiles. By considering each negative space as a four-bar linkage, we identify a simple recursive relationship between adjacent linkages, yielding an efficient method for creating kirigami patterns. This allows us to solve the kirigami design problem using elementary linear algebra, with compatibility, reconfigurability and rigid-deployability encoded into an iterative procedure involving simple matrix multiplications. The resulting linear design strategy circumvents the solution of a non-convex global optimization problem and allows us to control the degrees of freedom in the deployment angle field, linkage offsets and boundary conditions. We demonstrate this by creating a large variety of rigid-deployable, compact, reconfigurable kirigami patterns. We then realize our kirigami designs physically using two simple but effective fabrication strategies with very different materials. Altogether, our additive approaches present routes for efficient mechanical metamaterial design and fabrication based on ori/kirigami art forms. Main Kirigami and origami are ancient art forms that have been rejuvenated as paradigms of a class of structural mechanical metamaterials derived from thin sheets. Kirigami works with cuts to create a globally coordinated, articulated, deployable structure that can lead to spectacular patterns in two and three dimensions, while origami works with creases to create a similar effect, although almost always in three dimensions. Both kirigami and origami can lead to complex structures that have been studied extensively in art, mathematics, science and engineering 1 , 2 . However, the research literature on these subjects has had only a few points of convergence. Indeed, both artistic and technical books on origami 3 , 4 , 5 scarcely, if ever, mention, kirigami, and vice versa 6 . From a mathematical perspective, although there are deep similarities between kirigami and origami, there are some subtle differences that require qualitatively different approaches to understand the implications of the local constraints on the global properties that result. In particular, both origami and kirigami exploit coordinated rotations of individual facets to achieve collective geometric changes of the connected structures; that is, they use piecewise deformations (with strong discontinuities along cuts/creases) to affect complex shape-shifting abilities. However, the nature of the discontinuity differs between origami and kirigami. In origami, creases are locations identified with a discontinuous geometry (slope jump), whereas in kirigami, cuts are identified with a topological discontinuity (position jump). Numerous studies have explored different kirigami-based deployable structures, with a focus that is primarily on the forward problem, that of predicting the geometric and mechanical response of given designs 7 , 8 , 9 , 10 , 11 , 12 , 13 . The solution of the inverse problem typically involves setting up a global constrained optimization problem that encodes the geometric constraints in terms of the angles and lengths of the constituent tiles 14 , 15 , 16 , 17 , 18 . Although such an approach is capable of producing patterns and mechanisms with different shape changes, the process of finding a solution to the nonlinear global constrained optimization problem for large patterns is both computationally difficult and hard to control. Inspired by biological morphogenesis driven by growing matter 19 , and its synthetic analog, additive manufacturing 20 , one is naturally led to the question of whether it is possible to simplify the design of origami/kirigami metamaterials by switching from a global optimization perspective to some locally constrained additive process. In recent work, we showed that the use of local marching rules allows for an additive origami design approach 21 , converting a difficult non-convex global optimization problem 22 into a simpler, but still nonlinear, local problem. In this Article we show that kirigami also lends itself to a simple additive approach that identifies and exploits a linear marching construction to connect local growth rules to a global form. The subtle differences in the nature of the geometric and topological constraints between origami and kirigami imply that there are qualitative differences in these marching algorithms that lead to a much simpler algorithm for kirigami, despite it being a far richer paradigm for structural material design. Furthermore, we show that we can control the flexibility of encoding contractibility, compact reconfigurability and rigid-deployability for the design of quad kirigami in any contracted or deployed space using a simple design matrix characterized by a combination of certain edge-length and angle parameters. This substantially simplifies the process of designing kirigami patterns as matrix multiplications. Our approach of decoupling the length field, angle field and the boundary node constraints allows us to systematically analyze the degrees of freedom in the design space of different types of quad kirigami tessellations. Finally, to realize these designs in practice, we describe two manufacturing approaches using additive manufacturing and casting/molding for robust kirigami structures with soft, fabric hinges. Results Additive design framework We tackle the kirigami design problem by working our way up a ladder of hierarchical complexity, beginning with the smallest building block, a single four-bar linkage representing the negative space of a unit cell of four quads, before moving on to strips of linkages and finally linkage arrays. At each level, our strategy will be to describe a geometric marching construction, the forward process, which can be cast as matrix multiplication, allowing us then to convert the marching algorithm into a flexible and intuitive design framework using linear inverse design techniques. In Fig. 1 we present an overview of the marching construction for quad kirigami design. The key idea is to identify the constraints in the negative spaces in a deployed configuration, and use them to form a design matrix that is nonlinearly dependent on the deployment angles and edge lengths. However, once the matrix is determined, the coordinates of all nodes can be obtained by a simple matrix multiplication step, yielding a linear design method for quad kirigami. Fig. 1: Marching construction for quad kirigami design. a , Geometric design of a four-bar linkage representing a negative space in an ( m + 1) × (<|im_end|> <|im_start|>assistant Kirigami takes pop-up books to a whole new level. The Japanese paper craft involves cutting patterns in paper to transform a two-dimensional sheet into an intricate, three-dimensional structure when partially folded. In the hands of an artist, kirigami can yield remarkably detailed and delicate replicas of structures in nature, architecture, and more. Scientists and engineers have also taken inspiration from kirigami, applying principles from paper-cutting to design robotic grippers, stretchable electronics, water-harvesting sheets, and other shape-shifting materials and devices. For the most part, such inventions are products of from-scratch design. There's been no blueprint for engineers to determine the pattern of cuts that will transform a material from one desired shape to another—that is, until now. A new study in Nature Computational Science presents a general computational strategy that can solve any two-dimensional, kirigami-inspired transformation. The method can be used to determine the angle and length of cuts to make, such that a sheet can transform from one desired shape to another when pulled open and pushed back together, like an intricate, expandable lattice. With their new method, researchers designed and fabricated a number of transformable, 2D kirigami structures, including a circle that turns into a square, and a triangle that morphs into a heart. "People have talked of the square and circle as one of the impossible problems in mathematics: You cannot turn one into the other," says Gary Choi, a postdoctoral instructor in applied mathematics at MIT. "But with kirigami, we can actually turn a square shape into a circle shape." For engineers, the new method could be used to solve various design problems, such as how a robot can be engineered to transform from one shape to another to carry out a particular task or navigate certain spaces. There's also potential to design active materials, for instance as smart coverings for buildings and homes. "One of the first applications we thought of was building façades," says Kaitlyn Becker, an assistant professor of mechanical engineering at MIT. "This could help us to make large, kirigami-like façades that can transform their shape to control sunlight, ultraviolet radiation, and be adaptive to their environment." Becker and Choi are co-authors of the new study, along with Levi Dudte, a quantitative researcher at Optiver, and L. Mahadevan, a professor at Harvard University. Credit: Kaitlyn Becker/Gary Choi The space between The study grew out of the team's previous work in both kirigami and origami—the Japanese art of paper folding. "We found there are a lot of mathematical connections in kirigami and origami," Choi says. "So we wanted to come up with a mathematical formulation that can help people design a large variety of patterns." In 2019, the team devised an optimization approach for kirigami to find the pattern of cuts that would be required to turn one shape into another. But Choi says the approach was too computationally intensive, and it took a large amount of time to derive an optimal pattern to achieve a particular transformation. In 2021, the researchers took on a similar problem in origami and found that through a slightly different perspective, they were able to derive a more efficient strategy. Rather than planning out a pattern of individual folds (similar to kirigami's individual cuts), the team focused on growing a pattern from a simple folded seed. By working panel by panel, and establishing relationships between panels, such as how one panel would move if an adjacent panel were folded, they were able to derive a relatively efficient algorithm for planning out the design of any origami structure. The team wondered if a similar approach be applied to kirigami. In traditional kirigami, once cuts have been made in a sheet of paper, the sheet can be partially folded such that the resulting empty spaces create a three-dimensional structure. Like the panels between origami folds, could the empty spaces between cuts, and their relation to each other, yield a more efficient formula for kirigami design? This question motivated the team's new study. Math links The study focuses on two-dimensional kirigami transformations. The researchers considered a general kirigami design comprising a mosaic of interconnected quadrilateral tiles, each cut to various angles and sizes. The conceptual mosaic begins as one shape and can be pulled apart and pushed back together to form an entirely new shape. The challenge was to describe how one shape can transform into another, based on the empty spaces between tiles and how the spaces change as the tiles are pulled apart and pushed back together. "If the tiles themselves are solid and unchangeable, then it's the empty spaces between that are an opportunity for motion," Becker says. The team first considered the simplest representation of empty space, in the form of a rhombus, or what they term a "four-bar linkage." Each side of the rhombus represents a bar, or the edge of a solid tile. Each corner of the rhombus represents a linkage, or hinge that connects tiles. By changing the length and angle of the rhombus' edges, the team could study how the empty space in between changes. By studying progressively larger assemblages of four-bar linkages, the team identified relationships between the angle and length of bars, the shape of individual empty spaces, and the shape of the overall assemblage. They worked these relationships into a general formula, and found that it could efficiently identify the pattern of cuts—including their angle and length—that would be required to transform a two-dimensional sheet from one desired shape to another. "Without a tool like this, I might brute force this problem in Matlab, or guess and check, but it would take me a very long time to get something that can transform from a circle to a square," Becker says. In simulations, the team found that the formula could indeed find a pattern of tiles that would turn a circle-shaped mosaic into a square, as well as virtually any shape into any other desired shape. Going a step further, the team developed two fabrication methods to physically realize the formula's designs. They quickly realized that a key challenge in making the transformable mosaics was in finding the right material to serve as the tile-connecting hinges. The connections needed to be strong, yet easily bendable. "I thought, what is very strong in tension, and tear-resistant, but can have a zero bending radius, almost like a pinpoint hinge?" Becker says. "And the answer, it turns out, is fabric." The team used two methods—3D printing, and mold casting—to embed small strips of fabric into quadrilateral plastic tiles, in a way that closely connected the tiles while allowing them to bend against each other. Using these two methods, the team fabricated circle-shaped mosaics that transformed into squares, as well as simple triangle mosaics that morphed into more complex heart shapes. "We can basically go to any two-dimensional shape," Choi says. "That's guaranteed, using our mathematical formulation. Now we're looking to extend this to 3D kirigami." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Spatial navigation requires information about the relationship between current and future positions. The activity of hippocampal neurons appears to reflect such a relationship, representing not only instantaneous position but also the path towards a goal location. However, how the hippocampus obtains information about goal direction is poorly understood. Here we report a prefrontal–thalamic neural circuit that is required for hippocampal representation of routes or trajectories through the environment. Trajectory-dependent firing was observed in medial prefrontal cortex, the nucleus reuniens of the thalamus, and the CA1 region of the hippocampus in rats. Lesioning or optogenetic silencing of the nucleus reuniens substantially reduced trajectory-dependent CA1 firing. Trajectory-dependent activity was almost absent in CA3, which does not receive nucleus reuniens input. The data suggest that projections from medial prefrontal cortex, via the nucleus reuniens, are crucial for representation of the future path during goal-directed behaviour and point to the thalamus as a key node in networks for long-range communication between cortical regions involved in navigation. Main Hippocampal place cells are part of an allocentric representation of local space that allows animals to navigate to desired locations 1 , 2 . Place cells provide accurate information about current location, but it has remained unclear how the place-cell map is used for animals to navigate from their current position to a goal position elsewhere in the environment. To implement goal-directed navigation, previous studies have proposed the need for a separate representation of future positions that is somehow brought together with the representation of current location to point the network to the goal 3 , 4 , 5 . Such pointers may be expressed in the activity of hippocampal place cells. When rats are engaged in a T-maze-based alternation task, in which they take left or right trajectories on alternating laps, place cells with fields on the stem of the maze fire at different rates on left- and right-turn trajectories, without changes in the position of the firing field 6 , 7 . The dependence on trajectory has both retrospective and prospective components, reflecting both where the animal comes from and where it is going 8 . However, as the animal approaches the decision point at the junction of the maze, the representation becomes more forward-oriented 9 , often with trajectories to upcoming locations embedded into the representation 10 , 11 , in addition to mere changes in firing rate. The source of trajectory information in place cells has not been identified. Here we used a continuous version of the T-maze alternation task 6 to determine how information about succeeding choices is introduced in hippocampal place-cell activity. We hypothesized that the selection of future trajectories depends on a wider circuit including not only the hippocampus but also structures involved in the evaluation and selection of actions, such as the prefrontal cortex 12 , 13 , 14 . Neurons in medial prefrontal cortex (mPFC) do not project directly to the hippocampus 15 , 16 but the midline thalamic nucleus reuniens (NR), which has reciprocal anatomical connections with the mPFC, may serve as a functional bridge to the hippocampal region, since NR has strong terminal fields in the CA1 subfield 15 , 17 , 18 , 19 . To address this possibility, we recorded and manipulated activity at various nodes of the prefrontal–reuniens–CA1 circuit and determined whether this circuit is necessary for place cells to represent upcoming trajectories. Trajectory-dependent firing is stronger in CA1 than CA3 We first asked whether NR is the source of trajectory information in CA1. If it is, we should observe a difference in trajectory-dependent firing between CA1 and CA3, because NR has major excitatory projections to CA1 but not CA3 (refs 15 , 17 , 18 , 19 ). We thus recorded place cells in rat CA1 and CA3 in a continuous alternation task on a modified T-maze ( Fig. 1a, b and Extended Data Fig. 1 ). A total of 363 CA1 cells and 180 CA3 cells exhibited location-specific complex spiking (12 and 5 rats, respectively). Within this sample, 98 CA1 cells and 34 CA3 cells had place fields on the central stem. All subsequent analysis of these cells was restricted to parts of the stem where there was no significant difference in the animal’s head direction, lateral position, or running speed between left-turn and right-turn trajectories. Figure 1: Trajectory-dependent firing in CA1 but not CA3. a , Modified T-mazes used for the continuous alternation task. Red disk, food reward; arrows, running directions. b , Nissl-stained coronal sections through dorsal hippocampus. Red circles, tetrode tracks in CA1 and CA3. Original magnification, ×2.5. c , Trajectory-dependent firing in CA1. Left panel, rate maps for a representative CA1 place cell in the continuous alternation task (left to right: all laps, right-turn laps, left-turn laps). Identification number of animal (#16755) and unit number (TT11_1.t) are indicated on top. Right panel, means (solid lines) and 95% confidence intervals (shaded) for spike rates of a single cell across the stem of the maze. Raster plots above. Left-heading runs in blue, right-heading runs in red. d , Left panels, difference in mean rates between left and right trajectories for all CA1 cells with firing fields on the stem. Left- and right-turn trajectories were classified as high rate or low rate depending on which direction had the highest mean peak rate on the stem. Spike rates were normalized to the peak firing rate of each cell and sorted according to field position on high-rate trajectories. Each line shows one cell. Normalized spike rate is colour-coded (red for higher and blue for lower rates). Right top panel, distribution of normalized change in peak firing rate on the stem between high and low-rate trajectories . Right bottom panel, distribution of shift of field position between high- and low-rate trajectories. e , f , As in c , d but for CA3 place cells. PowerPoint slide Full size image Many place cells in CA1 expressed several-fold changes in peak firing rate between left- and right-turn trajectories on the stem, without changes", "role": "user" }, { "content": "Is it possible to tap into the signalling in the brain to figure out where you will go next? Hiroshi Ito, a researcher at the Kavli Institute for Systems Neuroscience at the Norwegian University of Science and Technology (NTNU), can now say yes. Ito has just published a description of how this happens in this week's edition of Nature. Ito and his colleagues, including his supervisors, 2014 Nobel Laureates May-Britt and Edvard Moser, sampled a specific neural pathway to figure out if it is the location of the mechanism that enables animals to code their plan to get from one place to another. Their study confirms that this pathway, the medial prefrontal cortex via a thalamic nucleus to the hippocampus, does. The code that predicts behaviour The researchers designed a study that would help them better understand how this signalling pathway works. They trained rats to run in an alternating fashion in a continuous T-maze that actually looks more like the infinity sign with a wide waist, or stem. \"We learned that the differential strength of firing of specific neurons accurately predicts the trajectory the animal will chose,\" Ito said. While the rats ran the maze, electrophysiological recordings were made from prefrontal cortex, thalamus and hippocampus. The researchers analysed the activity of neurons while the rat was on the stem of the maze, where it had to decide whether to go left or right at the upcoming junction. The decision pathway Researchers know there are pathways from the prefrontal cortex via the thalamus to the CA1 area of the hippocampus. However, there is no link to the CA3 area immediately adjacent to CA1 (which is also in the hippocampus). Given this, the researchers first checked to see if they could detect a difference in the coding between the two areas that would reflect the trajectory the rat would subsequently choose. There was a clear difference. The CA1 showed far more coding for any upcoming choice than the CA3. The code was visible in the intensity of firing, although not in which cell fired, or where. To understand how this works, think of a choir all singing the same song, but where different voices are louder at the same point in the song during different performances. The words, melody, and singers are the same, but the change in the volume of each voice changes the performance. Since they are familiar with \"the choir\", the researchers looked for the conductor, which they found in the frontal cortex. Researchers have known that the code for trajectory choice could be found in CA1. The researchers at the Kavli Institute showed that a similar code is present in nucleus reuniens (NR) in the thalamus as well as anterior cingulate (AC) and prelimbic cortex (PC), both in the medial prefrontal cortex (mPFC). The researchers continued to find out where the signals arise, and tested the contribution of the mPFC-NR pathway. The researchers were able to establish that without the input from mPFC through NR, the CA1 also loses its code for upcoming choice of trajectory. They were able to confirm this by blocking signalling in the NR, using two different approaches. This shows that the code needs mPFC and NR, much like a choir needs its conductor. \"Planning our movement to a desired location requires more than a map of where we are,\" Professor May-Britt Moser says. \"We must have a sense of both where we are at the moment, and where we want to go at the same time. It seems that the cells involved in navigation use both internal and external clues to pinpoint exact locations, and on top of the firing pattern there is a code of differential firing intensity that contains information on the next move.\" Moser explains that this intensity pattern appears to be under the guidance of the prefrontal cortex, a brain area known in primates for decision making and executive function. \"We believe these findings collectively suggest that the new pathway in charge of intended movement is crucial for animals to choose their actions to a desired place in a map,\" Moser said. \"The data also provide evidence for a role of the thalamus in long-range communication between cortical regions.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Spatial navigation requires information about the relationship between current and future positions. The activity of hippocampal neurons appears to reflect such a relationship, representing not only instantaneous position but also the path towards a goal location. However, how the hippocampus obtains information about goal direction is poorly understood. Here we report a prefrontal–thalamic neural circuit that is required for hippocampal representation of routes or trajectories through the environment. Trajectory-dependent firing was observed in medial prefrontal cortex, the nucleus reuniens of the thalamus, and the CA1 region of the hippocampus in rats. Lesioning or optogenetic silencing of the nucleus reuniens substantially reduced trajectory-dependent CA1 firing. Trajectory-dependent activity was almost absent in CA3, which does not receive nucleus reuniens input. The data suggest that projections from medial prefrontal cortex, via the nucleus reuniens, are crucial for representation of the future path during goal-directed behaviour and point to the thalamus as a key node in networks for long-range communication between cortical regions involved in navigation. Main Hippocampal place cells are part of an allocentric representation of local space that allows animals to navigate to desired locations 1 , 2 . Place cells provide accurate information about current location, but it has remained unclear how the place-cell map is used for animals to navigate from their current position to a goal position elsewhere in the environment. To implement goal-directed navigation, previous studies have proposed the need for a separate representation of future positions that is somehow brought together with the representation of current location to point the network to the goal 3 , 4 , 5 . Such pointers may be expressed in the activity of hippocampal place cells. When rats are engaged in a T-maze-based alternation task, in which they take left or right trajectories on alternating laps, place cells with fields on the stem of the maze fire at different rates on left- and right-turn trajectories, without changes in the position of the firing field 6 , 7 . The dependence on trajectory has both retrospective and prospective components, reflecting both where the animal comes from and where it is going 8 . However, as the animal approaches the decision point at the junction of the maze, the representation becomes more forward-oriented 9 , often with trajectories to upcoming locations embedded into the representation 10 , 11 , in addition to mere changes in firing rate. The source of trajectory information in place cells has not been identified. Here we used a continuous version of the T-maze alternation task 6 to determine how information about succeeding choices is introduced in hippocampal place-cell activity. We hypothesized that the selection of future trajectories depends on a wider circuit including not only the hippocampus but also structures involved in the evaluation and selection of actions, such as the prefrontal cortex 12 , 13 , 14 . Neurons in medial prefrontal cortex (mPFC) do not project directly to the hippocampus 15 , 16 but the midline thalamic nucleus reuniens (NR), which has reciprocal anatomical connections with the mPFC, may serve as a functional bridge to the hippocampal region, since NR has strong terminal fields in the CA1 subfield 15 , 17 , 18 , 19 . To address this possibility, we recorded and manipulated activity at various nodes of the prefrontal–reuniens–CA1 circuit and determined whether this circuit is necessary for place cells to represent upcoming trajectories. Trajectory-dependent firing is stronger in CA1 than CA3 We first asked whether NR is the source of trajectory information in CA1. If it is, we should observe a difference in trajectory-dependent firing between CA1 and CA3, because NR has major excitatory projections to CA1 but not CA3 (refs 15 , 17 , 18 , 19 ). We thus recorded place cells in rat CA1 and CA3 in a continuous alternation task on a modified T-maze ( Fig. 1a, b and Extended Data Fig. 1 ). A total of 363 CA1 cells and 180 CA3 cells exhibited location-specific complex spiking (12 and 5 rats, respectively). Within this sample, 98 CA1 cells and 34 CA3 cells had place fields on the central stem. All subsequent analysis of these cells was restricted to parts of the stem where there was no significant difference in the animal’s head direction, lateral position, or running speed between left-turn and right-turn trajectories. Figure 1: Trajectory-dependent firing in CA1 but not CA3. a , Modified T-mazes used for the continuous alternation task. Red disk, food reward; arrows, running directions. b , Nissl-stained coronal sections through dorsal hippocampus. Red circles, tetrode tracks in CA1 and CA3. Original magnification, ×2.5. c , Trajectory-dependent firing in CA1. Left panel, rate maps for a representative CA1 place cell in the continuous alternation task (left to right: all laps, right-turn laps, left-turn laps). Identification number of animal (#16755) and unit number (TT11_1.t) are indicated on top. Right panel, means (solid lines) and 95% confidence intervals (shaded) for spike rates of a single cell across the stem of the maze. Raster plots above. Left-heading runs in blue, right-heading runs in red. d , Left panels, difference in mean rates between left and right trajectories for all CA1 cells with firing fields on the stem. Left- and right-turn trajectories were classified as high rate or low rate depending on which direction had the highest mean peak rate on the stem. Spike rates were normalized to the peak firing rate of each cell and sorted according to field position on high-rate trajectories. Each line shows one cell. Normalized spike rate is colour-coded (red for higher and blue for lower rates). Right top panel, distribution of normalized change in peak firing rate on the stem between high and low-rate trajectories . Right bottom panel, distribution of shift of field position between high- and low-rate trajectories. e , f , As in c , d but for CA3 place cells. PowerPoint slide Full size image Many place cells in CA1 expressed several-fold changes in peak firing rate between left- and right-turn trajectories on the stem, without changes<|im_end|> <|im_start|>assistant Is it possible to tap into the signalling in the brain to figure out where you will go next? Hiroshi Ito, a researcher at the Kavli Institute for Systems Neuroscience at the Norwegian University of Science and Technology (NTNU), can now say yes. Ito has just published a description of how this happens in this week's edition of Nature. Ito and his colleagues, including his supervisors, 2014 Nobel Laureates May-Britt and Edvard Moser, sampled a specific neural pathway to figure out if it is the location of the mechanism that enables animals to code their plan to get from one place to another. Their study confirms that this pathway, the medial prefrontal cortex via a thalamic nucleus to the hippocampus, does. The code that predicts behaviour The researchers designed a study that would help them better understand how this signalling pathway works. They trained rats to run in an alternating fashion in a continuous T-maze that actually looks more like the infinity sign with a wide waist, or stem. "We learned that the differential strength of firing of specific neurons accurately predicts the trajectory the animal will chose," Ito said. While the rats ran the maze, electrophysiological recordings were made from prefrontal cortex, thalamus and hippocampus. The researchers analysed the activity of neurons while the rat was on the stem of the maze, where it had to decide whether to go left or right at the upcoming junction. The decision pathway Researchers know there are pathways from the prefrontal cortex via the thalamus to the CA1 area of the hippocampus. However, there is no link to the CA3 area immediately adjacent to CA1 (which is also in the hippocampus). Given this, the researchers first checked to see if they could detect a difference in the coding between the two areas that would reflect the trajectory the rat would subsequently choose. There was a clear difference. The CA1 showed far more coding for any upcoming choice than the CA3. The code was visible in the intensity of firing, although not in which cell fired, or where. To understand how this works, think of a choir all singing the same song, but where different voices are louder at the same point in the song during different performances. The words, melody, and singers are the same, but the change in the volume of each voice changes the performance. Since they are familiar with "the choir", the researchers looked for the conductor, which they found in the frontal cortex. Researchers have known that the code for trajectory choice could be found in CA1. The researchers at the Kavli Institute showed that a similar code is present in nucleus reuniens (NR) in the thalamus as well as anterior cingulate (AC) and prelimbic cortex (PC), both in the medial prefrontal cortex (mPFC). The researchers continued to find out where the signals arise, and tested the contribution of the mPFC-NR pathway. The researchers were able to establish that without the input from mPFC through NR, the CA1 also loses its code for upcoming choice of trajectory. They were able to confirm this by blocking signalling in the NR, using two different approaches. This shows that the code needs mPFC and NR, much like a choir needs its conductor. "Planning our movement to a desired location requires more than a map of where we are," Professor May-Britt Moser says. "We must have a sense of both where we are at the moment, and where we want to go at the same time. It seems that the cells involved in navigation use both internal and external clues to pinpoint exact locations, and on top of the firing pattern there is a code of differential firing intensity that contains information on the next move." Moser explains that this intensity pattern appears to be under the guidance of the prefrontal cortex, a brain area known in primates for decision making and executive function. "We believe these findings collectively suggest that the new pathway in charge of intended movement is crucial for animals to choose their actions to a desired place in a map," Moser said. "The data also provide evidence for a role of the thalamus in long-range communication between cortical regions." <|im_end|>

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2,199

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The European eel ( Anguilla anguilla ) hatches in the Sargasso Sea and migrates to European and North African freshwater. As glass eels, they reach estuaries where they become pigmented. Glass eels use a tidal phase-dependent magnetic compass for orientation, but whether their magnetic direction is innate or imprinted during migration is unknown. We tested the hypothesis that glass eels imprint their tidal-dependent magnetic compass direction at the estuaries where they recruit. We collected 222 glass eels from estuaries flowing in different cardinal directions in Austevoll, Norway. We observed the orientation of the glass eels in a magnetic laboratory where the magnetic North was rotated. Glass eels oriented towards the magnetic direction of the prevailing tidal current occurring at their recruitment estuary. Glass eels use their magnetic compass to memorize the magnetic direction of tidal flows. This mechanism could help them to maintain their position in an estuary and to migrate upstream. Introduction The European eel ( Anguilla anguilla ) is a migratory species that crosses the Atlantic Ocean twice during its life (Fig. 1 ). After hatching in the Sargasso Sea 1 , eel leptocephali larvae move with the gulf stream more than 5000 km until they reach the continental slope of Europe 2 , 3 . There, they metamorphose into the post-larval transparent glass eel 4 . At this stage, glass eels migrate across the continental shelf to the coast 2 , 5 . After reaching the coast, glass eels enter estuaries, where some of them continue their migration upstream into freshwater 6 . The eels that enter freshwater spend most of their lifetime (5–25 years) there, growing first into the adult yellow eel stage, and then into silver eels 2 . Silver eels then navigate back to the Sargasso Sea where they spawn and die 1 , 7 , 8 . Fig. 1 Life history of the European eel ( Anguilla anguilla ). Eels hatch as leptocephalus larvae in the Sargasso Sea. As larvae, they drift across the Atlantic Ocean to the continental slope of Europe, where they metamorphose into post-larval, transparent glass eels. The glass eels migrate across the continental shelf and eventually reach the brackish water of estuaries. After metamorphosing into pigmented juveniles, called elvers, they start the ascent into freshwater, where they will grow into adult yellow eels. After some years, yellow eels undergo another metamorphosis into silver eels, which migrate for thousands of kilometers to the Sargasso Sea where they spawn and die. Eels used in this study were at the stage of glass eel (red font), and the Hypothetical Period of Imprinting (H.P.I.) is highlighted by a dashed blue polygon. Artwork credit A. Cresci Full size image The European eel is a commercially important species that is critically endangered [International Union for Conservation of Nature (IUCN)]: eel populations have declined precipitously since the 1980s 9 , 10 , 11 . Much research on the conservation and management of eels has been undertaken 12 , 13 , driven to some extent by the requirement for member states of the European Union to develop management plans for the recovery of eel populations. The arrival of the early-life stages to estuaries (recruitment), is an important phase of their migration, and the number of recruiting glass eels have been consistently declining over the past decades 10 , 14 . Thus, a better understanding of the dynamics of this step of the migration, including deeper knowledge of the orientation mechanisms involved, is needed. Glass eels use multiple spatial and sensory cues for orientation 15 , 16 , 17 , which could hypothetically be imprinted and used years later during their return journey to the spawning areas. It is possible that eels imprint spatial information from the environment at several steps during their migration, such as at the time of hatching or during the journey to the European coast. Imprinting is associated with a broad variety of processes in animals, including food and habitat preference, host selection in parasitic animals, and homing 18 , 19 , 20 . Imprinting is a fast-learning process that typically occurs during a specific life history phase 18 , 19 , 21 . Imprinting of spatial cues, such as olfactory cues in salmon 22 , occurs in several aquatic animals. Animals can also imprint information from the magnetic field of the Earth. Aquatic species such as pacific salmon ( Oncorhynchus nerka ) 23 and sea turtles ( Caretta caretta ) 20 imprint specific features of the Earth’s magnetic field and use this to orient during migration. The European eel is a long distance migrator that also uses magnetic fields to orient during migration 24 , 25 . However, whether imprinting of magnetic cues occurs, either at the larval or glass eel stage (or both), remains unknown. Glass eels recruit at tidal estuaries along the European coast, where they are exposed to the alternation of ebbing and flooding tidal currents. In aquatic environments, fish display an unconditioned response to water currents (rheotaxis), which can be positive (the fish swims into the current) or negative (the fish swims in the same direction as the current) 26 , 27 . Rheotaxis is a major component of fish orientation in tidal estuaries in which currents can be fast and visibility low 27 . In such situations, fish use rheotaxis for both upstream migration and upstream-oriented station holding behavior to minimize energy expenditure in flowing water 28 . Glass eels display both of these rheotactic behaviors when they recruit to estuaries, showing rhythmic patterns of positive or negative rheotaxis synchronized to the tidal phase 29 . This tidal-dependent orientation is important during migration, as glass eels exploit tidal flows to enter brackish and freshwater using selective tidal stream transport (STST) 30 , 31 , 32 , 33 . This constitutes a deeply rooted behavior in many species of fish and invertebrates inhabiting tidal estuaries 34 . In order to orient with respect to water flow, fish rely on multiple sensory cues, including visual, vestibular, and tactile 35", "role": "user" }, { "content": "A new study led by researchers at the University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science and at the Institute of Marine Research in Norway found that European glass eels use their magnetic sense to \"imprint\" a memory of the direction of water currents in the estuary where they become juveniles. This is the first direct evidence that a species of fish uses its internal magnetic compass to form a memory of current direction. \"It's an important step forward in understanding the migratory behavior of the commercially important European eel and in expanding our knowledge of the orientation mechanisms that fish use to migrate,\" said Alessandro Cresci, a Ph.D. student at the UM Rosenstiel School and first author of the paper. \"This research should provide awareness that tiny young eels can accomplish incredible tasks to migrate.\" The European eel (Anguilla anguilla) is a migratory species that crosses the Atlantic Ocean twice during its life. After hatching in the Sargasso Sea, eel larvae move more than 5,000 kilometers with the Gulf Stream until reaching the continental slope of Europe. There, they metamorphose into the post-larval transparent glass eel and continue the migration across the continental shelf to the coast. After reaching the coast, glass eels enter estuaries, where some of them continue their migration upstream into freshwater until later in life (up to 50 years), when as silver eels, they navigate back to the Sargasso Sea to spawn and die. The research team collected over 200 glass eels from various estuaries in the archipelago of Austevoll, Norway flowing in different directions: north, south, southeast or northwest. The fish were then placed in a magnetic laboratory, the \"MagLab,\" where magnetic north was rotated to observe their magnetic orientation . In each case the eels oriented towards the magnetic direction of the prevailing tidal current occurring at their recruitment estuary at the time of the tests. The findings show that glass eels use their magnetic compass to memorize the magnetic direction of tidal flows in their recruitment estuary, which may help them orient in moving water during migration. \"Surprisingly, fish early life behavior can be goal oriented.\" said Claire Paris, professor of ocean sciences at the UM Rosenstiel School. \"This study complements previous findings showing innate magnetic sense in glass eels and highlights the importance of understanding the complexities of larval behavior. There is a lot we need to learn\". The European eel is a commercially important species that is critically endangered according to the International Union for Conservation of Nature. Eel populations have declined precipitously since the 1980. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The European eel ( Anguilla anguilla ) hatches in the Sargasso Sea and migrates to European and North African freshwater. As glass eels, they reach estuaries where they become pigmented. Glass eels use a tidal phase-dependent magnetic compass for orientation, but whether their magnetic direction is innate or imprinted during migration is unknown. We tested the hypothesis that glass eels imprint their tidal-dependent magnetic compass direction at the estuaries where they recruit. We collected 222 glass eels from estuaries flowing in different cardinal directions in Austevoll, Norway. We observed the orientation of the glass eels in a magnetic laboratory where the magnetic North was rotated. Glass eels oriented towards the magnetic direction of the prevailing tidal current occurring at their recruitment estuary. Glass eels use their magnetic compass to memorize the magnetic direction of tidal flows. This mechanism could help them to maintain their position in an estuary and to migrate upstream. Introduction The European eel ( Anguilla anguilla ) is a migratory species that crosses the Atlantic Ocean twice during its life (Fig. 1 ). After hatching in the Sargasso Sea 1 , eel leptocephali larvae move with the gulf stream more than 5000 km until they reach the continental slope of Europe 2 , 3 . There, they metamorphose into the post-larval transparent glass eel 4 . At this stage, glass eels migrate across the continental shelf to the coast 2 , 5 . After reaching the coast, glass eels enter estuaries, where some of them continue their migration upstream into freshwater 6 . The eels that enter freshwater spend most of their lifetime (5–25 years) there, growing first into the adult yellow eel stage, and then into silver eels 2 . Silver eels then navigate back to the Sargasso Sea where they spawn and die 1 , 7 , 8 . Fig. 1 Life history of the European eel ( Anguilla anguilla ). Eels hatch as leptocephalus larvae in the Sargasso Sea. As larvae, they drift across the Atlantic Ocean to the continental slope of Europe, where they metamorphose into post-larval, transparent glass eels. The glass eels migrate across the continental shelf and eventually reach the brackish water of estuaries. After metamorphosing into pigmented juveniles, called elvers, they start the ascent into freshwater, where they will grow into adult yellow eels. After some years, yellow eels undergo another metamorphosis into silver eels, which migrate for thousands of kilometers to the Sargasso Sea where they spawn and die. Eels used in this study were at the stage of glass eel (red font), and the Hypothetical Period of Imprinting (H.P.I.) is highlighted by a dashed blue polygon. Artwork credit A. Cresci Full size image The European eel is a commercially important species that is critically endangered [International Union for Conservation of Nature (IUCN)]: eel populations have declined precipitously since the 1980s 9 , 10 , 11 . Much research on the conservation and management of eels has been undertaken 12 , 13 , driven to some extent by the requirement for member states of the European Union to develop management plans for the recovery of eel populations. The arrival of the early-life stages to estuaries (recruitment), is an important phase of their migration, and the number of recruiting glass eels have been consistently declining over the past decades 10 , 14 . Thus, a better understanding of the dynamics of this step of the migration, including deeper knowledge of the orientation mechanisms involved, is needed. Glass eels use multiple spatial and sensory cues for orientation 15 , 16 , 17 , which could hypothetically be imprinted and used years later during their return journey to the spawning areas. It is possible that eels imprint spatial information from the environment at several steps during their migration, such as at the time of hatching or during the journey to the European coast. Imprinting is associated with a broad variety of processes in animals, including food and habitat preference, host selection in parasitic animals, and homing 18 , 19 , 20 . Imprinting is a fast-learning process that typically occurs during a specific life history phase 18 , 19 , 21 . Imprinting of spatial cues, such as olfactory cues in salmon 22 , occurs in several aquatic animals. Animals can also imprint information from the magnetic field of the Earth. Aquatic species such as pacific salmon ( Oncorhynchus nerka ) 23 and sea turtles ( Caretta caretta ) 20 imprint specific features of the Earth’s magnetic field and use this to orient during migration. The European eel is a long distance migrator that also uses magnetic fields to orient during migration 24 , 25 . However, whether imprinting of magnetic cues occurs, either at the larval or glass eel stage (or both), remains unknown. Glass eels recruit at tidal estuaries along the European coast, where they are exposed to the alternation of ebbing and flooding tidal currents. In aquatic environments, fish display an unconditioned response to water currents (rheotaxis), which can be positive (the fish swims into the current) or negative (the fish swims in the same direction as the current) 26 , 27 . Rheotaxis is a major component of fish orientation in tidal estuaries in which currents can be fast and visibility low 27 . In such situations, fish use rheotaxis for both upstream migration and upstream-oriented station holding behavior to minimize energy expenditure in flowing water 28 . Glass eels display both of these rheotactic behaviors when they recruit to estuaries, showing rhythmic patterns of positive or negative rheotaxis synchronized to the tidal phase 29 . This tidal-dependent orientation is important during migration, as glass eels exploit tidal flows to enter brackish and freshwater using selective tidal stream transport (STST) 30 , 31 , 32 , 33 . This constitutes a deeply rooted behavior in many species of fish and invertebrates inhabiting tidal estuaries 34 . In order to orient with respect to water flow, fish rely on multiple sensory cues, including visual, vestibular, and tactile 35<|im_end|> <|im_start|>assistant A new study led by researchers at the University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science and at the Institute of Marine Research in Norway found that European glass eels use their magnetic sense to "imprint" a memory of the direction of water currents in the estuary where they become juveniles. This is the first direct evidence that a species of fish uses its internal magnetic compass to form a memory of current direction. "It's an important step forward in understanding the migratory behavior of the commercially important European eel and in expanding our knowledge of the orientation mechanisms that fish use to migrate," said Alessandro Cresci, a Ph.D. student at the UM Rosenstiel School and first author of the paper. "This research should provide awareness that tiny young eels can accomplish incredible tasks to migrate." The European eel (Anguilla anguilla) is a migratory species that crosses the Atlantic Ocean twice during its life. After hatching in the Sargasso Sea, eel larvae move more than 5,000 kilometers with the Gulf Stream until reaching the continental slope of Europe. There, they metamorphose into the post-larval transparent glass eel and continue the migration across the continental shelf to the coast. After reaching the coast, glass eels enter estuaries, where some of them continue their migration upstream into freshwater until later in life (up to 50 years), when as silver eels, they navigate back to the Sargasso Sea to spawn and die. The research team collected over 200 glass eels from various estuaries in the archipelago of Austevoll, Norway flowing in different directions: north, south, southeast or northwest. The fish were then placed in a magnetic laboratory, the "MagLab," where magnetic north was rotated to observe their magnetic orientation . In each case the eels oriented towards the magnetic direction of the prevailing tidal current occurring at their recruitment estuary at the time of the tests. The findings show that glass eels use their magnetic compass to memorize the magnetic direction of tidal flows in their recruitment estuary, which may help them orient in moving water during migration. "Surprisingly, fish early life behavior can be goal oriented." said Claire Paris, professor of ocean sciences at the UM Rosenstiel School. "This study complements previous findings showing innate magnetic sense in glass eels and highlights the importance of understanding the complexities of larval behavior. There is a lot we need to learn". The European eel is a commercially important species that is critically endangered according to the International Union for Conservation of Nature. Eel populations have declined precipitously since the 1980. <|im_end|>

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1,905

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain. Introduction Infectious diseases are the second most common cause of death worldwide. While multidrug resistance is observed in both Gram-positive and Gram-negative bacteria, two thirds of deaths are due to infection by Gram-negative bacteria 1 . Antibiotic-resistant bacteria have emerged as a major problem, especially for hospital-acquired infections and the economic cost of multi-drug-resistant bacterial infections is immense. Of the 2 million people infected in the EU every year, some 175,000 (about 9%) die 2 . The Centre for Disease Control and Prevention (CDC) in Atlanta similarly estimates that in the USA, more than 2 million patients acquire antibiotic-resistant infections every year, of who at least 23,000 die 3 . Currently, more people die in USA of methicillin‐resistant Staphylococcus aureus than of AIDS. Meanwhile, the development of effective antibiotics has slowed down. Only seven new antibiotics were approved by the FDA from 2003 to 2012 (only two new classes since 1998), most of them effective against Gram-positive bacteria 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 . All this makes it clear that there is an urgent need to develop new antibiotics against bacteria that are prone to acquire resistance to the antibiotics currently in use. The Infectious Disease Society of America has issued a proposal to develop new antibacterial drugs by 2020 against “ESKAPE” bacteria, which include the Gram-negative Pseudomonas aeruginosa , Acinetobacter baumannii and Enterobacteriaceae (i.e. Escherichia coli and Klebsiella pneumoniae ) and the Gram-positive Enterococcus faecium and Staphylococcus aureus 13 . Furthermore, in 2012 the Innovative Medicines Initiative (IMI, co-funded by the European Union and EFPIA pharmaceutical companies) launched a €223 million New Drugs 4 Bad Bugs (ND4BB) program to spur the development of new antibiotics 5 , 14 , 15 . A major goal in antimicrobial drug discovery is the generation of new compounds capable of selectively killing resistant pathogens, possibly by novel mechanisms of action that could impede the development of resistance in the microorganisms. Natural antimicrobial peptides (AMPs) have become a new class of antibiotics used to treat resistant bacterial infections including septic-shock 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 . They are a unique and diverse group of molecules produced by a variety of plant, invertebrate and higher animal species. Despite the diversity of their structures, most of them share common features, such as an amphipathic character and several charged residues. Similar structural features have been successfully induced in biodegradable antimicrobial polymers and nanostructures 29 . It has been claimed that the use of antibacterial agents that disrupt the membrane bilayer is a promising alternative approach to regular antibiotic action, since such agents have the additional advantage of being active against dormant bacteria (with slow or even no growth). Such metabolically inactive organisms can survive high concentrations of classic antibiotics and extended treatment is therefore required for drug efficacy 30 . Altogether it is evident that there is a clear unmet medical need in the field of infectious diseases and new, broad-spectrum and safer antibiotics are urgently required, particularly to fight extended and pandrug-resistant bacteria. Results and Discussion Design of compounds Inspired by natural cyclic AMPs, particularly polymyxins, we embarked on a project to design cyclic lipopeptides with a chemically accessible scaffold structure, high activity and low toxicity. Since polymyxins are selective for Gram-negative bacteria, we also wished to explore features that could lead to potential activity against Gram-positive bacteria, particularly S. aureus . From the structural point of view, polymyxin B (PxB) and polymyxin E (PxE, colistin) are lipopeptide macrolactams with a tail-to-side-chain amide bond ( Fig. 1 ), while the fatty acid moiety typically contains a stereocenter. Although the preparation of natural polymyxins via different synthetic routes has been reported, these two structural features would presumably complicate the synthesis of multiple analogs and the large-scale preparation of multigram (or kg) amounts for future clinical and therapeutic applications. One of our first objectives was therefore to reduce the complexity of the macrocyclic backbone scaffold. A plausible approach would consist of substituting the amide bond by an isosteric and more chemically accessible link, such as a disulfide bond. Disulfides are also chemical linkages present in some cyclic peptide drugs, as discussed below. Loop structures linked by disulfide bonds are not uncommon in cyclic AMPs. Examples are found in bactenicin (from cattle), lactoferricin, brevinins (from the frog Rana brevipoda ), ranalexin (from the frog Rana catesbeiana ), esculentin (from the frog Rana esculenta ) and pipinin (from the frog Rana pipiens ). The similarity between the macrocyclic heptapeptide structure in ranalexin and polymyxin was already noted by Zasloff 31 . Figure 1 General structure of the cyclolipopeptide analogs (upper left, analog 1 , see Table 1 ). The structural and chemical features discussed for the design of the analogs are highlighted. Natural polymyxin B is shown below. The structure of lanreotide (right), a commercially available disulfide cyclic peptide having two D-amino acids is shown for comparison. Lanreotide is used for the treatment", "role": "user" }, { "content": "A group of researchers, led by Francesc Rabanal, professor in the Department of Organic Chemistry of the University of Barcelona (UB), has published the first results of a study of a new antibacterial compound based on natural peptides capable of selectively killing resistant pathogens. The study has proved that these compounds are highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests have showed compounds' low toxicity. Bacterial resistance to almost all available antibiotics is an important public health issue. Moreover, the development of effective antibiotics has slowed down. Only seven new antibiotics were approved by the Food and Drug Administration (FDA) from 2003 to 2012 (only two new classes since 1998). All this makes it clear that there is an urgent need to develop new antibiotics against bacteria that are prone to acquire resistance to the antibiotics currently in use, particularly Gram-negative bacteria. To give an example, more people die in USA of methicillin-resistant Staphylococcus aureus than of AIDS. \"The main goal of the study has been to design, synthetize and prove in vitro activity and in vivo toxicity of a new series of polymyxin, which present potential advantages over currently existing antibiotics\", explains Francesc Rabanal, member of the European consortium ENABLE. \"One of these advantages is that these antibiotics can act against Gram-negative bacteria, including resistant and multi-resistant strains, which are the most dangerous from the point of view of public health; in addition, they show activity against S. aureus (Gram-positive bacteria)\", concludes the UB researcher. The institutions who have participated in the project are the Faculty of Chemistry, the Faculty of Pharmacy and the Centre of Research in Toxicology (CERETOX), in the case of the University of Barcelona, as well as the Barcelona Institute for Global Health (CRESIB-ISGlobal) and the Hospital Clínic de Barcelona. Bioinspired compounds New compounds designed by Catalan researchers are inspired by cyclic natural antimicrobial peptides (AMPs), particularly polymyxins, a polypeptide antibiotic produced by a Bacillus polymyxa strain which shows some toxicity problems even if it is used as last resort option at hospitals. Design has included a disulphide bond in polymyxin structure which facilitates large-scale synthesis and reduces toxicity. \"The main objective of the study was to design cyclic lipopeptides with a chemically accessible structure, high activity and low toxicity\", emphasizes Rabanal. \"The next step is to optimise this prototype compound (named hit in the field of pharmacy) in order to obtain a therapeutic candidate (lead) that could be developed in clinical trials and get the market\", concludes the researcher. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain. Introduction Infectious diseases are the second most common cause of death worldwide. While multidrug resistance is observed in both Gram-positive and Gram-negative bacteria, two thirds of deaths are due to infection by Gram-negative bacteria 1 . Antibiotic-resistant bacteria have emerged as a major problem, especially for hospital-acquired infections and the economic cost of multi-drug-resistant bacterial infections is immense. Of the 2 million people infected in the EU every year, some 175,000 (about 9%) die 2 . The Centre for Disease Control and Prevention (CDC) in Atlanta similarly estimates that in the USA, more than 2 million patients acquire antibiotic-resistant infections every year, of who at least 23,000 die 3 . Currently, more people die in USA of methicillin‐resistant Staphylococcus aureus than of AIDS. Meanwhile, the development of effective antibiotics has slowed down. Only seven new antibiotics were approved by the FDA from 2003 to 2012 (only two new classes since 1998), most of them effective against Gram-positive bacteria 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 . All this makes it clear that there is an urgent need to develop new antibiotics against bacteria that are prone to acquire resistance to the antibiotics currently in use. The Infectious Disease Society of America has issued a proposal to develop new antibacterial drugs by 2020 against “ESKAPE” bacteria, which include the Gram-negative Pseudomonas aeruginosa , Acinetobacter baumannii and Enterobacteriaceae (i.e. Escherichia coli and Klebsiella pneumoniae ) and the Gram-positive Enterococcus faecium and Staphylococcus aureus 13 . Furthermore, in 2012 the Innovative Medicines Initiative (IMI, co-funded by the European Union and EFPIA pharmaceutical companies) launched a €223 million New Drugs 4 Bad Bugs (ND4BB) program to spur the development of new antibiotics 5 , 14 , 15 . A major goal in antimicrobial drug discovery is the generation of new compounds capable of selectively killing resistant pathogens, possibly by novel mechanisms of action that could impede the development of resistance in the microorganisms. Natural antimicrobial peptides (AMPs) have become a new class of antibiotics used to treat resistant bacterial infections including septic-shock 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 . They are a unique and diverse group of molecules produced by a variety of plant, invertebrate and higher animal species. Despite the diversity of their structures, most of them share common features, such as an amphipathic character and several charged residues. Similar structural features have been successfully induced in biodegradable antimicrobial polymers and nanostructures 29 . It has been claimed that the use of antibacterial agents that disrupt the membrane bilayer is a promising alternative approach to regular antibiotic action, since such agents have the additional advantage of being active against dormant bacteria (with slow or even no growth). Such metabolically inactive organisms can survive high concentrations of classic antibiotics and extended treatment is therefore required for drug efficacy 30 . Altogether it is evident that there is a clear unmet medical need in the field of infectious diseases and new, broad-spectrum and safer antibiotics are urgently required, particularly to fight extended and pandrug-resistant bacteria. Results and Discussion Design of compounds Inspired by natural cyclic AMPs, particularly polymyxins, we embarked on a project to design cyclic lipopeptides with a chemically accessible scaffold structure, high activity and low toxicity. Since polymyxins are selective for Gram-negative bacteria, we also wished to explore features that could lead to potential activity against Gram-positive bacteria, particularly S. aureus . From the structural point of view, polymyxin B (PxB) and polymyxin E (PxE, colistin) are lipopeptide macrolactams with a tail-to-side-chain amide bond ( Fig. 1 ), while the fatty acid moiety typically contains a stereocenter. Although the preparation of natural polymyxins via different synthetic routes has been reported, these two structural features would presumably complicate the synthesis of multiple analogs and the large-scale preparation of multigram (or kg) amounts for future clinical and therapeutic applications. One of our first objectives was therefore to reduce the complexity of the macrocyclic backbone scaffold. A plausible approach would consist of substituting the amide bond by an isosteric and more chemically accessible link, such as a disulfide bond. Disulfides are also chemical linkages present in some cyclic peptide drugs, as discussed below. Loop structures linked by disulfide bonds are not uncommon in cyclic AMPs. Examples are found in bactenicin (from cattle), lactoferricin, brevinins (from the frog Rana brevipoda ), ranalexin (from the frog Rana catesbeiana ), esculentin (from the frog Rana esculenta ) and pipinin (from the frog Rana pipiens ). The similarity between the macrocyclic heptapeptide structure in ranalexin and polymyxin was already noted by Zasloff 31 . Figure 1 General structure of the cyclolipopeptide analogs (upper left, analog 1 , see Table 1 ). The structural and chemical features discussed for the design of the analogs are highlighted. Natural polymyxin B is shown below. The structure of lanreotide (right), a commercially available disulfide cyclic peptide having two D-amino acids is shown for comparison. Lanreotide is used for the treatment<|im_end|> <|im_start|>assistant A group of researchers, led by Francesc Rabanal, professor in the Department of Organic Chemistry of the University of Barcelona (UB), has published the first results of a study of a new antibacterial compound based on natural peptides capable of selectively killing resistant pathogens. The study has proved that these compounds are highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests have showed compounds' low toxicity. Bacterial resistance to almost all available antibiotics is an important public health issue. Moreover, the development of effective antibiotics has slowed down. Only seven new antibiotics were approved by the Food and Drug Administration (FDA) from 2003 to 2012 (only two new classes since 1998). All this makes it clear that there is an urgent need to develop new antibiotics against bacteria that are prone to acquire resistance to the antibiotics currently in use, particularly Gram-negative bacteria. To give an example, more people die in USA of methicillin-resistant Staphylococcus aureus than of AIDS. "The main goal of the study has been to design, synthetize and prove in vitro activity and in vivo toxicity of a new series of polymyxin, which present potential advantages over currently existing antibiotics", explains Francesc Rabanal, member of the European consortium ENABLE. "One of these advantages is that these antibiotics can act against Gram-negative bacteria, including resistant and multi-resistant strains, which are the most dangerous from the point of view of public health; in addition, they show activity against S. aureus (Gram-positive bacteria)", concludes the UB researcher. The institutions who have participated in the project are the Faculty of Chemistry, the Faculty of Pharmacy and the Centre of Research in Toxicology (CERETOX), in the case of the University of Barcelona, as well as the Barcelona Institute for Global Health (CRESIB-ISGlobal) and the Hospital Clínic de Barcelona. Bioinspired compounds New compounds designed by Catalan researchers are inspired by cyclic natural antimicrobial peptides (AMPs), particularly polymyxins, a polypeptide antibiotic produced by a Bacillus polymyxa strain which shows some toxicity problems even if it is used as last resort option at hospitals. Design has included a disulphide bond in polymyxin structure which facilitates large-scale synthesis and reduces toxicity. "The main objective of the study was to design cyclic lipopeptides with a chemically accessible structure, high activity and low toxicity", emphasizes Rabanal. "The next step is to optimise this prototype compound (named hit in the field of pharmacy) in order to obtain a therapeutic candidate (lead) that could be developed in clinical trials and get the market", concludes the researcher. <|im_end|>

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9610, 315, 1694, 4642, 2403, 89460, 24032, 320, 4291, 6435, 477, 1524, 912, 6650, 570, 15483, 28168, 2740, 32899, 44304, 649, 18167, 1579, 32466, 315, 11670, 46850, 323, 11838, 6514, 374, 9093, 2631, 369, 5623, 41265, 220, 966, 662, 54370, 3522, 433, 374, 30576, 430, 1070, 374, 264, 2867, 653, 4150, 6593, 1205, 304, 279, 2115, 315, 50600, 19338, 323, 502, 11, 7353, 1355, 39806, 323, 30549, 46850, 527, 77720, 2631, 11, 8104, 311, 4465, 11838, 323, 12495, 73047, 47056, 24032, 13, 18591, 323, 36613, 7127, 315, 32246, 65925, 555, 5933, 77102, 64008, 82, 11, 8104, 46033, 52926, 1354, 11, 584, 79120, 389, 264, 2447, 311, 2955, 77102, 19588, 2862, 74489, 449, 264, 8590, 2740, 15987, 85552, 6070, 11, 1579, 5820, 323, 3428, 58011, 13, 8876, 46033, 52926, 1354, 527, 44010, 369, 29937, 62035, 24032, 11, 584, 1101, 37287, 311, 13488, 4519, 430, 1436, 3063, 311, 4754, 5820, 2403, 29937, 69788, 24032, 11, 8104, 328, 13, 86768, 355, 662, 5659, 279, 24693, 1486, 315, 1684, 11, 46033, 52926, 258, 426, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Familial Parkinson disease (PD) is associated with rare genetic mutations, but the etiology in most patients with sporadic (s)PD is largely unknown, and the basis for its progression to dementia (sPDD) is poorly characterized. We have identified that loss of IFNβ or IFNAR1, the receptor for IFNα/β, causes pathological and behavioral changes resembling PDD, prompting us to hypothesize that dysregulated genes in IFNβ-IFNAR signaling pathway predispose one to sPD. By transcriptomic analysis, we found defective neuronal IFNβ-IFNAR signaling, including particularly elevated PIAS2 associated with sPDD. With meta-analysis of GWASs, we identified sequence variants in IFNβ-IFNAR-related genes in sPD patients. Furthermore, sPDD patients expressed higher levels of PIAS2 mRNA and protein in neurons. To determine its function in brain, we overexpressed PIAS2 under a neuronal promoter, alone or with human α-synuclein, in the brains of mice, which caused motor and cognitive impairments and correlated with intraneuronal phosphorylated (p)α-synuclein accumulation and dopaminergic neuron loss. Ectopic expression of neuronal PIAS2 blocked mitophagy, increased the accumulation of senescent mitochondrial and oxidative stress, as evidenced by excessive oxDJ1 and 8OHdG, by inactivating ERK1/2-P53 signaling. Conversely, PIAS2 knockdown rescued the clinicopathological manifestations of PDD in Ifnb –/– mice on restoring mitochondrial homeostasis, oxidative stress, and pERK1/2-pP53 signaling. The regulation of JAK-STAT2-PIAS2 signaling was crucial for neurite outgrowth and neuronal survival and excitability and thus might prevent cognitive impairments. Our findings provide insights into the progression of sPD and dementia and have implications for new therapeutic approaches. Introduction The etiology of sporadic Parkinson disease (sPD) is unknown, which complicates its treatment. However, studies of rare familial forms of this disorder have prompted its examination genomewide. All PD patients experience motor dysfunction due to loss of dopaminergic neurons in the substantia nigra (SN), correlating with pathogenic α-synuclein (α-syn) aggregates and Lewy bodies [ 1 ]. These aggregates amass in an increasingly larger area of the brain as PD progresses and causes such secondary symptoms as dementia [ 1 , 2 ]. Several mutations have been identified (such as SNCA, LRRK2, DJ1, and Parkin) that are associated with familial PD [ 3 ] and some of which have been implicated in sPD [ 4 ]. However, familial forms only constitute approximately 5% of all PD cases [ 5 , 6 ]—the origin of the remaining sporadic cases remains unknown. Although sPD does not pass through familial inheritance, a genetic predisposition, in combination with environmental factors, could drive its pathology. If this predisposition is linked to several gene variants in the same pathway, the association of each gene with sPD might be weak and thus excluded in large conventional genetic association studies with strict thresholds. To include such variants, one could perform a meta-analysis of genomewide association studies (GWASs) [ 7 ] and gene set enrichment analysis (GSEA) [ 8 ]. We have reported that the lack of functional interferon-beta ( Ifnb ) or its receptor, interferon-α/β receptor ( Ifnar ), causes age-dependent development of PD-like pathology, including the accumulation of α-syn aggregates and Lewy bodies, in association with motor and cognitive dysfunction [ 9 ]. The absence of Ifnar from neuroectodermal cells (Nes cre Ifnar fl/fl ) is sufficient to drive the pathology. Ifnb is a type I IFN and an immunoregulatory cytokine that participates in innate antiviral immune defense and regulates neuroinflammation [ 10 , 11 , 12 , 13 , 14 , 15 ]. The progression of PD is associated with neuroinflammation, including the activation of resident microglia and astrocytes, which exacerbates the pathology in the late stage of the disease [ 16 ]. However, the function of Ifnb signaling in neurodegeneration and neuroinflammation in sPD patients has not been determined. The transcription and subsequent secretion of type I IFNs are induced on viral infection via Toll-like receptor signaling [ 11 ], MAVS [ 17 ], and RIG-I [ 18 ] and is orchestrated by STING-cGAS [ 19 ]. Extracellular IFN-β activates the JAK-STAT pathway on binding its receptor, IFNAR, inducing intracellular phosphorylation and nuclear translocation of STAT proteins for transcriptional initiation through interferon-stimulated responsive elements and gamma-activated sequences [ 20 ]. STATs are negatively regulated by protein inhibitors of STAT (PIASs), but their involvement in PD is unknown. Protein inhibitor of STAT2 (PIAS2) is a negative regulator of STAT [ 21 ] and IFN-β signaling [ 22 ] and has SUMO E3 ligase activity [ 23 ]. PIAS2 was recently shown to stabilize α-syn by counteracting its ubiquitin-mediated degradation, promoting its intracellular aggregation [ 24 ]. In light of our recent findings of the relevance of defective IFNβ−IFNAR1 signaling to cause a Parkinson disease dementia (PDD)-like pathology in mice [ 9 ], we examined whether and how defective type I IFN signaling is associated with sporadic PD and its progression to dementia. Notably, genes in this pathway were significantly dysregulated in sPD patients—especially those with dementia. Moreover, we identified single-nucleotide polymorphism (SNP) variants in several of these genes that correlated with sPD, including PIAS2. PIAS2 was upregulated in the neurons of sPD patients, particularly in the brains of patients with sPDD. These findings prompted us to study how PIAS2 impacts the clinical and pathological aspects of PD—specifically, the cognitive functions that are associated with its progression to dementia. Overexpression of PIAS2 alone was sufficient to cause PD-like dementia and major pathological trademarks of PDD in mice, whereas its knockdown in vivo reversed the PD-like dementia and pathology in Ifnb –/– mice, implicating it as a driver of PD pathology. Materials and methods Brain samples from sporadic PD patients and healthy controls Human brain samples for reverse-transcription quantitative real-time (RT-q)PCR and IHC were dissected from the medial frontal gyrus, snap-frozen, and stored at −80 °C prior to analysis. Sporadic PD brain samples—sporadic Parkinson disease nondementia (sPDND) ( n = 10), sPDD ( n = 3), and healthy controls (HCs) ( n = 10)—were acquired from the Harvard Brain Tissue Resource Center (Harvard Medical School, USA), Bispebjerg Hospital Brain Bank (Copenhagen, Denmark/BBH-2017-001, I-suite nr: 05190), and Netherlands Brain Bank (the Netherlands) [ethics (DNK) approval, jr. no. H-16025210].", "role": "user" }, { "content": "12,000 people in Denmark and 7 to 10 million people worldwide suffer from Parkinson's Disease (PD). It is the second most common neurogenerative disorder of aging and the most common movement disorder, but the cause of the disease is largely unknown. In a new study, researchers from the University of Copenhagen show that the most common form of the disease, encompassing 90 to 95 percent of all Parkinson's Disease cases known as sporadic PD, is caused by a blockage of a pathway that regulates the nerve cell's powerhouse, the mitochondria. \"Just like when people eat, cells take what they need and get rid of the rest waste products. But if our brain cells have this specific kind of signaling blockage, it means that the powerhouse of the cell—mitochondria—cannot get cleaned up after being damaged,\" explains corresponding author and group leader Professor Shohreh Issazadeh-Navikas at the Biotech Research & Innovation Centre. The blockage leads to an accumulation of high amounts of damaged mitochondria, while not being able to produce enough energy for the cells. It causes neurons to gradually die, which is the reason for the development of Parkinson's Disease symptoms, and why it leads to dementia. The blockage is caused by a dysregulation of the immune genes, more specifically a pathway called type 1 interferon, which is normally important for fight against viruses, but now we show that it is also responsible for regulating the energy supply of the nerve cells. \"Every part of our body needs to be regulated. We get a signal to stop eating, when we are full, and the same thing happens everywhere else in our body. If we get an infection, parts of our body need to fight it and stop it from replicating. But when the infection is cleaned up, the signal should subside. This is the job of a protein called PIAS2. That causes the blockage of the type 1 interferon-pathway, and when the infection is over, the blockage should stop and go back to normal. But that does not seem to be the case in patients with Parkinson's Disease. We further demonstrate that this dysregulation leads to a defect in the mitochondrial energy supply, as mentioned before,\" says Issazadeh-Navikas. These pathways are very important for brain functions, but they are also associated with microbial and virus recognition. For example, they are very important for fighting COVID-19, and a mutation in the related gene has been shown to be linked to a deadly outcome after contracting COVID-19. The researchers combined and analyzed four data sets, which studied neurons from brains with Parkinson's Disease and looked at what type of genes they express. They then looked at which gene patterns were disturbed in patients with Parkinson's Disease and especially those who had also developed PD with dementia. In order to test the results, the major findings of the combined data was tried in three different mouse models using a negative regulator of the type I interferon pathway, PIAS2, which had been identified from the patients study as one of the key proteins linked to the progression of Parkinson's Disease and dementia. \"We show that a high accumulation of the PIAS2-protein is what is causing the blockage in the pathway, which should have activated the processes responsible for removing damaged protein and mitochondrial garbage,\" says Issazadeh-Navikas. \"The accumulation of damaged mitochondrial mass further leads to increase of other toxic proteins. So when we compare patients to same-aged healthy patients without Parkinson's Disease, we see that this PIAS2-protein is highly expressed in the neurons, which is why this pathway should be evaluated for potential roles in the other forms of familial Parkinson's Disease that we have not studied here.\" The researchers hope the study will encourage research to counteract the pathway blockage, which could have a beneficial impact on the disease and towards preventing dementia. In the next stages, the Issazadeh-Navikas group will study how the pathway contributes to neuronal homeostasis and survival, as well as how its dysregulation causes neuronal cell death. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Familial Parkinson disease (PD) is associated with rare genetic mutations, but the etiology in most patients with sporadic (s)PD is largely unknown, and the basis for its progression to dementia (sPDD) is poorly characterized. We have identified that loss of IFNβ or IFNAR1, the receptor for IFNα/β, causes pathological and behavioral changes resembling PDD, prompting us to hypothesize that dysregulated genes in IFNβ-IFNAR signaling pathway predispose one to sPD. By transcriptomic analysis, we found defective neuronal IFNβ-IFNAR signaling, including particularly elevated PIAS2 associated with sPDD. With meta-analysis of GWASs, we identified sequence variants in IFNβ-IFNAR-related genes in sPD patients. Furthermore, sPDD patients expressed higher levels of PIAS2 mRNA and protein in neurons. To determine its function in brain, we overexpressed PIAS2 under a neuronal promoter, alone or with human α-synuclein, in the brains of mice, which caused motor and cognitive impairments and correlated with intraneuronal phosphorylated (p)α-synuclein accumulation and dopaminergic neuron loss. Ectopic expression of neuronal PIAS2 blocked mitophagy, increased the accumulation of senescent mitochondrial and oxidative stress, as evidenced by excessive oxDJ1 and 8OHdG, by inactivating ERK1/2-P53 signaling. Conversely, PIAS2 knockdown rescued the clinicopathological manifestations of PDD in Ifnb –/– mice on restoring mitochondrial homeostasis, oxidative stress, and pERK1/2-pP53 signaling. The regulation of JAK-STAT2-PIAS2 signaling was crucial for neurite outgrowth and neuronal survival and excitability and thus might prevent cognitive impairments. Our findings provide insights into the progression of sPD and dementia and have implications for new therapeutic approaches. Introduction The etiology of sporadic Parkinson disease (sPD) is unknown, which complicates its treatment. However, studies of rare familial forms of this disorder have prompted its examination genomewide. All PD patients experience motor dysfunction due to loss of dopaminergic neurons in the substantia nigra (SN), correlating with pathogenic α-synuclein (α-syn) aggregates and Lewy bodies [ 1 ]. These aggregates amass in an increasingly larger area of the brain as PD progresses and causes such secondary symptoms as dementia [ 1 , 2 ]. Several mutations have been identified (such as SNCA, LRRK2, DJ1, and Parkin) that are associated with familial PD [ 3 ] and some of which have been implicated in sPD [ 4 ]. However, familial forms only constitute approximately 5% of all PD cases [ 5 , 6 ]—the origin of the remaining sporadic cases remains unknown. Although sPD does not pass through familial inheritance, a genetic predisposition, in combination with environmental factors, could drive its pathology. If this predisposition is linked to several gene variants in the same pathway, the association of each gene with sPD might be weak and thus excluded in large conventional genetic association studies with strict thresholds. To include such variants, one could perform a meta-analysis of genomewide association studies (GWASs) [ 7 ] and gene set enrichment analysis (GSEA) [ 8 ]. We have reported that the lack of functional interferon-beta ( Ifnb ) or its receptor, interferon-α/β receptor ( Ifnar ), causes age-dependent development of PD-like pathology, including the accumulation of α-syn aggregates and Lewy bodies, in association with motor and cognitive dysfunction [ 9 ]. The absence of Ifnar from neuroectodermal cells (Nes cre Ifnar fl/fl ) is sufficient to drive the pathology. Ifnb is a type I IFN and an immunoregulatory cytokine that participates in innate antiviral immune defense and regulates neuroinflammation [ 10 , 11 , 12 , 13 , 14 , 15 ]. The progression of PD is associated with neuroinflammation, including the activation of resident microglia and astrocytes, which exacerbates the pathology in the late stage of the disease [ 16 ]. However, the function of Ifnb signaling in neurodegeneration and neuroinflammation in sPD patients has not been determined. The transcription and subsequent secretion of type I IFNs are induced on viral infection via Toll-like receptor signaling [ 11 ], MAVS [ 17 ], and RIG-I [ 18 ] and is orchestrated by STING-cGAS [ 19 ]. Extracellular IFN-β activates the JAK-STAT pathway on binding its receptor, IFNAR, inducing intracellular phosphorylation and nuclear translocation of STAT proteins for transcriptional initiation through interferon-stimulated responsive elements and gamma-activated sequences [ 20 ]. STATs are negatively regulated by protein inhibitors of STAT (PIASs), but their involvement in PD is unknown. Protein inhibitor of STAT2 (PIAS2) is a negative regulator of STAT [ 21 ] and IFN-β signaling [ 22 ] and has SUMO E3 ligase activity [ 23 ]. PIAS2 was recently shown to stabilize α-syn by counteracting its ubiquitin-mediated degradation, promoting its intracellular aggregation [ 24 ]. In light of our recent findings of the relevance of defective IFNβ−IFNAR1 signaling to cause a Parkinson disease dementia (PDD)-like pathology in mice [ 9 ], we examined whether and how defective type I IFN signaling is associated with sporadic PD and its progression to dementia. Notably, genes in this pathway were significantly dysregulated in sPD patients—especially those with dementia. Moreover, we identified single-nucleotide polymorphism (SNP) variants in several of these genes that correlated with sPD, including PIAS2. PIAS2 was upregulated in the neurons of sPD patients, particularly in the brains of patients with sPDD. These findings prompted us to study how PIAS2 impacts the clinical and pathological aspects of PD—specifically, the cognitive functions that are associated with its progression to dementia. Overexpression of PIAS2 alone was sufficient to cause PD-like dementia and major pathological trademarks of PDD in mice, whereas its knockdown in vivo reversed the PD-like dementia and pathology in Ifnb –/– mice, implicating it as a driver of PD pathology. Materials and methods Brain samples from sporadic PD patients and healthy controls Human brain samples for reverse-transcription quantitative real-time (RT-q)PCR and IHC were dissected from the medial frontal gyrus, snap-frozen, and stored at −80 °C prior to analysis. Sporadic PD brain samples—sporadic Parkinson disease nondementia (sPDND) ( n = 10), sPDD ( n = 3), and healthy controls (HCs) ( n = 10)—were acquired from the Harvard Brain Tissue Resource Center (Harvard Medical School, USA), Bispebjerg Hospital Brain Bank (Copenhagen, Denmark/BBH-2017-001, I-suite nr: 05190), and Netherlands Brain Bank (the Netherlands) [ethics (DNK) approval, jr. no. H-16025210].<|im_end|> <|im_start|>assistant 12,000 people in Denmark and 7 to 10 million people worldwide suffer from Parkinson's Disease (PD). It is the second most common neurogenerative disorder of aging and the most common movement disorder, but the cause of the disease is largely unknown. In a new study, researchers from the University of Copenhagen show that the most common form of the disease, encompassing 90 to 95 percent of all Parkinson's Disease cases known as sporadic PD, is caused by a blockage of a pathway that regulates the nerve cell's powerhouse, the mitochondria. "Just like when people eat, cells take what they need and get rid of the rest waste products. But if our brain cells have this specific kind of signaling blockage, it means that the powerhouse of the cell—mitochondria—cannot get cleaned up after being damaged," explains corresponding author and group leader Professor Shohreh Issazadeh-Navikas at the Biotech Research & Innovation Centre. The blockage leads to an accumulation of high amounts of damaged mitochondria, while not being able to produce enough energy for the cells. It causes neurons to gradually die, which is the reason for the development of Parkinson's Disease symptoms, and why it leads to dementia. The blockage is caused by a dysregulation of the immune genes, more specifically a pathway called type 1 interferon, which is normally important for fight against viruses, but now we show that it is also responsible for regulating the energy supply of the nerve cells. "Every part of our body needs to be regulated. We get a signal to stop eating, when we are full, and the same thing happens everywhere else in our body. If we get an infection, parts of our body need to fight it and stop it from replicating. But when the infection is cleaned up, the signal should subside. This is the job of a protein called PIAS2. That causes the blockage of the type 1 interferon-pathway, and when the infection is over, the blockage should stop and go back to normal. But that does not seem to be the case in patients with Parkinson's Disease. We further demonstrate that this dysregulation leads to a defect in the mitochondrial energy supply, as mentioned before," says Issazadeh-Navikas. These pathways are very important for brain functions, but they are also associated with microbial and virus recognition. For example, they are very important for fighting COVID-19, and a mutation in the related gene has been shown to be linked to a deadly outcome after contracting COVID-19. The researchers combined and analyzed four data sets, which studied neurons from brains with Parkinson's Disease and looked at what type of genes they express. They then looked at which gene patterns were disturbed in patients with Parkinson's Disease and especially those who had also developed PD with dementia. In order to test the results, the major findings of the combined data was tried in three different mouse models using a negative regulator of the type I interferon pathway, PIAS2, which had been identified from the patients study as one of the key proteins linked to the progression of Parkinson's Disease and dementia. "We show that a high accumulation of the PIAS2-protein is what is causing the blockage in the pathway, which should have activated the processes responsible for removing damaged protein and mitochondrial garbage," says Issazadeh-Navikas. "The accumulation of damaged mitochondrial mass further leads to increase of other toxic proteins. So when we compare patients to same-aged healthy patients without Parkinson's Disease, we see that this PIAS2-protein is highly expressed in the neurons, which is why this pathway should be evaluated for potential roles in the other forms of familial Parkinson's Disease that we have not studied here." The researchers hope the study will encourage research to counteract the pathway blockage, which could have a beneficial impact on the disease and towards preventing dementia. In the next stages, the Issazadeh-Navikas group will study how the pathway contributes to neuronal homeostasis and survival, as well as how its dysregulation causes neuronal cell death. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Four-dimensional (4D) printing of shape memory polymer (SMP) imparts time responsive properties to 3D structures. Here, we explore 4D printing of a SMP in the submicron length scale, extending its applications to nanophononics. We report a new SMP photoresist based on Vero Clear achieving print features at a resolution of ~300 nm half pitch using two-photon polymerization lithography (TPL). Prints consisting of grids with size-tunable multi-colours enabled the study of shape memory effects to achieve large visual shifts through nanoscale structure deformation. As the nanostructures are flattened, the colours and printed information become invisible. Remarkably, the shape memory effect recovers the original surface morphology of the nanostructures along with its structural colour within seconds of heating above its glass transition temperature. The high-resolution printing and excellent reversibility in both microtopography and optical properties promises a platform for temperature-sensitive labels, information hiding for anti-counterfeiting, and tunable photonic devices. Introduction 4D printing 1 , 2 , 3 brings together the design flexibility of 3D printing with stimuli responsive properties of its constituent materials. It continues to generate excitement in diverse fields, e.g., soft robotics 4 , 5 , 6 , drug delivery 7 , 8 , flexible electronics 9 , 10 and tissue engineering 11 . Commonly used printing methods for 4D printing include direct ink writing 3 , 12 , Polyjet 13 , 14 , Digital Light Processing (DLP) lithography 15 , 16 and Stereolithography (SLA) 17 , 18 . The material and lithographic challenges inherent to these methods limit the minimum feature size of printed structures to ~10 μm 19 . At an order of magnitude smaller, submicron scale features that interact strongly with light have yet to be systematically explored in 4D printing. The motivation to improve print resolution is fuelled by applications in optics, e.g. structural colour generation 20 , 21 , temperature-sensitive passive labels and colorimetric pressure sensors, all of which require submicron resolution and precision. Traditionally, different structures such as gratings 22 , 23 , thin films and multilayers 24 , 25 , localised resonance structures 26 , 27 generate fixed colours without the use of pigments. Recently, dynamically reconfigurable colours have gained interest, where optical responses of nanostructures can be tuned either by changing the refractive index 28 , 29 , 30 or dimensions 31 , 32 of the structures. Of these methods, tuning the dimensions of the optical devices by shape memory polymers (SMPs) is of interest due to their relatively short response times (seconds to minutes depending on actuation temperature 33 ). Distinct from the pattering of SMPs through nanoimprinting 34 , 35 , 36 and self-assembly 37 , 38 , 39 , our use of 3D printing introduced here will lead to direct patterning of complex structures at will, bringing together fields of mechanical and optical metamaterials with local control of properties, e.g., colours 40 , phase and Young’s modulus. To print finer 3D structures, we develop a new resist suited for two-photon polymerization lithography (TPL) 6 , 41 , 42 . Here, photo-initiators in a liquid resin are excited by a two-photon absorption process within the focal region of a femtosecond laser. Polymerisation and crosslinking then ensue. Printed features as small as ~10 nm can be achieved under specific conditions 43 . Due to the high resolution it provides, TPL has been used to print different stimuli responsive materials such as hydrogels 6 , 44 , liquid crystal elastomers 41 , 45 , magnetic nanoparticles embedded resists 46 , 47 , silicon functionalized monomers 48 and other examples printing 49 . Recently, hydrogel photoresists have been used for tunable photonic devices. Marc et al. 50 used a cholesteric liquid crystals (LC)-based hydrogel resist to change colours at microscale. In their work, colours were tuned within a limited range by changing the intrinsic periodicity of chiral LC. Tao et al. 51 demonstrated a hydrogel based reconfigurable photonic crystals exhibiting colour shifts in the presence of humidity. In contrast to previous works reporting colour shifts, our work investigates submicron 4D printing where large and rapid visual responses are achieved as nanostructures recover from a flattened (colourless) state to an upright (colourful) state. The visual effect is analogous to a letter written in multiple colours of invisible ink where secret information is revealed, e.g., with the application of heat. We tackled two key challenges in (1) developing and characterising new stimuli responsive resists suitable for TPL, and (2) designing and fabricating robust 3D photonic structures capable of rapid recovery after being flattened. In this work, we meet these challenges by additive manufacturing of SMP for programmable colour generation. We developed and characterised a SMP photoresist suited for TPL based on Vero Clear 13 , which is an optically transparent thermosetting polymer resin containing acrylate functional group. We performed resolution tests achieving ~300 nm half pitch gratings and measured the thermodynamic properties of the new resist to determine an optimal composition for robust mechanical performance. A range of structural colours were achieved by controlling the geometry of the crosslinked SMP structures at the submicron level. We realised colour switching behaviour by heating and deforming (i.e., programming) the printed structure at a temperature higher than the glass transition temperature ( T g ). Remarkably, the deformed nanostructures exhibited excellent recovery when heated above its composition-adjustable T g . This reversibility in both structural features and optical responses demonstrate significant promise for submicron scale additive manufacturing of SMPs. Results Two-photon polymerization lithography of shape memory polymer We designed structures consisting of a base layer with submicron-scale grids on top of it, as shown in Fig. 1 . Due to the interaction of these nanostructures with light, i.e., scattering and interference, the 3D printed structures function as colour filters, preferentially transmitting certain wavelength ranges of an incident white light illumination. Colours depend sensitively on the geometric parameters of the grid, i.e., grid height h 2 , and grid linewidth w 1 , while it is less sensitive to pitch w 2 and the thickness of the base", "role": "user" }, { "content": "The Singapore University of Technology and Design (SUTD) and its research collaborators have successfully demonstrated the four-dimensional (4-D) printing of shape memory polymers in submicron dimensions which are comparable to the wavelength of visible light. This novel development has allowed researchers to now explore new applications in the field of nanophotonics. 4-D printing enables 3-D printed structures to change its configurations over time and is used in a wide variety of fields such as soft robotics, flexible electronics, and medical devices. Different materials such as hydrogels, liquid crystal elastomers and magnetic nanoparticles embedded resists along with corresponding printing methods like Direct Ink Writing (DIW), Polyjet, Digital Light Processing (DLP) lithography and Stereolithography (SLA) have been developed for 4-D printing. However, the material and patterning challenges inherent to these methods limit the resolution of 4-D printing to ~10 μm at best. To improve the resolution of 4-D printing, the research team developed a shape memory polymer (SMP) photoresist suitable for two-photon polymerization lithography (TPL). Integrating this newly developed resist with TPL, they investigated submicron 4-D printing of SMPs at which scale the printed structures can interact strongly with visible light. By programming with pressure and heat, the submicron structures can switch between colorless and colorful states (see image). \"It's remarkable that these 3-D printed nanostructures are able to recover their shapes and structural color after they've been mechanically flattened into a colorless, transparent state. This new resist that we've concocted allows for really fine structures to be printed while still retaining their properties as a shape memory polymer,\" said Associate Professor Joel K. W. Yang, principal investigator of the team from SUTD. \"By characterizing the photoresist, we printed the SMPs with ~300nm half pitch. The resolution is an order of magnitude higher than traditional high-resolution printing methods such as DLP and SLA. The dimensions of the structures can be conveniently controlled by varying the printing parameters such as laser power, write speed and nominal height,\" added Wang Zhang, first author and Ph.D. student from SUTD. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Four-dimensional (4D) printing of shape memory polymer (SMP) imparts time responsive properties to 3D structures. Here, we explore 4D printing of a SMP in the submicron length scale, extending its applications to nanophononics. We report a new SMP photoresist based on Vero Clear achieving print features at a resolution of ~300 nm half pitch using two-photon polymerization lithography (TPL). Prints consisting of grids with size-tunable multi-colours enabled the study of shape memory effects to achieve large visual shifts through nanoscale structure deformation. As the nanostructures are flattened, the colours and printed information become invisible. Remarkably, the shape memory effect recovers the original surface morphology of the nanostructures along with its structural colour within seconds of heating above its glass transition temperature. The high-resolution printing and excellent reversibility in both microtopography and optical properties promises a platform for temperature-sensitive labels, information hiding for anti-counterfeiting, and tunable photonic devices. Introduction 4D printing 1 , 2 , 3 brings together the design flexibility of 3D printing with stimuli responsive properties of its constituent materials. It continues to generate excitement in diverse fields, e.g., soft robotics 4 , 5 , 6 , drug delivery 7 , 8 , flexible electronics 9 , 10 and tissue engineering 11 . Commonly used printing methods for 4D printing include direct ink writing 3 , 12 , Polyjet 13 , 14 , Digital Light Processing (DLP) lithography 15 , 16 and Stereolithography (SLA) 17 , 18 . The material and lithographic challenges inherent to these methods limit the minimum feature size of printed structures to ~10 μm 19 . At an order of magnitude smaller, submicron scale features that interact strongly with light have yet to be systematically explored in 4D printing. The motivation to improve print resolution is fuelled by applications in optics, e.g. structural colour generation 20 , 21 , temperature-sensitive passive labels and colorimetric pressure sensors, all of which require submicron resolution and precision. Traditionally, different structures such as gratings 22 , 23 , thin films and multilayers 24 , 25 , localised resonance structures 26 , 27 generate fixed colours without the use of pigments. Recently, dynamically reconfigurable colours have gained interest, where optical responses of nanostructures can be tuned either by changing the refractive index 28 , 29 , 30 or dimensions 31 , 32 of the structures. Of these methods, tuning the dimensions of the optical devices by shape memory polymers (SMPs) is of interest due to their relatively short response times (seconds to minutes depending on actuation temperature 33 ). Distinct from the pattering of SMPs through nanoimprinting 34 , 35 , 36 and self-assembly 37 , 38 , 39 , our use of 3D printing introduced here will lead to direct patterning of complex structures at will, bringing together fields of mechanical and optical metamaterials with local control of properties, e.g., colours 40 , phase and Young’s modulus. To print finer 3D structures, we develop a new resist suited for two-photon polymerization lithography (TPL) 6 , 41 , 42 . Here, photo-initiators in a liquid resin are excited by a two-photon absorption process within the focal region of a femtosecond laser. Polymerisation and crosslinking then ensue. Printed features as small as ~10 nm can be achieved under specific conditions 43 . Due to the high resolution it provides, TPL has been used to print different stimuli responsive materials such as hydrogels 6 , 44 , liquid crystal elastomers 41 , 45 , magnetic nanoparticles embedded resists 46 , 47 , silicon functionalized monomers 48 and other examples printing 49 . Recently, hydrogel photoresists have been used for tunable photonic devices. Marc et al. 50 used a cholesteric liquid crystals (LC)-based hydrogel resist to change colours at microscale. In their work, colours were tuned within a limited range by changing the intrinsic periodicity of chiral LC. Tao et al. 51 demonstrated a hydrogel based reconfigurable photonic crystals exhibiting colour shifts in the presence of humidity. In contrast to previous works reporting colour shifts, our work investigates submicron 4D printing where large and rapid visual responses are achieved as nanostructures recover from a flattened (colourless) state to an upright (colourful) state. The visual effect is analogous to a letter written in multiple colours of invisible ink where secret information is revealed, e.g., with the application of heat. We tackled two key challenges in (1) developing and characterising new stimuli responsive resists suitable for TPL, and (2) designing and fabricating robust 3D photonic structures capable of rapid recovery after being flattened. In this work, we meet these challenges by additive manufacturing of SMP for programmable colour generation. We developed and characterised a SMP photoresist suited for TPL based on Vero Clear 13 , which is an optically transparent thermosetting polymer resin containing acrylate functional group. We performed resolution tests achieving ~300 nm half pitch gratings and measured the thermodynamic properties of the new resist to determine an optimal composition for robust mechanical performance. A range of structural colours were achieved by controlling the geometry of the crosslinked SMP structures at the submicron level. We realised colour switching behaviour by heating and deforming (i.e., programming) the printed structure at a temperature higher than the glass transition temperature ( T g ). Remarkably, the deformed nanostructures exhibited excellent recovery when heated above its composition-adjustable T g . This reversibility in both structural features and optical responses demonstrate significant promise for submicron scale additive manufacturing of SMPs. Results Two-photon polymerization lithography of shape memory polymer We designed structures consisting of a base layer with submicron-scale grids on top of it, as shown in Fig. 1 . Due to the interaction of these nanostructures with light, i.e., scattering and interference, the 3D printed structures function as colour filters, preferentially transmitting certain wavelength ranges of an incident white light illumination. Colours depend sensitively on the geometric parameters of the grid, i.e., grid height h 2 , and grid linewidth w 1 , while it is less sensitive to pitch w 2 and the thickness of the base<|im_end|> <|im_start|>assistant The Singapore University of Technology and Design (SUTD) and its research collaborators have successfully demonstrated the four-dimensional (4-D) printing of shape memory polymers in submicron dimensions which are comparable to the wavelength of visible light. This novel development has allowed researchers to now explore new applications in the field of nanophotonics. 4-D printing enables 3-D printed structures to change its configurations over time and is used in a wide variety of fields such as soft robotics, flexible electronics, and medical devices. Different materials such as hydrogels, liquid crystal elastomers and magnetic nanoparticles embedded resists along with corresponding printing methods like Direct Ink Writing (DIW), Polyjet, Digital Light Processing (DLP) lithography and Stereolithography (SLA) have been developed for 4-D printing. However, the material and patterning challenges inherent to these methods limit the resolution of 4-D printing to ~10 μm at best. To improve the resolution of 4-D printing, the research team developed a shape memory polymer (SMP) photoresist suitable for two-photon polymerization lithography (TPL). Integrating this newly developed resist with TPL, they investigated submicron 4-D printing of SMPs at which scale the printed structures can interact strongly with visible light. By programming with pressure and heat, the submicron structures can switch between colorless and colorful states (see image). "It's remarkable that these 3-D printed nanostructures are able to recover their shapes and structural color after they've been mechanically flattened into a colorless, transparent state. This new resist that we've concocted allows for really fine structures to be printed while still retaining their properties as a shape memory polymer," said Associate Professor Joel K. W. Yang, principal investigator of the team from SUTD. "By characterizing the photoresist, we printed the SMPs with ~300nm half pitch. The resolution is an order of magnitude higher than traditional high-resolution printing methods such as DLP and SLA. The dimensions of the structures can be conveniently controlled by varying the printing parameters such as laser power, write speed and nominal height," added Wang Zhang, first author and Ph.D. student from SUTD. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Topological defects of spontaneous polarization are extensively studied as templates for unique physical phenomena and in the design of reconfigurable electronic devices. Experimental investigations of the complex topologies of polarization have been limited to surface phenomena, which has restricted the probing of the dynamic volumetric domain morphology in operando. Here, we utilize Bragg coherent diffractive imaging of a single BaTiO 3 nanoparticle in a composite polymer/ferroelectric capacitor to study the behavior of a three-dimensional vortex formed due to competing interactions involving ferroelectric domains. Our investigation of the structural phase transitions under the influence of an external electric field shows a mobile vortex core exhibiting a reversible hysteretic transformation path. We also study the toroidal moment of the vortex under the action of the field. Our results open avenues for the study of the structure and evolution of polar vortices and other topological structures in operando in functional materials under cross field configurations. Introduction Ferroelectric (FE) materials will likely have a broad range of applications in the next generation of electronics, such as non-volatile random access memorie (NRAM) 1 , 2 , 3 , 4 , 5 , and energy-storage and battery related technologies 6 , 7 , 8 . Nanoferroelectrics, unlike their bulk counterparts, show complex topological polarization textures 9 , including multi-stable states such as polar vortices 10 , which are formed due to long-range interactions mediated by elasticity and electrical boundary conditions. The influence of shape and size on vortex behavior has been extensively studied theoretically using electronic structure calculations and phase-field simulations 9 , 10 , 11 , 12 , 13 , 14 . Compared to bulk, nanoferroelectrics show promise of increasing the storage density of NRAMs 10,000-fold 1 . However, this expected benefit greatly relies on the possibility of observing and controlling structural transitions, including metastable states that allow for ease of switching of domains. While the two-dimensional (2D) vortex domains in nanoferoelectrics have been extensively studied theoretically 9 , 10 , 11 , 12 , 13 , 14 , experimental effort has been directed toward synthesizing and observing polar structures in BaTiO 3 (BTO) wires 15 , dots 16 , rods 17 , nanotubes 18 , as well as in Pb(Zr, Ti)O 3 thin films and heterostructures 19 , and nanoparticles 20 . High-resolution transmission electron microscopy 21 , 22 , 23 (HR-TEM), atomic force microscopy 24 , as well as numerous optical based experimental techniques 25 have been successfully utilized to probe 2D vortex structures 26 . Combining HR-TEM with synchrotron radiation-based reciprocal space mapping has recently permitted the observation of long-range 2D vortex distributions in perovskite superlattices 27 . However, these approaches have not been transferred to direct non-invasive whole-volume studies of vortex structure due to fundamental limitations of the methods, forcing restrictions on studies in the presence of external perturbations, such as applied electric or magnetic fields, and leaving a gap in our understanding of dynamical processes. Here, we use Bragg Coherent Diffraction Imaging (BCDI) to image the transformation path of the core of an individual vortex structure within a single BTO FE nanoparticle and elucidate the complex topologies of polarizations 9 , FE displacements, structural phases and mechanical responses of FE nanoparticles to electric fields. BCDI takes advantage of improvements in coherence at third and fourth generation light sources. Advancements in phase-retrieval algorithms enable the visualization of whole-volume information of the electron density distribution, atomic and ionic displacement fields within individual nanoparticles with nanoscale resolution 28 . For a review of advances in imaging of local structure using light sources, see refs 29 , 30 , 31 , 32 , 33 , 34 . Results Electric field control of ferroelectric polarization To study a single FE nanoparticle morphology and its vortex structure, we designed a composite consisting of BTO nanoparticles and carbon nanoparticles dispersed within a non-ferroelectric polymeric dielectric matrix (Fig. 1 , Supplementary Fig. 1 and the Methods section). Laboratory X-ray powder diffraction (Supplementary Fig. 2 ) confirms the crystalline nature of the BTO nanoparticles. In BCDI experiments the sample is illuminated with focused coherent X-ray beam (Fig. 1 ). A random orientation of the BTO nanoparticles along with the experimental geometry allows us to isolate and record the (111) Bragg reflections from a single BTO particle on an area detector. By applying an electric field in cycles and monitoring changes in diffraction pattern, we can differentiate BTO nanoparticles acting as nanocapacitor (Supplementary Fig. 3 ) from the particles which are electrically insulated in dielectric matrix (Supplementary Fig. 4 ). By iteratively inverting the coherent X-ray diffraction data, we obtain information on the three-dimensional (3D) Bragg-electron density distribution along with ionic displacement fields (Fig. 2b ) with 20 nm spatial resolution (Supplementary Fig. 5 ). Supplementary Note 1 for more information. Fig. 1 Experimental scheme of Bragg coherent diffraction imaging. Incident coherent X-ray beam is scattered by a nanoparticle embedded in conducting non-polarizing polymer with attached electrodes. Constructive interference patterns are recorded during application of an external electric field on the particle. Recorded high-resolution Bragg-peak diffraction carries information on the electron density and atomic displacement variations, allowing to reconstruct the complex process of defect evolution and monitoring of vortex. Scale bar corresponds to 0.1 Å −1 Full size image Fig. 2 Correlations between Bragg coherent diffraction measurements and phase-field simulations. a A blue isosurface shows the reconstructed particle shape (amplitude) with green planes marking the locations of 2D cuts through the volume for the extracted planes in d . b Under zero electric field (initial state), the 3D projection of displacement field along the [111] direction is mapped onto the surface of the particle. c Slices through the particle volume at cut planes of 30, 60, 100, and 145 nm showing the inhomogeneity of the displacement and dynamics under external electric field. d Phase-field simulations for similar cut planes of 30, 60, 100, and 145 nm support the interpretation of experimental results. Scale bars correspond to 60 nm Full size image Figure 2a shows the isosurface rendering of the", "role": "user" }, { "content": "A Tomsk Polytechnic University study reveals how topological vortices found in low-dimensional materials can be both displaced and erased and restored again by the electrical field within nanoparticles. This may open exciting opportunities for memory devices or quantum computers in which information will be encrypted in the characteristics of topological vortices. Scientists from TPU and international collaborators have discovered unusual self-organization of atoms in the volume of nanoparticles and have learned to control it via an electric field. Such controlled nanoparticles can be used to generate capacious non-volatile random access memory (NRAM), quantum computers and other next-generation electronics. The main author is Dmitriy Karpov, engineer of the Department of General Physics, TPU, who explains that in modern materials science, the defects of matter are divided into two large groups. The first group includes classical, well-studied defects, when atoms in matter are mechanically disordered, i.e., atoms are either removed or inserted into the lattice. In the other group, the spatial organization of the lattice itself changes and such defects are called topological. Topological defects can strongly influence matter, making it superfluid or superconductive, and therefore, it is very important to study them. Topological defects can be found only in low-dimensional materials—two-dimensional nanorods and nanofilms (just several atoms thick) and one-dimensional nanodots or nanoparticles, which are spherical particles consisting of several tens or hundreds of identical atoms. \"One of the important topological defects is a topological vortex which looks like a discernible twisting caused by a small displacement of all atoms. The vortex core is a nanostrand which can be both displaced by the field, and erased and restored again within nanoparticles,\" explains Edwin Fohtung, Professor of Los Alamos National Laboratory and New Mexico State University . The scientists studied barium titanate nanoparticles whose internal structure was visualized with the help of penetrating X-ray radiation from the synchrotron Advanced Photon Source (Chicago, USA). They obtained an image of the volume of nanoparticles with a resolution of 18 nanometers, which enabled them to analyze the slightest changes in the structure. As a result, the researchers showed that an external electric field can displace the core of the topological vortex inside the nanoparticle, and when the field is removed, it returns to its original position. Modern components of electronics are gradually becoming smaller. This can significantly influence the efficiency of devices, which will be significantly reduced due to quantum effects. One way to circumvent these limitations is to use topological vortices. Thus, they can be used to generate high density NRAM or quantum computers in which information will be encrypted in the characteristics of topological vortices. \"All in all, the possibility to control and adjust topological vortices in nanoparticles is important for the creation of new electronics,\" concludes Dmitriy Karpov. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Topological defects of spontaneous polarization are extensively studied as templates for unique physical phenomena and in the design of reconfigurable electronic devices. Experimental investigations of the complex topologies of polarization have been limited to surface phenomena, which has restricted the probing of the dynamic volumetric domain morphology in operando. Here, we utilize Bragg coherent diffractive imaging of a single BaTiO 3 nanoparticle in a composite polymer/ferroelectric capacitor to study the behavior of a three-dimensional vortex formed due to competing interactions involving ferroelectric domains. Our investigation of the structural phase transitions under the influence of an external electric field shows a mobile vortex core exhibiting a reversible hysteretic transformation path. We also study the toroidal moment of the vortex under the action of the field. Our results open avenues for the study of the structure and evolution of polar vortices and other topological structures in operando in functional materials under cross field configurations. Introduction Ferroelectric (FE) materials will likely have a broad range of applications in the next generation of electronics, such as non-volatile random access memorie (NRAM) 1 , 2 , 3 , 4 , 5 , and energy-storage and battery related technologies 6 , 7 , 8 . Nanoferroelectrics, unlike their bulk counterparts, show complex topological polarization textures 9 , including multi-stable states such as polar vortices 10 , which are formed due to long-range interactions mediated by elasticity and electrical boundary conditions. The influence of shape and size on vortex behavior has been extensively studied theoretically using electronic structure calculations and phase-field simulations 9 , 10 , 11 , 12 , 13 , 14 . Compared to bulk, nanoferroelectrics show promise of increasing the storage density of NRAMs 10,000-fold 1 . However, this expected benefit greatly relies on the possibility of observing and controlling structural transitions, including metastable states that allow for ease of switching of domains. While the two-dimensional (2D) vortex domains in nanoferoelectrics have been extensively studied theoretically 9 , 10 , 11 , 12 , 13 , 14 , experimental effort has been directed toward synthesizing and observing polar structures in BaTiO 3 (BTO) wires 15 , dots 16 , rods 17 , nanotubes 18 , as well as in Pb(Zr, Ti)O 3 thin films and heterostructures 19 , and nanoparticles 20 . High-resolution transmission electron microscopy 21 , 22 , 23 (HR-TEM), atomic force microscopy 24 , as well as numerous optical based experimental techniques 25 have been successfully utilized to probe 2D vortex structures 26 . Combining HR-TEM with synchrotron radiation-based reciprocal space mapping has recently permitted the observation of long-range 2D vortex distributions in perovskite superlattices 27 . However, these approaches have not been transferred to direct non-invasive whole-volume studies of vortex structure due to fundamental limitations of the methods, forcing restrictions on studies in the presence of external perturbations, such as applied electric or magnetic fields, and leaving a gap in our understanding of dynamical processes. Here, we use Bragg Coherent Diffraction Imaging (BCDI) to image the transformation path of the core of an individual vortex structure within a single BTO FE nanoparticle and elucidate the complex topologies of polarizations 9 , FE displacements, structural phases and mechanical responses of FE nanoparticles to electric fields. BCDI takes advantage of improvements in coherence at third and fourth generation light sources. Advancements in phase-retrieval algorithms enable the visualization of whole-volume information of the electron density distribution, atomic and ionic displacement fields within individual nanoparticles with nanoscale resolution 28 . For a review of advances in imaging of local structure using light sources, see refs 29 , 30 , 31 , 32 , 33 , 34 . Results Electric field control of ferroelectric polarization To study a single FE nanoparticle morphology and its vortex structure, we designed a composite consisting of BTO nanoparticles and carbon nanoparticles dispersed within a non-ferroelectric polymeric dielectric matrix (Fig. 1 , Supplementary Fig. 1 and the Methods section). Laboratory X-ray powder diffraction (Supplementary Fig. 2 ) confirms the crystalline nature of the BTO nanoparticles. In BCDI experiments the sample is illuminated with focused coherent X-ray beam (Fig. 1 ). A random orientation of the BTO nanoparticles along with the experimental geometry allows us to isolate and record the (111) Bragg reflections from a single BTO particle on an area detector. By applying an electric field in cycles and monitoring changes in diffraction pattern, we can differentiate BTO nanoparticles acting as nanocapacitor (Supplementary Fig. 3 ) from the particles which are electrically insulated in dielectric matrix (Supplementary Fig. 4 ). By iteratively inverting the coherent X-ray diffraction data, we obtain information on the three-dimensional (3D) Bragg-electron density distribution along with ionic displacement fields (Fig. 2b ) with 20 nm spatial resolution (Supplementary Fig. 5 ). Supplementary Note 1 for more information. Fig. 1 Experimental scheme of Bragg coherent diffraction imaging. Incident coherent X-ray beam is scattered by a nanoparticle embedded in conducting non-polarizing polymer with attached electrodes. Constructive interference patterns are recorded during application of an external electric field on the particle. Recorded high-resolution Bragg-peak diffraction carries information on the electron density and atomic displacement variations, allowing to reconstruct the complex process of defect evolution and monitoring of vortex. Scale bar corresponds to 0.1 Å −1 Full size image Fig. 2 Correlations between Bragg coherent diffraction measurements and phase-field simulations. a A blue isosurface shows the reconstructed particle shape (amplitude) with green planes marking the locations of 2D cuts through the volume for the extracted planes in d . b Under zero electric field (initial state), the 3D projection of displacement field along the [111] direction is mapped onto the surface of the particle. c Slices through the particle volume at cut planes of 30, 60, 100, and 145 nm showing the inhomogeneity of the displacement and dynamics under external electric field. d Phase-field simulations for similar cut planes of 30, 60, 100, and 145 nm support the interpretation of experimental results. Scale bars correspond to 60 nm Full size image Figure 2a shows the isosurface rendering of the<|im_end|> <|im_start|>assistant A Tomsk Polytechnic University study reveals how topological vortices found in low-dimensional materials can be both displaced and erased and restored again by the electrical field within nanoparticles. This may open exciting opportunities for memory devices or quantum computers in which information will be encrypted in the characteristics of topological vortices. Scientists from TPU and international collaborators have discovered unusual self-organization of atoms in the volume of nanoparticles and have learned to control it via an electric field. Such controlled nanoparticles can be used to generate capacious non-volatile random access memory (NRAM), quantum computers and other next-generation electronics. The main author is Dmitriy Karpov, engineer of the Department of General Physics, TPU, who explains that in modern materials science, the defects of matter are divided into two large groups. The first group includes classical, well-studied defects, when atoms in matter are mechanically disordered, i.e., atoms are either removed or inserted into the lattice. In the other group, the spatial organization of the lattice itself changes and such defects are called topological. Topological defects can strongly influence matter, making it superfluid or superconductive, and therefore, it is very important to study them. Topological defects can be found only in low-dimensional materials—two-dimensional nanorods and nanofilms (just several atoms thick) and one-dimensional nanodots or nanoparticles, which are spherical particles consisting of several tens or hundreds of identical atoms. "One of the important topological defects is a topological vortex which looks like a discernible twisting caused by a small displacement of all atoms. The vortex core is a nanostrand which can be both displaced by the field, and erased and restored again within nanoparticles," explains Edwin Fohtung, Professor of Los Alamos National Laboratory and New Mexico State University . The scientists studied barium titanate nanoparticles whose internal structure was visualized with the help of penetrating X-ray radiation from the synchrotron Advanced Photon Source (Chicago, USA). They obtained an image of the volume of nanoparticles with a resolution of 18 nanometers, which enabled them to analyze the slightest changes in the structure. As a result, the researchers showed that an external electric field can displace the core of the topological vortex inside the nanoparticle, and when the field is removed, it returns to its original position. Modern components of electronics are gradually becoming smaller. This can significantly influence the efficiency of devices, which will be significantly reduced due to quantum effects. One way to circumvent these limitations is to use topological vortices. Thus, they can be used to generate high density NRAM or quantum computers in which information will be encrypted in the characteristics of topological vortices. "All in all, the possibility to control and adjust topological vortices in nanoparticles is important for the creation of new electronics," concludes Dmitriy Karpov. <|im_end|>

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23966, 13, 220, 17, 4563, 66434, 1990, 3320, 16094, 56887, 3722, 16597, 22323, 323, 10474, 19677, 47590, 13, 264, 362, 6437, 374, 437, 10730, 5039, 279, 83104, 19320, 6211, 320, 309, 31150, 8, 449, 6307, 25761, 36024, 279, 10687, 315, 220, 17, 35, 15455, 1555, 279, 8286, 369, 279, 28532, 25761, 304, 294, 662, 293, 9636, 7315, 9249, 2115, 320, 9613, 1614, 705, 279, 220, 18, 35, 22343, 315, 44153, 2115, 3235, 279, 510, 5037, 60, 5216, 374, 24784, 8800, 279, 7479, 315, 279, 19320, 13, 272, 328, 38514, 1555, 279, 19320, 8286, 520, 4018, 25761, 315, 220, 966, 11, 220, 1399, 11, 220, 1041, 11, 323, 220, 9591, 26807, 9204, 279, 304, 35940, 76730, 315, 279, 44153, 323, 30295, 1234, 9434, 9249, 2115, 13, 294, 28673, 19677, 47590, 369, 4528, 4018, 25761, 315, 220, 966, 11, 220, 1399, 11, 220, 1041, 11, 323, 220, 9591, 26807, 1862, 279, 23692, 315, 22772, 3135, 13, 25635, 16283, 8024, 311, 220, 1399, 26807, 8797, 1404, 2217, 19575, 220, 17, 64, 5039, 279, 374, 437, 10730, 21568, 315, 279, 128257, 198, 128256, 78191, 198, 32, 8529, 4991, 19294, 26522, 292, 3907, 4007, 21667, 1268, 1948, 5848, 348, 371, 1238, 1766, 304, 3428, 33520, 7384, 649, 387, 2225, 49246, 323, 64800, 323, 28101, 1578, 555, 279, 20314, 2115, 2949, 94753, 13, 1115, 1253, 1825, 13548, 10708, 369, 5044, 7766, 477, 31228, 19002, 304, 902, 2038, 690, 387, 25461, 304, 279, 17910, 315, 1948, 5848, 348, 371, 1238, 13, 57116, 505, 350, 6459, 323, 6625, 79119, 617, 11352, 19018, 659, 12, 24844, 315, 33299, 304, 279, 8286, 315, 94753, 323, 617, 9687, 311, 2585, 433, 4669, 459, 9249, 2115, 13, 15483, 14400, 94753, 649, 387, 1511, 311, 7068, 2107, 19995, 2536, 8437, 26598, 4288, 2680, 5044, 320, 27416, 1428, 705, 31228, 19002, 323, 1023, 1828, 43927, 31591, 13, 578, 1925, 3229, 374, 67221, 462, 88, 735, 8035, 869, 11, 24490, 315, 279, 6011, 315, 3331, 28415, 11, 350, 6459, 11, 889, 15100, 430, 304, 6617, 7384, 8198, 11, 279, 42655, 315, 5030, 527, 18255, 1139, 1403, 3544, 5315, 13, 578, 1176, 1912, 5764, 29924, 11, 1664, 5594, 664, 1142, 42655, 11, 994, 33299, 304, 5030, 527, 99097, 834, 10767, 11, 602, 1770, 2637, 33299, 527, 3060, 7108, 477, 22306, 1139, 279, 55372, 13, 763, 279, 1023, 1912, 11, 279, 29079, 7471, 315, 279, 55372, 5196, 4442, 323, 1778, 42655, 527, 2663, 1948, 5848, 13, 7054, 5848, 42655, 649, 16917, 10383, 5030, 11, 3339, 433, 2307, 67125, 477, 2307, 444, 68243, 11, 323, 9093, 11, 433, 374, 1633, 3062, 311, 4007, 1124, 13, 7054, 5848, 42655, 649, 387, 1766, 1193, 304, 3428, 33520, 7384, 2345, 20375, 33520, 20622, 269, 30797, 323, 20622, 47899, 1026, 320, 4345, 3892, 33299, 12314, 8, 323, 832, 33520, 20622, 347, 2469, 477, 94753, 11, 902, 527, 65251, 19252, 31706, 315, 3892, 22781, 477, 11758, 315, 20086, 33299, 13, 330, 4054, 315, 279, 3062, 1948, 5848, 42655, 374, 264, 1948, 5848, 87627, 902, 5992, 1093, 264, 42645, 1260, 80654, 9057, 555, 264, 2678, 44153, 315, 682, 33299, 13, 578, 87627, 6332, 374, 264, 51593, 86981, 902, 649, 387, 2225, 49246, 555, 279, 2115, 11, 323, 64800, 323, 28101, 1578, 2949, 94753, 1359, 15100, 76249, 32757, 427, 2234, 11, 17054, 315, 9853, 1708, 10808, 5165, 32184, 323, 1561, 12550, 3314, 3907, 662, 578, 14248, 20041, 3703, 2411, 86612, 349, 94753, 6832, 5419, 6070, 574, 9302, 1534, 449, 279, 1520, 315, 90300, 1630, 30630, 25407, 505, 279, 6925, 331, 299, 35785, 21844, 63238, 8922, 320, 47275, 11, 7427, 570, 2435, 12457, 459, 2217, 315, 279, 8286, 315, 94753, 449, 264, 11175, 315, 220, 972, 20622, 33504, 11, 902, 9147, 1124, 311, 24564, 279, 60147, 4442, 304, 279, 6070, 13, 1666, 264, 1121, 11, 279, 12074, 8710, 430, 459, 9434, 9249, 2115, 649, 834, 2050, 279, 6332, 315, 279, 1948, 5848, 87627, 4871, 279, 76307, 7203, 11, 323, 994, 279, 2115, 374, 7108, 11, 433, 4780, 311, 1202, 4113, 2361, 13, 18766, 6956, 315, 31591, 527, 27115, 10671, 9333, 13, 1115, 649, 12207, 10383, 279, 15374, 315, 7766, 11, 902, 690, 387, 12207, 11293, 4245, 311, 31228, 6372, 13, 3861, 1648, 311, 10408, 688, 1521, 9669, 374, 311, 1005, 1948, 5848, 348, 371, 1238, 13, 14636, 11, 814, 649, 387, 1511, 311, 7068, 1579, 17915, 452, 35005, 477, 31228, 19002, 304, 902, 2038, 690, 387, 25461, 304, 279, 17910, 315, 1948, 5848, 348, 371, 1238, 13, 330, 2460, 304, 682, 11, 279, 13336, 311, 2585, 323, 7652, 1948, 5848, 348, 371, 1238, 304, 94753, 374, 3062, 369, 279, 9886, 315, 502, 31591, 1359, 45537, 67221, 462, 88, 735, 8035, 869, 13, 220, 128257, 198 ]

1,981

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract As the superconducting qubit platform matures towards ever-larger scales in the race towards a practical quantum computer, limitations due to qubit inhomogeneity through lack of process control become apparent. To benefit from the advanced process control in industry-scale CMOS fabrication facilities, different processing methods will be required. In particular, the double-angle evaporation and lift-off techniques used for current, state-of-the-art superconducting qubits are generally incompatible with modern-day manufacturable processes. Here, we demonstrate a fully CMOS compatible qubit fabrication method, and show results from overlap Josephson junction devices with long coherence and relaxation times, on par with the state-of-the-art. We experimentally verify that Argon milling—the critical step during junction fabrication—and a subtractive-etch process nevertheless result in qubits with average qubit energy relaxation times T 1 reaching 70 µs, with maximum values exceeding 100 µs. Furthermore, we show that our results are still limited by surface losses and not, crucially, by junction losses. The presented fabrication process, therefore, heralds an important milestone towards a manufacturable 300 mm CMOS process for high-coherence superconducting qubits and has the potential to advance the scaling of superconducting device architectures. Introduction Superconducting circuits have emerged as a leading candidate for realizing a scalable quantum computing platform. The improvements in qubit coherence times 1 and gate fidelities 2 , 3 , 4 , 5 enabled the demonstration of quantum simulators 6 , 7 , small-scale quantum algorithms 8 , 9 , and even the elusive demonstration of quantum supremacy 10 , 11 . State-of-the-art coherence times routinely reach 50 µs, with specific cases exceeding 100 µs 12 , 13 , 14 , 15 . These have been exclusively fabricated using aluminum (Al) double-angle evaporation and lift-off techniques on sapphire or high-resistivity silicon (Si) substrates. Double-angle evaporated junctions enabled the fabrication of Noisy Intermediate Scale Quantum (NISQ) processors with an intermediate scale number of qubits 10 , 11 , only recently exceeding 100 16 . To further advance the technological state-of-the-art, the design and device fabrication inevitably become increasingly complex 17 , 18 . This imposes tighter constraints on the design parameters of qubits, readout resonators, on-chip filters 19 , 20 , and tunable couplers 21 , 22 . To facilitate this upscaling, versatile, reliable, and reproducible fabrication processes are needed. The large-scale implementation of superconducting qubits is inherently hindered by the variability in Josephson energy of the double-angle evaporated junctions 23 , 24 . This is primarily a consequence of the variability in fabricated junction area, which results from the angle dependence across the wafer during metal deposition 24 , 25 , 26 . Another limitation is that polymer masks that are typically used during processing restrict the thermal budget. This further limits the choice of superconductor, limiting the potential optimization space for qubit improvement 27 , 28 . Furthermore, the fabrication itself requires dedicated evaporation tools with tilt capability. Double-angle evaporation with a required lift-off step introduces resist contaminations 29 and reduces reproducibility in larger diameter wafers 25 . This fabrication technique is therefore considered incompatible with advanced complementary metal-oxide semiconductor (CMOS) manufacturing, where large-scale integration of devices is instead generally based on subtractive etch, sputtering deposition, and advanced optical lithography 30 . To overcome these limitations, alternative junction fabrication techniques are being actively investigated. Several alternatives to double-angle evaporated junctions exist, including finMET 31 , trilayer 30 , 32 , and overlap 33 , 34 , 35 , 36 , 37 Josephson junctions. These are compatible with manufacturable CMOS processes. The advantages of overlap junctions compared to other alternatives are the reduced structural complexity and, therefore, a smaller number of fabrication steps. This reduces the processing-induced sources of loss and parameter variability. Recent work has shown promising overlap junction qubit performance, with energy relaxation T 1 times up to 80 µs 33 , 36 , 38 . However, these qubits were still created using a CMOS-incompatible lift-off process. Qubits with state-of-the-art coherence times, fabricated with a fully manufacturable CMOS process, i.e., without the use of lift-off techniques, sapphire, or high resistivity (above ~10 kΩ·cm) Si substrates, are yet to be demonstrated. Overlap junctions have two electrodes that are defined in two patterning cycles, with a vacuum break in between which results in the uncontrolled growth of native metal oxide. After the first cycle, the native oxide needs to be removed by in-situ argon (Ar) milling to enable controlled subsequent junction oxidation. This step is critical since Ar milling has been linked to superconducting device performance degradation 15 , 39 , 40 . Strong Ar milling can lead to amorphized Si 41 and sapphire 29 substrate layers, which were found to limit resonator quality factors and qubit coherence times. The milling has also been reported to introduce additional loss at metal–metal interfaces 15 . This indicates that the Ar milling could compromise the junction’s integrity and composition. However, the impact of Ar milling on the junction performance is still unexplored, and at present, it is unknown if it inherently limits the overlap junction qubit lifetimes. In our work, we perform an in-depth characterization of Al overlap junctions, fabricated with wet and dry subtractive-etch processes. Intrinsic Si substrate coupons with 3 kΩ·cm (3k) and 20 kΩ·cm (20k) specific resistivity are used from 300 and 100 mm wafers, respectively. Results for fixed frequency transmon qubits with overlap junctions show time-averaged energy relaxation T 1 times of 50–70 µs, with individual measurements surpassing 100 µs, and average Pauli gate fidelity of 99.94%. By comparing quality factors ( Q = 2 π T 1 f ) of qubits with different capacitor geometries, we find that the total loss (1/ Q) scales with the metal–air surface oxide participation ratio, suggesting that the qubits are limited by the surface losses residing at the capacitor pads instead of the junction. The dominant loss likely originates from the subtractive-etch-specific sidewall residues and native surface oxides. Our study reveals that the overlap junctions do not limit the T 1 coherence time up to at least 131 µs for qubits at 3 GHz. Results Overlap junction fabrication", "role": "user" }, { "content": "Quantum computers promise to dramatically affect selected application fields, including materials synthesis, pharmaceutical drug development, and cybersecurity—to name a few. In the quantum circuit model of computation, a quantum logic gate (or simply quantum gate) is a basic operation on a small number of qubits, which is analogous to a classical logic gate for conventional digital circuits. Qubits are the building blocks of quantum circuits. Different quantum computing platforms with diverse types of qubits are being developed and worldwide efforts are ongoing to bring them from the lab to the world. One of the promising technologies for quantum computing makes use of superconducting circuits. Anton Potočnik, senior researcher in quantum computing at IMEC, says, \"The energy states of superconducting qubits are relatively easy to control, and, throughout the years, researchers have been able to couple an increasing number of qubits together. This enables an ever-higher level of entanglement—which is one of the pillars of quantum computing. On top of that, research groups worldwide have demonstrated superconducting qubits with long coherence times (up to several 100 µs) and sufficiently high gate fidelities—two important benchmarks for quantum computation.\" While coherence time gives us information on how long a qubit retains its quantum state (and hence, its information), gate fidelity quantifies the difference in operation between an ideal gate and the corresponding physical gate in quantum hardware. Large-scale implementation hindered by variability issues The encouraging results mentioned above have so far only been obtained at lab scale, using double-angle evaporation and lift-off techniques for making the most critical element: the Josephson junction. \"The superconducting qubit is essentially a non-linear LC resonator circuit, containing a non-linear inductor (L) and a capacitor (C),\" explains Anton Potočnik. \"The Josephson junction takes the role of a non-linear, non-dissipating inductor, which allows us to manipulate qubit energy states to represent, for example, a superposition of 10> and 11>. To minimize any losses of energy or, in other words, maximize coherence time, the various interfaces contained in the structures that make up the junction and the capacitor must be as clean as possible. Even one atomic defect present at one of the interfaces can cause the qubit to lose energy. And that's why double-angle evaporation and lift-off are the preferred fabrication techniques: they can provide these extremely clean interfaces.\" But these fabrication techniques have a serious downside: they challenge a further upscaling towards larger numbers of qubits. Large-scale implementation is hindered by the variability in Josephson energy of the evaporated junction. In addition, the fabrication technique limits the choice of the superconducting material, and hence, the potential for qubit improvement. An alternative approach using CMOS-compatible fabrication techniques Jeroen Verjauw, Ph.D. researcher at IMEC, says, \"Our team at IMEC has explored alternative ways of fabricating the superconducting circuits. Our focus was on creating so-called overlap Josephson junctions using only CMOS-compatible materials and techniques, as this enables leveraging the reliability and reproducibility offered by state-of-the-art CMOS processing steps to control variability and facilitate upscaling.\" Overlap junctions have two electrodes (bottom (BE) and top (TE)) separated by a thin insulator layer. The electrodes are defined in two patterning cycles, with a vacuum break in between. The break introduces uncontrolled growth of native metal oxide, which must be removed during a so-called Ar-milling step. \"This Ar-milling step is however known to be very critical and has previously been reported to introduce unwanted energy losses,\" adds Jeroen Verjauw. (Left) Qubit energy relaxation measurement and (right) average gate fidelity and average error per gate. Credit: imec Coherence times up to 100 µs, gate fidelity of 99.94% Tsvetan Ivanov, researcher at IMEC, says, \"We have demonstrated in our lab superconducting qubits with coherence times exceeding 100 µs and an average single-qubit gate fidelity of 99.94%. These results are comparable with state-of-the-art devices, but, for the first time, have been obtained using CMOS-compatible fabrication techniques—such as state-of-the-art sputtering deposition and subtractive etch. These breakthrough results could be achieved by improving the known process for making the overlap junctions. The improvements include process optimization to reduce the number of process steps and interfaces (and hence, the risk for energy losses), an improved Ar-milling step, and the exclusive use of aluminum (Al) for making the electrodes.\" The next steps: 300 mm fabrication, reducing the losses and addressing reproducibility Our experiments described in NPJ Quantum Information have so far only been achieved in a lab environment, on substrate coupons. Tsvetan Ivanov: \"Yet, the presented fabrication method heralds an important milestone towards a manufacturable 300mm CMOS process for high-quality superconducting qubits. Soon, we will transfer the fabrication of these superconducting circuits into IMEC's 300mm fab. We are eager to verify whether the high coherence times can be reproduced on larger wafer substrates.\" Jeroen Verjauw: \"In addition, we designed our test vehicles such that we can study where the energy losses come from. First results have indicated that the losses mainly occur at the outer surface of the structure, and not, at the critical junction level. This is encouraging, as it leaves room for optimization by applying more dedicated surface treatment steps. And, finally, our fabrication method provides a path towards fabricating reproducible qubits over a large wafer area, with low variation in for example qubit frequency.\" Yet, there are other obstacles on the road towards practical superconducting-based quantum computers. Anton Potočnik concludes: \"Superconducting qubits are still relatively large (mm-sized) compared to for example semiconducting spin qubits (nm-sized). We investigate how we can further shrink the devices. Many efforts are also ongoing on the algorithmic side. The qubits that we make today are not ideal, so there is a huge effort from the theoretical side to develop algorithms that are more resilient to losses and errors, and to develop quantum error correction protocols. On top of that, our community will need scalable, very well calibrated instrumentation to interface with the growing number of superconducting qubits, to control them and readout meaningful results.\" Conclusion and outlook Kristiaan De Greve, program director quantum computing at IMEC, sees this work by Anton, Tsvetan, Jeroen and their coworkers as a crucial milestone towards being able to overcome fundamental barriers to upscaling of superconducting qubits by virtue of the control and accuracy benefits of industry-standard processing methods: \"As many thousands to millions of physical qubits will likely be required for the quantum processors of the future, overcoming limitations due to variability and low yield will be crucial. IMEC therefore invests significantly in understanding and benchmarking these limitations and introducing novel solutions that leverage our experience in advanced process control.\" Danny Wan, program manager quantum computing at IMEC, adds: \"Within IMEC's program on quantum computing, our scientists have set themselves the challenge to bring quantum computing (both semiconducting and superconducting based) from the lab to the world. Results as described in NPJ Quantum Information are extremely encouraging and confirm that we are on the right track in pursuing our mission.\" The study is published in npj Quantum Information. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract As the superconducting qubit platform matures towards ever-larger scales in the race towards a practical quantum computer, limitations due to qubit inhomogeneity through lack of process control become apparent. To benefit from the advanced process control in industry-scale CMOS fabrication facilities, different processing methods will be required. In particular, the double-angle evaporation and lift-off techniques used for current, state-of-the-art superconducting qubits are generally incompatible with modern-day manufacturable processes. Here, we demonstrate a fully CMOS compatible qubit fabrication method, and show results from overlap Josephson junction devices with long coherence and relaxation times, on par with the state-of-the-art. We experimentally verify that Argon milling—the critical step during junction fabrication—and a subtractive-etch process nevertheless result in qubits with average qubit energy relaxation times T 1 reaching 70 µs, with maximum values exceeding 100 µs. Furthermore, we show that our results are still limited by surface losses and not, crucially, by junction losses. The presented fabrication process, therefore, heralds an important milestone towards a manufacturable 300 mm CMOS process for high-coherence superconducting qubits and has the potential to advance the scaling of superconducting device architectures. Introduction Superconducting circuits have emerged as a leading candidate for realizing a scalable quantum computing platform. The improvements in qubit coherence times 1 and gate fidelities 2 , 3 , 4 , 5 enabled the demonstration of quantum simulators 6 , 7 , small-scale quantum algorithms 8 , 9 , and even the elusive demonstration of quantum supremacy 10 , 11 . State-of-the-art coherence times routinely reach 50 µs, with specific cases exceeding 100 µs 12 , 13 , 14 , 15 . These have been exclusively fabricated using aluminum (Al) double-angle evaporation and lift-off techniques on sapphire or high-resistivity silicon (Si) substrates. Double-angle evaporated junctions enabled the fabrication of Noisy Intermediate Scale Quantum (NISQ) processors with an intermediate scale number of qubits 10 , 11 , only recently exceeding 100 16 . To further advance the technological state-of-the-art, the design and device fabrication inevitably become increasingly complex 17 , 18 . This imposes tighter constraints on the design parameters of qubits, readout resonators, on-chip filters 19 , 20 , and tunable couplers 21 , 22 . To facilitate this upscaling, versatile, reliable, and reproducible fabrication processes are needed. The large-scale implementation of superconducting qubits is inherently hindered by the variability in Josephson energy of the double-angle evaporated junctions 23 , 24 . This is primarily a consequence of the variability in fabricated junction area, which results from the angle dependence across the wafer during metal deposition 24 , 25 , 26 . Another limitation is that polymer masks that are typically used during processing restrict the thermal budget. This further limits the choice of superconductor, limiting the potential optimization space for qubit improvement 27 , 28 . Furthermore, the fabrication itself requires dedicated evaporation tools with tilt capability. Double-angle evaporation with a required lift-off step introduces resist contaminations 29 and reduces reproducibility in larger diameter wafers 25 . This fabrication technique is therefore considered incompatible with advanced complementary metal-oxide semiconductor (CMOS) manufacturing, where large-scale integration of devices is instead generally based on subtractive etch, sputtering deposition, and advanced optical lithography 30 . To overcome these limitations, alternative junction fabrication techniques are being actively investigated. Several alternatives to double-angle evaporated junctions exist, including finMET 31 , trilayer 30 , 32 , and overlap 33 , 34 , 35 , 36 , 37 Josephson junctions. These are compatible with manufacturable CMOS processes. The advantages of overlap junctions compared to other alternatives are the reduced structural complexity and, therefore, a smaller number of fabrication steps. This reduces the processing-induced sources of loss and parameter variability. Recent work has shown promising overlap junction qubit performance, with energy relaxation T 1 times up to 80 µs 33 , 36 , 38 . However, these qubits were still created using a CMOS-incompatible lift-off process. Qubits with state-of-the-art coherence times, fabricated with a fully manufacturable CMOS process, i.e., without the use of lift-off techniques, sapphire, or high resistivity (above ~10 kΩ·cm) Si substrates, are yet to be demonstrated. Overlap junctions have two electrodes that are defined in two patterning cycles, with a vacuum break in between which results in the uncontrolled growth of native metal oxide. After the first cycle, the native oxide needs to be removed by in-situ argon (Ar) milling to enable controlled subsequent junction oxidation. This step is critical since Ar milling has been linked to superconducting device performance degradation 15 , 39 , 40 . Strong Ar milling can lead to amorphized Si 41 and sapphire 29 substrate layers, which were found to limit resonator quality factors and qubit coherence times. The milling has also been reported to introduce additional loss at metal–metal interfaces 15 . This indicates that the Ar milling could compromise the junction’s integrity and composition. However, the impact of Ar milling on the junction performance is still unexplored, and at present, it is unknown if it inherently limits the overlap junction qubit lifetimes. In our work, we perform an in-depth characterization of Al overlap junctions, fabricated with wet and dry subtractive-etch processes. Intrinsic Si substrate coupons with 3 kΩ·cm (3k) and 20 kΩ·cm (20k) specific resistivity are used from 300 and 100 mm wafers, respectively. Results for fixed frequency transmon qubits with overlap junctions show time-averaged energy relaxation T 1 times of 50–70 µs, with individual measurements surpassing 100 µs, and average Pauli gate fidelity of 99.94%. By comparing quality factors ( Q = 2 π T 1 f ) of qubits with different capacitor geometries, we find that the total loss (1/ Q) scales with the metal–air surface oxide participation ratio, suggesting that the qubits are limited by the surface losses residing at the capacitor pads instead of the junction. The dominant loss likely originates from the subtractive-etch-specific sidewall residues and native surface oxides. Our study reveals that the overlap junctions do not limit the T 1 coherence time up to at least 131 µs for qubits at 3 GHz. Results Overlap junction fabrication<|im_end|> <|im_start|>assistant Quantum computers promise to dramatically affect selected application fields, including materials synthesis, pharmaceutical drug development, and cybersecurity—to name a few. In the quantum circuit model of computation, a quantum logic gate (or simply quantum gate) is a basic operation on a small number of qubits, which is analogous to a classical logic gate for conventional digital circuits. Qubits are the building blocks of quantum circuits. Different quantum computing platforms with diverse types of qubits are being developed and worldwide efforts are ongoing to bring them from the lab to the world. One of the promising technologies for quantum computing makes use of superconducting circuits. Anton Potočnik, senior researcher in quantum computing at IMEC, says, "The energy states of superconducting qubits are relatively easy to control, and, throughout the years, researchers have been able to couple an increasing number of qubits together. This enables an ever-higher level of entanglement—which is one of the pillars of quantum computing. On top of that, research groups worldwide have demonstrated superconducting qubits with long coherence times (up to several 100 µs) and sufficiently high gate fidelities—two important benchmarks for quantum computation." While coherence time gives us information on how long a qubit retains its quantum state (and hence, its information), gate fidelity quantifies the difference in operation between an ideal gate and the corresponding physical gate in quantum hardware. Large-scale implementation hindered by variability issues The encouraging results mentioned above have so far only been obtained at lab scale, using double-angle evaporation and lift-off techniques for making the most critical element: the Josephson junction. "The superconducting qubit is essentially a non-linear LC resonator circuit, containing a non-linear inductor (L) and a capacitor (C)," explains Anton Potočnik. "The Josephson junction takes the role of a non-linear, non-dissipating inductor, which allows us to manipulate qubit energy states to represent, for example, a superposition of 10> and 11>. To minimize any losses of energy or, in other words, maximize coherence time, the various interfaces contained in the structures that make up the junction and the capacitor must be as clean as possible. Even one atomic defect present at one of the interfaces can cause the qubit to lose energy. And that's why double-angle evaporation and lift-off are the preferred fabrication techniques: they can provide these extremely clean interfaces." But these fabrication techniques have a serious downside: they challenge a further upscaling towards larger numbers of qubits. Large-scale implementation is hindered by the variability in Josephson energy of the evaporated junction. In addition, the fabrication technique limits the choice of the superconducting material, and hence, the potential for qubit improvement. An alternative approach using CMOS-compatible fabrication techniques Jeroen Verjauw, Ph.D. researcher at IMEC, says, "Our team at IMEC has explored alternative ways of fabricating the superconducting circuits. Our focus was on creating so-called overlap Josephson junctions using only CMOS-compatible materials and techniques, as this enables leveraging the reliability and reproducibility offered by state-of-the-art CMOS processing steps to control variability and facilitate upscaling." Overlap junctions have two electrodes (bottom (BE) and top (TE)) separated by a thin insulator layer. The electrodes are defined in two patterning cycles, with a vacuum break in between. The break introduces uncontrolled growth of native metal oxide, which must be removed during a so-called Ar-milling step. "This Ar-milling step is however known to be very critical and has previously been reported to introduce unwanted energy losses," adds Jeroen Verjauw. (Left) Qubit energy relaxation measurement and (right) average gate fidelity and average error per gate. Credit: imec Coherence times up to 100 µs, gate fidelity of 99.94% Tsvetan Ivanov, researcher at IMEC, says, "We have demonstrated in our lab superconducting qubits with coherence times exceeding 100 µs and an average single-qubit gate fidelity of 99.94%. These results are comparable with state-of-the-art devices, but, for the first time, have been obtained using CMOS-compatible fabrication techniques—such as state-of-the-art sputtering deposition and subtractive etch. These breakthrough results could be achieved by improving the known process for making the overlap junctions. The improvements include process optimization to reduce the number of process steps and interfaces (and hence, the risk for energy losses), an improved Ar-milling step, and the exclusive use of aluminum (Al) for making the electrodes." The next steps: 300 mm fabrication, reducing the losses and addressing reproducibility Our experiments described in NPJ Quantum Information have so far only been achieved in a lab environment, on substrate coupons. Tsvetan Ivanov: "Yet, the presented fabrication method heralds an important milestone towards a manufacturable 300mm CMOS process for high-quality superconducting qubits. Soon, we will transfer the fabrication of these superconducting circuits into IMEC's 300mm fab. We are eager to verify whether the high coherence times can be reproduced on larger wafer substrates." Jeroen Verjauw: "In addition, we designed our test vehicles such that we can study where the energy losses come from. First results have indicated that the losses mainly occur at the outer surface of the structure, and not, at the critical junction level. This is encouraging, as it leaves room for optimization by applying more dedicated surface treatment steps. And, finally, our fabrication method provides a path towards fabricating reproducible qubits over a large wafer area, with low variation in for example qubit frequency." Yet, there are other obstacles on the road towards practical superconducting-based quantum computers. Anton Potočnik concludes: "Superconducting qubits are still relatively large (mm-sized) compared to for example semiconducting spin qubits (nm-sized). We investigate how we can further shrink the devices. Many efforts are also ongoing on the algorithmic side. The qubits that we make today are not ideal, so there is a huge effort from the theoretical side to develop algorithms that are more resilient to losses and errors, and to develop quantum error correction protocols. On top of that, our community will need scalable, very well calibrated instrumentation to interface with the growing number of superconducting qubits, to control them and readout meaningful results." Conclusion and outlook Kristiaan De Greve, program director quantum computing at IMEC, sees this work by Anton, Tsvetan, Jeroen and their coworkers as a crucial milestone towards being able to overcome fundamental barriers to upscaling of superconducting qubits by virtue of the control and accuracy benefits of industry-standard processing methods: "As many thousands to millions of physical qubits will likely be required for the quantum processors of the future, overcoming limitations due to variability and low yield will be crucial. IMEC therefore invests significantly in understanding and benchmarking these limitations and introducing novel solutions that leverage our experience in advanced process control." Danny Wan, program manager quantum computing at IMEC, adds: "Within IMEC's program on quantum computing, our scientists have set themselves the challenge to bring quantum computing (both semiconducting and superconducting based) from the lab to the world. Results as described in NPJ Quantum Information are extremely encouraging and confirm that we are on the right track in pursuing our mission." The study is published in npj Quantum Information. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract When faced with threat, the survival of an organism is contingent upon the selection of appropriate active or passive behavioural responses 1 , 2 , 3 . Freezing is an evolutionarily conserved passive fear response that has been used extensively to study the neuronal mechanisms of fear and fear conditioning in rodents 4 . However, rodents also exhibit active responses such as flight under natural conditions 2 . The central amygdala (CEA) is a forebrain structure vital for the acquisition and expression of conditioned fear responses, and the role of specific neuronal sub-populations of the CEA in freezing behaviour is well-established 1 , 5 , 6 , 7 . Whether the CEA is also involved in flight behaviour, and how neuronal circuits for active and passive fear behaviour interact within the CEA, are not yet understood. Here, using in vivo optogenetics and extracellular recordings of identified cell types in a behavioural model in which mice switch between conditioned freezing and flight, we show that active and passive fear responses are mediated by distinct and mutually inhibitory CEA neurons. Cells expressing corticotropin-releasing factor (CRF + ) mediate conditioned flight, and activation of somatostatin-positive (SOM + ) neurons initiates passive freezing behaviour. Moreover, we find that the balance between conditioned flight and freezing behaviour is regulated by means of local inhibitory connections between CRF + and SOM + neurons, indicating that the selection of appropriate behavioural responses to threat is based on competitive interactions between two defined populations of inhibitory neurons, a circuit motif allowing for rapid and flexible action selection. Main Mammals express adaptive behavioural responses to threat 1 , 2 . The type of response depends on intensity and proximity of threat, as well as context 2 , 8 . Although different behavioural fear responses are inborn, associative learning enables organisms to use environmental cues to predict and respond to danger 9 . Pavlovian fear conditioning is one paradigm that has been used to understand the neural circuitry underlying associative learning 5 , 9 , 10 . In Pavlovian fear conditioning, a conditioned stimulus (CS; for example, an auditory stimulus) is paired with an aversive unconditioned stimulus (US; for example, electrical footshock). Electrical footshock, the most commonly used US, elicits a variety of defensive responses, including flight and freezing 4 ; however, freezing is the dominant conditioned response to the CS in most fear-conditioning experiments 5 . We developed a Pavlovian conditioning paradigm that promotes active defensive behaviour, including flight. Conditioned flight responses to the CS were elicited by extending standard conditioning protocols ( Extended Data Fig. 1 ). To allow for direct, within-subject comparison of active and passive behaviours, we tested different CSs and found that a serial compound stimulus (SCS) consisting of a pure tone followed by white noise induced rapid behavioural switches between conditioned freezing and flight behaviour ( Fig. 1a–d ). With conditioning, mice exhibited freezing in response to the tone, and flight during the white noise ( Fig. 1c, d , Supplementary Video 1 ). The conditioned flight response was characterized by increases in speed ( Fig. 1d ) and the number of escape jumps ( Fig. 1d , Supplementary Video 1 ). This behaviour was quantified as a flight score ( Fig. 1c, d , see Methods). Behavioural analysis revealed that tone exposure significantly enhanced freezing compared to contextual freezing, and that exposure to white noise, concomitant with the observed increase in flight score, resulted in a significant reduction of the time spent freezing ( Fig. 1d ). Importantly, the white noise stimulus was not in itself aversive ( Extended Data Fig. 1 ). Figure 1: Conditioned flight paradigm. a , Protocol used to elicit conditioned flight responses. On day 4, mice were split into two groups. b , The conditioned stimulus is a serial compound stimulus (SCS) which is paired with a 1 s footshock during conditioning. c , Top, comparison of flight scores across sessions (day 1 to day 3, n = 20, two-way repeated-measures ANOVA, cue × trial interaction, F (13,247) = 4.82, P < 0.01). AU, arbitrary units. Bottom, comparison of freezing responses across sessions (day 1 to day 3, n = 20; two-way repeated-measures ANOVA, cue × trial interaction, F (13,247) = 18.3, P < 0.01). d , Top, average speed trace of mice ( n = 10) from day 3, note increase in speed during exposure to white noise. Bottom left, the number of jump escape responses on day 3 ( n = 20, Friedman test, P < 0.01, Dunn’s multiple comparisons test). Bottom centre, flight scores on day 3 ( n = 20, Wilcoxon matched-pairs signed-rank test). Bottom right, freezing behaviour on day 3 ( n = 20; one-way repeated-measures ANOVA, F = 56.82, P < 0.01, Tukey’s multiple comparisons test). e , Top left, rapid extinction of conditioned flight ( n = 12, two-way repeated-measures ANOVA, cue × trial interaction, F (15,165) = 3.05, P < 0.01). Top right, flight scores from first block of four trials of extinction ( n = 12, Wilcoxon matched-pairs signed-rank test). Bottom left, freezing in response to white noise increases during extinction ( n = 12, two-way repeated-measures ANOVA, cue × trial interaction, F (15,165) = 3.55, P < 0.01). Bottom right, freezing for the first block of four trials during extinction ( n = 12, Wilcoxon matched-pairs signed-rank test). f , Top left, conditioned flight is context-dependent ( n = 8, two-way repeated-measures ANOVA, cue × trial interaction, F (1,7) = 27.44, P < 0.01). Top right, flight scores in the neutral context (two-tailed paired t -test). Bottom left, freezing responses across trials during retrieval ( n = 8, two-way repeated-measures ANOVA, effect of cue F (1,7) = 27.67, P < 0.01). Bottom right, freezing responses during retrieval are highest in response to white noise ( n = 8, two-tailed paired t -test). Box and whisker plots indicate median, interquartile range, and 5th to 95th percentiles of the distribution, crosses indicate means. All other values are means ±", "role": "user" }, { "content": "Andreas Lüthi and his group at the FMI have identified two types of neurons in the amygdala, each of which generates a distinct fear response – freezing or flight. In addition, these two cell types interact, thus creating a balance, which shifts in one direction or the other, depending on the particular situation. The researchers' findings were published today in Nature. Our fear responses can escalate from one level to another: while we may pause for a moment if we hear a cracking in the undergrowth as we walk through the woods at night, we will certainly take to our heels if the sound is louder and rapidly approaching. But how long can we simply freeze and when do we need to flee to ensure our safety? Rodents such as mice exhibit and can learn similar types of behavioral responses to real or perceived threats. They likewise switch between freezing and flight behavior. However, it has not been clear to date what causes the switch between the passive and active responses. Using a variety of behavioral tests and optogenetic methods, the research group led by Andreas Lüthi at the Friedrich Miescher Institute for Biomedical Research (FMI) has identified the neurons whose interactions in the mouse brain are responsible for the switch between passive and active fear responses. The scientists showed that in the amygdala – the almond shaped brain structure long known to be a fear center – two different types of inhibitory neurons are responsible for the distinct fear responses. Activation of one of these neuronal populations, which expresses corticotropin releasing factor (CRF), triggers flight. The other population, which expresses somatostatin, (SOM) initiates freezing. Interestingly, the two cell types are linked by synaptic connections and can inhibit each other. However, if one of the inhibitory actions is removed as a result of inputs from other brain regions, then the appropriate response is generated. First author Jonathan Fadok (a postdoc in Andreas Lüthi's group) explains: \"There's a balance which can rapidly shift one way or the other in the face of a threat. Here, the context, sensory input such as sounds or odors, but also experiences and internal states are taken into account.\" Whether the same types of cells are also involved in human fear responses remains to be shown. But the defensive strategies deployed to ensure survival in threatening situations are identical in many species. \"So it's conceivable,\" says Lüthi, \"that a similar balance also regulates fear responses in humans.\" And particularly in anxiety disorders, he adds, this balance could be shifted in the direction of escalating fear responses. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract When faced with threat, the survival of an organism is contingent upon the selection of appropriate active or passive behavioural responses 1 , 2 , 3 . Freezing is an evolutionarily conserved passive fear response that has been used extensively to study the neuronal mechanisms of fear and fear conditioning in rodents 4 . However, rodents also exhibit active responses such as flight under natural conditions 2 . The central amygdala (CEA) is a forebrain structure vital for the acquisition and expression of conditioned fear responses, and the role of specific neuronal sub-populations of the CEA in freezing behaviour is well-established 1 , 5 , 6 , 7 . Whether the CEA is also involved in flight behaviour, and how neuronal circuits for active and passive fear behaviour interact within the CEA, are not yet understood. Here, using in vivo optogenetics and extracellular recordings of identified cell types in a behavioural model in which mice switch between conditioned freezing and flight, we show that active and passive fear responses are mediated by distinct and mutually inhibitory CEA neurons. Cells expressing corticotropin-releasing factor (CRF + ) mediate conditioned flight, and activation of somatostatin-positive (SOM + ) neurons initiates passive freezing behaviour. Moreover, we find that the balance between conditioned flight and freezing behaviour is regulated by means of local inhibitory connections between CRF + and SOM + neurons, indicating that the selection of appropriate behavioural responses to threat is based on competitive interactions between two defined populations of inhibitory neurons, a circuit motif allowing for rapid and flexible action selection. Main Mammals express adaptive behavioural responses to threat 1 , 2 . The type of response depends on intensity and proximity of threat, as well as context 2 , 8 . Although different behavioural fear responses are inborn, associative learning enables organisms to use environmental cues to predict and respond to danger 9 . Pavlovian fear conditioning is one paradigm that has been used to understand the neural circuitry underlying associative learning 5 , 9 , 10 . In Pavlovian fear conditioning, a conditioned stimulus (CS; for example, an auditory stimulus) is paired with an aversive unconditioned stimulus (US; for example, electrical footshock). Electrical footshock, the most commonly used US, elicits a variety of defensive responses, including flight and freezing 4 ; however, freezing is the dominant conditioned response to the CS in most fear-conditioning experiments 5 . We developed a Pavlovian conditioning paradigm that promotes active defensive behaviour, including flight. Conditioned flight responses to the CS were elicited by extending standard conditioning protocols ( Extended Data Fig. 1 ). To allow for direct, within-subject comparison of active and passive behaviours, we tested different CSs and found that a serial compound stimulus (SCS) consisting of a pure tone followed by white noise induced rapid behavioural switches between conditioned freezing and flight behaviour ( Fig. 1a–d ). With conditioning, mice exhibited freezing in response to the tone, and flight during the white noise ( Fig. 1c, d , Supplementary Video 1 ). The conditioned flight response was characterized by increases in speed ( Fig. 1d ) and the number of escape jumps ( Fig. 1d , Supplementary Video 1 ). This behaviour was quantified as a flight score ( Fig. 1c, d , see Methods). Behavioural analysis revealed that tone exposure significantly enhanced freezing compared to contextual freezing, and that exposure to white noise, concomitant with the observed increase in flight score, resulted in a significant reduction of the time spent freezing ( Fig. 1d ). Importantly, the white noise stimulus was not in itself aversive ( Extended Data Fig. 1 ). Figure 1: Conditioned flight paradigm. a , Protocol used to elicit conditioned flight responses. On day 4, mice were split into two groups. b , The conditioned stimulus is a serial compound stimulus (SCS) which is paired with a 1 s footshock during conditioning. c , Top, comparison of flight scores across sessions (day 1 to day 3, n = 20, two-way repeated-measures ANOVA, cue × trial interaction, F (13,247) = 4.82, P < 0.01). AU, arbitrary units. Bottom, comparison of freezing responses across sessions (day 1 to day 3, n = 20; two-way repeated-measures ANOVA, cue × trial interaction, F (13,247) = 18.3, P < 0.01). d , Top, average speed trace of mice ( n = 10) from day 3, note increase in speed during exposure to white noise. Bottom left, the number of jump escape responses on day 3 ( n = 20, Friedman test, P < 0.01, Dunn’s multiple comparisons test). Bottom centre, flight scores on day 3 ( n = 20, Wilcoxon matched-pairs signed-rank test). Bottom right, freezing behaviour on day 3 ( n = 20; one-way repeated-measures ANOVA, F = 56.82, P < 0.01, Tukey’s multiple comparisons test). e , Top left, rapid extinction of conditioned flight ( n = 12, two-way repeated-measures ANOVA, cue × trial interaction, F (15,165) = 3.05, P < 0.01). Top right, flight scores from first block of four trials of extinction ( n = 12, Wilcoxon matched-pairs signed-rank test). Bottom left, freezing in response to white noise increases during extinction ( n = 12, two-way repeated-measures ANOVA, cue × trial interaction, F (15,165) = 3.55, P < 0.01). Bottom right, freezing for the first block of four trials during extinction ( n = 12, Wilcoxon matched-pairs signed-rank test). f , Top left, conditioned flight is context-dependent ( n = 8, two-way repeated-measures ANOVA, cue × trial interaction, F (1,7) = 27.44, P < 0.01). Top right, flight scores in the neutral context (two-tailed paired t -test). Bottom left, freezing responses across trials during retrieval ( n = 8, two-way repeated-measures ANOVA, effect of cue F (1,7) = 27.67, P < 0.01). Bottom right, freezing responses during retrieval are highest in response to white noise ( n = 8, two-tailed paired t -test). Box and whisker plots indicate median, interquartile range, and 5th to 95th percentiles of the distribution, crosses indicate means. All other values are means ±<|im_end|> <|im_start|>assistant Andreas Lüthi and his group at the FMI have identified two types of neurons in the amygdala, each of which generates a distinct fear response – freezing or flight. In addition, these two cell types interact, thus creating a balance, which shifts in one direction or the other, depending on the particular situation. The researchers' findings were published today in Nature. Our fear responses can escalate from one level to another: while we may pause for a moment if we hear a cracking in the undergrowth as we walk through the woods at night, we will certainly take to our heels if the sound is louder and rapidly approaching. But how long can we simply freeze and when do we need to flee to ensure our safety? Rodents such as mice exhibit and can learn similar types of behavioral responses to real or perceived threats. They likewise switch between freezing and flight behavior. However, it has not been clear to date what causes the switch between the passive and active responses. Using a variety of behavioral tests and optogenetic methods, the research group led by Andreas Lüthi at the Friedrich Miescher Institute for Biomedical Research (FMI) has identified the neurons whose interactions in the mouse brain are responsible for the switch between passive and active fear responses. The scientists showed that in the amygdala – the almond shaped brain structure long known to be a fear center – two different types of inhibitory neurons are responsible for the distinct fear responses. Activation of one of these neuronal populations, which expresses corticotropin releasing factor (CRF), triggers flight. The other population, which expresses somatostatin, (SOM) initiates freezing. Interestingly, the two cell types are linked by synaptic connections and can inhibit each other. However, if one of the inhibitory actions is removed as a result of inputs from other brain regions, then the appropriate response is generated. First author Jonathan Fadok (a postdoc in Andreas Lüthi's group) explains: "There's a balance which can rapidly shift one way or the other in the face of a threat. Here, the context, sensory input such as sounds or odors, but also experiences and internal states are taken into account." Whether the same types of cells are also involved in human fear responses remains to be shown. But the defensive strategies deployed to ensure survival in threatening situations are identical in many species. "So it's conceivable," says Lüthi, "that a similar balance also regulates fear responses in humans." And particularly in anxiety disorders, he adds, this balance could be shifted in the direction of escalating fear responses. <|im_end|>

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220, 16, 67, 1174, 99371, 8519, 220, 16, 7609, 1115, 17432, 574, 10484, 1908, 439, 264, 11213, 5573, 320, 23966, 13, 220, 16, 66, 11, 294, 1174, 1518, 19331, 570, 80354, 278, 6492, 10675, 430, 16630, 14675, 12207, 24872, 43318, 7863, 311, 66251, 43318, 11, 323, 430, 14675, 311, 4251, 12248, 11, 390, 884, 52044, 449, 279, 13468, 5376, 304, 11213, 5573, 11, 19543, 304, 264, 5199, 14278, 315, 279, 892, 7543, 43318, 320, 23966, 13, 220, 16, 67, 7609, 13516, 18007, 11, 279, 4251, 12248, 39535, 574, 539, 304, 5196, 1860, 53453, 320, 41665, 2956, 23966, 13, 220, 16, 7609, 19575, 220, 16, 25, 15534, 291, 11213, 49340, 13, 264, 1174, 25590, 1511, 311, 658, 19195, 66731, 11213, 14847, 13, 1952, 1938, 220, 19, 11, 24548, 1051, 6859, 1139, 1403, 5315, 13, 293, 1174, 578, 66731, 39535, 374, 264, 6275, 24549, 39535, 320, 3624, 50, 8, 902, 374, 35526, 449, 264, 220, 16, 274, 4579, 939, 1197, 2391, 35121, 13, 272, 1174, 7054, 11, 12593, 315, 11213, 12483, 4028, 16079, 320, 1316, 220, 16, 311, 1938, 220, 18, 11, 308, 284, 220, 508, 11, 1403, 27896, 11763, 35073, 24368, 2147, 46, 13114, 11, 50498, 25800, 9269, 16628, 11, 435, 320, 1032, 11, 14125, 8, 284, 220, 19, 13, 6086, 11, 393, 366, 220, 15, 13, 1721, 570, 40156, 11, 25142, 8316, 13, 26821, 11, 12593, 315, 43318, 14847, 4028, 16079, 320, 1316, 220, 16, 311, 1938, 220, 18, 11, 308, 284, 220, 508, 26, 1403, 27896, 11763, 35073, 24368, 2147, 46, 13114, 11, 50498, 25800, 9269, 16628, 11, 435, 320, 1032, 11, 14125, 8, 284, 220, 972, 13, 18, 11, 393, 366, 220, 15, 13, 1721, 570, 294, 1174, 7054, 11, 5578, 4732, 11917, 315, 24548, 320, 308, 284, 220, 605, 8, 505, 1938, 220, 18, 11, 5296, 5376, 304, 4732, 2391, 14675, 311, 4251, 12248, 13, 26821, 2163, 11, 279, 1396, 315, 7940, 12731, 14847, 389, 1938, 220, 18, 320, 308, 284, 220, 508, 11, 62458, 1296, 11, 393, 366, 220, 15, 13, 1721, 11, 64845, 753, 5361, 36595, 1296, 570, 26821, 12541, 11, 11213, 12483, 389, 1938, 220, 18, 320, 308, 284, 220, 508, 11, 10785, 1030, 62585, 18545, 2320, 4825, 8667, 3880, 1201, 1296, 570, 26821, 1314, 11, 43318, 17432, 389, 1938, 220, 18, 320, 308, 284, 220, 508, 26, 832, 27896, 11763, 35073, 24368, 2147, 46, 13114, 11, 435, 284, 220, 3487, 13, 6086, 11, 393, 366, 220, 15, 13, 1721, 11, 29749, 798, 753, 5361, 36595, 1296, 570, 384, 1174, 7054, 2163, 11, 11295, 52609, 315, 66731, 11213, 320, 308, 284, 220, 717, 11, 1403, 27896, 11763, 35073, 24368, 2147, 46, 13114, 11, 50498, 25800, 9269, 16628, 11, 435, 320, 868, 11, 10680, 8, 284, 220, 18, 13, 2304, 11, 393, 366, 220, 15, 13, 1721, 570, 7054, 1314, 11, 11213, 12483, 505, 1176, 2565, 315, 3116, 19622, 315, 52609, 320, 308, 284, 220, 717, 11, 10785, 1030, 62585, 18545, 2320, 4825, 8667, 3880, 1201, 1296, 570, 26821, 2163, 11, 43318, 304, 2077, 311, 4251, 12248, 12992, 2391, 52609, 320, 308, 284, 220, 717, 11, 1403, 27896, 11763, 35073, 24368, 2147, 46, 13114, 11, 50498, 25800, 9269, 16628, 11, 435, 320, 868, 11, 10680, 8, 284, 220, 18, 13, 2131, 11, 393, 366, 220, 15, 13, 1721, 570, 26821, 1314, 11, 43318, 369, 279, 1176, 2565, 315, 3116, 19622, 2391, 52609, 320, 308, 284, 220, 717, 11, 10785, 1030, 62585, 18545, 2320, 4825, 8667, 3880, 1201, 1296, 570, 282, 1174, 7054, 2163, 11, 66731, 11213, 374, 2317, 43918, 320, 308, 284, 220, 23, 11, 1403, 27896, 11763, 35073, 24368, 2147, 46, 13114, 11, 50498, 25800, 9269, 16628, 11, 435, 320, 16, 11, 22, 8, 284, 220, 1544, 13, 2096, 11, 393, 366, 220, 15, 13, 1721, 570, 7054, 1314, 11, 11213, 12483, 304, 279, 21277, 2317, 320, 20375, 2442, 5805, 35526, 259, 482, 1985, 570, 26821, 2163, 11, 43318, 14847, 4028, 19622, 2391, 57470, 320, 308, 284, 220, 23, 11, 1403, 27896, 11763, 35073, 24368, 2147, 46, 13114, 11, 2515, 315, 50498, 435, 320, 16, 11, 22, 8, 284, 220, 1544, 13, 3080, 11, 393, 366, 220, 15, 13, 1721, 570, 26821, 1314, 11, 43318, 14847, 2391, 57470, 527, 8592, 304, 2077, 311, 4251, 12248, 320, 308, 284, 220, 23, 11, 1403, 2442, 5805, 35526, 259, 482, 1985, 570, 8425, 323, 41759, 261, 31794, 13519, 23369, 11, 958, 447, 472, 458, 2134, 11, 323, 220, 20, 339, 311, 220, 2721, 339, 3346, 3742, 315, 279, 8141, 11, 50535, 13519, 3445, 13, 2052, 1023, 2819, 527, 3445, 20903, 128257, 198, 128256, 78191, 198, 3112, 51518, 445, 2448, 339, 72, 323, 813, 1912, 520, 279, 435, 9972, 617, 11054, 1403, 4595, 315, 34313, 304, 279, 64383, 29684, 6181, 11, 1855, 315, 902, 27983, 264, 12742, 8850, 2077, 1389, 43318, 477, 11213, 13, 763, 5369, 11, 1521, 1403, 2849, 4595, 16681, 11, 8617, 6968, 264, 8335, 11, 902, 29735, 304, 832, 5216, 477, 279, 1023, 11, 11911, 389, 279, 4040, 6671, 13, 578, 12074, 6, 14955, 1051, 4756, 3432, 304, 22037, 13, 5751, 8850, 14847, 649, 89690, 505, 832, 2237, 311, 2500, 25, 1418, 584, 1253, 18579, 369, 264, 4545, 422, 584, 6865, 264, 52829, 304, 279, 1234, 74189, 439, 584, 4321, 1555, 279, 33633, 520, 3814, 11, 584, 690, 7995, 1935, 311, 1057, 34460, 422, 279, 5222, 374, 62896, 323, 19019, 31047, 13, 2030, 1268, 1317, 649, 584, 5042, 31030, 323, 994, 656, 584, 1205, 311, 28500, 311, 6106, 1057, 7296, 30, 13611, 812, 1778, 439, 24548, 31324, 323, 649, 4048, 4528, 4595, 315, 36695, 14847, 311, 1972, 477, 26617, 18208, 13, 2435, 39022, 3480, 1990, 43318, 323, 11213, 7865, 13, 4452, 11, 433, 706, 539, 1027, 2867, 311, 2457, 1148, 11384, 279, 3480, 1990, 279, 28979, 323, 4642, 14847, 13, 12362, 264, 8205, 315, 36695, 7177, 323, 3469, 11968, 5411, 5528, 11, 279, 3495, 1912, 6197, 555, 51162, 445, 2448, 339, 72, 520, 279, 80474, 386, 552, 9211, 10181, 369, 12371, 61860, 8483, 320, 37, 9972, 8, 706, 11054, 279, 34313, 6832, 22639, 304, 279, 8814, 8271, 527, 8647, 369, 279, 3480, 1990, 28979, 323, 4642, 8850, 14847, 13, 578, 14248, 8710, 430, 304, 279, 64383, 29684, 6181, 1389, 279, 63168, 27367, 8271, 6070, 1317, 3967, 311, 387, 264, 8850, 4219, 1389, 1403, 2204, 4595, 315, 20747, 10843, 34313, 527, 8647, 369, 279, 12742, 8850, 14847, 13, 50747, 315, 832, 315, 1521, 79402, 22673, 11, 902, 61120, 23100, 87537, 897, 258, 28965, 8331, 320, 9150, 37, 705, 31854, 11213, 13, 578, 1023, 7187, 11, 902, 61120, 1794, 266, 537, 15111, 11, 320, 50, 1937, 8, 12961, 988, 43318, 13, 58603, 11, 279, 1403, 2849, 4595, 527, 10815, 555, 99827, 13537, 323, 649, 69033, 1855, 1023, 13, 4452, 11, 422, 832, 315, 279, 20747, 10843, 6299, 374, 7108, 439, 264, 1121, 315, 11374, 505, 1023, 8271, 13918, 11, 1243, 279, 8475, 2077, 374, 8066, 13, 5629, 3229, 24150, 435, 329, 564, 320, 64, 1772, 5349, 304, 51162, 445, 2448, 339, 72, 596, 1912, 8, 15100, 25, 330, 3947, 596, 264, 8335, 902, 649, 19019, 6541, 832, 1648, 477, 279, 1023, 304, 279, 3663, 315, 264, 6023, 13, 5810, 11, 279, 2317, 11, 49069, 1988, 1778, 439, 10578, 477, 11018, 1105, 11, 719, 1101, 11704, 323, 5419, 5415, 527, 4529, 1139, 2759, 1210, 13440, 279, 1890, 4595, 315, 7917, 527, 1101, 6532, 304, 3823, 8850, 14847, 8625, 311, 387, 6982, 13, 2030, 279, 16399, 15174, 27167, 311, 6106, 20237, 304, 27903, 15082, 527, 20086, 304, 1690, 9606, 13, 330, 4516, 433, 596, 95883, 1359, 2795, 445, 2448, 339, 72, 11, 330, 9210, 264, 4528, 8335, 1101, 80412, 8850, 14847, 304, 12966, 1210, 1628, 8104, 304, 18547, 24673, 11, 568, 11621, 11, 420, 8335, 1436, 387, 30073, 304, 279, 5216, 315, 77157, 8850, 14847, 13, 220, 128257, 198 ]

1,983

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Evidence association in forensic cases involving gunshot residue (GSR) remains very challenging. Herein, a new in silico approach, called quantitative profile–profile relationship (QPPR) modelling, is reported. This is based on the application of modern machine learning techniques to predict the pre-discharge chemical profiles of selected ammunition components from those of the respective post-discharge GSR. The obtained profiles can then be compared with one another and/or with other measured profiles to make evidential links during forensic investigations. In particular, the approach was optimised and successfully tested for the prediction of GC-MS profiles of smokeless powders (SLPs) from organic GSR in spent cases, for nine ammunition types. Results showed a high degree of similarity between predicted and experimentally measured profiles, after adequate combination and evaluation of fourteen machine learning techniques (median correlation of 0.982). Areas under the curve (AUCs) of 0.976 and 0.824 were observed after receiver operating characteristic (ROC) analysis of the results obtained in the comparisons between predicted–predicted and predicted–measured profiles, respectively, in the specific case that the ammunition types of interest were excluded from the training dataset ( i.e. , extrapolation). Furthermore, AUCs of 0.962 and 0.894 were observed in interpolation mode. These values were close to those of the comparison of the measured SLP profiles between themselves (AUC = 0.998), demonstrating excellent potential to correctly associate evidence in a number of different forensic scenarios. This work represents the first time that a quantitative approach has successfully been applied to associate a GSR to a specific ammunition. This article is part of the themed collections: #RSCPoster Twitter Conference and Analyst Recent Open Access Articles 1. Introduction Association is a key challenge in forensic science. 1 In the reconstruction of shooting events, in particular, associating a variety of different entities and/or items discovered during an investigation (as, for example, a spent cartridge case with a reference ammunition or entry hole) may provide law-enforcement authorities with crucial intelligence and scientific evidence. 2,3 As bullets and spent cartridges are primarily involved in discharge, they carry physical marks left by the used firearm and other intrinsic features. Thus, special emphasis is usually put on their examination. Their usefulness, however, may be limited in a number of cases. For example, physical characteristics may be poorly selective or not exploitable due to post-discharge deformations, poor impression quality or high frequency in the general population. Moreover, bullets, in particular, may pass through the target and/or be lost to inaccessible locations, whilst spent cartridges may be collected by the perpetrator or simply not released after the discharge ( e.g. , use of a revolver). Under these circumstances, and several more, alternative pieces of evidence, such as the gunshot residue (GSR), must be exploited. The GSR is the chemical trace systematically released as a secondary effect of a firearm discharge. 4–7 It is a heterogeneous mixture of different species containing contribution from all the cartridge elements. The most forensically relevant fractions are the so-called organic GSR (OGSR) and primer GSR (pGSR). The OGSR is primarily the residue from the explosion of the smokeless powder (SLP) and contains both the organic species originally present in it, as well as numerous transformation products. The pGSR is, on the contrary, mainly the residue of the explosion of the primer mixture and is composed of microscopic particles resulting from the condensation of vaporised metals. After discharge, these fractions are released from every opening of the firearm and deposited on surfaces nearby, such as the hands/body of the shooter. A large portion can also reach the target or remain inside the spent cartridge. For these reasons, GSR analysis already finds many successful applications in the investigation of firearm-related crimes, 8,9 such as, for example, the identification of persons involved in shooting events, the estimation of shooting distance and/or the time since discharge. Concerning evidence association, a number of works have explored the possibility to establish links between different GSRs found on a crime scene and/or between a GSR and a specific ammunition or firearm. In this regard, it has been observed that both pGSR and OGSR display large variation between different sources, at micro- and macro-physicochemical levels, in a number of different features, including particle/flake morphology, 10,11 chemical composition 12–18 and distribution of particle classes. 19,20 Through the comparison of quantitative chemical profiles, in particular, grouping different GSR traces released from the same source has been frequently proved to be achievable, as long as these were collected from similar deposition surfaces. 21–25 Clustering or classification models, such as hierarchical clustering analysis or linear discriminant analysis, have shown promise for this purpose. Additionally, comparison of qualitative or simple semi-quantitative characteristics, such as the occurrence of certain particle classes or ratios between specific chemical species, has been proved to provide some insight about the general type of ammunition or firearm used. 12,26–30 These reported approaches, however, suffer from some important limitations. In particular, association of evidence has essentially been limited to GSRs recovered from the same deposition surface. GSRs released by the same ammunition, but collected at different locations ( e.g. , spent cartridge cases and target entry holes) were found to potentially differ in their physicochemical characteristics. 23,31 Even more importantly, the profiles of GSRs and their original ammunition elements were generally observed to be inconsistent (even if mutually dependent), due to discharge-induced alterations, sampling effects and/or differences in analytical procedures. 14,16,32–34 As a result, only the comparison of the basic qualitative or semi-quantitative measurements was possible, which holds a weak association efficacy. When a stronger association needs to be established, indirect comparison is currently carried out. This involves the firing of reference ammunition (for example, seized from the suspect) using the suspected firearm, followed by the analysis and comparison of the reference GSRs deposited on the different surfaces of interest. 23 As a trial-and-error procedure, this is time consuming, laborious and depends on the availability of both reference ammunition and firearm. As a consequence, it can be applied only in selected cases. More flexible, rapid and efficient strategies are required, as highlighted", "role": "user" }, { "content": "Some of history's most notorious unsolved murder crimes could be laid bare thanks to new forensic research led at Northumbria University, in Newcastle. Dr. Matteo Gallidabino, Senior Lecturer in Forensic Science at Northumbria University, working with colleagues at King's College London and the Universities of Lausanne, Santiago de Compostela and Rome (La Sapienza), have revealed that machine learning – a field of artificial intelligence – could be used to determine which ammunition, and ultimately which firearm, was responsible for a particular gunshot from the residue it left behind. Their findings have been published in the Royal Society of Chemistry's Analyst journal – the home of fundamental discoveries, inventions and applications in analytical and bioanalytical sciences. \"Machine learning uses a series of algorithms to model complex data relationships\" explains Dr. Gallidabino. \"Through careful fine-tuning, these can be applied to predict important characteristics of the ammunition used in a particular shooting event from those of the respective gunshot residue (GSR) deposited on surrounding surfaces or items, such as spent cases, wounds and, potentially, also the shooter's hands.\" This is a ground-breaking progression when compared to techniques currently available in GSR analysis. Indeed, the complex computer statistics implemented by the research team allow identification of the ammunition responsible for the different gunshot traces left at a crime scene and eventual association of such traces, with unprecedented accuracy. Both capabilities are currently challenging using traditional forensic methods. With further developments of the suggested approach, new investigative leads could be rapidly pursued to avoid similar unsolved murders of the past, like Jill Dando in 1999 and the notorious Bloody Sunday killings of 1972. \"After Bloody Sunday, the problem was to determine if gunshots were fired by civilians or military staff\" states Dr. Gallidabino. \"The investigators found large amounts of GSR all over victims and concluded that these resulted from shooting activities. It was later established, however, that these were likely due to the secondary, post-event transfer of contaminations from military staff – whose hands were rich with GSRs – to dead bodies. Small amounts of GSR, indeed, may be transferred by prolonged contacts with contaminated surfaces, such as those that took place when soldiers helped transport victims to the hospital after the event. \"If techniques such as those we are developing now were available at the time, they could have been used to determine if GSRs came from civilian ammunition or military fire, which would have been a critical piece of evidence.\" Dr. Gallidabino specialises in statistical modelling and machine learning techniques for forensic applications. He personally developed and tested both the innovative chemical technique and the mathematical models used in the approach, after firing a range of ammunition. After collecting the gun cartridges, he analysed them, and particularly the volatile part of the GSR, before turning his attention to the original smokeless powders. From here, he was able to establish a relationship between the ammunition and the residue, with the same statistical methods used by computer scientists to train robots. Following on from this, the research team has called for this unique method to be applied much more widely in the field of forensic science and, more generally, analytical chemistry. \"The benefits are countless\" Dr. Gallidabino said. \"They may even extend to other fields in analytical sciences that routinely encounter changeable chemical traces, such as the analysis of improvised explosive devices, arson accelerants and environmental pollutants.\" Dr. Leon Barron, Senior Lecturer in Forensic Science from King's College London, added: \"The fusion of state-of-the-art laboratory analysis with computer-based machine learning will enable us to capitalise on the vast amounts of data we now generate to make ground-breaking advances like this more frequently. In forensic science, and often given the varied scenarios and sequences of events involved, machine learning represents one of the most promising ways to make sense of evidence more rapidly to support the Criminal Justice System.\" Jill Dando On April 26, 1999, the 38-year-old BBC star was shot dead on the doorstep of her home in Fulham, West London in what remains one of the UK's most high-profile unsolved murders. Barry George, who lived a few minutes from Jill's house, was jailed for eight years for her murder but was cleared after a retrial in 2008 following concerns raised over forensic evidence. The case remains open. Having more knowledge about the source of GSR at the time of the murder could have been useful, according to Dr. Gallidabino and the rest of the research team. \"One single GSR particle was found in the pocket of the coat of Barry George (the suspect)\" he says. \"This particle was shown to have a really similar composition to those found on the victim, Jill Dando, according to techniques available at time. As no approved method existed to compare GSR compositions on different surfaces, however, this evidence was strongly contested. With our approach, we hope in the future to provide robust tools to law enforcement agencies to more efficiently address this kind of situation.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Evidence association in forensic cases involving gunshot residue (GSR) remains very challenging. Herein, a new in silico approach, called quantitative profile–profile relationship (QPPR) modelling, is reported. This is based on the application of modern machine learning techniques to predict the pre-discharge chemical profiles of selected ammunition components from those of the respective post-discharge GSR. The obtained profiles can then be compared with one another and/or with other measured profiles to make evidential links during forensic investigations. In particular, the approach was optimised and successfully tested for the prediction of GC-MS profiles of smokeless powders (SLPs) from organic GSR in spent cases, for nine ammunition types. Results showed a high degree of similarity between predicted and experimentally measured profiles, after adequate combination and evaluation of fourteen machine learning techniques (median correlation of 0.982). Areas under the curve (AUCs) of 0.976 and 0.824 were observed after receiver operating characteristic (ROC) analysis of the results obtained in the comparisons between predicted–predicted and predicted–measured profiles, respectively, in the specific case that the ammunition types of interest were excluded from the training dataset ( i.e. , extrapolation). Furthermore, AUCs of 0.962 and 0.894 were observed in interpolation mode. These values were close to those of the comparison of the measured SLP profiles between themselves (AUC = 0.998), demonstrating excellent potential to correctly associate evidence in a number of different forensic scenarios. This work represents the first time that a quantitative approach has successfully been applied to associate a GSR to a specific ammunition. This article is part of the themed collections: #RSCPoster Twitter Conference and Analyst Recent Open Access Articles 1. Introduction Association is a key challenge in forensic science. 1 In the reconstruction of shooting events, in particular, associating a variety of different entities and/or items discovered during an investigation (as, for example, a spent cartridge case with a reference ammunition or entry hole) may provide law-enforcement authorities with crucial intelligence and scientific evidence. 2,3 As bullets and spent cartridges are primarily involved in discharge, they carry physical marks left by the used firearm and other intrinsic features. Thus, special emphasis is usually put on their examination. Their usefulness, however, may be limited in a number of cases. For example, physical characteristics may be poorly selective or not exploitable due to post-discharge deformations, poor impression quality or high frequency in the general population. Moreover, bullets, in particular, may pass through the target and/or be lost to inaccessible locations, whilst spent cartridges may be collected by the perpetrator or simply not released after the discharge ( e.g. , use of a revolver). Under these circumstances, and several more, alternative pieces of evidence, such as the gunshot residue (GSR), must be exploited. The GSR is the chemical trace systematically released as a secondary effect of a firearm discharge. 4–7 It is a heterogeneous mixture of different species containing contribution from all the cartridge elements. The most forensically relevant fractions are the so-called organic GSR (OGSR) and primer GSR (pGSR). The OGSR is primarily the residue from the explosion of the smokeless powder (SLP) and contains both the organic species originally present in it, as well as numerous transformation products. The pGSR is, on the contrary, mainly the residue of the explosion of the primer mixture and is composed of microscopic particles resulting from the condensation of vaporised metals. After discharge, these fractions are released from every opening of the firearm and deposited on surfaces nearby, such as the hands/body of the shooter. A large portion can also reach the target or remain inside the spent cartridge. For these reasons, GSR analysis already finds many successful applications in the investigation of firearm-related crimes, 8,9 such as, for example, the identification of persons involved in shooting events, the estimation of shooting distance and/or the time since discharge. Concerning evidence association, a number of works have explored the possibility to establish links between different GSRs found on a crime scene and/or between a GSR and a specific ammunition or firearm. In this regard, it has been observed that both pGSR and OGSR display large variation between different sources, at micro- and macro-physicochemical levels, in a number of different features, including particle/flake morphology, 10,11 chemical composition 12–18 and distribution of particle classes. 19,20 Through the comparison of quantitative chemical profiles, in particular, grouping different GSR traces released from the same source has been frequently proved to be achievable, as long as these were collected from similar deposition surfaces. 21–25 Clustering or classification models, such as hierarchical clustering analysis or linear discriminant analysis, have shown promise for this purpose. Additionally, comparison of qualitative or simple semi-quantitative characteristics, such as the occurrence of certain particle classes or ratios between specific chemical species, has been proved to provide some insight about the general type of ammunition or firearm used. 12,26–30 These reported approaches, however, suffer from some important limitations. In particular, association of evidence has essentially been limited to GSRs recovered from the same deposition surface. GSRs released by the same ammunition, but collected at different locations ( e.g. , spent cartridge cases and target entry holes) were found to potentially differ in their physicochemical characteristics. 23,31 Even more importantly, the profiles of GSRs and their original ammunition elements were generally observed to be inconsistent (even if mutually dependent), due to discharge-induced alterations, sampling effects and/or differences in analytical procedures. 14,16,32–34 As a result, only the comparison of the basic qualitative or semi-quantitative measurements was possible, which holds a weak association efficacy. When a stronger association needs to be established, indirect comparison is currently carried out. This involves the firing of reference ammunition (for example, seized from the suspect) using the suspected firearm, followed by the analysis and comparison of the reference GSRs deposited on the different surfaces of interest. 23 As a trial-and-error procedure, this is time consuming, laborious and depends on the availability of both reference ammunition and firearm. As a consequence, it can be applied only in selected cases. More flexible, rapid and efficient strategies are required, as highlighted<|im_end|> <|im_start|>assistant Some of history's most notorious unsolved murder crimes could be laid bare thanks to new forensic research led at Northumbria University, in Newcastle. Dr. Matteo Gallidabino, Senior Lecturer in Forensic Science at Northumbria University, working with colleagues at King's College London and the Universities of Lausanne, Santiago de Compostela and Rome (La Sapienza), have revealed that machine learning – a field of artificial intelligence – could be used to determine which ammunition, and ultimately which firearm, was responsible for a particular gunshot from the residue it left behind. Their findings have been published in the Royal Society of Chemistry's Analyst journal – the home of fundamental discoveries, inventions and applications in analytical and bioanalytical sciences. "Machine learning uses a series of algorithms to model complex data relationships" explains Dr. Gallidabino. "Through careful fine-tuning, these can be applied to predict important characteristics of the ammunition used in a particular shooting event from those of the respective gunshot residue (GSR) deposited on surrounding surfaces or items, such as spent cases, wounds and, potentially, also the shooter's hands." This is a ground-breaking progression when compared to techniques currently available in GSR analysis. Indeed, the complex computer statistics implemented by the research team allow identification of the ammunition responsible for the different gunshot traces left at a crime scene and eventual association of such traces, with unprecedented accuracy. Both capabilities are currently challenging using traditional forensic methods. With further developments of the suggested approach, new investigative leads could be rapidly pursued to avoid similar unsolved murders of the past, like Jill Dando in 1999 and the notorious Bloody Sunday killings of 1972. "After Bloody Sunday, the problem was to determine if gunshots were fired by civilians or military staff" states Dr. Gallidabino. "The investigators found large amounts of GSR all over victims and concluded that these resulted from shooting activities. It was later established, however, that these were likely due to the secondary, post-event transfer of contaminations from military staff – whose hands were rich with GSRs – to dead bodies. Small amounts of GSR, indeed, may be transferred by prolonged contacts with contaminated surfaces, such as those that took place when soldiers helped transport victims to the hospital after the event. "If techniques such as those we are developing now were available at the time, they could have been used to determine if GSRs came from civilian ammunition or military fire, which would have been a critical piece of evidence." Dr. Gallidabino specialises in statistical modelling and machine learning techniques for forensic applications. He personally developed and tested both the innovative chemical technique and the mathematical models used in the approach, after firing a range of ammunition. After collecting the gun cartridges, he analysed them, and particularly the volatile part of the GSR, before turning his attention to the original smokeless powders. From here, he was able to establish a relationship between the ammunition and the residue, with the same statistical methods used by computer scientists to train robots. Following on from this, the research team has called for this unique method to be applied much more widely in the field of forensic science and, more generally, analytical chemistry. "The benefits are countless" Dr. Gallidabino said. "They may even extend to other fields in analytical sciences that routinely encounter changeable chemical traces, such as the analysis of improvised explosive devices, arson accelerants and environmental pollutants." Dr. Leon Barron, Senior Lecturer in Forensic Science from King's College London, added: "The fusion of state-of-the-art laboratory analysis with computer-based machine learning will enable us to capitalise on the vast amounts of data we now generate to make ground-breaking advances like this more frequently. In forensic science, and often given the varied scenarios and sequences of events involved, machine learning represents one of the most promising ways to make sense of evidence more rapidly to support the Criminal Justice System." Jill Dando On April 26, 1999, the 38-year-old BBC star was shot dead on the doorstep of her home in Fulham, West London in what remains one of the UK's most high-profile unsolved murders. Barry George, who lived a few minutes from Jill's house, was jailed for eight years for her murder but was cleared after a retrial in 2008 following concerns raised over forensic evidence. The case remains open. Having more knowledge about the source of GSR at the time of the murder could have been useful, according to Dr. Gallidabino and the rest of the research team. "One single GSR particle was found in the pocket of the coat of Barry George (the suspect)" he says. "This particle was shown to have a really similar composition to those found on the victim, Jill Dando, according to techniques available at time. As no approved method existed to compare GSR compositions on different surfaces, however, this evidence was strongly contested. With our approach, we hope in the future to provide robust tools to law enforcement agencies to more efficiently address this kind of situation." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In the last decade record-breaking rainfall events have occurred in many places around the world causing severe impacts to human society and the environment including agricultural losses and floodings. There is now medium confidence that human-induced greenhouse gases have contributed to changes in heavy precipitation events at the global scale. Here, we present the first analysis of record-breaking daily rainfall events using observational data. We show that over the last three decades the number of record-breaking events has significantly increased in the global mean. Globally, this increase has led to 12 % more record-breaking rainfall events over 1981–2010 compared to those expected in stationary time series. The number of record-breaking rainfall events peaked in 2010 with an estimated 26 % chance that a new rainfall record is due to long-term climate change. This increase in record-breaking rainfall is explained by a statistical model which accounts for the warming of air and associated increasing water holding capacity only. Our results suggest that whilst the number of rainfall record-breaking events can be related to natural multi-decadal variability over the period from 1901 to 1980, observed record-breaking rainfall events significantly increased afterwards consistent with rising temperatures. Access provided by DEAL DE / Springer Compact Clearingstelle Uni Freiburg _ Working on a manuscript? Avoid the common mistakes 1 Introduction The last decade has produced a large number of extreme weather events worldwide, including record-breaking rainfall events (Coumou and Rahmstorf 2012 ). The year 2010 has so far been the wettest year on record over land in terms of total precipitation (NOAA National Climatic Data Center 2010 ), setting new record-breaking rainfall events on different time scales over many parts of the world (Trenberth 2012 ). This seeming accumulation of weather extremes in an exceptionally warm decade has raised the question of whether these events are related to climatic change. A number of studies have addressed this issue using observational data sets and climate models (Pall et al. 2007 ; Zhang et al. 2007 , 2013 ; Min et al. 2011 ; Shiu et al. 2012 ; Benestad 2013 ; Berg et al. 2013 ; Singh and O’Gorman 2014 ). The main finding is that over the recent past trends towards stronger precipitation extremes can be found over a larger fraction of the land area than trends towards weaker precipitation extremes (e.g. see references in Seneviratne et al. 2012 ). For example, Westra et al. ( 2013 ) found a significant increase in annual maximum daily precipitation extremes on a global scale. Climate models suggest that the thermodynamic change in saturation vapor pressure as described by the Clausius-Clapeyron relation is a good predictor for changes in extreme rainfall intensities (Pall et al. 2007 ). This relationship predicts an increase in water vapor of typically 7 % per degree of warming assuming constant relative humidity. However, dynamical changes can also influence the frequency and intensity of precipitation and thus disrupt the Clausius-Clapeyron expected change (Trenberth 2011 ). For example, changes in extratropical storm tracks will affect rainfall in mid-latitude regions (Scaife et al. 2011 ; Hawcroft et al. 2012 ). The response of convective precipitation to warming can exceed the Clausius-Clapeyron rate (Berg et al. 2013 ) which will have the strongest effects in the tropics. Most studies used extreme value theory to analyze changes in threshold events, i.e. those exceeding a specified threshold of the climatological precipitation distribution (e.g., Kharin et al. 2007 ; Trenberth et al. 2007 ; Min et al. 2011 ; Westra et al. 2013 ). This usually involves fitting an extreme value distribution to the tail of the observed distribution. However, small sample sizes in the tail result in unstable fits which can have strong affects on the results (Frei and Schär 2001 ). Here, we present the first global analysis of observed record-breaking daily precipitation events between 1901 and 2010 and how their frequency differs from that expected in a stationary climate. Analyzing record-breaking events has the advantage that no assumption on the underlying probability distribution function has to be made. This also implies that with this method no statements can be made about the exact changes in the underlying probability distribution in terms of shifts in the mean or higher order moments. However, here, we are interested in whether record-breaking rainfall events have increased or not, irrespective of the exact underlying changes in probability distribution. Thereby, the number of observed record-breaking rainfall events can be compared to the number expected in a climate with no long-term trend. This approach has been proven insightful for understanding the increase of heat extremes in a warming world (Benestad 2003 , 2004 ; Redner and Petersen 2005 ; Meehl et al. 2009 ; Anderson and Kostinski 2011 ; Coumou et al. 2013 ). 2 Data and method 2.1 Data We use monthly maximum 1-day precipitation data (Rx1day) from HadEX2 (Donat et al. 2013b ), a 3.75 × 2.5° gridded data set covering 1901–2010 (Fig. S1 in Supplementary Information (SI)). Globally aggregated quantities over land are dominated by the northern extratropics which account for roughly 2/3 of the total available data (Fig. 1 , Fig. S2 b). Spatial coverage varies over time with best coverage between 1960 and 2000 (Fig. S2 a). Fig. 1 Time series length of monthly maximum 1-day precipitation data covered at each grid point with a value of 110 indicating full coverage over 1901–2010. The magnitude is represented by the color and size of the dots Full size image We analyze record-breaking events in each monthly Rx1day time series and subsequently take annual (12 calendar months) and boreal winter (Nov-Dec-Jan-Feb-Mar (NDJFM)) and summer (May-Jun-Jul-Aug-Sep (MJJAS)) averages. To ensure feasible statistics we restrict analysis to (1) time series with at least 30 years of data and (2) regions and time periods which had at least 100 non-missing values at each time slice. The maximum time period was found for which these criteria hold. To test the robustness of our findings, we applied the analysis also to a second data set,", "role": "user" }, { "content": "Heavy rainfall events setting ever new records have been increasing strikingly in the past thirty years. While before 1980, multi-decadal fluctuations in extreme rainfall events are explained by natural variability, a team of scientists of the Potsdam Institute for Climate Impact Research detected a clear upward trend in the past few decades towards more unprecedented daily rainfall events. They find the worldwide increase to be consistent with rising global temperatures which are caused by greenhouse-gas emissions from burning fossil fuels. Short-term torrential rains can lead to high-impact floodings. Extreme rainfall in Pakistan 2010 caused devastating flooding which killed hundreds and lead to a cholera outbreak. Other examples of record-breaking precipitation events in the period studied include rainstorms in Texas in the US, 2010, which caused dozens of flash-floods. And no less than three so-called 'once-in-a-century' flooding events in Germany all happened in just a couple of years, starting 1997. \"In all of these places, the amount of rain pouring down in one day broke local records - and while each of these individual events has been caused by a number of different factors, we find a clear overall upward trend for these unprecedented hazards\", says lead-author Jascha Lehmann. The average increase is 12 percent globally - but 56 percent in South East Asia An advanced statistical analysis of rainfall data from the years 1901 to 2010 derived from thousands of weather stations around the globe shows that over 1980-2010 there were 12 percent more of these events than expected in a stationary climate, a scenario without global warming. \"Due to the upward trend, the worldwide increase of record-breaking daily rainfall events in the very last year of the studied period reaches even 26 percent\", Lehmann adds. The record-breaking anomaly has distinct patterns across Earth's continents with generally wet regions seeing an over-proportional increase and drier regions less so. In South East Asian countries the observed increase in record-breaking rainfall events is as high as 56 percent, in Europe 31 percent, in the central US 24 percent. In contrast, some regions experienced a significant decrease of record-breaking daily rainfall events. In the Mediterranean, the reduction is 27 percent, and in the Western US 21 percent. Both regions are at risk of severe droughts. The link to climate change: warmer air can hold more water While a statistical analysis of course cannot provide direct physical cause-effect relations, the scientists compared their findings to existing knowledge about how much more water can be stored in the atmosphere when temperatures rise, as given by the well-known Clausius-Clapeyron equation. This additional moisture can be released during short-term heavy rainfall events. The scientists show that the observed increase in unprecedented heavy rainfall events generally fits with this thermodynamically expected increase under global warming. \"One out of ten record-breaking rainfall events observed globally in the past thirty years can only be explained if the long-term warming is taken into account,\" says co-author Dim Coumou. \"For the last year studied, 2010, it is even one event out of four, as the trend is upward\". Up to now, studies could add up to only medium confidence on how human induced greenhouse gases have contributed to changes in heavy precipitation events at the global and regional scale. The new analysis now helps to fill this research gap. Building on previous work on extreme precipitation, it is the first to study worldwide observational data of record-breaking daily rainfall events in this context. \"The recent upward trend is worrying\" The scientists took into account that the quality of historic weather data differs from one place to another. For instance, rainfall measurements from the Sahara desert are scarce which inhibits making any conclusions for this particular region. Other regions like Europe or the US are well covered with rainfall measurements stretching back over a century which enables the authors to draw conclusions with high levels of confidence \"The pronounced recent increase in record-breaking rainfall events is of course worrying,\" Coumou concludes. \"Yet since it is consistent with human-caused global warming, it can also be curbed if greenhouse gas emissions from fossil fuels are substantially reduced.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In the last decade record-breaking rainfall events have occurred in many places around the world causing severe impacts to human society and the environment including agricultural losses and floodings. There is now medium confidence that human-induced greenhouse gases have contributed to changes in heavy precipitation events at the global scale. Here, we present the first analysis of record-breaking daily rainfall events using observational data. We show that over the last three decades the number of record-breaking events has significantly increased in the global mean. Globally, this increase has led to 12 % more record-breaking rainfall events over 1981–2010 compared to those expected in stationary time series. The number of record-breaking rainfall events peaked in 2010 with an estimated 26 % chance that a new rainfall record is due to long-term climate change. This increase in record-breaking rainfall is explained by a statistical model which accounts for the warming of air and associated increasing water holding capacity only. Our results suggest that whilst the number of rainfall record-breaking events can be related to natural multi-decadal variability over the period from 1901 to 1980, observed record-breaking rainfall events significantly increased afterwards consistent with rising temperatures. Access provided by DEAL DE / Springer Compact Clearingstelle Uni Freiburg _ Working on a manuscript? Avoid the common mistakes 1 Introduction The last decade has produced a large number of extreme weather events worldwide, including record-breaking rainfall events (Coumou and Rahmstorf 2012 ). The year 2010 has so far been the wettest year on record over land in terms of total precipitation (NOAA National Climatic Data Center 2010 ), setting new record-breaking rainfall events on different time scales over many parts of the world (Trenberth 2012 ). This seeming accumulation of weather extremes in an exceptionally warm decade has raised the question of whether these events are related to climatic change. A number of studies have addressed this issue using observational data sets and climate models (Pall et al. 2007 ; Zhang et al. 2007 , 2013 ; Min et al. 2011 ; Shiu et al. 2012 ; Benestad 2013 ; Berg et al. 2013 ; Singh and O’Gorman 2014 ). The main finding is that over the recent past trends towards stronger precipitation extremes can be found over a larger fraction of the land area than trends towards weaker precipitation extremes (e.g. see references in Seneviratne et al. 2012 ). For example, Westra et al. ( 2013 ) found a significant increase in annual maximum daily precipitation extremes on a global scale. Climate models suggest that the thermodynamic change in saturation vapor pressure as described by the Clausius-Clapeyron relation is a good predictor for changes in extreme rainfall intensities (Pall et al. 2007 ). This relationship predicts an increase in water vapor of typically 7 % per degree of warming assuming constant relative humidity. However, dynamical changes can also influence the frequency and intensity of precipitation and thus disrupt the Clausius-Clapeyron expected change (Trenberth 2011 ). For example, changes in extratropical storm tracks will affect rainfall in mid-latitude regions (Scaife et al. 2011 ; Hawcroft et al. 2012 ). The response of convective precipitation to warming can exceed the Clausius-Clapeyron rate (Berg et al. 2013 ) which will have the strongest effects in the tropics. Most studies used extreme value theory to analyze changes in threshold events, i.e. those exceeding a specified threshold of the climatological precipitation distribution (e.g., Kharin et al. 2007 ; Trenberth et al. 2007 ; Min et al. 2011 ; Westra et al. 2013 ). This usually involves fitting an extreme value distribution to the tail of the observed distribution. However, small sample sizes in the tail result in unstable fits which can have strong affects on the results (Frei and Schär 2001 ). Here, we present the first global analysis of observed record-breaking daily precipitation events between 1901 and 2010 and how their frequency differs from that expected in a stationary climate. Analyzing record-breaking events has the advantage that no assumption on the underlying probability distribution function has to be made. This also implies that with this method no statements can be made about the exact changes in the underlying probability distribution in terms of shifts in the mean or higher order moments. However, here, we are interested in whether record-breaking rainfall events have increased or not, irrespective of the exact underlying changes in probability distribution. Thereby, the number of observed record-breaking rainfall events can be compared to the number expected in a climate with no long-term trend. This approach has been proven insightful for understanding the increase of heat extremes in a warming world (Benestad 2003 , 2004 ; Redner and Petersen 2005 ; Meehl et al. 2009 ; Anderson and Kostinski 2011 ; Coumou et al. 2013 ). 2 Data and method 2.1 Data We use monthly maximum 1-day precipitation data (Rx1day) from HadEX2 (Donat et al. 2013b ), a 3.75 × 2.5° gridded data set covering 1901–2010 (Fig. S1 in Supplementary Information (SI)). Globally aggregated quantities over land are dominated by the northern extratropics which account for roughly 2/3 of the total available data (Fig. 1 , Fig. S2 b). Spatial coverage varies over time with best coverage between 1960 and 2000 (Fig. S2 a). Fig. 1 Time series length of monthly maximum 1-day precipitation data covered at each grid point with a value of 110 indicating full coverage over 1901–2010. The magnitude is represented by the color and size of the dots Full size image We analyze record-breaking events in each monthly Rx1day time series and subsequently take annual (12 calendar months) and boreal winter (Nov-Dec-Jan-Feb-Mar (NDJFM)) and summer (May-Jun-Jul-Aug-Sep (MJJAS)) averages. To ensure feasible statistics we restrict analysis to (1) time series with at least 30 years of data and (2) regions and time periods which had at least 100 non-missing values at each time slice. The maximum time period was found for which these criteria hold. To test the robustness of our findings, we applied the analysis also to a second data set,<|im_end|> <|im_start|>assistant Heavy rainfall events setting ever new records have been increasing strikingly in the past thirty years. While before 1980, multi-decadal fluctuations in extreme rainfall events are explained by natural variability, a team of scientists of the Potsdam Institute for Climate Impact Research detected a clear upward trend in the past few decades towards more unprecedented daily rainfall events. They find the worldwide increase to be consistent with rising global temperatures which are caused by greenhouse-gas emissions from burning fossil fuels. Short-term torrential rains can lead to high-impact floodings. Extreme rainfall in Pakistan 2010 caused devastating flooding which killed hundreds and lead to a cholera outbreak. Other examples of record-breaking precipitation events in the period studied include rainstorms in Texas in the US, 2010, which caused dozens of flash-floods. And no less than three so-called 'once-in-a-century' flooding events in Germany all happened in just a couple of years, starting 1997. "In all of these places, the amount of rain pouring down in one day broke local records - and while each of these individual events has been caused by a number of different factors, we find a clear overall upward trend for these unprecedented hazards", says lead-author Jascha Lehmann. The average increase is 12 percent globally - but 56 percent in South East Asia An advanced statistical analysis of rainfall data from the years 1901 to 2010 derived from thousands of weather stations around the globe shows that over 1980-2010 there were 12 percent more of these events than expected in a stationary climate, a scenario without global warming. "Due to the upward trend, the worldwide increase of record-breaking daily rainfall events in the very last year of the studied period reaches even 26 percent", Lehmann adds. The record-breaking anomaly has distinct patterns across Earth's continents with generally wet regions seeing an over-proportional increase and drier regions less so. In South East Asian countries the observed increase in record-breaking rainfall events is as high as 56 percent, in Europe 31 percent, in the central US 24 percent. In contrast, some regions experienced a significant decrease of record-breaking daily rainfall events. In the Mediterranean, the reduction is 27 percent, and in the Western US 21 percent. Both regions are at risk of severe droughts. The link to climate change: warmer air can hold more water While a statistical analysis of course cannot provide direct physical cause-effect relations, the scientists compared their findings to existing knowledge about how much more water can be stored in the atmosphere when temperatures rise, as given by the well-known Clausius-Clapeyron equation. This additional moisture can be released during short-term heavy rainfall events. The scientists show that the observed increase in unprecedented heavy rainfall events generally fits with this thermodynamically expected increase under global warming. "One out of ten record-breaking rainfall events observed globally in the past thirty years can only be explained if the long-term warming is taken into account," says co-author Dim Coumou. "For the last year studied, 2010, it is even one event out of four, as the trend is upward". Up to now, studies could add up to only medium confidence on how human induced greenhouse gases have contributed to changes in heavy precipitation events at the global and regional scale. The new analysis now helps to fill this research gap. Building on previous work on extreme precipitation, it is the first to study worldwide observational data of record-breaking daily rainfall events in this context. "The recent upward trend is worrying" The scientists took into account that the quality of historic weather data differs from one place to another. For instance, rainfall measurements from the Sahara desert are scarce which inhibits making any conclusions for this particular region. Other regions like Europe or the US are well covered with rainfall measurements stretching back over a century which enables the authors to draw conclusions with high levels of confidence "The pronounced recent increase in record-breaking rainfall events is of course worrying," Coumou concludes. "Yet since it is consistent with human-caused global warming, it can also be curbed if greenhouse gas emissions from fossil fuels are substantially reduced." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The ability of particles to flow with very low resistance is characteristic of superfluid and superconducting states, leading to their discovery in the past century 1 , 2 . Although measuring the particle flow in liquid helium or superconducting materials is essential to identify superfluidity or superconductivity, no analogous measurement has been performed for superfluids based on ultracold Fermi gases. Here we report direct measurements of the conduction properties of strongly interacting fermions, observing the well-known drop in resistance that is associated with the onset of superfluidity. By varying the depth of the trapping potential in a narrow channel connecting two atomic reservoirs, we observed variations of the atomic current over several orders of magnitude. We related the intrinsic conduction properties to the thermodynamic functions in a model-independent way, by making use of high-resolution in situ imaging in combination with current measurements. Our results show that, as in solid-state systems, current and resistance measurements in quantum gases provide a sensitive probe with which to explore many-body physics. Our method is closely analogous to the operation of a solid-state field-effect transistor and could be applied as a probe for optical lattices and disordered systems, paving the way for modelling complex superconducting devices. Main Over the past decade, cold atoms have emerged as a many-body system with a uniquely high level of control 3 . Experiments have shown that interacting atomic Fermi gases, analogous to electrons in a solid, can display superfluidity 4 . The equilibrium properties of such gases have been measured with increasing precision 5 , 6 , 7 , 8 and the superfluid character of the ground state has been investigated via the response to external perturbations 9 and the direct observation of vortices 10 , in the same way as for Bose–Einstein condensates 11 , 12 , 13 , 14 , 15 . Using new techniques to create and observe directed currents in a closed atomic circuit 16 or between two large reservoirs 17 , it is now possible to study the transport properties of mesoscopic systems that are directly analogous to electronic devices 18 . Here we investigated the conduction properties of strongly interacting fermions flowing through a quasi-two-dimensional, multimode channel, which connects two atomic reservoirs. Going beyond our previous work 17 , we now obtained full control over the atomic current by tuning a repulsive gate potential in the channel. The gate potential was created by an off-resonant laser beam, as illustrated in Fig. 1 . In analogy with an electronic field-effect transistor, this gate potential controls the chemical potential in the channel while keeping the temperature imposed by the reservoirs unchanged. With the gate potential as a control parameter, we measured the current through the channel over a large dynamic range and related it to the observed density in the channel region. This allowed us to observe the onset of superfluid flow of strongly interacting fermions. We compared these measurements to the case of weakly interacting fermions. In our experiment, the current established in the channel was a response to the longitudinal perturbation induced by a difference in chemical potential between the two reservoirs. This is complementary to experiments probing the response of isolated atomic clouds to transverse excitation via rotation 10 or shear 19 . Figure 1: Principle of the experiment. Two atomic reservoirs (source and drain) are connected by a quasi-two-dimensional conducting channel. An atom number imbalance N left > N right between source and drain drives an atom current through the channel, indicated by the arrows. A repulsive laser beam (gate beam) propagating along the z -axis is focused on the channel. It creates a repulsive potential with a gaussian envelope and a tunable amplitude. The lighter region in the channel indicates the reduced density due to the repulsive potential. PowerPoint slide Full size image Our experiments were performed with strongly and weakly interacting quantum degenerate gases of fermionic 6 Li atoms, equally populating the lowest two hyperfine states. To obtain a strongly interacting gas, the atoms were placed in a homogeneous magnetic field of 834 G where the s -wave scattering length diverges and leads to the formation of pairs, while a weakly interacting gas was studied at a field of 475 G (see Methods and Supplementary Information ). The atoms were radially confined in the x–z plane by an optical dipole trap oriented along the y -axis with a 1/ e 2 beam radius of 22(1) µm; here and elsewhere, the value in parentheses is the 1- σ error of the last significant digit. Along the y -direction, the curvature of the magnetic field yielded a harmonic confinement with a frequency of ω y = 2π × 32(1) Hz. To engineer the reservoirs, we split the cloud into two parts using a repulsive laser beam at a wavelength of 532 nm that points along the x -direction (beam not shown in Fig. 1 ). The intensity profile of this beam has a holographically imprinted nodal line along the y -axis. As a result, a channel in the x–y plane was formed, which confined the atoms along the z -direction with a centre trap frequency of 2.9 kHz. The gate potential was created by another laser beam at 532 nm that was sent along the z -axis onto the channel and had a waist of 18 µm. We refer to the maximum of the repulsive potential created by this beam as the gate potential U . Along the z -axis, a high-resolution microscope objective was used for in situ absorption imaging of the atoms in the channel. The atom number in the reservoirs was measured by absorption imaging along the x -direction. By creating an atom number imbalance between the two reservoirs, we created a chemical potential bias that induced a current through the channel 17 . The inset to Fig. 2a presents an example of the time evolution of the relative number imbalance between the two reservoirs, measured for strongly interacting (red) and weakly interacting (blue) fermions, using the", "role": "user" }, { "content": "(Phys.org)—Physicists working at the Institute for Quantum Electronics in Switzerland have succeeded in building an apparatus that has allowed for the observation of the drop of resistance in the flow of a superfluid Fermi gas. They describe their work in a paper they've had published in the journal Nature. Researchers have known about superfluidity – materials that have particles that are able to flow with minimal resistance – for approximately 75 years, but up till now have never been able to observe the drop in resistance in an atomic gas superfluid. In this new work, the researchers built an apparatus that allowed them to do just that using nothing but lasers, magnetism and lithium gas. The team first created a cloud of supercooled lithium gas, then manipulated its shape using laser beams. In so doing they created a dumbbell shaped cloud – two chambers with a channel running between them. Another laser was used to block the lithium atoms from moving across the channel between the chambers serving as a gate. By forcing one chamber to have more lithium atoms than the other, the researchers created an imbalance between the two which caused atoms to flow naturally from one chamber to the other when the laser gate was \"lifted.\" In this controlled manner, the researchers were able to measure the rate at which the atoms moved across the chamber. In a normal state, they found it to be approximately 5 millimeters per second. In the second stage of the experiment, the researchers added a magnetic field to the same dumbbell shaped lithium cloud to cause the gas to become a superfluid. This time they found when lifting the laser gate and measuring the rate at which the atoms moved across the channel, their speed had risen to 30 millimeters per second. The increased speed came about due to the absence of resistance. The creation of this simple apparatus marks the first time that scientists have been able to observe the changes that occur when a Fermi gas moves from an ordinary gas to one that is a superfluid. The researchers suggest that observing gases changing this way could lead to advances in supercomputing devices and might even be used to serve as models to help describe the history of the early universe. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The ability of particles to flow with very low resistance is characteristic of superfluid and superconducting states, leading to their discovery in the past century 1 , 2 . Although measuring the particle flow in liquid helium or superconducting materials is essential to identify superfluidity or superconductivity, no analogous measurement has been performed for superfluids based on ultracold Fermi gases. Here we report direct measurements of the conduction properties of strongly interacting fermions, observing the well-known drop in resistance that is associated with the onset of superfluidity. By varying the depth of the trapping potential in a narrow channel connecting two atomic reservoirs, we observed variations of the atomic current over several orders of magnitude. We related the intrinsic conduction properties to the thermodynamic functions in a model-independent way, by making use of high-resolution in situ imaging in combination with current measurements. Our results show that, as in solid-state systems, current and resistance measurements in quantum gases provide a sensitive probe with which to explore many-body physics. Our method is closely analogous to the operation of a solid-state field-effect transistor and could be applied as a probe for optical lattices and disordered systems, paving the way for modelling complex superconducting devices. Main Over the past decade, cold atoms have emerged as a many-body system with a uniquely high level of control 3 . Experiments have shown that interacting atomic Fermi gases, analogous to electrons in a solid, can display superfluidity 4 . The equilibrium properties of such gases have been measured with increasing precision 5 , 6 , 7 , 8 and the superfluid character of the ground state has been investigated via the response to external perturbations 9 and the direct observation of vortices 10 , in the same way as for Bose–Einstein condensates 11 , 12 , 13 , 14 , 15 . Using new techniques to create and observe directed currents in a closed atomic circuit 16 or between two large reservoirs 17 , it is now possible to study the transport properties of mesoscopic systems that are directly analogous to electronic devices 18 . Here we investigated the conduction properties of strongly interacting fermions flowing through a quasi-two-dimensional, multimode channel, which connects two atomic reservoirs. Going beyond our previous work 17 , we now obtained full control over the atomic current by tuning a repulsive gate potential in the channel. The gate potential was created by an off-resonant laser beam, as illustrated in Fig. 1 . In analogy with an electronic field-effect transistor, this gate potential controls the chemical potential in the channel while keeping the temperature imposed by the reservoirs unchanged. With the gate potential as a control parameter, we measured the current through the channel over a large dynamic range and related it to the observed density in the channel region. This allowed us to observe the onset of superfluid flow of strongly interacting fermions. We compared these measurements to the case of weakly interacting fermions. In our experiment, the current established in the channel was a response to the longitudinal perturbation induced by a difference in chemical potential between the two reservoirs. This is complementary to experiments probing the response of isolated atomic clouds to transverse excitation via rotation 10 or shear 19 . Figure 1: Principle of the experiment. Two atomic reservoirs (source and drain) are connected by a quasi-two-dimensional conducting channel. An atom number imbalance N left > N right between source and drain drives an atom current through the channel, indicated by the arrows. A repulsive laser beam (gate beam) propagating along the z -axis is focused on the channel. It creates a repulsive potential with a gaussian envelope and a tunable amplitude. The lighter region in the channel indicates the reduced density due to the repulsive potential. PowerPoint slide Full size image Our experiments were performed with strongly and weakly interacting quantum degenerate gases of fermionic 6 Li atoms, equally populating the lowest two hyperfine states. To obtain a strongly interacting gas, the atoms were placed in a homogeneous magnetic field of 834 G where the s -wave scattering length diverges and leads to the formation of pairs, while a weakly interacting gas was studied at a field of 475 G (see Methods and Supplementary Information ). The atoms were radially confined in the x–z plane by an optical dipole trap oriented along the y -axis with a 1/ e 2 beam radius of 22(1) µm; here and elsewhere, the value in parentheses is the 1- σ error of the last significant digit. Along the y -direction, the curvature of the magnetic field yielded a harmonic confinement with a frequency of ω y = 2π × 32(1) Hz. To engineer the reservoirs, we split the cloud into two parts using a repulsive laser beam at a wavelength of 532 nm that points along the x -direction (beam not shown in Fig. 1 ). The intensity profile of this beam has a holographically imprinted nodal line along the y -axis. As a result, a channel in the x–y plane was formed, which confined the atoms along the z -direction with a centre trap frequency of 2.9 kHz. The gate potential was created by another laser beam at 532 nm that was sent along the z -axis onto the channel and had a waist of 18 µm. We refer to the maximum of the repulsive potential created by this beam as the gate potential U . Along the z -axis, a high-resolution microscope objective was used for in situ absorption imaging of the atoms in the channel. The atom number in the reservoirs was measured by absorption imaging along the x -direction. By creating an atom number imbalance between the two reservoirs, we created a chemical potential bias that induced a current through the channel 17 . The inset to Fig. 2a presents an example of the time evolution of the relative number imbalance between the two reservoirs, measured for strongly interacting (red) and weakly interacting (blue) fermions, using the<|im_end|> <|im_start|>assistant (Phys.org)—Physicists working at the Institute for Quantum Electronics in Switzerland have succeeded in building an apparatus that has allowed for the observation of the drop of resistance in the flow of a superfluid Fermi gas. They describe their work in a paper they've had published in the journal Nature. Researchers have known about superfluidity – materials that have particles that are able to flow with minimal resistance – for approximately 75 years, but up till now have never been able to observe the drop in resistance in an atomic gas superfluid. In this new work, the researchers built an apparatus that allowed them to do just that using nothing but lasers, magnetism and lithium gas. The team first created a cloud of supercooled lithium gas, then manipulated its shape using laser beams. In so doing they created a dumbbell shaped cloud – two chambers with a channel running between them. Another laser was used to block the lithium atoms from moving across the channel between the chambers serving as a gate. By forcing one chamber to have more lithium atoms than the other, the researchers created an imbalance between the two which caused atoms to flow naturally from one chamber to the other when the laser gate was "lifted." In this controlled manner, the researchers were able to measure the rate at which the atoms moved across the chamber. In a normal state, they found it to be approximately 5 millimeters per second. In the second stage of the experiment, the researchers added a magnetic field to the same dumbbell shaped lithium cloud to cause the gas to become a superfluid. This time they found when lifting the laser gate and measuring the rate at which the atoms moved across the channel, their speed had risen to 30 millimeters per second. The increased speed came about due to the absence of resistance. The creation of this simple apparatus marks the first time that scientists have been able to observe the changes that occur when a Fermi gas moves from an ordinary gas to one that is a superfluid. The researchers suggest that observing gases changing this way could lead to advances in supercomputing devices and might even be used to serve as models to help describe the history of the early universe. <|im_end|>

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279, 5613, 13, 578, 18618, 4754, 574, 3549, 555, 459, 1022, 11849, 263, 519, 21120, 24310, 11, 439, 36762, 304, 23966, 13, 220, 16, 662, 763, 56203, 449, 459, 14683, 2115, 23937, 99041, 11, 420, 18618, 4754, 11835, 279, 11742, 4754, 304, 279, 5613, 1418, 10494, 279, 9499, 27070, 555, 279, 45512, 82, 35957, 13, 3161, 279, 18618, 4754, 439, 264, 2585, 5852, 11, 584, 17303, 279, 1510, 1555, 279, 5613, 927, 264, 3544, 8915, 2134, 323, 5552, 433, 311, 279, 13468, 17915, 304, 279, 5613, 5654, 13, 1115, 5535, 603, 311, 23846, 279, 42080, 315, 2307, 67125, 6530, 315, 16917, 45830, 81682, 919, 13, 1226, 7863, 1521, 22323, 311, 279, 1162, 315, 7621, 398, 45830, 81682, 919, 13, 763, 1057, 9526, 11, 279, 1510, 9749, 304, 279, 5613, 574, 264, 2077, 311, 279, 68102, 18713, 65916, 36572, 555, 264, 6811, 304, 11742, 4754, 1990, 279, 1403, 45512, 82, 13, 1115, 374, 58535, 311, 21896, 84072, 279, 2077, 315, 25181, 25524, 30614, 311, 1380, 4550, 3521, 7709, 4669, 12984, 220, 605, 477, 65344, 220, 777, 662, 19575, 220, 16, 25, 82086, 315, 279, 9526, 13, 9220, 25524, 45512, 82, 320, 2484, 323, 24659, 8, 527, 8599, 555, 264, 48844, 38502, 33520, 31474, 5613, 13, 1556, 19670, 1396, 68331, 452, 2163, 871, 452, 1314, 1990, 2592, 323, 24659, 20722, 459, 19670, 1510, 1555, 279, 5613, 11, 16717, 555, 279, 38057, 13, 362, 2109, 58921, 21120, 24310, 320, 25623, 24310, 8, 17425, 1113, 3235, 279, 1167, 482, 7332, 374, 10968, 389, 279, 5613, 13, 1102, 11705, 264, 2109, 58921, 4754, 449, 264, 64547, 35498, 323, 264, 11716, 481, 45209, 13, 578, 30673, 5654, 304, 279, 5613, 15151, 279, 11293, 17915, 4245, 311, 279, 2109, 58921, 4754, 13, 54600, 15332, 8797, 1404, 2217, 5751, 21896, 1051, 10887, 449, 16917, 323, 7621, 398, 45830, 31228, 5367, 13523, 45612, 315, 81682, 21427, 220, 21, 14851, 33299, 11, 18813, 2477, 15853, 279, 15821, 1403, 17508, 63157, 5415, 13, 2057, 6994, 264, 16917, 45830, 6962, 11, 279, 33299, 1051, 9277, 304, 264, 87282, 24924, 2115, 315, 220, 26223, 480, 1405, 279, 274, 482, 31498, 72916, 3160, 37441, 4282, 323, 11767, 311, 279, 18488, 315, 13840, 11, 1418, 264, 7621, 398, 45830, 6962, 574, 20041, 520, 264, 2115, 315, 220, 19799, 480, 320, 4151, 19331, 323, 99371, 8245, 7609, 578, 33299, 1051, 9038, 34575, 45408, 304, 279, 865, 4235, 89, 11277, 555, 459, 29393, 24522, 1286, 23709, 42208, 3235, 279, 379, 482, 7332, 449, 264, 220, 16, 14, 384, 220, 17, 24310, 10801, 315, 220, 1313, 7, 16, 8, 64012, 76, 26, 1618, 323, 18403, 11, 279, 907, 304, 75075, 374, 279, 220, 16, 12, 48823, 1493, 315, 279, 1566, 5199, 16099, 13, 32944, 279, 379, 482, 19612, 11, 279, 83233, 315, 279, 24924, 2115, 58487, 264, 82341, 66678, 449, 264, 11900, 315, 117774, 379, 284, 220, 17, 49345, 25800, 220, 843, 7, 16, 8, 37192, 13, 2057, 24490, 279, 45512, 82, 11, 584, 6859, 279, 9624, 1139, 1403, 5596, 1701, 264, 2109, 58921, 21120, 24310, 520, 264, 46406, 315, 220, 20711, 26807, 430, 3585, 3235, 279, 865, 482, 19612, 320, 54971, 539, 6982, 304, 23966, 13, 220, 16, 7609, 578, 21261, 5643, 315, 420, 24310, 706, 264, 72927, 1976, 2740, 737, 53313, 16387, 278, 1584, 3235, 279, 379, 482, 7332, 13, 1666, 264, 1121, 11, 264, 5613, 304, 279, 865, 4235, 88, 11277, 574, 14454, 11, 902, 45408, 279, 33299, 3235, 279, 1167, 482, 19612, 449, 264, 12541, 23709, 11900, 315, 220, 17, 13, 24, 70726, 13, 578, 18618, 4754, 574, 3549, 555, 2500, 21120, 24310, 520, 220, 20711, 26807, 430, 574, 3288, 3235, 279, 1167, 482, 7332, 8800, 279, 5613, 323, 1047, 264, 29142, 315, 220, 972, 64012, 76, 13, 1226, 8464, 311, 279, 7340, 315, 279, 2109, 58921, 4754, 3549, 555, 420, 24310, 439, 279, 18618, 4754, 549, 662, 32944, 279, 1167, 482, 7332, 11, 264, 1579, 64036, 73757, 16945, 574, 1511, 369, 304, 10109, 44225, 32758, 315, 279, 33299, 304, 279, 5613, 13, 578, 19670, 1396, 304, 279, 45512, 82, 574, 17303, 555, 44225, 32758, 3235, 279, 865, 482, 19612, 13, 3296, 6968, 459, 19670, 1396, 68331, 1990, 279, 1403, 45512, 82, 11, 584, 3549, 264, 11742, 4754, 15837, 430, 36572, 264, 1510, 1555, 279, 5613, 220, 1114, 662, 578, 55959, 311, 23966, 13, 220, 17, 64, 18911, 459, 3187, 315, 279, 892, 15740, 315, 279, 8844, 1396, 68331, 1990, 279, 1403, 45512, 82, 11, 17303, 369, 16917, 45830, 320, 1171, 8, 323, 7621, 398, 45830, 320, 12481, 8, 81682, 919, 11, 1701, 279, 128257, 198, 128256, 78191, 198, 7, 67171, 2726, 68850, 67171, 292, 1705, 3318, 520, 279, 10181, 369, 56413, 38784, 304, 30221, 617, 26399, 304, 4857, 459, 41705, 430, 706, 5535, 369, 279, 22695, 315, 279, 6068, 315, 13957, 304, 279, 6530, 315, 264, 2307, 67125, 99362, 72, 6962, 13, 2435, 7664, 872, 990, 304, 264, 5684, 814, 3077, 1047, 4756, 304, 279, 8486, 22037, 13, 59250, 617, 3967, 922, 2307, 67125, 488, 1389, 7384, 430, 617, 19252, 430, 527, 3025, 311, 6530, 449, 17832, 13957, 1389, 369, 13489, 220, 2075, 1667, 11, 719, 709, 12222, 1457, 617, 2646, 1027, 3025, 311, 23846, 279, 6068, 304, 13957, 304, 459, 25524, 6962, 2307, 67125, 13, 763, 420, 502, 990, 11, 279, 12074, 5918, 459, 41705, 430, 5535, 1124, 311, 656, 1120, 430, 1701, 4400, 719, 72475, 11, 33297, 2191, 323, 57907, 6962, 13, 578, 2128, 1176, 3549, 264, 9624, 315, 2307, 1030, 42831, 57907, 6962, 11, 1243, 55315, 1202, 6211, 1701, 21120, 51045, 13, 763, 779, 3815, 814, 3549, 264, 30355, 17696, 27367, 9624, 1389, 1403, 53279, 449, 264, 5613, 4401, 1990, 1124, 13, 13596, 21120, 574, 1511, 311, 2565, 279, 57907, 33299, 505, 7366, 4028, 279, 5613, 1990, 279, 53279, 13788, 439, 264, 18618, 13, 3296, 25957, 832, 25199, 311, 617, 810, 57907, 33299, 1109, 279, 1023, 11, 279, 12074, 3549, 459, 68331, 1990, 279, 1403, 902, 9057, 33299, 311, 6530, 18182, 505, 832, 25199, 311, 279, 1023, 994, 279, 21120, 18618, 574, 330, 36069, 291, 1210, 763, 420, 14400, 11827, 11, 279, 12074, 1051, 3025, 311, 6767, 279, 4478, 520, 902, 279, 33299, 7882, 4028, 279, 25199, 13, 763, 264, 4725, 1614, 11, 814, 1766, 433, 311, 387, 13489, 220, 20, 2606, 55336, 824, 2132, 13, 763, 279, 2132, 6566, 315, 279, 9526, 11, 279, 12074, 3779, 264, 24924, 2115, 311, 279, 1890, 30355, 17696, 27367, 57907, 9624, 311, 5353, 279, 6962, 311, 3719, 264, 2307, 67125, 13, 1115, 892, 814, 1766, 994, 33510, 279, 21120, 18618, 323, 30090, 279, 4478, 520, 902, 279, 33299, 7882, 4028, 279, 5613, 11, 872, 4732, 1047, 41482, 311, 220, 966, 2606, 55336, 824, 2132, 13, 578, 7319, 4732, 3782, 922, 4245, 311, 279, 19821, 315, 13957, 13, 578, 9886, 315, 420, 4382, 41705, 15785, 279, 1176, 892, 430, 14248, 617, 1027, 3025, 311, 23846, 279, 4442, 430, 12446, 994, 264, 99362, 72, 6962, 11031, 505, 459, 19664, 6962, 311, 832, 430, 374, 264, 2307, 67125, 13, 578, 12074, 4284, 430, 46071, 45612, 10223, 420, 1648, 1436, 3063, 311, 31003, 304, 2307, 66047, 287, 7766, 323, 2643, 1524, 387, 1511, 311, 8854, 439, 4211, 311, 1520, 7664, 279, 3925, 315, 279, 4216, 15861, 13, 220, 128257, 198 ]

1,715

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Neuronal ensembles that hold specific memory (memory engrams) have been identified in the hippocampus, amygdala, or cortex. However, it has been hypothesized that engrams of a specific memory are distributed among multiple brain regions that are functionally connected, referred to as a unified engram complex. Here, we report a partial map of the engram complex for contextual fear conditioning memory by characterizing encoding activated neuronal ensembles in 247 regions using tissue phenotyping in mice. The mapping was aided by an engram index, which identified 117 cFos + brain regions holding engrams with high probability, and brain-wide reactivation of these neuronal ensembles by recall. Optogenetic manipulation experiments revealed engram ensembles, many of which were functionally connected to hippocampal or amygdala engrams. Simultaneous chemogenetic reactivation of multiple engram ensembles conferred a greater level of memory recall than reactivation of a single engram ensemble, reflecting the natural memory recall process. Overall, our study supports the unified engram complex hypothesis for memory storage. Introduction A memory engram is the enduring physical or chemical changes that occur in brain networks upon learning representing acquired memory information, and it is thought that recall is realized by the expression of these changes 1 . Neuronal ensembles that are activated by learning hold engrams and a reactivation of these neurons gives rise to recall of the specific memory 1 , 2 , 3 . Following the initial demonstrations of memory engram cell ensembles 2 , 4 , 5 , studies have identified engram cell ensembles for several memories in different brain regions, such as hippocampal subfields 6 , 7 , amygdala subregions 8 , retrosplenial cortex 9 , and prefrontal cortex 10 . Semon’s engram concept as the storage site of memory suggested that a given memory is stored not in a single engram ensemble localized in a brain site but instead in a unified engram complex—a network of engram cell ensembles connected and distributed in dispersed brain regions 1 , 11 , 12 . Indeed, early limited studies supported this concept for contextual fear memory 4 , 5 , 9 , 10 . While these findings enhanced our understanding of engram-based memory storage, a thorough mapping of a unified engram complex for a specific memory has been a challenging endeavor. The development of tissue clearing techniques, such as CLARITY 13 and iDISCO 14 , combined with advanced microscopy has enabled high-throughput analyses of intact mouse brain samples. Brain-wide mapping of neurons activated upon learning in the form of the expression of an immediate early gene, for instance, cFos, so-called “brain-wide activity mapping” has been applied to haloperidol administration, whisker stimulation, and parental behavior 15 , foot shocks and cocaine administration 16 , and fear memory 17 , 18 . Some of these studies, however, did not ascertain whether the activated neurons satisfied the basic criteria for engram-holding ensembles 15 , 17 . In the other studies, engram ensembles were demonstrated only in a limited brain region namely in the prefrontal cortex rather than in a brain-wide manner 16 , 18 . To further our understanding of the organization of memory engram cell ensembles, the experiment should be designed in the first step to identify neuronal activity patterns induced by memory formation in a more holistic manner. Since the recall-induced reactivation of neuronal ensembles that was previously activated by learning is also a crucial criterion of an engram cell ensemble 1 , 2 , 3 , it is essential for engram mapping studies to demonstrate this property. In the present study, we identified engram cell ensembles and their high probability candidates for a contextual fear memory, by following a four-step approach. First, we applied in a significantly broader set of brain regions SHIELD-based tissue phenotyping 19 for brain-wide mapping of activated neurons using the Fos-TRAP mouse line 20 . Using an unbiased and automated approach, we cross-compared the activity of 247 brain regions during contextual fear memory encoding and recent memory recall. Second, we devised an engram index to rank-order putative engram cell ensemble candidates because conducting optogenetic or chemogenetic manipulations that permit an assertion of engrams in hundreds of brain regions that display activity-dependent labeling is impractical. Third, we performed brain-wide engram reactivation studies, which revealed engrams that are reactivated by recall. Fourth, focusing on a dozen significant brain regions, narrowed down by the engram index and the engram reactivation experiments, we conducted optogenetic manipulations. This not only confirmed previously identified engrams but also revealed engrams in additional brain regions. Furthermore, many of these engrams and engram candidates were functionally connected to hippocampal CA1 or basolateral amygdala engrams. Finally, simultaneous reactivation of multiple engram cell ensembles using chemogenetics conferred greater levels of memory recall than reactivation of their subsets, as would be expected from the natural process of memory recall. Together, our study supports Semon’s unified engram complex hypothesis 1 that a specific memory is stored in functionally connected engram cell ensembles that are widely distributed in multiple brain regions. Results Brain-wide 3D imaging and mapping of activated neurons The first step of our unbiased engram mapping approach required brain-wide 3D imaging and mapping of activated neurons using the Fos-TRAP mouse line and SHIELD. Expression of immediate-early genes (IEGs) has been used to visualize neuronal activity in a given brain region 21 . By linking the expression of Cre ERT2 to the IEG cFos in a tamoxifen-dependent manner, the Fos-TRAP mouse line permits brain-wide labeling of activated neurons within a user-defined time window of several hours 20 . We crossed Fos-TRAP mice with a Cre-dependent tdTomato reporter mouse line (Fig. 1a ). Using the fast-acting 4-hydroxytamoxifen (4-OHT), we prepared three behavioral cohorts: mice that received 4-OHT and remained in their home cage for the labeling duration (home cage group), mice that received 4-OHT followed by contextual fear conditioning training and were returned to their home cage (CFC group), and mice that received 4-OHT followed by fear memory recall 24 h after CFC and were returned to their home cage (recall group). One week after labeling, brains", "role": "user" }, { "content": "A new study by scientists at The Picower Institute for Learning and Memory at MIT provides the most comprehensive and rigorous evidence yet that the mammalian brain stores a single memory across a widely distributed, functionally connected complex spanning many brain regions, rather than in just one or even a few places. Memory pioneer Richard Semon had predicted such a \"unified engram complex\" more than a century ago, but achieving the new study's affirmation of his hypothesis required the application of several technologies developed only recently. In the study, the team identified and ranked dozens of areas that were not previously known to be involved in memory and showed that memory recall becomes more behaviorally powerful when multiple memory-storing regions are reactivated, rather than just one. \"When talking about memory storage we all usually talk about the hippocampus or the cortex,\" said co-lead and co-corresponding author Dheeraj Roy. He began the research while a graduate student in the RIKEN-MIT Laboratory for Neural Circuit Genetics at The Picower Institute led by senior author and Picower Professor Susumu Tonegawa. \"This study reflects the most comprehensive description of memory encoding cells, or memory 'engrams,' distributed across the brain, not just in the well-known memory regions. It basically provides the first rank-ordered list for high-probability engram regions. This list should lead to many future studies, which we are excited about, both in our labs and by other groups.\" In addition to Roy, who is now a McGovern Fellow in the Broad Institute of MIT and Harvard and the lab of MIT neuroscience Professor Guoping Feng, the study's other lead authors are Young-Gyun Park, Minyoung Kim, Ying Zhang and Sachie Ogawa. Mapping Memory The team was able to map regions participating in an engram complex by conducting an unbiased analysis of more than 247 brain regions in mice who were taken from their home cage to another cage where they felt a small but memorable electrical zap. In one group of mice their neurons were engineered to become fluorescent when they expressed a gene required for memory encoding. In another group, cells activated by naturally recalling the zap memory (e.g. when the mice returned to the scene of the zap) were fluorescently labeled instead. Cells that were activated by memory encoding or by recall could therefore readily be seen under a microscope after the brains were preserved and optically cleared using a technology called SHIELD, developed by co-corresponding author Kwanghun Chung, Associate Professor in The Picower Institute, the Institute for Medical Engineering & Science and the Department of Chemical Engineering. By using a computer to count fluorescing cells in each sample, the team produced brain-wide maps of regions with apparently significant memory encoding or recall activity. The maps highlighted many regions expected to participate in memory but also many that were not. To help factor out regions that might have been activated by activity unrelated to the zap memory, the team compared what they saw in zap-encoding or zap-recalling mice to what they saw in the brains of controls who were simply left in their home cage. This allowed them to calculate an \"engram index\" to rank order 117 brain regions with a significant likelihood of being involved in the memory engram complex. They deepened the analysis by engineering new mice in which neurons involved in both memory encoding and in recall could be doubly labeled, thereby revealing which cells exhibited overlap of those activities. To really be an engram cell, the authors noted, a neuron should be activated both in encoding and recall. \"These experiments not only revealed significant engram reactivation in known hippocampal and amygdala regions, but also showed reactivation in many thalamic, cortical, midbrain and brainstem structures,\" the authors wrote. \"Importantly when we compared the brain regions identified by the engram index analysis with these reactivated regions, we observed that ~60 percent of the regions were consistent between analyses.\" Many brain regions found likely to be involved in encoding a memory (top) were also found to be involved in recall upon reactivation (bottom). Credit: Tonegawa Lab/MIT Picower Institute Memory manipulations Having ranked regions significantly likely to be involved in the engram complex, the team engaged in several manipulations to directly test their predictions and to determine how engram complex regions might work together. For instance, they engineered mice such that cells activated by memory encoding would also become controllable with flashes of light (a technique called \"optogenetics\"). The researchers then applied light flashes to select brain regions from their engram index list to see if stimulating those would artificially reproduce the fear memory behavior of freezing in place, even when mice were placed in a \"neutral\" cage where the zap had not occurred. \"Strikingly, all these brain regions induced robust memory recall when they were optogenetically stimulated,\" the researchers observed. Moreover, stimulating areas that their analysis suggested were insignificant to zap memory indeed produced no freezing behavior. The team then demonstrated how different regions within an engram complex connect. They chose two well-known memory regions, CA1 of the hippocampus and the basolateral amygdala (BLA), and optogenetically activated engram cells there to induce memory recall behavior in a neutral cage. They found that stimulating those regions produced memory recall activity in specific \"downstream\" areas identified as being probable members of the engram complex. Meanwhile, optogenetically inhibiting natural zap memory recall in CA1 or the BLA (i.e. when mice were placed back in the cage where they experienced the zap) led to reduced activity in downstream engram complex areas compared to what they measured in mice with unhindered natural recall. Further experiments showed that optogenetic reactivations of engram complex neurons followed similar patterns as those observed in natural memory recall. So having established that natural memory encoding and recall appears to occur across a wide engram complex, the team decided to test whether reactivating multiple regions would improve memory recall compared to reactivating just one. After all, prior experiments have shown that activating just one engram area does not produce recall as vividly as natural recall. This time the team used a chemical means to stimulate different engram complex regions and when they did, they found that indeed stimulating up to three involved regions simultaneously produced more robust freezing behavior than stimulating just one or two. Meaning of distributed storage Roy said that by storing a single memory across such a widespread complex the brain might be making memory more efficient and resilient. \"Different memory engrams may allow us to recreate memories more efficiently when we are trying to remember a previous event (and similarly for the initial encoding where different engrams may contribute different information from the original experience),\" he said. \"Secondly, in disease states, if a few regions are impaired, distributed memories would allow us to remember previous events and in some ways be more robust against regional damages.\" In the long term that second idea might suggest a clinical strategy for dealing with memory impairment: \"If some memory impairments are because of hippocampal or cortical dysfunction, could we target understudied engram cells in other regions and could such a manipulation restore some memory functions?\" That's just one of many new questions researchers can ask now that the study has revealed a listing of where to look for at least one kind of memory in the mammalian brain. The paper's other authors are Nicholas DiNapoli, Xinyi Gu, Jae Cho, Heejin Choi, Lee Kamentsky, Jared Martin, Olivia Mosto and Tomomi Aida. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Neuronal ensembles that hold specific memory (memory engrams) have been identified in the hippocampus, amygdala, or cortex. However, it has been hypothesized that engrams of a specific memory are distributed among multiple brain regions that are functionally connected, referred to as a unified engram complex. Here, we report a partial map of the engram complex for contextual fear conditioning memory by characterizing encoding activated neuronal ensembles in 247 regions using tissue phenotyping in mice. The mapping was aided by an engram index, which identified 117 cFos + brain regions holding engrams with high probability, and brain-wide reactivation of these neuronal ensembles by recall. Optogenetic manipulation experiments revealed engram ensembles, many of which were functionally connected to hippocampal or amygdala engrams. Simultaneous chemogenetic reactivation of multiple engram ensembles conferred a greater level of memory recall than reactivation of a single engram ensemble, reflecting the natural memory recall process. Overall, our study supports the unified engram complex hypothesis for memory storage. Introduction A memory engram is the enduring physical or chemical changes that occur in brain networks upon learning representing acquired memory information, and it is thought that recall is realized by the expression of these changes 1 . Neuronal ensembles that are activated by learning hold engrams and a reactivation of these neurons gives rise to recall of the specific memory 1 , 2 , 3 . Following the initial demonstrations of memory engram cell ensembles 2 , 4 , 5 , studies have identified engram cell ensembles for several memories in different brain regions, such as hippocampal subfields 6 , 7 , amygdala subregions 8 , retrosplenial cortex 9 , and prefrontal cortex 10 . Semon’s engram concept as the storage site of memory suggested that a given memory is stored not in a single engram ensemble localized in a brain site but instead in a unified engram complex—a network of engram cell ensembles connected and distributed in dispersed brain regions 1 , 11 , 12 . Indeed, early limited studies supported this concept for contextual fear memory 4 , 5 , 9 , 10 . While these findings enhanced our understanding of engram-based memory storage, a thorough mapping of a unified engram complex for a specific memory has been a challenging endeavor. The development of tissue clearing techniques, such as CLARITY 13 and iDISCO 14 , combined with advanced microscopy has enabled high-throughput analyses of intact mouse brain samples. Brain-wide mapping of neurons activated upon learning in the form of the expression of an immediate early gene, for instance, cFos, so-called “brain-wide activity mapping” has been applied to haloperidol administration, whisker stimulation, and parental behavior 15 , foot shocks and cocaine administration 16 , and fear memory 17 , 18 . Some of these studies, however, did not ascertain whether the activated neurons satisfied the basic criteria for engram-holding ensembles 15 , 17 . In the other studies, engram ensembles were demonstrated only in a limited brain region namely in the prefrontal cortex rather than in a brain-wide manner 16 , 18 . To further our understanding of the organization of memory engram cell ensembles, the experiment should be designed in the first step to identify neuronal activity patterns induced by memory formation in a more holistic manner. Since the recall-induced reactivation of neuronal ensembles that was previously activated by learning is also a crucial criterion of an engram cell ensemble 1 , 2 , 3 , it is essential for engram mapping studies to demonstrate this property. In the present study, we identified engram cell ensembles and their high probability candidates for a contextual fear memory, by following a four-step approach. First, we applied in a significantly broader set of brain regions SHIELD-based tissue phenotyping 19 for brain-wide mapping of activated neurons using the Fos-TRAP mouse line 20 . Using an unbiased and automated approach, we cross-compared the activity of 247 brain regions during contextual fear memory encoding and recent memory recall. Second, we devised an engram index to rank-order putative engram cell ensemble candidates because conducting optogenetic or chemogenetic manipulations that permit an assertion of engrams in hundreds of brain regions that display activity-dependent labeling is impractical. Third, we performed brain-wide engram reactivation studies, which revealed engrams that are reactivated by recall. Fourth, focusing on a dozen significant brain regions, narrowed down by the engram index and the engram reactivation experiments, we conducted optogenetic manipulations. This not only confirmed previously identified engrams but also revealed engrams in additional brain regions. Furthermore, many of these engrams and engram candidates were functionally connected to hippocampal CA1 or basolateral amygdala engrams. Finally, simultaneous reactivation of multiple engram cell ensembles using chemogenetics conferred greater levels of memory recall than reactivation of their subsets, as would be expected from the natural process of memory recall. Together, our study supports Semon’s unified engram complex hypothesis 1 that a specific memory is stored in functionally connected engram cell ensembles that are widely distributed in multiple brain regions. Results Brain-wide 3D imaging and mapping of activated neurons The first step of our unbiased engram mapping approach required brain-wide 3D imaging and mapping of activated neurons using the Fos-TRAP mouse line and SHIELD. Expression of immediate-early genes (IEGs) has been used to visualize neuronal activity in a given brain region 21 . By linking the expression of Cre ERT2 to the IEG cFos in a tamoxifen-dependent manner, the Fos-TRAP mouse line permits brain-wide labeling of activated neurons within a user-defined time window of several hours 20 . We crossed Fos-TRAP mice with a Cre-dependent tdTomato reporter mouse line (Fig. 1a ). Using the fast-acting 4-hydroxytamoxifen (4-OHT), we prepared three behavioral cohorts: mice that received 4-OHT and remained in their home cage for the labeling duration (home cage group), mice that received 4-OHT followed by contextual fear conditioning training and were returned to their home cage (CFC group), and mice that received 4-OHT followed by fear memory recall 24 h after CFC and were returned to their home cage (recall group). One week after labeling, brains<|im_end|> <|im_start|>assistant A new study by scientists at The Picower Institute for Learning and Memory at MIT provides the most comprehensive and rigorous evidence yet that the mammalian brain stores a single memory across a widely distributed, functionally connected complex spanning many brain regions, rather than in just one or even a few places. Memory pioneer Richard Semon had predicted such a "unified engram complex" more than a century ago, but achieving the new study's affirmation of his hypothesis required the application of several technologies developed only recently. In the study, the team identified and ranked dozens of areas that were not previously known to be involved in memory and showed that memory recall becomes more behaviorally powerful when multiple memory-storing regions are reactivated, rather than just one. "When talking about memory storage we all usually talk about the hippocampus or the cortex," said co-lead and co-corresponding author Dheeraj Roy. He began the research while a graduate student in the RIKEN-MIT Laboratory for Neural Circuit Genetics at The Picower Institute led by senior author and Picower Professor Susumu Tonegawa. "This study reflects the most comprehensive description of memory encoding cells, or memory 'engrams,' distributed across the brain, not just in the well-known memory regions. It basically provides the first rank-ordered list for high-probability engram regions. This list should lead to many future studies, which we are excited about, both in our labs and by other groups." In addition to Roy, who is now a McGovern Fellow in the Broad Institute of MIT and Harvard and the lab of MIT neuroscience Professor Guoping Feng, the study's other lead authors are Young-Gyun Park, Minyoung Kim, Ying Zhang and Sachie Ogawa. Mapping Memory The team was able to map regions participating in an engram complex by conducting an unbiased analysis of more than 247 brain regions in mice who were taken from their home cage to another cage where they felt a small but memorable electrical zap. In one group of mice their neurons were engineered to become fluorescent when they expressed a gene required for memory encoding. In another group, cells activated by naturally recalling the zap memory (e.g. when the mice returned to the scene of the zap) were fluorescently labeled instead. Cells that were activated by memory encoding or by recall could therefore readily be seen under a microscope after the brains were preserved and optically cleared using a technology called SHIELD, developed by co-corresponding author Kwanghun Chung, Associate Professor in The Picower Institute, the Institute for Medical Engineering & Science and the Department of Chemical Engineering. By using a computer to count fluorescing cells in each sample, the team produced brain-wide maps of regions with apparently significant memory encoding or recall activity. The maps highlighted many regions expected to participate in memory but also many that were not. To help factor out regions that might have been activated by activity unrelated to the zap memory, the team compared what they saw in zap-encoding or zap-recalling mice to what they saw in the brains of controls who were simply left in their home cage. This allowed them to calculate an "engram index" to rank order 117 brain regions with a significant likelihood of being involved in the memory engram complex. They deepened the analysis by engineering new mice in which neurons involved in both memory encoding and in recall could be doubly labeled, thereby revealing which cells exhibited overlap of those activities. To really be an engram cell, the authors noted, a neuron should be activated both in encoding and recall. "These experiments not only revealed significant engram reactivation in known hippocampal and amygdala regions, but also showed reactivation in many thalamic, cortical, midbrain and brainstem structures," the authors wrote. "Importantly when we compared the brain regions identified by the engram index analysis with these reactivated regions, we observed that ~60 percent of the regions were consistent between analyses." Many brain regions found likely to be involved in encoding a memory (top) were also found to be involved in recall upon reactivation (bottom). Credit: Tonegawa Lab/MIT Picower Institute Memory manipulations Having ranked regions significantly likely to be involved in the engram complex, the team engaged in several manipulations to directly test their predictions and to determine how engram complex regions might work together. For instance, they engineered mice such that cells activated by memory encoding would also become controllable with flashes of light (a technique called "optogenetics"). The researchers then applied light flashes to select brain regions from their engram index list to see if stimulating those would artificially reproduce the fear memory behavior of freezing in place, even when mice were placed in a "neutral" cage where the zap had not occurred. "Strikingly, all these brain regions induced robust memory recall when they were optogenetically stimulated," the researchers observed. Moreover, stimulating areas that their analysis suggested were insignificant to zap memory indeed produced no freezing behavior. The team then demonstrated how different regions within an engram complex connect. They chose two well-known memory regions, CA1 of the hippocampus and the basolateral amygdala (BLA), and optogenetically activated engram cells there to induce memory recall behavior in a neutral cage. They found that stimulating those regions produced memory recall activity in specific "downstream" areas identified as being probable members of the engram complex. Meanwhile, optogenetically inhibiting natural zap memory recall in CA1 or the BLA (i.e. when mice were placed back in the cage where they experienced the zap) led to reduced activity in downstream engram complex areas compared to what they measured in mice with unhindered natural recall. Further experiments showed that optogenetic reactivations of engram complex neurons followed similar patterns as those observed in natural memory recall. So having established that natural memory encoding and recall appears to occur across a wide engram complex, the team decided to test whether reactivating multiple regions would improve memory recall compared to reactivating just one. After all, prior experiments have shown that activating just one engram area does not produce recall as vividly as natural recall. This time the team used a chemical means to stimulate different engram complex regions and when they did, they found that indeed stimulating up to three involved regions simultaneously produced more robust freezing behavior than stimulating just one or two. Meaning of distributed storage Roy said that by storing a single memory across such a widespread complex the brain might be making memory more efficient and resilient. "Different memory engrams may allow us to recreate memories more efficiently when we are trying to remember a previous event (and similarly for the initial encoding where different engrams may contribute different information from the original experience)," he said. "Secondly, in disease states, if a few regions are impaired, distributed memories would allow us to remember previous events and in some ways be more robust against regional damages." In the long term that second idea might suggest a clinical strategy for dealing with memory impairment: "If some memory impairments are because of hippocampal or cortical dysfunction, could we target understudied engram cells in other regions and could such a manipulation restore some memory functions?" That's just one of many new questions researchers can ask now that the study has revealed a listing of where to look for at least one kind of memory in the mammalian brain. The paper's other authors are Nicholas DiNapoli, Xinyi Gu, Jae Cho, Heejin Choi, Lee Kamentsky, Jared Martin, Olivia Mosto and Tomomi Aida. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The class 2 type V CRISPR effector Cas12 is thought to have evolved from the IS200/IS605 superfamily of transposon-associated TnpB proteins 1 . Recent studies have identified TnpB proteins as miniature RNA-guided DNA endonucleases 2 , 3 . TnpB associates with a single, long RNA (ωRNA) and cleaves double-stranded DNA targets complementary to the ωRNA guide. However, the RNA-guided DNA cleavage mechanism of TnpB and its evolutionary relationship with Cas12 enzymes remain unknown. Here we report the cryo-electron microscopy (cryo-EM) structure of Deinococcus radiodurans ISDra2 TnpB in complex with its cognate ωRNA and target DNA. In the structure, the ωRNA adopts an unexpected architecture and forms a pseudoknot, which is conserved among all guide RNAs of Cas12 enzymes. Furthermore, the structure, along with our functional analysis, reveals how the compact TnpB recognizes the ωRNA and cleaves target DNA complementary to the guide. A structural comparison of TnpB with Cas12 enzymes suggests that CRISPR–Cas12 effectors acquired an ability to recognize the protospacer-adjacent motif-distal end of the guide RNA–target DNA heteroduplex, by either asymmetric dimer formation or diverse REC2 insertions, enabling engagement in CRISPR–Cas adaptive immunity. Collectively, our findings provide mechanistic insights into TnpB function and advance our understanding of the evolution from transposon-encoded TnpB proteins to CRISPR–Cas12 effectors. Main CRISPR–Cas systems in prokaryotes provide adaptive immunity against foreign nucleic acids, and are divided into two classes (classes 1 and 2) and six types 1 , 4 (types I–VI). The class 2 systems include types II, V and VI, in which Cas9, Cas12 and Cas13, respectively, function as effector enzymes responsible for interference. Type II Cas9 effector proteins associate with dual RNA guides (CRISPR RNA (crRNA) and trans -activating crRNA (tracrRNA) or their artificially connected single-guide RNA (sgRNA)) and cleave double-stranded DNA (dsDNA) targets using the HNH and RuvC nuclease domains 5 , 6 . Type V Cas12 effector proteins are further divided into Cas12a–m subtypes and span diverse functionalities 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 . Although the Cas12 proteins commonly have a single RuvC nuclease domain, they share low sequence similarity outside this conserved region. Cas12 enzymes associate with either crRNA guides or dual RNA guides (crRNA and tracrRNA) to cleave dsDNA targets, using their single RuvC domain. Recent reports have demonstrated that the class 2 CRISPR effectors Cas9 and Cas12 evolved independently from two members of the IS200/IS605 transposon-encoded nuclease superfamily, IscB and TnpB, respectively 1 , 2 , 3 . Functional and structural studies of IscB revealed that an associated ωRNA (obligate mobile element guided activity (OMEGA)) has a crucial role in recognizing the guide RNA–target DNA heteroduplex, enabling IscB to cleave its target DNA using the HNH and RuvC domains 16 , 17 . TnpB proteins are also RNA-guided DNA endonucleases 2 , 3 . TnpB associates with a single, long non-coding RNA (referred to as ωRNA, also known as right end element RNA (reRNA)). The gene encoding the ωRNA overlaps with the 3′ end of the tnpB gene and the non-coding right end element of the transposon (Fig. 1a ), and TnpB cleaves dsDNA targets complementary to the ωRNA guide sequence by using its RuvC domain. In addition, TnpB requires a target-adjacent motif (TAM) upstream of the target sequence to cleave the target DNA, similar to the Cas enzymes, which require a protospacer-adjacent motif (PAM) sequence to cleave their target DNAs 18 . TnpB from D. radiodurans ISDra2 (hereafter referred to as TnpB for simplicity) consists of 408 residues (Extended Data Fig. 1 ) and has a similar domain organization to Cas12f, which is the smallest subtype among the type V Cas12 enzymes 11 . However, a recent molecular mass analysis revealed that TnpB functions as a monomer, whereas Cas12f functions as a dimer 3 , 19 . Moreover, whereas Cas12f associates with dual RNA guides, TnpB associates with the single ωRNA. Therefore, how the compact TnpB protein assembles with its cognate ωRNAs to mediate the RNA-guided double-stranded DNA breaks remains unknown. Fig. 1: Cryo-EM structure of the TnpB–ωRNA–target DNA ternary complex. a , Schematic of the D. radiodurans ISDra2 locus. The MGE consists of the tnpA and tnpB genes flanked by the left end (LE) and right end (RE) elements of the transposon. The ωRNA is derived from the 3′ end of the tnpB gene and the RE element. b , Diagram of the ωRNA and target DNA used for cryo-EM analysis. The target strand (TS) and non-target strand (NTS) each comprise 35 nucleotides, and the non-target strand contains a TTGAT TAM sequence. The 247-nt ωRNA was co-expressed and co-purified with TnpB. Nucleotides −231 to −117, −70 to −49, −20 to −17 and 13 to 16 of the ωRNA, nucleotides −8 to 4 and 27 of the target strand, and nucleotides −11* and 1* to 24* of the non-target strand were not included in the final model. c , The domain structure of TnpB. CTD, C-terminal domain. Residues 281 to 296 and 379 to 408 were not included in the final model. d , Cryo-EM density map of the TnpB–ωRNA–target DNA complex. e , The overall structure of the TnpB–ωRNA–target DNA complex. Disordered regions are indicated as dotted lines. Full size image Structure of TnpB–ωRNA–target DNA To elucidate the molecular mechanism of TnpB, we co-expressed TnpB and its cognate 247-nucleotide (nt) ωRNA containing a 16-nt guide segment at the 3′ end, and then purified the TnpB–ωRNA complex. We reconstituted the ternary TnpB–ωRNA–target DNA complex by mixing the purified TnpB–ωRNA complex and a 35-base pair (bp) double-stranded DNA with phosphorothioate modifications within the DNA backbone around the cleavage site and the TTGAT TAM sequence, and analysed its ternary structure by cryo-EM (Fig. 1b ). We obtained a three-dimensional reconstruction of the ternary complex with an overall resolution of 3.2 Å (Fig. 1c–e , Extended Data Fig. 2 , Extended Data Table 1 and Supplementary Fig. 1 ). The cryo-EM structure revealed that a single TnpB molecule assembles with a single ωRNA molecule to form", "role": "user" }, { "content": "Gene editing is one of the latest breakthroughs in biology. The widely known CRISPR-Cas gene editing system provided prokaryotes (organisms that lack cell nuclei) an immunity against foreign DNA. Since the discovery of the CRISPR gene editing technology, scientists are revealing the evolution of the CRISPR-Cas proteins from their precursors. That knowledge will help them develop other small and new genome editing tools for gene therapy. At the University of Tokyo, Prof. Osamu Nureki's group works on identifying the structure and function of the proteins involved in genome editing. In a recent study by the team, they discovered the 3D structure of a protein called TnpB, a probable precursor to the CRISPR-Cas12 enzyme. Their findings appeared in the journal Nature. Previous research suggests that the TnpB protein may work like a pair of molecular scissors, cutting DNA with the help of a special non-coding RNA called ωRNA. But exactly how the RNA-guided DNA cleavage works and its evolutionary relationship with Cas12 enzymes was unknown, which prompted Nureki lab's investigation. Their first and most crucial step toward understanding that was to reveal the protein structure. To determine the three-dimensional structure of TnpB, the researchers took the protein TnpB from a bacterium called Deinococcus radiodurans and used cryo-electron microscopy. In the cryo-electron microscopy technique, the protein sample is cooled to -196° C using liquid nitrogen and irradiated with electron beams, which reveals the protein's 3D structure. Structural comparison of TnpB with Cas12 enzymes with high sequence similarity to TnpB revealed that Cas12 enzymes recognize longer target DNA sequences than TnpB by either asymmetric dimer formation or diverse REC2 insertions, allowing for engagement in CRISPR-Cas adaptive immunity. Credit: Nature (2023). DOI: 10.1038/s41586-023-05933-9 The team found that the ωRNA in TnpB has a unique pseudoknot shape similar to that found in the guide RNAs of Cas12 enzymes. The study also revealed how TnpB recognizes the ωRNA and cuts the target DNA. And when they compared the structure of this protein to Cas12 enzymes, they learned two possible ways TnpB might have evolved into CRISPR-Cas12 enzymes. \"Our findings provide mechanistic insights into the TnpB function and advance our understanding of the evolution from TnpB proteins to CRISPR-Cas12 effectors,\" says Ryoya Nakagawa, a graduate student and one of the first authors of the research paper. In the future, he added, \"We will explore the potential applications of TnpB-based gene editing techniques.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The class 2 type V CRISPR effector Cas12 is thought to have evolved from the IS200/IS605 superfamily of transposon-associated TnpB proteins 1 . Recent studies have identified TnpB proteins as miniature RNA-guided DNA endonucleases 2 , 3 . TnpB associates with a single, long RNA (ωRNA) and cleaves double-stranded DNA targets complementary to the ωRNA guide. However, the RNA-guided DNA cleavage mechanism of TnpB and its evolutionary relationship with Cas12 enzymes remain unknown. Here we report the cryo-electron microscopy (cryo-EM) structure of Deinococcus radiodurans ISDra2 TnpB in complex with its cognate ωRNA and target DNA. In the structure, the ωRNA adopts an unexpected architecture and forms a pseudoknot, which is conserved among all guide RNAs of Cas12 enzymes. Furthermore, the structure, along with our functional analysis, reveals how the compact TnpB recognizes the ωRNA and cleaves target DNA complementary to the guide. A structural comparison of TnpB with Cas12 enzymes suggests that CRISPR–Cas12 effectors acquired an ability to recognize the protospacer-adjacent motif-distal end of the guide RNA–target DNA heteroduplex, by either asymmetric dimer formation or diverse REC2 insertions, enabling engagement in CRISPR–Cas adaptive immunity. Collectively, our findings provide mechanistic insights into TnpB function and advance our understanding of the evolution from transposon-encoded TnpB proteins to CRISPR–Cas12 effectors. Main CRISPR–Cas systems in prokaryotes provide adaptive immunity against foreign nucleic acids, and are divided into two classes (classes 1 and 2) and six types 1 , 4 (types I–VI). The class 2 systems include types II, V and VI, in which Cas9, Cas12 and Cas13, respectively, function as effector enzymes responsible for interference. Type II Cas9 effector proteins associate with dual RNA guides (CRISPR RNA (crRNA) and trans -activating crRNA (tracrRNA) or their artificially connected single-guide RNA (sgRNA)) and cleave double-stranded DNA (dsDNA) targets using the HNH and RuvC nuclease domains 5 , 6 . Type V Cas12 effector proteins are further divided into Cas12a–m subtypes and span diverse functionalities 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 . Although the Cas12 proteins commonly have a single RuvC nuclease domain, they share low sequence similarity outside this conserved region. Cas12 enzymes associate with either crRNA guides or dual RNA guides (crRNA and tracrRNA) to cleave dsDNA targets, using their single RuvC domain. Recent reports have demonstrated that the class 2 CRISPR effectors Cas9 and Cas12 evolved independently from two members of the IS200/IS605 transposon-encoded nuclease superfamily, IscB and TnpB, respectively 1 , 2 , 3 . Functional and structural studies of IscB revealed that an associated ωRNA (obligate mobile element guided activity (OMEGA)) has a crucial role in recognizing the guide RNA–target DNA heteroduplex, enabling IscB to cleave its target DNA using the HNH and RuvC domains 16 , 17 . TnpB proteins are also RNA-guided DNA endonucleases 2 , 3 . TnpB associates with a single, long non-coding RNA (referred to as ωRNA, also known as right end element RNA (reRNA)). The gene encoding the ωRNA overlaps with the 3′ end of the tnpB gene and the non-coding right end element of the transposon (Fig. 1a ), and TnpB cleaves dsDNA targets complementary to the ωRNA guide sequence by using its RuvC domain. In addition, TnpB requires a target-adjacent motif (TAM) upstream of the target sequence to cleave the target DNA, similar to the Cas enzymes, which require a protospacer-adjacent motif (PAM) sequence to cleave their target DNAs 18 . TnpB from D. radiodurans ISDra2 (hereafter referred to as TnpB for simplicity) consists of 408 residues (Extended Data Fig. 1 ) and has a similar domain organization to Cas12f, which is the smallest subtype among the type V Cas12 enzymes 11 . However, a recent molecular mass analysis revealed that TnpB functions as a monomer, whereas Cas12f functions as a dimer 3 , 19 . Moreover, whereas Cas12f associates with dual RNA guides, TnpB associates with the single ωRNA. Therefore, how the compact TnpB protein assembles with its cognate ωRNAs to mediate the RNA-guided double-stranded DNA breaks remains unknown. Fig. 1: Cryo-EM structure of the TnpB–ωRNA–target DNA ternary complex. a , Schematic of the D. radiodurans ISDra2 locus. The MGE consists of the tnpA and tnpB genes flanked by the left end (LE) and right end (RE) elements of the transposon. The ωRNA is derived from the 3′ end of the tnpB gene and the RE element. b , Diagram of the ωRNA and target DNA used for cryo-EM analysis. The target strand (TS) and non-target strand (NTS) each comprise 35 nucleotides, and the non-target strand contains a TTGAT TAM sequence. The 247-nt ωRNA was co-expressed and co-purified with TnpB. Nucleotides −231 to −117, −70 to −49, −20 to −17 and 13 to 16 of the ωRNA, nucleotides −8 to 4 and 27 of the target strand, and nucleotides −11* and 1* to 24* of the non-target strand were not included in the final model. c , The domain structure of TnpB. CTD, C-terminal domain. Residues 281 to 296 and 379 to 408 were not included in the final model. d , Cryo-EM density map of the TnpB–ωRNA–target DNA complex. e , The overall structure of the TnpB–ωRNA–target DNA complex. Disordered regions are indicated as dotted lines. Full size image Structure of TnpB–ωRNA–target DNA To elucidate the molecular mechanism of TnpB, we co-expressed TnpB and its cognate 247-nucleotide (nt) ωRNA containing a 16-nt guide segment at the 3′ end, and then purified the TnpB–ωRNA complex. We reconstituted the ternary TnpB–ωRNA–target DNA complex by mixing the purified TnpB–ωRNA complex and a 35-base pair (bp) double-stranded DNA with phosphorothioate modifications within the DNA backbone around the cleavage site and the TTGAT TAM sequence, and analysed its ternary structure by cryo-EM (Fig. 1b ). We obtained a three-dimensional reconstruction of the ternary complex with an overall resolution of 3.2 Å (Fig. 1c–e , Extended Data Fig. 2 , Extended Data Table 1 and Supplementary Fig. 1 ). The cryo-EM structure revealed that a single TnpB molecule assembles with a single ωRNA molecule to form<|im_end|> <|im_start|>assistant Gene editing is one of the latest breakthroughs in biology. The widely known CRISPR-Cas gene editing system provided prokaryotes (organisms that lack cell nuclei) an immunity against foreign DNA. Since the discovery of the CRISPR gene editing technology, scientists are revealing the evolution of the CRISPR-Cas proteins from their precursors. That knowledge will help them develop other small and new genome editing tools for gene therapy. At the University of Tokyo, Prof. Osamu Nureki's group works on identifying the structure and function of the proteins involved in genome editing. In a recent study by the team, they discovered the 3D structure of a protein called TnpB, a probable precursor to the CRISPR-Cas12 enzyme. Their findings appeared in the journal Nature. Previous research suggests that the TnpB protein may work like a pair of molecular scissors, cutting DNA with the help of a special non-coding RNA called ωRNA. But exactly how the RNA-guided DNA cleavage works and its evolutionary relationship with Cas12 enzymes was unknown, which prompted Nureki lab's investigation. Their first and most crucial step toward understanding that was to reveal the protein structure. To determine the three-dimensional structure of TnpB, the researchers took the protein TnpB from a bacterium called Deinococcus radiodurans and used cryo-electron microscopy. In the cryo-electron microscopy technique, the protein sample is cooled to -196° C using liquid nitrogen and irradiated with electron beams, which reveals the protein's 3D structure. Structural comparison of TnpB with Cas12 enzymes with high sequence similarity to TnpB revealed that Cas12 enzymes recognize longer target DNA sequences than TnpB by either asymmetric dimer formation or diverse REC2 insertions, allowing for engagement in CRISPR-Cas adaptive immunity. Credit: Nature (2023). DOI: 10.1038/s41586-023-05933-9 The team found that the ωRNA in TnpB has a unique pseudoknot shape similar to that found in the guide RNAs of Cas12 enzymes. The study also revealed how TnpB recognizes the ωRNA and cuts the target DNA. And when they compared the structure of this protein to Cas12 enzymes, they learned two possible ways TnpB might have evolved into CRISPR-Cas12 enzymes. "Our findings provide mechanistic insights into the TnpB function and advance our understanding of the evolution from TnpB proteins to CRISPR-Cas12 effectors," says Ryoya Nakagawa, a graduate student and one of the first authors of the research paper. In the future, he added, "We will explore the potential applications of TnpB-based gene editing techniques." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Preparation for motherhood requires a myriad of physiological and behavioural adjustments throughout gestation to provide an adequate environment for proper embryonic development 1 . Cravings for highly palatable foods are highly prevalent during pregnancy 2 and contribute to the maintenance and development of gestational overweight or obesity 3 . However, the neurobiology underlying the distinct ingestive behaviours that result from craving specific foods remain unknown. Here we show that mice, similarly to humans, experience gestational food craving-like episodes. These episodes are associated with a brain connectivity reorganization that affects key components of the dopaminergic mesolimbic circuitry, which drives motivated appetitive behaviours and facilitates the perception of rewarding stimuli. Pregnancy engages a dynamic modulation of dopaminergic signalling through neurons expressing dopamine D2 receptors in the nucleus accumbens, which directly modulate food craving-like events. Importantly, persistent maternal food craving-like behaviour has long-lasting effects on the offspring, particularly in males, leading to glucose intolerance, increased body weight and increased susceptibility to develop eating disorders and anxiety-like behaviours during adulthood. Our results reveal the cognitively motivated nature of pregnancy food cravings and advocates for moderating emotional eating during gestation to prevent deterioration of the offspring’s neuropsychological and metabolic health. Main Pregnancy demands multiple physiological and behavioural adaptations to ensure a healthy embryonic development and preparation for maternal care 1 . Among them, metabolic and eating behaviour changes have been reported in diverse species 4 , 5 , 6 . A distinct example are food cravings, which are common features of human pregnancy, resulting in notable variations in maternal ingestive patterns towards consumption of highly palatable foods (HPF) 2 . Problematically, recurrent food cravings contribute to the development and maintenance of gestational overweight/obesity 3 , with potential adverse health consequences for the offspring 7 , 8 , 9 . However, despite the widespread occurrence of gestational food cravings and having been documented for centuries 10 , its underlying neurobiology remains unknown. To verify the suitability of the mouse as a model to investigate food craving-like behaviour characteristic of pregnancy, we determined their drive to overconsume sweet-tasting items, which are predominant cravings during human gestation 2 . We exposed C57BL/6 virgin and pregnant mice to a two-bottle choice paradigm (Fig. 1a ). To ensure a dynamic window of detectable preference changes, we identified the lowest sucralose and sucrose concentration that did not shift tastant selection in virgin females (Extended Data Fig. 1a,b and Fig. 1b,d ). Remarkably, pregnant mice exhibited a higher inclination for both sweet compounds, suggesting increased sweetness sensitivity (Fig. 1b–e ). Gestation did not disrupt the perception of the nutritional value of sugar because overall food intake was compensated (Extended Data Fig. 1c ). To mimic human food cravings, we examined the motivation of pregnant mice to consume a pleasant diet in a ‘limited access’ paradigm 11 (Fig. 1f and Extended Data Fig. 1d ). Pregnant females increased craving-like behaviour and daily food intake from the second week of pregnancy (Fig. 1g and Extended Data Fig. 1e ). These results recapitulate the accentuated ingestion of palatable food observed during human gestation, thus validating the mouse as an appropriate model. Fig. 1: Sweet taste perception and food craving-like behaviour increase during pregnancy. a , Schematic illustration of two-bottle paradigm and experimental timeline. b , c , Sucralose (0.05 mM) preference ( b ) and area under the curve (AUC) ( c ) throughout the study of virgin ( n = 5), pseudopregnant ( n = 5) and pregnant ( n = 5) mice. a.u., arbitrary units. d , e , Sucrose (25 mM) preference ( d ) and AUC ( e ) throughout the study of virgin ( n = 5), pseudopregnant ( n = 5) and pregnant ( n = 5) mice. f , Schematic illustration of the ‘limited access’ paradigm and experimental timeline. g , Percentage of daily caloric intake, consumed during the 2 h of HPF access throughout the study, of virgin ( n = 8), pseudopregnant ( n = 22) and pregnant ( n = 13) mice. Dots represent individual sample data. Data are expressed as the mean ± s.e.m. Exact P values are shown. One-way analysis of variance (ANOVA) with Tukey’s multiple-comparisons test was performed for c and e , two-way ANOVA with Dunnett’s multiple-comparisons test for b and d and two-way ANOVA with Tukey’s multiple-comparisons test for g . When the factors ‘group’, ‘time’ and/or the interaction ‘group:time’ were considered significant, results are shown with the significant factor or the interaction effect next to it ( b and d ). BP, before pregnancy; W1, first week of pregnancy (or concomitant experimental week for virgin and pseudopregnant mice); W2, second week of pregnancy (or concomitant experimental week for virgin and pseudopregnant mice); W3, third week of pregnancy (or concomitant experimental week for virgin and pseudopregnant mice); AP, after pregnancy. Source data Full size image A prevalent hypothesis posits that gestational food cravings are necessary to support embryonic growth 12 . To test this, we generated pseudopregnant females thus mimicking gestational features without actual embryonic development. Pseudopregnancy was validated by the presence of vaginal plugs and increased progesterone levels (Extended Data Fig. 1f ). Pseudopregnant mice exhibited enhanced sweet sensitivity (Fig. 1b–e ) and exacerbated compulsive eating similar to their genuinely pregnant counterparts (Fig. 1g ), without changes in daily food intake (Extended Data Fig. 1e ). These results suggest that pregnancy food craving-like behaviour does not arise to support embryonic growth. Anxiety-like states can also promote compulsive eating 13 . Therefore, we questioned if gestation was associated with anxiety-like phenotypes that could alter eating patterns. Pregnant females showed unchanged exploratory time in the anxiety-related central area and total distance in the open field test, as well as equivalent performance in the dark–light box test when compared to virgin females (Extended Data Fig. 1g–j ). Although not exhaustive, our results suggest that the distinct ingestive habits during gestation are not caused by major anxiety-related states. Appetite and dietary patterns are controlled by a coordinated network of multiple and distributed", "role": "user" }, { "content": "Many people have felt the sudden and uncontrollable urge to eat a certain food. These urges—known as cravings—are very common, mostly during pregnancy. At this stage, the mother's body undergoes a series of physiological and behavioral changes to create a favorable environment for the embryo's development. However, the frequent consumption of tasty and high calorie foods—derived from the cravings—contributes to weight gain and obesity in pregnancy, which can have negative effects on the baby's health. \"There are many myths and popular beliefs regarding these cravings, although the neuronal mechanisms that cause them are not widely known,\" notes March Claret, lecturer at the Faculty of Medicine and Health Sciences of the University of Barcelona and head of the IDIBAPS Neuronal Control of Metabolism Group. Claret leads, together with the researcher Roberta Haddad-Tóvolli, a study published in the journal Nature Metabolism that provides new evidence on the alterations of the neuronal activity that drive cravings in an animal model. Dopamine and compulsive eating behavior According to the results, during pregnancy, the brain of female mice undergoes changes in the functional connections of the brain reward circuits, as well as the taste and sensorimotor centers. Moreover, just like pregnant women, female mice are more sensitive to sweet food, and they develop binge-eating behaviors towards high calorie foods. \"The alteration of these structures made us explore the mesolimbic pathway, one of the signal transmission pathways of dopaminergic neurons. Dopamine is a key neurotransmitter in motivational behaviors,\" notes Claret, member of the Department of Medicine of the UB and the Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (CIBERDEM). The team observed the levels of dopamine—and the activity of its receptor, D2R—to increase in the nucleus accumbens, a brain region involved in the reward circuit. \"This finding suggests that the pregnancy induces a full reorganization of the mesolimbic neural circuits through the D2R neurons,\" notes Haddad-Tóvolli. \"These neuronal cells—and their alteration—would be responsible for the cravings, since food anxiety, typical during pregnancy, disappeared after blocking their activity.\" The team led by Claret and Haddad-Tóvolli showed that persistent cravings have consequences for the offspring. They affect the metabolism and development of neural circuits that regulate food intake, which leads to weight gain, anxiety and eating disorders. \"These results are shocking, since many of the studies are focused on the analysis of how the mother's permanent habits—such as obesity, malnutrition, or chronic stress—affect the health of the baby. However, this study indicates that short but recurrent behaviors, such as cravings, are enough to increase the psychological and metabolic vulnerability of the offspring,\" concludes Claret. The conclusions of the study could contribute to the improvement of nutritional guidelines for pregnant women in order to ensure a proper prenatal nutrition and prevent the development of diseases. Among the participants in the study were Guadalupe Soria and Emma Muñoz-Moreno (IDIBAPS), Analía Bortolozzi (IIBB-CSIC-IDIBAPS) and Emmanuel Valjent (INSERM and University of Montpelier). ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Preparation for motherhood requires a myriad of physiological and behavioural adjustments throughout gestation to provide an adequate environment for proper embryonic development 1 . Cravings for highly palatable foods are highly prevalent during pregnancy 2 and contribute to the maintenance and development of gestational overweight or obesity 3 . However, the neurobiology underlying the distinct ingestive behaviours that result from craving specific foods remain unknown. Here we show that mice, similarly to humans, experience gestational food craving-like episodes. These episodes are associated with a brain connectivity reorganization that affects key components of the dopaminergic mesolimbic circuitry, which drives motivated appetitive behaviours and facilitates the perception of rewarding stimuli. Pregnancy engages a dynamic modulation of dopaminergic signalling through neurons expressing dopamine D2 receptors in the nucleus accumbens, which directly modulate food craving-like events. Importantly, persistent maternal food craving-like behaviour has long-lasting effects on the offspring, particularly in males, leading to glucose intolerance, increased body weight and increased susceptibility to develop eating disorders and anxiety-like behaviours during adulthood. Our results reveal the cognitively motivated nature of pregnancy food cravings and advocates for moderating emotional eating during gestation to prevent deterioration of the offspring’s neuropsychological and metabolic health. Main Pregnancy demands multiple physiological and behavioural adaptations to ensure a healthy embryonic development and preparation for maternal care 1 . Among them, metabolic and eating behaviour changes have been reported in diverse species 4 , 5 , 6 . A distinct example are food cravings, which are common features of human pregnancy, resulting in notable variations in maternal ingestive patterns towards consumption of highly palatable foods (HPF) 2 . Problematically, recurrent food cravings contribute to the development and maintenance of gestational overweight/obesity 3 , with potential adverse health consequences for the offspring 7 , 8 , 9 . However, despite the widespread occurrence of gestational food cravings and having been documented for centuries 10 , its underlying neurobiology remains unknown. To verify the suitability of the mouse as a model to investigate food craving-like behaviour characteristic of pregnancy, we determined their drive to overconsume sweet-tasting items, which are predominant cravings during human gestation 2 . We exposed C57BL/6 virgin and pregnant mice to a two-bottle choice paradigm (Fig. 1a ). To ensure a dynamic window of detectable preference changes, we identified the lowest sucralose and sucrose concentration that did not shift tastant selection in virgin females (Extended Data Fig. 1a,b and Fig. 1b,d ). Remarkably, pregnant mice exhibited a higher inclination for both sweet compounds, suggesting increased sweetness sensitivity (Fig. 1b–e ). Gestation did not disrupt the perception of the nutritional value of sugar because overall food intake was compensated (Extended Data Fig. 1c ). To mimic human food cravings, we examined the motivation of pregnant mice to consume a pleasant diet in a ‘limited access’ paradigm 11 (Fig. 1f and Extended Data Fig. 1d ). Pregnant females increased craving-like behaviour and daily food intake from the second week of pregnancy (Fig. 1g and Extended Data Fig. 1e ). These results recapitulate the accentuated ingestion of palatable food observed during human gestation, thus validating the mouse as an appropriate model. Fig. 1: Sweet taste perception and food craving-like behaviour increase during pregnancy. a , Schematic illustration of two-bottle paradigm and experimental timeline. b , c , Sucralose (0.05 mM) preference ( b ) and area under the curve (AUC) ( c ) throughout the study of virgin ( n = 5), pseudopregnant ( n = 5) and pregnant ( n = 5) mice. a.u., arbitrary units. d , e , Sucrose (25 mM) preference ( d ) and AUC ( e ) throughout the study of virgin ( n = 5), pseudopregnant ( n = 5) and pregnant ( n = 5) mice. f , Schematic illustration of the ‘limited access’ paradigm and experimental timeline. g , Percentage of daily caloric intake, consumed during the 2 h of HPF access throughout the study, of virgin ( n = 8), pseudopregnant ( n = 22) and pregnant ( n = 13) mice. Dots represent individual sample data. Data are expressed as the mean ± s.e.m. Exact P values are shown. One-way analysis of variance (ANOVA) with Tukey’s multiple-comparisons test was performed for c and e , two-way ANOVA with Dunnett’s multiple-comparisons test for b and d and two-way ANOVA with Tukey’s multiple-comparisons test for g . When the factors ‘group’, ‘time’ and/or the interaction ‘group:time’ were considered significant, results are shown with the significant factor or the interaction effect next to it ( b and d ). BP, before pregnancy; W1, first week of pregnancy (or concomitant experimental week for virgin and pseudopregnant mice); W2, second week of pregnancy (or concomitant experimental week for virgin and pseudopregnant mice); W3, third week of pregnancy (or concomitant experimental week for virgin and pseudopregnant mice); AP, after pregnancy. Source data Full size image A prevalent hypothesis posits that gestational food cravings are necessary to support embryonic growth 12 . To test this, we generated pseudopregnant females thus mimicking gestational features without actual embryonic development. Pseudopregnancy was validated by the presence of vaginal plugs and increased progesterone levels (Extended Data Fig. 1f ). Pseudopregnant mice exhibited enhanced sweet sensitivity (Fig. 1b–e ) and exacerbated compulsive eating similar to their genuinely pregnant counterparts (Fig. 1g ), without changes in daily food intake (Extended Data Fig. 1e ). These results suggest that pregnancy food craving-like behaviour does not arise to support embryonic growth. Anxiety-like states can also promote compulsive eating 13 . Therefore, we questioned if gestation was associated with anxiety-like phenotypes that could alter eating patterns. Pregnant females showed unchanged exploratory time in the anxiety-related central area and total distance in the open field test, as well as equivalent performance in the dark–light box test when compared to virgin females (Extended Data Fig. 1g–j ). Although not exhaustive, our results suggest that the distinct ingestive habits during gestation are not caused by major anxiety-related states. Appetite and dietary patterns are controlled by a coordinated network of multiple and distributed<|im_end|> <|im_start|>assistant Many people have felt the sudden and uncontrollable urge to eat a certain food. These urges—known as cravings—are very common, mostly during pregnancy. At this stage, the mother's body undergoes a series of physiological and behavioral changes to create a favorable environment for the embryo's development. However, the frequent consumption of tasty and high calorie foods—derived from the cravings—contributes to weight gain and obesity in pregnancy, which can have negative effects on the baby's health. "There are many myths and popular beliefs regarding these cravings, although the neuronal mechanisms that cause them are not widely known," notes March Claret, lecturer at the Faculty of Medicine and Health Sciences of the University of Barcelona and head of the IDIBAPS Neuronal Control of Metabolism Group. Claret leads, together with the researcher Roberta Haddad-Tóvolli, a study published in the journal Nature Metabolism that provides new evidence on the alterations of the neuronal activity that drive cravings in an animal model. Dopamine and compulsive eating behavior According to the results, during pregnancy, the brain of female mice undergoes changes in the functional connections of the brain reward circuits, as well as the taste and sensorimotor centers. Moreover, just like pregnant women, female mice are more sensitive to sweet food, and they develop binge-eating behaviors towards high calorie foods. "The alteration of these structures made us explore the mesolimbic pathway, one of the signal transmission pathways of dopaminergic neurons. Dopamine is a key neurotransmitter in motivational behaviors," notes Claret, member of the Department of Medicine of the UB and the Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (CIBERDEM). The team observed the levels of dopamine—and the activity of its receptor, D2R—to increase in the nucleus accumbens, a brain region involved in the reward circuit. "This finding suggests that the pregnancy induces a full reorganization of the mesolimbic neural circuits through the D2R neurons," notes Haddad-Tóvolli. "These neuronal cells—and their alteration—would be responsible for the cravings, since food anxiety, typical during pregnancy, disappeared after blocking their activity." The team led by Claret and Haddad-Tóvolli showed that persistent cravings have consequences for the offspring. They affect the metabolism and development of neural circuits that regulate food intake, which leads to weight gain, anxiety and eating disorders. "These results are shocking, since many of the studies are focused on the analysis of how the mother's permanent habits—such as obesity, malnutrition, or chronic stress—affect the health of the baby. However, this study indicates that short but recurrent behaviors, such as cravings, are enough to increase the psychological and metabolic vulnerability of the offspring," concludes Claret. The conclusions of the study could contribute to the improvement of nutritional guidelines for pregnant women in order to ensure a proper prenatal nutrition and prevent the development of diseases. Among the participants in the study were Guadalupe Soria and Emma Muñoz-Moreno (IDIBAPS), Analía Bortolozzi (IIBB-CSIC-IDIBAPS) and Emmanuel Valjent (INSERM and University of Montpelier). <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract SARS-CoV-2, the virus causing the COVID-19 pandemic emerged in December 2019 in China and raised fears it could overwhelm healthcare systems worldwide. Mutations of the virus are monitored by the GISAID database from which we downloaded sequences from four West African countries Ghana, Gambia, Senegal and Nigeria from February 2020 to April 2020. We subjected the sequences to phylogenetic analysis employing the nextstrain pipeline. We found country-specific patterns of viral variants and supplemented that with data on novel variants from June 2021. Until April 2020, variants carrying the crucial Europe-associated D614G amino acid change were predominantly found in Senegal and Gambia, and combinations of late variants with and early variants without D614G in Ghana and Nigeria. In June 2021 all variants carried the D614G amino acid substitution. Senegal and Gambia exhibited again variants transmitted from Europe (alpha or delta), Ghana a combination of several variants and in Nigeria the original Eta variant. Detailed analysis of distinct samples revealed that some might have circulated latently and some reflect migration routes. The distinct patterns of variants within the West African countries point at their global transmission via air traffic predominantly from Europe and only limited transmission between the West African countries. Introduction The COVID-19 pandemic resulting from the SARS-CoV-2 coronavirus infection which emerged in December 2019 in Wuhan, China, spread all over the world and after a delay of a few months also appeared on the African continent. Early in June 2020, all African countries registered human infections with SARS-CoV-2. Starting with the first sequenced human sample of SARS-CoV-2, several mutations of the virus sequence arose which could be grouped into clades allowing associations with regional prevalence. In this study, we focused on samples from West Africa which was the region from which the first African SARS-CoV-2 sequences became available. We aimed at analysing phylogenetic characteristics possibly giving hints on the distribution between countries and eventually even about putative severity changes between specific clades. We use the nomenclature of clades suggested by the GISAID initiativewhich has now been adopted in several publications. Previous studies reported the potential impact of the D614G amino acid substitution which is a result of the A23403G single nucleotide polymorphism (SNP) 1 and associated with the branch of the phylogenetic tree referred to as clade G. Brufsky hypothesized that the higher number of deaths on the East coast of the United States compared to the West coast could be due to the higher prevalence of the D614G amino acid substitution on the East coast 2 . The D614G amino acid substitution has been suggested to affect the adherence of the virus to the cell membrane and consequently results in higher virulence. Supportive evidence was reported in mice 3 , 4 . Korber et al. hypothesized that the D614 amino acid on the surface of the subunit S1 of the spike protein of the virus might have a hydrogen bond to the T859 amino acid in the subunit S2 residing on the membrane 1 . Furthermore, they showed that clade G rapidly starts to replace other clades associated with the D614 amino acid in each country entered 1 . In mid-March 2020, the G clade was found almost exclusively in Europe 5 but soon after spread all over the world. Korber et al. see its origin from China or Europe 1 . In China, four early samples carried the D614G amino acid substitution. One sample from January 24th 2020 had only the A23403G (D614G) but not the C3037T and C14408T mutations which usually associate with A23403T in clade G. Three samples with the D614G were related to the first German sample. In Europe the first German sample from January 28th carried the A-to-G mutation at nucleotide position 23403 (D614G) mutation and the C-to-T mutation at position 3037, but not the mutation at position 14408. The first sample carrying all of the above mentioned mutations plus the C241T in the Untranslated Region (UTR) was identified in Italy on February 20th, 2020 1 . Another interesting feature of the G clades is that the associated C14408T mutation adjacent to the RNA dependent RNA polymerase (RdRp) putatively increases the mutation rate as Pachetti et al . report 5 . Detailed analyses of virus evolution have been performed for some countries, e.g. France 6 , New York 7 and India 8 . For France it could be deduced by the distinction between clade G and the earlier phylogenetic branches that the first SARS-CoV-2 did not lead to local transmission while the clade G was circulating for a considerable time before the first recorded case which was of clade G and had no travel events or traveler contact 6 . Since the declaration of COVID-19 as pandemic by the WHO on March 11th, 2020, fears were expressed that it could overwhelm weaker healthcare systems in many African countries. Furthermore, hygiene, social distancing and lockdown has caused many challenges in countries with high percentages of its citizens living without clean running water, cramped confines and the dependence on a daily income. However, Africa has the advantage of having a very young population, e.g. in Sub-Saharan Africa with a median age of 19.7 years 9 for which on average milder etiopathologies can be expected. Additionally, for the early outbreak a study evaluating air traffic from affected regions in China calculated relatively low transmission risks for most African countries except South Africa and Ethiopia 10 . For later phases, Cabore et al. proposed a model estimating risk of exposure for African countries based on a Hidden Markov model which accounts for factors such as gathering, weather, distribution and hygiene with the conclusion that with respect to the high calculated infection rates effective containment is indispensable 11 . Here, we analysed SARS-CoV-2 nucleotide sequences from samples obtained from the West African countries of Gambia, Ghana, Nigeria and Senegal in order to identify characteristic mutations and to dissect their patterns of distribution. The rationale of this study was to investigate commonalities and differences between SARS-CoV-2 transmission in West", "role": "user" }, { "content": "At the onset of the SARS-CoV-2 pandemic, fears emerged that it would overwhelm the weak health systems in many African countries. However, it turned out that Europe and America had much higher incidences and fatality rates compared to Africa. Reasons for this may lie in the relatively young populations, previous viral infections and the warm climate. Nevertheless, SARS-CoV-2 affected all African countries and thus initiatives for a global distribution of vaccines were initiated. The genomes of viral isolates are continuously sequenced in most countries. The DNA sequences can be subjected to phylogenetic analysis to identify the origins of viral variants and to monitor the development and distribution of new variants which may be milder or in the worst case more deadly. Researchers from Heinrich-Heine University Düsseldorf have now unveiled distinct patterns of SARS-CoV-2 variants in a phylogenetic analysis of viral sequences from the West African countries—Gambia, Ghana, Nigeria and Senegal. Prof. Dr. James Adjaye is the senior author of the study, published in Scientific Reports. Bioinformatician Wasco Wruck is the first author of the paper. Although the four investigated countries have similar geographic and climatic conditions the researchers found distinct patterns of virus variants. This may reflect a genetic drift mechanism called the \"Founder effect\" where genetic diversity is driven by only a small part of a population forming a new separate population, for instance the particular infected persons transmitting virus variants from France to Senegal. \"When you look at the distinct patterns of virus variants you can directly see the historic relationships, e.g. Senegal was a French colony and has a similar pattern as France because there is still much traffic and trade between Senegal and France. Ghana and Nigeria are both former British colonies with similar viral-patterns. Both countries have trade and labor ties with Europe and China,\" says James Adjaye, a Ghanaian-British Professor at the Medical Faculty of the Heinrich-Heine University Düsseldorf and the Director of the Institute for Stem Cell Research and Regenerative Medicine. Wruck adds that \"surprisingly, we found that later variants from Europe were detected before the earlier variants. Explanations for this could be that the earlier virus variants circulated latently, and the later variants were detected earlier because of higher virus transmissibility.\" As SARS-CoV-2 is a RNA virus, mutations can arise when the RNA is copied inside the human host cells. In phylogenetic analysis, similar patterns of mutations pointing to similar origins are clustered together in branches of a tree which if they are big enough can be called variants. Mutations can have no effect or can lead to amino-acid substitutions which may alter the function or structure of the viral proteins. Prof. Adjaye and his colleague downloaded SARS-CoV-2 sequences from the four West African countries from the GISAID database and used sequences from China, Europe and America as reference. Employing phylogenetic analysis, these sequences could be associated with viral variants, additionally distinct patterns ofl variants could be detected for each country. In the first phase of the study in April 2020, the most outstanding amino-acid substitution was a change of Aspartic acid (D) by Glycine (G) at position 614 (D614G) within the spike protein of the virus (caused by the RNA mutation A23403G). Wruck says that \"we saw that D614G gradually replaced other variants in April 2020. In June 2021, it had replaced them and was included in all new variants such as alpha (α) and delta (δ). In October 2021, the delta variant dominated and in the future the question will be which sub-variant of delta will prevail?\" The delta variant spreads with an evolutionary advantage because the amino-acid substitution leads to higher transmission within the population. \"In April 2020 we could only detect few rare mutations which appeared to originate from West Africa, in June 2021 there was the Eta (η) variant which originated from Nigeria,\" Wruck comments. Adjaye adds that \"continual monitoring of viral sequences is needed to enable the control of transmission of new variants and to assess vaccine efficacy. However, for future therapies it is also crucial to better understand the mechanisms underlying COVID19 as we did in an earlier publication elucidating molecular changes resulting from infection of SARS-CoV-2 in lung cells. The kidney is the second most affected organ and there have been reports of adults infected with COVID-19 to have developed acute kidney injury (AKI) and a sudden loss of kidney function. We are currently introducing laboratory-produced spike protein (which is the basis of current vaccines) into human kidney cells isolated from urine samples. This work should shed light on the genes and druggable pathways associated with cytokine storm, cellular damage and kidney injury.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract SARS-CoV-2, the virus causing the COVID-19 pandemic emerged in December 2019 in China and raised fears it could overwhelm healthcare systems worldwide. Mutations of the virus are monitored by the GISAID database from which we downloaded sequences from four West African countries Ghana, Gambia, Senegal and Nigeria from February 2020 to April 2020. We subjected the sequences to phylogenetic analysis employing the nextstrain pipeline. We found country-specific patterns of viral variants and supplemented that with data on novel variants from June 2021. Until April 2020, variants carrying the crucial Europe-associated D614G amino acid change were predominantly found in Senegal and Gambia, and combinations of late variants with and early variants without D614G in Ghana and Nigeria. In June 2021 all variants carried the D614G amino acid substitution. Senegal and Gambia exhibited again variants transmitted from Europe (alpha or delta), Ghana a combination of several variants and in Nigeria the original Eta variant. Detailed analysis of distinct samples revealed that some might have circulated latently and some reflect migration routes. The distinct patterns of variants within the West African countries point at their global transmission via air traffic predominantly from Europe and only limited transmission between the West African countries. Introduction The COVID-19 pandemic resulting from the SARS-CoV-2 coronavirus infection which emerged in December 2019 in Wuhan, China, spread all over the world and after a delay of a few months also appeared on the African continent. Early in June 2020, all African countries registered human infections with SARS-CoV-2. Starting with the first sequenced human sample of SARS-CoV-2, several mutations of the virus sequence arose which could be grouped into clades allowing associations with regional prevalence. In this study, we focused on samples from West Africa which was the region from which the first African SARS-CoV-2 sequences became available. We aimed at analysing phylogenetic characteristics possibly giving hints on the distribution between countries and eventually even about putative severity changes between specific clades. We use the nomenclature of clades suggested by the GISAID initiativewhich has now been adopted in several publications. Previous studies reported the potential impact of the D614G amino acid substitution which is a result of the A23403G single nucleotide polymorphism (SNP) 1 and associated with the branch of the phylogenetic tree referred to as clade G. Brufsky hypothesized that the higher number of deaths on the East coast of the United States compared to the West coast could be due to the higher prevalence of the D614G amino acid substitution on the East coast 2 . The D614G amino acid substitution has been suggested to affect the adherence of the virus to the cell membrane and consequently results in higher virulence. Supportive evidence was reported in mice 3 , 4 . Korber et al. hypothesized that the D614 amino acid on the surface of the subunit S1 of the spike protein of the virus might have a hydrogen bond to the T859 amino acid in the subunit S2 residing on the membrane 1 . Furthermore, they showed that clade G rapidly starts to replace other clades associated with the D614 amino acid in each country entered 1 . In mid-March 2020, the G clade was found almost exclusively in Europe 5 but soon after spread all over the world. Korber et al. see its origin from China or Europe 1 . In China, four early samples carried the D614G amino acid substitution. One sample from January 24th 2020 had only the A23403G (D614G) but not the C3037T and C14408T mutations which usually associate with A23403T in clade G. Three samples with the D614G were related to the first German sample. In Europe the first German sample from January 28th carried the A-to-G mutation at nucleotide position 23403 (D614G) mutation and the C-to-T mutation at position 3037, but not the mutation at position 14408. The first sample carrying all of the above mentioned mutations plus the C241T in the Untranslated Region (UTR) was identified in Italy on February 20th, 2020 1 . Another interesting feature of the G clades is that the associated C14408T mutation adjacent to the RNA dependent RNA polymerase (RdRp) putatively increases the mutation rate as Pachetti et al . report 5 . Detailed analyses of virus evolution have been performed for some countries, e.g. France 6 , New York 7 and India 8 . For France it could be deduced by the distinction between clade G and the earlier phylogenetic branches that the first SARS-CoV-2 did not lead to local transmission while the clade G was circulating for a considerable time before the first recorded case which was of clade G and had no travel events or traveler contact 6 . Since the declaration of COVID-19 as pandemic by the WHO on March 11th, 2020, fears were expressed that it could overwhelm weaker healthcare systems in many African countries. Furthermore, hygiene, social distancing and lockdown has caused many challenges in countries with high percentages of its citizens living without clean running water, cramped confines and the dependence on a daily income. However, Africa has the advantage of having a very young population, e.g. in Sub-Saharan Africa with a median age of 19.7 years 9 for which on average milder etiopathologies can be expected. Additionally, for the early outbreak a study evaluating air traffic from affected regions in China calculated relatively low transmission risks for most African countries except South Africa and Ethiopia 10 . For later phases, Cabore et al. proposed a model estimating risk of exposure for African countries based on a Hidden Markov model which accounts for factors such as gathering, weather, distribution and hygiene with the conclusion that with respect to the high calculated infection rates effective containment is indispensable 11 . Here, we analysed SARS-CoV-2 nucleotide sequences from samples obtained from the West African countries of Gambia, Ghana, Nigeria and Senegal in order to identify characteristic mutations and to dissect their patterns of distribution. The rationale of this study was to investigate commonalities and differences between SARS-CoV-2 transmission in West<|im_end|> <|im_start|>assistant At the onset of the SARS-CoV-2 pandemic, fears emerged that it would overwhelm the weak health systems in many African countries. However, it turned out that Europe and America had much higher incidences and fatality rates compared to Africa. Reasons for this may lie in the relatively young populations, previous viral infections and the warm climate. Nevertheless, SARS-CoV-2 affected all African countries and thus initiatives for a global distribution of vaccines were initiated. The genomes of viral isolates are continuously sequenced in most countries. The DNA sequences can be subjected to phylogenetic analysis to identify the origins of viral variants and to monitor the development and distribution of new variants which may be milder or in the worst case more deadly. Researchers from Heinrich-Heine University Düsseldorf have now unveiled distinct patterns of SARS-CoV-2 variants in a phylogenetic analysis of viral sequences from the West African countries—Gambia, Ghana, Nigeria and Senegal. Prof. Dr. James Adjaye is the senior author of the study, published in Scientific Reports. Bioinformatician Wasco Wruck is the first author of the paper. Although the four investigated countries have similar geographic and climatic conditions the researchers found distinct patterns of virus variants. This may reflect a genetic drift mechanism called the "Founder effect" where genetic diversity is driven by only a small part of a population forming a new separate population, for instance the particular infected persons transmitting virus variants from France to Senegal. "When you look at the distinct patterns of virus variants you can directly see the historic relationships, e.g. Senegal was a French colony and has a similar pattern as France because there is still much traffic and trade between Senegal and France. Ghana and Nigeria are both former British colonies with similar viral-patterns. Both countries have trade and labor ties with Europe and China," says James Adjaye, a Ghanaian-British Professor at the Medical Faculty of the Heinrich-Heine University Düsseldorf and the Director of the Institute for Stem Cell Research and Regenerative Medicine. Wruck adds that "surprisingly, we found that later variants from Europe were detected before the earlier variants. Explanations for this could be that the earlier virus variants circulated latently, and the later variants were detected earlier because of higher virus transmissibility." As SARS-CoV-2 is a RNA virus, mutations can arise when the RNA is copied inside the human host cells. In phylogenetic analysis, similar patterns of mutations pointing to similar origins are clustered together in branches of a tree which if they are big enough can be called variants. Mutations can have no effect or can lead to amino-acid substitutions which may alter the function or structure of the viral proteins. Prof. Adjaye and his colleague downloaded SARS-CoV-2 sequences from the four West African countries from the GISAID database and used sequences from China, Europe and America as reference. Employing phylogenetic analysis, these sequences could be associated with viral variants, additionally distinct patterns ofl variants could be detected for each country. In the first phase of the study in April 2020, the most outstanding amino-acid substitution was a change of Aspartic acid (D) by Glycine (G) at position 614 (D614G) within the spike protein of the virus (caused by the RNA mutation A23403G). Wruck says that "we saw that D614G gradually replaced other variants in April 2020. In June 2021, it had replaced them and was included in all new variants such as alpha (α) and delta (δ). In October 2021, the delta variant dominated and in the future the question will be which sub-variant of delta will prevail?" The delta variant spreads with an evolutionary advantage because the amino-acid substitution leads to higher transmission within the population. "In April 2020 we could only detect few rare mutations which appeared to originate from West Africa, in June 2021 there was the Eta (η) variant which originated from Nigeria," Wruck comments. Adjaye adds that "continual monitoring of viral sequences is needed to enable the control of transmission of new variants and to assess vaccine efficacy. However, for future therapies it is also crucial to better understand the mechanisms underlying COVID19 as we did in an earlier publication elucidating molecular changes resulting from infection of SARS-CoV-2 in lung cells. The kidney is the second most affected organ and there have been reports of adults infected with COVID-19 to have developed acute kidney injury (AKI) and a sudden loss of kidney function. We are currently introducing laboratory-produced spike protein (which is the basis of current vaccines) into human kidney cells isolated from urine samples. This work should shed light on the genes and druggable pathways associated with cytokine storm, cellular damage and kidney injury." <|im_end|>

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4455, 477, 63865, 3729, 220, 21, 662, 8876, 279, 18489, 315, 20562, 12, 777, 439, 28522, 555, 279, 40312, 389, 5587, 220, 806, 339, 11, 220, 2366, 15, 11, 24087, 1051, 13605, 430, 433, 1436, 96848, 43383, 18985, 6067, 304, 1690, 11904, 5961, 13, 24296, 11, 53056, 11, 3674, 73669, 323, 51235, 706, 9057, 1690, 11774, 304, 5961, 449, 1579, 54208, 315, 1202, 10495, 5496, 2085, 4335, 4401, 3090, 11, 99832, 91120, 323, 279, 44393, 389, 264, 7446, 8070, 13, 4452, 11, 10384, 706, 279, 9610, 315, 3515, 264, 1633, 3995, 7187, 11, 384, 1326, 13, 304, 3804, 97519, 10384, 449, 264, 23369, 4325, 315, 220, 777, 13, 22, 1667, 220, 24, 369, 902, 389, 5578, 296, 21439, 1880, 72, 36211, 9268, 649, 387, 3685, 13, 23212, 11, 369, 279, 4216, 31188, 264, 4007, 38663, 3805, 9629, 505, 11754, 13918, 304, 5734, 16997, 12309, 3428, 18874, 15635, 369, 1455, 11904, 5961, 3734, 4987, 10384, 323, 60457, 220, 605, 662, 1789, 3010, 35530, 11, 27200, 461, 1880, 453, 13, 11223, 264, 1646, 77472, 5326, 315, 14675, 369, 11904, 5961, 3196, 389, 264, 35342, 4488, 869, 1646, 902, 9815, 369, 9547, 1778, 439, 23738, 11, 9282, 11, 8141, 323, 53056, 449, 279, 17102, 430, 449, 5201, 311, 279, 1579, 16997, 19405, 7969, 7524, 46311, 374, 64284, 220, 806, 662, 5810, 11, 584, 67458, 328, 17485, 87271, 53, 12, 17, 31484, 69044, 24630, 505, 10688, 12457, 505, 279, 4410, 11904, 5961, 315, 480, 53937, 11, 48668, 11, 29258, 323, 5476, 62421, 304, 2015, 311, 10765, 29683, 34684, 323, 311, 75050, 872, 12912, 315, 8141, 13, 578, 57916, 315, 420, 4007, 574, 311, 19874, 4279, 278, 1385, 323, 12062, 1990, 328, 17485, 87271, 53, 12, 17, 18874, 304, 4410, 128257, 198, 128256, 78191, 198, 1688, 279, 42080, 315, 279, 328, 17485, 87271, 53, 12, 17, 28522, 11, 24087, 22763, 430, 433, 1053, 96848, 279, 7621, 2890, 6067, 304, 1690, 11904, 5961, 13, 4452, 11, 433, 6656, 704, 430, 4606, 323, 5270, 1047, 1790, 5190, 62960, 2436, 323, 8834, 2786, 7969, 7863, 311, 10384, 13, 66131, 369, 420, 1253, 10457, 304, 279, 12309, 3995, 22673, 11, 3766, 29962, 30020, 323, 279, 8369, 10182, 13, 35053, 11, 328, 17485, 87271, 53, 12, 17, 11754, 682, 11904, 5961, 323, 8617, 28271, 369, 264, 3728, 8141, 315, 40300, 1051, 33230, 13, 578, 85381, 315, 29962, 13399, 988, 527, 31978, 11506, 5886, 304, 1455, 5961, 13, 578, 15922, 24630, 649, 387, 38126, 311, 37555, 86945, 5411, 6492, 311, 10765, 279, 33472, 315, 29962, 27103, 323, 311, 8891, 279, 4500, 323, 8141, 315, 502, 27103, 902, 1253, 387, 296, 21439, 477, 304, 279, 12047, 1162, 810, 25114, 13, 59250, 505, 64782, 14172, 12, 1548, 483, 3907, 423, 86135, 617, 1457, 39297, 12742, 12912, 315, 328, 17485, 87271, 53, 12, 17, 27103, 304, 264, 37555, 86945, 5411, 6492, 315, 29962, 24630, 505, 279, 4410, 11904, 5961, 2345, 38, 53937, 11, 48668, 11, 29258, 323, 5476, 62421, 13, 8626, 13, 2999, 13, 7957, 64016, 61055, 374, 279, 10195, 3229, 315, 279, 4007, 11, 4756, 304, 38130, 29140, 13, 24432, 41540, 780, 1122, 15148, 1030, 32730, 1983, 374, 279, 1176, 3229, 315, 279, 5684, 13, 10541, 279, 3116, 27313, 5961, 617, 4528, 46139, 323, 11323, 780, 4787, 279, 12074, 1766, 12742, 12912, 315, 17188, 27103, 13, 1115, 1253, 8881, 264, 19465, 34738, 17383, 2663, 279, 330, 83834, 2515, 1, 1405, 19465, 20057, 374, 16625, 555, 1193, 264, 2678, 961, 315, 264, 7187, 30164, 264, 502, 8821, 7187, 11, 369, 2937, 279, 4040, 29374, 11434, 78768, 17188, 27103, 505, 9822, 311, 5476, 62421, 13, 330, 4599, 499, 1427, 520, 279, 12742, 12912, 315, 17188, 27103, 499, 649, 6089, 1518, 279, 18526, 12135, 11, 384, 1326, 13, 5476, 62421, 574, 264, 8753, 42036, 323, 706, 264, 4528, 5497, 439, 9822, 1606, 1070, 374, 2103, 1790, 9629, 323, 6696, 1990, 5476, 62421, 323, 9822, 13, 48668, 323, 29258, 527, 2225, 4846, 8013, 49028, 449, 4528, 29962, 80669, 82, 13, 11995, 5961, 617, 6696, 323, 9511, 20405, 449, 4606, 323, 5734, 1359, 2795, 7957, 64016, 61055, 11, 264, 48668, 1122, 7826, 1018, 819, 17054, 520, 279, 13235, 42904, 315, 279, 64782, 14172, 12, 1548, 483, 3907, 423, 86135, 323, 279, 10783, 315, 279, 10181, 369, 81948, 14299, 8483, 323, 3263, 75989, 19152, 13, 32730, 1983, 11621, 430, 330, 20370, 49264, 11, 584, 1766, 430, 3010, 27103, 505, 4606, 1051, 16914, 1603, 279, 6931, 27103, 13, 1398, 10609, 811, 369, 420, 1436, 387, 430, 279, 6931, 17188, 27103, 63973, 6987, 4501, 11, 323, 279, 3010, 27103, 1051, 16914, 6931, 1606, 315, 5190, 17188, 1380, 1869, 3225, 1210, 1666, 328, 17485, 87271, 53, 12, 17, 374, 264, 41214, 17188, 11, 34684, 649, 31889, 994, 279, 41214, 374, 22523, 4871, 279, 3823, 3552, 7917, 13, 763, 37555, 86945, 5411, 6492, 11, 4528, 12912, 315, 34684, 22364, 311, 4528, 33472, 527, 93858, 3871, 304, 23962, 315, 264, 5021, 902, 422, 814, 527, 2466, 3403, 649, 387, 2663, 27103, 13, 32328, 811, 649, 617, 912, 2515, 477, 649, 3063, 311, 42500, 38698, 307, 94750, 902, 1253, 11857, 279, 734, 477, 6070, 315, 279, 29962, 28896, 13, 8626, 13, 64016, 61055, 323, 813, 37444, 24174, 328, 17485, 87271, 53, 12, 17, 24630, 505, 279, 3116, 4410, 11904, 5961, 505, 279, 480, 35301, 926, 4729, 323, 1511, 24630, 505, 5734, 11, 4606, 323, 5270, 439, 5905, 13, 21445, 287, 37555, 86945, 5411, 6492, 11, 1521, 24630, 1436, 387, 5938, 449, 29962, 27103, 11, 37938, 12742, 12912, 315, 75, 27103, 1436, 387, 16914, 369, 1855, 3224, 13, 763, 279, 1176, 10474, 315, 279, 4007, 304, 5936, 220, 2366, 15, 11, 279, 1455, 19310, 42500, 38698, 307, 50068, 574, 264, 2349, 315, 1666, 4581, 292, 13935, 320, 35, 8, 555, 79183, 66, 483, 320, 38, 8, 520, 2361, 220, 22638, 320, 35, 22638, 38, 8, 2949, 279, 37393, 13128, 315, 279, 17188, 320, 936, 2656, 555, 279, 41214, 27472, 362, 11727, 2839, 38, 570, 32730, 1983, 2795, 430, 330, 906, 5602, 430, 423, 22638, 38, 27115, 12860, 1023, 27103, 304, 5936, 220, 2366, 15, 13, 763, 5651, 220, 2366, 16, 11, 433, 1047, 12860, 1124, 323, 574, 5343, 304, 682, 502, 27103, 1778, 439, 8451, 320, 19481, 8, 323, 9665, 320, 86486, 570, 763, 6664, 220, 2366, 16, 11, 279, 9665, 11678, 30801, 323, 304, 279, 3938, 279, 3488, 690, 387, 902, 1207, 12, 16349, 315, 9665, 690, 66828, 7673, 578, 9665, 11678, 43653, 449, 459, 41993, 9610, 1606, 279, 42500, 38698, 307, 50068, 11767, 311, 5190, 18874, 2949, 279, 7187, 13, 330, 644, 5936, 220, 2366, 15, 584, 1436, 1193, 11388, 2478, 9024, 34684, 902, 9922, 311, 82316, 505, 4410, 10384, 11, 304, 5651, 220, 2366, 16, 1070, 574, 279, 469, 2629, 320, 42524, 8, 11678, 902, 44853, 505, 29258, 1359, 32730, 1983, 6170, 13, 64016, 61055, 11621, 430, 330, 22025, 940, 16967, 315, 29962, 24630, 374, 4460, 311, 7431, 279, 2585, 315, 18874, 315, 502, 27103, 323, 311, 8720, 25474, 41265, 13, 4452, 11, 369, 3938, 52312, 433, 374, 1101, 16996, 311, 2731, 3619, 279, 24717, 16940, 20562, 777, 439, 584, 1550, 304, 459, 6931, 17009, 97298, 1113, 31206, 4442, 13239, 505, 19405, 315, 328, 17485, 87271, 53, 12, 17, 304, 21271, 7917, 13, 578, 39042, 374, 279, 2132, 1455, 11754, 2942, 323, 1070, 617, 1027, 6821, 315, 12884, 29374, 449, 20562, 12, 777, 311, 617, 8040, 30883, 39042, 11134, 320, 12173, 40, 8, 323, 264, 11210, 4814, 315, 39042, 734, 13, 1226, 527, 5131, 33018, 27692, 84561, 37393, 13128, 320, 8370, 374, 279, 8197, 315, 1510, 40300, 8, 1139, 3823, 39042, 7917, 25181, 505, 40335, 10688, 13, 1115, 990, 1288, 25351, 3177, 389, 279, 21389, 323, 1377, 2661, 481, 44014, 5938, 449, 83185, 483, 13766, 11, 35693, 5674, 323, 39042, 11134, 1210, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Tropical dry woodlands are rapidly being lost to agricultural expansion, but how deforestation dynamics play out in these woodlands remains poorly understood. We have developed an approach to detect and map high-level patterns of deforestation frontiers, that is, the expansion of woodland loss across continents in unprecedented spatio-temporal detail. Deforestation in tropical dry woodlands is pervasive, with over 71 Mha lost since 2000 and one-third of wooded areas located in deforestation frontiers. Over 24.3 Mha of deforestation frontiers fall into what we term ‘rampant frontiers’. These are characterized by drastic woodland loss and conditions favourable for capital-intensive agriculture, as seen in the South American Chaco and Southeast Asia. We have found many active and emerging frontiers (~59% of all frontiers), mostly in the understudied dry woodlands of Africa and Asia, where greater frontier monitoring is needed. Our approach enables consistent, repeatable frontier monitoring, and our global frontier typology fosters comparative research and context-specific policymaking. Main Tropical deforestation is the principal driver of biodiversity loss as well as contributing to climate change, the spread of zoonotic diseases and the widespread degradation of ecosystem services, which disproportionately affects marginalized communities 1 , 2 . A major cause of deforestation is agricultural expansion 3 , 4 by different types of smallholders and agribusinesses 3 , 4 . The diverse forms of agricultural expansion, embedded in different social-ecological contexts, produce deforestation frontiers with heterogeneous severity, speed and spatial patterns of forest loss 5 , 6 , 7 . Navigating and structuring this complexity remains a major challenge for sustainability science 8 . In particular, identifying high-level, recurring frontier types is essential for the more context-specific policy responses often called for to govern frontier regions 9 . Likewise, identifying high-level frontier types would enable learning and comparative research across geographies 10 and help to build theory in sustainability science 8 . However, whether such generalizable, high-level deforestation frontier types exist remains very unclear. Three factors have contributed to this knowledge gap. First, there are major geographical research biases towards a few specific regions 11 , while many others remain entirely overlooked 12 . Second, research on deforestation frontiers has typically focused on investigating dynamics within certain places or regions, such as in Amazonia 13 , Indonesia 14 or the Congo Basin 15 , but there is a clear lack of cross-regional and comparative assessments 16 . Third, global satellite-based time-series products describing forest and woodland loss at high spatial resolution have only recently become available 17 . These data could provide deep insights into how deforestation frontiers advance and help to identify typical, recurrent patterns of deforestation frontiers. Recently, detecting and assessing such archetypical human–environment interactions has become a major focus in sustainability science 18 , 19 , including for identifying static land systems 20 or driver/outcome constellations 8 , 21 , 22 . In this study we have pioneered the use of archetype analyses to identify the major, recurring patterns in global deforestation frontiers. Deforestation frontiers, in particular, are poorly understood in the world’s tropical woodlands (defined in our manuscript as including tropical dry forests, shrublands and wooded savannas with more than 10% tree cover). When compared with humid forests, these woodlands are overlooked by researchers, policymakers and the general public 23 , 24 , 25 . Yet these ecosystems harbour unique biodiversity, including many endemic species, and are some of the last refuges for iconic megafauna 24 , 25 , 26 . Tropical dry woodlands provide important ecosystem services that sustain the livelihoods of hundreds of millions of people and store globally relevant amounts of carbon 24 , 26 , 27 . Despite this, many woodland regions today are global deforestation hotspots 17 , including regions in South America (for example, Gran Chaco 28 and Cerrado 29 ) and Southeast Asia (for example, Cambodia 30 , 31 ). There is also increasing evidence that the same pervasive dynamics are emerging in African dry woodlands, such as in the miombo woodlands 17 , 25 , 32 . This translates into an urgent need to identify and monitor how deforestation frontiers expand into woodlands to allow for timely policy responses. We have developed a methodology to identify and map deforestation frontiers, and applied it to carry out a global, high-resolution assessment of frontier dynamics in tropical dry woodlands. Specifically, we used a 20-year time series of tree loss to develop a consistent, high-resolution set of frontier metrics describing frontier severity, spatio-temporal patterns and development stage. Based on these data, we have established a nested typology of deforestation frontiers, allowing us to (1) map archetypical frontiers across all tropical dry woodlands, (2) describe the social-ecological characteristics of major frontier types and (3) assess the research effort across these types. Results Major frontier types Our analytical framework to typify and map deforestation frontiers in tropical dry woodlands involved four main steps (Fig. 1 ). In step 1, we detected candidate areas for frontiers for the period 2000 to 2020. In step 2, we derived a set of metrics characterizing the deforestation process itself, which we then used in step 3 to develop three thematic typologies describing the severity, spatio-temporal patterns and development stage of the frontiers. Finally, in step 4, we grouped these thematic types into frontier archetypes. Fig. 1: Analytical framework to derive major deforestation frontiers in the world’s tropical dry woodlands. The schematic shows that the analytical framework comprises four main steps. Step 1 detects frontier processes, step 2 derives metrics to describe the frontiers, step 3 builds frontier typologies and step 4 develops frontier archetypes. Full size image Applying this framework across the world’s tropical dry woodlands, according to our definition (Supplementary Fig. 1 ), revealed that woodland grid cells occupied 1,884.97 Mha and contained about 1,044.13 Mha of woodland in the year 2000. We identified 577.36 Mha of woodland cells undergoing substantial deforestation processes from 2001 to 2020 (~31% of woodland cells in 2000), accounting for around 71.7 Mha of woodlands loss (92% of total loss). Of the frontier area, three-quarters (76.5%)", "role": "user" }, { "content": "Dry tropical forests are important ecosystems, yet these forests are increasingly threatened, a new study discovers. An innovative approach to characterize how deforestation took place since 2000 showed that more than 71 million hectares of tropical dry forests were lost, particularly in South America and Asia. Even more worrisome, one third of remaining forests are under threat as they are located in so-called frontier areas where deforestation is progressing rapidly. African tropical dry forests are still comparatively less disturbed, but in many of them deforestation has recently emerged. Forward-looking monitoring and land-use planning is urgently needed to safeguard the world's tropical dry forests. In a new study published in Nature Sustainability, researchers from the Geography Department of Humboldt-Universität zu Berlin and the Earth and Life Institute of University Catholique de Louvain provide the most comprehensive global assessment of deforestation processes in the world's dry forests and woodlands to date. Using high-resolution satellite imagery time series of forest loss for the period of 2000 to 2020, the team analyzed the spatial and temporal patterns of deforestation across more than 18 million square kilometers of tropical dry forests and woodlands. \"The main innovation of our study is that we developed a methodology that goes beyond just flagging deforestation,\" Tobias Kuemmerle, professor at the Geography Department of Humboldt-Universität explains. \"In other words, we can now detect and map in detail where deforestation is speeding up and where it has slowed down, and whether it results in fragmented landscapes or whether forests are lost entirely.\" Hotspots of deforestation in South America and Asia The results are alarming. Since 2000, more than 71 million hectares of dry forest have been destroyed, an area about twice the size of Germany. Many hotspots of deforestation are concentrated in South America, such as in the Gran Chaco in Argentina, Paraguay, and Bolivia, or the Cerrado in Brazil, as well as in Asia, such as the dry forests of Cambodia, Laos and Vietnam. \"What is worrying is also that we found one third of all remaining dry forests to be located in areas where deforestation is already taking place,\" Matthias Baumann, a co-author of the study, highlights, and adds: \"We are going to lose many of these unique forests in the near future, if we do not better protect them.\" Much of the deforestation happens as capital-intensive agriculture spreads into dry forests. \"Surprisingly, around 55% of the areas where deforestation frontiers recently emerged are located in African dry forests,\" Patrick Meyfroidt, another co-author of the study, and highlights: \"We can expect agricultural expansion to speed up there a lot in the future, because many global producers have an eye towards the region. If we want to safeguard Africa's dry forests and savannas, the time to act is now.\" Dry forests equally threatened as rainforests Deforestation in the tropics leads to major environmental and social problems, including biodiversity loss, carbon emissions, the spread of zoonotic diseases, or the marginalization of millions of local people that depend on these forests for their livelihoods. Unfortunately, the fate of dry forest and savannas is frequently overlooked by research, by policymakers and by the public. Ana Buchadas, researcher at the Geography Department of Humboldt-Universität zu Berlin says, \"This is problematic because these ecosystems are really exceptional and equally threatened as rainforests in many parts of the world.\" Improved deforestation monitoring and better land-use and sustainability planning is needed, according to the authors. \"Our work allowed us to identify re-occurring patterns of deforestation processes across different continents. This can be a good starting point for developing policy tools that are more adapted to local conditions,\" Ana Buchadas says. According to the researchers, the results also are a huge opportunity to learn from one situation, for example policy interventions that have worked in South America, for other situations, such as where deforestation is starting like in Africa. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Tropical dry woodlands are rapidly being lost to agricultural expansion, but how deforestation dynamics play out in these woodlands remains poorly understood. We have developed an approach to detect and map high-level patterns of deforestation frontiers, that is, the expansion of woodland loss across continents in unprecedented spatio-temporal detail. Deforestation in tropical dry woodlands is pervasive, with over 71 Mha lost since 2000 and one-third of wooded areas located in deforestation frontiers. Over 24.3 Mha of deforestation frontiers fall into what we term ‘rampant frontiers’. These are characterized by drastic woodland loss and conditions favourable for capital-intensive agriculture, as seen in the South American Chaco and Southeast Asia. We have found many active and emerging frontiers (~59% of all frontiers), mostly in the understudied dry woodlands of Africa and Asia, where greater frontier monitoring is needed. Our approach enables consistent, repeatable frontier monitoring, and our global frontier typology fosters comparative research and context-specific policymaking. Main Tropical deforestation is the principal driver of biodiversity loss as well as contributing to climate change, the spread of zoonotic diseases and the widespread degradation of ecosystem services, which disproportionately affects marginalized communities 1 , 2 . A major cause of deforestation is agricultural expansion 3 , 4 by different types of smallholders and agribusinesses 3 , 4 . The diverse forms of agricultural expansion, embedded in different social-ecological contexts, produce deforestation frontiers with heterogeneous severity, speed and spatial patterns of forest loss 5 , 6 , 7 . Navigating and structuring this complexity remains a major challenge for sustainability science 8 . In particular, identifying high-level, recurring frontier types is essential for the more context-specific policy responses often called for to govern frontier regions 9 . Likewise, identifying high-level frontier types would enable learning and comparative research across geographies 10 and help to build theory in sustainability science 8 . However, whether such generalizable, high-level deforestation frontier types exist remains very unclear. Three factors have contributed to this knowledge gap. First, there are major geographical research biases towards a few specific regions 11 , while many others remain entirely overlooked 12 . Second, research on deforestation frontiers has typically focused on investigating dynamics within certain places or regions, such as in Amazonia 13 , Indonesia 14 or the Congo Basin 15 , but there is a clear lack of cross-regional and comparative assessments 16 . Third, global satellite-based time-series products describing forest and woodland loss at high spatial resolution have only recently become available 17 . These data could provide deep insights into how deforestation frontiers advance and help to identify typical, recurrent patterns of deforestation frontiers. Recently, detecting and assessing such archetypical human–environment interactions has become a major focus in sustainability science 18 , 19 , including for identifying static land systems 20 or driver/outcome constellations 8 , 21 , 22 . In this study we have pioneered the use of archetype analyses to identify the major, recurring patterns in global deforestation frontiers. Deforestation frontiers, in particular, are poorly understood in the world’s tropical woodlands (defined in our manuscript as including tropical dry forests, shrublands and wooded savannas with more than 10% tree cover). When compared with humid forests, these woodlands are overlooked by researchers, policymakers and the general public 23 , 24 , 25 . Yet these ecosystems harbour unique biodiversity, including many endemic species, and are some of the last refuges for iconic megafauna 24 , 25 , 26 . Tropical dry woodlands provide important ecosystem services that sustain the livelihoods of hundreds of millions of people and store globally relevant amounts of carbon 24 , 26 , 27 . Despite this, many woodland regions today are global deforestation hotspots 17 , including regions in South America (for example, Gran Chaco 28 and Cerrado 29 ) and Southeast Asia (for example, Cambodia 30 , 31 ). There is also increasing evidence that the same pervasive dynamics are emerging in African dry woodlands, such as in the miombo woodlands 17 , 25 , 32 . This translates into an urgent need to identify and monitor how deforestation frontiers expand into woodlands to allow for timely policy responses. We have developed a methodology to identify and map deforestation frontiers, and applied it to carry out a global, high-resolution assessment of frontier dynamics in tropical dry woodlands. Specifically, we used a 20-year time series of tree loss to develop a consistent, high-resolution set of frontier metrics describing frontier severity, spatio-temporal patterns and development stage. Based on these data, we have established a nested typology of deforestation frontiers, allowing us to (1) map archetypical frontiers across all tropical dry woodlands, (2) describe the social-ecological characteristics of major frontier types and (3) assess the research effort across these types. Results Major frontier types Our analytical framework to typify and map deforestation frontiers in tropical dry woodlands involved four main steps (Fig. 1 ). In step 1, we detected candidate areas for frontiers for the period 2000 to 2020. In step 2, we derived a set of metrics characterizing the deforestation process itself, which we then used in step 3 to develop three thematic typologies describing the severity, spatio-temporal patterns and development stage of the frontiers. Finally, in step 4, we grouped these thematic types into frontier archetypes. Fig. 1: Analytical framework to derive major deforestation frontiers in the world’s tropical dry woodlands. The schematic shows that the analytical framework comprises four main steps. Step 1 detects frontier processes, step 2 derives metrics to describe the frontiers, step 3 builds frontier typologies and step 4 develops frontier archetypes. Full size image Applying this framework across the world’s tropical dry woodlands, according to our definition (Supplementary Fig. 1 ), revealed that woodland grid cells occupied 1,884.97 Mha and contained about 1,044.13 Mha of woodland in the year 2000. We identified 577.36 Mha of woodland cells undergoing substantial deforestation processes from 2001 to 2020 (~31% of woodland cells in 2000), accounting for around 71.7 Mha of woodlands loss (92% of total loss). Of the frontier area, three-quarters (76.5%)<|im_end|> <|im_start|>assistant Dry tropical forests are important ecosystems, yet these forests are increasingly threatened, a new study discovers. An innovative approach to characterize how deforestation took place since 2000 showed that more than 71 million hectares of tropical dry forests were lost, particularly in South America and Asia. Even more worrisome, one third of remaining forests are under threat as they are located in so-called frontier areas where deforestation is progressing rapidly. African tropical dry forests are still comparatively less disturbed, but in many of them deforestation has recently emerged. Forward-looking monitoring and land-use planning is urgently needed to safeguard the world's tropical dry forests. In a new study published in Nature Sustainability, researchers from the Geography Department of Humboldt-Universität zu Berlin and the Earth and Life Institute of University Catholique de Louvain provide the most comprehensive global assessment of deforestation processes in the world's dry forests and woodlands to date. Using high-resolution satellite imagery time series of forest loss for the period of 2000 to 2020, the team analyzed the spatial and temporal patterns of deforestation across more than 18 million square kilometers of tropical dry forests and woodlands. "The main innovation of our study is that we developed a methodology that goes beyond just flagging deforestation," Tobias Kuemmerle, professor at the Geography Department of Humboldt-Universität explains. "In other words, we can now detect and map in detail where deforestation is speeding up and where it has slowed down, and whether it results in fragmented landscapes or whether forests are lost entirely." Hotspots of deforestation in South America and Asia The results are alarming. Since 2000, more than 71 million hectares of dry forest have been destroyed, an area about twice the size of Germany. Many hotspots of deforestation are concentrated in South America, such as in the Gran Chaco in Argentina, Paraguay, and Bolivia, or the Cerrado in Brazil, as well as in Asia, such as the dry forests of Cambodia, Laos and Vietnam. "What is worrying is also that we found one third of all remaining dry forests to be located in areas where deforestation is already taking place," Matthias Baumann, a co-author of the study, highlights, and adds: "We are going to lose many of these unique forests in the near future, if we do not better protect them." Much of the deforestation happens as capital-intensive agriculture spreads into dry forests. "Surprisingly, around 55% of the areas where deforestation frontiers recently emerged are located in African dry forests," Patrick Meyfroidt, another co-author of the study, and highlights: "We can expect agricultural expansion to speed up there a lot in the future, because many global producers have an eye towards the region. If we want to safeguard Africa's dry forests and savannas, the time to act is now." Dry forests equally threatened as rainforests Deforestation in the tropics leads to major environmental and social problems, including biodiversity loss, carbon emissions, the spread of zoonotic diseases, or the marginalization of millions of local people that depend on these forests for their livelihoods. Unfortunately, the fate of dry forest and savannas is frequently overlooked by research, by policymakers and by the public. Ana Buchadas, researcher at the Geography Department of Humboldt-Universität zu Berlin says, "This is problematic because these ecosystems are really exceptional and equally threatened as rainforests in many parts of the world." Improved deforestation monitoring and better land-use and sustainability planning is needed, according to the authors. "Our work allowed us to identify re-occurring patterns of deforestation processes across different continents. This can be a good starting point for developing policy tools that are more adapted to local conditions," Ana Buchadas says. According to the researchers, the results also are a huge opportunity to learn from one situation, for example policy interventions that have worked in South America, for other situations, such as where deforestation is starting like in Africa. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Deconvolution analyses have been widely used to track compositional alterations of cell types in gene expression data. Although a large number of novel methods have been developed, due to a lack of understanding of the effects of modeling assumptions and tuning parameters, it is challenging for researchers to select an optimal deconvolution method suitable for the targeted biological conditions. Results To systematically reveal the pitfalls and challenges of deconvolution analyses, we investigate the impact of several technical and biological factors including simulation model, quantification unit, component number, weight matrix, and unknown content by constructing three benchmarking frameworks. These frameworks cover comparative analysis of 11 popular deconvolution methods under 1766 conditions. Conclusions We provide new insights to researchers for future application, standardization, and development of deconvolution tools on RNA-seq data. Introduction Deconvolution refers to a process that separates a heterogeneous mixture signal into its constituent components. In the biomedical field, researchers have used deconvolution methods to derive cell type-specific signals [ 1 , 2 , 3 ] from heterogeneous mixture data. Cellular composition information is crucial for developing sophisticated diagnostic techniques because it enables researchers to track each cellular component’s contribution during disease progressions [ 4 ]. Although some experimental approaches like fluorescence-activated cell sorting (FACS), immunohistochemistry (IHC), and single-cell RNA-seq can derive cellular composition information [ 3 ], all these approaches are either restricted by their throughput or remain too costly and laborious for large-scale clinical applications. Deconvolution, which computationally decomposes mixture signals, provides a cost-effective way to derive cellular composition information and has the potential to bring considerable improvements in the speed and scale of relevant applications. By January 2018, approximately 50 deconvolution methods had been developed [ 2 ]. While the speed of method development is increasing, researchers now face the new challenge of selecting appropriate methods for their analysis. In methodological papers, authors often use small benchmarks to illustrate the improvements of their methods. These benchmarks only contain a limited number of deconvolution methods and samples. Moreover, different research groups applied inconsistent testing frameworks with different simulation strategies, evaluation metrics, and cell type annotations, making it difficult for researchers to reach a solid conclusion on the method’s performance. Therefore, independent benchmarks are usually in need of rigorous and comprehensive comparisons [ 5 ]. Previously, Sturm et al. [ 3 ] and Cobos et al. [ 6 ] have generated independent benchmarks of reference-based and marker-based deconvolution methods on RNA-seq data. Focusing on spill-over effects, minimal detection fraction, and background predictions, Sturm et al. [ 3 ] suggested refining signature gene lists to improve deconvolution accuracy. On the other hand, Cobos et al. [ 6 ] focused on the impact of different normalization strategies, sequencing platforms of reference data, marker gene selection strategies, and missing cellular components in the reference. Compared with previous benchmarks, which mainly focused on the influence of reference profile and feature selection, our study focused on factors directly related to the mixture samples such as mixture noise level, quantification unit, cellular component number, weight matrix property, and unknown cellular contents. In addition to these factors, we also studied factors related to the testing framework construction, such as simulation model selection, evaluation metric selection, and measurement scale selection. There are three types of benchmarking frameworks for the evaluation of deconvolution methods: in vivo framework [ 7 ], in vitro framework [ 8 ], and in silico framework [ 9 , 10 ] (Additional file 2 : Table S1). The in vivo testing framework mainly relies on indirect performance assessments and usually cannot derive a definite conclusion of the method’s performance. Only a few in vivo benchmarking datasets [ 3 , 10 ] have coupled FACS results for direct performance assessments. Nevertheless, these benchmarking datasets only contain limited sample numbers and cannot provide a comprehensive performance assessment [ 3 , 10 ]. The in vitro testing framework where mixtures are generated in the tube with predefined mixing compositions also suffers from limited sample numbers. Moreover, most benchmarks generated from the in vitro testing framework used “orthogonal” weights [ 8 ] during the mixing process, which would potentially result in over-optimistic conclusions. The in silico testing framework synthesizes heterogeneous mixture data by simulation. The primary goal of this study is to systematically investigate the impact of different biological and technical factors, where numerous finely tuned conditions need to be created [ 11 ]. A few biologically relevant cases cannot reveal the systematic biases since all technical and biological factors are confounded. Therefore, both in vivo and in vitro frameworks are not feasible for this type of systematic comparison due to the limitation in sample number and confounding factors. Careful consideration of these issues led us to select the in silico testing framework to systematically examine the impact of different biological and technical factors, which require large amounts of benchmarking datasets under controlled and finely tuned multi-factor testing environments (Fig. 1 a and Table 1 ). Fig. 1 Overview of three in silico testing frameworks. a Three benchmarking frameworks were constructed to investigate the impact of seven factors that affect deconvolution analysis: noise level, noise structure, other noise sources, quantification unit, unknown content, component number, and weight matrix. b Eleven deconvolution methods are tested and have been categorized based on the required reference input: marker-based, reference-based, and reference-free. c Performance of the methods is assessed through Pearson’s correlation coefficient ( R ) and mean absolute deviance (mAD). Evaluation results are illustrated by heatmaps and scatter plots. When unknown content is involved, we derive evaluation metrics in both relative and absolute measurement scales Full size image Table 1 Cellular components and datasets involved in three testing frameworks and variance analysis Full size table To provide a reliable reference for the application and development of deconvolution methods, we compared 11 deconvolution methods (Fig. 1 b) that cover three categories: marker-based, reference-based, and reference-free. To establish sophisticated benchmarking frameworks that mimic application scenarios of diverse biological systems, we designed three sets of benchmarking frameworks that simulated up to 1766", "role": "user" }, { "content": "Biomedical scientists are increasingly using deconvolution methods, those used to computationally analyze the composition of complex mixtures of cells. One of their challenges is to select one method that is appropriate for their experimental conditions among nearly 50 available. To help with method selection, researchers at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital have extensively evaluated 11 deconvolution methods that are based on RNA-sequencing (RNA-seq) data analysis, determining each method's individual strengths and weaknesses in a variety of scenarios. From these analyses, the researchers derived guidelines that scientists can use to determine the deconvolution method that optimally fits their needs. The study appears in the journal Genome Biology. \"A great deal of work in biomedical research involves analyzing heterogeneous biological tissues to gain insight into the contribution of individual cells in, for instance, cancer growth or brain development,\" said corresponding author Dr. Zhandong Liu, associate professor of pediatrics-neurology at Baylor and director of the Bioinformatics Core of the Jan and Dan Duncan Neurological Research Institute. Analyzing complex cellular mixtures is a difficult task. Researchers can conduct such analyses with laboratory techniques that physically separate and/or identify cellular components, but this method is time consuming and expensive. Alternatively, researchers can use deconvolution methods that computationally extract information about individual cells in a mixture by analyzing large datasets derived from the bulk, such as RNA sequencing data. For example, some researchers studying stem cells, a rare type of cell, might be interested in the percentage of these cells in the total blood cell population. They could conduct RNA-seq analysis of the bulk of cells and then apply a deconvolution method to determine the percentage of stem cells in the mixture. But, what method should they use? In another example, if a scientist were interested only in the relative proportions of different cell types in a mixture, then one method would be best for deconvolution. But if the scientist wanted to find out the actual percentage of each cell type, then that deconvolution method would not be the best for that job, but another one that works better at providing that kind of answer. How can a scientist know which method works best in each situation? \"Our lab is one of many that developed deconvolution methods early on, contributing to the nearly 50 deconvolution methods currently out there to do this type of job,\" said first author Haijing Jin, a graduate student in Baylor's graduate program of quantitative and computational biosciences working in the Liu lab. \"The methods are based on different mathematical models and/or different assumptions to try to solve deconvolution problems, which involve basically how to go from a bulk heterogeneous tissue to profiles of individual cells.\" Because of this growing interest in deconvolution and the abundance of methods available, Liu and Jin felt that it was time to establish a guideline or benchmark to understand the strengths and the weaknesses of each method. Running thousands of scenarios The team studied 11 methods. They selected them according to the quality of the programing, the number of citations in the scientific literature and their popularity in the field. \"One of the challenges we faced was how to best test the strengths and weaknesses of each method in many possible scenarios,\" Jin said. The researchers decided to use a computational or in silico approach that enabled them to simulate the thousands of scenarios necessary to test all the methods. \"All these scenarios represented real-life experimental situations in cell research, cancer research or developmental biology. We simulated each one of them so we could identify the best deconvolution method for each scenario for people who are interested in applying these methods to their experiments,\" Jin said. \"That's the value of this work,\" Liu said. \"We are providing a benchmark study on various deconvolution methods and guidance for people working on different topics in biology to facilitate the analysis of their experimental results.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Deconvolution analyses have been widely used to track compositional alterations of cell types in gene expression data. Although a large number of novel methods have been developed, due to a lack of understanding of the effects of modeling assumptions and tuning parameters, it is challenging for researchers to select an optimal deconvolution method suitable for the targeted biological conditions. Results To systematically reveal the pitfalls and challenges of deconvolution analyses, we investigate the impact of several technical and biological factors including simulation model, quantification unit, component number, weight matrix, and unknown content by constructing three benchmarking frameworks. These frameworks cover comparative analysis of 11 popular deconvolution methods under 1766 conditions. Conclusions We provide new insights to researchers for future application, standardization, and development of deconvolution tools on RNA-seq data. Introduction Deconvolution refers to a process that separates a heterogeneous mixture signal into its constituent components. In the biomedical field, researchers have used deconvolution methods to derive cell type-specific signals [ 1 , 2 , 3 ] from heterogeneous mixture data. Cellular composition information is crucial for developing sophisticated diagnostic techniques because it enables researchers to track each cellular component’s contribution during disease progressions [ 4 ]. Although some experimental approaches like fluorescence-activated cell sorting (FACS), immunohistochemistry (IHC), and single-cell RNA-seq can derive cellular composition information [ 3 ], all these approaches are either restricted by their throughput or remain too costly and laborious for large-scale clinical applications. Deconvolution, which computationally decomposes mixture signals, provides a cost-effective way to derive cellular composition information and has the potential to bring considerable improvements in the speed and scale of relevant applications. By January 2018, approximately 50 deconvolution methods had been developed [ 2 ]. While the speed of method development is increasing, researchers now face the new challenge of selecting appropriate methods for their analysis. In methodological papers, authors often use small benchmarks to illustrate the improvements of their methods. These benchmarks only contain a limited number of deconvolution methods and samples. Moreover, different research groups applied inconsistent testing frameworks with different simulation strategies, evaluation metrics, and cell type annotations, making it difficult for researchers to reach a solid conclusion on the method’s performance. Therefore, independent benchmarks are usually in need of rigorous and comprehensive comparisons [ 5 ]. Previously, Sturm et al. [ 3 ] and Cobos et al. [ 6 ] have generated independent benchmarks of reference-based and marker-based deconvolution methods on RNA-seq data. Focusing on spill-over effects, minimal detection fraction, and background predictions, Sturm et al. [ 3 ] suggested refining signature gene lists to improve deconvolution accuracy. On the other hand, Cobos et al. [ 6 ] focused on the impact of different normalization strategies, sequencing platforms of reference data, marker gene selection strategies, and missing cellular components in the reference. Compared with previous benchmarks, which mainly focused on the influence of reference profile and feature selection, our study focused on factors directly related to the mixture samples such as mixture noise level, quantification unit, cellular component number, weight matrix property, and unknown cellular contents. In addition to these factors, we also studied factors related to the testing framework construction, such as simulation model selection, evaluation metric selection, and measurement scale selection. There are three types of benchmarking frameworks for the evaluation of deconvolution methods: in vivo framework [ 7 ], in vitro framework [ 8 ], and in silico framework [ 9 , 10 ] (Additional file 2 : Table S1). The in vivo testing framework mainly relies on indirect performance assessments and usually cannot derive a definite conclusion of the method’s performance. Only a few in vivo benchmarking datasets [ 3 , 10 ] have coupled FACS results for direct performance assessments. Nevertheless, these benchmarking datasets only contain limited sample numbers and cannot provide a comprehensive performance assessment [ 3 , 10 ]. The in vitro testing framework where mixtures are generated in the tube with predefined mixing compositions also suffers from limited sample numbers. Moreover, most benchmarks generated from the in vitro testing framework used “orthogonal” weights [ 8 ] during the mixing process, which would potentially result in over-optimistic conclusions. The in silico testing framework synthesizes heterogeneous mixture data by simulation. The primary goal of this study is to systematically investigate the impact of different biological and technical factors, where numerous finely tuned conditions need to be created [ 11 ]. A few biologically relevant cases cannot reveal the systematic biases since all technical and biological factors are confounded. Therefore, both in vivo and in vitro frameworks are not feasible for this type of systematic comparison due to the limitation in sample number and confounding factors. Careful consideration of these issues led us to select the in silico testing framework to systematically examine the impact of different biological and technical factors, which require large amounts of benchmarking datasets under controlled and finely tuned multi-factor testing environments (Fig. 1 a and Table 1 ). Fig. 1 Overview of three in silico testing frameworks. a Three benchmarking frameworks were constructed to investigate the impact of seven factors that affect deconvolution analysis: noise level, noise structure, other noise sources, quantification unit, unknown content, component number, and weight matrix. b Eleven deconvolution methods are tested and have been categorized based on the required reference input: marker-based, reference-based, and reference-free. c Performance of the methods is assessed through Pearson’s correlation coefficient ( R ) and mean absolute deviance (mAD). Evaluation results are illustrated by heatmaps and scatter plots. When unknown content is involved, we derive evaluation metrics in both relative and absolute measurement scales Full size image Table 1 Cellular components and datasets involved in three testing frameworks and variance analysis Full size table To provide a reliable reference for the application and development of deconvolution methods, we compared 11 deconvolution methods (Fig. 1 b) that cover three categories: marker-based, reference-based, and reference-free. To establish sophisticated benchmarking frameworks that mimic application scenarios of diverse biological systems, we designed three sets of benchmarking frameworks that simulated up to 1766<|im_end|> <|im_start|>assistant Biomedical scientists are increasingly using deconvolution methods, those used to computationally analyze the composition of complex mixtures of cells. One of their challenges is to select one method that is appropriate for their experimental conditions among nearly 50 available. To help with method selection, researchers at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital have extensively evaluated 11 deconvolution methods that are based on RNA-sequencing (RNA-seq) data analysis, determining each method's individual strengths and weaknesses in a variety of scenarios. From these analyses, the researchers derived guidelines that scientists can use to determine the deconvolution method that optimally fits their needs. The study appears in the journal Genome Biology. "A great deal of work in biomedical research involves analyzing heterogeneous biological tissues to gain insight into the contribution of individual cells in, for instance, cancer growth or brain development," said corresponding author Dr. Zhandong Liu, associate professor of pediatrics-neurology at Baylor and director of the Bioinformatics Core of the Jan and Dan Duncan Neurological Research Institute. Analyzing complex cellular mixtures is a difficult task. Researchers can conduct such analyses with laboratory techniques that physically separate and/or identify cellular components, but this method is time consuming and expensive. Alternatively, researchers can use deconvolution methods that computationally extract information about individual cells in a mixture by analyzing large datasets derived from the bulk, such as RNA sequencing data. For example, some researchers studying stem cells, a rare type of cell, might be interested in the percentage of these cells in the total blood cell population. They could conduct RNA-seq analysis of the bulk of cells and then apply a deconvolution method to determine the percentage of stem cells in the mixture. But, what method should they use? In another example, if a scientist were interested only in the relative proportions of different cell types in a mixture, then one method would be best for deconvolution. But if the scientist wanted to find out the actual percentage of each cell type, then that deconvolution method would not be the best for that job, but another one that works better at providing that kind of answer. How can a scientist know which method works best in each situation? "Our lab is one of many that developed deconvolution methods early on, contributing to the nearly 50 deconvolution methods currently out there to do this type of job," said first author Haijing Jin, a graduate student in Baylor's graduate program of quantitative and computational biosciences working in the Liu lab. "The methods are based on different mathematical models and/or different assumptions to try to solve deconvolution problems, which involve basically how to go from a bulk heterogeneous tissue to profiles of individual cells." Because of this growing interest in deconvolution and the abundance of methods available, Liu and Jin felt that it was time to establish a guideline or benchmark to understand the strengths and the weaknesses of each method. Running thousands of scenarios The team studied 11 methods. They selected them according to the quality of the programing, the number of citations in the scientific literature and their popularity in the field. "One of the challenges we faced was how to best test the strengths and weaknesses of each method in many possible scenarios," Jin said. The researchers decided to use a computational or in silico approach that enabled them to simulate the thousands of scenarios necessary to test all the methods. "All these scenarios represented real-life experimental situations in cell research, cancer research or developmental biology. We simulated each one of them so we could identify the best deconvolution method for each scenario for people who are interested in applying these methods to their experiments," Jin said. "That's the value of this work," Liu said. "We are providing a benchmark study on various deconvolution methods and guidance for people working on different topics in biology to facilitate the analysis of their experimental results." <|im_end|>

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2,084

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract CRISPR-Cas9 genome editing technology holds great promise for discovering therapeutic targets in cancer and other diseases. Current screening strategies target CRISPR-Cas9–induced mutations to the 5′ exons of candidate genes 1 , 2 , 3 , 4 , 5 , but this approach often produces in-frame variants that retain functionality, which can obscure even strong genetic dependencies. Here we overcome this limitation by targeting CRISPR-Cas9 mutagenesis to exons encoding functional protein domains. This generates a higher proportion of null mutations and substantially increases the potency of negative selection. We also show that the magnitude of negative selection can be used to infer the functional importance of individual protein domains of interest. A screen of 192 chromatin regulatory domains in murine acute myeloid leukemia cells identifies six known drug targets and 19 additional dependencies. A broader application of this approach may allow comprehensive identification of protein domains that sustain cancer cells and are suitable for drug targeting. Main The RNA-guided endonuclease Cas9 (CRISPR-associated protein 9), a component of the type II CRISPR (clustered, regularly interspaced, short palindromic repeats) system of bacterial host defense, is a powerful tool for genome editing 6 . Ectopic expression of Cas9 and a single guide RNA (sgRNA) is sufficient to direct the formation of a DNA double-strand break (DSB) at a specific region of interest 7 , 8 , 9 . In the absence of a homology-directed repair DNA template, these DSBs are repaired in an error-prone manner by means of the nonhomologous end-joining pathway to generate an assortment of short deletion and insertion mutations (indels) in the vicinity of the sgRNA recognition site 7 , 8 . This approach has been widely used to generate gene-specific knockouts in a variety of biological systems 6 . Recent studies have demonstrated the use of CRISPR-Cas9 mutagenesis for genetic screens in mammalian cell culture, which have relied on sgRNA libraries that target constitutive 5′ coding exons to achieve gene inactivation 1 , 2 , 3 , 4 . The capabilities of CRISPR-based genetic screens are particularly evident in the setting of positive selection, such as identifying mutations that confer drug resistance 1 , 2 , 3 , 4 . In negative selection screens, it has been shown that sgRNA hits are statistically enriched for essential gene classes (ribosomal, RNA processing and DNA replication factors); however, the overall accuracy of CRISPR-Cas9 for annotating genetic dependencies is currently unclear 1 , 2 . We investigated the performance of CRISPR-Cas9 indel mutagenesis as a tool to identify essential genes in cancer cells. We employed a murine MLL-AF9/Nras G12D acute myeloid leukemia cell line (RN2), which has been used extensively to identify genetic dependencies and therapeutic targets by RNA interference (RNAi) 10 , 11 . We derived a clonal Cas9-expressing RN2 cell line (RN2c), which is diploid and remains genomically stable during passaging ( Fig. 1a and data not shown). Lentiviral transduction of RN2c cells with a vector expressing GFP and an sgRNA targeting the Rosa26 locus resulted in a high efficiency of indel mutagenesis near the predicted cut site, reaching >95% editing efficiency by day 7 post-infection ( Fig. 1b ). Next, we designed three sgRNAs targeting the first exon of Rpa3 , which encodes a 17-kD protein required for DNA replication 12 . Unlike the effects of targeting Rosa26 , we found that cells expressing Rpa3 sgRNAs were rapidly outcompeted by nontransduced cells over 8 days in culture, as shown by flow cytometry–based tracking of GFP expression ( Fig. 1c ). These effects were rescued by the presence of a human RPA3 cDNA that contains several mismatches with mouse Rpa3 sgRNAs, indicating that negative selection induced by CRISPR-Cas9 can be attributed to mutational effects at a single essential gene ( Fig. 1c,d ). Figure 1: Negative-selection CRISPR-Cas9 experiments in murine MLL-AF9/Nras G12D acute myeloid leukemia cells. ( a ) Experimental strategy. (top) Vectors used to derive clonal MLL-AF9/Nras G12D leukemia RN2c cells that express a human codon-optimized Cas9 (hCas9) and vectors used for sgRNA transduction. GFP or mCherry reporters were used where indicated to track sgRNA negative selection. LTR, long terminal repeat promoter; PGK, phosphoglycerate kinase 1 promoter; Puro, puromycin resistance gene; U6, a Pol III-driven promoter; EFS, EF1α promoter. ( b ) Analysis of CRISPR-Cas9 editing efficiency at the Rosa26 locus in RN2c cells. Illumina sequencing was used to quantify the abundance of indel mutations occuring in the vicinity of the Rosa26 sgRNA cut site. ( c ) Negative-selection competition assay that plots the percentage of GFP + /mCherry + cells over time following transduction of RN2c with the indicated sgRNAs. Experiments were performed in RN2c cells transduced with either an empty murine stem cell virus (MSCV) vector or MSCV expressing human RPA3, which are linked with a GFP reporter. The mCherry/GFP double-positive percentage is normalized to the day-2 measurement. e1 labeling of sgRNAs refers to targeting of exon 1. n = 3. ( d ) Comparison of mouse Rpa3 and human RPA3 sequences at the indicated sgRNA recognition sites. Red indicates mismatches. PAM, protospacer-adjacent motif. ( e ) Summary of negative selection experiments with sgRNAs targeting the indicated genes. Negative selection is plotted as the fold depletion of GFP + cells (d2 GFP% divided by d10 GFP%) during 8 days in culture. Each bar represents an independent sgRNA targeting a 5′ exon of the indicated gene. The dashed line indicates a twofold change. The fold depletion for two Brd4 sgRNAs was >50, but the axis was limited to a 20-fold maximum for visualization purposes. The data shown are the mean value of three independent replicates. ( f – i ) Negative-selection time course experiments, as described in c , except a GFP reporter was used exclusively. n = 3. Error bars, mean ± s.e.m. Full size image To further evaluate the performance of CRISPR-Cas9 mutagenesis as a negative-selection screening strategy, we targeted ten additional negative-control genes, chosen on the basis of having undetectable expression in RN2 (ref. 13 ). We also targeted five essential genes encoding chromatin regulators", "role": "user" }, { "content": "Imagine having a complete catalog of the best drug targets to hit in a particularly deadly form of cancer. Imagine having a master catalog of such targets for all the major cancer types and subtypes. Scientists at Cold Spring Harbor Laboratory (CSHL) today publish in Nature Biotechnology a method of compiling just such a catalog, using the revolutionary gene-editing technology called CRISPR. CRISPR enables biologists to manipulate the genetic material of cells with unprecedented precision and ease - letter by DNA letter. CSHL Assistant Professor Chris Vakoc, M.D., Ph.D., and Junwei Shi, a Ph.D. student investigator in his lab, have figured out how to harness CRISPR's elegant power to the task that preoccupies their lab and so many others across the world: finding binding pockets inside cancer cells that when blocked prevent the cells from proliferating and cause them to die. Several years ago Vakoc used the best available technologies to find one such binding pocket - on an obscure protein called BRD4—that when blocked with an existing drug called JQ1 dealt a crippling blow to cells of acute myeloid leukemia (AML), an often fatal form of blood cancer. The drug is now in human clinical trials. \"That experience got us thinking,\" explains Vakoc, \"Is there a way we can look at hundreds or thousands of proteins at a time in a given cancer cell type - proteins with druggable binding pockets—and in a single experiment find more BRD4s?\" The short answer is yes. Their paper provides a proof of principle of the method they have devised. In leukemia cells, the CRISPR-based method surveyed about 200 potential targets and successfully identified the six targets already known and validated by pharmaceutical scientists, most of which are at the focus of existing drug development efforts; and found an additional 19 targets never before recognized. \"This is just a single demonstration,\" says Vakoc. \"More broadly, what we provide is a way to comprehensively identify specific vulnerabilities in cancer cells, across cancer types.\" Fascinated with CRISPR, Ph.D. student Shi spent much of the last year devising a way to use it to rapidly and accurately identify the best leukemia drug targets. The concept is not difficult to explain. It begins with the notion that genes provide cells with the code to build proteins - the molecules that do all the work in cells and support the tissues of our bodily organs. Since completion of the full human genome sequence over a dozen years ago, scientists have been amassing databases that document or predict how specific stretches of DNA letters in the genome encode specific segments of proteins, called domains. Among the domains of greatest interest to drug developers are those that form pocket-like features on the surface of proteins that other molecules can fit into, as keys fit into locks. Drugs are keys that fit into binding-pocket locks, sometimes for the purpose of blocking access to the lock, and other times to initiate a cascade of signaling inside the cell. \"My lab is focused on finding a small number of these binding pockets - ones whose function cancer cells are addicted to,\" Vakoc says. \"There are a vast number of pockets encoded in our genome; and many of them are present in the proteins found in leukemia cells. We now have a test that will tell you whether a particular pocket matters to a given cancer cell. Which pockets, if you block or disable them, will really hurt a cancer cell? Which ones does the cell rely on to live and prosper?\" CRISPR is a wonderful tool of discovery, since it can be used to change the DNA letters that \"spell out\" particular binding pockets. If you want to know if a cancer cell depends upon a particular pocket, you mutate it - change its DNA code, causing the pocket to take on an unnatural shape. You mimic the action of an effective drug targeting that particular pocket. The technique worked precisely and powerfully in the leukemia cells used for demonstration purposes, reported in the paper published today. \"If you change the pocket so the protein is no longer functional and you find the cancer can't survive, then you have a good shot at a useful drug target. We can't tell if any particular pocket will lead to a fully effective drug; but this is a way to annotate every critical pocket in cancer cells.\" Vakoc's lab is starting with the kinds of binding pockets that drug makers like to target - considered \"druggable\" for various technical reasons. \"For entirely pragmatic reasons, our lab is prioritizing our search to the kinds of targets chemists like and are willing to design drugs against,\" Vakoc says. \"We want to have an impact on cancers in the near-term. We want to provide pharmaceutical companies the kind of targets that they have extensive experience figuring out how to hit. And it all comes back to the question: can we identify specific things that cancer cells need—and then deprive them of those things. CRISPR should bring us to the end-game of finding all of the critical pockets of vulnerability in cancer.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract CRISPR-Cas9 genome editing technology holds great promise for discovering therapeutic targets in cancer and other diseases. Current screening strategies target CRISPR-Cas9–induced mutations to the 5′ exons of candidate genes 1 , 2 , 3 , 4 , 5 , but this approach often produces in-frame variants that retain functionality, which can obscure even strong genetic dependencies. Here we overcome this limitation by targeting CRISPR-Cas9 mutagenesis to exons encoding functional protein domains. This generates a higher proportion of null mutations and substantially increases the potency of negative selection. We also show that the magnitude of negative selection can be used to infer the functional importance of individual protein domains of interest. A screen of 192 chromatin regulatory domains in murine acute myeloid leukemia cells identifies six known drug targets and 19 additional dependencies. A broader application of this approach may allow comprehensive identification of protein domains that sustain cancer cells and are suitable for drug targeting. Main The RNA-guided endonuclease Cas9 (CRISPR-associated protein 9), a component of the type II CRISPR (clustered, regularly interspaced, short palindromic repeats) system of bacterial host defense, is a powerful tool for genome editing 6 . Ectopic expression of Cas9 and a single guide RNA (sgRNA) is sufficient to direct the formation of a DNA double-strand break (DSB) at a specific region of interest 7 , 8 , 9 . In the absence of a homology-directed repair DNA template, these DSBs are repaired in an error-prone manner by means of the nonhomologous end-joining pathway to generate an assortment of short deletion and insertion mutations (indels) in the vicinity of the sgRNA recognition site 7 , 8 . This approach has been widely used to generate gene-specific knockouts in a variety of biological systems 6 . Recent studies have demonstrated the use of CRISPR-Cas9 mutagenesis for genetic screens in mammalian cell culture, which have relied on sgRNA libraries that target constitutive 5′ coding exons to achieve gene inactivation 1 , 2 , 3 , 4 . The capabilities of CRISPR-based genetic screens are particularly evident in the setting of positive selection, such as identifying mutations that confer drug resistance 1 , 2 , 3 , 4 . In negative selection screens, it has been shown that sgRNA hits are statistically enriched for essential gene classes (ribosomal, RNA processing and DNA replication factors); however, the overall accuracy of CRISPR-Cas9 for annotating genetic dependencies is currently unclear 1 , 2 . We investigated the performance of CRISPR-Cas9 indel mutagenesis as a tool to identify essential genes in cancer cells. We employed a murine MLL-AF9/Nras G12D acute myeloid leukemia cell line (RN2), which has been used extensively to identify genetic dependencies and therapeutic targets by RNA interference (RNAi) 10 , 11 . We derived a clonal Cas9-expressing RN2 cell line (RN2c), which is diploid and remains genomically stable during passaging ( Fig. 1a and data not shown). Lentiviral transduction of RN2c cells with a vector expressing GFP and an sgRNA targeting the Rosa26 locus resulted in a high efficiency of indel mutagenesis near the predicted cut site, reaching >95% editing efficiency by day 7 post-infection ( Fig. 1b ). Next, we designed three sgRNAs targeting the first exon of Rpa3 , which encodes a 17-kD protein required for DNA replication 12 . Unlike the effects of targeting Rosa26 , we found that cells expressing Rpa3 sgRNAs were rapidly outcompeted by nontransduced cells over 8 days in culture, as shown by flow cytometry–based tracking of GFP expression ( Fig. 1c ). These effects were rescued by the presence of a human RPA3 cDNA that contains several mismatches with mouse Rpa3 sgRNAs, indicating that negative selection induced by CRISPR-Cas9 can be attributed to mutational effects at a single essential gene ( Fig. 1c,d ). Figure 1: Negative-selection CRISPR-Cas9 experiments in murine MLL-AF9/Nras G12D acute myeloid leukemia cells. ( a ) Experimental strategy. (top) Vectors used to derive clonal MLL-AF9/Nras G12D leukemia RN2c cells that express a human codon-optimized Cas9 (hCas9) and vectors used for sgRNA transduction. GFP or mCherry reporters were used where indicated to track sgRNA negative selection. LTR, long terminal repeat promoter; PGK, phosphoglycerate kinase 1 promoter; Puro, puromycin resistance gene; U6, a Pol III-driven promoter; EFS, EF1α promoter. ( b ) Analysis of CRISPR-Cas9 editing efficiency at the Rosa26 locus in RN2c cells. Illumina sequencing was used to quantify the abundance of indel mutations occuring in the vicinity of the Rosa26 sgRNA cut site. ( c ) Negative-selection competition assay that plots the percentage of GFP + /mCherry + cells over time following transduction of RN2c with the indicated sgRNAs. Experiments were performed in RN2c cells transduced with either an empty murine stem cell virus (MSCV) vector or MSCV expressing human RPA3, which are linked with a GFP reporter. The mCherry/GFP double-positive percentage is normalized to the day-2 measurement. e1 labeling of sgRNAs refers to targeting of exon 1. n = 3. ( d ) Comparison of mouse Rpa3 and human RPA3 sequences at the indicated sgRNA recognition sites. Red indicates mismatches. PAM, protospacer-adjacent motif. ( e ) Summary of negative selection experiments with sgRNAs targeting the indicated genes. Negative selection is plotted as the fold depletion of GFP + cells (d2 GFP% divided by d10 GFP%) during 8 days in culture. Each bar represents an independent sgRNA targeting a 5′ exon of the indicated gene. The dashed line indicates a twofold change. The fold depletion for two Brd4 sgRNAs was >50, but the axis was limited to a 20-fold maximum for visualization purposes. The data shown are the mean value of three independent replicates. ( f – i ) Negative-selection time course experiments, as described in c , except a GFP reporter was used exclusively. n = 3. Error bars, mean ± s.e.m. Full size image To further evaluate the performance of CRISPR-Cas9 mutagenesis as a negative-selection screening strategy, we targeted ten additional negative-control genes, chosen on the basis of having undetectable expression in RN2 (ref. 13 ). We also targeted five essential genes encoding chromatin regulators<|im_end|> <|im_start|>assistant Imagine having a complete catalog of the best drug targets to hit in a particularly deadly form of cancer. Imagine having a master catalog of such targets for all the major cancer types and subtypes. Scientists at Cold Spring Harbor Laboratory (CSHL) today publish in Nature Biotechnology a method of compiling just such a catalog, using the revolutionary gene-editing technology called CRISPR. CRISPR enables biologists to manipulate the genetic material of cells with unprecedented precision and ease - letter by DNA letter. CSHL Assistant Professor Chris Vakoc, M.D., Ph.D., and Junwei Shi, a Ph.D. student investigator in his lab, have figured out how to harness CRISPR's elegant power to the task that preoccupies their lab and so many others across the world: finding binding pockets inside cancer cells that when blocked prevent the cells from proliferating and cause them to die. Several years ago Vakoc used the best available technologies to find one such binding pocket - on an obscure protein called BRD4—that when blocked with an existing drug called JQ1 dealt a crippling blow to cells of acute myeloid leukemia (AML), an often fatal form of blood cancer. The drug is now in human clinical trials. "That experience got us thinking," explains Vakoc, "Is there a way we can look at hundreds or thousands of proteins at a time in a given cancer cell type - proteins with druggable binding pockets—and in a single experiment find more BRD4s?" The short answer is yes. Their paper provides a proof of principle of the method they have devised. In leukemia cells, the CRISPR-based method surveyed about 200 potential targets and successfully identified the six targets already known and validated by pharmaceutical scientists, most of which are at the focus of existing drug development efforts; and found an additional 19 targets never before recognized. "This is just a single demonstration," says Vakoc. "More broadly, what we provide is a way to comprehensively identify specific vulnerabilities in cancer cells, across cancer types." Fascinated with CRISPR, Ph.D. student Shi spent much of the last year devising a way to use it to rapidly and accurately identify the best leukemia drug targets. The concept is not difficult to explain. It begins with the notion that genes provide cells with the code to build proteins - the molecules that do all the work in cells and support the tissues of our bodily organs. Since completion of the full human genome sequence over a dozen years ago, scientists have been amassing databases that document or predict how specific stretches of DNA letters in the genome encode specific segments of proteins, called domains. Among the domains of greatest interest to drug developers are those that form pocket-like features on the surface of proteins that other molecules can fit into, as keys fit into locks. Drugs are keys that fit into binding-pocket locks, sometimes for the purpose of blocking access to the lock, and other times to initiate a cascade of signaling inside the cell. "My lab is focused on finding a small number of these binding pockets - ones whose function cancer cells are addicted to," Vakoc says. "There are a vast number of pockets encoded in our genome; and many of them are present in the proteins found in leukemia cells. We now have a test that will tell you whether a particular pocket matters to a given cancer cell. Which pockets, if you block or disable them, will really hurt a cancer cell? Which ones does the cell rely on to live and prosper?" CRISPR is a wonderful tool of discovery, since it can be used to change the DNA letters that "spell out" particular binding pockets. If you want to know if a cancer cell depends upon a particular pocket, you mutate it - change its DNA code, causing the pocket to take on an unnatural shape. You mimic the action of an effective drug targeting that particular pocket. The technique worked precisely and powerfully in the leukemia cells used for demonstration purposes, reported in the paper published today. "If you change the pocket so the protein is no longer functional and you find the cancer can't survive, then you have a good shot at a useful drug target. We can't tell if any particular pocket will lead to a fully effective drug; but this is a way to annotate every critical pocket in cancer cells." Vakoc's lab is starting with the kinds of binding pockets that drug makers like to target - considered "druggable" for various technical reasons. "For entirely pragmatic reasons, our lab is prioritizing our search to the kinds of targets chemists like and are willing to design drugs against," Vakoc says. "We want to have an impact on cancers in the near-term. We want to provide pharmaceutical companies the kind of targets that they have extensive experience figuring out how to hit. And it all comes back to the question: can we identify specific things that cancer cells need—and then deprive them of those things. CRISPR should bring us to the end-game of finding all of the critical pockets of vulnerability in cancer." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The increasing vulnerability of the population from frequent disasters requires quick and effective responses to provide the required relief through effective humanitarian supply chain distribution networks. We develop scenario-robust optimization models for stocking multiple disaster relief items at strategic facility locations for disaster response. Our models improve the robustness of solutions by easing the difficult, and usually impossible, task of providing exact probability distributions for uncertain parameters in a stochastic programming model. Our models allow decision makers to specify uncertainty parameters (i.e., point and probability estimates) based on their degrees of knowledge, using distribution-free uncertainty sets in the form of ranges. The applicability of our generalized approach is illustrated via a case study of hurricane preparedness in the Southeastern United States. In addition, we conduct simulation studies to show the effectiveness of our approach when conditions deviate from the model assumptions. Working on a manuscript? Avoid the common mistakes 1 Introduction In a 2014 presentation, Dr. Steven Chu, Nobel Laureate and former US Energy Secretary, noted that natural disasters are occurring with increasing frequency worldwide, citing climate change as epidemiological evidence for the increase (Chu, 2014 ). Historical data clearly indicate that the number of natural disasters per year has been climbing dramatically since 1980. In North America alone, the number of annual natural catastrophes has jumped fourfold, from approximately 50 to 200, since the early 1980s, according to the world's largest reinsurer, Munich Re (Sturdevant, 2013 ). A closer look at the report reveals that the increase is not uniform across different types of natural disasters. The occurrence of geophysical disasters such as earthquakes and tsunamis has remained relatively stable between 1980 and 2011. However, weather-related disasters such as hurricanes; hydrological disasters such as floods; and climatological disasters such as droughts have been increasing steadily during the same period. All three of these increasing occurrence types of disasters are cyclic in nature, which provides valuable information for disaster preparedness planning. Pandemics can also be considered natural disasters. The Black Death pandemic in the fourteenth century resulted in an estimated 50 million deaths, and is considered to be the most fatal pandemic in human history (World Health Organization, 2017 ). Pandemics occurring in the twenty-first century include COVID-19, Ebola, MERS, 2009 Swine Flu, and SARS. The occurrences of pandemics (including type, timing, and magnitude) are especially difficult to predict. The recent COVID-19 pandemic has presented an enormous global challenge. Hospitals and clinics generally serve as the bulk of the humanitarian supply chain for pandemic response. The supplies required for pandemic response include personal-protective equipment (PPE), vaccines, ventilators, and other medical equipment. COVID-19 has illustrated the challenges of responding to a global pandemic where nearly every country in the world is affected by the pandemic and response supplies are extremely limited. The United States government maintains a strategic national stockpile of emergency medical supplies for pandemic response, but it is seriously depleted. It is crucial that these supplies are restocked and that the necessary planning is done so that these critical relief supplies are available to respond to the next natural disaster. Pre-positioning relief supplies at strategic facility locations is a critical part of disaster preparedness planning. It ensures availability of emergency relief commodities at the right time and at the right place. Despite recent efforts to establish advance contracts for relief items with partners that can be activated when needed, i.e., “virtual warehouses” (Balcik & Ak, 2014 ), pre-positioning of life-saving and life-sustaining resources such as water, tarps, and meals that allow for quick response remains as prevailing practice for most disaster relief agencies. As an illustrative example of pre-positioning, during the 2005 Hurricane Katrina that devastated New Orleans, Wal-Mart began pre-positioning high demand items including bottled water, flashlights and batteries six days prior to the hurricane’s landfall based on information collected on past purchase behaviors of customers in hurricane-prone areas (Shughart, 2011 ). Compared to the relatively small-scale relief efforts organized by commercial firms, government agencies such as the Federal Emergency Management Agency (FEMA) face a daunting task of preparedness at both county and state levels. During Hurricane Katrina relief supplies included 11,322,000 L of water, 18,960,000 pounds of ice, 5,997,312 meals ready to eat (MREs), and 17 truckloads of tarps. These materials were pre-positioned at key strategic locations prior to Katrina’s landfall; this represented the largest preparedness effort in the agency’s history (Davis, 2005 ). Still, criticism of FEMA’s slow, ineffective response, especially its failure to pre-deploy sufficient supplies, was frequent as the storm led to a confirmed death toll of 1833. Scott Wells, the Deputy Federal Coordinating Officer in Louisiana, pinpointed one source of the problem: “the response was not robust ; it was not enough for the catastrophe at hand” in his testimony to Congress (Townsend, 2006 ). The destruction created a massive, unexpected demand for emergency supplies, and the damaged infrastructure intensified logistics difficulties. Better coordination amongst the SC echelons before and after the disruption with the use of information-sharing is also an important mitigation strategy for such disruptive events. Investing in appropriate technology and quality information sharing improves supply chain visibility, enhances trust and cooperation among supply chain partners and eventually leads to a more resilient supply chain (Dubey et al., 2019a , 2019b , 2019c ). Further, humanitarian organizations must recognize how information sharing and supply chain visibility is key to swift-trust among humanitarian actors and agility in humanitarian supply chains (Dubey et al., 2020a , 2020b ). Starr and Van Wassenhove ( 2014 ), among others, emphasize the urgent need for robust solutions to account for the inherent uncertainty in humanitarian logistics. This is traditionally handled by stochastic programing models (e.g., Bozorgi-Amiri et al., 2013 ; Mete & Zabinsky, 2010 ; Rawls & Turnquist, 2009; Salmeron & Apte, 2010 ), which rely on specifying an exact probability distribution for uncertain parameters and then optimizing the expected value of a known objective function. However, as noted by Ergun et al. ( 2010 ), Starr and Van Wassenhove ( 2014 ) and others,", "role": "user" }, { "content": "With hurricanes, floods, wildfires, earthquakes, the COVID-19 pandemic and more, the world has seen a multitude of natural disasters recently. Research by University of Cincinnati professor Michael J. Fry that published in the Annals of Operations Research has provided insight into how the government and relief organizations could best prepare to respond to disasters, providing aid in an efficient and cost-effective manner while reducing human suffering. \"Anything that has a large impact on the public with uncertainty, we have to do some planning for that,\" said Fry, who is a professor in UC's Department of Operations, Business Analytics, and Information Systems in the Carl H. Lindner College of Business. \"If you have a natural disaster and people can't get food or water or medical supplies, the cost to society is huge because it can be life, death and human suffering.\" Balancing risks, costs Fry has worked alongside Muer Yang and Sameer Kumar from the University of St. Thomas in Minnesota and Xinfang Wang from Georgia Southern University in Statesboro, Georgia, for several years on research into \"robust optimization\"—how you think about decision making under uncertain circumstances. Prior to looking at disaster preparedness, they applied their research to voting applications. Wang, who earned a doctorate in business analytics from UC, suggested their studies into uncertainty would have applications in disaster preparedness. Their research determined a single warehouse for the nation's disaster relief supplies would be very cost efficient. However, a single location would be vulnerable to being damaged or destroyed by a disaster. Having many small warehouses would help mitigate the risk of a disaster destroying supplies but could be very costly. The researchers concluded having fewer, large facilities likely would be the best approach—although Fry said the exact solution is dependent on scenario-specific factors. \"The challenge is trying to think about given that we have limited information on where hurricanes are going to hit or earthquakes or whatever disaster you're talking about, how many facilities do I need and where should I put them to keep this emergency response stock so then I can respond when an actual natural disaster happens?\" he said. Cooperation leads to best results The research also found cooperation between the government and relief organizations, which Fry called \"risk pooling,\" can allow inventory to go where it's most needed and provide the best possible response. \"If we can kind of centralize this and coordinate it, then it makes it much easier and more effective to respond,\" he said. \"If you have every regional municipality, city, state doing this, you're going to end up with lots of different places of inventory who don't share well. It's going to be really expensive and really inefficient.\" Fry, who has studied \"decision making under uncertainty\" for more than 20 years, said people in government and academia seem to be coming to an agreement on how to best prepare for natural disasters. He thinks the research he and his colleagues worked on can further improve the planning as it accounts for uncertainty about when and where future disasters will occur—something that is happening more frequently as a result of climate change. \"What climate change is doing, it seems to be saying that historical data is less meaningful for the future because things have changed,\" Fry said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The increasing vulnerability of the population from frequent disasters requires quick and effective responses to provide the required relief through effective humanitarian supply chain distribution networks. We develop scenario-robust optimization models for stocking multiple disaster relief items at strategic facility locations for disaster response. Our models improve the robustness of solutions by easing the difficult, and usually impossible, task of providing exact probability distributions for uncertain parameters in a stochastic programming model. Our models allow decision makers to specify uncertainty parameters (i.e., point and probability estimates) based on their degrees of knowledge, using distribution-free uncertainty sets in the form of ranges. The applicability of our generalized approach is illustrated via a case study of hurricane preparedness in the Southeastern United States. In addition, we conduct simulation studies to show the effectiveness of our approach when conditions deviate from the model assumptions. Working on a manuscript? Avoid the common mistakes 1 Introduction In a 2014 presentation, Dr. Steven Chu, Nobel Laureate and former US Energy Secretary, noted that natural disasters are occurring with increasing frequency worldwide, citing climate change as epidemiological evidence for the increase (Chu, 2014 ). Historical data clearly indicate that the number of natural disasters per year has been climbing dramatically since 1980. In North America alone, the number of annual natural catastrophes has jumped fourfold, from approximately 50 to 200, since the early 1980s, according to the world's largest reinsurer, Munich Re (Sturdevant, 2013 ). A closer look at the report reveals that the increase is not uniform across different types of natural disasters. The occurrence of geophysical disasters such as earthquakes and tsunamis has remained relatively stable between 1980 and 2011. However, weather-related disasters such as hurricanes; hydrological disasters such as floods; and climatological disasters such as droughts have been increasing steadily during the same period. All three of these increasing occurrence types of disasters are cyclic in nature, which provides valuable information for disaster preparedness planning. Pandemics can also be considered natural disasters. The Black Death pandemic in the fourteenth century resulted in an estimated 50 million deaths, and is considered to be the most fatal pandemic in human history (World Health Organization, 2017 ). Pandemics occurring in the twenty-first century include COVID-19, Ebola, MERS, 2009 Swine Flu, and SARS. The occurrences of pandemics (including type, timing, and magnitude) are especially difficult to predict. The recent COVID-19 pandemic has presented an enormous global challenge. Hospitals and clinics generally serve as the bulk of the humanitarian supply chain for pandemic response. The supplies required for pandemic response include personal-protective equipment (PPE), vaccines, ventilators, and other medical equipment. COVID-19 has illustrated the challenges of responding to a global pandemic where nearly every country in the world is affected by the pandemic and response supplies are extremely limited. The United States government maintains a strategic national stockpile of emergency medical supplies for pandemic response, but it is seriously depleted. It is crucial that these supplies are restocked and that the necessary planning is done so that these critical relief supplies are available to respond to the next natural disaster. Pre-positioning relief supplies at strategic facility locations is a critical part of disaster preparedness planning. It ensures availability of emergency relief commodities at the right time and at the right place. Despite recent efforts to establish advance contracts for relief items with partners that can be activated when needed, i.e., “virtual warehouses” (Balcik & Ak, 2014 ), pre-positioning of life-saving and life-sustaining resources such as water, tarps, and meals that allow for quick response remains as prevailing practice for most disaster relief agencies. As an illustrative example of pre-positioning, during the 2005 Hurricane Katrina that devastated New Orleans, Wal-Mart began pre-positioning high demand items including bottled water, flashlights and batteries six days prior to the hurricane’s landfall based on information collected on past purchase behaviors of customers in hurricane-prone areas (Shughart, 2011 ). Compared to the relatively small-scale relief efforts organized by commercial firms, government agencies such as the Federal Emergency Management Agency (FEMA) face a daunting task of preparedness at both county and state levels. During Hurricane Katrina relief supplies included 11,322,000 L of water, 18,960,000 pounds of ice, 5,997,312 meals ready to eat (MREs), and 17 truckloads of tarps. These materials were pre-positioned at key strategic locations prior to Katrina’s landfall; this represented the largest preparedness effort in the agency’s history (Davis, 2005 ). Still, criticism of FEMA’s slow, ineffective response, especially its failure to pre-deploy sufficient supplies, was frequent as the storm led to a confirmed death toll of 1833. Scott Wells, the Deputy Federal Coordinating Officer in Louisiana, pinpointed one source of the problem: “the response was not robust ; it was not enough for the catastrophe at hand” in his testimony to Congress (Townsend, 2006 ). The destruction created a massive, unexpected demand for emergency supplies, and the damaged infrastructure intensified logistics difficulties. Better coordination amongst the SC echelons before and after the disruption with the use of information-sharing is also an important mitigation strategy for such disruptive events. Investing in appropriate technology and quality information sharing improves supply chain visibility, enhances trust and cooperation among supply chain partners and eventually leads to a more resilient supply chain (Dubey et al., 2019a , 2019b , 2019c ). Further, humanitarian organizations must recognize how information sharing and supply chain visibility is key to swift-trust among humanitarian actors and agility in humanitarian supply chains (Dubey et al., 2020a , 2020b ). Starr and Van Wassenhove ( 2014 ), among others, emphasize the urgent need for robust solutions to account for the inherent uncertainty in humanitarian logistics. This is traditionally handled by stochastic programing models (e.g., Bozorgi-Amiri et al., 2013 ; Mete & Zabinsky, 2010 ; Rawls & Turnquist, 2009; Salmeron & Apte, 2010 ), which rely on specifying an exact probability distribution for uncertain parameters and then optimizing the expected value of a known objective function. However, as noted by Ergun et al. ( 2010 ), Starr and Van Wassenhove ( 2014 ) and others,<|im_end|> <|im_start|>assistant With hurricanes, floods, wildfires, earthquakes, the COVID-19 pandemic and more, the world has seen a multitude of natural disasters recently. Research by University of Cincinnati professor Michael J. Fry that published in the Annals of Operations Research has provided insight into how the government and relief organizations could best prepare to respond to disasters, providing aid in an efficient and cost-effective manner while reducing human suffering. "Anything that has a large impact on the public with uncertainty, we have to do some planning for that," said Fry, who is a professor in UC's Department of Operations, Business Analytics, and Information Systems in the Carl H. Lindner College of Business. "If you have a natural disaster and people can't get food or water or medical supplies, the cost to society is huge because it can be life, death and human suffering." Balancing risks, costs Fry has worked alongside Muer Yang and Sameer Kumar from the University of St. Thomas in Minnesota and Xinfang Wang from Georgia Southern University in Statesboro, Georgia, for several years on research into "robust optimization"—how you think about decision making under uncertain circumstances. Prior to looking at disaster preparedness, they applied their research to voting applications. Wang, who earned a doctorate in business analytics from UC, suggested their studies into uncertainty would have applications in disaster preparedness. Their research determined a single warehouse for the nation's disaster relief supplies would be very cost efficient. However, a single location would be vulnerable to being damaged or destroyed by a disaster. Having many small warehouses would help mitigate the risk of a disaster destroying supplies but could be very costly. The researchers concluded having fewer, large facilities likely would be the best approach—although Fry said the exact solution is dependent on scenario-specific factors. "The challenge is trying to think about given that we have limited information on where hurricanes are going to hit or earthquakes or whatever disaster you're talking about, how many facilities do I need and where should I put them to keep this emergency response stock so then I can respond when an actual natural disaster happens?" he said. Cooperation leads to best results The research also found cooperation between the government and relief organizations, which Fry called "risk pooling," can allow inventory to go where it's most needed and provide the best possible response. "If we can kind of centralize this and coordinate it, then it makes it much easier and more effective to respond," he said. "If you have every regional municipality, city, state doing this, you're going to end up with lots of different places of inventory who don't share well. It's going to be really expensive and really inefficient." Fry, who has studied "decision making under uncertainty" for more than 20 years, said people in government and academia seem to be coming to an agreement on how to best prepare for natural disasters. He thinks the research he and his colleagues worked on can further improve the planning as it accounts for uncertainty about when and where future disasters will occur—something that is happening more frequently as a result of climate change. "What climate change is doing, it seems to be saying that historical data is less meaningful for the future because things have changed," Fry said. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Understanding why some evolutionary lineages generate exceptionally high species diversity is an important goal in evolutionary biology. Haplochromine cichlid fishes of Africa’s Lake Victoria region encompass >700 diverse species that all evolved in the last 150,000 years. How this ‘Lake Victoria Region Superflock’ could evolve on such rapid timescales is an enduring question. Here, we demonstrate that hybridization between two divergent lineages facilitated this process by providing genetic variation that subsequently became recombined and sorted into many new species. Notably, the hybridization event generated exceptional allelic variation at an opsin gene known to be involved in adaptation and speciation. More generally, differentiation between new species is accentuated around variants that were fixed differences between the parental lineages, and that now appear in many new combinations in the radiation species. We conclude that hybridization between divergent lineages, when coincident with ecological opportunity, may facilitate rapid and extensive adaptive radiation. Introduction Heterogeneity in diversification rates among lineages is a major factor shaping biodiversity. Yet, biological and environmental factors underlying this variation are incompletely understood 1 . Adaptive radiations are prime study systems to learn about these factors as they are characterized by a rapid origin of many species showing a diversity of ecological adaptations. This process requires high levels of heritable variation in traits related to ecological and reproductive isolation. However, adaptive radiations are often too rapid for the emergence of new relevant mutations between successive speciation events 2 and are thus more likely to stem from standing variation. Hybridization between species can instantaneously boost genetic variation, which may facilitate speciation and adaptive radiation 3 , 4 , 5 , 6 , 7 , 8 , 9 . Hybridization among members of an adaptive radiation, has been suggested to potentially facilitate speciation events, an idea known as the ‘syngameon hypothesis’ 3 . Introgression of traits involved in adaptation or reproductive isolation has been demonstrated among members of several adaptive radiations (for example, traits related to host shift in Rhagoletis fruit flies 10 , wing patterns in Heliconius butterflies 11 , 12 or beak shape in Darwin’s finches 13 ). In other radiations, the hybrid ancestry of some species has been inferred, but a direct link between introgressed traits and speciation awaits further testing (for example, cichlid fishes of Lakes Tanganyika 14 , 15 , 16 , Malawi 17 , Victoria 18 , 19 and Barombi Mbo 20 ). Another hypothesis for a perhaps more fundamental role of hybridization in adaptive radiation, distinct from the ‘syngameon hypothesis’, is the idea that hybridization between distinct lineages may seed the onset of an entire adaptive radiation 3 . Such hybridization can be common when allopatric lineages come into secondary contact 4 , and selection against hybrids may be weak during colonization of new environments. In this situation, the formation of a hybrid swarm, if coincident with ecological opportunity, may accelerate adaptive radiation by (i) providing functional genetic variation that can recombine into novel trait combinations favoured by selection and mate choice, and (ii) breaking genetic correlations that constrained the evolvability of parental lineages 3 . In addition, hybridization may facilitate speciation when multiple fixed differences that confer reproductive isolation between the two parental species decouple and segregate in a hybrid swarm, such that selection against incompatible gene combinations can generate more than two new reproductively isolated species 21 , 22 , 23 . This ‘hybrid swarm origin of adaptive radiation’ hypothesis has been more challenging to test. So far the only adaptive radiation for which a hybrid origin has been robustly demonstrated is the Hawaiian silverswords, which have radiated from an allopolyploid hybrid population between two North American tarweed species 24 . Because gene and genome duplication are also proposed to facilitate adaptive radiation 25 , it is difficult to distinguish between effects of hybridization per se and those of gene or genome duplication in this case. Evidence consistent with a hybrid swarm origin of entire radiations has also been found in Alpine whitefish 26 , the ‘mbuna’ group of the Lake Malawi cichlid fish radiation 27 , and allopolyploid Hawaiian endemic mints 28 , 29 and possibly other polyploid plant radiations on Hawaii 30 . However, it remains to be tested if, in these systems, hybridization occurred before or after the radiation had started, and if hybridization-derived polymorphisms played a role in speciation and adaptive diversification. The Lake Victoria Region Superflock of cichlid fish (LVRS) is a group of 700 haplochromine cichlid species endemic to the region around Lake Victoria and nearby western rift lakes in East Africa that started diversifying about 100–200 thousand years ago 31 , 32 , 33 , 34 . It includes several adaptive radiations, one in each of the major lakes of the region (Lakes Victoria, Edward, Albert and Kivu). The largest of them is in Lake Victoria, which has at least 500 endemic species that evolved in the past 15,000 years 34 , 35 , 36 . Each radiation comprises enormous diversity in habitat occupation, trophic ecology, colouration and behaviour. The high diversification rate but also the high nuclear genomic variation in the LVRS despite its young age 34 , 37 suggest that large amounts of standing genetic variation must have been present at the onset of the radiation 2 , 3 . Previous work showing cytonuclear discordance in phylogenetic reconstructions between LVRS and several riverine cichlid species raised the possibility of ancient hybridization between divergent species at the base of the radiation but could not demonstrate it 37 . Hybridization on secondary contact is not unlikely, as allopatric cichlid species, divergent by even millions of years, readily produce fertile offspring in the lab 38 . Using genomic data from riverine haplochromine cichlids sampled from all major African drainage systems, and representative species from all lineages within the Lake Victoria region, we demonstrate here that the LVRS evolved from a hybrid swarm. All lake radiations show very similar proportions of mixed ancestry derived from two distantly related haplochromine lineages that had evolved in isolation from one another", "role": "user" }, { "content": "A University of Wyoming researcher is part of an international team that has discovered how more than 700 species of fish have evolved in East Africa's Lake Victoria region over the past 150,000 years. Catherine Wagner, a UW assistant professor in the Department of Botany and the UW Biodiversity Institute, describes the phenomenon—unparalleled in the animal and plant world—as \"one of the most spectacular examples of the evolution of modern biodiversity.\" She and fellow researchers from Switzerland's University of Bern and the Swiss Federal Institute of Aquatic Science and Technology have demonstrated for the first time that the rapid evolution of Lake Victoria cichlids—brightly colored, perch-like fish—was facilitated by earlier hybridization between two distantly related cichlid species from the Upper Nile and Congo drainage systems. The research is published today (Friday) in the journal Nature Communications. The first author on the paper, Joana Meier, is a Ph.D. student Wagner co-supervised at the University of Bern. Wagner, along with Meier's other supervisors—Laurent Excoffier and Ole Seehausen—are senior authors of the paper. Wagner says the rapid evolution of the East African cichlids had puzzled researchers, who didn't understand how a single common ancestor could divide into 700 species so quickly. The discovery that the ancestor of these fish species was actually a mixture of two different ancestors from different parts of Africa makes it \"much easier to understand how the immense variety of fishes in this region have evolved,\" she says. \"An analogy is: If you combined the pieces from two very different Lego sets—say, a tractor and an airplane—you could get a much wider variety of possible structures,\" Wagner says. This modified diagram from Nature Communications shows the region of Africa and the different types of fish that have evolved from hybridization that took place about 150,000 years ago. Credit: Swiss Institute of Aquatic Science and Technology The species that evolved exhibit many combinations of colors and are adapted to different habitats, such as sandy bottoms, rocky shores or open waters—ranging from the clear shallows to the permanent darkness of the turbid depths, according to a media release from the Swiss Federal Institute of Aquatic Science and Technology. Depending on the species, cichlids may scrape algae from rocks, feed on plankton, crack open snail shells, forage for insect larvae or prey on other fish, including their eggs or scales. The hybridization event probably took place around 150,000 years ago, when—during a wet period—a Congolese lineage colonized the Lake Victoria region and encountered representatives of the Upper Nile lineage. Across the large lakes of this region, the hybrid population then diversified in a process known as adaptive radiation, or evolution of multiple new species adapted to different ecological niches. While the precise course of events in ancestral Lake Victoria has yet to be reconstructed, it is clear that, after a dry period, it filled up again about 15,000 years ago. Descendants of the genetically diverse hybrid population colonized the lake and, within the evolutionarily short period of several thousand years, diverged to form at least 500 new cichlid species, with a wide variety of ecological specializations. The particular genetic diversity and adaptive capacity of Lake Victoria's cichlids is demonstrated by the fact that more than 40 other fish species—which colonized the lake at the same time—have barely changed since then. The study involved sequencing over 3 million sites in the genome of 100 cichlid species—a task which, until recently, would not have been feasible. Wagner's study of evolutionary adaptive radiation earned her the 2015 Theodosius Dobzhansky Prize as an outstanding young evolutionary biologist from the Society for the Study of Evolution. Wagner has published a range of papers in top-tier journals, including Nature, Nature Reviews Genetics, Evolution and Molecular Ecology. At UW, she and her lab focus on using genetic and ecological data to study the evolution of biodiversity, primarily in freshwater fish. Her research uses population genetic, genomic, phylogenetic and comparative methods to study diversification, from speciation processes to macro-evolutionary patterns of biodiversity. Wagner received her Ph.D. from Cornell University in 2011, and she was a postdoctoral research associate at the Swiss Federal Institute of Aquatic Science and Technology before starting as an assistant professor at UW in 2015. She received her bachelor's degree in biology and geology from Whitman College. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Understanding why some evolutionary lineages generate exceptionally high species diversity is an important goal in evolutionary biology. Haplochromine cichlid fishes of Africa’s Lake Victoria region encompass >700 diverse species that all evolved in the last 150,000 years. How this ‘Lake Victoria Region Superflock’ could evolve on such rapid timescales is an enduring question. Here, we demonstrate that hybridization between two divergent lineages facilitated this process by providing genetic variation that subsequently became recombined and sorted into many new species. Notably, the hybridization event generated exceptional allelic variation at an opsin gene known to be involved in adaptation and speciation. More generally, differentiation between new species is accentuated around variants that were fixed differences between the parental lineages, and that now appear in many new combinations in the radiation species. We conclude that hybridization between divergent lineages, when coincident with ecological opportunity, may facilitate rapid and extensive adaptive radiation. Introduction Heterogeneity in diversification rates among lineages is a major factor shaping biodiversity. Yet, biological and environmental factors underlying this variation are incompletely understood 1 . Adaptive radiations are prime study systems to learn about these factors as they are characterized by a rapid origin of many species showing a diversity of ecological adaptations. This process requires high levels of heritable variation in traits related to ecological and reproductive isolation. However, adaptive radiations are often too rapid for the emergence of new relevant mutations between successive speciation events 2 and are thus more likely to stem from standing variation. Hybridization between species can instantaneously boost genetic variation, which may facilitate speciation and adaptive radiation 3 , 4 , 5 , 6 , 7 , 8 , 9 . Hybridization among members of an adaptive radiation, has been suggested to potentially facilitate speciation events, an idea known as the ‘syngameon hypothesis’ 3 . Introgression of traits involved in adaptation or reproductive isolation has been demonstrated among members of several adaptive radiations (for example, traits related to host shift in Rhagoletis fruit flies 10 , wing patterns in Heliconius butterflies 11 , 12 or beak shape in Darwin’s finches 13 ). In other radiations, the hybrid ancestry of some species has been inferred, but a direct link between introgressed traits and speciation awaits further testing (for example, cichlid fishes of Lakes Tanganyika 14 , 15 , 16 , Malawi 17 , Victoria 18 , 19 and Barombi Mbo 20 ). Another hypothesis for a perhaps more fundamental role of hybridization in adaptive radiation, distinct from the ‘syngameon hypothesis’, is the idea that hybridization between distinct lineages may seed the onset of an entire adaptive radiation 3 . Such hybridization can be common when allopatric lineages come into secondary contact 4 , and selection against hybrids may be weak during colonization of new environments. In this situation, the formation of a hybrid swarm, if coincident with ecological opportunity, may accelerate adaptive radiation by (i) providing functional genetic variation that can recombine into novel trait combinations favoured by selection and mate choice, and (ii) breaking genetic correlations that constrained the evolvability of parental lineages 3 . In addition, hybridization may facilitate speciation when multiple fixed differences that confer reproductive isolation between the two parental species decouple and segregate in a hybrid swarm, such that selection against incompatible gene combinations can generate more than two new reproductively isolated species 21 , 22 , 23 . This ‘hybrid swarm origin of adaptive radiation’ hypothesis has been more challenging to test. So far the only adaptive radiation for which a hybrid origin has been robustly demonstrated is the Hawaiian silverswords, which have radiated from an allopolyploid hybrid population between two North American tarweed species 24 . Because gene and genome duplication are also proposed to facilitate adaptive radiation 25 , it is difficult to distinguish between effects of hybridization per se and those of gene or genome duplication in this case. Evidence consistent with a hybrid swarm origin of entire radiations has also been found in Alpine whitefish 26 , the ‘mbuna’ group of the Lake Malawi cichlid fish radiation 27 , and allopolyploid Hawaiian endemic mints 28 , 29 and possibly other polyploid plant radiations on Hawaii 30 . However, it remains to be tested if, in these systems, hybridization occurred before or after the radiation had started, and if hybridization-derived polymorphisms played a role in speciation and adaptive diversification. The Lake Victoria Region Superflock of cichlid fish (LVRS) is a group of 700 haplochromine cichlid species endemic to the region around Lake Victoria and nearby western rift lakes in East Africa that started diversifying about 100–200 thousand years ago 31 , 32 , 33 , 34 . It includes several adaptive radiations, one in each of the major lakes of the region (Lakes Victoria, Edward, Albert and Kivu). The largest of them is in Lake Victoria, which has at least 500 endemic species that evolved in the past 15,000 years 34 , 35 , 36 . Each radiation comprises enormous diversity in habitat occupation, trophic ecology, colouration and behaviour. The high diversification rate but also the high nuclear genomic variation in the LVRS despite its young age 34 , 37 suggest that large amounts of standing genetic variation must have been present at the onset of the radiation 2 , 3 . Previous work showing cytonuclear discordance in phylogenetic reconstructions between LVRS and several riverine cichlid species raised the possibility of ancient hybridization between divergent species at the base of the radiation but could not demonstrate it 37 . Hybridization on secondary contact is not unlikely, as allopatric cichlid species, divergent by even millions of years, readily produce fertile offspring in the lab 38 . Using genomic data from riverine haplochromine cichlids sampled from all major African drainage systems, and representative species from all lineages within the Lake Victoria region, we demonstrate here that the LVRS evolved from a hybrid swarm. All lake radiations show very similar proportions of mixed ancestry derived from two distantly related haplochromine lineages that had evolved in isolation from one another<|im_end|> <|im_start|>assistant A University of Wyoming researcher is part of an international team that has discovered how more than 700 species of fish have evolved in East Africa's Lake Victoria region over the past 150,000 years. Catherine Wagner, a UW assistant professor in the Department of Botany and the UW Biodiversity Institute, describes the phenomenon—unparalleled in the animal and plant world—as "one of the most spectacular examples of the evolution of modern biodiversity." She and fellow researchers from Switzerland's University of Bern and the Swiss Federal Institute of Aquatic Science and Technology have demonstrated for the first time that the rapid evolution of Lake Victoria cichlids—brightly colored, perch-like fish—was facilitated by earlier hybridization between two distantly related cichlid species from the Upper Nile and Congo drainage systems. The research is published today (Friday) in the journal Nature Communications. The first author on the paper, Joana Meier, is a Ph.D. student Wagner co-supervised at the University of Bern. Wagner, along with Meier's other supervisors—Laurent Excoffier and Ole Seehausen—are senior authors of the paper. Wagner says the rapid evolution of the East African cichlids had puzzled researchers, who didn't understand how a single common ancestor could divide into 700 species so quickly. The discovery that the ancestor of these fish species was actually a mixture of two different ancestors from different parts of Africa makes it "much easier to understand how the immense variety of fishes in this region have evolved," she says. "An analogy is: If you combined the pieces from two very different Lego sets—say, a tractor and an airplane—you could get a much wider variety of possible structures," Wagner says. This modified diagram from Nature Communications shows the region of Africa and the different types of fish that have evolved from hybridization that took place about 150,000 years ago. Credit: Swiss Institute of Aquatic Science and Technology The species that evolved exhibit many combinations of colors and are adapted to different habitats, such as sandy bottoms, rocky shores or open waters—ranging from the clear shallows to the permanent darkness of the turbid depths, according to a media release from the Swiss Federal Institute of Aquatic Science and Technology. Depending on the species, cichlids may scrape algae from rocks, feed on plankton, crack open snail shells, forage for insect larvae or prey on other fish, including their eggs or scales. The hybridization event probably took place around 150,000 years ago, when—during a wet period—a Congolese lineage colonized the Lake Victoria region and encountered representatives of the Upper Nile lineage. Across the large lakes of this region, the hybrid population then diversified in a process known as adaptive radiation, or evolution of multiple new species adapted to different ecological niches. While the precise course of events in ancestral Lake Victoria has yet to be reconstructed, it is clear that, after a dry period, it filled up again about 15,000 years ago. Descendants of the genetically diverse hybrid population colonized the lake and, within the evolutionarily short period of several thousand years, diverged to form at least 500 new cichlid species, with a wide variety of ecological specializations. The particular genetic diversity and adaptive capacity of Lake Victoria's cichlids is demonstrated by the fact that more than 40 other fish species—which colonized the lake at the same time—have barely changed since then. The study involved sequencing over 3 million sites in the genome of 100 cichlid species—a task which, until recently, would not have been feasible. Wagner's study of evolutionary adaptive radiation earned her the 2015 Theodosius Dobzhansky Prize as an outstanding young evolutionary biologist from the Society for the Study of Evolution. Wagner has published a range of papers in top-tier journals, including Nature, Nature Reviews Genetics, Evolution and Molecular Ecology. At UW, she and her lab focus on using genetic and ecological data to study the evolution of biodiversity, primarily in freshwater fish. Her research uses population genetic, genomic, phylogenetic and comparative methods to study diversification, from speciation processes to macro-evolutionary patterns of biodiversity. Wagner received her Ph.D. from Cornell University in 2011, and she was a postdoctoral research associate at the Swiss Federal Institute of Aquatic Science and Technology before starting as an assistant professor at UW in 2015. She received her bachelor's degree in biology and geology from Whitman College. <|im_end|>

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2,257

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The evolution rate and genetic changes that occur during chronic infection with Helicobacter pylori have been analysed, but little is known about the genomic changes during the initial, acute bacterial infection phase. Here we analyse the rate and pattern of genome evolution in H. pylori from the genomes of two input strains isolated from human volunteers with asymptomatic infection, and the genomes of two output strains collected 20 and 44 days after re-infection. Similarly, we analyse genome evolution in bacteria from the genome sequences of input and output strains sequentially taken after experimental infection of a rhesus macaque. The estimated mutation rate reveals a mutation burst during the acute infection phase that is over 10 times faster than the mutation rate during chronic infection, and orders of magnitude faster than mutation rates in any other bacteria. The elevated frequency of mutations in outer membrane protein genes suggests that the mutation burst facilitates rapid host adaptation of the bacteria. Introduction The stomach bacterium Helicobacter pylori has infected anatomically modern humans since their origins 1 , 2 , which implies perfect adaptation of the bacterial parasite to its human host. This remarkable adaptive capacity can be partly attributed to the enormous plasticity of the Helicobacter genome 3 caused by high mutation and recombination rates 4 , 5 , 6 , and by the ability for aberrant genomic rearrangements and incorporation of non-homologous DNA. This results in an exceptionally high sequence diversity among strains that were isolated from unrelated human hosts 1 , 2 , 7 , 8 , and in an H. pylori core genome that consists of only ~1,100 genes while the other ~400–500 genes per strain are strain-specific and variably present 9 . The initial infection with H. pylori induces an acute polymorphonuclear (PMN) reaction, most likely owing to the activation of the innate immune system. The acute inflammatory response involves the release of reactive oxygen and nitrogen species that were shown to trigger mutations and intra-chromosomal recombination in vitro 10 . After 2–4 weeks, the acute inflammation subsides and develops into a less severe chronic active gastritis, characterized by infiltration with PMNs, Th1-biased CD4+ T cells, plasma cells and even dendritic cells, which generally persists throughout the host’s life. Numerous genomic changes have been identified in studies where sequential H. pylori isolates have been recovered several years apart from patients with chronic infection. Whole-genome microarray analyses identified gene acquisitions and gene losses 11 . In addition, sequencing of gene fragments 4 , 12 , 13 and whole-draft genomes 5 , 6 revealed point mutations, imported DNA fragments and extensive recombination with co-colonizing strains, whereby genes encoding outer membrane proteins (OMPs) were at significantly increased frequency among the imported DNA fragments, suggesting diversifying selection 5 . During chronic infection, sequence differences accumulated in a clock-like manner 4 at a median mutation rate of 1.55 × 10 −5 changes per site per year and a recombination rate of 5.5 × 10 −5 per initiation site per year 5 , 6 . However, little is known about the mutation rate and genomic changes induced by the inflammatory response during the initial, acute bacterial infection. We hypothesized that the selection pressure during the acute inflammation would likely be higher than during chronic infection and result in a faster substitution rate. Here we test this hypothesis using experimental infection of human volunteers and a rhesus macaque. We determine the sequence differences that accumulate in the genomes of H. pylori output strains taken at several time points post infection, covering both the acute and chronic infection phases. Our genome comparisons reveal a mutation burst during the acute phase of H. pylori infection that is over 10 times faster than the mutation rate during chronic infection and orders of magnitude faster than mutation rates in any other bacteria. We show that genetic changes in OMP genes accumulate at elevated frequencies, suggesting that the mutation burst facilitates rapid adaptation of H. pylori to the individual human host. Results Re-infection of human volunteers Two human volunteers with asymptomatic H. pylori infections underwent gastroendoscopy and were then cured by antibiotic therapy. Eradication was confirmed 1 and 2 months later by two consecutive, clearly negative carbon-14 urea breath tests (UBTs). Three months later, the volunteers were re-infected with their own original strains BM012A and BM013A. H. pylori was grown from antral biopsy material that was collected during the initial endoscopic examinations as well as 20 days (strain BM013B) and 44 days (BM012B) after the re-infections. Visual inspection during the endoscopy as well as the histological analysis of the biopsies revealed moderate inflammation of the stomach epithelium ( Supplementary Fig. 1 ). Ultimately, H. pylori was eradicated with antibiotic treatment. We sequenced the genomes of the two re-infection input strains BM012A and BM013A, and of the two output strains BM012B and BM013B using a Roche 454-Titanium FLX sequencer to >60 × coverage, assembled the reads and closed the genomes by PCR and Sanger sequencing. The original strain BM012A that was used for the re-infection experiment possessed a genome with a length of 1,660,425 bp ( Fig. 1 ) that contained the cag pathogenicity island ( cag PAI), nine copies of the insertion element IS607 and an apparently non-functional vacA gene that was disrupted by a frameshift. Strain BM013A had a genome of 1,604,233 bp length that did not possess the cag PAI, and contained an apparently non-cytotoxic vacA allele (s2m2) and four IS607 copies. An additional IS607 copy was located on a 16.7-kb plasmid. Figure 1: Accumulation of SNPs and CNPs in the H. pylori genomes after re-infection of human hosts. (Circle contents from outside to inside). Circle 1: Genomes of H. pylori strains BM012A ( a ) and BM013A ( b ) with the positions of IS607 (red), the cag PAI, the vacA gene and ticks every 100 kb. Circle 2: Distribution of non-coding (black), non-synonymous (red) and synonymous (blue) SNPs in the genomes of the output strains BM012B (168 SNPs) and BM013B (54 SNPs). Circle 3: Distribution of", "role": "user" }, { "content": "(Medical Xpress)—Bacteria that cause ulcers in humans undergo accelerated evolution during the initial stages of infection, allowing them to evade the immune system, according to new research by an international team of researchers including Penn State scientists. The study shows, for the first time, and in real-time, the interplay between the human immune system and invading bacteria that allows the bacteria to counter the immune response by quickly evolving. A paper describing the research was published in the June 13, 2014 issue of the journal Nature Communications. \"Our next-generation sequencing approach enabled, for the first time, the tracing of Helicobacter pylori infections in human patients,\" said Stephan Schuster, professor of biochemistry and molecular biology at Penn State. The scientists compared the genome sequence of the stomach bacterium Helicobacter pylori just prior to infection and at several time points after infection. \"We were blown away by the very high mutation rate that we found during the initial phase of infection,\" said Bodo Linz, research associate at Penn State and lead author of the paper. Patients infected with H. pylori, experience an initial, acute phase of infection during which symptoms are most severe and the immune response is strongest. \"We found that the bacteria accumulated mutations at a rate 30 to 50 times faster during this acute phase than during the later, chronic phase of infection when an equilibrium was reached between the bacteria and the immune response,\" Linz said. Although the rate at which mutations accumulate in the genome of H. pylori during the chronic phase of infection had been determined previously, no one yet had looked at the initial, acute phase because it is so difficult to capture and sequence the bacteria at the time of initial infection. To determine the mutation rate during this early phase, the research team took two approaches. First, the researchers isolated the bacteria from two previously-infected human volunteers and determined its genome sequence. After eradicating the bacteria from the volunteers through treatment with antibiotics, they then re-infected the now-cured patients with their own strain of H. pylori. At 20 days after infection in one case and at 44 days after infection in the other, the scientists again isolated the bacteria from the volunteers and sequenced its genome. The patients then received another antibiotic treatment to eliminate the bacteria. \"By comparing the genome sequence of the bacteria before and after re-infection, we were able to determine the rate at which the bacterial genome changes during this early, acute phase of infection in a human host,\" said Linz. In a parallel experiment, the team infected a rhesus monkey with H. pylori and collected samples of the bacteria from the monkey for genome sequencing at one week, one month, two months, and six months after initial infection. In the monkey, the scientists were able to directly compare the rate of DNA changes in the bacterial genome between the acute and chronic stages. Although mutations continued to accumulate in the bacterial genome during the chronic phase, the rate of substitutions dropped considerably after the initial four-week period. An infection with H. pylori triggers an immune response that involves the release of reactive oxygen and nitrogen molecules that are known to induce mutations in the DNA sequence and to cause chromosomes to break apart and recombine. Previous studies had shown that the H. pylori genome is forgiving of this kind of abuse. \"Strains of the bacterium isolated from different human hosts vary immensely, both in DNA sequence and in gene content\" Schuster said. \"There are about 1,100 core genes that individual strains of H. pylori share, but another four-to-five-hundred genes vary between strains. The high mutation and recombination rates that produce this variation allow the bacteria to be exquisitely adapted to its host and to evade eradication by the host's immune system.\" Of particular importance in the battle between the immune system and invading bacteria are the proteins that protrude through the outer cell membrane of the bacteria. Because these outer-membrane proteins are on the outside of the bacterial cell, they are visible to the human immune system and therefore are targeted by antibodies. \"Antibodies are so tuned to recognize the three-dimensional structure of outer-membrane proteins that they can attach to them with lock-and-key specificity, thereby labeling the foreign bacteria cell for elimination,\" said Linz. Mutations in the genes that code for outer-membrane proteins can produce changes in the protein's structure and, if the key then no longer fits the lock, the genetic mutations allow the bacterium to evade recognition by antibodies. \"The intense selective pressure on the bacteria to survive the immune response, coupled with increased mutation rates, produces the incredibly fast rate of genomic change that we discovered in this study,\" Linz said. \"Mutations occur randomly throughout the genome, but because they help the bacteria avoid elimination by the immune system, changes in outer-membrane proteins appear much more often than would be expected by chance in the surviving bacteria.\" This initial burst of mutations during the acute phase of infection allows the bacteria to survive the host's immune response and to establish a chronic infection. Whether bacteria other than H. pylori undergo a similar burst of accelerated evolution immediately after infection is not yet known, but the team plans to investigate other common human pathogens in future research. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The evolution rate and genetic changes that occur during chronic infection with Helicobacter pylori have been analysed, but little is known about the genomic changes during the initial, acute bacterial infection phase. Here we analyse the rate and pattern of genome evolution in H. pylori from the genomes of two input strains isolated from human volunteers with asymptomatic infection, and the genomes of two output strains collected 20 and 44 days after re-infection. Similarly, we analyse genome evolution in bacteria from the genome sequences of input and output strains sequentially taken after experimental infection of a rhesus macaque. The estimated mutation rate reveals a mutation burst during the acute infection phase that is over 10 times faster than the mutation rate during chronic infection, and orders of magnitude faster than mutation rates in any other bacteria. The elevated frequency of mutations in outer membrane protein genes suggests that the mutation burst facilitates rapid host adaptation of the bacteria. Introduction The stomach bacterium Helicobacter pylori has infected anatomically modern humans since their origins 1 , 2 , which implies perfect adaptation of the bacterial parasite to its human host. This remarkable adaptive capacity can be partly attributed to the enormous plasticity of the Helicobacter genome 3 caused by high mutation and recombination rates 4 , 5 , 6 , and by the ability for aberrant genomic rearrangements and incorporation of non-homologous DNA. This results in an exceptionally high sequence diversity among strains that were isolated from unrelated human hosts 1 , 2 , 7 , 8 , and in an H. pylori core genome that consists of only ~1,100 genes while the other ~400–500 genes per strain are strain-specific and variably present 9 . The initial infection with H. pylori induces an acute polymorphonuclear (PMN) reaction, most likely owing to the activation of the innate immune system. The acute inflammatory response involves the release of reactive oxygen and nitrogen species that were shown to trigger mutations and intra-chromosomal recombination in vitro 10 . After 2–4 weeks, the acute inflammation subsides and develops into a less severe chronic active gastritis, characterized by infiltration with PMNs, Th1-biased CD4+ T cells, plasma cells and even dendritic cells, which generally persists throughout the host’s life. Numerous genomic changes have been identified in studies where sequential H. pylori isolates have been recovered several years apart from patients with chronic infection. Whole-genome microarray analyses identified gene acquisitions and gene losses 11 . In addition, sequencing of gene fragments 4 , 12 , 13 and whole-draft genomes 5 , 6 revealed point mutations, imported DNA fragments and extensive recombination with co-colonizing strains, whereby genes encoding outer membrane proteins (OMPs) were at significantly increased frequency among the imported DNA fragments, suggesting diversifying selection 5 . During chronic infection, sequence differences accumulated in a clock-like manner 4 at a median mutation rate of 1.55 × 10 −5 changes per site per year and a recombination rate of 5.5 × 10 −5 per initiation site per year 5 , 6 . However, little is known about the mutation rate and genomic changes induced by the inflammatory response during the initial, acute bacterial infection. We hypothesized that the selection pressure during the acute inflammation would likely be higher than during chronic infection and result in a faster substitution rate. Here we test this hypothesis using experimental infection of human volunteers and a rhesus macaque. We determine the sequence differences that accumulate in the genomes of H. pylori output strains taken at several time points post infection, covering both the acute and chronic infection phases. Our genome comparisons reveal a mutation burst during the acute phase of H. pylori infection that is over 10 times faster than the mutation rate during chronic infection and orders of magnitude faster than mutation rates in any other bacteria. We show that genetic changes in OMP genes accumulate at elevated frequencies, suggesting that the mutation burst facilitates rapid adaptation of H. pylori to the individual human host. Results Re-infection of human volunteers Two human volunteers with asymptomatic H. pylori infections underwent gastroendoscopy and were then cured by antibiotic therapy. Eradication was confirmed 1 and 2 months later by two consecutive, clearly negative carbon-14 urea breath tests (UBTs). Three months later, the volunteers were re-infected with their own original strains BM012A and BM013A. H. pylori was grown from antral biopsy material that was collected during the initial endoscopic examinations as well as 20 days (strain BM013B) and 44 days (BM012B) after the re-infections. Visual inspection during the endoscopy as well as the histological analysis of the biopsies revealed moderate inflammation of the stomach epithelium ( Supplementary Fig. 1 ). Ultimately, H. pylori was eradicated with antibiotic treatment. We sequenced the genomes of the two re-infection input strains BM012A and BM013A, and of the two output strains BM012B and BM013B using a Roche 454-Titanium FLX sequencer to >60 × coverage, assembled the reads and closed the genomes by PCR and Sanger sequencing. The original strain BM012A that was used for the re-infection experiment possessed a genome with a length of 1,660,425 bp ( Fig. 1 ) that contained the cag pathogenicity island ( cag PAI), nine copies of the insertion element IS607 and an apparently non-functional vacA gene that was disrupted by a frameshift. Strain BM013A had a genome of 1,604,233 bp length that did not possess the cag PAI, and contained an apparently non-cytotoxic vacA allele (s2m2) and four IS607 copies. An additional IS607 copy was located on a 16.7-kb plasmid. Figure 1: Accumulation of SNPs and CNPs in the H. pylori genomes after re-infection of human hosts. (Circle contents from outside to inside). Circle 1: Genomes of H. pylori strains BM012A ( a ) and BM013A ( b ) with the positions of IS607 (red), the cag PAI, the vacA gene and ticks every 100 kb. Circle 2: Distribution of non-coding (black), non-synonymous (red) and synonymous (blue) SNPs in the genomes of the output strains BM012B (168 SNPs) and BM013B (54 SNPs). Circle 3: Distribution of<|im_end|> <|im_start|>assistant (Medical Xpress)—Bacteria that cause ulcers in humans undergo accelerated evolution during the initial stages of infection, allowing them to evade the immune system, according to new research by an international team of researchers including Penn State scientists. The study shows, for the first time, and in real-time, the interplay between the human immune system and invading bacteria that allows the bacteria to counter the immune response by quickly evolving. A paper describing the research was published in the June 13, 2014 issue of the journal Nature Communications. "Our next-generation sequencing approach enabled, for the first time, the tracing of Helicobacter pylori infections in human patients," said Stephan Schuster, professor of biochemistry and molecular biology at Penn State. The scientists compared the genome sequence of the stomach bacterium Helicobacter pylori just prior to infection and at several time points after infection. "We were blown away by the very high mutation rate that we found during the initial phase of infection," said Bodo Linz, research associate at Penn State and lead author of the paper. Patients infected with H. pylori, experience an initial, acute phase of infection during which symptoms are most severe and the immune response is strongest. "We found that the bacteria accumulated mutations at a rate 30 to 50 times faster during this acute phase than during the later, chronic phase of infection when an equilibrium was reached between the bacteria and the immune response," Linz said. Although the rate at which mutations accumulate in the genome of H. pylori during the chronic phase of infection had been determined previously, no one yet had looked at the initial, acute phase because it is so difficult to capture and sequence the bacteria at the time of initial infection. To determine the mutation rate during this early phase, the research team took two approaches. First, the researchers isolated the bacteria from two previously-infected human volunteers and determined its genome sequence. After eradicating the bacteria from the volunteers through treatment with antibiotics, they then re-infected the now-cured patients with their own strain of H. pylori. At 20 days after infection in one case and at 44 days after infection in the other, the scientists again isolated the bacteria from the volunteers and sequenced its genome. The patients then received another antibiotic treatment to eliminate the bacteria. "By comparing the genome sequence of the bacteria before and after re-infection, we were able to determine the rate at which the bacterial genome changes during this early, acute phase of infection in a human host," said Linz. In a parallel experiment, the team infected a rhesus monkey with H. pylori and collected samples of the bacteria from the monkey for genome sequencing at one week, one month, two months, and six months after initial infection. In the monkey, the scientists were able to directly compare the rate of DNA changes in the bacterial genome between the acute and chronic stages. Although mutations continued to accumulate in the bacterial genome during the chronic phase, the rate of substitutions dropped considerably after the initial four-week period. An infection with H. pylori triggers an immune response that involves the release of reactive oxygen and nitrogen molecules that are known to induce mutations in the DNA sequence and to cause chromosomes to break apart and recombine. Previous studies had shown that the H. pylori genome is forgiving of this kind of abuse. "Strains of the bacterium isolated from different human hosts vary immensely, both in DNA sequence and in gene content" Schuster said. "There are about 1,100 core genes that individual strains of H. pylori share, but another four-to-five-hundred genes vary between strains. The high mutation and recombination rates that produce this variation allow the bacteria to be exquisitely adapted to its host and to evade eradication by the host's immune system." Of particular importance in the battle between the immune system and invading bacteria are the proteins that protrude through the outer cell membrane of the bacteria. Because these outer-membrane proteins are on the outside of the bacterial cell, they are visible to the human immune system and therefore are targeted by antibodies. "Antibodies are so tuned to recognize the three-dimensional structure of outer-membrane proteins that they can attach to them with lock-and-key specificity, thereby labeling the foreign bacteria cell for elimination," said Linz. Mutations in the genes that code for outer-membrane proteins can produce changes in the protein's structure and, if the key then no longer fits the lock, the genetic mutations allow the bacterium to evade recognition by antibodies. "The intense selective pressure on the bacteria to survive the immune response, coupled with increased mutation rates, produces the incredibly fast rate of genomic change that we discovered in this study," Linz said. "Mutations occur randomly throughout the genome, but because they help the bacteria avoid elimination by the immune system, changes in outer-membrane proteins appear much more often than would be expected by chance in the surviving bacteria." This initial burst of mutations during the acute phase of infection allows the bacteria to survive the host's immune response and to establish a chronic infection. Whether bacteria other than H. pylori undergo a similar burst of accelerated evolution immediately after infection is not yet known, but the team plans to investigate other common human pathogens in future research. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The integrity of genomes is constantly threatened by problems encountered by the replication fork. BRCA1, BRCA2 and a subset of Fanconi anaemia proteins protect stalled replication forks from degradation by nucleases, through pathways that involve RAD51. The contribution and regulation of BRCA1 in replication fork protection, and how this role relates to its role in homologous recombination, is unclear. Here we show that BRCA1 in complex with BARD1, and not the canonical BRCA1–PALB2 interaction, is required for fork protection. BRCA1–BARD1 is regulated by a conformational change mediated by the phosphorylation-directed prolyl isomerase PIN1. PIN1 activity enhances BRCA1–BARD1 interaction with RAD51, thereby increasing the presence of RAD51 at stalled replication structures. We identify genetic variants of BRCA1–BARD1 in patients with cancer that exhibit poor protection of nascent strands but retain homologous recombination proficiency, thus defining domains of BRCA1–BARD1 that are required for fork protection and associated with cancer development. Together, these findings reveal a BRCA1-mediated pathway that governs replication fork protection. Main The progression of DNA replication forks can be slowed by factors such as conflicts between replication and transcription, a shortage of deoxyribonucleotides or the presence of sequences that are difficult to replicate. These factors frequently cause forks to stall 1 . To prevent stalled forks collapsing into DNA double-strand breaks, a number of responses are elicited, which include the remodelling of forks and subsequent protection of nascent strands. Agents that cause replicative stress or that compromise the function of DNA polymerase α result in the reversing of a proportion of forks (reviewed in previous studies 2 , 3 ). The regressed arm of nascent DNA in reversed forks resembles a single-ended DNA double-strand break, and breaks of this type are protected from excessive resection by RAD51. Several proteins contribute to RAD51-mediated fork protection, including BRCA1 and BRCA2, FANCA and FANCD2, RAD51 paralogues (such as RAD51C), BOD1L, SETD1A, WRNIP and ABRO1 2 . One emerging theme is that stabilization of RAD51 within the nucleoprotein filament is critical for the protection of stalled forks 4 , 5 , 6 . RAD51 mutants that show increased dissociation from DNA are compromised in their ability to prevent fork degradation 6 , 7 , 8 , whereas factors that stabilize the interaction between RAD51 and single-stranded DNA (such as BOD1L) promote fork protection 9 . Other factors (for example, RADX) compete with or dissociate RAD51, and depletion of these factors rescues fork protection in cells that are deficient in BRCA1 or BRCA2 10 , 11 . Failure to protect stalled forks is associated with genomic instability. Furthermore, restoration of replication fork protection in BRCA1- or BRCA2-deficient cells is linked to resistance to chemotherapy in some cell types and contexts 12 , 13 , 14 . Thus, a better mechanistic understanding of the role of BRCA1 in fork protection is needed to inform the care and treatment of patients with cancer. BRCA1 is found at ongoing and stalled replication forks 15 , 16 and, similar to BRCA2, contributes to RAD51-mediated protection of stalled forks from MRE11-dependent degradation 17 . However, how BRCA1 contributes to fork protection is unclear. Here we show that BRCA1 promotes the protection of nascent DNA at stalled replication forks independently of the canonical BRCA1–PALB2 interaction. We find that an enhanced, direct interaction between the BRCA1–BARD1 complex and RAD51 is associated with protection of the nascent strand, and that interaction and fork protection depend on the activity of the phosphorylation-directed prolyl isomerase, PIN1. We identify regions of the BRCA1 and BARD1 proteins that are required for fork protection, and show that genetic variants of BRCA1 and BARD1 that are associated with familial and sporadic cancer inhibit fork protection. Phosphorylation of BRCA1 S114 promotes fork protection During the repair of DNA double-strand breaks by homologous recombination, BRCA1–BARD1 regulates the localization and loading of RAD51 at break sites through PALB2–BRCA2 18 , 19 , 20 , but it is unclear whether BRCA1 acts through this pathway in replication fork protection. We examined nascent DNA sequentially labelled with the thymidine analogues 5-chloro-2′-deoxyuridine (CldU) and 5-iodo-2′-deoxyuridine (IdU) at forks stalled by hydroxyurea (5 mM, 3 h) 5 , 17 in human cells in which the expression of BRCA1 or PALB2 was knocked down by transfection with short interfering RNA (siRNA). Both BRCA1- and PALB2-depleted cells showed a decreased IdU:CldU ratio, which is consistent with defective fork protection (Extended Data Fig. 1a–c ). Variants of BRCA1 and PALB2 that have mutations in the coiled-coil domains (BRCA1(M1411T) or PALB2 with an N-terminal deletion, PALB2(ΔNT)) are unable to directly interact with one another, fail to support the repair of DNA by homologous recombination and exhibit increased sensitivity to the inter-strand cross-linker cisplatin 19 , 20 (Extended Data Fig. 1d–i ). Although cells complemented with BRCA1(M1411T) or PALB2(ΔNT) showed increased fork stalling and defects in restarting of the replication fork after treatment with hydroxyurea, the mutants were still proficient in protection of stalled replication forks (Extended Data Fig. 1j–o ). These results demonstrate that fork protection is independent of the canonical BRCA1–PALB2 interaction. BRCA1 and BARD1 interact directly with RAD51 21 , 22 and mutation of the BARD1 residues Phe133, Asp135 and Ala136 (F133A/D135A/A136E; hereafter termed AAE) disrupts the BARD1–RAD51 interaction, causing reduced resistance to mitomycin C 21 , olaparib and hydroxyurea (Extended Data Fig. 2a, b ). Complementation of cells with BARD1(AAE) did not support protection of nascent strands, in contrast to cells that were complemented with wild-type BARD1 or with BARD1(R99E), a BARD1 mutant that is deficient in ubiquitin ligase activity 23 (Extended Data Fig. 2c–f ). Thus, protection of stalled replication forks requires the region of BARD1 that contains the RAD51-binding site, but does not require ligase activity of the BRCA1–BARD1 heterodimer. BRCA1 and BARD1 are phosphorylated at residues that are potentially located close to the site of interaction between BARD1 and RAD51: Ser148 of BARD1 24 and Ser114 of BRCA1 25 . Substitution of these sites to alanine residues (BRCA1(S114A) and BARD1(S148A)) caused a reduction of IdU:CldU ratios and CldU tract lengths after treatment with", "role": "user" }, { "content": "Research led by the University of Birmingham has found important new ways that the BRCA1 gene functions which could help develop our understanding of the development of ovarian and breast cancers. The research, published in Nature today, was led by experts at the University of Birmingham's Birmingham Centre for Genome Biology and Institute of Cancer and Genomic Sciences and is part of a five-year research project which is playing a pivotal role in identifying and understanding breast cancer genes. First author Manolo Daza-Martin, of the University of Birmingham, explained: \"No two people are born the same and, as a result, we all have slightly different chances of developing diseases during our lifetimes—this is the result of natural variation in our genes. \"On top of this natural variation, about one in a thousand people inherit from one of their parents a damaged, or 'mutated', copy of a gene called BRCA1. \"Previous research has shown us that in cells the BRCA1 gene makes a protein that helps repair damage to broken DNA. Therefore, people who inherit a faulty BRCA1 gene are less able to repair damage that inevitably accumulates in their DNA over time—putting them at higher risk of ovarian and breast cancer. Hollywood actress Angelina Jolie had a double mastectomy and announced she was to have her ovaries removed in 2013 after being tested positive for the BRCA1 genetic mutation. Her mother died at the young age of 56 due to cancer. DNA damage can also occur when cells have difficulties copying their DNA leaving it vulnerable to breakage. BRCA1 helps protect DNA when the copying machinery gets stuck, but it was not known how. Now University of Birmingham researchers, in collaboration with scientists at Imperial College London, have found that BRCA1 changes shape in order to protect vulnerable DNA until the copying machinery can be restarted. In addition, the researchers found that in some patients with a personal or family history of breast and ovarian cancer, the protective role of BRCA1 in DNA-copying is disabled—while its break repair function is still active. Joint corresponding author Dr. Ruth Densham, of the University of Birmingham's Institute of Cancer and Genomic Sciences, added: \"BRCA1 is like a DNA Damage Scene Coordinator, whose role is to coordinate emergency response units at a damage site in order to help repair. It was surprising to find out that BRCA1 changes shape depending on the type of damage it finds at the scene, and this shape change alters the way the cell responds.\" Lead and corresponding author Professor Jo Morris, also of the University of Birmingham's Institute of Cancer and Genomic Sciences, said: \"Our research could be important for understanding how cancers develop and means we could have identified a new way of supressing tumours. \"We are long way from it, but ultimately this may alter how cancer patients are treated. We will now continue this important research into the role of BRCA1's DNA copying function in cancer development.\" The average woman in the UK has a 12.5 per cent chance of developing breast cancer at some point in her life. About one in 20 (five per cent) of the 50,000 women diagnosed with breast cancer every year carries an inherited gene fault like BRCA1. A female BRCA1 carrier has between a 60 and 90 per cent chance of developing breast cancer, and around a 40 to 60 per cent chance of ovarian cancer. The precise figure for an individual woman will vary according to several things, such as her age, the number of affected family members, and the exact nature of the fault in the gene. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The integrity of genomes is constantly threatened by problems encountered by the replication fork. BRCA1, BRCA2 and a subset of Fanconi anaemia proteins protect stalled replication forks from degradation by nucleases, through pathways that involve RAD51. The contribution and regulation of BRCA1 in replication fork protection, and how this role relates to its role in homologous recombination, is unclear. Here we show that BRCA1 in complex with BARD1, and not the canonical BRCA1–PALB2 interaction, is required for fork protection. BRCA1–BARD1 is regulated by a conformational change mediated by the phosphorylation-directed prolyl isomerase PIN1. PIN1 activity enhances BRCA1–BARD1 interaction with RAD51, thereby increasing the presence of RAD51 at stalled replication structures. We identify genetic variants of BRCA1–BARD1 in patients with cancer that exhibit poor protection of nascent strands but retain homologous recombination proficiency, thus defining domains of BRCA1–BARD1 that are required for fork protection and associated with cancer development. Together, these findings reveal a BRCA1-mediated pathway that governs replication fork protection. Main The progression of DNA replication forks can be slowed by factors such as conflicts between replication and transcription, a shortage of deoxyribonucleotides or the presence of sequences that are difficult to replicate. These factors frequently cause forks to stall 1 . To prevent stalled forks collapsing into DNA double-strand breaks, a number of responses are elicited, which include the remodelling of forks and subsequent protection of nascent strands. Agents that cause replicative stress or that compromise the function of DNA polymerase α result in the reversing of a proportion of forks (reviewed in previous studies 2 , 3 ). The regressed arm of nascent DNA in reversed forks resembles a single-ended DNA double-strand break, and breaks of this type are protected from excessive resection by RAD51. Several proteins contribute to RAD51-mediated fork protection, including BRCA1 and BRCA2, FANCA and FANCD2, RAD51 paralogues (such as RAD51C), BOD1L, SETD1A, WRNIP and ABRO1 2 . One emerging theme is that stabilization of RAD51 within the nucleoprotein filament is critical for the protection of stalled forks 4 , 5 , 6 . RAD51 mutants that show increased dissociation from DNA are compromised in their ability to prevent fork degradation 6 , 7 , 8 , whereas factors that stabilize the interaction between RAD51 and single-stranded DNA (such as BOD1L) promote fork protection 9 . Other factors (for example, RADX) compete with or dissociate RAD51, and depletion of these factors rescues fork protection in cells that are deficient in BRCA1 or BRCA2 10 , 11 . Failure to protect stalled forks is associated with genomic instability. Furthermore, restoration of replication fork protection in BRCA1- or BRCA2-deficient cells is linked to resistance to chemotherapy in some cell types and contexts 12 , 13 , 14 . Thus, a better mechanistic understanding of the role of BRCA1 in fork protection is needed to inform the care and treatment of patients with cancer. BRCA1 is found at ongoing and stalled replication forks 15 , 16 and, similar to BRCA2, contributes to RAD51-mediated protection of stalled forks from MRE11-dependent degradation 17 . However, how BRCA1 contributes to fork protection is unclear. Here we show that BRCA1 promotes the protection of nascent DNA at stalled replication forks independently of the canonical BRCA1–PALB2 interaction. We find that an enhanced, direct interaction between the BRCA1–BARD1 complex and RAD51 is associated with protection of the nascent strand, and that interaction and fork protection depend on the activity of the phosphorylation-directed prolyl isomerase, PIN1. We identify regions of the BRCA1 and BARD1 proteins that are required for fork protection, and show that genetic variants of BRCA1 and BARD1 that are associated with familial and sporadic cancer inhibit fork protection. Phosphorylation of BRCA1 S114 promotes fork protection During the repair of DNA double-strand breaks by homologous recombination, BRCA1–BARD1 regulates the localization and loading of RAD51 at break sites through PALB2–BRCA2 18 , 19 , 20 , but it is unclear whether BRCA1 acts through this pathway in replication fork protection. We examined nascent DNA sequentially labelled with the thymidine analogues 5-chloro-2′-deoxyuridine (CldU) and 5-iodo-2′-deoxyuridine (IdU) at forks stalled by hydroxyurea (5 mM, 3 h) 5 , 17 in human cells in which the expression of BRCA1 or PALB2 was knocked down by transfection with short interfering RNA (siRNA). Both BRCA1- and PALB2-depleted cells showed a decreased IdU:CldU ratio, which is consistent with defective fork protection (Extended Data Fig. 1a–c ). Variants of BRCA1 and PALB2 that have mutations in the coiled-coil domains (BRCA1(M1411T) or PALB2 with an N-terminal deletion, PALB2(ΔNT)) are unable to directly interact with one another, fail to support the repair of DNA by homologous recombination and exhibit increased sensitivity to the inter-strand cross-linker cisplatin 19 , 20 (Extended Data Fig. 1d–i ). Although cells complemented with BRCA1(M1411T) or PALB2(ΔNT) showed increased fork stalling and defects in restarting of the replication fork after treatment with hydroxyurea, the mutants were still proficient in protection of stalled replication forks (Extended Data Fig. 1j–o ). These results demonstrate that fork protection is independent of the canonical BRCA1–PALB2 interaction. BRCA1 and BARD1 interact directly with RAD51 21 , 22 and mutation of the BARD1 residues Phe133, Asp135 and Ala136 (F133A/D135A/A136E; hereafter termed AAE) disrupts the BARD1–RAD51 interaction, causing reduced resistance to mitomycin C 21 , olaparib and hydroxyurea (Extended Data Fig. 2a, b ). Complementation of cells with BARD1(AAE) did not support protection of nascent strands, in contrast to cells that were complemented with wild-type BARD1 or with BARD1(R99E), a BARD1 mutant that is deficient in ubiquitin ligase activity 23 (Extended Data Fig. 2c–f ). Thus, protection of stalled replication forks requires the region of BARD1 that contains the RAD51-binding site, but does not require ligase activity of the BRCA1–BARD1 heterodimer. BRCA1 and BARD1 are phosphorylated at residues that are potentially located close to the site of interaction between BARD1 and RAD51: Ser148 of BARD1 24 and Ser114 of BRCA1 25 . Substitution of these sites to alanine residues (BRCA1(S114A) and BARD1(S148A)) caused a reduction of IdU:CldU ratios and CldU tract lengths after treatment with<|im_end|> <|im_start|>assistant Research led by the University of Birmingham has found important new ways that the BRCA1 gene functions which could help develop our understanding of the development of ovarian and breast cancers. The research, published in Nature today, was led by experts at the University of Birmingham's Birmingham Centre for Genome Biology and Institute of Cancer and Genomic Sciences and is part of a five-year research project which is playing a pivotal role in identifying and understanding breast cancer genes. First author Manolo Daza-Martin, of the University of Birmingham, explained: "No two people are born the same and, as a result, we all have slightly different chances of developing diseases during our lifetimes—this is the result of natural variation in our genes. "On top of this natural variation, about one in a thousand people inherit from one of their parents a damaged, or 'mutated', copy of a gene called BRCA1. "Previous research has shown us that in cells the BRCA1 gene makes a protein that helps repair damage to broken DNA. Therefore, people who inherit a faulty BRCA1 gene are less able to repair damage that inevitably accumulates in their DNA over time—putting them at higher risk of ovarian and breast cancer. Hollywood actress Angelina Jolie had a double mastectomy and announced she was to have her ovaries removed in 2013 after being tested positive for the BRCA1 genetic mutation. Her mother died at the young age of 56 due to cancer. DNA damage can also occur when cells have difficulties copying their DNA leaving it vulnerable to breakage. BRCA1 helps protect DNA when the copying machinery gets stuck, but it was not known how. Now University of Birmingham researchers, in collaboration with scientists at Imperial College London, have found that BRCA1 changes shape in order to protect vulnerable DNA until the copying machinery can be restarted. In addition, the researchers found that in some patients with a personal or family history of breast and ovarian cancer, the protective role of BRCA1 in DNA-copying is disabled—while its break repair function is still active. Joint corresponding author Dr. Ruth Densham, of the University of Birmingham's Institute of Cancer and Genomic Sciences, added: "BRCA1 is like a DNA Damage Scene Coordinator, whose role is to coordinate emergency response units at a damage site in order to help repair. It was surprising to find out that BRCA1 changes shape depending on the type of damage it finds at the scene, and this shape change alters the way the cell responds." Lead and corresponding author Professor Jo Morris, also of the University of Birmingham's Institute of Cancer and Genomic Sciences, said: "Our research could be important for understanding how cancers develop and means we could have identified a new way of supressing tumours. "We are long way from it, but ultimately this may alter how cancer patients are treated. We will now continue this important research into the role of BRCA1's DNA copying function in cancer development." The average woman in the UK has a 12.5 per cent chance of developing breast cancer at some point in her life. About one in 20 (five per cent) of the 50,000 women diagnosed with breast cancer every year carries an inherited gene fault like BRCA1. A female BRCA1 carrier has between a 60 and 90 per cent chance of developing breast cancer, and around a 40 to 60 per cent chance of ovarian cancer. The precise figure for an individual woman will vary according to several things, such as her age, the number of affected family members, and the exact nature of the fault in the gene. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Regenerating pancreatic β-cells is a potential curative approach for diabetes. We previously identified the small molecule CID661578 as a potent inducer of β-cell regeneration, but its target and mechanism of action have remained unknown. We now screened 257 million yeast clones and determined that CID661578 targets MAP kinase-interacting serine/threonine kinase 2 (MNK2), an interaction we genetically validated in vivo. CID661578 increased β-cell neogenesis from ductal cells in zebrafish, neonatal pig islet aggregates and human pancreatic ductal organoids. Mechanistically, we found that CID661578 boosts protein synthesis and regeneration by blocking MNK2 from binding eIF4G in the translation initiation complex at the mRNA cap. Unexpectedly, this blocking activity augmented eIF4E phosphorylation depending on MNK1 and bolstered the interaction between eIF4E and eIF4G, which is necessary for both hypertranslation and β-cell regeneration. Taken together, our findings demonstrate a targetable role of MNK2-controlled translation in β-cell regeneration, a role that warrants further investigation in diabetes. Main Both type 1 and type 2 diabetes manifest with elevated circulating glucose levels caused by the deregulation of insulin signaling and/or the loss of functional insulin-producing β-cells 1 . Although daily insulin injection, lifestyle interventions and various drug treatments can manage the disease, there is currently no available cure. Therefore, stimulating endogenous β-cell regeneration is an attractive curative approach for diabetes; however, current efforts have failed to translate into a clinically approved drug. Drug screening in vivo for chemicals stimulating β-cell regeneration has the potential to accelerate the drug discovery process as it is performed in a physiological, whole-organism setting. The zebrafish model has emerged as a powerful tool for performing unbiased, large-scale chemical/genetic screens that are directly coupled to phenotypic analyses. These types of screens have identified molecules that have already entered clinical development 2 , 3 , showcasing the translational potential of the approach. Metabolism, and in particular diabetes research, is an area in which chemical screens using zebrafish have grown in popularity. Such screens have already identified compounds that can stimulate β-cell proliferation 4 , 5 , 6 and neogenesis from duct-residing pancreatic progenitors 7 , 8 , 9 , two of the main known mechanisms of endogenous β-cell regeneration. Moreover, zebrafish chemical screens for regulators of glucose metabolism have identified compounds with potential use as antidiabetic treatments 10 , 11 , 12 . Collectively, these studies have demonstrated the power of the zebrafish model for performing chemical screens to identify compounds that could be repurposed as antidiabetic drugs. However, many hits from phenotypic screens have unknown targets and mechanisms of action that create a bottleneck for further development but, if the targets are defined, can open up new research areas. In this work, we aimed to identify the molecular mechanism of action of CID661578 ( 1 ), the most striking hit from a zebrafish chemical screen for stimulators of β-cell regeneration 4 . By performing a modified yeast two-hybrid screen suited for drug target deconvolution, we identified MAP kinase-interacting serine/threonine kinase 2 (MNK2) as the molecular target of CID661578 and validated this interaction in vivo. MNK2 participates in initiation of mRNA translation and has been postulated to modulate the process in a transcript-selective fashion 13 . Here, we show that kinase-independent blocking of MNK2 leads to bolstered protein synthesis in the pancreatic duct and that the effects are conserved across zebrafish, pig and organoid cultures of human pancreatic ducts. Overall, our results demonstrate a conserved pathway to stimulate β-cell neogenesis by boosting protein synthesis through targeting MNK2. Results Yeast chemical hybrid screen identifies MNK2 as the molecular target of CID661578 In a previous large-scale chemical screen, we identified five small molecules that potently drove β-cell regeneration in zebrafish larvae 4 . Four of the five hit compounds converged on the adenosine pathway and stimulated β-cell proliferation, while the fifth hit compound, named CID661578, had no known molecular target or cellular mechanism of action (Fig. 1a ). To identify the molecular target of CID661578, we used yeast chemical hybrid (YChemH) screening technology, which takes advantage of the classical yeast two-hybrid system for protein–protein interactions but enables screening for protein targets of small molecules. First, we generated a series of structural analogs of CID661578 to simplify the structure and identified one (termed CID661578.6 ( 2 )) that exerted similar effects on β-cell regeneration as CID661578 (Extended Data Fig. 1 ). We used yeast clones with a construct that expressed a DNA-binding domain (LexA) coupled to the enzyme dihydrofolate reductase (DHFR) along with a GAL4 activation domain fused to each cDNA in the libraries. We screened two different cDNA libraries, one derived from human islets and another derived from zebrafish embryos, with a total of 135 million and 122 million clones, respectively. The rationale of this approach is that when yeast are incubated with the CID661578.6-derived bait ( 3 ), the attached trimethoprim will interact with DHFR on the DNA-binding site of LexA. Interaction between CID661578.6 and a protein fragment (that is, the prey) generated from the cDNA library will lead to yeast survival on the selective histidine-free medium (Fig. 1b ). The most likely targets of CID661578 were classified as A hits, and less likely targets were classified as B hits, C hits and so forth, depending on the confidence in the interaction (Fig. 1c ). Fig. 1: YChemH screen identifies MNK2 as the molecular target of CID661578. a , Schema for the screening of compounds increasing β-cell regeneration using a transgenic zebrafish model for β-cell ablation and approximately 10,000 compounds. The hits included four compounds affecting adenosine signaling and CID661578 with an unknown mechanism. b , Schematic showing the structures of CID661578 and the analog CID661578.6 along with the screening strategy (YChemH). The red circles highlight the structures that were altered in CID661578. Survival of yeast on selective histidine-free medium was the output of the screen for clones expressing interactors of the CID661578.6 bait; TMP, trimethoprim; AD, activation domain. c , Table summarizing the top hits of the YChemH screen from the two cDNA libraries. The A-classified hits ( drl and acin1b from the", "role": "user" }, { "content": "Researchers at Karolinska Institutet in Sweden show how a molecule that they have identified stimulates the formation of new insulin-producing cells in zebrafish and mammalian tissue, through a newly described mechanism for regulating protein synthesis. The results are published in Nature Chemical Biology. \"Our findings indicate a new potential target for treating diabetes, in that we demonstrate a possible way of stimulating the formation of new insulin-producing cells,\" says the study's last author Olov Andersson, senior researcher at the Department of Cell and Molecular Biology at Karolinska Institutet. Both type 1 and type 2 diabetes are characterized by raised levels of blood sugar, the result of low levels of endogenous insulin, the hormone needed for glucose uptake from the blood, or a physiological inability to utilize the insulin secreted—or both. Insulin injections and glucose-lowering drugs can control the disease, but not cure it. Regeneration of pancreatic β cells \"One alternative could be a treatment that regulates blood glucose by increasing the number of insulin-producing pancreatic β cells, so we're researching the possible regeneration of these cells,\" says the study's first author Christos Karampelias, former doctoral student at the Department of Cell and Molecular Biology at Karolinska Institutet. The team from Karolinska Institutet has previously identified a small molecule able to stimulate the regeneration of insulin-producing β cells. This they did by analyzing a large quantity of substances in a zebrafish model. In this present study, they examined the molecular mechanism of this stimulation. By analyzing a large number of molecular interactions in yeast cells, the researchers show that their molecule binds to a protein called MNK2. Subsequent studies of zebrafish and cell cultures indicate that the molecule operates by regulating the translation of mRNA and boosting the synthesis of proteins, without which the formation of new β cells cannot be increased. Zebrafish given the molecule also showed lower levels of blood glucose than controls. The study also shows that the molecule can induce the formation of new pancreatic β cells from pigs and stimulate the expression of insulin in human organoids (organ-like cell formations). Studies of human tissue \"We'll now be studying the effect of this and similar molecules in human tissue and analyzing the molecule's target protein, MNK2, in tissue from healthy donors and donors with diabetes,\" says Dr. Andersson. The studied molecule was found through studies on zebrafish, providing a valuable model for testing a large number of potential diabetes drug candidates. Since the fish embryo is transparent, its development is easy to monitor with a microscope. Zebrafish larvae also have only one cluster of β cells, a so-called islet of Langerhans, which facilitates studies of how new β cells are formed after the population have been decreased in a way that mimics the onset of type 1 diabetes. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Regenerating pancreatic β-cells is a potential curative approach for diabetes. We previously identified the small molecule CID661578 as a potent inducer of β-cell regeneration, but its target and mechanism of action have remained unknown. We now screened 257 million yeast clones and determined that CID661578 targets MAP kinase-interacting serine/threonine kinase 2 (MNK2), an interaction we genetically validated in vivo. CID661578 increased β-cell neogenesis from ductal cells in zebrafish, neonatal pig islet aggregates and human pancreatic ductal organoids. Mechanistically, we found that CID661578 boosts protein synthesis and regeneration by blocking MNK2 from binding eIF4G in the translation initiation complex at the mRNA cap. Unexpectedly, this blocking activity augmented eIF4E phosphorylation depending on MNK1 and bolstered the interaction between eIF4E and eIF4G, which is necessary for both hypertranslation and β-cell regeneration. Taken together, our findings demonstrate a targetable role of MNK2-controlled translation in β-cell regeneration, a role that warrants further investigation in diabetes. Main Both type 1 and type 2 diabetes manifest with elevated circulating glucose levels caused by the deregulation of insulin signaling and/or the loss of functional insulin-producing β-cells 1 . Although daily insulin injection, lifestyle interventions and various drug treatments can manage the disease, there is currently no available cure. Therefore, stimulating endogenous β-cell regeneration is an attractive curative approach for diabetes; however, current efforts have failed to translate into a clinically approved drug. Drug screening in vivo for chemicals stimulating β-cell regeneration has the potential to accelerate the drug discovery process as it is performed in a physiological, whole-organism setting. The zebrafish model has emerged as a powerful tool for performing unbiased, large-scale chemical/genetic screens that are directly coupled to phenotypic analyses. These types of screens have identified molecules that have already entered clinical development 2 , 3 , showcasing the translational potential of the approach. Metabolism, and in particular diabetes research, is an area in which chemical screens using zebrafish have grown in popularity. Such screens have already identified compounds that can stimulate β-cell proliferation 4 , 5 , 6 and neogenesis from duct-residing pancreatic progenitors 7 , 8 , 9 , two of the main known mechanisms of endogenous β-cell regeneration. Moreover, zebrafish chemical screens for regulators of glucose metabolism have identified compounds with potential use as antidiabetic treatments 10 , 11 , 12 . Collectively, these studies have demonstrated the power of the zebrafish model for performing chemical screens to identify compounds that could be repurposed as antidiabetic drugs. However, many hits from phenotypic screens have unknown targets and mechanisms of action that create a bottleneck for further development but, if the targets are defined, can open up new research areas. In this work, we aimed to identify the molecular mechanism of action of CID661578 ( 1 ), the most striking hit from a zebrafish chemical screen for stimulators of β-cell regeneration 4 . By performing a modified yeast two-hybrid screen suited for drug target deconvolution, we identified MAP kinase-interacting serine/threonine kinase 2 (MNK2) as the molecular target of CID661578 and validated this interaction in vivo. MNK2 participates in initiation of mRNA translation and has been postulated to modulate the process in a transcript-selective fashion 13 . Here, we show that kinase-independent blocking of MNK2 leads to bolstered protein synthesis in the pancreatic duct and that the effects are conserved across zebrafish, pig and organoid cultures of human pancreatic ducts. Overall, our results demonstrate a conserved pathway to stimulate β-cell neogenesis by boosting protein synthesis through targeting MNK2. Results Yeast chemical hybrid screen identifies MNK2 as the molecular target of CID661578 In a previous large-scale chemical screen, we identified five small molecules that potently drove β-cell regeneration in zebrafish larvae 4 . Four of the five hit compounds converged on the adenosine pathway and stimulated β-cell proliferation, while the fifth hit compound, named CID661578, had no known molecular target or cellular mechanism of action (Fig. 1a ). To identify the molecular target of CID661578, we used yeast chemical hybrid (YChemH) screening technology, which takes advantage of the classical yeast two-hybrid system for protein–protein interactions but enables screening for protein targets of small molecules. First, we generated a series of structural analogs of CID661578 to simplify the structure and identified one (termed CID661578.6 ( 2 )) that exerted similar effects on β-cell regeneration as CID661578 (Extended Data Fig. 1 ). We used yeast clones with a construct that expressed a DNA-binding domain (LexA) coupled to the enzyme dihydrofolate reductase (DHFR) along with a GAL4 activation domain fused to each cDNA in the libraries. We screened two different cDNA libraries, one derived from human islets and another derived from zebrafish embryos, with a total of 135 million and 122 million clones, respectively. The rationale of this approach is that when yeast are incubated with the CID661578.6-derived bait ( 3 ), the attached trimethoprim will interact with DHFR on the DNA-binding site of LexA. Interaction between CID661578.6 and a protein fragment (that is, the prey) generated from the cDNA library will lead to yeast survival on the selective histidine-free medium (Fig. 1b ). The most likely targets of CID661578 were classified as A hits, and less likely targets were classified as B hits, C hits and so forth, depending on the confidence in the interaction (Fig. 1c ). Fig. 1: YChemH screen identifies MNK2 as the molecular target of CID661578. a , Schema for the screening of compounds increasing β-cell regeneration using a transgenic zebrafish model for β-cell ablation and approximately 10,000 compounds. The hits included four compounds affecting adenosine signaling and CID661578 with an unknown mechanism. b , Schematic showing the structures of CID661578 and the analog CID661578.6 along with the screening strategy (YChemH). The red circles highlight the structures that were altered in CID661578. Survival of yeast on selective histidine-free medium was the output of the screen for clones expressing interactors of the CID661578.6 bait; TMP, trimethoprim; AD, activation domain. c , Table summarizing the top hits of the YChemH screen from the two cDNA libraries. The A-classified hits ( drl and acin1b from the<|im_end|> <|im_start|>assistant Researchers at Karolinska Institutet in Sweden show how a molecule that they have identified stimulates the formation of new insulin-producing cells in zebrafish and mammalian tissue, through a newly described mechanism for regulating protein synthesis. The results are published in Nature Chemical Biology. "Our findings indicate a new potential target for treating diabetes, in that we demonstrate a possible way of stimulating the formation of new insulin-producing cells," says the study's last author Olov Andersson, senior researcher at the Department of Cell and Molecular Biology at Karolinska Institutet. Both type 1 and type 2 diabetes are characterized by raised levels of blood sugar, the result of low levels of endogenous insulin, the hormone needed for glucose uptake from the blood, or a physiological inability to utilize the insulin secreted—or both. Insulin injections and glucose-lowering drugs can control the disease, but not cure it. Regeneration of pancreatic β cells "One alternative could be a treatment that regulates blood glucose by increasing the number of insulin-producing pancreatic β cells, so we're researching the possible regeneration of these cells," says the study's first author Christos Karampelias, former doctoral student at the Department of Cell and Molecular Biology at Karolinska Institutet. The team from Karolinska Institutet has previously identified a small molecule able to stimulate the regeneration of insulin-producing β cells. This they did by analyzing a large quantity of substances in a zebrafish model. In this present study, they examined the molecular mechanism of this stimulation. By analyzing a large number of molecular interactions in yeast cells, the researchers show that their molecule binds to a protein called MNK2. Subsequent studies of zebrafish and cell cultures indicate that the molecule operates by regulating the translation of mRNA and boosting the synthesis of proteins, without which the formation of new β cells cannot be increased. Zebrafish given the molecule also showed lower levels of blood glucose than controls. The study also shows that the molecule can induce the formation of new pancreatic β cells from pigs and stimulate the expression of insulin in human organoids (organ-like cell formations). Studies of human tissue "We'll now be studying the effect of this and similar molecules in human tissue and analyzing the molecule's target protein, MNK2, in tissue from healthy donors and donors with diabetes," says Dr. Andersson. The studied molecule was found through studies on zebrafish, providing a valuable model for testing a large number of potential diabetes drug candidates. Since the fish embryo is transparent, its development is easy to monitor with a microscope. Zebrafish larvae also have only one cluster of β cells, a so-called islet of Langerhans, which facilitates studies of how new β cells are formed after the population have been decreased in a way that mimics the onset of type 1 diabetes. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstracting/Indexing TWEB Author List TWEB Affiliations ACM Award Winners Resources Contact Us More window.addEventListener(\"load\", function() { document.getElementsByClassName('sub-nav__container')[0].appendChild(document.getElementById('temp-prog')); }); Home ACM Journals ACM Transactions on the Web Vol. 17, No. 2 Disentangling Decentralized Finance (DeFi) Compositions research-article Open Access Go to to customize your tools Share on Disentangling Decentralized Finance (DeFi) Compositions Authors: Stefan Kitzler Complexity Science Hub Vienna and AIT - Austrian Institute of Technology, Giefinggasse, Vienna, Austria Complexity Science Hub Vienna and AIT - Austrian Institute of Technology, Giefinggasse, Vienna, Austria 0000-0001-8454-167X View Profile , Friedhelm Victor Technische Universität Berlin, Berlin, Germany Technische Universität Berlin, Berlin, Germany 0000-0001-8329-3133 View Profile , Pietro Saggese Complexity Science Hub Vienna and AIT - Austrian Institute of Technology, Giefinggasse, Vienna, Austria Complexity Science Hub Vienna and AIT - Austrian Institute of Technology, Giefinggasse, Vienna, Austria 0000-0002-7387-0846 View Profile , Bernhard Haslhofer Complexity Science Hub Vienna, Vienna, Austria Complexity Science Hub Vienna, Vienna, Austria 0000-0002-0415-4491 View Profile Authors Info & Claims ACM Transactions on the Web Volume 17 Issue 2 27 March 2023 Article No.: 10 pp 1–26 Published: 27 March 2023 Publication History 2 citation 1,004 Downloads Metrics Total Citations 2 Total Downloads 1,004 Last 12 Months 1,004 Last 6 weeks 724 Get Citation Alerts Save to Binder Close modal Save to Binder Create a New Binder Name 256 Cancel Create Export Citation Publisher Site View all Formats PDF ACM Transactions on the Web Volume 17, Issue 2 Previous Article Next Article Abstract 1 INTRODUCTION 1.1 Motivation 1.2 Contributions 2 BACKGROUND AND DEFINITIONS 2.1 Ethereum Account Types 2.2 Decentralized Finance (DeFi) Protocol 2.3 DeFi Protocol Compositions 2.4 Related Work 3 DATASET AND NETWORK CONSTRUCTION 3.1 Dataset Collection 3.1.1 On-chain Transaction Data. 3.1.2 Ground Truth Data. 3.1.3 Dataset Reduction. 3.2 Network Construction 4 TOPOLOGY MEASUREMENTS 4.1 Degree Distribution 4.2 Centrality Measures 4.3 Reciprocity and Assortativity 4.4 Components 4.5 Community Detection 5 MEASURING DEFI COMPOSITIONS 5.1 Building Block Extraction Algorithm 5.2 Building Block Analysis 5.2.1 Protocol Building Block Composition. 5.2.2 Flattening Composition Hierarchies. 5.3 Case Study: A Hypothetical Run on the Tether 6 DISCUSSION 6.1 Insights 6.2 Limitations 7 CONCLUSION Footnotes REFERENCES Cited By Index Terms Recommendations Comments abstract content Skip Abstract Section Abstract We present a measurement study on compositions of Decentralized Finance (DeFi) protocols, which aim to disrupt traditional finance and offer services on top of distributed ledgers, such as Ethereum. Understanding DeFi compositions is of great importance, as they may impact the development of ecosystem interoperability, are increasingly integrated with web technologies, and may introduce risks through complexity. Starting from a dataset of 23 labeled DeFi protocols and 10,663,881 associated Ethereum accounts, we study the interactions of protocols and associated smart contracts. From a network perspective, we find that decentralized exchange (DEX) and lending protocol account nodes have high degree and centrality values, that interactions among protocol nodes primarily occur in a strongly connected component, and that known community detection methods cannot disentangle DeFi protocols. Therefore, we propose an algorithm to decompose a protocol call into a nested set of building blocks that may be part of other DeFi protocols. This allows us to untangle and study protocol compositions. With a ground truth dataset that we have collected, we can demonstrate the algorithm’s capability by finding that swaps are the most frequently used building blocks. As building blocks can be nested, that is, contained in each other, we provide visualizations of composition trees for deeper inspections. We also present a broad picture of DeFi compositions by extracting and flattening the entire nested building block structure across multiple DeFi protocols. Finally, to demonstrate the practicality of our approach, we present a case study that is inspired by the recent collapse of the UST stablecoin in the Terra ecosystem. Under the hypothetical assumption that the stablecoin USD Tether would experience a similar fate, we study which building blocks — and, thereby, DeFi protocols — would be affected. Overall, our results and methods contribute to a better understanding of a new family of financial products. /abstract content fulltext content Skip 1INTRODUCTION Section 1 INTRODUCTION Decentralized Finance (DeFi) stands for a new paradigm that aims to disrupt established financial markets. It offers financial services in the form of smart contracts , which are executable software programs deployed on top of distributed ledger technologies (DLT) such as Ethereum. Despite being a relatively recent development, we can already observe rapid growth in DeFi protocols, enabling lending of virtual assets, exchanging them for other virtual assets without intermediaries, or betting on future price developments in the form of derivatives such as options and futures. The term “financial lego” is sometimes used because DeFi services can be composed into new financial products and services. As an example of a DeFi composition, consider Figure 1 , which illustrates a user interacting with the 1inch decentralized exchange (DEX) aggregator Web service. 1 The user holds an amount of USDT tokens and wants to swap them to KYL tokens. Using the Web application and the user’s externally owned account (EOA) , the user creates a transaction against the 1inch contract. This, in turn, triggers a sequence of two swaps on two DeFi protocols within the same transaction, from USDT to WETH on SushiSwap and thereafter from WETH to KYL on UniSwap . In this article, we study such single-transaction DeFi interactions and the networks that arise when combining multiple DeFi transactions. Fig. 1. View Figure Fig. 1. A DeFi composition in which USDT tokens are swapped against KYL tokens through the DeFi service 1inch in a single transaction. 1inch executes the swap sequentially through the DeFi services SushiSwap and UniSwap, using WETH as an intermediary token. In the transaction trace graph, we can see the user calling the 1inch smart contract, which, in turn, triggers several calls to DeFi protocol-, and token smart contracts. 1.1 Motivation In 2021, the total value of tokens held by smart contracts underlying the DeFi protocols reached 106 billion USD [ 12 ], demonstrating rapid growth. As composability of DeFi protocols is frequently seen as one of the", "role": "user" }, { "content": "It has been an extremely turbulent year for the crypto world. In particular, the collapses of the stablecoin Terra at the beginning of the year and the one of the crypto exchange FTX two weeks ago left many investors stunned. New research from CSH Vienna shows how hypothetical cryptoasset failures could affect other financial services on Ethereum. \"After the collapse of the algorithmic stablecoin TerraUSD and its sister coin Luna earlier this year, other stablecoins have become the focus of attention. It is important to understand them, because they are an interface to the traditional financial sector and might propagate failures,\" explains Bernhard Haslhofer, head of the Cryptofinance research group at the Complexity Science Hub Vienna (CSH Vienna). Stablecoins are cryptocurrencies whose value is supposed to be bound to some other asset, like the US dollar. However, a series of coordinated speculative trades broke these ties, and TerraUSD as well as Luna were suddenly worthless. Stablecoins are an essential building block While analyzing several Decentralized Finance (DeFi) services, CSH researchers found that many rely on stablecoins like Tether. \"Individual financial service providers use Tether in more than 14% of their executions, leading to a comparably high dependency on this particular asset,\" says CSH researcher Stefan Kitzler. If Tether loses it's value for whatever reason, many other DeFi services would be affected. Besides this incident, 2022 experienced hacks, exploits, or collapses of crypto-related projects almost every month. With a record of around $760 million stolen in October, it's not called Hacktober for no reason. \"While the Bitcoin blockchain only enables the transfer of bitcoins between users, new blockchains such as Ethereum also allow for more complex financial operations such as lending or trading multiple cryptoassets that reflect assets outside the blockchain,\" Kitzler says. New algorithm unravels financial services on the Ethereum blockchain For end users, the inner mechanisms of these financial services remain hidden and they are usually not aware of which other services are being used in the background. Fortunately, CSH researchers have now unraveled the structure and building blocks of financial services on the Ethereum blockchain. They developed an algorithm that dissects these financial transactions and shows how the services are interwoven. What they found were highly intertwined structures. \"We are dealing here with complex financial products that are very difficult to understand and involve risks that are not yet fully understood,\" says Kitzler. Strong dependencies and unknown risks The internal structure of these financial services can be imagined as a construct made up of several building blocks. \"The upper building blocks depend on the lower ones. Because of this structure and the repeated use of certain blocks, the entire system is heavily dependent on very specific basic service blocks,\" Kitzler says. If such a building block breaks away, it will affect other blocks building on it. Decentralized Finance (DeFi) services—this entire complex of financial services related to crypto-assets—typically offer easy access through their websites, like e-banking offered by traditional banks. This low barrier to entry, or even gamification, has led to the popularity of DeFi and billions of dollars invested in the market. Recent events in the crypto space and these research findings clearly show that cryptoassets are risky investments and that failures might affect financial services in the crypto and possibly also in the traditional financial world. \"The first thing we need to do is create transparency and awareness. Users need to understand what exactly is behind a certain crypto financial service and what risks are involved,\" says Kitzler. \"In light of recent events, it is clear that understanding potential systemic risks associated with cryptoassets and decentralized financial services must also become a top priority for regulators and policymakers,\" concludes Bernhard Haslhofer. The work is published in the journal ACM Transactions on the Web. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstracting/Indexing TWEB Author List TWEB Affiliations ACM Award Winners Resources Contact Us More window.addEventListener("load", function() { document.getElementsByClassName('sub-nav__container')[0].appendChild(document.getElementById('temp-prog')); }); Home ACM Journals ACM Transactions on the Web Vol. 17, No. 2 Disentangling Decentralized Finance (DeFi) Compositions research-article Open Access Go to to customize your tools Share on Disentangling Decentralized Finance (DeFi) Compositions Authors: Stefan Kitzler Complexity Science Hub Vienna and AIT - Austrian Institute of Technology, Giefinggasse, Vienna, Austria Complexity Science Hub Vienna and AIT - Austrian Institute of Technology, Giefinggasse, Vienna, Austria 0000-0001-8454-167X View Profile , Friedhelm Victor Technische Universität Berlin, Berlin, Germany Technische Universität Berlin, Berlin, Germany 0000-0001-8329-3133 View Profile , Pietro Saggese Complexity Science Hub Vienna and AIT - Austrian Institute of Technology, Giefinggasse, Vienna, Austria Complexity Science Hub Vienna and AIT - Austrian Institute of Technology, Giefinggasse, Vienna, Austria 0000-0002-7387-0846 View Profile , Bernhard Haslhofer Complexity Science Hub Vienna, Vienna, Austria Complexity Science Hub Vienna, Vienna, Austria 0000-0002-0415-4491 View Profile Authors Info & Claims ACM Transactions on the Web Volume 17 Issue 2 27 March 2023 Article No.: 10 pp 1–26 Published: 27 March 2023 Publication History 2 citation 1,004 Downloads Metrics Total Citations 2 Total Downloads 1,004 Last 12 Months 1,004 Last 6 weeks 724 Get Citation Alerts Save to Binder Close modal Save to Binder Create a New Binder Name 256 Cancel Create Export Citation Publisher Site View all Formats PDF ACM Transactions on the Web Volume 17, Issue 2 Previous Article Next Article Abstract 1 INTRODUCTION 1.1 Motivation 1.2 Contributions 2 BACKGROUND AND DEFINITIONS 2.1 Ethereum Account Types 2.2 Decentralized Finance (DeFi) Protocol 2.3 DeFi Protocol Compositions 2.4 Related Work 3 DATASET AND NETWORK CONSTRUCTION 3.1 Dataset Collection 3.1.1 On-chain Transaction Data. 3.1.2 Ground Truth Data. 3.1.3 Dataset Reduction. 3.2 Network Construction 4 TOPOLOGY MEASUREMENTS 4.1 Degree Distribution 4.2 Centrality Measures 4.3 Reciprocity and Assortativity 4.4 Components 4.5 Community Detection 5 MEASURING DEFI COMPOSITIONS 5.1 Building Block Extraction Algorithm 5.2 Building Block Analysis 5.2.1 Protocol Building Block Composition. 5.2.2 Flattening Composition Hierarchies. 5.3 Case Study: A Hypothetical Run on the Tether 6 DISCUSSION 6.1 Insights 6.2 Limitations 7 CONCLUSION Footnotes REFERENCES Cited By Index Terms Recommendations Comments abstract content Skip Abstract Section Abstract We present a measurement study on compositions of Decentralized Finance (DeFi) protocols, which aim to disrupt traditional finance and offer services on top of distributed ledgers, such as Ethereum. Understanding DeFi compositions is of great importance, as they may impact the development of ecosystem interoperability, are increasingly integrated with web technologies, and may introduce risks through complexity. Starting from a dataset of 23 labeled DeFi protocols and 10,663,881 associated Ethereum accounts, we study the interactions of protocols and associated smart contracts. From a network perspective, we find that decentralized exchange (DEX) and lending protocol account nodes have high degree and centrality values, that interactions among protocol nodes primarily occur in a strongly connected component, and that known community detection methods cannot disentangle DeFi protocols. Therefore, we propose an algorithm to decompose a protocol call into a nested set of building blocks that may be part of other DeFi protocols. This allows us to untangle and study protocol compositions. With a ground truth dataset that we have collected, we can demonstrate the algorithm’s capability by finding that swaps are the most frequently used building blocks. As building blocks can be nested, that is, contained in each other, we provide visualizations of composition trees for deeper inspections. We also present a broad picture of DeFi compositions by extracting and flattening the entire nested building block structure across multiple DeFi protocols. Finally, to demonstrate the practicality of our approach, we present a case study that is inspired by the recent collapse of the UST stablecoin in the Terra ecosystem. Under the hypothetical assumption that the stablecoin USD Tether would experience a similar fate, we study which building blocks — and, thereby, DeFi protocols — would be affected. Overall, our results and methods contribute to a better understanding of a new family of financial products. /abstract content fulltext content Skip 1INTRODUCTION Section 1 INTRODUCTION Decentralized Finance (DeFi) stands for a new paradigm that aims to disrupt established financial markets. It offers financial services in the form of smart contracts , which are executable software programs deployed on top of distributed ledger technologies (DLT) such as Ethereum. Despite being a relatively recent development, we can already observe rapid growth in DeFi protocols, enabling lending of virtual assets, exchanging them for other virtual assets without intermediaries, or betting on future price developments in the form of derivatives such as options and futures. The term “financial lego” is sometimes used because DeFi services can be composed into new financial products and services. As an example of a DeFi composition, consider Figure 1 , which illustrates a user interacting with the 1inch decentralized exchange (DEX) aggregator Web service. 1 The user holds an amount of USDT tokens and wants to swap them to KYL tokens. Using the Web application and the user’s externally owned account (EOA) , the user creates a transaction against the 1inch contract. This, in turn, triggers a sequence of two swaps on two DeFi protocols within the same transaction, from USDT to WETH on SushiSwap and thereafter from WETH to KYL on UniSwap . In this article, we study such single-transaction DeFi interactions and the networks that arise when combining multiple DeFi transactions. Fig. 1. View Figure Fig. 1. A DeFi composition in which USDT tokens are swapped against KYL tokens through the DeFi service 1inch in a single transaction. 1inch executes the swap sequentially through the DeFi services SushiSwap and UniSwap, using WETH as an intermediary token. In the transaction trace graph, we can see the user calling the 1inch smart contract, which, in turn, triggers several calls to DeFi protocol-, and token smart contracts. 1.1 Motivation In 2021, the total value of tokens held by smart contracts underlying the DeFi protocols reached 106 billion USD [ 12 ], demonstrating rapid growth. As composability of DeFi protocols is frequently seen as one of the<|im_end|> <|im_start|>assistant It has been an extremely turbulent year for the crypto world. In particular, the collapses of the stablecoin Terra at the beginning of the year and the one of the crypto exchange FTX two weeks ago left many investors stunned. New research from CSH Vienna shows how hypothetical cryptoasset failures could affect other financial services on Ethereum. "After the collapse of the algorithmic stablecoin TerraUSD and its sister coin Luna earlier this year, other stablecoins have become the focus of attention. It is important to understand them, because they are an interface to the traditional financial sector and might propagate failures," explains Bernhard Haslhofer, head of the Cryptofinance research group at the Complexity Science Hub Vienna (CSH Vienna). Stablecoins are cryptocurrencies whose value is supposed to be bound to some other asset, like the US dollar. However, a series of coordinated speculative trades broke these ties, and TerraUSD as well as Luna were suddenly worthless. Stablecoins are an essential building block While analyzing several Decentralized Finance (DeFi) services, CSH researchers found that many rely on stablecoins like Tether. "Individual financial service providers use Tether in more than 14% of their executions, leading to a comparably high dependency on this particular asset," says CSH researcher Stefan Kitzler. If Tether loses it's value for whatever reason, many other DeFi services would be affected. Besides this incident, 2022 experienced hacks, exploits, or collapses of crypto-related projects almost every month. With a record of around $760 million stolen in October, it's not called Hacktober for no reason. "While the Bitcoin blockchain only enables the transfer of bitcoins between users, new blockchains such as Ethereum also allow for more complex financial operations such as lending or trading multiple cryptoassets that reflect assets outside the blockchain," Kitzler says. New algorithm unravels financial services on the Ethereum blockchain For end users, the inner mechanisms of these financial services remain hidden and they are usually not aware of which other services are being used in the background. Fortunately, CSH researchers have now unraveled the structure and building blocks of financial services on the Ethereum blockchain. They developed an algorithm that dissects these financial transactions and shows how the services are interwoven. What they found were highly intertwined structures. "We are dealing here with complex financial products that are very difficult to understand and involve risks that are not yet fully understood," says Kitzler. Strong dependencies and unknown risks The internal structure of these financial services can be imagined as a construct made up of several building blocks. "The upper building blocks depend on the lower ones. Because of this structure and the repeated use of certain blocks, the entire system is heavily dependent on very specific basic service blocks," Kitzler says. If such a building block breaks away, it will affect other blocks building on it. Decentralized Finance (DeFi) services—this entire complex of financial services related to crypto-assets—typically offer easy access through their websites, like e-banking offered by traditional banks. This low barrier to entry, or even gamification, has led to the popularity of DeFi and billions of dollars invested in the market. Recent events in the crypto space and these research findings clearly show that cryptoassets are risky investments and that failures might affect financial services in the crypto and possibly also in the traditional financial world. "The first thing we need to do is create transparency and awareness. Users need to understand what exactly is behind a certain crypto financial service and what risks are involved," says Kitzler. "In light of recent events, it is clear that understanding potential systemic risks associated with cryptoassets and decentralized financial services must also become a top priority for regulators and policymakers," concludes Bernhard Haslhofer. The work is published in the journal ACM Transactions on the Web. <|im_end|>

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2,308

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Despite the importance of precipitation phase to global hydroclimate simulations, many land surface models use spatially uniform air temperature thresholds to partition rain and snow. Here we show, through the analysis of a 29-year observational dataset ( n = 17.8 million), that the air temperature at which rain and snow fall in equal frequency varies significantly across the Northern Hemisphere, averaging 1.0 °C and ranging from –0.4 to 2.4 °C for 95% of the stations. Continental climates generally exhibit the warmest rain–snow thresholds and maritime the coolest. Simulations show precipitation phase methods incorporating humidity perform better than air temperature-only methods, particularly at relative humidity values below saturation and air temperatures between 0.6 and 3.4 °C. We also present the first continuous Northern Hemisphere map of rain–snow thresholds, underlining the spatial variability of precipitation phase partitioning. These results suggest precipitation phase could be better predicted using humidity and air temperature in large-scale land surface model runs. Introduction Precipitation phase plays a critical role in the global hydrologic cycle and climate system, with snowfall and rainfall having divergent effects on land surface water and energy fluxes. Snow accumulation increases surface albedo, acting as a primary driver on the climate system 1 , while winter snowpacks provide water storage for more than one billion people globally 2 , 3 . Climate warming has decreased the proportional amount of snowfall versus rainfall 4 , 5 , 6 , reduced snow water equivalent (SWE) accumulation 5 , 7 , 8 , 9 , 10 , shifted snowmelt earlier in spring 11 , 12 , 13 , and diminished annual streamflow 14 , 15 . A greater proportion of future precipitation is predicted to fall as rain, further reducing snow accumulation in cold regions across the globe 16 , 17 , 18 , 19 , 20 , 21 . Climate warming is also predicted to increase the frequency and intensity of rain-on-snow events 22 , which may significantly increase flood risks 23 . In this context, many land surface models (LSMs) estimate precipitation phase based on a simple, spatially uniform air temperature threshold and/or a range between two air temperatures in which a mix of rain and snow falls 24 , 25 . Incorrectly partitioning precipitation phase leads to significant biases in SWE, snow depth, and snow cover duration at both the point and basin scale 26 , 27 , 28 , 29 , 30 , 31 , 32 . These biases then propagate into errors in streamflow, land surface albedo, and surface–atmosphere energy exchange 26 , 29 , 30 , 33 . According to the Intergovernmental Panel on Climate Change, modeling the snow-albedo feedback—a function of snow cover extent and duration—represents a large source of uncertainty in LSM simulations of future hydroclimatic conditions 34 . There is therefore a need to critically analyze the way LSMs partition rain and snow. Another method for predicting precipitation phase is through the application of atmospheric models with microphysics schemes that track a hydrometeor from its formation in the upper atmosphere to its deposition at the land surface 25 . Such an approach has been used to accurately simulate snowfall in several locations, including the Colorado Rocky Mountains 35 and the French Alps 26 . However, this manuscript focuses exclusively on methods that partition precipitation phase at the land surface due to the greater availability of surface forcing and validation data, the computational challenge of producing high-resolution, hemispherical-scale atmospheric model simulations, and the very wide use of LSMs using surface-based precipitation phase partitioning methods (greater than 2000 combined citations for the VIC and NOAH LSMs alone, according to the Web of Science). Furthermore, coarse-scale global circulation models (GCMs), such as those used in the Coupled Model Intercomparison Project 36 , employ either surface or microphysics precipitation phase partitioning methods. Thus, a critical examination of rain–snow thresholds stands to benefit both the land surface and climate modeling communities. Given the impact precipitation phase has on LSM output, it is essential that models accurately partition rain and snow. However, such a task is nontrivial, particularly at air temperatures near 0 °C 37 . Observational work indicates the temperature dependence of rain–snow partitioning follows a sigmoidal S-shaped curve with snowfall common above a surface air temperature ( T s ) of 0 °C and increasingly less probable when approaching 4 °C 38 , 39 , 40 . Previous studies have developed rain–snow partitioning schemes based solely on T s 41 , 42 or on T s plus near-surface humidity and/or air pressure 43 , 44 , 45 , 46 , 47 , 48 , 49 ; yet, the broader applicability of these analyses is hindered by the limited spatial extent and range of conditions explored. In this regard, detailed analyses of phase partitioning—as well as its spatial variability and meteorological controls—over hemispherical scales have yet to be conducted. A useful metric for defining the partitioning of precipitation phase at a given location is the 50% rain–snow T s threshold 42 , 48 . At this temperature precipitation occurs as rain and snow with equal frequency, while above the threshold precipitation is primarily rain and below primarily snow. The objectives of this study are to quantify the 50% rain–snow T s threshold over the Northern Hemisphere land surface, to assess how it varies with relative humidity (RH) and surface pressure ( P s ), and to evaluate the impact of threshold selection on simulated snowfall frequency. We accomplish this through an analysis of a comprehensive 29-year (1978–2007) observational precipitation phase and meteorological dataset from 11,924 stations across the Northern Hemisphere ( n obs = 17.8 million), the application of a binary logistic regression phase prediction model using a spatially and temporally continuous reanalysis product in the Northern Hemisphere, and simulations of snowfall frequency using reanalysis data and a selection of precipitation phase methods. This study provides the most extensive empirical evaluation of precipitation phase over land, and the results have implications for predicting the response of rain–snow partitioning to climate change and", "role": "user" }, { "content": "University of Colorado Boulder researchers have created a map of the Northern Hemisphere showing how location and humidity can affect precipitation, illustrating wide variability in how and why different areas receive snow or rain. 32 degrees Fahrenheit is commonly considered to be the air temperature threshold for rain versus snow, thus informing meteorological forecasting and climate simulations. The new findings, however, show that coastal areas have a cooler threshold for rain, meaning that even temperatures below freezing might not produce snow. Inland and mountainous areas, meanwhile, are likelier to see flurries even when temperatures are several degrees above freezing. \"In Denver, Colorado, it might be 40 degrees and snowing. But in Charleston, South Carolina, it could be 28 degrees and raining,\" said Noah Molotch, Director of the Center for Water Earth Science & Technology (CWEST) at CU Boulder and a co-author of the study. \"This study shows these fine-grain differences on a hemisphere-level scale for the first time.\" The research, which compiled nearly 18 million precipitation observations spanning over 100 countries and four continents across the Northern Hemisphere, was published today in the journal Nature Communications. The ability to differentiate rain from snow has important ramifications for Earth's hydrologic cycle and water management, especially in drought-stricken areas of the American west. Winter snowfall is estimated to provide water storage for one billion people worldwide while climate warming could increase the amount of future rain-on-snow events, raising the risk of flooding. \"Snow and rain differ greatly in the ways they affect climate,\" said Ben Livneh, an assistant professor in CU Boulder's Department of Civil, Environmental and Architectural Engineering and a co-author of the study. \"Snow acts as a water reservoir and reflects incoming sunlight, whereas if the same amount of precipitation falls as rain, that can dramatically change water resource management decisions.\" To date, land surface models have typically predicted rain and snow based on a single, consistent air temperature threshold: snow below it and rain above it. But the CU Boulder researchers found that the threshold is not static and that relative humidity and surface pressure play an important role as well. \"The rain-snow air temperature threshold is primarily a function of relative humidity and methods incorporating humidity and elevation are more likely to predict rain and snow correctly,\" said Keith Jennings, a graduate researcher in CU Boulder's Institute of Arctic and Alpine Research (INSTAAR) and the lead author of the study. \"If you just use 32 degrees Fahrenheit across the board, your estimates will be wrong in lots of places.\" The continental U.S. had the most rain-snow variability of any country included in the study. Some of the coolest northern hemisphere thresholds were observed in the southeastern United States while the Rockies and intermountain West had some of the warmest thresholds. The new study could inform the future of climate and land surface modeling as researchers look for ways to predict snowfall versus rainfall more accurately, especially in areas crucial for freshwater, agriculture and biodiversity. Future research will look to improve the map and simulations by incorporating even more meteorological data points from around the world. \"The great thing about this research is that anyone can observe these variables right in their own backyard,\" said Molotch. \"The topic lends itself well to future citizen science.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Despite the importance of precipitation phase to global hydroclimate simulations, many land surface models use spatially uniform air temperature thresholds to partition rain and snow. Here we show, through the analysis of a 29-year observational dataset ( n = 17.8 million), that the air temperature at which rain and snow fall in equal frequency varies significantly across the Northern Hemisphere, averaging 1.0 °C and ranging from –0.4 to 2.4 °C for 95% of the stations. Continental climates generally exhibit the warmest rain–snow thresholds and maritime the coolest. Simulations show precipitation phase methods incorporating humidity perform better than air temperature-only methods, particularly at relative humidity values below saturation and air temperatures between 0.6 and 3.4 °C. We also present the first continuous Northern Hemisphere map of rain–snow thresholds, underlining the spatial variability of precipitation phase partitioning. These results suggest precipitation phase could be better predicted using humidity and air temperature in large-scale land surface model runs. Introduction Precipitation phase plays a critical role in the global hydrologic cycle and climate system, with snowfall and rainfall having divergent effects on land surface water and energy fluxes. Snow accumulation increases surface albedo, acting as a primary driver on the climate system 1 , while winter snowpacks provide water storage for more than one billion people globally 2 , 3 . Climate warming has decreased the proportional amount of snowfall versus rainfall 4 , 5 , 6 , reduced snow water equivalent (SWE) accumulation 5 , 7 , 8 , 9 , 10 , shifted snowmelt earlier in spring 11 , 12 , 13 , and diminished annual streamflow 14 , 15 . A greater proportion of future precipitation is predicted to fall as rain, further reducing snow accumulation in cold regions across the globe 16 , 17 , 18 , 19 , 20 , 21 . Climate warming is also predicted to increase the frequency and intensity of rain-on-snow events 22 , which may significantly increase flood risks 23 . In this context, many land surface models (LSMs) estimate precipitation phase based on a simple, spatially uniform air temperature threshold and/or a range between two air temperatures in which a mix of rain and snow falls 24 , 25 . Incorrectly partitioning precipitation phase leads to significant biases in SWE, snow depth, and snow cover duration at both the point and basin scale 26 , 27 , 28 , 29 , 30 , 31 , 32 . These biases then propagate into errors in streamflow, land surface albedo, and surface–atmosphere energy exchange 26 , 29 , 30 , 33 . According to the Intergovernmental Panel on Climate Change, modeling the snow-albedo feedback—a function of snow cover extent and duration—represents a large source of uncertainty in LSM simulations of future hydroclimatic conditions 34 . There is therefore a need to critically analyze the way LSMs partition rain and snow. Another method for predicting precipitation phase is through the application of atmospheric models with microphysics schemes that track a hydrometeor from its formation in the upper atmosphere to its deposition at the land surface 25 . Such an approach has been used to accurately simulate snowfall in several locations, including the Colorado Rocky Mountains 35 and the French Alps 26 . However, this manuscript focuses exclusively on methods that partition precipitation phase at the land surface due to the greater availability of surface forcing and validation data, the computational challenge of producing high-resolution, hemispherical-scale atmospheric model simulations, and the very wide use of LSMs using surface-based precipitation phase partitioning methods (greater than 2000 combined citations for the VIC and NOAH LSMs alone, according to the Web of Science). Furthermore, coarse-scale global circulation models (GCMs), such as those used in the Coupled Model Intercomparison Project 36 , employ either surface or microphysics precipitation phase partitioning methods. Thus, a critical examination of rain–snow thresholds stands to benefit both the land surface and climate modeling communities. Given the impact precipitation phase has on LSM output, it is essential that models accurately partition rain and snow. However, such a task is nontrivial, particularly at air temperatures near 0 °C 37 . Observational work indicates the temperature dependence of rain–snow partitioning follows a sigmoidal S-shaped curve with snowfall common above a surface air temperature ( T s ) of 0 °C and increasingly less probable when approaching 4 °C 38 , 39 , 40 . Previous studies have developed rain–snow partitioning schemes based solely on T s 41 , 42 or on T s plus near-surface humidity and/or air pressure 43 , 44 , 45 , 46 , 47 , 48 , 49 ; yet, the broader applicability of these analyses is hindered by the limited spatial extent and range of conditions explored. In this regard, detailed analyses of phase partitioning—as well as its spatial variability and meteorological controls—over hemispherical scales have yet to be conducted. A useful metric for defining the partitioning of precipitation phase at a given location is the 50% rain–snow T s threshold 42 , 48 . At this temperature precipitation occurs as rain and snow with equal frequency, while above the threshold precipitation is primarily rain and below primarily snow. The objectives of this study are to quantify the 50% rain–snow T s threshold over the Northern Hemisphere land surface, to assess how it varies with relative humidity (RH) and surface pressure ( P s ), and to evaluate the impact of threshold selection on simulated snowfall frequency. We accomplish this through an analysis of a comprehensive 29-year (1978–2007) observational precipitation phase and meteorological dataset from 11,924 stations across the Northern Hemisphere ( n obs = 17.8 million), the application of a binary logistic regression phase prediction model using a spatially and temporally continuous reanalysis product in the Northern Hemisphere, and simulations of snowfall frequency using reanalysis data and a selection of precipitation phase methods. This study provides the most extensive empirical evaluation of precipitation phase over land, and the results have implications for predicting the response of rain–snow partitioning to climate change and<|im_end|> <|im_start|>assistant University of Colorado Boulder researchers have created a map of the Northern Hemisphere showing how location and humidity can affect precipitation, illustrating wide variability in how and why different areas receive snow or rain. 32 degrees Fahrenheit is commonly considered to be the air temperature threshold for rain versus snow, thus informing meteorological forecasting and climate simulations. The new findings, however, show that coastal areas have a cooler threshold for rain, meaning that even temperatures below freezing might not produce snow. Inland and mountainous areas, meanwhile, are likelier to see flurries even when temperatures are several degrees above freezing. "In Denver, Colorado, it might be 40 degrees and snowing. But in Charleston, South Carolina, it could be 28 degrees and raining," said Noah Molotch, Director of the Center for Water Earth Science & Technology (CWEST) at CU Boulder and a co-author of the study. "This study shows these fine-grain differences on a hemisphere-level scale for the first time." The research, which compiled nearly 18 million precipitation observations spanning over 100 countries and four continents across the Northern Hemisphere, was published today in the journal Nature Communications. The ability to differentiate rain from snow has important ramifications for Earth's hydrologic cycle and water management, especially in drought-stricken areas of the American west. Winter snowfall is estimated to provide water storage for one billion people worldwide while climate warming could increase the amount of future rain-on-snow events, raising the risk of flooding. "Snow and rain differ greatly in the ways they affect climate," said Ben Livneh, an assistant professor in CU Boulder's Department of Civil, Environmental and Architectural Engineering and a co-author of the study. "Snow acts as a water reservoir and reflects incoming sunlight, whereas if the same amount of precipitation falls as rain, that can dramatically change water resource management decisions." To date, land surface models have typically predicted rain and snow based on a single, consistent air temperature threshold: snow below it and rain above it. But the CU Boulder researchers found that the threshold is not static and that relative humidity and surface pressure play an important role as well. "The rain-snow air temperature threshold is primarily a function of relative humidity and methods incorporating humidity and elevation are more likely to predict rain and snow correctly," said Keith Jennings, a graduate researcher in CU Boulder's Institute of Arctic and Alpine Research (INSTAAR) and the lead author of the study. "If you just use 32 degrees Fahrenheit across the board, your estimates will be wrong in lots of places." The continental U.S. had the most rain-snow variability of any country included in the study. Some of the coolest northern hemisphere thresholds were observed in the southeastern United States while the Rockies and intermountain West had some of the warmest thresholds. The new study could inform the future of climate and land surface modeling as researchers look for ways to predict snowfall versus rainfall more accurately, especially in areas crucial for freshwater, agriculture and biodiversity. Future research will look to improve the map and simulations by incorporating even more meteorological data points from around the world. "The great thing about this research is that anyone can observe these variables right in their own backyard," said Molotch. "The topic lends itself well to future citizen science." <|im_end|>

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2225, 279, 4363, 7479, 323, 10182, 34579, 10977, 13, 16644, 279, 5536, 61050, 10474, 706, 389, 91574, 2612, 11, 433, 374, 7718, 430, 4211, 30357, 17071, 11422, 323, 12056, 13, 4452, 11, 1778, 264, 3465, 374, 2536, 376, 27756, 11, 8104, 520, 3805, 20472, 3221, 220, 15, 37386, 34, 220, 1806, 662, 31943, 1697, 990, 15151, 279, 9499, 44393, 315, 11422, 4235, 75578, 17071, 287, 11263, 264, 65990, 278, 328, 35831, 16029, 449, 12056, 13772, 4279, 3485, 264, 7479, 3805, 9499, 320, 350, 274, 883, 315, 220, 15, 37386, 34, 323, 15098, 2753, 35977, 994, 31047, 220, 19, 37386, 34, 220, 1987, 1174, 220, 2137, 1174, 220, 1272, 662, 30013, 7978, 617, 8040, 11422, 4235, 75578, 17071, 287, 31956, 3196, 21742, 389, 350, 274, 220, 3174, 1174, 220, 2983, 477, 389, 350, 274, 5636, 3221, 1355, 10730, 38193, 323, 5255, 3805, 7410, 220, 3391, 1174, 220, 2096, 1174, 220, 1774, 1174, 220, 2790, 1174, 220, 2618, 1174, 220, 2166, 1174, 220, 2491, 2652, 3686, 11, 279, 27927, 4666, 2968, 315, 1521, 29060, 374, 57780, 291, 555, 279, 7347, 29079, 13112, 323, 2134, 315, 4787, 36131, 13, 763, 420, 5363, 11, 11944, 29060, 315, 10474, 17071, 287, 60654, 1664, 439, 1202, 29079, 54709, 323, 42142, 5848, 11835, 2345, 2017, 17728, 285, 45845, 29505, 617, 3686, 311, 387, 13375, 13, 362, 5505, 18767, 369, 27409, 279, 17071, 287, 315, 61050, 10474, 520, 264, 2728, 3813, 374, 279, 220, 1135, 4, 11422, 4235, 75578, 350, 274, 12447, 220, 2983, 1174, 220, 2166, 662, 2468, 420, 9499, 61050, 13980, 439, 11422, 323, 12056, 449, 6273, 11900, 11, 1418, 3485, 279, 12447, 61050, 374, 15871, 11422, 323, 3770, 15871, 12056, 13, 578, 26470, 315, 420, 4007, 527, 311, 76498, 279, 220, 1135, 4, 11422, 4235, 75578, 350, 274, 12447, 927, 279, 17355, 96878, 4363, 7479, 11, 311, 8720, 1268, 433, 35327, 449, 8844, 38193, 320, 68073, 8, 323, 7479, 7410, 320, 393, 274, 7026, 323, 311, 15806, 279, 5536, 315, 12447, 6727, 389, 46836, 12056, 13772, 11900, 13, 1226, 22829, 420, 1555, 459, 6492, 315, 264, 16195, 220, 1682, 4771, 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1,982

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract A mine waste deposit known as a tailings dam recently failed in the town of Jagersfontein, South Africa. The failure occurred amidst global concern about the safety record of these structures. Herein we use public remotely sensed data to gain insights into the construction history of the dam. The data suggest a construction sequence that is inconsistent with sound tailings management practices: asymmetric deposition, erosion gullies, large ponds and absence of beaches. These observations highlight the criticality of adhering to good construction practices and the potential of public data to monitor such adherence. Additionally, we present commercially available very high resolution satellite images to illustrate some of the immediate consequences of the failure. Introduction On Sunday 11 September, 2022 a diamond mine waste storage facility, known as a tailings dam, failed in the town of Jagersfontein, South Africa 1 . The failure released a mudflow that killed at least one person and destroyed multiple houses. Figure 1 presents the immediate surroundings of the tailings dam prior to failure and highlights the proximity of residential areas to the dam. The tragic failure occurred at a time of heightened global concern around the safety of tailings dams, especially after a failure in Brumadinho, Brazil killed 270 people in 2019 2 , 3 , 4 . The Brumadinho failure prompted the creation of the Global Industry Standard for Tailings Management which strives to achieve \"zero harm to people and the environment\" 5 . The Jagersfontein failure was a reminder that there is still much work to do to achieve this objective. Herein we use the power of optical remotely sensed data to gain insights into the construction history of the Jagersfontein dam, precursors of failure and the immediate failure consequences. Figure 1 The Jagersfontein dam and its surroundings 19 months before failure, created using QGIS software version 3.26 ( ). Full size image Mining activities in Jagersfontein date back to the 1870s. The mine was initially operated as an open pit and changed to underground mining in 1913. The De Beers Group acquired the mine in 1931 and operated it until 1971 when underground ore extraction ceased. The De Beers Group sold the mine in 2010 and subsequent owners reprocessed the legacy mine waste already on surface without further ore extraction. At least two more ownership changes happened after 2010 including one that took place only months before the failure of the dam. At the time of the failure, and during most of the post-2010 period, the mine was owned by the subsidiary company Jagersfontein Developments 6 , 7 , 8 . Unlike conventional water retention dams, tailings dams are often constructed progressively over their entire operational life which can easily span decades 9 , 10 . This poses the double challenge of ensuring that high construction quality standards are maintained over a long period of time and that the construction process is duly documented 11 . Optical remotely sensed data are valuable for monitoring certain aspects of the operation and to investigate the construction history 12 , 13 , 14 . For instance, investigations into the failure of the Fundão and Brumadinho tailings dams in Brazil used public and commercial optical satellite images to investigate their construction and operation histories 13 , 14 . Herein we use optical satellite imagery in a similar manner to investigate the history of the Jagersfontein dam and some of the immediate consequences of the failure. Importantly, our investigation into the pre-failure history of the dam relies exclusively on open access data. As such, our work contributes to empower a wide variety of stakeholders interested in proactively monitoring the safety of tailings dams. We also employed commercial satellite imagery although only to assess the consequences of failure. Because we have not accessed the site, our observations have not been validated by ground truth. However, they illustrate situations that should trigger site inspections by those tasked with ensuring the stability of these structures. Our analysis also informs hypotheses that can be further explored during an in situ investigation into the causes of failure 15 . Results Construction and operation history of the Jagersfontein dam after 2010 Aerial and satellite images suggest that the Jagersfontein tailings dam and nearby mine waste stockpiles did not undergo significant changes between mine closure in 1971 and the onset of surface mine waste reprocessing in 2010 (Fig. S1 ). Accordingly, the focus herein is on the post-2010 development of the dam (Fig. 2 ). Hereafter we use the phrase 'original dam' to refer to the 2010 configuration of the dam prior to the deposition of tailings resulting from waste reprocessing (Fig. 2 a). The images show that by April 2013, the original dam had almost doubled its footprint due to an expansion built on its west side (Fig. 2 b). By August 2015, all tailings were being deposited in the west expansion while parts of the original dam were being reworked and activity in the area that would become an east expansion was also underway (Fig. 2 c). By July 2017, tailings were being initially deposited into the west expansion and subsequently transported to the original dam and east expansion via two furrows connected to a gap in the internal wall (Figs. 2 d, 3 a,b). By February 2019, erosion gullies 4 to 5 m wide had developed on the internal face of the northern wall and on the external face of the portion of the southeastern wall that eventually failed (Figs. 2 e, 3 c,d). By May 2019, the furrows were almost entirely buried but eastward migration of tailings deposited in the west expansion continued through the gap in the internal wall (Fig. 2 f). The increased width of the southeastern wall, which eventually failed, may indicate that buttressing efforts were underway. The southeastern corner of the dam exhibited an irregular geometry which may have been due to erosion or slope instability 16 . Eastward migration of tailings continued during 2020 (Fig. 2 g) and by February 2021, the internal wall", "role": "user" }, { "content": "On 11 September 2022, a diamond mine waste storage facility, known as a tailings dam, failed in the town of Jagersfontein in the Free State province of South Africa. In the failure, one person was killed and multiple homes destroyed. Tailings are the finely ground leftovers that remain after valuable metals are removed from rock ore. Tailings are generally transported jointly with water and deposited in a tailings dam for storage. Now, six months later in 2023, civil engineers at the University of the Witwatersrand, Johannesburg (Wits), have used public satellite and aerial imagery in a study to investigate the history of the Jagersfontein dam. Satellite images show what went wrong Sources of public satellite images used in the study included Google Earth Pro and the Sentinel-2 and Landsat 8 satellite missions. Additionally, some of the immediate consequences of the failure were assessed using commercial satellite images. Dr. Luis Torres-Cruz and Mr. Christopher O'Donovan in the School of Civil and Environmental Engineering at Wits authored the paper which was published in the journal Scientific Reports. The study found that the history of the Jagersfontein dam deviates from best engineering practice. The deviations include mine waste deposition from predominantly one side of the dam, erosion gullies on the dam wall, and significant amounts of ponded water at times positioned against the retaining structure. Based on the analyzed images, the study hypothesizes that percolation of water through the dam, followed by external erosion, ultimately triggered instability. \"We expect our paper to be useful to those interested in understanding how this tragic event came to be and also to help prevent future failures,\" says Torres-Cruz, corresponding author and a Senior Lecturer in the School of Civil and Environmental Engineering, who specializes in geotechnical aspects of tailings dams. O'Donovan, study co-author and a Wits Master's candidate interested in efficient engineering practices and creating access to information, adds, \"The fact that our study relies on publicly available data to investigate the history of the dam implies that anyone can independently verify our observations.\" Assessment of consequences To assess the impact and consequences of the dam failure, Torres-Cruz and O'Donovan captured two high-resolution satellite images that illustrate the damage inflicted on the surrounding residential areas. Based on a three-dimensional reconstruction of the failed dam, the authors estimate that between four and six million cubic meters of mine waste were released. The study also includes an animation that illustrates the post-failure geometry. Additional satellite imagery shows that the mine waste traveled 7km over dry land and 56km along streams and rivers to reach the reservoir of the Kalkfontein dam. Outlook The paper notes that some of the satellite imagery viewing platforms used in the analysis are free for non-commercial purposes and relatively easy to use. Accordingly, when coupled with an understanding of tailings dams, these platforms can empower stakeholders to adopt public satellite imagery as a starting point to proactively monitor tailings dams. Furthermore, the study suggests that greater awareness of the capabilities of public satellite imagery can encourage greater adherence to good construction practices. The study also emphasizes that a robust monitoring strategy of tailings dams should focus on their adequate construction and operation. It also draws attention to the importance of conducting an official and independent site investigation to better understand the failure sequence and the conditions that led to it. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract A mine waste deposit known as a tailings dam recently failed in the town of Jagersfontein, South Africa. The failure occurred amidst global concern about the safety record of these structures. Herein we use public remotely sensed data to gain insights into the construction history of the dam. The data suggest a construction sequence that is inconsistent with sound tailings management practices: asymmetric deposition, erosion gullies, large ponds and absence of beaches. These observations highlight the criticality of adhering to good construction practices and the potential of public data to monitor such adherence. Additionally, we present commercially available very high resolution satellite images to illustrate some of the immediate consequences of the failure. Introduction On Sunday 11 September, 2022 a diamond mine waste storage facility, known as a tailings dam, failed in the town of Jagersfontein, South Africa 1 . The failure released a mudflow that killed at least one person and destroyed multiple houses. Figure 1 presents the immediate surroundings of the tailings dam prior to failure and highlights the proximity of residential areas to the dam. The tragic failure occurred at a time of heightened global concern around the safety of tailings dams, especially after a failure in Brumadinho, Brazil killed 270 people in 2019 2 , 3 , 4 . The Brumadinho failure prompted the creation of the Global Industry Standard for Tailings Management which strives to achieve "zero harm to people and the environment" 5 . The Jagersfontein failure was a reminder that there is still much work to do to achieve this objective. Herein we use the power of optical remotely sensed data to gain insights into the construction history of the Jagersfontein dam, precursors of failure and the immediate failure consequences. Figure 1 The Jagersfontein dam and its surroundings 19 months before failure, created using QGIS software version 3.26 ( ). Full size image Mining activities in Jagersfontein date back to the 1870s. The mine was initially operated as an open pit and changed to underground mining in 1913. The De Beers Group acquired the mine in 1931 and operated it until 1971 when underground ore extraction ceased. The De Beers Group sold the mine in 2010 and subsequent owners reprocessed the legacy mine waste already on surface without further ore extraction. At least two more ownership changes happened after 2010 including one that took place only months before the failure of the dam. At the time of the failure, and during most of the post-2010 period, the mine was owned by the subsidiary company Jagersfontein Developments 6 , 7 , 8 . Unlike conventional water retention dams, tailings dams are often constructed progressively over their entire operational life which can easily span decades 9 , 10 . This poses the double challenge of ensuring that high construction quality standards are maintained over a long period of time and that the construction process is duly documented 11 . Optical remotely sensed data are valuable for monitoring certain aspects of the operation and to investigate the construction history 12 , 13 , 14 . For instance, investigations into the failure of the Fundão and Brumadinho tailings dams in Brazil used public and commercial optical satellite images to investigate their construction and operation histories 13 , 14 . Herein we use optical satellite imagery in a similar manner to investigate the history of the Jagersfontein dam and some of the immediate consequences of the failure. Importantly, our investigation into the pre-failure history of the dam relies exclusively on open access data. As such, our work contributes to empower a wide variety of stakeholders interested in proactively monitoring the safety of tailings dams. We also employed commercial satellite imagery although only to assess the consequences of failure. Because we have not accessed the site, our observations have not been validated by ground truth. However, they illustrate situations that should trigger site inspections by those tasked with ensuring the stability of these structures. Our analysis also informs hypotheses that can be further explored during an in situ investigation into the causes of failure 15 . Results Construction and operation history of the Jagersfontein dam after 2010 Aerial and satellite images suggest that the Jagersfontein tailings dam and nearby mine waste stockpiles did not undergo significant changes between mine closure in 1971 and the onset of surface mine waste reprocessing in 2010 (Fig. S1 ). Accordingly, the focus herein is on the post-2010 development of the dam (Fig. 2 ). Hereafter we use the phrase 'original dam' to refer to the 2010 configuration of the dam prior to the deposition of tailings resulting from waste reprocessing (Fig. 2 a). The images show that by April 2013, the original dam had almost doubled its footprint due to an expansion built on its west side (Fig. 2 b). By August 2015, all tailings were being deposited in the west expansion while parts of the original dam were being reworked and activity in the area that would become an east expansion was also underway (Fig. 2 c). By July 2017, tailings were being initially deposited into the west expansion and subsequently transported to the original dam and east expansion via two furrows connected to a gap in the internal wall (Figs. 2 d, 3 a,b). By February 2019, erosion gullies 4 to 5 m wide had developed on the internal face of the northern wall and on the external face of the portion of the southeastern wall that eventually failed (Figs. 2 e, 3 c,d). By May 2019, the furrows were almost entirely buried but eastward migration of tailings deposited in the west expansion continued through the gap in the internal wall (Fig. 2 f). The increased width of the southeastern wall, which eventually failed, may indicate that buttressing efforts were underway. The southeastern corner of the dam exhibited an irregular geometry which may have been due to erosion or slope instability 16 . Eastward migration of tailings continued during 2020 (Fig. 2 g) and by February 2021, the internal wall<|im_end|> <|im_start|>assistant On 11 September 2022, a diamond mine waste storage facility, known as a tailings dam, failed in the town of Jagersfontein in the Free State province of South Africa. In the failure, one person was killed and multiple homes destroyed. Tailings are the finely ground leftovers that remain after valuable metals are removed from rock ore. Tailings are generally transported jointly with water and deposited in a tailings dam for storage. Now, six months later in 2023, civil engineers at the University of the Witwatersrand, Johannesburg (Wits), have used public satellite and aerial imagery in a study to investigate the history of the Jagersfontein dam. Satellite images show what went wrong Sources of public satellite images used in the study included Google Earth Pro and the Sentinel-2 and Landsat 8 satellite missions. Additionally, some of the immediate consequences of the failure were assessed using commercial satellite images. Dr. Luis Torres-Cruz and Mr. Christopher O'Donovan in the School of Civil and Environmental Engineering at Wits authored the paper which was published in the journal Scientific Reports. The study found that the history of the Jagersfontein dam deviates from best engineering practice. The deviations include mine waste deposition from predominantly one side of the dam, erosion gullies on the dam wall, and significant amounts of ponded water at times positioned against the retaining structure. Based on the analyzed images, the study hypothesizes that percolation of water through the dam, followed by external erosion, ultimately triggered instability. "We expect our paper to be useful to those interested in understanding how this tragic event came to be and also to help prevent future failures," says Torres-Cruz, corresponding author and a Senior Lecturer in the School of Civil and Environmental Engineering, who specializes in geotechnical aspects of tailings dams. O'Donovan, study co-author and a Wits Master's candidate interested in efficient engineering practices and creating access to information, adds, "The fact that our study relies on publicly available data to investigate the history of the dam implies that anyone can independently verify our observations." Assessment of consequences To assess the impact and consequences of the dam failure, Torres-Cruz and O'Donovan captured two high-resolution satellite images that illustrate the damage inflicted on the surrounding residential areas. Based on a three-dimensional reconstruction of the failed dam, the authors estimate that between four and six million cubic meters of mine waste were released. The study also includes an animation that illustrates the post-failure geometry. Additional satellite imagery shows that the mine waste traveled 7km over dry land and 56km along streams and rivers to reach the reservoir of the Kalkfontein dam. Outlook The paper notes that some of the satellite imagery viewing platforms used in the analysis are free for non-commercial purposes and relatively easy to use. Accordingly, when coupled with an understanding of tailings dams, these platforms can empower stakeholders to adopt public satellite imagery as a starting point to proactively monitor tailings dams. Furthermore, the study suggests that greater awareness of the capabilities of public satellite imagery can encourage greater adherence to good construction practices. The study also emphasizes that a robust monitoring strategy of tailings dams should focus on their adequate construction and operation. It also draws attention to the importance of conducting an official and independent site investigation to better understand the failure sequence and the conditions that led to it. <|im_end|>

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1,979

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract As the risks of tobacco use become recognized and smoking becomes stigmatized, new smokers may be increasingly driven to smoke by biological or genetic vulnerabilities rather than social desirability. Given that genetic risk for deviant proneness is shared across other psychiatric and addictive disorders, we predicted that as rates of smoking decreased through the latter half of the twentieth century, associations between smoking and psychopathology would increase. Participants ( N =25 412) from a large US study—the National Epidemiologic Survey on Alcohol and Related Conditions, NESARC—were interviewed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule – DSM-IV Version (AUDADIS-IV) and classified into one of five birth cohort decades (1940s to 1980s) and three smoking history (nonsmokers, never-dependent smokers and ever-dependent smokers) groups. We found that the prevalence of smoking decreased across the five birth cohorts, but associations of smoking with drug and AUDs, attention-deficit hyperactivity disorder, bipolar disorder and antisocial personality disorder, each increased monotonically in more recently born cohorts, even after adjusting for concurrent demographic and socioeconomic changes. For drug and AUDs, increases were observed among smokers both with and without a history of nicotine dependence; for other outcomes, increases were entirely driven by nicotine-dependent smokers. Findings suggest that smokers in more recent cohorts have disproportionately high psychiatric vulnerability, and may benefit from greater mental health screenings. Differentiating between casual and dependent smokers may further help prioritize those at greatest risk. Researchers should also be aware of potential variation in psychiatric comorbidity based on cohort of birth when defining groups of smokers, to minimize confounding. Introduction Cigarette smoking has undergone substantial cultural shifts in the Western hemisphere through the last 100 years. The early decades of the twentieth century saw rapidly expanding use, contributed to in part by automation of cigarette manufacturing technology, growing advertising and marketing, free distribution of cigarettes during the World Wars, and increased acceptance of smoking among women. 1 , 2 , 3 Subsequently, as tobacco became recognized as a cause of multiple cancers, cardiovascular and other disease, the tide began to shift. Beginning in the early 1960s, a series of prevention measures, including US Surgeon General’s warnings, advertising bans, stringent labeling requirements, and tax policies were introduced. In the latter half of the 20th century, smoking rates declined, 4 , 5 from almost half of the US population in the 1950s to <20% in 2010. 6 Comparable shifts in policies and use have occurred in other Western countries. 7 , 8 These shifts raise a larger question of whether smokers today might systematically differ from those who grew up and began smoking in periods when smoking was widespread, and attitudes toward smoking more permissive. Evidence shows that population-level changes in attitudes influence individual behaviors: 9 , 10 for example, individuals who mature in birth cohorts with more restrictive social norms related to drinking and drug use are themselves less likely to use alcohol or cannabis as adolescents and vice versa . Similarly, as adverse consequences of tobacco have become more recognized, smoking rates have fallen. However, as smoking has become increasingly viewed as a medically risky and socially undesirable behavior over the last several decades, and restrictions of smoking have proliferated in many states (for example, smoke-free workplaces and public spaces), initiation of smoking may have become increasingly concentrated within population subgroups who are intrinsically more prone to deviant behaviors. 11 Previous research has indicated that individuals who use illicit substances during periods of lower prevalence compared with other periods have higher levels of deviance 10 suggesting that a similar mechanism may be possible for smokers over time. If so, then because deviance proneness has genetic underpinnings and is associated with an array of other risky behaviors and externalizing disorders, smokers today may have higher associated rates of associated psychopathology than their counterparts from earlier generations when tobacco use was normative. 12 , 13 , 14 Although a relationship between smoking a range of externalizing outcomes and disorders is long established, 15 , 16 , 17 , 18 few studies have examined whether this relationship itself varies as a function of time. One Canadian study reported increased associations between smoking and depression in the 1990s, as compared with the 50 s and 70 s; 19 however, no other psychiatric outcomes were assessed. We previously reported that the relationship between smoking and drug dependence as well as the personality trait of neuroticism increased across cohorts of smokers born in 1920s to 1980s. 20 However, these studies were limited by the size and characteristics of the samples, potential lack of differentiation between cohort and age effects, and assessment of few psychiatric disorders. In the present study, we investigate changes in associations between smoking and psychopathology across five birth cohorts of the twentieth century (1940s to 1980s), using the National Epidemiological Survey of Alcohol and Related Conditions (NESARC), 21 , 22 a large, nationally representative US survey with detailed diagnostic assessments. In order to identify changes in associations, we model six disorders that already have well documented associations with tobacco use: drug-use disorder, alcohol-use disorder (AUD), attention-deficit hyperactivity disorder, bipolar disorder and antisocial personality disorder. We restrict our analysis to cigarette smoking, as not only is the proportion of non-cigarette tobacco users in this sample small, 23 but the secular trends motivating our hypotheses may not apply to other forms of tobacco use (for example, cigars, snuff and e-cigarettes). We hypothesize that (1) smokers born in later, more recently born cohorts as compared with earlier birth cohorts will have higher psychiatric comorbidity by age 25, even after adjusting for demographic and socioeconomic changes; and (2) given the greater severity and genetic underpinnings associated with substance dependence relative to substance use, 7 , 24 , 25 the gradient of change will be larger for smoker groups with, as compared to without, a history of nicotine dependence. Materials and methods Sample The study is based on the participants who completed both Waves 1 and 2 of the National Epidemiological Survey for Alcohol and Related Conditions (NESARC).", "role": "user" }, { "content": "Researchers at Columbia University Medical Center (CUMC) and New York State Psychiatric Institute have found that while cigarette smoking rates have declined among younger people in the United States, those who do smoke are more likely to have a psychiatric or substance use disorder compared with those who began smoking in earlier decades. The findings were published today in Molecular Psychiatry. The study revealed that as overall rates of smoking decreased, beginning in the 1960s, the proportion of smokers who are nicotine-dependent increased. The study also found that the likelihood of having a substance use disorder increased among all smokers with each decade, regardless of their dependence on nicotine. Nicotine-dependent smokers who began lighting up in the 1980s were also more likely than older smokers to have a psychiatric condition such as attention deficit hyperactivity disorder (ADHD), bipolar disorder, or antisocial personality disorder. \"Our study confirms that recent smokers, though a relatively smaller group than those who started smoking decades ago, are more vulnerable to psychiatric and substance use disorders,\" said lead author Ardesheer Talati, PhD, assistant professor of clinical neurobiology (in Psychiatry) at CUMC and NYSPI and a co-author of the study. \"These findings suggest that today's adolescent and young adult smokers may benefit from mental health screening so that any related psychiatric or substance use problems can be identified and addressed early.\" Smoking rates steadily increased during the first half of the 20th century. Beginning in the 1960s, growing recognition of the health risks associated with smoking led to a gradual decline in smoking rates, from nearly half of the US population in the 1950s to fewer than 20 percent today. Researchers from Columbia University Medical Center (CUMC) and New York State Psychiatric Institute (NYSPI) speculated that as smoking became increasingly stigmatized, the relative few who began smoking in later decades may be more susceptible to psychiatric and substance use disorders. \"The association between smoking and psychiatric and substance use problems has been well documented,\" says Deborah Hasin, PhD, professor of epidemiology (in Psychiatry) at CUMC, director of the Substance Abuse Research Group at NYSPI, and a co-author of the study. \"The current question is whether people who began smoking when it was less socially acceptable to do so were also somehow more likely to have mental health and substance use problems.\" The researchers investigated this hypothesis among 25,000 people who participated in the National Epidemiological Survey of Alcohol and Related Conditions (NESARC), a large epidemiological survey funded by the National Institute of Alcohol Abuse and Alcoholism. The participants were divided into five birth groups: those who were born in the 1940s, 1950s, 1960s, 1970s, or 1980s. \"These findings also have implications for ongoing nationwide efforts to support smoking cessation efforts,\" notes Katherine Keyes, PhD, assistant professor of Epidemiology at Columbia's Mailman School of Public Health, and a co-author. \"Given that mental health problems are also predictive of unsuccessful efforts to reduce or quit smoking, these findings suggest that cessation efforts that treat both withdrawal from nicotine and underlying mental health conditions are increasingly crucial.\" The authors noted that additional studies are needed to determine if there is a causal relationship between biological or genetic factors and mental health or substance use problems in smokers. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract As the risks of tobacco use become recognized and smoking becomes stigmatized, new smokers may be increasingly driven to smoke by biological or genetic vulnerabilities rather than social desirability. Given that genetic risk for deviant proneness is shared across other psychiatric and addictive disorders, we predicted that as rates of smoking decreased through the latter half of the twentieth century, associations between smoking and psychopathology would increase. Participants ( N =25 412) from a large US study—the National Epidemiologic Survey on Alcohol and Related Conditions, NESARC—were interviewed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule – DSM-IV Version (AUDADIS-IV) and classified into one of five birth cohort decades (1940s to 1980s) and three smoking history (nonsmokers, never-dependent smokers and ever-dependent smokers) groups. We found that the prevalence of smoking decreased across the five birth cohorts, but associations of smoking with drug and AUDs, attention-deficit hyperactivity disorder, bipolar disorder and antisocial personality disorder, each increased monotonically in more recently born cohorts, even after adjusting for concurrent demographic and socioeconomic changes. For drug and AUDs, increases were observed among smokers both with and without a history of nicotine dependence; for other outcomes, increases were entirely driven by nicotine-dependent smokers. Findings suggest that smokers in more recent cohorts have disproportionately high psychiatric vulnerability, and may benefit from greater mental health screenings. Differentiating between casual and dependent smokers may further help prioritize those at greatest risk. Researchers should also be aware of potential variation in psychiatric comorbidity based on cohort of birth when defining groups of smokers, to minimize confounding. Introduction Cigarette smoking has undergone substantial cultural shifts in the Western hemisphere through the last 100 years. The early decades of the twentieth century saw rapidly expanding use, contributed to in part by automation of cigarette manufacturing technology, growing advertising and marketing, free distribution of cigarettes during the World Wars, and increased acceptance of smoking among women. 1 , 2 , 3 Subsequently, as tobacco became recognized as a cause of multiple cancers, cardiovascular and other disease, the tide began to shift. Beginning in the early 1960s, a series of prevention measures, including US Surgeon General’s warnings, advertising bans, stringent labeling requirements, and tax policies were introduced. In the latter half of the 20th century, smoking rates declined, 4 , 5 from almost half of the US population in the 1950s to <20% in 2010. 6 Comparable shifts in policies and use have occurred in other Western countries. 7 , 8 These shifts raise a larger question of whether smokers today might systematically differ from those who grew up and began smoking in periods when smoking was widespread, and attitudes toward smoking more permissive. Evidence shows that population-level changes in attitudes influence individual behaviors: 9 , 10 for example, individuals who mature in birth cohorts with more restrictive social norms related to drinking and drug use are themselves less likely to use alcohol or cannabis as adolescents and vice versa . Similarly, as adverse consequences of tobacco have become more recognized, smoking rates have fallen. However, as smoking has become increasingly viewed as a medically risky and socially undesirable behavior over the last several decades, and restrictions of smoking have proliferated in many states (for example, smoke-free workplaces and public spaces), initiation of smoking may have become increasingly concentrated within population subgroups who are intrinsically more prone to deviant behaviors. 11 Previous research has indicated that individuals who use illicit substances during periods of lower prevalence compared with other periods have higher levels of deviance 10 suggesting that a similar mechanism may be possible for smokers over time. If so, then because deviance proneness has genetic underpinnings and is associated with an array of other risky behaviors and externalizing disorders, smokers today may have higher associated rates of associated psychopathology than their counterparts from earlier generations when tobacco use was normative. 12 , 13 , 14 Although a relationship between smoking a range of externalizing outcomes and disorders is long established, 15 , 16 , 17 , 18 few studies have examined whether this relationship itself varies as a function of time. One Canadian study reported increased associations between smoking and depression in the 1990s, as compared with the 50 s and 70 s; 19 however, no other psychiatric outcomes were assessed. We previously reported that the relationship between smoking and drug dependence as well as the personality trait of neuroticism increased across cohorts of smokers born in 1920s to 1980s. 20 However, these studies were limited by the size and characteristics of the samples, potential lack of differentiation between cohort and age effects, and assessment of few psychiatric disorders. In the present study, we investigate changes in associations between smoking and psychopathology across five birth cohorts of the twentieth century (1940s to 1980s), using the National Epidemiological Survey of Alcohol and Related Conditions (NESARC), 21 , 22 a large, nationally representative US survey with detailed diagnostic assessments. In order to identify changes in associations, we model six disorders that already have well documented associations with tobacco use: drug-use disorder, alcohol-use disorder (AUD), attention-deficit hyperactivity disorder, bipolar disorder and antisocial personality disorder. We restrict our analysis to cigarette smoking, as not only is the proportion of non-cigarette tobacco users in this sample small, 23 but the secular trends motivating our hypotheses may not apply to other forms of tobacco use (for example, cigars, snuff and e-cigarettes). We hypothesize that (1) smokers born in later, more recently born cohorts as compared with earlier birth cohorts will have higher psychiatric comorbidity by age 25, even after adjusting for demographic and socioeconomic changes; and (2) given the greater severity and genetic underpinnings associated with substance dependence relative to substance use, 7 , 24 , 25 the gradient of change will be larger for smoker groups with, as compared to without, a history of nicotine dependence. Materials and methods Sample The study is based on the participants who completed both Waves 1 and 2 of the National Epidemiological Survey for Alcohol and Related Conditions (NESARC).<|im_end|> <|im_start|>assistant Researchers at Columbia University Medical Center (CUMC) and New York State Psychiatric Institute have found that while cigarette smoking rates have declined among younger people in the United States, those who do smoke are more likely to have a psychiatric or substance use disorder compared with those who began smoking in earlier decades. The findings were published today in Molecular Psychiatry. The study revealed that as overall rates of smoking decreased, beginning in the 1960s, the proportion of smokers who are nicotine-dependent increased. The study also found that the likelihood of having a substance use disorder increased among all smokers with each decade, regardless of their dependence on nicotine. Nicotine-dependent smokers who began lighting up in the 1980s were also more likely than older smokers to have a psychiatric condition such as attention deficit hyperactivity disorder (ADHD), bipolar disorder, or antisocial personality disorder. "Our study confirms that recent smokers, though a relatively smaller group than those who started smoking decades ago, are more vulnerable to psychiatric and substance use disorders," said lead author Ardesheer Talati, PhD, assistant professor of clinical neurobiology (in Psychiatry) at CUMC and NYSPI and a co-author of the study. "These findings suggest that today's adolescent and young adult smokers may benefit from mental health screening so that any related psychiatric or substance use problems can be identified and addressed early." Smoking rates steadily increased during the first half of the 20th century. Beginning in the 1960s, growing recognition of the health risks associated with smoking led to a gradual decline in smoking rates, from nearly half of the US population in the 1950s to fewer than 20 percent today. Researchers from Columbia University Medical Center (CUMC) and New York State Psychiatric Institute (NYSPI) speculated that as smoking became increasingly stigmatized, the relative few who began smoking in later decades may be more susceptible to psychiatric and substance use disorders. "The association between smoking and psychiatric and substance use problems has been well documented," says Deborah Hasin, PhD, professor of epidemiology (in Psychiatry) at CUMC, director of the Substance Abuse Research Group at NYSPI, and a co-author of the study. "The current question is whether people who began smoking when it was less socially acceptable to do so were also somehow more likely to have mental health and substance use problems." The researchers investigated this hypothesis among 25,000 people who participated in the National Epidemiological Survey of Alcohol and Related Conditions (NESARC), a large epidemiological survey funded by the National Institute of Alcohol Abuse and Alcoholism. The participants were divided into five birth groups: those who were born in the 1940s, 1950s, 1960s, 1970s, or 1980s. "These findings also have implications for ongoing nationwide efforts to support smoking cessation efforts," notes Katherine Keyes, PhD, assistant professor of Epidemiology at Columbia's Mailman School of Public Health, and a co-author. "Given that mental health problems are also predictive of unsuccessful efforts to reduce or quit smoking, these findings suggest that cessation efforts that treat both withdrawal from nicotine and underlying mental health conditions are increasingly crucial." The authors noted that additional studies are needed to determine if there is a causal relationship between biological or genetic factors and mental health or substance use problems in smokers. <|im_end|>

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1,982

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background CRISPR-Cas systems endow bacterial and archaeal species with adaptive immunity mechanisms to fend off invading phages and foreign genetic elements. CRISPR-Cas9 has been harnessed to confer virus interference against DNA viruses in eukaryotes, including plants. In addition, CRISPR-Cas13 systems have been used to target RNA viruses and the transcriptome in mammalian and plant cells. Recently, CRISPR-Cas13a has been shown to confer modest interference against RNA viruses. Here, we characterized a set of different Cas13 variants to identify those with the most efficient, robust, and specific interference activities against RNA viruses in planta using Nicotiana benthamiana . Results Our data show that LwaCas13a, PspCas13b, and CasRx variants mediate high interference activities against RNA viruses in transient assays. Moreover, CasRx mediated robust interference in both transient and stable overexpression assays when compared to the other variants tested. CasRx targets either one virus alone or two RNA viruses simultaneously, with robust interference efficiencies. In addition, CasRx exhibits strong specificity against the target virus and does not exhibit collateral activity in planta . Conclusions Our data establish CasRx as the most robust Cas13 variant for RNA virus interference applications in planta and demonstrate its suitability for studying key questions relating to virus biology. Introduction Plant viruses are obligate parasites that rely mostly on host cells to complete their life (infection) cycle. They infect many economically important crops, leading to a significant decrease in crop yields worldwide. It is estimated that plant diseases cause 10 to 15% reduction in global crop yields each year, and 47% of this loss is caused by viruses [ 1 , 2 , 3 ]. Therefore, plant viruses threaten world agriculture and the food security of the rapidly growing world population. Most viruses infecting plants are RNA viruses, which comprise diverse groups and subgroups that are classified based on phylogenetic relationships determined by sequence homologies among the conserved virus genes, such as RNA-dependent RNA polymerase (RdRp), coat protein (CP), and movement protein (MP) [ 4 ]. Viruses with positive-sense, single-stranded RNA genomes represent most of these viruses. Therefore, we urgently need to develop effective antiviral agents to preserve crop yields from such viruses [ 5 ]. Various strategies, based on genome and genetic engineering approaches, have been developed to combat viruses, including directly inhibiting virus replication or targeting host factors required by viruses to replicate and persist [ 6 ]. RNA interference (RNAi), for example, is an innate antiviral immunity mechanism that has been successfully used to combat various plant viruses [ 7 , 8 ]. Nevertheless, the availability of such antiviral strategies is still limited to specific virus groups, and many viruses, through evolution, mutate readily and have developed various counter-defense mechanisms, leading to rapid emergence of new viruses and nullifying the available antiviral approaches. Bacterial and archaeal species employ CRISPR-Cas systems to fend off foreign genetic elements from invading phages and nucleic acids [ 9 ]. CRISPR-Cas adaptive immunity involves three main stages: (1) adaptation and spacer acquisition, where a piece of the invader genome is incorporated into the CRISPR array proximal to the 5′ leader sequence; (2) biogenesis of the CRISPR array into pre-CRISPR RNA (crRNA) to provide targeting specificity and processing into mature crRNA; and (3) interference, where the crRNA binds and guides the effector protein to the invader’s genome for cleavage or degradation [ 10 ]. These systems are divided into two classes: class I systems, which rely on multiple Cas proteins that mediate the target interference, and class II systems, which are represented by single, multidomain effector proteins. The class II CRISPR/Cas systems include types II, V, and VI. Types II and V comprise endonucleases that operate at the DNA level. On the other hand, type VI CRISPR/Cas systems are distinct in that they exclusively target RNA molecules [ 10 , 11 ]. Because class II CRISPR-Cas systems are composed of a single effector to mediate the interference and immunity against the invader’s genomes, their engineering is simple; therefore, they are widely adopted in genome and transcriptome engineering. In recent years, class II CRISPR/Cas systems have been extensively developed to provide powerful and versatile tools for various genome engineering purposes [ 12 , 13 , 14 ]. Several studies have interrogated genomic and metagenomic sequencing data through the use of signature proteins to identify novel RNA-guided DNA and RNA endonucleases [ 11 , 15 ]. Class II type II CRISPR-Cas9 targets DNA and has been used for genome engineering across eukaryotic species [ 16 ]. The impressive success of the DNA-targeting CRISPR/Cas systems in engineering and specifically editing the genome of different eukaryotic cells has led to the exploitation of this technology as a programmable antiviral defense strategy to confer resistance to many eukaryotic viruses, including human viruses [ 17 , 18 , 19 ]. In plants, CRISPR/Cas9 efficiently confers viral resistance to host plants. We and others have shown that CRISPR/Cas9 mediates strong interference against various DNA viruses. We have also shown that a single guide RNA targeting a conserved intergenic region in multiple Gemini viruses guides Cas9 to target different viruses simultaneously, providing interference against these DNA viruses [ 20 , 21 , 22 , 23 ]. These studies demonstrate the enormous potential of CRISPR/Cas9 as a promising strategy against plant DNA viruses [ 17 ]. Nevertheless, such DNA-targeting CRISPR modalities cannot target RNA molecules and therefore limit their applicability for targeted interference against RNA viruses. Class II type VI CRISPR-Cas systems are RNA-guided and RNA-targeting machineries that provide prokaryotes with immunity against RNA [ 24 ] and DNA phages [ 25 ]. All type VI CRISPR-Cas systems have a single effector protein known as the Cas13 effector, formerly the C2c2 CRISPR-Cas system [ 24 ]. Cas13 effectors possess two distinct catalytic activities; one is RNase activity provided by the two higher eukaryotic and prokaryotic nucleotide binding domains (HEPN), which is required for target RNA degradation, and the other is RNase activity that catalyzes the processing and maturation of the pre-crRNA into mature crRNA [ 26 , 27 ]. Intriguingly,", "role": "user" }, { "content": "A novel CRISPR/Cas system that can efficiently attack and destroy several prolific plant viruses has been developed by KAUST using tobacco plants and is now being extended to rice and other crops. This research aims to reduce the impact of plant viral infections, which cause losses of 10-15 percent of the global crop yield every year. CRISPR is a natural system found in bacteria that confers adaptive immunity by copying and \"storing\" elements of viral DNA, which remind the organism of that particular virus and ready it for a future attack. When the virus attacks again, the bacteria's CRISPR system releases CRISPR RNAs, which are small molecules that guide CRISPR-associated (Cas) proteins to bind to the viral DNA and attack and destroy the virus. Scientists have harnessed this system and developed CRISPR/Cas technology, most notably as a genome editing tool used to modify segments of DNA. Recently, scientists from KAUST developed CRISPR/Cas13, a promising method of quelling RNA-based viral attacks in plants. \"Most plant viral genomes are based on single-stranded RNA,\" says Magdy Mahfouz, who supervised his Ph.D. student Ahmed Mahas and postdoc Rashid Aman through the research. \"So we needed a Cas protein that would cleave RNA to destroy the viruses. Our first study used variant Cas13a, which attacked the turnip mosaic virus, but it was not efficient enough. We decided to search for an alternative Cas13 variant that was more robust.\" The variant CasRx (right) is robust and only targeted viral RNA, while doing no damage to the plant itself. Credit: Mahas et al. In their latest study, the team trialed nine Cas13 variants to assess specificity and efficiency against three RNA viruses in Nicotiana benthamiana plants. \"Our main challenge was to devise an efficient, easy-to-use assay system to help us screen all the variants quickly,\" says Aman. \"One variant in particular, CasRx, stood out as robust and highly virus-specific—meaning it only targeted viral RNA and did no damage to the plant itself.\" \"CasRx might be more efficient because it is one of the smallest Cas13 proteins found to date,\" notes Mahas. \"Unlike other Cas13 proteins, it doesn't require binding to specific structures at the target RNA site, meaning it could access and degrade almost all the viral RNA sequences we tested,\" he adds. Furthermore, CasRx can target up to two viruses in the same plant at the same time. This would enable the simultaneous targeting of multiple viruses in mixed viral infections, like those found under natural conditions. \"We will harness CasRx to engineer different plant species against RNA- and DNA-based viruses,\" says Mahas. \"Our results also open up the potential for many other potential applications.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background CRISPR-Cas systems endow bacterial and archaeal species with adaptive immunity mechanisms to fend off invading phages and foreign genetic elements. CRISPR-Cas9 has been harnessed to confer virus interference against DNA viruses in eukaryotes, including plants. In addition, CRISPR-Cas13 systems have been used to target RNA viruses and the transcriptome in mammalian and plant cells. Recently, CRISPR-Cas13a has been shown to confer modest interference against RNA viruses. Here, we characterized a set of different Cas13 variants to identify those with the most efficient, robust, and specific interference activities against RNA viruses in planta using Nicotiana benthamiana . Results Our data show that LwaCas13a, PspCas13b, and CasRx variants mediate high interference activities against RNA viruses in transient assays. Moreover, CasRx mediated robust interference in both transient and stable overexpression assays when compared to the other variants tested. CasRx targets either one virus alone or two RNA viruses simultaneously, with robust interference efficiencies. In addition, CasRx exhibits strong specificity against the target virus and does not exhibit collateral activity in planta . Conclusions Our data establish CasRx as the most robust Cas13 variant for RNA virus interference applications in planta and demonstrate its suitability for studying key questions relating to virus biology. Introduction Plant viruses are obligate parasites that rely mostly on host cells to complete their life (infection) cycle. They infect many economically important crops, leading to a significant decrease in crop yields worldwide. It is estimated that plant diseases cause 10 to 15% reduction in global crop yields each year, and 47% of this loss is caused by viruses [ 1 , 2 , 3 ]. Therefore, plant viruses threaten world agriculture and the food security of the rapidly growing world population. Most viruses infecting plants are RNA viruses, which comprise diverse groups and subgroups that are classified based on phylogenetic relationships determined by sequence homologies among the conserved virus genes, such as RNA-dependent RNA polymerase (RdRp), coat protein (CP), and movement protein (MP) [ 4 ]. Viruses with positive-sense, single-stranded RNA genomes represent most of these viruses. Therefore, we urgently need to develop effective antiviral agents to preserve crop yields from such viruses [ 5 ]. Various strategies, based on genome and genetic engineering approaches, have been developed to combat viruses, including directly inhibiting virus replication or targeting host factors required by viruses to replicate and persist [ 6 ]. RNA interference (RNAi), for example, is an innate antiviral immunity mechanism that has been successfully used to combat various plant viruses [ 7 , 8 ]. Nevertheless, the availability of such antiviral strategies is still limited to specific virus groups, and many viruses, through evolution, mutate readily and have developed various counter-defense mechanisms, leading to rapid emergence of new viruses and nullifying the available antiviral approaches. Bacterial and archaeal species employ CRISPR-Cas systems to fend off foreign genetic elements from invading phages and nucleic acids [ 9 ]. CRISPR-Cas adaptive immunity involves three main stages: (1) adaptation and spacer acquisition, where a piece of the invader genome is incorporated into the CRISPR array proximal to the 5′ leader sequence; (2) biogenesis of the CRISPR array into pre-CRISPR RNA (crRNA) to provide targeting specificity and processing into mature crRNA; and (3) interference, where the crRNA binds and guides the effector protein to the invader’s genome for cleavage or degradation [ 10 ]. These systems are divided into two classes: class I systems, which rely on multiple Cas proteins that mediate the target interference, and class II systems, which are represented by single, multidomain effector proteins. The class II CRISPR/Cas systems include types II, V, and VI. Types II and V comprise endonucleases that operate at the DNA level. On the other hand, type VI CRISPR/Cas systems are distinct in that they exclusively target RNA molecules [ 10 , 11 ]. Because class II CRISPR-Cas systems are composed of a single effector to mediate the interference and immunity against the invader’s genomes, their engineering is simple; therefore, they are widely adopted in genome and transcriptome engineering. In recent years, class II CRISPR/Cas systems have been extensively developed to provide powerful and versatile tools for various genome engineering purposes [ 12 , 13 , 14 ]. Several studies have interrogated genomic and metagenomic sequencing data through the use of signature proteins to identify novel RNA-guided DNA and RNA endonucleases [ 11 , 15 ]. Class II type II CRISPR-Cas9 targets DNA and has been used for genome engineering across eukaryotic species [ 16 ]. The impressive success of the DNA-targeting CRISPR/Cas systems in engineering and specifically editing the genome of different eukaryotic cells has led to the exploitation of this technology as a programmable antiviral defense strategy to confer resistance to many eukaryotic viruses, including human viruses [ 17 , 18 , 19 ]. In plants, CRISPR/Cas9 efficiently confers viral resistance to host plants. We and others have shown that CRISPR/Cas9 mediates strong interference against various DNA viruses. We have also shown that a single guide RNA targeting a conserved intergenic region in multiple Gemini viruses guides Cas9 to target different viruses simultaneously, providing interference against these DNA viruses [ 20 , 21 , 22 , 23 ]. These studies demonstrate the enormous potential of CRISPR/Cas9 as a promising strategy against plant DNA viruses [ 17 ]. Nevertheless, such DNA-targeting CRISPR modalities cannot target RNA molecules and therefore limit their applicability for targeted interference against RNA viruses. Class II type VI CRISPR-Cas systems are RNA-guided and RNA-targeting machineries that provide prokaryotes with immunity against RNA [ 24 ] and DNA phages [ 25 ]. All type VI CRISPR-Cas systems have a single effector protein known as the Cas13 effector, formerly the C2c2 CRISPR-Cas system [ 24 ]. Cas13 effectors possess two distinct catalytic activities; one is RNase activity provided by the two higher eukaryotic and prokaryotic nucleotide binding domains (HEPN), which is required for target RNA degradation, and the other is RNase activity that catalyzes the processing and maturation of the pre-crRNA into mature crRNA [ 26 , 27 ]. Intriguingly,<|im_end|> <|im_start|>assistant A novel CRISPR/Cas system that can efficiently attack and destroy several prolific plant viruses has been developed by KAUST using tobacco plants and is now being extended to rice and other crops. This research aims to reduce the impact of plant viral infections, which cause losses of 10-15 percent of the global crop yield every year. CRISPR is a natural system found in bacteria that confers adaptive immunity by copying and "storing" elements of viral DNA, which remind the organism of that particular virus and ready it for a future attack. When the virus attacks again, the bacteria's CRISPR system releases CRISPR RNAs, which are small molecules that guide CRISPR-associated (Cas) proteins to bind to the viral DNA and attack and destroy the virus. Scientists have harnessed this system and developed CRISPR/Cas technology, most notably as a genome editing tool used to modify segments of DNA. Recently, scientists from KAUST developed CRISPR/Cas13, a promising method of quelling RNA-based viral attacks in plants. "Most plant viral genomes are based on single-stranded RNA," says Magdy Mahfouz, who supervised his Ph.D. student Ahmed Mahas and postdoc Rashid Aman through the research. "So we needed a Cas protein that would cleave RNA to destroy the viruses. Our first study used variant Cas13a, which attacked the turnip mosaic virus, but it was not efficient enough. We decided to search for an alternative Cas13 variant that was more robust." The variant CasRx (right) is robust and only targeted viral RNA, while doing no damage to the plant itself. Credit: Mahas et al. In their latest study, the team trialed nine Cas13 variants to assess specificity and efficiency against three RNA viruses in Nicotiana benthamiana plants. "Our main challenge was to devise an efficient, easy-to-use assay system to help us screen all the variants quickly," says Aman. "One variant in particular, CasRx, stood out as robust and highly virus-specific—meaning it only targeted viral RNA and did no damage to the plant itself." "CasRx might be more efficient because it is one of the smallest Cas13 proteins found to date," notes Mahas. "Unlike other Cas13 proteins, it doesn't require binding to specific structures at the target RNA site, meaning it could access and degrade almost all the viral RNA sequences we tested," he adds. Furthermore, CasRx can target up to two viruses in the same plant at the same time. This would enable the simultaneous targeting of multiple viruses in mixed viral infections, like those found under natural conditions. "We will harness CasRx to engineer different plant species against RNA- and DNA-based viruses," says Mahas. "Our results also open up the potential for many other potential applications." <|im_end|>

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1,991

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract A substantial area of the new almond plantations in Spain is under irrigation, but due to recurring severe droughts, the irrigation water allocation for agriculture can be drastically reduced eventually. This study assesses the physiological and yields effects of a single-season water deprivation (2017) over three seasons (2017–2019) on a previously well-irrigated mature almond [ Prunus dulcis (Mill) D.A. Web, cv. Guara] orchard in southern Spain. Three irrigation treatments were imposed during 2017: full irrigation, applying the amount required to match maximum crop evapotranspiration (FI); sustained deficit irrigation applying 25% of FI (DI); and rain-fed which received no irrigation at all (RF). During 2018 and 2019, all treatments were irrigated as FI. The results document the vulnerability of irrigated almond orchards to severe water stress, as the rainfed treatment resulted in 92% tree mortality. In relation to FI, yield and quality were reduced in RF and DI by the negative impact of water stress on kernel weight and the formation of hull tights in the season of water deprivation. In the two following years, the negative impact on yields persisted due to reductions in fruit load (carry-over effects) even though trees in DI and RF were restored to full-irrigation levels. The three-year average yields of DI and RF treatments were less than what could be predicted from an almond production function obtained in the same orchard. This highlights the long-term negative impacts that severe water stress resulting from suspending or reducing drastically irrigation in a single season has on almond trees. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Almond cultivation is concentrated in Mediterranean climate areas around the world, with California, Australia and Spain producing 77, 8 and 6% of the world production, respectively (International Nut and Dried Fruit Council 2019 ). In California and Australia, where irrigation water availability is commonly higher than in Spain, most of the orchards are irrigated to meet their maximum evapotranspiration (ET C ), with kernel yields above 2000 kg ha −1 (Almond Board of California 2019 ) and irrigation water requirements that can exceed 1300 mm (Goldhamer and Fereres 2017 ). By contrast, the acreage devoted to almond orchards in Spain has been traditionally dominated by low-yielding (c.a. 200 kg ha −1 ) rainfed orchards located in marginal areas and characterized by low planting densities and canopy cover. However, a number of factors affecting almond world markets, including the recent California drought, have led to the expansion of intensive almond orchards under irrigation in Spain in the last decade. Irrigated almond plantations in Spain have been growing rapidly, reaching almost 140,000 ha in 2020, 326% more than in 2014 (MAPA 2020 ). The production model adopted in Spain also targets average kernel yields above 2000 kg ha −1 and is based on the use of new varieties and rootstocks from European breeding programs; higher tree density on good quality soils; intensive fertilization and tree health measures; minimal pruning; and irrigation programs similar to those used in USA and Australia. The amounts of irrigation needed to meet ET C can exceed 900 mm in southern Spain (López-López et al. 2018a , b ) but the use of deficit irrigation (DI) strategies is common in many areas limited by irrigation water availability (Moldero et al. 2021 ). In most almond growing regions, but particularly in many areas of Spain, water is a scarce resource and irrigation water shortage is a chronic problem, so that deficit irrigation strategies (Fereres and Soriano 2007 ) must be applied. Tree water relations have been deeply studied in almond and it is well known that water stress affects stomatal conductance and CO 2 assimilation (Castel and Fereres 1982 ; Romero et al. 2004 ). Furthermore, the effects of water stress on tree growth and yield are also known. In this regard, yield is considered to be particularly sensitive to water stress in the periods of flowering, rapid vegetative growth in spring (Goldhamer and Smith 1995 ) and post-harvest (Goldhamer and Viveros 2000 ), while the kernel-filling phase seems to be less sensitive (Romero et al. 2004 ; Girona et al. 2005 ). Based on this knowledge, DI strategies have been tested in almond by reducing irrigation applications from 30 to 60% of ETc (Romero et al. 2004 ; Girona et al. 2005 ; Egea et al. 2010 , 2013 ; López-López et al. 2018b ; Moldero et al. 2021 ). An important problem arises when these regions are impacted by severe and persistent drought events that can cause substantial deprivations in irrigation water for agriculture. Irrigation water allotments can be drastically reduced to 20–30% of the historical levels for almond as it occurred in California during 2011–2016 (Doll and Shackel 2015 ) and in Australia during 1995–2007, or, in the worst case, reaching total cut-off, as it happened in Spain during the 1991–1995 drought. In severe drought situations, growers have reacted with a number of measures including procuring additional irrigation water by purchasing water rights from other growers, extracting more groundwater or reducing demand by removing the older and/or less productive blocks of the orchard. Other practices, such as reduction of evaporation losses (decreasing irrigation frequency) and severe pruning, have been used as well. However, severe pruning has been shown to be ineffective as it leads to long-lasting effects of yield (Proebsting et al. 1981 ; Shackel et al. 2011 ). Scientific literature only shows two studies where almond trees were subjected to severe water stress to investigate the effects of a severe water shortage due to a drought. First, Goldhamer and Smith ( 1995 ) imposed a single-season irrigation water deprivation on a mature ‘Nonpareil’ almond orchard in California. Treatments consisted of a control (FI) and four deficit irrigation strategies (406 mm; 36% of FI) differing in the temporal distribution of the deficits. Although there were no direct measurements of tree water status, the severe water stress suffered by trees caused a significative reduction in", "role": "user" }, { "content": "In Spain, the drought between 1991 and 1995 led to restrictions in the allocation of water for crops and cuts in supplies. What would have happened at that time to the intensive, irrigated almond plantations that have been planted in Spain for more than a decade? These plantations, planted on productive soils featuring high tree density, continuous irrigation, and the use of fertilizers, occupy 140,000 hectares in the country―326% more than in 2015 according to the Ministry of Agriculture, Fisheries and Food. Therefore, knowing what would happen to them if a drought situation such as that of the 1990s arose is crucial to enable both regulatory agencies and the agricultural community to make evidence-based decisions. In this context, a team made up of Elías Fereres and Álvaro López, researchers from the María de Maeztu Unit of Excellence in the Department of Agronomy at the University of Córdoba, together with researchers David Moldero, Luca Testi and Francisco Orgaz from the CSIC's (IAS-CSIC) Institute of Sustainable Agriculture, and Ignacio Jesús Lorite from IFAPA, have evaluated the physiological and productive effects of water deprivation during a single season on an irrigated almond plantation. The experimental plantation featured a 7 x 6 m frame and trees of the Guara variety (very commonly used) established in 2009 at IFAPA—Alameda del Obispo. In it, three different irrigation treatments were compared in 2017: full irrigation for the crop's maximum evapotranspiration (as a control group, since it is the irrigation method that had been applied throughout the plantation in previous years); deficit irrigation, applying 25% of the maximum that would be required; and the complete suspension of irrigation throughout the season. In the subsequent two years, all the treatments were watered like the control group. The impact of the water reductions introduced in 2017 were evaluated both during that season and those of 2018 and 2019. \"In 2017 the trees' hydriccondition, under both reduced and suspended irrigation, worsened very quickly, resulting in partial and total defoliation, respectively, but there was a harvest: 1,400 kg per hectare were harvested after both treatments compared to 2,200 kg per hectare with the trees in the control group,\" explained researcher Álvaro López. \"This is explained by the fact that this acute hydric stress resulted in a drastic reduction in the weight of the almond trees\", he concluded. The problem arose later, when it was found that the treatment in which irrigation was completely suspended in 2017 ultimately resulted in a 92% mortality rate for the trees. In addition, in the only surviving tree there was a \"protracted effect\" rendering \"its production negligible in 2018 and close to 50% of the control group's in 2019, despite the fact that maximum irrigation was resumed in 2018,\" said López. In the plantation in which irrigation was reduced to 25%, however, there were no significant differences with the control treatment in the 2018 and 2019 seasons. \"This is an exceptional result because it shows us the danger that new irrigated almond plantations run in the face of severe reductions in irrigation resources,\" emphasized researcher David Moldero. The results of this work suggest that both hydrographic conferences and the agricultural community should establish contingency plans to prevent the loss of plantations, which would have a devastating economic impact on farmers. The researchers also point out that it may be much more beneficial to ensure guaranteed supply during drought years than to strive for greater average supply volumes. Considering this study together with that determining that almond production remains stable despite reduced irrigation (also published by this group), it seems that these new almond plantations would be better off employing sustained deficit irrigation than constant, maximized irrigation, as a very bad year could lead to irreversible damage (such as loss of the plantation) or depressed production for several years. The research was published in Irrigation Science. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract A substantial area of the new almond plantations in Spain is under irrigation, but due to recurring severe droughts, the irrigation water allocation for agriculture can be drastically reduced eventually. This study assesses the physiological and yields effects of a single-season water deprivation (2017) over three seasons (2017–2019) on a previously well-irrigated mature almond [ Prunus dulcis (Mill) D.A. Web, cv. Guara] orchard in southern Spain. Three irrigation treatments were imposed during 2017: full irrigation, applying the amount required to match maximum crop evapotranspiration (FI); sustained deficit irrigation applying 25% of FI (DI); and rain-fed which received no irrigation at all (RF). During 2018 and 2019, all treatments were irrigated as FI. The results document the vulnerability of irrigated almond orchards to severe water stress, as the rainfed treatment resulted in 92% tree mortality. In relation to FI, yield and quality were reduced in RF and DI by the negative impact of water stress on kernel weight and the formation of hull tights in the season of water deprivation. In the two following years, the negative impact on yields persisted due to reductions in fruit load (carry-over effects) even though trees in DI and RF were restored to full-irrigation levels. The three-year average yields of DI and RF treatments were less than what could be predicted from an almond production function obtained in the same orchard. This highlights the long-term negative impacts that severe water stress resulting from suspending or reducing drastically irrigation in a single season has on almond trees. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Almond cultivation is concentrated in Mediterranean climate areas around the world, with California, Australia and Spain producing 77, 8 and 6% of the world production, respectively (International Nut and Dried Fruit Council 2019 ). In California and Australia, where irrigation water availability is commonly higher than in Spain, most of the orchards are irrigated to meet their maximum evapotranspiration (ET C ), with kernel yields above 2000 kg ha −1 (Almond Board of California 2019 ) and irrigation water requirements that can exceed 1300 mm (Goldhamer and Fereres 2017 ). By contrast, the acreage devoted to almond orchards in Spain has been traditionally dominated by low-yielding (c.a. 200 kg ha −1 ) rainfed orchards located in marginal areas and characterized by low planting densities and canopy cover. However, a number of factors affecting almond world markets, including the recent California drought, have led to the expansion of intensive almond orchards under irrigation in Spain in the last decade. Irrigated almond plantations in Spain have been growing rapidly, reaching almost 140,000 ha in 2020, 326% more than in 2014 (MAPA 2020 ). The production model adopted in Spain also targets average kernel yields above 2000 kg ha −1 and is based on the use of new varieties and rootstocks from European breeding programs; higher tree density on good quality soils; intensive fertilization and tree health measures; minimal pruning; and irrigation programs similar to those used in USA and Australia. The amounts of irrigation needed to meet ET C can exceed 900 mm in southern Spain (López-López et al. 2018a , b ) but the use of deficit irrigation (DI) strategies is common in many areas limited by irrigation water availability (Moldero et al. 2021 ). In most almond growing regions, but particularly in many areas of Spain, water is a scarce resource and irrigation water shortage is a chronic problem, so that deficit irrigation strategies (Fereres and Soriano 2007 ) must be applied. Tree water relations have been deeply studied in almond and it is well known that water stress affects stomatal conductance and CO 2 assimilation (Castel and Fereres 1982 ; Romero et al. 2004 ). Furthermore, the effects of water stress on tree growth and yield are also known. In this regard, yield is considered to be particularly sensitive to water stress in the periods of flowering, rapid vegetative growth in spring (Goldhamer and Smith 1995 ) and post-harvest (Goldhamer and Viveros 2000 ), while the kernel-filling phase seems to be less sensitive (Romero et al. 2004 ; Girona et al. 2005 ). Based on this knowledge, DI strategies have been tested in almond by reducing irrigation applications from 30 to 60% of ETc (Romero et al. 2004 ; Girona et al. 2005 ; Egea et al. 2010 , 2013 ; López-López et al. 2018b ; Moldero et al. 2021 ). An important problem arises when these regions are impacted by severe and persistent drought events that can cause substantial deprivations in irrigation water for agriculture. Irrigation water allotments can be drastically reduced to 20–30% of the historical levels for almond as it occurred in California during 2011–2016 (Doll and Shackel 2015 ) and in Australia during 1995–2007, or, in the worst case, reaching total cut-off, as it happened in Spain during the 1991–1995 drought. In severe drought situations, growers have reacted with a number of measures including procuring additional irrigation water by purchasing water rights from other growers, extracting more groundwater or reducing demand by removing the older and/or less productive blocks of the orchard. Other practices, such as reduction of evaporation losses (decreasing irrigation frequency) and severe pruning, have been used as well. However, severe pruning has been shown to be ineffective as it leads to long-lasting effects of yield (Proebsting et al. 1981 ; Shackel et al. 2011 ). Scientific literature only shows two studies where almond trees were subjected to severe water stress to investigate the effects of a severe water shortage due to a drought. First, Goldhamer and Smith ( 1995 ) imposed a single-season irrigation water deprivation on a mature ‘Nonpareil’ almond orchard in California. Treatments consisted of a control (FI) and four deficit irrigation strategies (406 mm; 36% of FI) differing in the temporal distribution of the deficits. Although there were no direct measurements of tree water status, the severe water stress suffered by trees caused a significative reduction in<|im_end|> <|im_start|>assistant In Spain, the drought between 1991 and 1995 led to restrictions in the allocation of water for crops and cuts in supplies. What would have happened at that time to the intensive, irrigated almond plantations that have been planted in Spain for more than a decade? These plantations, planted on productive soils featuring high tree density, continuous irrigation, and the use of fertilizers, occupy 140,000 hectares in the country―326% more than in 2015 according to the Ministry of Agriculture, Fisheries and Food. Therefore, knowing what would happen to them if a drought situation such as that of the 1990s arose is crucial to enable both regulatory agencies and the agricultural community to make evidence-based decisions. In this context, a team made up of Elías Fereres and Álvaro López, researchers from the María de Maeztu Unit of Excellence in the Department of Agronomy at the University of Córdoba, together with researchers David Moldero, Luca Testi and Francisco Orgaz from the CSIC's (IAS-CSIC) Institute of Sustainable Agriculture, and Ignacio Jesús Lorite from IFAPA, have evaluated the physiological and productive effects of water deprivation during a single season on an irrigated almond plantation. The experimental plantation featured a 7 x 6 m frame and trees of the Guara variety (very commonly used) established in 2009 at IFAPA—Alameda del Obispo. In it, three different irrigation treatments were compared in 2017: full irrigation for the crop's maximum evapotranspiration (as a control group, since it is the irrigation method that had been applied throughout the plantation in previous years); deficit irrigation, applying 25% of the maximum that would be required; and the complete suspension of irrigation throughout the season. In the subsequent two years, all the treatments were watered like the control group. The impact of the water reductions introduced in 2017 were evaluated both during that season and those of 2018 and 2019. "In 2017 the trees' hydriccondition, under both reduced and suspended irrigation, worsened very quickly, resulting in partial and total defoliation, respectively, but there was a harvest: 1,400 kg per hectare were harvested after both treatments compared to 2,200 kg per hectare with the trees in the control group," explained researcher Álvaro López. "This is explained by the fact that this acute hydric stress resulted in a drastic reduction in the weight of the almond trees", he concluded. The problem arose later, when it was found that the treatment in which irrigation was completely suspended in 2017 ultimately resulted in a 92% mortality rate for the trees. In addition, in the only surviving tree there was a "protracted effect" rendering "its production negligible in 2018 and close to 50% of the control group's in 2019, despite the fact that maximum irrigation was resumed in 2018," said López. In the plantation in which irrigation was reduced to 25%, however, there were no significant differences with the control treatment in the 2018 and 2019 seasons. "This is an exceptional result because it shows us the danger that new irrigated almond plantations run in the face of severe reductions in irrigation resources," emphasized researcher David Moldero. The results of this work suggest that both hydrographic conferences and the agricultural community should establish contingency plans to prevent the loss of plantations, which would have a devastating economic impact on farmers. The researchers also point out that it may be much more beneficial to ensure guaranteed supply during drought years than to strive for greater average supply volumes. Considering this study together with that determining that almond production remains stable despite reduced irrigation (also published by this group), it seems that these new almond plantations would be better off employing sustained deficit irrigation than constant, maximized irrigation, as a very bad year could lead to irreversible damage (such as loss of the plantation) or depressed production for several years. The research was published in Irrigation Science. <|im_end|>

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40028, 555, 15748, 323, 26048, 37846, 4455, 430, 649, 5353, 12190, 409, 12151, 811, 304, 63566, 3090, 369, 30029, 13, 79141, 18413, 3090, 85274, 1392, 649, 387, 48863, 11293, 311, 220, 508, 4235, 966, 4, 315, 279, 13970, 5990, 369, 63168, 439, 433, 10222, 304, 7188, 2391, 220, 679, 16, 4235, 679, 21, 320, 35, 980, 323, 86523, 301, 220, 679, 20, 883, 323, 304, 8494, 2391, 220, 2550, 20, 4235, 1049, 22, 11, 477, 11, 304, 279, 12047, 1162, 11, 19261, 2860, 4018, 12744, 11, 439, 433, 7077, 304, 18157, 2391, 279, 220, 2550, 16, 4235, 2550, 20, 37846, 13, 763, 15748, 37846, 15082, 11, 70077, 617, 55841, 449, 264, 1396, 315, 11193, 2737, 13988, 1711, 5217, 63566, 3090, 555, 23395, 3090, 3268, 505, 1023, 70077, 11, 60508, 810, 72329, 477, 18189, 7631, 555, 18054, 279, 9191, 323, 5255, 2753, 27331, 10215, 315, 279, 41245, 569, 13, 7089, 12659, 11, 1778, 439, 14278, 315, 3721, 96649, 18151, 320, 451, 76562, 63566, 11900, 8, 323, 15748, 86292, 11, 617, 1027, 1511, 439, 1664, 13, 4452, 11, 15748, 86292, 706, 1027, 6982, 311, 387, 55288, 439, 433, 11767, 311, 1317, 65265, 6372, 315, 7692, 320, 1360, 3141, 267, 287, 1880, 453, 13, 220, 3753, 16, 2652, 86523, 301, 1880, 453, 13, 220, 679, 16, 7609, 38130, 17649, 1193, 5039, 1403, 7978, 1405, 63168, 12690, 1051, 38126, 311, 15748, 3090, 8631, 311, 19874, 279, 6372, 315, 264, 15748, 3090, 39259, 4245, 311, 264, 37846, 13, 5629, 11, 7573, 5721, 261, 323, 9259, 320, 220, 2550, 20, 883, 27070, 264, 3254, 31300, 63566, 3090, 69764, 389, 264, 15196, 3451, 8284, 3462, 321, 529, 63168, 41245, 569, 304, 7188, 13, 19409, 1392, 44660, 315, 264, 2585, 320, 19991, 8, 323, 3116, 29287, 63566, 15174, 320, 17264, 9653, 26, 220, 1927, 4, 315, 51635, 8, 61469, 304, 279, 37015, 8141, 315, 279, 57096, 13, 10541, 1070, 1051, 912, 2167, 22323, 315, 5021, 3090, 2704, 11, 279, 15748, 3090, 8631, 16654, 555, 12690, 9057, 264, 4698, 1413, 14278, 304, 128257, 198, 128256, 78191, 198, 644, 18157, 11, 279, 37846, 1990, 220, 2550, 16, 323, 220, 2550, 20, 6197, 311, 17294, 304, 279, 24691, 315, 3090, 369, 31665, 323, 15455, 304, 17135, 13, 3639, 1053, 617, 7077, 520, 430, 892, 311, 279, 37295, 11, 53105, 660, 63168, 6136, 811, 430, 617, 1027, 39441, 304, 18157, 369, 810, 1109, 264, 13515, 30, 4314, 6136, 811, 11, 39441, 389, 27331, 69561, 16850, 1579, 5021, 17915, 11, 19815, 63566, 11, 323, 279, 1005, 315, 36214, 12509, 11, 48678, 220, 6860, 11, 931, 81743, 304, 279, 3224, 63072, 17470, 4, 810, 1109, 304, 220, 679, 20, 4184, 311, 279, 20214, 315, 37963, 11, 94505, 323, 12369, 13, 15636, 11, 14392, 1148, 1053, 3621, 311, 1124, 422, 264, 37846, 6671, 1778, 439, 430, 315, 279, 220, 2550, 15, 82, 51063, 374, 16996, 311, 7431, 2225, 23331, 13607, 323, 279, 29149, 4029, 311, 1304, 6029, 6108, 11429, 13, 763, 420, 2317, 11, 264, 2128, 1903, 709, 315, 4072, 25318, 29562, 13213, 323, 43912, 75, 959, 78, 92075, 11, 12074, 505, 279, 83305, 409, 65914, 11949, 84, 8113, 315, 58240, 304, 279, 6011, 315, 72808, 17404, 520, 279, 3907, 315, 108430, 6634, 27931, 11, 3871, 449, 12074, 6941, 386, 2061, 78, 11, 84278, 3475, 72, 323, 13175, 34806, 1394, 505, 279, 10211, 1341, 596, 320, 32922, 79413, 1341, 8, 10181, 315, 61593, 37963, 11, 323, 34881, 36970, 9243, 34862, 69830, 635, 505, 11812, 89769, 11, 617, 26126, 279, 53194, 323, 27331, 6372, 315, 3090, 69764, 2391, 264, 3254, 3280, 389, 459, 53105, 660, 63168, 83052, 13, 578, 22772, 83052, 15109, 264, 220, 22, 865, 220, 21, 296, 4124, 323, 12690, 315, 279, 4673, 5169, 8205, 320, 1225, 17037, 1511, 8, 9749, 304, 220, 1049, 24, 520, 11812, 89769, 2345, 2149, 99171, 1624, 4761, 285, 5481, 13, 763, 433, 11, 2380, 2204, 63566, 22972, 1051, 7863, 304, 220, 679, 22, 25, 2539, 63566, 369, 279, 19641, 596, 7340, 3721, 91001, 34489, 29579, 320, 300, 264, 2585, 1912, 11, 2533, 433, 374, 279, 63566, 1749, 430, 1047, 1027, 9435, 6957, 279, 83052, 304, 3766, 1667, 1237, 29287, 63566, 11, 19486, 220, 914, 4, 315, 279, 7340, 430, 1053, 387, 2631, 26, 323, 279, 4686, 25288, 315, 63566, 6957, 279, 3280, 13, 763, 279, 17876, 1403, 1667, 11, 682, 279, 22972, 1051, 3090, 291, 1093, 279, 2585, 1912, 13, 578, 5536, 315, 279, 3090, 47311, 11784, 304, 220, 679, 22, 1051, 26126, 2225, 2391, 430, 3280, 323, 1884, 315, 220, 679, 23, 323, 220, 679, 24, 13, 330, 644, 220, 679, 22, 279, 12690, 6, 6409, 67, 2265, 9233, 11, 1234, 2225, 11293, 323, 22340, 63566, 11, 47293, 6901, 1633, 6288, 11, 13239, 304, 7276, 323, 2860, 711, 337, 7246, 11, 15947, 11, 719, 1070, 574, 264, 24322, 25, 220, 16, 11, 3443, 21647, 824, 48101, 548, 1051, 67572, 1306, 2225, 22972, 7863, 311, 220, 17, 11, 1049, 21647, 824, 48101, 548, 449, 279, 12690, 304, 279, 2585, 1912, 1359, 11497, 32185, 43912, 75, 959, 78, 92075, 13, 330, 2028, 374, 11497, 555, 279, 2144, 430, 420, 30883, 6409, 67, 2265, 8631, 19543, 304, 264, 60883, 14278, 304, 279, 4785, 315, 279, 63168, 12690, 498, 568, 20536, 13, 578, 3575, 51063, 3010, 11, 994, 433, 574, 1766, 430, 279, 6514, 304, 902, 63566, 574, 6724, 22340, 304, 220, 679, 22, 13967, 19543, 304, 264, 220, 6083, 4, 29528, 4478, 369, 279, 12690, 13, 763, 5369, 11, 304, 279, 1193, 40746, 5021, 1070, 574, 264, 330, 782, 55535, 2515, 1, 21568, 330, 1220, 5788, 82802, 304, 220, 679, 23, 323, 3345, 311, 220, 1135, 4, 315, 279, 2585, 1912, 596, 304, 220, 679, 24, 11, 8994, 279, 2144, 430, 7340, 63566, 574, 58505, 304, 220, 679, 23, 1359, 1071, 92075, 13, 763, 279, 83052, 304, 902, 63566, 574, 11293, 311, 220, 914, 13689, 4869, 11, 1070, 1051, 912, 5199, 12062, 449, 279, 2585, 6514, 304, 279, 220, 679, 23, 323, 220, 679, 24, 15956, 13, 330, 2028, 374, 459, 25363, 1121, 1606, 433, 5039, 603, 279, 8137, 430, 502, 53105, 660, 63168, 6136, 811, 1629, 304, 279, 3663, 315, 15748, 47311, 304, 63566, 5070, 1359, 46728, 32185, 6941, 386, 2061, 78, 13, 578, 3135, 315, 420, 990, 4284, 430, 2225, 17055, 86972, 38614, 323, 279, 29149, 4029, 1288, 5813, 83549, 6787, 311, 5471, 279, 4814, 315, 6136, 811, 11, 902, 1053, 617, 264, 33318, 7100, 5536, 389, 20957, 13, 578, 12074, 1101, 1486, 704, 430, 433, 1253, 387, 1790, 810, 24629, 311, 6106, 19883, 8312, 2391, 37846, 1667, 1109, 311, 37106, 369, 7191, 5578, 8312, 27378, 13, 56877, 420, 4007, 3871, 449, 430, 26679, 430, 63168, 5788, 8625, 15528, 8994, 11293, 63566, 320, 19171, 4756, 555, 420, 1912, 705, 433, 5084, 430, 1521, 502, 63168, 6136, 811, 1053, 387, 2731, 1022, 51297, 29759, 29287, 63566, 1109, 6926, 11, 31127, 1534, 63566, 11, 439, 264, 1633, 3958, 1060, 1436, 3063, 311, 93294, 5674, 320, 21470, 439, 4814, 315, 279, 83052, 8, 477, 42642, 5788, 369, 3892, 1667, 13, 578, 3495, 574, 4756, 304, 79141, 18413, 10170, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The gut microbiota is emerging as an important modulator of neurodegenerative diseases, and accumulating evidence has linked gut microbes to Parkinson’s disease (PD) symptomatology and pathophysiology. PD is often preceded by gastrointestinal symptoms and alterations of the enteric nervous system accompany the disease. Several studies have analyzed the gut microbiome in PD, but a consensus on the features of the PD-specific microbiota is missing. Here, we conduct a meta-analysis re-analyzing the ten currently available 16S microbiome datasets to investigate whether common alterations in the gut microbiota of PD patients exist across cohorts. We found significant alterations in the PD-associated microbiome, which are robust to study-specific technical heterogeneities, although differences in microbiome structure between PD and controls are small. Enrichment of the genera Lactobacillus , Akkermansia , and Bifidobacterium and depletion of bacteria belonging to the Lachnospiraceae family and the Faecalibacterium genus, both important short-chain fatty acids producers, emerged as the most consistent PD gut microbiome alterations. This dysbiosis might result in a pro-inflammatory status which could be linked to the recurrent gastrointestinal symptoms affecting PD patients. Introduction Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease 1 . Globally, it has an incidence of 10–50/100,000 person/year and a prevalence of 100–300/100,000 people, and due to the progressive aging of the world population, the number of people with PD is expected to double by 2030 1 . PD affects predominantly dopaminergic neurons in the brain, leading to decreased dopamine levels and motor impairments, such as tremor, rigidity, balance difficulties, and loss of spontaneous movement (akinesia) 2 . Its pathological hallmark has long been considered to be the intracellular deposition of aggregated α-synuclein, leading to neuronal cell death and neuroinflammation 3 . PD is now considered a multi-systemic disease, affecting the central as well as the peripheral nervous system (CNS, PNS), resulting in several non-motor symptoms, often including gastroparesis or constipation. Due to the early involvement of the gastrointestinal tract, often preceding motor symptoms for years 4 , changes in gut-microbiota composition have been studied in relation to the pathophysiology of PD. The potential role of gut microbiota in PD 3 and other neurodegenerative diseases 5 is supported by animal studies 6 , showing that the microbiota can affect α-synucleinopathy as well as neuroinflammation. Thus, the microbiota is a putative therapeutic target and has the potential for developing diagnostic biomarkers. PD patients can have increased gut permeability and inflammation 7 , 8 , and these have been hypothesized to be linked to low gastrointestinal short-chain fatty acids (SCFA) concentrations 9 . SCFA are the end products of bacterial fermentation of dietary components and play a pivotal role in fueling and maintaining the integrity of the colonic epithelium. Low levels of SCFA have been considered to be a consequence of a decreased abundance of SCFA-producing taxa in PD patients 10 , 11 . To date, more than 20 case–control studies have investigated the composition of the PD gut microbiota. Over 100 differently abundant taxa between PD patients and controls have been reported 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , and in some cases, an association between taxa abundances and disease severity has been detected 11 , 12 , 16 . Several studies suggested that individuals with PD have an altered gut microbiota compared to controls, even though findings are often inconsistent and a consensus on the taxa associated with the disease is still lacking. Across most studies, the genus Akkermansia and the Verrucomicrobiaceae family have been found to be enriched in PD patients, while bacteria belonging to the Lachnospiraceae family are depleted. On the other hand, various inconsistencies have been found among the different sampling cohorts. For example, the Lactobacillaceae family has been generally detected to be enriched in PD in the Western cohorts but never in Chinese studies 18 , 20 , 21 . Similarly, conflicting results have been obtained for bacteria within the Prevotellaceae family. Several studies detected these taxa to be highly depleted in PD patients 16 , 17 , 22 , 23 , compared to controls, whereas others found no differences in abundances 11 or found these taxa enriched in PD patients 13 , 20 . Inconsistencies amongst studies might arise from variations in study designs and methods used for producing and analyzing 16S rRNA-gene amplicon data, as well as from the natural variability of the gut microbiota across populations, lifestyles, and diets 24 . To further elucidate the significance of changes in the intestinal microbiota composition in PD and to evaluate its potential as a biomarker for PD risk, diagnosis, and prognosis it is important to perform cross-study comparisons and identify disease-specific alterations. Here, we provide an individual patient data meta-analysis (pooled re-analysis) of all ten available studies that described the gut microbiome in PD through 16S rRNA-gene amplicon sequencing. We apply a standardized workflow to analyze each study individually and combined different statistical approaches to identify the major changes affecting the gut microbiome of PD patients across sampling cohorts. Results Study selection We identified a total of 22 studies that investigated the PD-associated gut microbiome using 16S rRNA-gene amplicon sequencing (March 2020; Supplementary Table 1 ). Of these, only ten made raw sequencing data available and could be re-analyzed in our study. These ten studies covered nine different cohorts (one was reported at baseline then at follow-up 2 years later), across six countries (Table 1 ). Overall, this resulted in 1269 samples (1211 after filtration of samples with low read counts) (Fig. 1a ) all obtained from case–control studies. Cases were usually selected from clinics local to the investigating teams, were at different stages of the disease, and almost all were using some form of PD medication (Table 1 ). Controls were typically sampled by convenience from the local population or from families of the PD patients. All studies except one 16 applied the UK brain bank criteria to define PD. Cases had an average age of between 60", "role": "user" }, { "content": "Researchers from the Quadram Institute have carried out a meta-analysis of the gut microbiome in Parkinson's disease, giving the clearest picture to date of the changes associated with the condition. By re-analyzing data from ten different studies, a common pattern of changes in the abundance of bacteria types in Parkinson's disease emerges, suggesting that the alteration in the gut microbiome might trigger some of the gastrointestinal problems seen in patients. Parkinson's is a progressive condition that affects nerve cells that produce dopamine, which coordinates movement. As more nerve cells die, less dopamine is produced, leading to gradually worsening tremors, slower movement and muscle stiffness. In addition, many people with Parkinson's disease have gastrointestinal problems that can show several years before the physical movement symptoms. They may also have inflammation and \"leaky\" gut, signs of an imbalanced gut microbiome. These observations have prompted genome sequencing studies to identify the types of bacteria in the microbiome of people with Parkinson's disease, and compare that with people without the condition. Several studies have shown differences in the Parkinson's microbiome, but no clear consensus has emerged. Differences across studies may reflect different methodologies, but also the inherent variability in the human microbiome, shaped by lifestyle and dietary variations in different populations around the world. Drug treatment regimens and antibiotic usage also impact on gut bacteria, so variability between different studies isn't a surprise, but it does make drawing definitive conclusions on the association between the microbiome and Parkinson's harder. To address this, the Quadram Institute researchers sought to reanalyse the patient data paired with their control collected across studies from six different countries. This large pool of 1200 samples allowed the researches to identify robust differences between the microbiomes of people with or without Parkinson's disease. The study was supported by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UKRI. The meta-analysis, published in the journal npj Parkinson's Disease, confirmed that the Parkinson's microbiome is different with a reduction in the dominant bacteria usually found in a healthy human gut. But to understand how changes in the microbiome affect health, we need to know what those bacteria are doing. What chemicals, metabolites or signals do they produce and how does this change with the disease? The researchers report that some of the depleted bacteria in Parkinson's produce butyrate, which is used by the cells that line the gut to maintain its integrity as a barrier. Butyrate and other short chain fatty acids also play important roles in interactions between the gut, the nervous system and the brain. In previous studies, Parkinson's disease patients were shown to have lower butyrate levels and increased gut lining inflammation and permeability. Similar depletions in key bacterial species, butyrate levels and gut lining integrity are seen in patients with Inflammatory Bowel Disease (IBD) and IBD patients have a 20%-30% higher risk of developing Parkinson's disease. Other bacteria involved in methane production are enriched in the gut of Parkinson's patients. This together with an increased abundance of bacteria able to degrade the mucus within the gut might affect transit time and explain the constipation problems that are recurrently observed in Parkinson's patients. This study backs up and adds to the evidence linking the gut microbiome, gut inflammation and immune function in Parkinson's, and provides intriguing hints into potential mechanisms by which the gut microbiome influences the disease. However, the team underlines that the available data can't answer the question of whether the microbiome alterations cause Parkinson's Disease or are an effect of it, and suggest sampling strategies that could help understand the causal link between the disease and the gut microbiome. Dr. Stefano Romano who led the study commented \"The variability across studies is very big. However, we can still detect differences between the gut microbiome of patients and controls. This means that microbiome alterations in Parkinson's disease are consistent across sampling cohorts.\" \"There is a clear need to further research gut microbial changes linked to diseases in diagnostic or prognostic applications.\" Microbiome alterations may also be used as biomarkers, especially useful for spotting the earliest onset of the disease, and open new targets for therapies. \"The restoration of a balanced microbiome in patients might alleviate some of the symptoms of Parkinson's, and this is a really exciting route of research we are exploring.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The gut microbiota is emerging as an important modulator of neurodegenerative diseases, and accumulating evidence has linked gut microbes to Parkinson’s disease (PD) symptomatology and pathophysiology. PD is often preceded by gastrointestinal symptoms and alterations of the enteric nervous system accompany the disease. Several studies have analyzed the gut microbiome in PD, but a consensus on the features of the PD-specific microbiota is missing. Here, we conduct a meta-analysis re-analyzing the ten currently available 16S microbiome datasets to investigate whether common alterations in the gut microbiota of PD patients exist across cohorts. We found significant alterations in the PD-associated microbiome, which are robust to study-specific technical heterogeneities, although differences in microbiome structure between PD and controls are small. Enrichment of the genera Lactobacillus , Akkermansia , and Bifidobacterium and depletion of bacteria belonging to the Lachnospiraceae family and the Faecalibacterium genus, both important short-chain fatty acids producers, emerged as the most consistent PD gut microbiome alterations. This dysbiosis might result in a pro-inflammatory status which could be linked to the recurrent gastrointestinal symptoms affecting PD patients. Introduction Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease 1 . Globally, it has an incidence of 10–50/100,000 person/year and a prevalence of 100–300/100,000 people, and due to the progressive aging of the world population, the number of people with PD is expected to double by 2030 1 . PD affects predominantly dopaminergic neurons in the brain, leading to decreased dopamine levels and motor impairments, such as tremor, rigidity, balance difficulties, and loss of spontaneous movement (akinesia) 2 . Its pathological hallmark has long been considered to be the intracellular deposition of aggregated α-synuclein, leading to neuronal cell death and neuroinflammation 3 . PD is now considered a multi-systemic disease, affecting the central as well as the peripheral nervous system (CNS, PNS), resulting in several non-motor symptoms, often including gastroparesis or constipation. Due to the early involvement of the gastrointestinal tract, often preceding motor symptoms for years 4 , changes in gut-microbiota composition have been studied in relation to the pathophysiology of PD. The potential role of gut microbiota in PD 3 and other neurodegenerative diseases 5 is supported by animal studies 6 , showing that the microbiota can affect α-synucleinopathy as well as neuroinflammation. Thus, the microbiota is a putative therapeutic target and has the potential for developing diagnostic biomarkers. PD patients can have increased gut permeability and inflammation 7 , 8 , and these have been hypothesized to be linked to low gastrointestinal short-chain fatty acids (SCFA) concentrations 9 . SCFA are the end products of bacterial fermentation of dietary components and play a pivotal role in fueling and maintaining the integrity of the colonic epithelium. Low levels of SCFA have been considered to be a consequence of a decreased abundance of SCFA-producing taxa in PD patients 10 , 11 . To date, more than 20 case–control studies have investigated the composition of the PD gut microbiota. Over 100 differently abundant taxa between PD patients and controls have been reported 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , and in some cases, an association between taxa abundances and disease severity has been detected 11 , 12 , 16 . Several studies suggested that individuals with PD have an altered gut microbiota compared to controls, even though findings are often inconsistent and a consensus on the taxa associated with the disease is still lacking. Across most studies, the genus Akkermansia and the Verrucomicrobiaceae family have been found to be enriched in PD patients, while bacteria belonging to the Lachnospiraceae family are depleted. On the other hand, various inconsistencies have been found among the different sampling cohorts. For example, the Lactobacillaceae family has been generally detected to be enriched in PD in the Western cohorts but never in Chinese studies 18 , 20 , 21 . Similarly, conflicting results have been obtained for bacteria within the Prevotellaceae family. Several studies detected these taxa to be highly depleted in PD patients 16 , 17 , 22 , 23 , compared to controls, whereas others found no differences in abundances 11 or found these taxa enriched in PD patients 13 , 20 . Inconsistencies amongst studies might arise from variations in study designs and methods used for producing and analyzing 16S rRNA-gene amplicon data, as well as from the natural variability of the gut microbiota across populations, lifestyles, and diets 24 . To further elucidate the significance of changes in the intestinal microbiota composition in PD and to evaluate its potential as a biomarker for PD risk, diagnosis, and prognosis it is important to perform cross-study comparisons and identify disease-specific alterations. Here, we provide an individual patient data meta-analysis (pooled re-analysis) of all ten available studies that described the gut microbiome in PD through 16S rRNA-gene amplicon sequencing. We apply a standardized workflow to analyze each study individually and combined different statistical approaches to identify the major changes affecting the gut microbiome of PD patients across sampling cohorts. Results Study selection We identified a total of 22 studies that investigated the PD-associated gut microbiome using 16S rRNA-gene amplicon sequencing (March 2020; Supplementary Table 1 ). Of these, only ten made raw sequencing data available and could be re-analyzed in our study. These ten studies covered nine different cohorts (one was reported at baseline then at follow-up 2 years later), across six countries (Table 1 ). Overall, this resulted in 1269 samples (1211 after filtration of samples with low read counts) (Fig. 1a ) all obtained from case–control studies. Cases were usually selected from clinics local to the investigating teams, were at different stages of the disease, and almost all were using some form of PD medication (Table 1 ). Controls were typically sampled by convenience from the local population or from families of the PD patients. All studies except one 16 applied the UK brain bank criteria to define PD. Cases had an average age of between 60<|im_end|> <|im_start|>assistant Researchers from the Quadram Institute have carried out a meta-analysis of the gut microbiome in Parkinson's disease, giving the clearest picture to date of the changes associated with the condition. By re-analyzing data from ten different studies, a common pattern of changes in the abundance of bacteria types in Parkinson's disease emerges, suggesting that the alteration in the gut microbiome might trigger some of the gastrointestinal problems seen in patients. Parkinson's is a progressive condition that affects nerve cells that produce dopamine, which coordinates movement. As more nerve cells die, less dopamine is produced, leading to gradually worsening tremors, slower movement and muscle stiffness. In addition, many people with Parkinson's disease have gastrointestinal problems that can show several years before the physical movement symptoms. They may also have inflammation and "leaky" gut, signs of an imbalanced gut microbiome. These observations have prompted genome sequencing studies to identify the types of bacteria in the microbiome of people with Parkinson's disease, and compare that with people without the condition. Several studies have shown differences in the Parkinson's microbiome, but no clear consensus has emerged. Differences across studies may reflect different methodologies, but also the inherent variability in the human microbiome, shaped by lifestyle and dietary variations in different populations around the world. Drug treatment regimens and antibiotic usage also impact on gut bacteria, so variability between different studies isn't a surprise, but it does make drawing definitive conclusions on the association between the microbiome and Parkinson's harder. To address this, the Quadram Institute researchers sought to reanalyse the patient data paired with their control collected across studies from six different countries. This large pool of 1200 samples allowed the researches to identify robust differences between the microbiomes of people with or without Parkinson's disease. The study was supported by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UKRI. The meta-analysis, published in the journal npj Parkinson's Disease, confirmed that the Parkinson's microbiome is different with a reduction in the dominant bacteria usually found in a healthy human gut. But to understand how changes in the microbiome affect health, we need to know what those bacteria are doing. What chemicals, metabolites or signals do they produce and how does this change with the disease? The researchers report that some of the depleted bacteria in Parkinson's produce butyrate, which is used by the cells that line the gut to maintain its integrity as a barrier. Butyrate and other short chain fatty acids also play important roles in interactions between the gut, the nervous system and the brain. In previous studies, Parkinson's disease patients were shown to have lower butyrate levels and increased gut lining inflammation and permeability. Similar depletions in key bacterial species, butyrate levels and gut lining integrity are seen in patients with Inflammatory Bowel Disease (IBD) and IBD patients have a 20%-30% higher risk of developing Parkinson's disease. Other bacteria involved in methane production are enriched in the gut of Parkinson's patients. This together with an increased abundance of bacteria able to degrade the mucus within the gut might affect transit time and explain the constipation problems that are recurrently observed in Parkinson's patients. This study backs up and adds to the evidence linking the gut microbiome, gut inflammation and immune function in Parkinson's, and provides intriguing hints into potential mechanisms by which the gut microbiome influences the disease. However, the team underlines that the available data can't answer the question of whether the microbiome alterations cause Parkinson's Disease or are an effect of it, and suggest sampling strategies that could help understand the causal link between the disease and the gut microbiome. Dr. Stefano Romano who led the study commented "The variability across studies is very big. However, we can still detect differences between the gut microbiome of patients and controls. This means that microbiome alterations in Parkinson's disease are consistent across sampling cohorts." "There is a clear need to further research gut microbial changes linked to diseases in diagnostic or prognostic applications." Microbiome alterations may also be used as biomarkers, especially useful for spotting the earliest onset of the disease, and open new targets for therapies. "The restoration of a balanced microbiome in patients might alleviate some of the symptoms of Parkinson's, and this is a really exciting route of research we are exploring." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract While severe social-distancing measures have proven effective in slowing the coronavirus disease 2019 (COVID-19) pandemic, second-wave scenarios are likely to emerge as restrictions are lifted. Here we integrate anonymized, geolocalized mobility data with census and demographic data to build a detailed agent-based model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in the Boston metropolitan area. We find that a period of strict social distancing followed by a robust level of testing, contact-tracing and household quarantine could keep the disease within the capacity of the healthcare system while enabling the reopening of economic activities. Our results show that a response system based on enhanced testing and contact tracing can have a major role in relaxing social-distancing interventions in the absence of herd immunity against SARS-CoV-2. Main The first report of a new infectious disease, later called COVID-19, appeared on 31 December 2019 1 . As of 15 July 2020, the disease has spread to 188 countries, with more than 13.3 million confirmed cases, and has killed more than 579,500 people 2 . As the number of confirmed COVID-19 cases increased and the expansion of the disease entered into a global exponential growth phase, a large number of affected countries were forced to adopt non-pharmaceutical interventions at an unprecedented scale. Given the absence of specific antiviral prophylaxis, therapeutics or a vaccine, non-pharmaceutical interventions ranging from case isolation and quarantine of contacts, to the lockdown of entire populations have been implemented with the aim of suppressing and mitigating the epidemic before it could overwhelm the healthcare system. Although these aggressive measures appear to be successful in reducing the number of deaths and hospitalizations 3 , 4 , and in reducing the transmission of the SARS-CoV-2 virus, the absence of herd immunity after the first wave of the epidemic points to a high risk of resurgence when interventions are relaxed and societies return to a ‘business as usual’ lifestyle 5 , 6 , 7 . It is therefore of paramount importance to analyse different mitigation and containment strategies aimed at minimizing the risk of potential additional waves of the COVID-19 epidemic, while providing an acceptable trade-off between economic and public health objectives. In this study, through the integration of anonymized and privacy-enhanced data from mobile devices and census data, we build a detailed sample of the synthetic population of the Boston metropolitan area (BMA) in the United States (see Fig. 1a,b ). This synthetic population (Fig. 1a ) is used to define a data-driven agent-based model of SARS-CoV-2 transmission and to provide a quantitative analysis of the evolution of the epidemic and the effectiveness of social-distancing interventions. The model allows us to explore strategies concerning the lifting of social-distancing interventions in conjunction with testing and isolation of cases and tracing and quarantine of exposed contacts. Our results indicate that, after the abatement of the epidemic through the ‘stay-at-home’ orders and halt to all non-essential activities, a proactive policy of testing, contact tracing and household quarantine of contacts enables the gradual reopening of economic activities and workplaces, with a low COVID-19 incidence in the population and a manageable impact on the healthcare system. Fig. 1: Model components. a , Schematic illustration of the weighted multilayer synthetic population built from mobility data in the metropolitan area of Boston. The agent-based system comprises around 64,000 adults and 21,000 children. b , Geographical distribution of the agents in a . MA, Massachusetts. Nodes in a are connected by more than five million weighted edges. Community layers (which include workplaces), are further classified into categories according to Foursquare’s taxonomy of places. c , The compartmental model used to describe the natural history of the disease and the transition rates (represented alongside the connecting arrows, and described in Methods, “Stochastic simulations of COVID-19 dynamics”) between the different states. Specifically, we consider susceptible (S), latent asymptomatic (L A ), latent symptomatic (L S ), presymptomatic (P S ), infectious asymptomatic (I A ), infectious symptomatic (I S ), hospitalized (H), hospitalized in intensive care (ICU) and recovered (R) individuals. More details of the model and the transitions between compartments are provided in Methods and the Supplementary Information . Full size image To provide a quantitative estimate of the contact patterns for the population of agents and to build the synthetic population of the BMA, we used detailed mobility and socio-demographic data and generated a network that encodes the contact patterns of around 85,000 agents in the area during a period of six months (see Supplementary Information ). Agents are chosen to be representative of the different census areas in the Boston area following the methodology used in ref. 8 . This defines a weighted multilayer network consisting of three layers representing the network of social interactions at (1) workplace and community level, (2) households, and (3) schools, as shown in Fig. 1a . Connections between two agents in the workplace and community layer are estimated from the data by the probability of both being present in a specific place (for example, a restaurant, workplace or shop) weighted according to the time they have spent in the same place. A second layer represents the households of each anonymous individual. Using the home census block group of each anonymous user, we associate each individual with a specific household profile on the basis of socio-demographic data at US census block group level 9 . Families are generated by randomly mixing nodes from the community living in the same census block group, following the statistical features of family types and sizes. Finally, a third layer represents the contacts in schools (that is, every node represents one synthetic student and has contacts only with other individuals attending the same school). To study the evolving dynamics of the infection, we implemented a stochastic, discrete-time compartmental model in which individuals transition from one state to the other according to key time-to-event intervals (for example, incubation period, serial interval and time from symptom onset to hospital admission), as from available data on SARS-CoV-2 transmission. The natural", "role": "user" }, { "content": "Early on in the pandemic, lockdown and physical distancing measures were able to slow the spread of COVID-19 and bring case numbers down. But as the U.S. has begun to reopen, the number of new cases has surged in many places. To reopen safely and keep from overwhelming hospital capacities, according to public health officials, we need adequate testing, contact tracing, and quarantining to stop localized outbreaks before they get out of hand. But how much testing is enough? What percentage of people who've been unwittingly exposed to the virus do we need to track down? How many people will need to be quarantined? In a recent study published in Nature Human Behavior, researchers at Northeastern's Network Science Institute sought to quantify these answers. \"Finding the right balance between when and how you reopen and how much you do testing and contract tracing is important, because none of those approaches alone is the optimal solution,\" says Matteo Chinazzi, a senior research scientist in Northeastern's Laboratory for the Modeling of Biological and Socio-Technical Systems. \"The optimal solution is to find a trade-off, a good mixing, between all of these different parameters.\" Using a model based on population dynamics in Boston and the surrounding areas, the group, which also included researchers from the Institute for Scientific Interchange Foundation, Universidad Carlos III de Madrid, Bruno Kessler Foundation, University of Washington, University of Florida, and MIT, examined three scenarios. In every scenario, they assumed that schools would remain closed for the 2019-2020 school year and through the summer. \"We are not trying here to actually represent the outbreak in the Boston metropolitan area, but to see 'what-if' scenarios,\" says Ana Pastore y Piontti, an associate research scientist at Northeastern. In the first scenario, there was no lockdown and the pandemic grew unabated, as expected. In the second scenario, there was a strict lockdown, which significantly dropped case numbers, and then a staged reopening as stay-at-home orders were lifted. In the first stage, work and community locations were allowed to reopen, excluding \"mass-gathering locations\" such as restaurants and theaters. After four weeks, everything reopened. While this scenario showed that the lockdown successfully brought case numbers under control, it did not stop them from resurging as people began moving around again. \"When we do nothing, basically, after we reopen, the epidemic starts increasing again and eventually the health system will collapse,\" Pastore y Piontti says. The third scenario followed a similar progression—lockdown, followed by a staged reopening—but included enhanced testing and tracing efforts as reopening occurred. The researchers assumed there would be enough testing to catch half of all symptomatic cases within two days of the onset of symptoms, and that those people and all members of their household would be isolated for two weeks. Within this third scenario, they obtained results for three different levels of contact tracing; tracking down 0, 20, or 40 percent of non-household contacts of sick individuals and isolating those people and their households for two weeks as well. In the best scenario, with 40 percent of contacts traced and quarantined, along with their households, the curve was flattened and there wasn't a second surge of infections. About 9 percent of the population was in quarantine at any point in time. \"Even though those numbers don't seem so high, logistically it's not that easy,\" Pastore y Piontti says. \"It's still better than having everybody stay home, but it's a lot of people.\" And what about without any contact tracing? \"We find that quarantining households of symptomatic individuals alone is not sufficient to substantially change the course of the epidemic,\" the researchers wrote. So we need contact tracing, too. But testing and contact tracing are most effective when case numbers are low, Chinazzi says. That's why the models all began with a strict lockdown. \"Contact tracing is extremely important at the beginning of an outbreak, when you start having the ability to quickly identify clusters and put the fire down as soon as it starts, in a sense,\" Chinazzi says. When case numbers are already out of hand, as they were, and still are, in many parts of the U.S., \"you first have to try to reduce the number of circulating cases and transmission, and then you can do contact tracing and case isolation.\" The researchers specify that they did not factor in the effects of mask-wearing and physical distancing measures, which could help reduce the spread of the coronavirus. But their model provides a way to help policymakers make informed choices at a local level, and understand what it will take to bring the epidemic under control. \"It's the difference between having the list of ingredients for a recipe and actually having the quantities, in a sense,\" Chinazzi says. \"Maybe you know that you need testing; maybe you know that you need contact tracing; but the point is, how much? What level of the population will have to be quarantined to have that effect?\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract While severe social-distancing measures have proven effective in slowing the coronavirus disease 2019 (COVID-19) pandemic, second-wave scenarios are likely to emerge as restrictions are lifted. Here we integrate anonymized, geolocalized mobility data with census and demographic data to build a detailed agent-based model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in the Boston metropolitan area. We find that a period of strict social distancing followed by a robust level of testing, contact-tracing and household quarantine could keep the disease within the capacity of the healthcare system while enabling the reopening of economic activities. Our results show that a response system based on enhanced testing and contact tracing can have a major role in relaxing social-distancing interventions in the absence of herd immunity against SARS-CoV-2. Main The first report of a new infectious disease, later called COVID-19, appeared on 31 December 2019 1 . As of 15 July 2020, the disease has spread to 188 countries, with more than 13.3 million confirmed cases, and has killed more than 579,500 people 2 . As the number of confirmed COVID-19 cases increased and the expansion of the disease entered into a global exponential growth phase, a large number of affected countries were forced to adopt non-pharmaceutical interventions at an unprecedented scale. Given the absence of specific antiviral prophylaxis, therapeutics or a vaccine, non-pharmaceutical interventions ranging from case isolation and quarantine of contacts, to the lockdown of entire populations have been implemented with the aim of suppressing and mitigating the epidemic before it could overwhelm the healthcare system. Although these aggressive measures appear to be successful in reducing the number of deaths and hospitalizations 3 , 4 , and in reducing the transmission of the SARS-CoV-2 virus, the absence of herd immunity after the first wave of the epidemic points to a high risk of resurgence when interventions are relaxed and societies return to a ‘business as usual’ lifestyle 5 , 6 , 7 . It is therefore of paramount importance to analyse different mitigation and containment strategies aimed at minimizing the risk of potential additional waves of the COVID-19 epidemic, while providing an acceptable trade-off between economic and public health objectives. In this study, through the integration of anonymized and privacy-enhanced data from mobile devices and census data, we build a detailed sample of the synthetic population of the Boston metropolitan area (BMA) in the United States (see Fig. 1a,b ). This synthetic population (Fig. 1a ) is used to define a data-driven agent-based model of SARS-CoV-2 transmission and to provide a quantitative analysis of the evolution of the epidemic and the effectiveness of social-distancing interventions. The model allows us to explore strategies concerning the lifting of social-distancing interventions in conjunction with testing and isolation of cases and tracing and quarantine of exposed contacts. Our results indicate that, after the abatement of the epidemic through the ‘stay-at-home’ orders and halt to all non-essential activities, a proactive policy of testing, contact tracing and household quarantine of contacts enables the gradual reopening of economic activities and workplaces, with a low COVID-19 incidence in the population and a manageable impact on the healthcare system. Fig. 1: Model components. a , Schematic illustration of the weighted multilayer synthetic population built from mobility data in the metropolitan area of Boston. The agent-based system comprises around 64,000 adults and 21,000 children. b , Geographical distribution of the agents in a . MA, Massachusetts. Nodes in a are connected by more than five million weighted edges. Community layers (which include workplaces), are further classified into categories according to Foursquare’s taxonomy of places. c , The compartmental model used to describe the natural history of the disease and the transition rates (represented alongside the connecting arrows, and described in Methods, “Stochastic simulations of COVID-19 dynamics”) between the different states. Specifically, we consider susceptible (S), latent asymptomatic (L A ), latent symptomatic (L S ), presymptomatic (P S ), infectious asymptomatic (I A ), infectious symptomatic (I S ), hospitalized (H), hospitalized in intensive care (ICU) and recovered (R) individuals. More details of the model and the transitions between compartments are provided in Methods and the Supplementary Information . Full size image To provide a quantitative estimate of the contact patterns for the population of agents and to build the synthetic population of the BMA, we used detailed mobility and socio-demographic data and generated a network that encodes the contact patterns of around 85,000 agents in the area during a period of six months (see Supplementary Information ). Agents are chosen to be representative of the different census areas in the Boston area following the methodology used in ref. 8 . This defines a weighted multilayer network consisting of three layers representing the network of social interactions at (1) workplace and community level, (2) households, and (3) schools, as shown in Fig. 1a . Connections between two agents in the workplace and community layer are estimated from the data by the probability of both being present in a specific place (for example, a restaurant, workplace or shop) weighted according to the time they have spent in the same place. A second layer represents the households of each anonymous individual. Using the home census block group of each anonymous user, we associate each individual with a specific household profile on the basis of socio-demographic data at US census block group level 9 . Families are generated by randomly mixing nodes from the community living in the same census block group, following the statistical features of family types and sizes. Finally, a third layer represents the contacts in schools (that is, every node represents one synthetic student and has contacts only with other individuals attending the same school). To study the evolving dynamics of the infection, we implemented a stochastic, discrete-time compartmental model in which individuals transition from one state to the other according to key time-to-event intervals (for example, incubation period, serial interval and time from symptom onset to hospital admission), as from available data on SARS-CoV-2 transmission. The natural<|im_end|> <|im_start|>assistant Early on in the pandemic, lockdown and physical distancing measures were able to slow the spread of COVID-19 and bring case numbers down. But as the U.S. has begun to reopen, the number of new cases has surged in many places. To reopen safely and keep from overwhelming hospital capacities, according to public health officials, we need adequate testing, contact tracing, and quarantining to stop localized outbreaks before they get out of hand. But how much testing is enough? What percentage of people who've been unwittingly exposed to the virus do we need to track down? How many people will need to be quarantined? In a recent study published in Nature Human Behavior, researchers at Northeastern's Network Science Institute sought to quantify these answers. "Finding the right balance between when and how you reopen and how much you do testing and contract tracing is important, because none of those approaches alone is the optimal solution," says Matteo Chinazzi, a senior research scientist in Northeastern's Laboratory for the Modeling of Biological and Socio-Technical Systems. "The optimal solution is to find a trade-off, a good mixing, between all of these different parameters." Using a model based on population dynamics in Boston and the surrounding areas, the group, which also included researchers from the Institute for Scientific Interchange Foundation, Universidad Carlos III de Madrid, Bruno Kessler Foundation, University of Washington, University of Florida, and MIT, examined three scenarios. In every scenario, they assumed that schools would remain closed for the 2019-2020 school year and through the summer. "We are not trying here to actually represent the outbreak in the Boston metropolitan area, but to see 'what-if' scenarios," says Ana Pastore y Piontti, an associate research scientist at Northeastern. In the first scenario, there was no lockdown and the pandemic grew unabated, as expected. In the second scenario, there was a strict lockdown, which significantly dropped case numbers, and then a staged reopening as stay-at-home orders were lifted. In the first stage, work and community locations were allowed to reopen, excluding "mass-gathering locations" such as restaurants and theaters. After four weeks, everything reopened. While this scenario showed that the lockdown successfully brought case numbers under control, it did not stop them from resurging as people began moving around again. "When we do nothing, basically, after we reopen, the epidemic starts increasing again and eventually the health system will collapse," Pastore y Piontti says. The third scenario followed a similar progression—lockdown, followed by a staged reopening—but included enhanced testing and tracing efforts as reopening occurred. The researchers assumed there would be enough testing to catch half of all symptomatic cases within two days of the onset of symptoms, and that those people and all members of their household would be isolated for two weeks. Within this third scenario, they obtained results for three different levels of contact tracing; tracking down 0, 20, or 40 percent of non-household contacts of sick individuals and isolating those people and their households for two weeks as well. In the best scenario, with 40 percent of contacts traced and quarantined, along with their households, the curve was flattened and there wasn't a second surge of infections. About 9 percent of the population was in quarantine at any point in time. "Even though those numbers don't seem so high, logistically it's not that easy," Pastore y Piontti says. "It's still better than having everybody stay home, but it's a lot of people." And what about without any contact tracing? "We find that quarantining households of symptomatic individuals alone is not sufficient to substantially change the course of the epidemic," the researchers wrote. So we need contact tracing, too. But testing and contact tracing are most effective when case numbers are low, Chinazzi says. That's why the models all began with a strict lockdown. "Contact tracing is extremely important at the beginning of an outbreak, when you start having the ability to quickly identify clusters and put the fire down as soon as it starts, in a sense," Chinazzi says. When case numbers are already out of hand, as they were, and still are, in many parts of the U.S., "you first have to try to reduce the number of circulating cases and transmission, and then you can do contact tracing and case isolation." The researchers specify that they did not factor in the effects of mask-wearing and physical distancing measures, which could help reduce the spread of the coronavirus. But their model provides a way to help policymakers make informed choices at a local level, and understand what it will take to bring the epidemic under control. "It's the difference between having the list of ingredients for a recipe and actually having the quantities, in a sense," Chinazzi says. "Maybe you know that you need testing; maybe you know that you need contact tracing; but the point is, how much? What level of the population will have to be quarantined to have that effect?" <|im_end|>

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2,322

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract One of the most remarkable aspects of our species is that while we show surprisingly little genetic diversity, we demonstrate astonishing amounts of cultural diversity. Perhaps most impressive is the diversity of our technologies, broadly defined as all the physical objects we produce and the skills we use to produce them. Despite considerable focus on the evolution of technology by social scientists and philosophers, there have been few attempts to systematically quantify technological diversity, and therefore the dynamics of technological change remain poorly understood. Here we show a novel Bayesian model for examining technological diversification adopted from palaeontological analysis of occurrence data. We use this framework to estimate the tempo of diversification in American car and truck models produced between 1896 and 2014, and to test the relative importance of competition and extrinsic factors in shaping changes in macro-evolutionary rates. Our results identify a four-fold decrease in the origination and extinction rates of car models, and a negative net diversification rate over the last 30 years. We also demonstrate that competition played a more significant role in car model diversification than either changes in oil prices or gross domestic product. Together our analyses provide a set of tools that can enhance current research on technological and cultural evolution by providing a flexible and quantitative framework for exploring the dynamics of diversification. Despite the ubiquity of technology in our society, there remains no widely accepted view or quantitative framework for understanding technological change ( Arthur, 2009 ). Rather, the subject is characterized by a series of generic frameworks ( David, 1985 ; Stack and Gartland, 2003 ) and unrelated case studies of successful or popular designs ( Diamond, 1997 ; Lake and Venti, 2009 ; Schiffer, 1994 ; Bijker, 1995 ). This myopic focus on “success stories” poorly characterizes the dynamic processes that shape cultural diversity through time and does not provide a framework for evaluating alternative hypotheses for successes or failures. We argue here that the field of macroevolution provides novel perspectives and tools for understanding the dynamics of technological diversification. Our research introduces a flexible statistical framework adopted from paleobiology that provides for the quantification of evolutionary rates of cultural change through time. Macroevolution, technology and diversity Evolution has been and continues to be a valuable source of methods and theories for the study of human culture. Previous research has demonstrated that human culture undeniably evolves, but to what degree cultural change mirrors biological change remains an unsettled question ( Tëmkin and Eldredge, 2007 ). The evolution of technology is a topic in which the evolutionary analogy has been particularly contentious, with debate often centred on the unit of evolutionary analysis, the replication of technological designs and the applicability of branching models to understanding the evolution to intentionally designed objects. This article presents an alternative perspective to the study of technological evolution that highlights the concept of diversity and a suite of macro-evolutionary methods useful in quantifying the dynamics of technological diversification. In this research, technological diversity is conceptualized as the number of different technological lineages represented in a system. This definition of diversity is different from disciplines that acknowledge diversity as having the additional dimensions of balance and disparity ( Stirling, 2007 ), but is analogous to the concept of species richness in biology, where a large number of methods are available for characterizing this component of diversity through time. The emphasis on the richness or variety of technological lineages is not to diminish the importance of balance and disparity , but rather to acknowledge that the information necessary to examine these components of diversity is not often available for historical or complex technological systems. For example, in order to evaluate balance , it is necessary to have an accurate estimate of the abundance of technological products over multiple time periods, which is often unavailable or unreliable when using historical or archaeological data. Alternatively, the calculation of disparity requires the detailed knowledge of product characteristics to distinguish between product classes, an arduous task for comple technologies. To gain deeper insight into the diversification dynamics of technological systems, this article presents a flexible set of macroevolutionary methods for examining the rate of diversification of technological linages through time. This methodology has several advantages to existing frameworks. First, diversity (variety) in our approach is determined by both the rate of origination and extinction of technological lineages. This is a more comprehensive representation of diversity than studies of technological evolution that analyse only the emergence of specific or successful designs. Second, our approach explores diversification dynamics in continuous time through the implementation of a birth–death model. One advantage of the birth–death framework for cultural and technological systems is that the process does not require the construction of evolutionary histories connecting material objects or the construction of detailed lists of product traits. The central assumption of this birth–death process is simply that novel variants emerge from the pool of existing variation in the previous time period. Third, our method can be applied to any dataset in which the dates of origination and extinction are known or only partially known. Our method is fully integrated into a Bayesian modelling framework allowing for the testing of competing hypotheses through the comparison of Bayes Factors. Through the implementation of our method we are able to (1) identify a continuous rate of technological origination and extinction through time, (2) compare the effects of intrinsic and extrinsic factors on rates of technological diversity and (3) explore the future rate of technological diversification. American automobiles We investigated the diversification of American commercial automobiles following their origin in the nineteenth century to present. Automobiles are one of the most iconic examples of American mass technology in the twentieth century and represent a successful, enduring and widespread human technology that is exceptionally diverse. Using the rich historical record of American automobiles, we focus our analysis at the level of the car model as models have a commercial and cultural reality that persists through time despite generational changes in features", "role": "user" }, { "content": "A UCLA-led team of researchers has taken a unique approach to explain the way in which technologies evolve in modern society. Borrowing a technique that biologists might use to study the evolution of plants or animals, the scientists plotted the \"births\" and \"deaths\" of every American-made car and truck model from 1896 to 2014. In addition to uncovering interesting insights about the auto industry, the strategy—which could be used to study the evolution of phones, music, TVs or any number of other products—offers a new lens through which researchers could study cultural and technological change. The research, which was published in the open-access journal Palgrave Communications, was led by Erik Gjesfjeld, a postdoctoral scholar in UCLA's Institute for Society and Genetics. \"Cars are exceptionally diverse but also have a detailed history of changes, making them a model system for investigating the evolution of technology,\" Gjesfjeld said. The team drew data from 3,575 car models made by 172 different manufacturers, noting the first and last year each was manufactured. \"This is similar to when a paleontologist first dates a particular fossil and last sees a particular fossil,\" Gjesfjeld said. The approach allowed them to identify periods of time when new car models were being introduced at faster- or slower-than-usual rates; and to identify periods when cars were being discontinued in greater or lesser numbers. For example, the study found that after World War II, when car models and manufacturers established themselves as the dominant players, the number of new car models declined significantly; the authors write that this was in part because producing entirely new cars would have been more expensive than continuing established designs. 1950 Packard. Credit: Sedan Byron Krystad So although sustaining car models for long periods of time—the Chevrolet Corvette and Ford Mustang are prime examples—might make more sense from a management standpoint than introducing new ones every year, the approach has had a clear effect on the diversity and evolution of the industry: fewer new car models, less diversity among the models in the marketplace, and less of a chance for radical new designs and models to emerge. One advantage of the new approach is that it enables scientists to test theories about a product's evolution. \"This is a framework that allows for data-based testing of hypotheses, which is not common,\" said Michael Alfaro, a UCLA professor of ecology and evolutionary biology in the UCLA College and senior author of the study. Applying the technique to American cars enabled the scientists to test three hypotheses: The variety of car models would increase during periods of economic growth and decline during times with less economic growth.Changes in the diversity of car models would be driven by changes in oil prices.The diversity of car models would be influenced by the number of other car models on the market. 1962 Studebaker Hawk. Credit: Greg Gjerdingen What they found was that competition in the marketplace played a bigger role in the variety of car models than either economic growth or oil prices. Alfaro said applying an evolutionary biology approach worked so well because the automotive industry's technological records are very similar to the paleontological fossil record. \"In many instances, it is superior,\" he said. \"We find in only a handful of cases a fossil record this complete.\" Based on the study, the researchers can project how the electric car marketplace will evolve over the next several years. Alfaro said the field now is in an early phase of rapid diversification, and although it's likely that many more electric and hybrid models will be introduced over the next 15 to 20 years, many won't survive for very long due to increasing competition. This, he said, will eventually lead to consolidation, with a small number of dominant models that will thrive. Ultimately, Gjesfjeld said, the technique could help us make sense of the bewildering array of technologies humans have created. \"Despite the use of numerous technologies in our everyday life, we lack a basic understanding of how all this technological diversity came to be,\" he said. 1980s DeLorean DMC-12. Credit: Grenex ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract One of the most remarkable aspects of our species is that while we show surprisingly little genetic diversity, we demonstrate astonishing amounts of cultural diversity. Perhaps most impressive is the diversity of our technologies, broadly defined as all the physical objects we produce and the skills we use to produce them. Despite considerable focus on the evolution of technology by social scientists and philosophers, there have been few attempts to systematically quantify technological diversity, and therefore the dynamics of technological change remain poorly understood. Here we show a novel Bayesian model for examining technological diversification adopted from palaeontological analysis of occurrence data. We use this framework to estimate the tempo of diversification in American car and truck models produced between 1896 and 2014, and to test the relative importance of competition and extrinsic factors in shaping changes in macro-evolutionary rates. Our results identify a four-fold decrease in the origination and extinction rates of car models, and a negative net diversification rate over the last 30 years. We also demonstrate that competition played a more significant role in car model diversification than either changes in oil prices or gross domestic product. Together our analyses provide a set of tools that can enhance current research on technological and cultural evolution by providing a flexible and quantitative framework for exploring the dynamics of diversification. Despite the ubiquity of technology in our society, there remains no widely accepted view or quantitative framework for understanding technological change ( Arthur, 2009 ). Rather, the subject is characterized by a series of generic frameworks ( David, 1985 ; Stack and Gartland, 2003 ) and unrelated case studies of successful or popular designs ( Diamond, 1997 ; Lake and Venti, 2009 ; Schiffer, 1994 ; Bijker, 1995 ). This myopic focus on “success stories” poorly characterizes the dynamic processes that shape cultural diversity through time and does not provide a framework for evaluating alternative hypotheses for successes or failures. We argue here that the field of macroevolution provides novel perspectives and tools for understanding the dynamics of technological diversification. Our research introduces a flexible statistical framework adopted from paleobiology that provides for the quantification of evolutionary rates of cultural change through time. Macroevolution, technology and diversity Evolution has been and continues to be a valuable source of methods and theories for the study of human culture. Previous research has demonstrated that human culture undeniably evolves, but to what degree cultural change mirrors biological change remains an unsettled question ( Tëmkin and Eldredge, 2007 ). The evolution of technology is a topic in which the evolutionary analogy has been particularly contentious, with debate often centred on the unit of evolutionary analysis, the replication of technological designs and the applicability of branching models to understanding the evolution to intentionally designed objects. This article presents an alternative perspective to the study of technological evolution that highlights the concept of diversity and a suite of macro-evolutionary methods useful in quantifying the dynamics of technological diversification. In this research, technological diversity is conceptualized as the number of different technological lineages represented in a system. This definition of diversity is different from disciplines that acknowledge diversity as having the additional dimensions of balance and disparity ( Stirling, 2007 ), but is analogous to the concept of species richness in biology, where a large number of methods are available for characterizing this component of diversity through time. The emphasis on the richness or variety of technological lineages is not to diminish the importance of balance and disparity , but rather to acknowledge that the information necessary to examine these components of diversity is not often available for historical or complex technological systems. For example, in order to evaluate balance , it is necessary to have an accurate estimate of the abundance of technological products over multiple time periods, which is often unavailable or unreliable when using historical or archaeological data. Alternatively, the calculation of disparity requires the detailed knowledge of product characteristics to distinguish between product classes, an arduous task for comple technologies. To gain deeper insight into the diversification dynamics of technological systems, this article presents a flexible set of macroevolutionary methods for examining the rate of diversification of technological linages through time. This methodology has several advantages to existing frameworks. First, diversity (variety) in our approach is determined by both the rate of origination and extinction of technological lineages. This is a more comprehensive representation of diversity than studies of technological evolution that analyse only the emergence of specific or successful designs. Second, our approach explores diversification dynamics in continuous time through the implementation of a birth–death model. One advantage of the birth–death framework for cultural and technological systems is that the process does not require the construction of evolutionary histories connecting material objects or the construction of detailed lists of product traits. The central assumption of this birth–death process is simply that novel variants emerge from the pool of existing variation in the previous time period. Third, our method can be applied to any dataset in which the dates of origination and extinction are known or only partially known. Our method is fully integrated into a Bayesian modelling framework allowing for the testing of competing hypotheses through the comparison of Bayes Factors. Through the implementation of our method we are able to (1) identify a continuous rate of technological origination and extinction through time, (2) compare the effects of intrinsic and extrinsic factors on rates of technological diversity and (3) explore the future rate of technological diversification. American automobiles We investigated the diversification of American commercial automobiles following their origin in the nineteenth century to present. Automobiles are one of the most iconic examples of American mass technology in the twentieth century and represent a successful, enduring and widespread human technology that is exceptionally diverse. Using the rich historical record of American automobiles, we focus our analysis at the level of the car model as models have a commercial and cultural reality that persists through time despite generational changes in features<|im_end|> <|im_start|>assistant A UCLA-led team of researchers has taken a unique approach to explain the way in which technologies evolve in modern society. Borrowing a technique that biologists might use to study the evolution of plants or animals, the scientists plotted the "births" and "deaths" of every American-made car and truck model from 1896 to 2014. In addition to uncovering interesting insights about the auto industry, the strategy—which could be used to study the evolution of phones, music, TVs or any number of other products—offers a new lens through which researchers could study cultural and technological change. The research, which was published in the open-access journal Palgrave Communications, was led by Erik Gjesfjeld, a postdoctoral scholar in UCLA's Institute for Society and Genetics. "Cars are exceptionally diverse but also have a detailed history of changes, making them a model system for investigating the evolution of technology," Gjesfjeld said. The team drew data from 3,575 car models made by 172 different manufacturers, noting the first and last year each was manufactured. "This is similar to when a paleontologist first dates a particular fossil and last sees a particular fossil," Gjesfjeld said. The approach allowed them to identify periods of time when new car models were being introduced at faster- or slower-than-usual rates; and to identify periods when cars were being discontinued in greater or lesser numbers. For example, the study found that after World War II, when car models and manufacturers established themselves as the dominant players, the number of new car models declined significantly; the authors write that this was in part because producing entirely new cars would have been more expensive than continuing established designs. 1950 Packard. Credit: Sedan Byron Krystad So although sustaining car models for long periods of time—the Chevrolet Corvette and Ford Mustang are prime examples—might make more sense from a management standpoint than introducing new ones every year, the approach has had a clear effect on the diversity and evolution of the industry: fewer new car models, less diversity among the models in the marketplace, and less of a chance for radical new designs and models to emerge. One advantage of the new approach is that it enables scientists to test theories about a product's evolution. "This is a framework that allows for data-based testing of hypotheses, which is not common," said Michael Alfaro, a UCLA professor of ecology and evolutionary biology in the UCLA College and senior author of the study. Applying the technique to American cars enabled the scientists to test three hypotheses: The variety of car models would increase during periods of economic growth and decline during times with less economic growth.Changes in the diversity of car models would be driven by changes in oil prices.The diversity of car models would be influenced by the number of other car models on the market. 1962 Studebaker Hawk. Credit: Greg Gjerdingen What they found was that competition in the marketplace played a bigger role in the variety of car models than either economic growth or oil prices. Alfaro said applying an evolutionary biology approach worked so well because the automotive industry's technological records are very similar to the paleontological fossil record. "In many instances, it is superior," he said. "We find in only a handful of cases a fossil record this complete." Based on the study, the researchers can project how the electric car marketplace will evolve over the next several years. Alfaro said the field now is in an early phase of rapid diversification, and although it's likely that many more electric and hybrid models will be introduced over the next 15 to 20 years, many won't survive for very long due to increasing competition. This, he said, will eventually lead to consolidation, with a small number of dominant models that will thrive. Ultimately, Gjesfjeld said, the technique could help us make sense of the bewildering array of technologies humans have created. "Despite the use of numerous technologies in our everyday life, we lack a basic understanding of how all this technological diversity came to be," he said. 1980s DeLorean DMC-12. Credit: Grenex <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract It is well known that both recipient cells and donor nuclei demonstrate a mitotic advantage as observed in the traditional reprogramming with somatic cell nuclear transfer (SCNT). However, it is not known whether a specific mitotic factor plays a critical role in reprogramming. Here we identify an isoform of human bromodomain-containing 3 (BRD3), BRD3R (BRD3 with Reprogramming activity), as a reprogramming factor. BRD3R positively regulates mitosis during reprogramming, upregulates a large set of mitotic genes at early stages of reprogramming, and associates with mitotic chromatin. Interestingly, a set of the mitotic genes upregulated by BRD3R constitutes a pluripotent molecular signature. The two BRD3 isoforms display differential binding to acetylated histones. Our results suggest a molecular interpretation for the mitotic advantage in reprogramming and show that mitosis may be a driving force of reprogramming. Introduction Pluripotent stem cells (PSCs) offer great opportunities for regenerative medicine and stem cell biology due to their differentiation potentials and unlimited growth 1 . PSCs can be derived from inner cell mass of preimplantation embryos 2 , or generated by reprogramming of somatic cells 3 . The historically most powerful reprogramming is by somatic cell nuclear transfer (SCNT) into enucleated totipotent cells 4 . SCNT needs embryo and is technically demanding. Induction of pluripotent stem cells (iPSCs) from somatic cells by overexpression of transgenes is the most advanced and simplest reprogramming 5 . Despite extensive improvement, iPSC technology still faces many problems including stochastic, incomplete and aberrant reprogramming, reprogramming-associated mutagenesis, cell senescence, apoptosis and transformation, and use of oncogenes as reprogramming factors 6 , 7 , 8 , 9 , 10 , 11 . Compared with SCNT, iPSC reprogramming has a very low efficiency and slow kinetics, suggesting the existence of additional yet-to-be discovered reprogramming factors. PSCs have a unique cell cycle structure characterized by a truncated G1 phase, lack of a G1 checkpoint, lack of CDK periodicity, and a greater portion of cells in S/G2/M phases as compared with somatic cells 12 . During the reprogramming process, the pluripotent cell cycle structure has to be reset along with many other pluripotent features including differentiation potential, self-renewal, epigenetic landscape, transcriptome and the unique morphologies of the pluripotent cells and their colonies. In SCNT reprogramming, one consistent observation has been that only oocytes at the mitosis stage (metaphase II) possess high enough reprogramming activity to clone animals successfully 13 . On fertilization, such a reprogramming capacity becomes lost in the zygote 14 , but it can be restored when a zygote is arrested in mitosis 15 . When in mitosis, even the enucleated blastomeres from two-cell-stage embryos display animal cloning capacity 16 . In addition, the donor nucleus in SCNT also exhibits a 100 × mitotic advantage 17 . The underlying molecular basis for both the potent reprogramming power and the higher reprogrammability of mitotic cells is unknown. It is possible that the observed mitotic advantage is a technical artifact associated with SCNT because reprogramming factors within nuclei may have been removed from the interphase recipient cells and are released and remain in the reprogramming-competent mitotic cytoplasts due to the breakdown of nuclear envelopes in mitosis 18 , 19 . Efforts have been made to investigate the role of acetyl epigenetics in reprogramming because of the importance of histone acetylation in transcription controls and pluripotency, but these efforts have been restricted to the use of HDAC inhibitors 20 . Here we provide an example that an epigenetic reader BRD3R, rather than writers, erasers or chromatin remodelers is a reprogramming factor. We present evidence that the mitotic protein BRD3R facilitates resetting of the pluripotent cell cycle structure and increases the number of reprogramming-privileged mitotic cells by upregulating as many as 128 mitotic genes, without compromising the p53–p21 surveillance pathway. At least 19 of these BRD3R-upregulated mitotic genes constitute an expression fingerprint of PSCs. Our findings provide molecular insights into the mitotic advantage of reprogramming. Results BRD3R is a robust human reprogramming factor We hypothesized that there are additional undiscovered reprogramming factor(s) to account for the higher efficiency and faster kinetics of SCNT compared with factor reprogramming. We directly searched for new human reprogramming factor, expecting more clinical values of the possible new findings than mouse ones. Thus, we prepared and screened a lentiviral expression library of 89 human kinase cDNAs on account of the importance of phosphorylation in general cell biology and in pluripotency in particular. The importance of phosphorylation in pluripotency and reprogramming is suggested by the simple fact that there are 8,359 phosphorylation sites in human embryonic stem cells (hESC) 21 , the majority of which are believed to be differentially phosphorylated relative to somatic cells 22 . We first established a sensitive protocol that enables simultaneous evaluation of 22 individual cDNAs with a 24-well plate in a long process as reprogramming ( Fig. 1a ; Supplementary Fig. 1 ). We used the serum-free/feeder-free E8 human cell reprogramming system because this xeno-free defined medium is more consistent and efficient, and is more relevant to clinical applications 23 . Our basic reprogramming protocol includes three of the Yamanaka factors OCT4, SOX2 and KLF4 (three factors, 3F). We excluded MYC because, consistent with previous report, MYC is slightly detrimental to reprogramming in the feeder-free/serum-free system ( Fig. 1d,e ) 23 , 24 . Furthermore, MYC is a strong oncogene, which transforms starting cells during reprogramming and compromises the quality of iPSCs generated 25 , 26 . In fact, Yamanaka’s group later reported that MYC is non-essential for reprogramming 25 . Figure 1: BRD3R is a robust reprogramming factor. ( a ) Schematic of the screening protocol. D, days. ( b ) Fold changes of ALP + colonies for the 89 human kinase cDNAs in primary screen as compared with GFP control. #, Genes for the secondary screen. ( c ) Fold change as in b for the 11 candidate genes in the secondary screen. ( d ) Validation of the reprogramming activity of BRD3R as evaluated by number of TRA-1-60 + colonies ( n =3; mean ±", "role": "user" }, { "content": "Kejin Hu, Ph.D., of the University of Alabama at Birmingham, has found a robust reprogramming factor that increases the efficiency of creating human induced pluripotent stem cells (HiPSCs) from skin fibroblasts more than 20-fold, speeds the reprogramming time by several days and enhances the quality of reprogramming. HiPSCs are believed to hold great promise for medical research and disease treatments. They are man-made versions of human embryonic stem cells (hESCs). Biomedical researchers can generate HiPSCs from many somatic cells such as fibroblasts from a skin biopsy, without destroying any human embryo. Like hESCs, HiPSCs have the ability to differentiate into any type of specialized cell. Thus, they can differentiate into any of the 200-plus different types of human cells. These cells are potent tools for drug development and modeling of disease, and they also hold potential to transform transplantation medicine by creating patient-specific pluripotent stem cells for cell-replacement therapies. Targets may include neurological diseases, heart ailments, blood diseases and diabetes. But this promise of iPSCs is hobbled by a low efficiency, less than 0.1 to 1 percent, in producing these cells, along with many other significant hurdles. In a paper published March 7 in Nature Communications, Hu and fellow UAB researchers describe their successful hunt for a reprogramming factor that boosts the efficiency and shortens the time the cell takes to reprogram. The reprogramming factor is a kinase-family protein called BRD3R that reads acetylated histone codes in the chromosome. When the Hu lab looked at the gene expression induced by overexpression of BRD3R during the reprogramming of human fibroblasts into iPSCs, they also solved a mystery that had endured half a century since 1962, when the Nobel Laureate John Gurdon first cloned a frog by placing the nucleus of an intestinal cell into an enucleated frog egg cell—namely, why does animal cloning succeed only with oocytes that are in the metaphase II stage of mitosis? Hu found that the BRD3R gene, when introduced into fibroblasts, upregulated 128 mitotic genes, which yields a molecular insight into the mitotic advantage of reprogramming. \"When we saw the mRNA sequencing data, they explained why mitosis is so important in reprogramming,\" Hu said. \"I was excited when we found a new reprogramming factor and also by this second discovery.\" To reprogram the fibroblasts, the Hu lab used BRD3R delivered by a lentiviral vector, along with three of the genes that the Japanese Nobel Laureate Shinya Yamanaka used in his first successful reprogramming of mature mouse cells into iPSCs in 2006—OCT4, SOX2 and KLF4. BRD3R was unable to replace any of the three essential Yamanaka reprogramming factors, indicating that BRD3R has a distinct role from them in reprogramming. Hu and his colleagues did their reprogramming of the human somatic cells in xeno-free media, without using mouse feeder cells or serum from any sources. Xeno-free production will be an FDA good manufacturing practice requirement for future clinical use of human iPSCs. Hu started his search for a new reprogramming factor after arriving at the Stem Cell Institute, UAB Department of Biochemistry and Genetics, in 2011. \"I believed that new reprogramming factors would produce more authentic iPSCs in a more efficient, faster way.\" He acquired a library of 558 human kinase genes and began to screen a batch of the first 89. After introducing the three Yamanaka genes and his test kinase genes into fibroblast cells, he looked for an increase in efficiency in iPSC generation, as judged by increased colony numbers of the successfully reprogrammed pluripotent cells that express pluripotent markers alkaline phosphatase and TRA-1-60. Hu's primary screen revealed 11 candidates, but only BRD3R acted as a new reprogramming factor in a more rigorous secondary screen. None of the BET subfamily genes similar to BRD3R—BRD2, BRD3 and BRD4—showed reprogramming activity. The iPSCs generated by BRD3R were shown to be pluripotent by the standard criteria. Although a member of the kinase library, BRD3R has not yet been demonstrated to have a kinase activity. But among the genes most consistently upregulated by BRD3R in the early stages of reprogramming were those encoding four kinases, including a master mitotic kinase and a critical mitotic kinase, five genes that regulate kinase activities, and one phosphatase gene. Therefore, Hu and colleagues write, \"Even though BRD3R may not have a kinase activity, it appears to regulate an important mitotic kinase network to promote reprogramming.\" In another paper published at the same time in Stem Cells and Development, Hu's lab reports a promising solution to an issue associated with the clinical application of human iPSCs. HiPSCs possess rampant growth like cancer cells, and the contamination of a single HiPSC cell in HiPSC-based transplants will pose a risk of tumor development in recipient patients. In addition, incompletely differentiated HiPSCs are believe to be tumorigenic as well. With HiPSC-based cell therapy entering into clinical trials already, there is no safety protocol to eliminate the risk of tumor development in patients receiving HiPSC-based transplants. One goal of Hu's research is to establish protocols to eliminate the tumorigenic cells in HiPSC-based transplants. His laboratory discovered that targeting an HiPSC marker surface protein PODXL using a well-established antibody kills pluripotent cells. \"We suggest,\" the authors write, \"that the antibody could be employed to eliminate the tumorigenic pluripotent cells in human PSC-derived cells for cell transplantation.\" PODXL is known to be involved in more than 10 different human malignancies and has a reported role in metastasis and tumor invasion. Hu's laboratory is interested in finding whether the same antibody can kill other malignant cells in cancer patients. Hu and colleagues found that PODXL has high gene expression in HiPSCs, and it is downregulated when the cells differentiate. They recently found that a residual PODXL-positive population persists, even after extended differentiation. Hu said it is urgent to examine the tumorigenicity of this residual PODXL-positive cell population in HiPSC-based transplants. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract It is well known that both recipient cells and donor nuclei demonstrate a mitotic advantage as observed in the traditional reprogramming with somatic cell nuclear transfer (SCNT). However, it is not known whether a specific mitotic factor plays a critical role in reprogramming. Here we identify an isoform of human bromodomain-containing 3 (BRD3), BRD3R (BRD3 with Reprogramming activity), as a reprogramming factor. BRD3R positively regulates mitosis during reprogramming, upregulates a large set of mitotic genes at early stages of reprogramming, and associates with mitotic chromatin. Interestingly, a set of the mitotic genes upregulated by BRD3R constitutes a pluripotent molecular signature. The two BRD3 isoforms display differential binding to acetylated histones. Our results suggest a molecular interpretation for the mitotic advantage in reprogramming and show that mitosis may be a driving force of reprogramming. Introduction Pluripotent stem cells (PSCs) offer great opportunities for regenerative medicine and stem cell biology due to their differentiation potentials and unlimited growth 1 . PSCs can be derived from inner cell mass of preimplantation embryos 2 , or generated by reprogramming of somatic cells 3 . The historically most powerful reprogramming is by somatic cell nuclear transfer (SCNT) into enucleated totipotent cells 4 . SCNT needs embryo and is technically demanding. Induction of pluripotent stem cells (iPSCs) from somatic cells by overexpression of transgenes is the most advanced and simplest reprogramming 5 . Despite extensive improvement, iPSC technology still faces many problems including stochastic, incomplete and aberrant reprogramming, reprogramming-associated mutagenesis, cell senescence, apoptosis and transformation, and use of oncogenes as reprogramming factors 6 , 7 , 8 , 9 , 10 , 11 . Compared with SCNT, iPSC reprogramming has a very low efficiency and slow kinetics, suggesting the existence of additional yet-to-be discovered reprogramming factors. PSCs have a unique cell cycle structure characterized by a truncated G1 phase, lack of a G1 checkpoint, lack of CDK periodicity, and a greater portion of cells in S/G2/M phases as compared with somatic cells 12 . During the reprogramming process, the pluripotent cell cycle structure has to be reset along with many other pluripotent features including differentiation potential, self-renewal, epigenetic landscape, transcriptome and the unique morphologies of the pluripotent cells and their colonies. In SCNT reprogramming, one consistent observation has been that only oocytes at the mitosis stage (metaphase II) possess high enough reprogramming activity to clone animals successfully 13 . On fertilization, such a reprogramming capacity becomes lost in the zygote 14 , but it can be restored when a zygote is arrested in mitosis 15 . When in mitosis, even the enucleated blastomeres from two-cell-stage embryos display animal cloning capacity 16 . In addition, the donor nucleus in SCNT also exhibits a 100 × mitotic advantage 17 . The underlying molecular basis for both the potent reprogramming power and the higher reprogrammability of mitotic cells is unknown. It is possible that the observed mitotic advantage is a technical artifact associated with SCNT because reprogramming factors within nuclei may have been removed from the interphase recipient cells and are released and remain in the reprogramming-competent mitotic cytoplasts due to the breakdown of nuclear envelopes in mitosis 18 , 19 . Efforts have been made to investigate the role of acetyl epigenetics in reprogramming because of the importance of histone acetylation in transcription controls and pluripotency, but these efforts have been restricted to the use of HDAC inhibitors 20 . Here we provide an example that an epigenetic reader BRD3R, rather than writers, erasers or chromatin remodelers is a reprogramming factor. We present evidence that the mitotic protein BRD3R facilitates resetting of the pluripotent cell cycle structure and increases the number of reprogramming-privileged mitotic cells by upregulating as many as 128 mitotic genes, without compromising the p53–p21 surveillance pathway. At least 19 of these BRD3R-upregulated mitotic genes constitute an expression fingerprint of PSCs. Our findings provide molecular insights into the mitotic advantage of reprogramming. Results BRD3R is a robust human reprogramming factor We hypothesized that there are additional undiscovered reprogramming factor(s) to account for the higher efficiency and faster kinetics of SCNT compared with factor reprogramming. We directly searched for new human reprogramming factor, expecting more clinical values of the possible new findings than mouse ones. Thus, we prepared and screened a lentiviral expression library of 89 human kinase cDNAs on account of the importance of phosphorylation in general cell biology and in pluripotency in particular. The importance of phosphorylation in pluripotency and reprogramming is suggested by the simple fact that there are 8,359 phosphorylation sites in human embryonic stem cells (hESC) 21 , the majority of which are believed to be differentially phosphorylated relative to somatic cells 22 . We first established a sensitive protocol that enables simultaneous evaluation of 22 individual cDNAs with a 24-well plate in a long process as reprogramming ( Fig. 1a ; Supplementary Fig. 1 ). We used the serum-free/feeder-free E8 human cell reprogramming system because this xeno-free defined medium is more consistent and efficient, and is more relevant to clinical applications 23 . Our basic reprogramming protocol includes three of the Yamanaka factors OCT4, SOX2 and KLF4 (three factors, 3F). We excluded MYC because, consistent with previous report, MYC is slightly detrimental to reprogramming in the feeder-free/serum-free system ( Fig. 1d,e ) 23 , 24 . Furthermore, MYC is a strong oncogene, which transforms starting cells during reprogramming and compromises the quality of iPSCs generated 25 , 26 . In fact, Yamanaka’s group later reported that MYC is non-essential for reprogramming 25 . Figure 1: BRD3R is a robust reprogramming factor. ( a ) Schematic of the screening protocol. D, days. ( b ) Fold changes of ALP + colonies for the 89 human kinase cDNAs in primary screen as compared with GFP control. #, Genes for the secondary screen. ( c ) Fold change as in b for the 11 candidate genes in the secondary screen. ( d ) Validation of the reprogramming activity of BRD3R as evaluated by number of TRA-1-60 + colonies ( n =3; mean ±<|im_end|> <|im_start|>assistant Kejin Hu, Ph.D., of the University of Alabama at Birmingham, has found a robust reprogramming factor that increases the efficiency of creating human induced pluripotent stem cells (HiPSCs) from skin fibroblasts more than 20-fold, speeds the reprogramming time by several days and enhances the quality of reprogramming. HiPSCs are believed to hold great promise for medical research and disease treatments. They are man-made versions of human embryonic stem cells (hESCs). Biomedical researchers can generate HiPSCs from many somatic cells such as fibroblasts from a skin biopsy, without destroying any human embryo. Like hESCs, HiPSCs have the ability to differentiate into any type of specialized cell. Thus, they can differentiate into any of the 200-plus different types of human cells. These cells are potent tools for drug development and modeling of disease, and they also hold potential to transform transplantation medicine by creating patient-specific pluripotent stem cells for cell-replacement therapies. Targets may include neurological diseases, heart ailments, blood diseases and diabetes. But this promise of iPSCs is hobbled by a low efficiency, less than 0.1 to 1 percent, in producing these cells, along with many other significant hurdles. In a paper published March 7 in Nature Communications, Hu and fellow UAB researchers describe their successful hunt for a reprogramming factor that boosts the efficiency and shortens the time the cell takes to reprogram. The reprogramming factor is a kinase-family protein called BRD3R that reads acetylated histone codes in the chromosome. When the Hu lab looked at the gene expression induced by overexpression of BRD3R during the reprogramming of human fibroblasts into iPSCs, they also solved a mystery that had endured half a century since 1962, when the Nobel Laureate John Gurdon first cloned a frog by placing the nucleus of an intestinal cell into an enucleated frog egg cell—namely, why does animal cloning succeed only with oocytes that are in the metaphase II stage of mitosis? Hu found that the BRD3R gene, when introduced into fibroblasts, upregulated 128 mitotic genes, which yields a molecular insight into the mitotic advantage of reprogramming. "When we saw the mRNA sequencing data, they explained why mitosis is so important in reprogramming," Hu said. "I was excited when we found a new reprogramming factor and also by this second discovery." To reprogram the fibroblasts, the Hu lab used BRD3R delivered by a lentiviral vector, along with three of the genes that the Japanese Nobel Laureate Shinya Yamanaka used in his first successful reprogramming of mature mouse cells into iPSCs in 2006—OCT4, SOX2 and KLF4. BRD3R was unable to replace any of the three essential Yamanaka reprogramming factors, indicating that BRD3R has a distinct role from them in reprogramming. Hu and his colleagues did their reprogramming of the human somatic cells in xeno-free media, without using mouse feeder cells or serum from any sources. Xeno-free production will be an FDA good manufacturing practice requirement for future clinical use of human iPSCs. Hu started his search for a new reprogramming factor after arriving at the Stem Cell Institute, UAB Department of Biochemistry and Genetics, in 2011. "I believed that new reprogramming factors would produce more authentic iPSCs in a more efficient, faster way." He acquired a library of 558 human kinase genes and began to screen a batch of the first 89. After introducing the three Yamanaka genes and his test kinase genes into fibroblast cells, he looked for an increase in efficiency in iPSC generation, as judged by increased colony numbers of the successfully reprogrammed pluripotent cells that express pluripotent markers alkaline phosphatase and TRA-1-60. Hu's primary screen revealed 11 candidates, but only BRD3R acted as a new reprogramming factor in a more rigorous secondary screen. None of the BET subfamily genes similar to BRD3R—BRD2, BRD3 and BRD4—showed reprogramming activity. The iPSCs generated by BRD3R were shown to be pluripotent by the standard criteria. Although a member of the kinase library, BRD3R has not yet been demonstrated to have a kinase activity. But among the genes most consistently upregulated by BRD3R in the early stages of reprogramming were those encoding four kinases, including a master mitotic kinase and a critical mitotic kinase, five genes that regulate kinase activities, and one phosphatase gene. Therefore, Hu and colleagues write, "Even though BRD3R may not have a kinase activity, it appears to regulate an important mitotic kinase network to promote reprogramming." In another paper published at the same time in Stem Cells and Development, Hu's lab reports a promising solution to an issue associated with the clinical application of human iPSCs. HiPSCs possess rampant growth like cancer cells, and the contamination of a single HiPSC cell in HiPSC-based transplants will pose a risk of tumor development in recipient patients. In addition, incompletely differentiated HiPSCs are believe to be tumorigenic as well. With HiPSC-based cell therapy entering into clinical trials already, there is no safety protocol to eliminate the risk of tumor development in patients receiving HiPSC-based transplants. One goal of Hu's research is to establish protocols to eliminate the tumorigenic cells in HiPSC-based transplants. His laboratory discovered that targeting an HiPSC marker surface protein PODXL using a well-established antibody kills pluripotent cells. "We suggest," the authors write, "that the antibody could be employed to eliminate the tumorigenic pluripotent cells in human PSC-derived cells for cell transplantation." PODXL is known to be involved in more than 10 different human malignancies and has a reported role in metastasis and tumor invasion. Hu's laboratory is interested in finding whether the same antibody can kill other malignant cells in cancer patients. Hu and colleagues found that PODXL has high gene expression in HiPSCs, and it is downregulated when the cells differentiate. They recently found that a residual PODXL-positive population persists, even after extended differentiation. Hu said it is urgent to examine the tumorigenicity of this residual PODXL-positive cell population in HiPSC-based transplants. <|im_end|>

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2,827

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The development of a new methodology for visualizing and detecting gases is imperative for various applications. Here, we report a novel strategy in which gas molecules are detected by signals from a reporter guest that can read out a host structural transformation. A composite between a flexible porous coordination polymer and fluorescent reporter distyrylbenzene (DSB) selectively adsorbed CO 2 over other atmospheric gases. This adsorption induced a host transformation, which was accompanied by conformational variations of the included DSB. This read-out process resulted in a critical change in DSB fluorescence at a specific threshold pressure. The composite shows different fluorescence responses to CO 2 and acetylene, compounds that have similar physicochemical properties. Our system showed, for the first time, that fluorescent molecules can detect gases without any chemical interaction or energy transfer. The host–guest coupled transformations play a pivotal role in converting the gas adsorption events into detectable output signals. Main Recently, luminescence gas sensors have attracted considerable attention for a wide variety of applications, because the sensing output is visible to the naked eye, which allows on-site and instantaneous decision-making even in explosive and flammable locations and complex environments 1 , 2 , 3 . There have been many examples of gas detection that use luminescence quenching by energy transfer between gases and luminescent materials 4 , 5 . However, only a limited number of gases, such as O 2 and NO 2 , can induce such quenching, and it is difficult to attain sensitive monitoring with the quenching mechanism 6 . A few materials have offered gas detection with luminescence colour switching or turn-on switching properties by chemical interactions and reactions, which have problems such as responsivity to only a single specific (reactive) gas, solution-containing device, difficulty in reuse, and slow response 7 , 8 , 9 . These problems can be overcome by the construction of a gas detection system that responds precisely and quickly to weaker interactions such as physical adsorption. However, there has been no strategy to achieve luminescence materials that can read out such weak interactions. Porous coordination polymers (PCPs) or metal organic frameworks (MOFs) have emerged as particularly exciting solid porous materials 10 , 11 , 12 , 13 , 14 , and they offer a wide range of potential applications, such as gas storage, separation, catalysis, sensing and drug delivery 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 . The size, shape, and surface functionality of pores can be controlled through the proper combination of organic ligands and metal ions. Compared with conventional porous materials, one of the most intriguing advantages of PCPs is their flexible frameworks 11 , 15 , 21 , 24 , 25 , 26 . This structural flexibility, causing a structural transformation from a closed form to an open form, is the key factor for the selective uptake of target gas molecules by recognizing small differences in their physicochemical properties. Our strategy to achieve gas detection includes the accommodation of a reporter molecule that can read out structural transformations of a flexible PCP ( Fig. 1 ). The obtained composite material can further adsorb gas molecules as a second guest, providing a ‘co-adsorption state’. The structural transformation of PCPs on gas adsorption results in a dynamic change in the pore size and shape with adjusting host–guest interactions, which will alter the conformations of the reporter molecule. Such conformational variations of the reporter molecule can lead to different output signals, where the adsorbed gas molecules will be successfully detected. Although many types of host–guest materials have been reported, there have been few examples in which host structural transformations affect not only the guest structures but also the guest properties 27 . Figure 1: Schematic illustration for detection of gas molecules by coupled structural transformations of a flexible PCP framework and a reporter molecule. The induced-fit-type structural change of the flexible PCP framework occurs by inclusion of a reporter molecule. The subsequent structural transformation of PCP during the gas adsorption process leads to a large change of pore structure. This is accompanied by the conformational variations of the reporter molecule, which leads to the change of output signal. Full size image This strategy has several advantages for effective gas detection. The flexible PCPs entrap reporter molecules by changing the pore structures to maximize the host–guest interactions; thus, the obtained composites are closed forms. Such composites would selectively adsorb gases for which interactions with the composites were strong enough to change the framework structures from closed to open forms 28 . A gate effect often occurs during such a gas adsorption process involving framework transformations, which generates abrupt adsorptions at particular threshold pressures 11 , 15 , 21 , 24 , 25 , 26 . Thus, the specific gases and their pressures can be monitored by the change in output from the reporter molecules. In addition, there are diverse combinations of flexible PCPs and reporter molecules, which expands the versatility and possibility of gas detection. In this paper, we demonstrate the luminescence detection of gas molecules by means of coupled transformations of a flexible PCP and a fluorescent reporter molecule, distyrylbenzene (DSB). It has been reported that the conformational variations of DSB and its derivatives lead to large changes in their fluorescence properties 29 , 30 , 31 . We introduced the DSB molecules into nanochannels of a flexible host compound [Zn 2 (terephthalate) 2 (triethylenediamine)] n ( 1 ; channel size=7.5×7.5 Å 2 ) in which two-dimensional (2D) square grids are bridged by triethylenediamine 32 . The obtained PCP–DSB composite material selectively adsorbed CO 2 over other atmospheric gases, such as N 2 , O 2 , and Ar. Interestingly, during the adsorption process of CO 2 , the conformation of DSB varied concurrently with an expansion of the host framework, which resulted in a critical response for the DSB fluorescence at a particular threshold pressure. In addition, the PCP–DSB composite can distinguish two gases with similar physicochemical properties, CO", "role": "user" }, { "content": "In an emergency such as a factory fire, ascertaining which gases are present in the air is critical to preventing or minimizing poisoning (Fig. 1). This requires gas sensors that react quickly and provide a visual signal. However, many existing detection systems work for only one gas, or they use a chemical reaction that is too slow to respond in emergency situations. Now, Takashi Uemura of Kyoto University and colleagues at several other Japanese institutes, including the RIKEN SPring-8 Center, have created a gas sensor that works rapidly, emits a clear fluorescent signal, and detects different gases. Most importantly, the new sensor can distinguish between gases with similar chemical and physical properties. Uemura and colleagues’ sensor contains so-called ‘flexible porous coordination polymers’ coupled with fluorescent reporter molecules that change structure, and therefore emit signals, according to different gases present in the air. “We thought that the incorporation of functional polymers into flexible porous coordination matrices would show unique dynamic properties,” says Uemura. He and his colleagues therefore inserted a fluorescent reporter molecule into the coordination polymer, whereupon the whole combined structure twisted out of shape. In this normal and twisted state, the fluorescent light from the reporter is quite dim and green. Once gas molecules are introduced, the structure begins to return to its original shape, and the fluorescence returns, brightening as the gas pressure intensifies. For example, the fluorescence changes from green to blue when the molecule adsorbs carbon dioxide. By this method, the sensor allows regular monitoring of both the type of gas and its concentration in the air. Crucially, the fluorescent response begins within seconds upon interaction with the gas and is complete within minutes, allowing emergency responders to make decisions quickly (Fig. 1). In addition to these attributes, this is the first such detection system shown to work for gases with almost identical physical properties, the team notes. “Physical properties, such as size, shape, and boiling points, are very similar between carbon dioxide and acetylene, for example, so it is difficult to distinguish between them,” explains Uemura. “Our material has carboxylate sites in the pore, and these sites can bind to acetylene more strongly than carbon dioxide. “This unique cooperative change of host and guest could allow us to design new advanced materials,” he adds. By investigating different flexible host structures and other ‘guest’ reporter molecules, the researchers believe they could create gas detection systems for a variety of different gases and other applications in the future. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The development of a new methodology for visualizing and detecting gases is imperative for various applications. Here, we report a novel strategy in which gas molecules are detected by signals from a reporter guest that can read out a host structural transformation. A composite between a flexible porous coordination polymer and fluorescent reporter distyrylbenzene (DSB) selectively adsorbed CO 2 over other atmospheric gases. This adsorption induced a host transformation, which was accompanied by conformational variations of the included DSB. This read-out process resulted in a critical change in DSB fluorescence at a specific threshold pressure. The composite shows different fluorescence responses to CO 2 and acetylene, compounds that have similar physicochemical properties. Our system showed, for the first time, that fluorescent molecules can detect gases without any chemical interaction or energy transfer. The host–guest coupled transformations play a pivotal role in converting the gas adsorption events into detectable output signals. Main Recently, luminescence gas sensors have attracted considerable attention for a wide variety of applications, because the sensing output is visible to the naked eye, which allows on-site and instantaneous decision-making even in explosive and flammable locations and complex environments 1 , 2 , 3 . There have been many examples of gas detection that use luminescence quenching by energy transfer between gases and luminescent materials 4 , 5 . However, only a limited number of gases, such as O 2 and NO 2 , can induce such quenching, and it is difficult to attain sensitive monitoring with the quenching mechanism 6 . A few materials have offered gas detection with luminescence colour switching or turn-on switching properties by chemical interactions and reactions, which have problems such as responsivity to only a single specific (reactive) gas, solution-containing device, difficulty in reuse, and slow response 7 , 8 , 9 . These problems can be overcome by the construction of a gas detection system that responds precisely and quickly to weaker interactions such as physical adsorption. However, there has been no strategy to achieve luminescence materials that can read out such weak interactions. Porous coordination polymers (PCPs) or metal organic frameworks (MOFs) have emerged as particularly exciting solid porous materials 10 , 11 , 12 , 13 , 14 , and they offer a wide range of potential applications, such as gas storage, separation, catalysis, sensing and drug delivery 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 . The size, shape, and surface functionality of pores can be controlled through the proper combination of organic ligands and metal ions. Compared with conventional porous materials, one of the most intriguing advantages of PCPs is their flexible frameworks 11 , 15 , 21 , 24 , 25 , 26 . This structural flexibility, causing a structural transformation from a closed form to an open form, is the key factor for the selective uptake of target gas molecules by recognizing small differences in their physicochemical properties. Our strategy to achieve gas detection includes the accommodation of a reporter molecule that can read out structural transformations of a flexible PCP ( Fig. 1 ). The obtained composite material can further adsorb gas molecules as a second guest, providing a ‘co-adsorption state’. The structural transformation of PCPs on gas adsorption results in a dynamic change in the pore size and shape with adjusting host–guest interactions, which will alter the conformations of the reporter molecule. Such conformational variations of the reporter molecule can lead to different output signals, where the adsorbed gas molecules will be successfully detected. Although many types of host–guest materials have been reported, there have been few examples in which host structural transformations affect not only the guest structures but also the guest properties 27 . Figure 1: Schematic illustration for detection of gas molecules by coupled structural transformations of a flexible PCP framework and a reporter molecule. The induced-fit-type structural change of the flexible PCP framework occurs by inclusion of a reporter molecule. The subsequent structural transformation of PCP during the gas adsorption process leads to a large change of pore structure. This is accompanied by the conformational variations of the reporter molecule, which leads to the change of output signal. Full size image This strategy has several advantages for effective gas detection. The flexible PCPs entrap reporter molecules by changing the pore structures to maximize the host–guest interactions; thus, the obtained composites are closed forms. Such composites would selectively adsorb gases for which interactions with the composites were strong enough to change the framework structures from closed to open forms 28 . A gate effect often occurs during such a gas adsorption process involving framework transformations, which generates abrupt adsorptions at particular threshold pressures 11 , 15 , 21 , 24 , 25 , 26 . Thus, the specific gases and their pressures can be monitored by the change in output from the reporter molecules. In addition, there are diverse combinations of flexible PCPs and reporter molecules, which expands the versatility and possibility of gas detection. In this paper, we demonstrate the luminescence detection of gas molecules by means of coupled transformations of a flexible PCP and a fluorescent reporter molecule, distyrylbenzene (DSB). It has been reported that the conformational variations of DSB and its derivatives lead to large changes in their fluorescence properties 29 , 30 , 31 . We introduced the DSB molecules into nanochannels of a flexible host compound [Zn 2 (terephthalate) 2 (triethylenediamine)] n ( 1 ; channel size=7.5×7.5 Å 2 ) in which two-dimensional (2D) square grids are bridged by triethylenediamine 32 . The obtained PCP–DSB composite material selectively adsorbed CO 2 over other atmospheric gases, such as N 2 , O 2 , and Ar. Interestingly, during the adsorption process of CO 2 , the conformation of DSB varied concurrently with an expansion of the host framework, which resulted in a critical response for the DSB fluorescence at a particular threshold pressure. In addition, the PCP–DSB composite can distinguish two gases with similar physicochemical properties, CO<|im_end|> <|im_start|>assistant In an emergency such as a factory fire, ascertaining which gases are present in the air is critical to preventing or minimizing poisoning (Fig. 1). This requires gas sensors that react quickly and provide a visual signal. However, many existing detection systems work for only one gas, or they use a chemical reaction that is too slow to respond in emergency situations. Now, Takashi Uemura of Kyoto University and colleagues at several other Japanese institutes, including the RIKEN SPring-8 Center, have created a gas sensor that works rapidly, emits a clear fluorescent signal, and detects different gases. Most importantly, the new sensor can distinguish between gases with similar chemical and physical properties. Uemura and colleagues’ sensor contains so-called ‘flexible porous coordination polymers’ coupled with fluorescent reporter molecules that change structure, and therefore emit signals, according to different gases present in the air. “We thought that the incorporation of functional polymers into flexible porous coordination matrices would show unique dynamic properties,” says Uemura. He and his colleagues therefore inserted a fluorescent reporter molecule into the coordination polymer, whereupon the whole combined structure twisted out of shape. In this normal and twisted state, the fluorescent light from the reporter is quite dim and green. Once gas molecules are introduced, the structure begins to return to its original shape, and the fluorescence returns, brightening as the gas pressure intensifies. For example, the fluorescence changes from green to blue when the molecule adsorbs carbon dioxide. By this method, the sensor allows regular monitoring of both the type of gas and its concentration in the air. Crucially, the fluorescent response begins within seconds upon interaction with the gas and is complete within minutes, allowing emergency responders to make decisions quickly (Fig. 1). In addition to these attributes, this is the first such detection system shown to work for gases with almost identical physical properties, the team notes. “Physical properties, such as size, shape, and boiling points, are very similar between carbon dioxide and acetylene, for example, so it is difficult to distinguish between them,” explains Uemura. “Our material has carboxylate sites in the pore, and these sites can bind to acetylene more strongly than carbon dioxide. “This unique cooperative change of host and guest could allow us to design new advanced materials,” he adds. By investigating different flexible host structures and other ‘guest’ reporter molecules, the researchers believe they could create gas detection systems for a variety of different gases and other applications in the future. <|im_end|>

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1,848

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Nanostructures of transition metal oxides, such as zinc oxide, have attracted considerable interest for solar-energy conversion and photocatalysis. Both applications are sensitive to the transport and trapping of photoexcited charge carriers. The probing of electron trapping has recently become possible using time-resolved element-sensitive methods, such as X-ray spectroscopy. However, valence-band-trapped holes have so far escaped observation. Herein we use X-ray absorption spectroscopy combined with a dispersive X-ray emission spectrometer to probe the charge carrier relaxation and trapping processes in zinc oxide nanoparticles after above band-gap photoexcitation. Our results, supported by simulations, demonstrate that within 80 ps, photoexcited holes are trapped at singly charged oxygen vacancies, which causes an outward displacement by ~15% of the four surrounding zinc atoms away from the doubly charged vacancy. This identification of the hole traps provides insight for future developments of transition metal oxide-based nanodevices. Introduction Devices for solar-energy conversion 1 and photocatalysis 2 based on transition metal oxide (TMO) nanoparticles (NPs) and mesoporous films are amongst the most promising routes for addressing our escalating energy demands. These rely on sunlight to generate charge carriers and consequently, it is crucial to understand the room temperature (RT) creation, transport, and trapping of the photogenerated holes and electrons over a wide distribution of time and length scales. Yet, the dynamics of these processes remain poorly understood, in part due to the complex interplay of structural and electronic effects that affect the various relaxation pathways. The most promising TMO solar devices use nanostructures of titanium dioxide 3 (TiO 2 ) and zinc oxide 4 (ZnO). While historically TiO 2 has been the most prominent, ZnO has also attracted significant interest owing to an electron mobility two orders of magnitude larger than TiO 2 5 . In addition, ZnO can be easily synthesised in a wide variety of nanostructures 4 , which enables control of its properties via the NPs’ size and shape. However, two limitations have restricted the application of ZnO in solar energy conversion. First, rapid recombination of photo-generated charge carriers 6 results in short-lived electrons and holes (~1–2 ns), limiting device efficiency. Second is its instability in aqueous solution arising from photocorrosion under UV irradiation 7 . Both limitations are strongly correlated to the nature of the defect sites in ZnO NPs, which are thought to act as charge traps within the nanostructure. Though many techniques have attempted to shed light on the structure and energetics of these defects, their exact nature at RT remains under debate 8 . Several studies have been performed on ZnO using steady-state and time-resolved luminescence 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , and transient absorption optical spectroscopy 6 , 9 , 10 . Luminescence spectra of RT ZnO consist of visible and UV emission bands, which encompass several sub-bands that are observed at low temperatures 16 . The UV band lies close to the band gap absorption (3.3 eV for bulk ZnO 4 ) and is assigned to the radiative recombination of free excitons in hundreds of ps (Supplementary Table 1 ). In contrast, the visible emission, usually in the green, is associated with deeply trapped charge carriers. Its position depends on the particle size, suggesting that one of the band edges must be involved in the radiative transition 11 , 18 . There is evidence that the green emission is related to the concentration of oxygen vacancies ( V O ) 9 , 10 , 11 , 12 , 18 , 19 , 20 , 21 , although several alternatives, such as Zn vacancies ( V Zn ) 22 , 23 , ZnO divacancies ( V ZnO ) 8 , and Zn interstitial defects 15 , have also been proposed. These trapping sites may be expected to be predominantly located in the surface region of the nanoparticles as the green emission is quenched by the addition of hole scavengers (I − or SCN − ) 9 . An excess of Zn 2+ has no effect on the green emission, further suggesting its connection to an anion vacancy, such as an oxygen vacancy ( V O ). EPR studies on ZnO nanopowders have shown that oxygen vacancies containing one electron \$\\left( {V}_{\\mathrm{O}}^ +\\right)\$ are the predominant paramagnetic defects 20 , 24 , 25 , 26 , and the concentration of this defect is directly correlated with the green luminescence, leading to the conclusion that \${V}_{\\mathrm{O}}^ +\$ is involved in the emission process. Based on these studies, along with temperature-dependence experiments 11 , 27 , it was concluded that the green emission stems from a shallowly trapped electron, forming a large polaron in the conduction band (CB), recombining with a \$V_{\\rm{O}}^{2 + }\$ defect site that has been created through trapping of a photogenerated hole at a pre-existing \$V_{\\mathrm{O}}^ +\$ site in the surface region. This mechanism clearly depends on the native \$V_{\\mathrm{O}}^ +\$ concentration within the NP. Theory has calculated the energies and structures of the various defects 28 , 29 , 30 , 31 , 32 , but has not managed to resolve the nature of the green emission because the large variety of defects leads to many acceptor/donor combinations, which can match the experimental energies. The aforementioned optical studies are neither element-specific nor structure-sensitive. To identify the nature of the photoinduced trapping sites in RT ZnO NPs, time-resolved X-ray absorption spectroscopy (XAS) 33 has proved ideal with its sensitivity to the electronic structure of the absorber and to the local geometry of its surroundings. It was used to investigate electron injection from an adsorbed dye into iron oxide NPs in solution 34 , 35 , as well as colloidal solutions of bare and dye-sensitized anatase and amorphous TiO 2 NPs after photoexcitation 36 , 37 , 38 . Because time-resolved XAS directly probes changes in the unoccupied density of states (DOS), which includes the CB of semiconductors, these studies, but also previous ultrafast optical domain measurements 39 , 40 , 41 , 42 , were sensitive", "role": "user" }, { "content": "When a solar cell absorbs a photon of light, it starts an electronic race against time. Two particles—a negatively charged electron and positively charged \"hole\"—generate electricity if they fully separate. However, when these particles become trapped within a solar material before they can fully separate, it can diminish the ability of the material to convert light into electricity. Scientists at the U.S. Department of Energy's (DOE) Argonne National Laboratory have published a new study that identifies the process by which holes get trapped in nanoparticles made of zinc oxide, a material of potential interest for solar applications because it absorbs ultraviolet light. \"If you are making a solar cell, you want to avoid trapping holes; but if you're making a photocatalyst, you want to trap them.\"—X-ray scientist Christopher Milne of Switzerland's Paul Scherrer Institute. Using X-rays produced by Argonne's Advanced Photon Source (APS), the researchers were able to see the trapping of holes in specific regions of the nanoparticle. This represents a notable advance, as previous experiments were able to detect the migration and trapping of electrons but not holes. According to Stephen Southworth, an author of the study, some have considered zinc oxide as a possible alternative to titanium dioxide, the most commonly used photovoltaic material. Understanding the hole trapping behavior is necessary to evaluate the viability of the material in solar energy applications, he said. Although hole trapping impairs the performance of photovoltaic devices, it can improve the ability of zinc oxide to act as a photocatalyst, as positive charges stored in the traps within the material can go on to act as participants in chemical reactions. \"If you are making a solar cell, you want to avoid trapping holes; but if you're making a photocatalyst, you want to trap them,\" said project lead Christopher Milne, an X-ray scientist at the Paul Scherrer Institute in Switzerland. \"Regardless, understanding how these atoms get trapped—and for how long—is crucially important for making functional materials that convert light into usable energy.\" The researchers determined that the holes became trapped in \"oxygen vacancies\"—places within the crystal lattice where an oxygen atom is missing. Zinc oxide, Milne said, has a crystalline structure that allows it to have many of these vacancies. The trapping happens because the vacancies have a lower energy level than the surrounding environment, creating an energetic crevasse for passing holes. To make their measurements, the researchers combined two different X-ray techniques: X-ray absorption spectroscopy and resonant X-ray emission spectroscopy. \"Combining these techniques is uniquely possible with the setup we have at the APS, giving us a view that shows us both the atomic geometry and the electronic structure of the material,\" said Argonne X-ray physicist Gilles Doumy, an author of the study, which used the 7ID-D beamline at the APS. \"APS was one of the only places in the world we could have done this experiment. It was a very fruitful collaboration,\" said Milne. The APS is a DOE Office of Science User Facility. The researchers indicated that future studies of the system could benefit from having the ability to take extremely quick snapshots of the trapping behavior. Such an experiment could be conducted at X-ray free-electron laser facilities like SLAC's Linac Coherent Light Source, also a DOE Office of Science User Facility. \"Essentially, we want to see the same process but have the ability to take images a thousand times faster,\" said Southworth. \"The functionality of the material is always going to rely on how behavior at early times in the process influences the behavior at later and longer times,\" added Doumy. \"We need both pictures for a comprehensive understanding.\" An article based on the research, \"Revealing hole trapping in zinc oxide nanoparticles by time-resolved X-ray spectroscopy,\" appeared in the February 2 online issue of Nature Communications. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Nanostructures of transition metal oxides, such as zinc oxide, have attracted considerable interest for solar-energy conversion and photocatalysis. Both applications are sensitive to the transport and trapping of photoexcited charge carriers. The probing of electron trapping has recently become possible using time-resolved element-sensitive methods, such as X-ray spectroscopy. However, valence-band-trapped holes have so far escaped observation. Herein we use X-ray absorption spectroscopy combined with a dispersive X-ray emission spectrometer to probe the charge carrier relaxation and trapping processes in zinc oxide nanoparticles after above band-gap photoexcitation. Our results, supported by simulations, demonstrate that within 80 ps, photoexcited holes are trapped at singly charged oxygen vacancies, which causes an outward displacement by ~15% of the four surrounding zinc atoms away from the doubly charged vacancy. This identification of the hole traps provides insight for future developments of transition metal oxide-based nanodevices. Introduction Devices for solar-energy conversion 1 and photocatalysis 2 based on transition metal oxide (TMO) nanoparticles (NPs) and mesoporous films are amongst the most promising routes for addressing our escalating energy demands. These rely on sunlight to generate charge carriers and consequently, it is crucial to understand the room temperature (RT) creation, transport, and trapping of the photogenerated holes and electrons over a wide distribution of time and length scales. Yet, the dynamics of these processes remain poorly understood, in part due to the complex interplay of structural and electronic effects that affect the various relaxation pathways. The most promising TMO solar devices use nanostructures of titanium dioxide 3 (TiO 2 ) and zinc oxide 4 (ZnO). While historically TiO 2 has been the most prominent, ZnO has also attracted significant interest owing to an electron mobility two orders of magnitude larger than TiO 2 5 . In addition, ZnO can be easily synthesised in a wide variety of nanostructures 4 , which enables control of its properties via the NPs’ size and shape. However, two limitations have restricted the application of ZnO in solar energy conversion. First, rapid recombination of photo-generated charge carriers 6 results in short-lived electrons and holes (~1–2 ns), limiting device efficiency. Second is its instability in aqueous solution arising from photocorrosion under UV irradiation 7 . Both limitations are strongly correlated to the nature of the defect sites in ZnO NPs, which are thought to act as charge traps within the nanostructure. Though many techniques have attempted to shed light on the structure and energetics of these defects, their exact nature at RT remains under debate 8 . Several studies have been performed on ZnO using steady-state and time-resolved luminescence 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , and transient absorption optical spectroscopy 6 , 9 , 10 . Luminescence spectra of RT ZnO consist of visible and UV emission bands, which encompass several sub-bands that are observed at low temperatures 16 . The UV band lies close to the band gap absorption (3.3 eV for bulk ZnO 4 ) and is assigned to the radiative recombination of free excitons in hundreds of ps (Supplementary Table 1 ). In contrast, the visible emission, usually in the green, is associated with deeply trapped charge carriers. Its position depends on the particle size, suggesting that one of the band edges must be involved in the radiative transition 11 , 18 . There is evidence that the green emission is related to the concentration of oxygen vacancies ( V O ) 9 , 10 , 11 , 12 , 18 , 19 , 20 , 21 , although several alternatives, such as Zn vacancies ( V Zn ) 22 , 23 , ZnO divacancies ( V ZnO ) 8 , and Zn interstitial defects 15 , have also been proposed. These trapping sites may be expected to be predominantly located in the surface region of the nanoparticles as the green emission is quenched by the addition of hole scavengers (I − or SCN − ) 9 . An excess of Zn 2+ has no effect on the green emission, further suggesting its connection to an anion vacancy, such as an oxygen vacancy ( V O ). EPR studies on ZnO nanopowders have shown that oxygen vacancies containing one electron $\left( {V}_{\mathrm{O}}^ +\right)$ are the predominant paramagnetic defects 20 , 24 , 25 , 26 , and the concentration of this defect is directly correlated with the green luminescence, leading to the conclusion that ${V}_{\mathrm{O}}^ +$ is involved in the emission process. Based on these studies, along with temperature-dependence experiments 11 , 27 , it was concluded that the green emission stems from a shallowly trapped electron, forming a large polaron in the conduction band (CB), recombining with a $V_{\rm{O}}^{2 + }$ defect site that has been created through trapping of a photogenerated hole at a pre-existing $V_{\mathrm{O}}^ +$ site in the surface region. This mechanism clearly depends on the native $V_{\mathrm{O}}^ +$ concentration within the NP. Theory has calculated the energies and structures of the various defects 28 , 29 , 30 , 31 , 32 , but has not managed to resolve the nature of the green emission because the large variety of defects leads to many acceptor/donor combinations, which can match the experimental energies. The aforementioned optical studies are neither element-specific nor structure-sensitive. To identify the nature of the photoinduced trapping sites in RT ZnO NPs, time-resolved X-ray absorption spectroscopy (XAS) 33 has proved ideal with its sensitivity to the electronic structure of the absorber and to the local geometry of its surroundings. It was used to investigate electron injection from an adsorbed dye into iron oxide NPs in solution 34 , 35 , as well as colloidal solutions of bare and dye-sensitized anatase and amorphous TiO 2 NPs after photoexcitation 36 , 37 , 38 . Because time-resolved XAS directly probes changes in the unoccupied density of states (DOS), which includes the CB of semiconductors, these studies, but also previous ultrafast optical domain measurements 39 , 40 , 41 , 42 , were sensitive<|im_end|> <|im_start|>assistant When a solar cell absorbs a photon of light, it starts an electronic race against time. Two particles—a negatively charged electron and positively charged "hole"—generate electricity if they fully separate. However, when these particles become trapped within a solar material before they can fully separate, it can diminish the ability of the material to convert light into electricity. Scientists at the U.S. Department of Energy's (DOE) Argonne National Laboratory have published a new study that identifies the process by which holes get trapped in nanoparticles made of zinc oxide, a material of potential interest for solar applications because it absorbs ultraviolet light. "If you are making a solar cell, you want to avoid trapping holes; but if you're making a photocatalyst, you want to trap them."—X-ray scientist Christopher Milne of Switzerland's Paul Scherrer Institute. Using X-rays produced by Argonne's Advanced Photon Source (APS), the researchers were able to see the trapping of holes in specific regions of the nanoparticle. This represents a notable advance, as previous experiments were able to detect the migration and trapping of electrons but not holes. According to Stephen Southworth, an author of the study, some have considered zinc oxide as a possible alternative to titanium dioxide, the most commonly used photovoltaic material. Understanding the hole trapping behavior is necessary to evaluate the viability of the material in solar energy applications, he said. Although hole trapping impairs the performance of photovoltaic devices, it can improve the ability of zinc oxide to act as a photocatalyst, as positive charges stored in the traps within the material can go on to act as participants in chemical reactions. "If you are making a solar cell, you want to avoid trapping holes; but if you're making a photocatalyst, you want to trap them," said project lead Christopher Milne, an X-ray scientist at the Paul Scherrer Institute in Switzerland. "Regardless, understanding how these atoms get trapped—and for how long—is crucially important for making functional materials that convert light into usable energy." The researchers determined that the holes became trapped in "oxygen vacancies"—places within the crystal lattice where an oxygen atom is missing. Zinc oxide, Milne said, has a crystalline structure that allows it to have many of these vacancies. The trapping happens because the vacancies have a lower energy level than the surrounding environment, creating an energetic crevasse for passing holes. To make their measurements, the researchers combined two different X-ray techniques: X-ray absorption spectroscopy and resonant X-ray emission spectroscopy. "Combining these techniques is uniquely possible with the setup we have at the APS, giving us a view that shows us both the atomic geometry and the electronic structure of the material," said Argonne X-ray physicist Gilles Doumy, an author of the study, which used the 7ID-D beamline at the APS. "APS was one of the only places in the world we could have done this experiment. It was a very fruitful collaboration," said Milne. The APS is a DOE Office of Science User Facility. The researchers indicated that future studies of the system could benefit from having the ability to take extremely quick snapshots of the trapping behavior. Such an experiment could be conducted at X-ray free-electron laser facilities like SLAC's Linac Coherent Light Source, also a DOE Office of Science User Facility. "Essentially, we want to see the same process but have the ability to take images a thousand times faster," said Southworth. "The functionality of the material is always going to rely on how behavior at early times in the process influences the behavior at later and longer times," added Doumy. "We need both pictures for a comprehensive understanding." An article based on the research, "Revealing hole trapping in zinc oxide nanoparticles by time-resolved X-ray spectroscopy," appeared in the February 2 online issue of Nature Communications. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract There has long been debate over the origins of dairy consumption within European populations. Whilst it was previously assumed that lactase persistence (LP) was under positive selection following the advent of agriculture, recent genetic studies of prehistoric human remains have revealed LP may have only emerged in Europe in the last 4000 years. These findings stand in contrast to organic residue analysis of Neolithic pottery indicating the utilisation of dairy products, and zooarchaeological mortality profiles consistent with dairying herds at Neolithic sites. The recent discovery of the milk protein β-lactoglobulin (BLG) within human dental calculus presents a new method via which to explore dairy product consumption in the archaeological past. Here, we apply shotgun proteomic analysis to dental calculus samples from three British Neolithic sites, revealing the earliest identification of BLG in human dental calculus to date. The presence of BLG peptides in individuals who are unlikely to possess LP provides new insight into dairying in the British Neolithic, suggesting the potential processing of milk by Neolithic populations to reduce the lactose content of dairy products. Working on a manuscript? Avoid the common mistakes Introduction The British Neolithic is a period which has long been characterised by the arrival and adoption of agriculture and perceived associated sedentary lifestyle, alongside the emergence of new forms of material culture and the construction of a range of monumental forms. Most recently, more support for the hypothesis that this ‘Neolithic package’ was brought to Britain by incoming European farmers has been recognised (Brace et al. 2019 ). Importantly, the Neolithic heralds a significant shift in subsistence, characterised by the introduction of domesticates into Britain, which included emmer wheat ( Triticum dicoccum ), einkorn wheat ( Triticum momococcum ) and barley ( Hordeum vulgare ), alongside emerging animal husbandry of domesticated species—predominately cattle, pig, sheep and goats (Thomas 1999 ; Rowley-Conwy 2004 ; Brown 2007 ). Our understanding of Neolithic subsistence has been obtained from a range of archaeological evidence, such as the faunal remains of domesticated animals (e.g., Albarella and Serjeantson 2002 ; Mulville and Grigson 2007 ), evidence of cereal cultivation—including carbonised cereal grains (e.g., Robinson 2000 ; Jones and Legge 2008 ), stable isotope analysis of skeletal material (e.g., Richards and Hedges 1999 ; Hedges et al. 2006 ; Richards 2008 ; Stevens et al. 2012 ; Schulting 2013 ), and organic residue analysis of pottery (e.g., Copley et al. 2008 ; Craig et al. 2015 ). Nevertheless, whilst we know that British Neolithic diets appear to be (isotopically) dominated by C3 terrestrial plant resources and terrestrial animals, with little to no marine input, there are still aspects of Neolithic subsistence which remain unclear. The contribution of wild plants, cereals, dairy and aquatic foodstuffs to the diet have all been debated (e.g., Robinson 2000 ; Thomas 2003 ; Richards et al. 2003 ; Milner et al. 2004 ; Rowley-Conwy 2004 ), and the contribution of crop-derived protein to Neolithic diets has also been suggested to typically be underestimated (Bogaard et al. 2013 ). The potential variability or homogeneity within British Neolithic diets is also still not fully understood. Dental calculus, the mineralised bacterial biofilm of dental plaque, is consistently found within Neolithic skeletal assemblages and is now known to be a rich source of ancient biomolecules, notably ancient DNA and proteins (Warinner et al. 2014a , b ), which can provide new insights not only into the oral microbiome but also past diet. Metaproteomic analysis of Neolithic dental calculus may therefore provide a new approach to early prehistoric dietary reconstruction, by providing direct and diagnostic evidence of consumed foodstuffs, including the consumption of milk or dairy products. Here we apply metaproteomic analysis to human dental calculus samples from three British Neolithic sites to assess the prevalence of dietary and milk proteins, and its efficacy as a method via which to increase our understanding of Neolithic diets. To date, the calculus from only a single Middle Neolithic individual has yet been analysed using metaproteomic methods (Mays et al. 2018 ). To our knowledge, this study represents the oldest human dental calculus samples analysed proteomically to date globally. Dietary proteins within dental calculus The periodic mineralisation of dental plaque to form calculus serendipitously entraps and preserves ancient biomolecules and microdebris, providing a direct record of consumed foodstuffs. A small number of studies have now explored dietary proteins preserved within human dental calculus. To date, evidence of putative plant proteins originating from oats ( Avena sativa ), peas ( Pisum sativum ) and Brassicaceae in archaeological dental calculus have been recovered, as well as a putative faunal blood haemoglobin (HBB) protein, and the milk proteins lactoperoxidase (LPO) and α-S1-casein (CSN1S1) (Hendy et al. 2018a ; Jersie-Christensen et al. 2018 ; Mays et al. 2018 ). The detection of these proteins showcases how metaproteomic analysis can provide a new direct way of determining dietary information from the archaeological past. The most frequently detected dietary protein within metaproteomic studies of dental calculus has however thus far been the milk protein β-lactoglobulin (BLG). Lactase persistence and the origins of milk consumption Within the archaeological literature, there has long been a debate over the origins of milk drinking and dairy product consumption (Leonardi et al. 2012 ). Milk is a significant nutritional resource, containing fats, sugars and proteins, as well as vitamins, minerals and essential amino acids (Bovenhuis et al. 2013 ). Lactose, a type of disaccharide sugar, is the main carbohydrate in milk, comprising 3.8–5.3% of total content. In order for humans to digest lactose however, it must be broken down by the β-galactosidase lactase-phloritzin hydrolase (more commonly known simply as ‘lactase’; EC 3.2.1.108), which allows it to be absorbed within the intestine (Luinge et al. 1993 ; Vesa et al. 2000 ; Ségurel and Bon 2017 ). As infants, humans have the ability to break down lactose. However, after weaning, the body naturally stops producing lactase, unless the individual has a genetic mutation which allows for its continued production into adulthood—known as lactase persistence (LP). Indeed,", "role": "user" }, { "content": "Researchers have found the earliest direct evidence of milk consumption anywhere in the world in the teeth of prehistoric British farmers. The research team, led by archaeologists at the University of York, identified a milk protein called beta lactoglobulin (BLG) entombed in the mineralised dental plaque of seven individuals who lived in the Neolithic period around 6,000 years-ago. The human dental plaque samples in the study are the oldest to be analysed for ancient proteins to date globally and the study represents the earliest identification of the milk whey protein BLG so far. The Neolithic period in Britain ran from 4,000 to 2,400 cal. BC and saw the emergence of farming, with the use of domesticated animals such as cows, sheep, pig and goats, alongside crops such as wheat and barley. Archaeologists have also discovered evidence of complex cultural practices, with Neolithic communities building large monumental and burial sites. The ancient human remains tested in the study come from three different Neolithic sites—Hambledon Hill and Hazleton North in the south of England, and Banbury Lane in the East Midlands. Individuals from all three sites showed the presence of milk proteins from cows, sheep or goats, suggesting people were exploiting multiple species for dairy products. Dental plaque can offer unique insights into the diets of ancient people because dietary proteins are entrapped within it when it is mineralised by components of saliva to form tartar or 'dental calculus'. Lead author of the study, Dr. Sophy Charlton, from the Department of Archaeology at the University of York, said: \"The fact that we found this protein in the dental calculus of individuals from three different Neolithic sites may suggest that dairy consumption was a widespread dietary practice in the past. \"It would be a fascinating avenue for further research to look at more individuals and see if we can determine whether there are any patterns as to who was consuming milk in the archaeological past—perhaps the amount of dairy products consumed or the animals utilised varied along the lines of sex, gender, age or social standing.\" The discovery of milk proteins is particularly interesting as recent genetic studies suggest that people who lived at this time did not yet have the ability to digest the lactose in milk. To get around this, the ancient farmers may have been drinking just small amounts of milk or processing it into other foodstuffs such as cheese (which removes most of the lactose), the researchers say. 'Lactase persistence', which allows for the continued consumption of milk into adulthood, is the result of a genetic mutation in a section of DNA that controls the activity of the lactase gene. However, the mechanisms behind how and when we evolved this ability remain a mystery. Dr. Charlton added: \"Because drinking any more than very small amounts of milk would have made people from this period really quite ill, these early farmers may have been processing milk, perhaps into foodstuffs such as cheese, to reduce its lactose content.\" \"Identifying more ancient individuals with evidence of BLG in the future may provide further insights into milk consumption and processing in the past, and increase our understanding of how genetics and culture have interacted to produce lactase persistence.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract There has long been debate over the origins of dairy consumption within European populations. Whilst it was previously assumed that lactase persistence (LP) was under positive selection following the advent of agriculture, recent genetic studies of prehistoric human remains have revealed LP may have only emerged in Europe in the last 4000 years. These findings stand in contrast to organic residue analysis of Neolithic pottery indicating the utilisation of dairy products, and zooarchaeological mortality profiles consistent with dairying herds at Neolithic sites. The recent discovery of the milk protein β-lactoglobulin (BLG) within human dental calculus presents a new method via which to explore dairy product consumption in the archaeological past. Here, we apply shotgun proteomic analysis to dental calculus samples from three British Neolithic sites, revealing the earliest identification of BLG in human dental calculus to date. The presence of BLG peptides in individuals who are unlikely to possess LP provides new insight into dairying in the British Neolithic, suggesting the potential processing of milk by Neolithic populations to reduce the lactose content of dairy products. Working on a manuscript? Avoid the common mistakes Introduction The British Neolithic is a period which has long been characterised by the arrival and adoption of agriculture and perceived associated sedentary lifestyle, alongside the emergence of new forms of material culture and the construction of a range of monumental forms. Most recently, more support for the hypothesis that this ‘Neolithic package’ was brought to Britain by incoming European farmers has been recognised (Brace et al. 2019 ). Importantly, the Neolithic heralds a significant shift in subsistence, characterised by the introduction of domesticates into Britain, which included emmer wheat ( Triticum dicoccum ), einkorn wheat ( Triticum momococcum ) and barley ( Hordeum vulgare ), alongside emerging animal husbandry of domesticated species—predominately cattle, pig, sheep and goats (Thomas 1999 ; Rowley-Conwy 2004 ; Brown 2007 ). Our understanding of Neolithic subsistence has been obtained from a range of archaeological evidence, such as the faunal remains of domesticated animals (e.g., Albarella and Serjeantson 2002 ; Mulville and Grigson 2007 ), evidence of cereal cultivation—including carbonised cereal grains (e.g., Robinson 2000 ; Jones and Legge 2008 ), stable isotope analysis of skeletal material (e.g., Richards and Hedges 1999 ; Hedges et al. 2006 ; Richards 2008 ; Stevens et al. 2012 ; Schulting 2013 ), and organic residue analysis of pottery (e.g., Copley et al. 2008 ; Craig et al. 2015 ). Nevertheless, whilst we know that British Neolithic diets appear to be (isotopically) dominated by C3 terrestrial plant resources and terrestrial animals, with little to no marine input, there are still aspects of Neolithic subsistence which remain unclear. The contribution of wild plants, cereals, dairy and aquatic foodstuffs to the diet have all been debated (e.g., Robinson 2000 ; Thomas 2003 ; Richards et al. 2003 ; Milner et al. 2004 ; Rowley-Conwy 2004 ), and the contribution of crop-derived protein to Neolithic diets has also been suggested to typically be underestimated (Bogaard et al. 2013 ). The potential variability or homogeneity within British Neolithic diets is also still not fully understood. Dental calculus, the mineralised bacterial biofilm of dental plaque, is consistently found within Neolithic skeletal assemblages and is now known to be a rich source of ancient biomolecules, notably ancient DNA and proteins (Warinner et al. 2014a , b ), which can provide new insights not only into the oral microbiome but also past diet. Metaproteomic analysis of Neolithic dental calculus may therefore provide a new approach to early prehistoric dietary reconstruction, by providing direct and diagnostic evidence of consumed foodstuffs, including the consumption of milk or dairy products. Here we apply metaproteomic analysis to human dental calculus samples from three British Neolithic sites to assess the prevalence of dietary and milk proteins, and its efficacy as a method via which to increase our understanding of Neolithic diets. To date, the calculus from only a single Middle Neolithic individual has yet been analysed using metaproteomic methods (Mays et al. 2018 ). To our knowledge, this study represents the oldest human dental calculus samples analysed proteomically to date globally. Dietary proteins within dental calculus The periodic mineralisation of dental plaque to form calculus serendipitously entraps and preserves ancient biomolecules and microdebris, providing a direct record of consumed foodstuffs. A small number of studies have now explored dietary proteins preserved within human dental calculus. To date, evidence of putative plant proteins originating from oats ( Avena sativa ), peas ( Pisum sativum ) and Brassicaceae in archaeological dental calculus have been recovered, as well as a putative faunal blood haemoglobin (HBB) protein, and the milk proteins lactoperoxidase (LPO) and α-S1-casein (CSN1S1) (Hendy et al. 2018a ; Jersie-Christensen et al. 2018 ; Mays et al. 2018 ). The detection of these proteins showcases how metaproteomic analysis can provide a new direct way of determining dietary information from the archaeological past. The most frequently detected dietary protein within metaproteomic studies of dental calculus has however thus far been the milk protein β-lactoglobulin (BLG). Lactase persistence and the origins of milk consumption Within the archaeological literature, there has long been a debate over the origins of milk drinking and dairy product consumption (Leonardi et al. 2012 ). Milk is a significant nutritional resource, containing fats, sugars and proteins, as well as vitamins, minerals and essential amino acids (Bovenhuis et al. 2013 ). Lactose, a type of disaccharide sugar, is the main carbohydrate in milk, comprising 3.8–5.3% of total content. In order for humans to digest lactose however, it must be broken down by the β-galactosidase lactase-phloritzin hydrolase (more commonly known simply as ‘lactase’; EC 3.2.1.108), which allows it to be absorbed within the intestine (Luinge et al. 1993 ; Vesa et al. 2000 ; Ségurel and Bon 2017 ). As infants, humans have the ability to break down lactose. However, after weaning, the body naturally stops producing lactase, unless the individual has a genetic mutation which allows for its continued production into adulthood—known as lactase persistence (LP). Indeed,<|im_end|> <|im_start|>assistant Researchers have found the earliest direct evidence of milk consumption anywhere in the world in the teeth of prehistoric British farmers. The research team, led by archaeologists at the University of York, identified a milk protein called beta lactoglobulin (BLG) entombed in the mineralised dental plaque of seven individuals who lived in the Neolithic period around 6,000 years-ago. The human dental plaque samples in the study are the oldest to be analysed for ancient proteins to date globally and the study represents the earliest identification of the milk whey protein BLG so far. The Neolithic period in Britain ran from 4,000 to 2,400 cal. BC and saw the emergence of farming, with the use of domesticated animals such as cows, sheep, pig and goats, alongside crops such as wheat and barley. Archaeologists have also discovered evidence of complex cultural practices, with Neolithic communities building large monumental and burial sites. The ancient human remains tested in the study come from three different Neolithic sites—Hambledon Hill and Hazleton North in the south of England, and Banbury Lane in the East Midlands. Individuals from all three sites showed the presence of milk proteins from cows, sheep or goats, suggesting people were exploiting multiple species for dairy products. Dental plaque can offer unique insights into the diets of ancient people because dietary proteins are entrapped within it when it is mineralised by components of saliva to form tartar or 'dental calculus'. Lead author of the study, Dr. Sophy Charlton, from the Department of Archaeology at the University of York, said: "The fact that we found this protein in the dental calculus of individuals from three different Neolithic sites may suggest that dairy consumption was a widespread dietary practice in the past. "It would be a fascinating avenue for further research to look at more individuals and see if we can determine whether there are any patterns as to who was consuming milk in the archaeological past—perhaps the amount of dairy products consumed or the animals utilised varied along the lines of sex, gender, age or social standing." The discovery of milk proteins is particularly interesting as recent genetic studies suggest that people who lived at this time did not yet have the ability to digest the lactose in milk. To get around this, the ancient farmers may have been drinking just small amounts of milk or processing it into other foodstuffs such as cheese (which removes most of the lactose), the researchers say. 'Lactase persistence', which allows for the continued consumption of milk into adulthood, is the result of a genetic mutation in a section of DNA that controls the activity of the lactase gene. However, the mechanisms behind how and when we evolved this ability remain a mystery. Dr. Charlton added: "Because drinking any more than very small amounts of milk would have made people from this period really quite ill, these early farmers may have been processing milk, perhaps into foodstuffs such as cheese, to reduce its lactose content." "Identifying more ancient individuals with evidence of BLG in the future may provide further insights into milk consumption and processing in the past, and increase our understanding of how genetics and culture have interacted to produce lactase persistence." <|im_end|>

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2,121

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Cavity–polaritons in semiconductor microstructures have emerged as a promising system for exploring non-equilibrium dynamics of many-body systems 1 . Key advances in this field, including the observation of polariton condensation 2 , superfluidity 3 , realization of topological photonic bands 4 , and dissipative phase transitions 5 , 6 , 7 , generically allow for a description based on a mean-field Gross–Pitaevskii formalism. Observation of polariton intensity squeezing 8 , 9 and decoherence of a polarization entangled photon pair by a polariton condensate 10 , on the other hand, demonstrate quantum effects that show up at high polariton occupancy. Going beyond and into the regime of strongly correlated polaritons requires the observation of a photon blockade effect 11 , 12 where interactions are strong enough to suppress double occupancy of a photonic lattice site. Here, we report evidence of quantum correlations between polaritons spatially confined in a fibre cavity. Photon correlation measurements show that careful tuning of the coupled system can lead to a modest reduction of simultaneous two-polariton generation probability by 5%. Concurrently, our experiments allow us to measure the polariton interaction strength, thereby resolving the controversy stemming from recent experimental reports 13 . Our findings constitute an essential step towards the realization of strongly interacting photonic systems. Main Photon blockade can be described as strong conditional modification of the optical properties of a medium by a single photonic excitation. Early demonstrations of photon blockade were based on the realization of the Jaynes–Cummings model, consisting of a single anharmonic quantum emitter strongly coupled to a cavity mode 14 , 15 , 16 , 17 . The requisite optical nonlinearity in this case originates from the impossibility of double excitation of the anharmonic emitter and consequently of the cavity–emitter system under resonant excitation. In the opposite limit of collective excitation of a large number of two-level emitters coupled to a cavity mode, photon blockade can only be observed if there is strong interaction between optically excited collective states. This, for example, is manifestly the case if the incident field creates a collective excitation to a Rydberg state with large van der Waals interactions 18 , 19 . In condensed matter, an analogous situation can be obtained using quantum-well excitons non-perturbatively coupled to a cavity mode, leading to the formation of hybrid light–matter eigenstates, termed polaritons. In this system, exciton–exciton interactions ensure that the polariton spectrum is anharmonic, provided that polaritons are confined to maximize their in-plane spatial overlap. If the interaction-induced energy shift is larger than the polariton linewidth, the system exhibits polariton blockade 12 . A convenient verification of the blockade phenomenon is provided by photon antibunching—a vanishing photon correlation function g (2) ( τ ) for delays τ smaller than the polariton lifetime. Even in the limit where the nonlinearity is smaller than the linewidth, finite photon antibunching can be observed provided that the laser is detuned from the polariton centre frequency. Such an observation confirms a first-order modification of the cavity transmission conditioned on the excitation of a single polariton 20 . To demonstrate quantum correlations of confined polaritons, we measure g (2) ( τ ) using photons transmitted from a resonantly driven zero-dimensional cavity that is strongly coupled to the excitonic transition of a quantum well 7 , 21 . Figure 1a depicts the experimental set-up based on a semi-integrated fibre cavity whose length is tunable in situ using a piezo-based nanopositioner. The concave surface of the fibre leads to lateral confinement with a mode waist of w 0 = 1.0 μm. A single InGaAs quantum well is placed at an antinode of the fundamental TEM 00 mode (see Methods ). When scanning the cavity mode energy across the exciton resonance, we observe a large Rabi splitting of E R = 3.5 meV between the two polariton eigenmodes, signalling the strong coupling regime (Fig. 1b ). Focusing exclusively on the lower polariton (LP) mode and neglecting the role of the far-detuned upper polariton branch, the Hamiltonian describing the system in the rotating basis under resonant drive is given by $$H=\\left(\\hslash {\\omega }_{\\rm{L}}-{E}_{\\rm{LP}}\\right){\\hat{p}}^{\\dagger }\\hat{p}+\\frac{{U}_{\\rm{pp}}}{2}{\\hat{p}}^{\\dagger }{\\hat{p}}^{\\dagger }\\hat{p}\\hat{p}+\\hslash {F}^{* }{\\hat{p}}^{\\dagger }+\\hslash F\\hat{p}$$ (1) where \$\\widehat{p}\$ denotes the lower polariton annihilation operator, ω L the excitation laser frequency, E LP the LP energy, F the drive strength and U pp the polariton–polariton interaction strength. The polariton annihilation operator \$\\widehat{p}\$ can be decomposed into its exciton and photon components as \$\\widehat{p}={c}_{\\rm{p}}\\hat{a}+{c}_{\\rm{x}}\\widehat{x}\$ , where \${\\hat{a}}\$ \$\\left(\\widehat{x}\\right)\$ denotes the annihilation operator associated with the cavity mode (quantum well exciton). The corresponding Hopfield coefficients c p and c x , satisfying | c p | 2 + | c x | 2 = 1, depend on the cavity–exciton detuning and therefore can be adjusted by changing the cavity length. Fig. 1: Experimental set-up for cavity–polaritons. a , A fibre cavity is driven by either a continuous-wave laser or picosecond laser pulses (with pulse width prolonged by a monochromator). The polarization, set by fibre polarization controllers (FPCs), is chosen to match the lowest linearly polarized cavity mode. The transmitted light is collected in a fibre and guided to a Hanbury Brown and Twiss (HBT) set-up where photon statistics are measured. Enlarged view: structure of the semi-integrated cavity. QW, quantum well. b , White light transmission spectra as a function of the piezo voltage controlling the cavity length, revealing a Rabi splitting of 3.5 meV. At low piezo voltages, a transverse mode multiplet strongly coupled to the exciton is visible. Additionally, at ~1.478 eV an impurity resonance is also coupled to the cavity mode. Orange box: region of interest for the present work. Full size image In the limit of a small nonlinearity, the maximum degree of antibunching \$A= \\max\\left(1-{g}^{(2)}(0)\\right)\$ is approximately given by the ratio between the polariton–polariton interaction energy and the linewidth Γ p : A ≈ U pp / Γ p = U xx | c x | 4 / Γ p where U xx is the exciton–exciton interaction energy (see Supplementary Information ). Thus, the maximum antibunching is the result of", "role": "user" }, { "content": "Light particles normally do not \"feel\" each other because there is no interaction acting between them. Researchers at ETH have now succeeded in manipulating photons inside a semiconductor material in such a way as to make them repel each other nevertheless. Two light beams crossing each other do not deflect one another. That is because, according to the laws of quantum physics, there is no interaction between light particles or photons. Therefore, in a collision two photons simply pass through each other instead of bouncing off one another – unless one helps them along in some way. In fact, researchers have tried for quite some time now to find techniques for making photons \"feel\" each other. The hope is that this will result in many new possibilities for research as well as for practical applications. Ataç Imamoğlu, professor at the Institute for Quantum Electronics at ETH in Zurich, and his collaborators have now taken a further important step towards the realization of strongly interacting photons. Their research results were recently published in the scientific journal Nature Materials. Transformation into polaritons \"Strongly interacting photons are something of a Holy Grail in our field of research, photonics\", explains Aymeric Delteil, who works as a post-doc in Imamoğlu's laboratory. To make light particles repel each other, he and his colleagues have to go to some length, though. Using an optical fibre, they send short laser pulses into an optical resonator, inside of which the light is strongly focused and finally hits a semiconductor material. That material (produced by Imamoğlu's colleagues in Würzburg and St. Andrew's in Scotland) is cooled inside a cryostat – a kind of extremely powerful refrigerator – down to minus 269 degrees centigrade. At those low temperatures the photons can combine with electronic excitations of the material. That combination results in so called polaritons. At the opposite end of the material the polaritons become photons again, which can then exit the resonator. As there are electromagnetic forces acting between the electronic excitations, an interaction arises also between the polaritons. \"We were able to detect that phenomenon already a while ago\", says Imamoğlu. \"However, at the time the effect was so weak that only the interactions between a large number of polaritons played a role, but not the pairwise repulsion between individual polaritons.\" Correlations signal interactions In their new experiment, the researchers were now able to demonstrate that single polaritons – and hence, indirectly, the photons contained in them – can, indeed, interact with each other. This can be inferred from the way in which the photons leaving the resonator correlate with each other. To reveal those so called quantum correlations, one measures the probability of a second photon leaving the resonator shortly after another one. If the photons get in each other's way through their polaritons inside the semiconductor, that probability will be smaller than one would expect from non-interacting photons. In the extreme case there should even be a \"photon blockade\", an effect which Imamoğlu already postulated 20 years ago. A photon in the semiconductor that has created a polariton then completely prevents a second photon from entering the material and turning into a polariton itself. \"We are quite some way from realizing this\", Imamoğlu admits, \"but in the meantime we have improved further on our result that has just been published. This means that we are on the right track.\" Imamoğlu's long-term objective is to make photons interact so strongly with each other that they start behaving like fermions – like quantum particles, in other words, that can never be found at the same place. Interest in strongly interacting polaritons In the first instance, Imamoğlu is not interested in applications. \"That's really basic research,\" he says. \"But we do hope to be able, one day, to create polaritons that interact so strongly that we can use them to study new effects in quantum physics which are difficult to observe otherwise.\" The physicist is particularly interested in situations in which the polaritons are also in contact with their environment and exchange energy with it. That energy exchange, combined with the interactions between the polaritons, should, according to calculations by theoretical physicists. lead to phenomena for which there are only rudimentary explanations so far. Experiments such as those carried out by Imamoğlu could, therefore, help to understand the theoretical models better. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Cavity–polaritons in semiconductor microstructures have emerged as a promising system for exploring non-equilibrium dynamics of many-body systems 1 . Key advances in this field, including the observation of polariton condensation 2 , superfluidity 3 , realization of topological photonic bands 4 , and dissipative phase transitions 5 , 6 , 7 , generically allow for a description based on a mean-field Gross–Pitaevskii formalism. Observation of polariton intensity squeezing 8 , 9 and decoherence of a polarization entangled photon pair by a polariton condensate 10 , on the other hand, demonstrate quantum effects that show up at high polariton occupancy. Going beyond and into the regime of strongly correlated polaritons requires the observation of a photon blockade effect 11 , 12 where interactions are strong enough to suppress double occupancy of a photonic lattice site. Here, we report evidence of quantum correlations between polaritons spatially confined in a fibre cavity. Photon correlation measurements show that careful tuning of the coupled system can lead to a modest reduction of simultaneous two-polariton generation probability by 5%. Concurrently, our experiments allow us to measure the polariton interaction strength, thereby resolving the controversy stemming from recent experimental reports 13 . Our findings constitute an essential step towards the realization of strongly interacting photonic systems. Main Photon blockade can be described as strong conditional modification of the optical properties of a medium by a single photonic excitation. Early demonstrations of photon blockade were based on the realization of the Jaynes–Cummings model, consisting of a single anharmonic quantum emitter strongly coupled to a cavity mode 14 , 15 , 16 , 17 . The requisite optical nonlinearity in this case originates from the impossibility of double excitation of the anharmonic emitter and consequently of the cavity–emitter system under resonant excitation. In the opposite limit of collective excitation of a large number of two-level emitters coupled to a cavity mode, photon blockade can only be observed if there is strong interaction between optically excited collective states. This, for example, is manifestly the case if the incident field creates a collective excitation to a Rydberg state with large van der Waals interactions 18 , 19 . In condensed matter, an analogous situation can be obtained using quantum-well excitons non-perturbatively coupled to a cavity mode, leading to the formation of hybrid light–matter eigenstates, termed polaritons. In this system, exciton–exciton interactions ensure that the polariton spectrum is anharmonic, provided that polaritons are confined to maximize their in-plane spatial overlap. If the interaction-induced energy shift is larger than the polariton linewidth, the system exhibits polariton blockade 12 . A convenient verification of the blockade phenomenon is provided by photon antibunching—a vanishing photon correlation function g (2) ( τ ) for delays τ smaller than the polariton lifetime. Even in the limit where the nonlinearity is smaller than the linewidth, finite photon antibunching can be observed provided that the laser is detuned from the polariton centre frequency. Such an observation confirms a first-order modification of the cavity transmission conditioned on the excitation of a single polariton 20 . To demonstrate quantum correlations of confined polaritons, we measure g (2) ( τ ) using photons transmitted from a resonantly driven zero-dimensional cavity that is strongly coupled to the excitonic transition of a quantum well 7 , 21 . Figure 1a depicts the experimental set-up based on a semi-integrated fibre cavity whose length is tunable in situ using a piezo-based nanopositioner. The concave surface of the fibre leads to lateral confinement with a mode waist of w 0 = 1.0 μm. A single InGaAs quantum well is placed at an antinode of the fundamental TEM 00 mode (see Methods ). When scanning the cavity mode energy across the exciton resonance, we observe a large Rabi splitting of E R = 3.5 meV between the two polariton eigenmodes, signalling the strong coupling regime (Fig. 1b ). Focusing exclusively on the lower polariton (LP) mode and neglecting the role of the far-detuned upper polariton branch, the Hamiltonian describing the system in the rotating basis under resonant drive is given by $$H=\left(\hslash {\omega }_{\rm{L}}-{E}_{\rm{LP}}\right){\hat{p}}^{\dagger }\hat{p}+\frac{{U}_{\rm{pp}}}{2}{\hat{p}}^{\dagger }{\hat{p}}^{\dagger }\hat{p}\hat{p}+\hslash {F}^{* }{\hat{p}}^{\dagger }+\hslash F\hat{p}$$ (1) where $\widehat{p}$ denotes the lower polariton annihilation operator, ω L the excitation laser frequency, E LP the LP energy, F the drive strength and U pp the polariton–polariton interaction strength. The polariton annihilation operator $\widehat{p}$ can be decomposed into its exciton and photon components as $\widehat{p}={c}_{\rm{p}}\hat{a}+{c}_{\rm{x}}\widehat{x}$ , where ${\hat{a}}$ $\left(\widehat{x}\right)$ denotes the annihilation operator associated with the cavity mode (quantum well exciton). The corresponding Hopfield coefficients c p and c x , satisfying | c p | 2 + | c x | 2 = 1, depend on the cavity–exciton detuning and therefore can be adjusted by changing the cavity length. Fig. 1: Experimental set-up for cavity–polaritons. a , A fibre cavity is driven by either a continuous-wave laser or picosecond laser pulses (with pulse width prolonged by a monochromator). The polarization, set by fibre polarization controllers (FPCs), is chosen to match the lowest linearly polarized cavity mode. The transmitted light is collected in a fibre and guided to a Hanbury Brown and Twiss (HBT) set-up where photon statistics are measured. Enlarged view: structure of the semi-integrated cavity. QW, quantum well. b , White light transmission spectra as a function of the piezo voltage controlling the cavity length, revealing a Rabi splitting of 3.5 meV. At low piezo voltages, a transverse mode multiplet strongly coupled to the exciton is visible. Additionally, at ~1.478 eV an impurity resonance is also coupled to the cavity mode. Orange box: region of interest for the present work. Full size image In the limit of a small nonlinearity, the maximum degree of antibunching $A= \max\left(1-{g}^{(2)}(0)\right)$ is approximately given by the ratio between the polariton–polariton interaction energy and the linewidth Γ p : A ≈ U pp / Γ p = U xx | c x | 4 / Γ p where U xx is the exciton–exciton interaction energy (see Supplementary Information ). Thus, the maximum antibunching is the result of<|im_end|> <|im_start|>assistant Light particles normally do not "feel" each other because there is no interaction acting between them. Researchers at ETH have now succeeded in manipulating photons inside a semiconductor material in such a way as to make them repel each other nevertheless. Two light beams crossing each other do not deflect one another. That is because, according to the laws of quantum physics, there is no interaction between light particles or photons. Therefore, in a collision two photons simply pass through each other instead of bouncing off one another – unless one helps them along in some way. In fact, researchers have tried for quite some time now to find techniques for making photons "feel" each other. The hope is that this will result in many new possibilities for research as well as for practical applications. Ataç Imamoğlu, professor at the Institute for Quantum Electronics at ETH in Zurich, and his collaborators have now taken a further important step towards the realization of strongly interacting photons. Their research results were recently published in the scientific journal Nature Materials. Transformation into polaritons "Strongly interacting photons are something of a Holy Grail in our field of research, photonics", explains Aymeric Delteil, who works as a post-doc in Imamoğlu's laboratory. To make light particles repel each other, he and his colleagues have to go to some length, though. Using an optical fibre, they send short laser pulses into an optical resonator, inside of which the light is strongly focused and finally hits a semiconductor material. That material (produced by Imamoğlu's colleagues in Würzburg and St. Andrew's in Scotland) is cooled inside a cryostat – a kind of extremely powerful refrigerator – down to minus 269 degrees centigrade. At those low temperatures the photons can combine with electronic excitations of the material. That combination results in so called polaritons. At the opposite end of the material the polaritons become photons again, which can then exit the resonator. As there are electromagnetic forces acting between the electronic excitations, an interaction arises also between the polaritons. "We were able to detect that phenomenon already a while ago", says Imamoğlu. "However, at the time the effect was so weak that only the interactions between a large number of polaritons played a role, but not the pairwise repulsion between individual polaritons." Correlations signal interactions In their new experiment, the researchers were now able to demonstrate that single polaritons – and hence, indirectly, the photons contained in them – can, indeed, interact with each other. This can be inferred from the way in which the photons leaving the resonator correlate with each other. To reveal those so called quantum correlations, one measures the probability of a second photon leaving the resonator shortly after another one. If the photons get in each other's way through their polaritons inside the semiconductor, that probability will be smaller than one would expect from non-interacting photons. In the extreme case there should even be a "photon blockade", an effect which Imamoğlu already postulated 20 years ago. A photon in the semiconductor that has created a polariton then completely prevents a second photon from entering the material and turning into a polariton itself. "We are quite some way from realizing this", Imamoğlu admits, "but in the meantime we have improved further on our result that has just been published. This means that we are on the right track." Imamoğlu's long-term objective is to make photons interact so strongly with each other that they start behaving like fermions – like quantum particles, in other words, that can never be found at the same place. Interest in strongly interacting polaritons In the first instance, Imamoğlu is not interested in applications. "That's really basic research," he says. "But we do hope to be able, one day, to create polaritons that interact so strongly that we can use them to study new effects in quantum physics which are difficult to observe otherwise." The physicist is particularly interested in situations in which the polaritons are also in contact with their environment and exchange energy with it. That energy exchange, combined with the interactions between the polaritons, should, according to calculations by theoretical physicists. lead to phenomena for which there are only rudimentary explanations so far. Experiments such as those carried out by Imamoğlu could, therefore, help to understand the theoretical models better. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The constituent particles of matter can arrange themselves in various ways, giving rise to emergent phenomena that can be surprisingly rich and often cannot be understood by studying only the individual constituents. Discovering and understanding the emergence of such phenomena in quantum materials—especially those in which multiple degrees of freedom or energy scales are delicately balanced—is of fundamental interest to condensed-matter research 1 , 2 . Here we report on the surprising observation of emergent ferroelectricity in graphene-based moiré heterostructures. Ferroelectric materials show electrically switchable electric dipoles, which are usually formed by spatial separation between the average centres of positive and negative charge within the unit cell. On this basis, it is difficult to imagine graphene—a material composed of only carbon atoms—exhibiting ferroelectricity 3 . However, in this work we realize switchable ferroelectricity in Bernal-stacked bilayer graphene sandwiched between two hexagonal boron nitride layers. By introducing a moiré superlattice potential (via aligning bilayer graphene with the top and/or bottom boron nitride crystals), we observe prominent and robust hysteretic behaviour of the graphene resistance with an externally applied out-of-plane displacement field. Our systematic transport measurements reveal a rich and striking response as a function of displacement field and electron filling, and beyond the framework of conventional ferroelectrics. We further directly probe the ferroelectric polarization through a non-local monolayer graphene sensor. Our results suggest an unconventional, odd-parity electronic ordering in the bilayer graphene/boron nitride moiré system. This emergent moiré ferroelectricity may enable ultrafast, programmable and atomically thin carbon-based memory devices. Main Discovering and classifying novel phases of matter has been a constant driving force throughout condensed-matter research. For example, the recognition of spontaneous symmetry breaking has enabled the study and understanding of superconductors, magnets and many other correlated electronic states under a unifying principle. The concepts of Berry phase and topology have led to novel topological phases, including quantum spin Hall insulators, three-dimensional topological insulators and Weyl semimetals 4 . With these exciting advances, it is increasingly recognized that one of the next frontiers to discover new physics lies in systems where electronic correlations, spontaneous symmetry breaking and Berry phase are all at play 1 , 2 . The realization of such systems with a variety of degrees of freedom in a delicate balance calls for unprecedented ability to design, engineer and control the electronic and symmetry properties of quantum materials. In that sense, two-dimensional (2D) moiré superlattices offer a uniquely suitable platform because they allow for a powerful, yet generic, way to induce electronic correlations into systems where interactions are otherwise not strong. For instance, monolayer graphene is a weakly interacting 2D semimetal. However, stacking one monolayer of graphene on another at the magic angle (around 1.1°) strongly modifies the electronic structure 5 , 6 , 7 , giving rise to emergent phenomena 8 , 9 . Current research, which has included a number of different moiré superlattices 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , has uncovered superconducting and magnetic states, among others. Superconductivity and magnetism correspond to the spontaneous breaking of gauge symmetry (charge conservation) and spin rotational symmetry, respectively. Another class of symmetry that plays an important role in both correlated physics and topology is the point group symmetries, such as inversion, mirror reflection and rotation. The spontaneous breaking of point group symmetries can give rise to a wide range of novel electronic orders 22 , 23 , 24 , 25 . Moreover, these electronic orders are predicted to serve as precursors to unconventional superconducting pairing 26 or novel magnetism 27 . However, apart from a few studies reporting evidence of nematicity in magic-angle graphene 28 , 29 , 30 and the observation of the quantum anomalous Hall effect in boron nitride (BN)-aligned magic-angle and ABC graphene 11 , 12 , 14 , 31 , the role of point group symmetries in moiré systems remains largely under-explored. Here we study Bernal-stacked bilayer graphene (BLG) 32 aligned with BN, a simple yet rich moiré system where electronic correlations, Berry phase and point group symmetries (such as inversion symmetry) are simultaneously important. In Bernal-stacked BLG, the unit cell consists of two inversion pairs (Fig. 1a ). The space inversion symmetry is effectively equivalent to the layer degeneracy. The application of an external out-of-plane displacement field breaks the layer degeneracy and gives rise to a layer polarization in the quantum wavefunction near the band edges, and hence a non-zero Berry curvature (Fig. 1b ). Such Berry curvature lies at the heart of the topological valley transport as well as chiral optical and excitonic properties in BLG 33 , 34 , 35 , 36 , 37 . Owing to this unique electronic structure, theory has long predicted a wide range of spontaneous electronic order in pristine BLG 32 . Under high magnetic fields at very low temperatures, experiments have indeed revealed a number of broken symmetry phases in the Landau levels 38 , 39 . In contrast, in the absence of a magnetic field, interesting experimental results have suggested electronic correlations 40 , 41 , 42 , 43 , but the effects remain relatively subtle even at very low temperatures with ultrahigh-quality samples, and their exact nature remains unsettled. Here we put such chiral, quadratic gapless fermions that are protected by the layer degeneracy onto a moiré superlattice potential (Fig. 1c ), to search for correlation-driven spontaneous symmetry breaking. In the following, we report on the observation of emergent unconventional ferroelectricity in this system. Fig. 1: Quadratic, chiral fermions on a moiré potential in a BLG/BN moiré superlattice. a , Lattice structure of Bernal-stacked BLG. The triangle marks its inversion centre. A t(b) and B t(b) are the A and B sublattices on the top (bottom) layer, which forms two inversion pairs, (A t , B b ) and (A b , B t ), connected by dashed lines. b , Schematic of the band dispersion and layer polarization of the low-energy electronic states of", "role": "user" }, { "content": "MIT researchers and colleagues have discovered an important—and unexpected—electronic property of graphene, a material discovered only about 17 years ago that continues to surprise scientists with its interesting physics. The work, which involves structures composed of atomically thin layers of materials that are also biocompatible, could usher in new, faster information-processing paradigms. One potential application is in neuromorphic computing, which aims to replicate the neuronal cells in the body responsible for everything from behavior to memories. The work also introduces new physics that the researchers are excited to explore. \"Graphene-based heterostructures continue to produce fascinating surprises. Our observation of unconventional ferroelectricity in this simple and ultra-thin system challenges many of the prevailing assumptions about ferroelectric systems and it may pave the way for an entire generation of new ferroelectrics materials,\" says Pablo Jarillo-Herrero, the Cecil and Ida Green Professor of Physics at MIT and leader of the work, which involved a collaboration with five other MIT faculty from three departments. A New Property Graphene is composed of a single layer of carbon atoms arranged in hexagons resembling a honeycomb structure. Since the material's discovery, scientists have shown that different configurations of graphene layers can give rise to a variety of important properties. Graphene-based structures can be either superconductors, which conduct electricity without resistance, or insulators, which prevent the movement of electricity. They have even been found to display magnetism. In the current work, which was reported last December in Nature, the MIT researchers and colleagues show that bilayer graphene can also be ferroelectric. This means that positive and negative charges in the material can spontaneously separate into different layers. In most materials, opposite charges are attracted to each other; they want to combine. Only the application of an electric field will force them to opposite sides, or poles. In a ferroelectric material, no external electric field is necessary to keep the charges apart, giving rise to a spontaneous polarization. However, the application of an external electric field does have an effect: an electric field of opposite direction will cause the charges to switch sides and reverse the polarization. Zhiren (Isaac) Zheng holds up a sample of the new ferroelectric structure created by MIT researchers and colleagues (small black square with gold edges above Zheng’s head). The gold structure is the inside of a Cryogen Free Dilution Refrigerator that the researchers used to measure the new ferroelectric structures. Credit: Sergio de la Barrera, MIT For all of these reasons, ferroelectric materials are used in a variety of electronic systems, from medical ultrasounds to radio frequency identification (RFID) cards. Conventional ferroelectrics, however, are insulators. The MIT-led team's ferroelectric based on graphene operates through a completely different mechanism—different physics—that allows it to conduct electricity. And that opens up myriad additional applications. \"What we've found here is a new type of ferroelectric material,\" says Zhiren (Isaac) Zheng, an MIT graduate student in physics and first author of the Nature paper. Qiong Ma, MIT Ph.D. 2016, a co-author of the paper and an assistant professor at Boston College, puts the work in perspective. \"There are challenges associated with conventional ferroelectrics that people have been working to overcome. For example, the ferroelectric phase becomes unstable as the device continues to be miniaturized. With our material, some of those challenges may be automatically solved.\" Ma conducted the current work as a postdoctoral associate through MIT's Materials Research Laboratory (MRL). Important Patterns The structure the team created is composed of two layers of graphene—a bilayer—sandwiched between atomically thin layers of boron nitride (BN) above and below. Each BN layer is at a slightly different angle from the other. Looking from above, the result is a unique pattern called a moiré superlattice. A moiré pattern, in turn, \"can dramatically change the properties of a material,\" Zheng says. Jarillo-Herrero's group demonstrated an important example of this in 2018. In that work, also reported in Nature, the researchers stacked two layers of graphene. Those layers, however, weren't exactly on top of each other; rather, one was slightly rotated at a \"magic angle\" of 1.1 degrees. The resulting structure created a moiré pattern that in turn allowed the graphene to be either a superconductor or an insulator depending on the number of electrons in the system as provided by an electric field. Essentially the team was able to \"tune graphene to behave at two electrical extremes,\" according to an MIT news story at the time. \"So by creating this moiré structure, graphene is not graphene anymore. It almost magically turns into something very, very different,\" Ma says. In the current work, the researchers created a moiré pattern with sheets of graphene and boron nitride that has resulted in a new form of ferroelectricity. The physics involved in the movement of electrons through the structure is different from that of conventional ferroelectrics. \"The ferroelectricity demonstrated by the MIT group is fascinating,\" says Philip Kim, a Professor of Physics and Applied Physics at Harvard University, who was not involved in the research. \"This work is the first demonstration that reports pure electronic ferroelectricity, which exhibits charge polarization without ionic motion in the underlying lattice. This surprising discovery will surely invite further studies that can reveal more exciting emergent phenomena and provide an opportunity to utilize them for ultrafast memory applications.\" The researchers aim to continue the work by not only demonstrating the new material's potential for a variety of applications, but also developing a better understanding of its physics. \"There are still many mysteries that we don't fully understand and that are fundamentally very intriguing,\" Ma says. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The constituent particles of matter can arrange themselves in various ways, giving rise to emergent phenomena that can be surprisingly rich and often cannot be understood by studying only the individual constituents. Discovering and understanding the emergence of such phenomena in quantum materials—especially those in which multiple degrees of freedom or energy scales are delicately balanced—is of fundamental interest to condensed-matter research 1 , 2 . Here we report on the surprising observation of emergent ferroelectricity in graphene-based moiré heterostructures. Ferroelectric materials show electrically switchable electric dipoles, which are usually formed by spatial separation between the average centres of positive and negative charge within the unit cell. On this basis, it is difficult to imagine graphene—a material composed of only carbon atoms—exhibiting ferroelectricity 3 . However, in this work we realize switchable ferroelectricity in Bernal-stacked bilayer graphene sandwiched between two hexagonal boron nitride layers. By introducing a moiré superlattice potential (via aligning bilayer graphene with the top and/or bottom boron nitride crystals), we observe prominent and robust hysteretic behaviour of the graphene resistance with an externally applied out-of-plane displacement field. Our systematic transport measurements reveal a rich and striking response as a function of displacement field and electron filling, and beyond the framework of conventional ferroelectrics. We further directly probe the ferroelectric polarization through a non-local monolayer graphene sensor. Our results suggest an unconventional, odd-parity electronic ordering in the bilayer graphene/boron nitride moiré system. This emergent moiré ferroelectricity may enable ultrafast, programmable and atomically thin carbon-based memory devices. Main Discovering and classifying novel phases of matter has been a constant driving force throughout condensed-matter research. For example, the recognition of spontaneous symmetry breaking has enabled the study and understanding of superconductors, magnets and many other correlated electronic states under a unifying principle. The concepts of Berry phase and topology have led to novel topological phases, including quantum spin Hall insulators, three-dimensional topological insulators and Weyl semimetals 4 . With these exciting advances, it is increasingly recognized that one of the next frontiers to discover new physics lies in systems where electronic correlations, spontaneous symmetry breaking and Berry phase are all at play 1 , 2 . The realization of such systems with a variety of degrees of freedom in a delicate balance calls for unprecedented ability to design, engineer and control the electronic and symmetry properties of quantum materials. In that sense, two-dimensional (2D) moiré superlattices offer a uniquely suitable platform because they allow for a powerful, yet generic, way to induce electronic correlations into systems where interactions are otherwise not strong. For instance, monolayer graphene is a weakly interacting 2D semimetal. However, stacking one monolayer of graphene on another at the magic angle (around 1.1°) strongly modifies the electronic structure 5 , 6 , 7 , giving rise to emergent phenomena 8 , 9 . Current research, which has included a number of different moiré superlattices 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , has uncovered superconducting and magnetic states, among others. Superconductivity and magnetism correspond to the spontaneous breaking of gauge symmetry (charge conservation) and spin rotational symmetry, respectively. Another class of symmetry that plays an important role in both correlated physics and topology is the point group symmetries, such as inversion, mirror reflection and rotation. The spontaneous breaking of point group symmetries can give rise to a wide range of novel electronic orders 22 , 23 , 24 , 25 . Moreover, these electronic orders are predicted to serve as precursors to unconventional superconducting pairing 26 or novel magnetism 27 . However, apart from a few studies reporting evidence of nematicity in magic-angle graphene 28 , 29 , 30 and the observation of the quantum anomalous Hall effect in boron nitride (BN)-aligned magic-angle and ABC graphene 11 , 12 , 14 , 31 , the role of point group symmetries in moiré systems remains largely under-explored. Here we study Bernal-stacked bilayer graphene (BLG) 32 aligned with BN, a simple yet rich moiré system where electronic correlations, Berry phase and point group symmetries (such as inversion symmetry) are simultaneously important. In Bernal-stacked BLG, the unit cell consists of two inversion pairs (Fig. 1a ). The space inversion symmetry is effectively equivalent to the layer degeneracy. The application of an external out-of-plane displacement field breaks the layer degeneracy and gives rise to a layer polarization in the quantum wavefunction near the band edges, and hence a non-zero Berry curvature (Fig. 1b ). Such Berry curvature lies at the heart of the topological valley transport as well as chiral optical and excitonic properties in BLG 33 , 34 , 35 , 36 , 37 . Owing to this unique electronic structure, theory has long predicted a wide range of spontaneous electronic order in pristine BLG 32 . Under high magnetic fields at very low temperatures, experiments have indeed revealed a number of broken symmetry phases in the Landau levels 38 , 39 . In contrast, in the absence of a magnetic field, interesting experimental results have suggested electronic correlations 40 , 41 , 42 , 43 , but the effects remain relatively subtle even at very low temperatures with ultrahigh-quality samples, and their exact nature remains unsettled. Here we put such chiral, quadratic gapless fermions that are protected by the layer degeneracy onto a moiré superlattice potential (Fig. 1c ), to search for correlation-driven spontaneous symmetry breaking. In the following, we report on the observation of emergent unconventional ferroelectricity in this system. Fig. 1: Quadratic, chiral fermions on a moiré potential in a BLG/BN moiré superlattice. a , Lattice structure of Bernal-stacked BLG. The triangle marks its inversion centre. A t(b) and B t(b) are the A and B sublattices on the top (bottom) layer, which forms two inversion pairs, (A t , B b ) and (A b , B t ), connected by dashed lines. b , Schematic of the band dispersion and layer polarization of the low-energy electronic states of<|im_end|> <|im_start|>assistant MIT researchers and colleagues have discovered an important—and unexpected—electronic property of graphene, a material discovered only about 17 years ago that continues to surprise scientists with its interesting physics. The work, which involves structures composed of atomically thin layers of materials that are also biocompatible, could usher in new, faster information-processing paradigms. One potential application is in neuromorphic computing, which aims to replicate the neuronal cells in the body responsible for everything from behavior to memories. The work also introduces new physics that the researchers are excited to explore. "Graphene-based heterostructures continue to produce fascinating surprises. Our observation of unconventional ferroelectricity in this simple and ultra-thin system challenges many of the prevailing assumptions about ferroelectric systems and it may pave the way for an entire generation of new ferroelectrics materials," says Pablo Jarillo-Herrero, the Cecil and Ida Green Professor of Physics at MIT and leader of the work, which involved a collaboration with five other MIT faculty from three departments. A New Property Graphene is composed of a single layer of carbon atoms arranged in hexagons resembling a honeycomb structure. Since the material's discovery, scientists have shown that different configurations of graphene layers can give rise to a variety of important properties. Graphene-based structures can be either superconductors, which conduct electricity without resistance, or insulators, which prevent the movement of electricity. They have even been found to display magnetism. In the current work, which was reported last December in Nature, the MIT researchers and colleagues show that bilayer graphene can also be ferroelectric. This means that positive and negative charges in the material can spontaneously separate into different layers. In most materials, opposite charges are attracted to each other; they want to combine. Only the application of an electric field will force them to opposite sides, or poles. In a ferroelectric material, no external electric field is necessary to keep the charges apart, giving rise to a spontaneous polarization. However, the application of an external electric field does have an effect: an electric field of opposite direction will cause the charges to switch sides and reverse the polarization. Zhiren (Isaac) Zheng holds up a sample of the new ferroelectric structure created by MIT researchers and colleagues (small black square with gold edges above Zheng’s head). The gold structure is the inside of a Cryogen Free Dilution Refrigerator that the researchers used to measure the new ferroelectric structures. Credit: Sergio de la Barrera, MIT For all of these reasons, ferroelectric materials are used in a variety of electronic systems, from medical ultrasounds to radio frequency identification (RFID) cards. Conventional ferroelectrics, however, are insulators. The MIT-led team's ferroelectric based on graphene operates through a completely different mechanism—different physics—that allows it to conduct electricity. And that opens up myriad additional applications. "What we've found here is a new type of ferroelectric material," says Zhiren (Isaac) Zheng, an MIT graduate student in physics and first author of the Nature paper. Qiong Ma, MIT Ph.D. 2016, a co-author of the paper and an assistant professor at Boston College, puts the work in perspective. "There are challenges associated with conventional ferroelectrics that people have been working to overcome. For example, the ferroelectric phase becomes unstable as the device continues to be miniaturized. With our material, some of those challenges may be automatically solved." Ma conducted the current work as a postdoctoral associate through MIT's Materials Research Laboratory (MRL). Important Patterns The structure the team created is composed of two layers of graphene—a bilayer—sandwiched between atomically thin layers of boron nitride (BN) above and below. Each BN layer is at a slightly different angle from the other. Looking from above, the result is a unique pattern called a moiré superlattice. A moiré pattern, in turn, "can dramatically change the properties of a material," Zheng says. Jarillo-Herrero's group demonstrated an important example of this in 2018. In that work, also reported in Nature, the researchers stacked two layers of graphene. Those layers, however, weren't exactly on top of each other; rather, one was slightly rotated at a "magic angle" of 1.1 degrees. The resulting structure created a moiré pattern that in turn allowed the graphene to be either a superconductor or an insulator depending on the number of electrons in the system as provided by an electric field. Essentially the team was able to "tune graphene to behave at two electrical extremes," according to an MIT news story at the time. "So by creating this moiré structure, graphene is not graphene anymore. It almost magically turns into something very, very different," Ma says. In the current work, the researchers created a moiré pattern with sheets of graphene and boron nitride that has resulted in a new form of ferroelectricity. The physics involved in the movement of electrons through the structure is different from that of conventional ferroelectrics. "The ferroelectricity demonstrated by the MIT group is fascinating," says Philip Kim, a Professor of Physics and Applied Physics at Harvard University, who was not involved in the research. "This work is the first demonstration that reports pure electronic ferroelectricity, which exhibits charge polarization without ionic motion in the underlying lattice. This surprising discovery will surely invite further studies that can reveal more exciting emergent phenomena and provide an opportunity to utilize them for ultrafast memory applications." The researchers aim to continue the work by not only demonstrating the new material's potential for a variety of applications, but also developing a better understanding of its physics. "There are still many mysteries that we don't fully understand and that are fundamentally very intriguing," Ma says. <|im_end|>

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1253, 94123, 279, 1648, 369, 459, 4553, 9659, 315, 502, 18728, 299, 19493, 6329, 7384, 1359, 2795, 53863, 31651, 22532, 11529, 618, 2382, 11, 279, 90227, 323, 358, 3315, 7997, 17054, 315, 28415, 520, 15210, 323, 7808, 315, 279, 990, 11, 902, 6532, 264, 20632, 449, 4330, 1023, 15210, 22291, 505, 2380, 26280, 13, 362, 1561, 8825, 12441, 1994, 374, 24306, 315, 264, 3254, 6324, 315, 12782, 33299, 28902, 304, 12651, 351, 2439, 71707, 264, 26828, 22631, 6070, 13, 8876, 279, 3769, 596, 18841, 11, 14248, 617, 6982, 430, 2204, 33483, 315, 66192, 13931, 649, 3041, 10205, 311, 264, 8205, 315, 3062, 6012, 13, 12441, 1994, 6108, 14726, 649, 387, 3060, 2307, 77752, 1105, 11, 902, 6929, 18200, 2085, 13957, 11, 477, 1672, 42391, 11, 902, 5471, 279, 7351, 315, 18200, 13, 2435, 617, 1524, 1027, 1766, 311, 3113, 33297, 2191, 13, 763, 279, 1510, 990, 11, 902, 574, 5068, 1566, 6790, 304, 22037, 11, 279, 15210, 12074, 323, 18105, 1501, 430, 20934, 1155, 66192, 649, 1101, 387, 18728, 299, 64465, 13, 1115, 3445, 430, 6928, 323, 8389, 10405, 304, 279, 3769, 649, 88558, 8821, 1139, 2204, 13931, 13, 763, 1455, 7384, 11, 14329, 10405, 527, 29123, 311, 1855, 1023, 26, 814, 1390, 311, 16343, 13, 8442, 279, 3851, 315, 459, 9249, 2115, 690, 5457, 1124, 311, 14329, 11314, 11, 477, 51879, 13, 763, 264, 18728, 299, 64465, 3769, 11, 912, 9434, 9249, 2115, 374, 5995, 311, 2567, 279, 10405, 10980, 11, 7231, 10205, 311, 264, 54557, 83245, 13, 4452, 11, 279, 3851, 315, 459, 9434, 9249, 2115, 1587, 617, 459, 2515, 25, 459, 9249, 2115, 315, 14329, 5216, 690, 5353, 279, 10405, 311, 3480, 11314, 323, 10134, 279, 83245, 13, 34449, 47435, 320, 3957, 65805, 8, 77547, 10187, 709, 264, 6205, 315, 279, 502, 18728, 299, 64465, 6070, 3549, 555, 15210, 12074, 323, 18105, 320, 9181, 3776, 9518, 449, 6761, 13116, 3485, 77547, 753, 2010, 570, 578, 6761, 6070, 374, 279, 4871, 315, 264, 43805, 11968, 3658, 53867, 1516, 75258, 859, 430, 279, 12074, 1511, 311, 6767, 279, 502, 18728, 299, 64465, 14726, 13, 16666, 25, 66294, 409, 1208, 32817, 2473, 11, 15210, 1789, 682, 315, 1521, 8125, 11, 18728, 299, 64465, 7384, 527, 1511, 304, 264, 8205, 315, 14683, 6067, 11, 505, 6593, 8725, 13811, 3171, 311, 9063, 11900, 22654, 320, 18077, 926, 8, 7563, 13, 1221, 44322, 18728, 299, 19493, 6329, 11, 4869, 11, 527, 1672, 42391, 13, 578, 15210, 35054, 2128, 596, 18728, 299, 64465, 3196, 389, 66192, 27149, 1555, 264, 6724, 2204, 17383, 2345, 64750, 22027, 41128, 6276, 433, 311, 6929, 18200, 13, 1628, 430, 16264, 709, 52909, 5217, 8522, 13, 330, 3923, 584, 3077, 1766, 1618, 374, 264, 502, 955, 315, 18728, 299, 64465, 3769, 1359, 2795, 34449, 47435, 320, 3957, 65805, 8, 77547, 11, 459, 15210, 19560, 5575, 304, 22027, 323, 1176, 3229, 315, 279, 22037, 5684, 13, 1229, 290, 70, 11583, 11, 15210, 2405, 920, 13, 220, 679, 21, 11, 264, 1080, 43802, 315, 279, 5684, 323, 459, 18328, 14561, 520, 10406, 9304, 11, 9711, 279, 990, 304, 13356, 13, 330, 3947, 527, 11774, 5938, 449, 21349, 18728, 299, 19493, 6329, 430, 1274, 617, 1027, 3318, 311, 23075, 13, 1789, 3187, 11, 279, 18728, 299, 64465, 10474, 9221, 45311, 439, 279, 3756, 9731, 311, 387, 13726, 2693, 1534, 13, 3161, 1057, 3769, 11, 1063, 315, 1884, 11774, 1253, 387, 9651, 29056, 1210, 11583, 13375, 279, 1510, 990, 439, 264, 1772, 38083, 278, 22712, 1555, 15210, 596, 32009, 8483, 32184, 320, 44, 4833, 570, 44921, 63823, 578, 6070, 279, 2128, 3549, 374, 24306, 315, 1403, 13931, 315, 66192, 29096, 20934, 1155, 2345, 92346, 17316, 291, 1990, 19670, 2740, 15792, 13931, 315, 32732, 263, 25719, 1425, 320, 15967, 8, 3485, 323, 3770, 13, 9062, 46416, 6324, 374, 520, 264, 10284, 2204, 9392, 505, 279, 1023, 13, 21815, 505, 3485, 11, 279, 1121, 374, 264, 5016, 5497, 2663, 264, 4647, 404, 978, 2307, 75, 32891, 13, 362, 4647, 404, 978, 5497, 11, 304, 2543, 11, 330, 4919, 29057, 2349, 279, 6012, 315, 264, 3769, 1359, 77547, 2795, 13, 31651, 22532, 11529, 618, 2382, 596, 1912, 21091, 459, 3062, 3187, 315, 420, 304, 220, 679, 23, 13, 763, 430, 990, 11, 1101, 5068, 304, 22037, 11, 279, 12074, 42415, 1403, 13931, 315, 66192, 13, 13266, 13931, 11, 4869, 11, 15058, 956, 7041, 389, 1948, 315, 1855, 1023, 26, 4856, 11, 832, 574, 10284, 46720, 520, 264, 330, 38551, 9392, 1, 315, 220, 16, 13, 16, 12628, 13, 578, 13239, 6070, 3549, 264, 4647, 404, 978, 5497, 430, 304, 2543, 5535, 279, 66192, 311, 387, 3060, 264, 2307, 444, 36869, 477, 459, 1672, 10733, 11911, 389, 279, 1396, 315, 57678, 304, 279, 1887, 439, 3984, 555, 459, 9249, 2115, 13, 71854, 279, 2128, 574, 3025, 311, 330, 83, 2957, 66192, 311, 36792, 520, 1403, 20314, 69971, 1359, 4184, 311, 459, 15210, 3754, 3446, 520, 279, 892, 13, 330, 4516, 555, 6968, 420, 4647, 404, 978, 6070, 11, 66192, 374, 539, 66192, 14926, 13, 1102, 4661, 78825, 10800, 1139, 2555, 1633, 11, 1633, 2204, 1359, 11583, 2795, 13, 763, 279, 1510, 990, 11, 279, 12074, 3549, 264, 4647, 404, 978, 5497, 449, 25112, 315, 66192, 323, 32732, 263, 25719, 1425, 430, 706, 19543, 304, 264, 502, 1376, 315, 18728, 299, 64465, 488, 13, 578, 22027, 6532, 304, 279, 7351, 315, 57678, 1555, 279, 6070, 374, 2204, 505, 430, 315, 21349, 18728, 299, 19493, 6329, 13, 330, 791, 18728, 299, 64465, 488, 21091, 555, 279, 15210, 1912, 374, 27387, 1359, 2795, 26241, 13818, 11, 264, 17054, 315, 28415, 323, 43608, 28415, 520, 25996, 3907, 11, 889, 574, 539, 6532, 304, 279, 3495, 13, 330, 2028, 990, 374, 279, 1176, 30816, 430, 6821, 10748, 14683, 18728, 299, 64465, 488, 11, 902, 50829, 6900, 83245, 2085, 220, 21427, 11633, 304, 279, 16940, 55372, 13, 1115, 15206, 18841, 690, 22225, 22114, 4726, 7978, 430, 649, 16805, 810, 13548, 7425, 306, 44247, 323, 3493, 459, 6776, 311, 29166, 1124, 369, 24955, 9533, 5044, 8522, 1210, 578, 12074, 9395, 311, 3136, 279, 990, 555, 539, 1193, 45296, 279, 502, 3769, 596, 4754, 369, 264, 8205, 315, 8522, 11, 719, 1101, 11469, 264, 2731, 8830, 315, 1202, 22027, 13, 330, 3947, 527, 2103, 1690, 57700, 430, 584, 1541, 956, 7373, 3619, 323, 430, 527, 43593, 1633, 41765, 1359, 11583, 2795, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In condensed matter systems, out of a large number of interacting degrees of freedom emerge weakly coupled quasiparticles (QPs), in terms of which most physical properties are described. The lack of identification of such QPs is a major barrier for understanding myriad exotic properties of correlated electrons, such as unconventional superconductivity and non-Fermi liquid behaviours. Here we report the observation of a composite particle in a quasi-two-dimensional spin–1/2 antiferromagnet Sr 2 IrO 4 —an exciton dressed with magnons—that propagates with the canonical characteristics of a QP: a finite QP residue and a lifetime longer than the hopping time scale. The dynamics of this charge-neutral excitation mirrors the fundamental process of the analogous one-hole propagation in the background of spins–1/2, and reveals the same intrinsic dynamics that is obscured for a single, charged-hole doped into two-dimensional cuprates. Introduction The dynamics of a single hole doped into a low-dimensional quantum antiferromagnet (AF) constitutes one of the classic unsolved problems, which has drawn much interest in the context of cuprate high-temperature superconductors 1 , 2 , 3 . In one picture, the single hole forms a coherent QP propagating in a medium of quantum-fluctuating spins, which strongly renormalizes the dispersion relations and the mutual interactions of the holes at finite doping. This spin–polaron picture is supported by numerical approaches, such as quantum Monte Carlo 4 , exact diagonalization 5 and self-consistent Born approximation (SCBA) 2 . In a contrasting picture, the notion of QP can break down due to various mechanism such as orthogonality catastrophe 6 , spin–charge separation 7 and/or localization effects 8 , reflecting the unconventional nature of two-dimensional (2D), strongly interacting fermions. To date, no evidence for a QP has been found in experiments 9 , 10 , 11 , 12 that probe the dynamics of a single hole doped into a 2D spin–1/2 quantum AFs. Motivated by the recent discovery of a new pseudospin–1/2 Heisenberg AF on a square lattice, Sr 2 IrO 4 (refs 13 , 14 , 15 , 16 , 17 , 18 ), we demonstrate a novel experimental approach using resonant inelastic X-ray scattering (RIXS), which is a rapidly evolving tool especially well suited for such 5 d transition-metal oxides, to address this longstanding problem. On the basis of its remarkable similarity to superconducting cuprates in structural 18 , electronic 13 and magnetic aspects 14 , 15 , 16 , superconductivity has been predicted in Sr 2 IrO 4 (ref. 19 ). Although the electron correlation strength in Sr 2 IrO 4 has been under much debate 20 , 21 , 22 , 23 , 24 , questioning the validity of classifying this compound as a Mott insulator, Sr 2 IrO 4 shares the same phenomenology that the hole spectral function as measured by angle-resolved photoemission spectroscopy (ARPES) lacks a legitimate QP 13 . This similarity suggests a common origin for the absence of a well-defined QP in the ARPES spectra for two distinct but similar classes of materials. As we shall see, however, Sr 2 IrO 4 supports a well-defined QP in another excitation channel, which RIXS is sensitive to and reflects the same dynamics as that of a hole, offering a novel route to studying elementary excitations in correlated oxides. In an earlier RIXS study of Sr 2 IrO 4 , excitations of a hole across the spin–orbit coupling split levels (from the j =1/2 manifold to the j =3/2 manifold) have been identified and it has been shown that their dispersions can be understood in close analogy to the single-hole problem 16 . Figure 1 depicts the hole-versus-exciton analogy: a ‘foreign’ object injected into a quantum Heisenberg AF, be it a hole or an exciton, creates a string of flipped spins along its hopping path. This analogy, in principle, suggests that the dynamics of a particle moving in a magnetic medium can also be studied using the exciton. However, the energy resolution of RIXS used in the earlier study (≈130 meV) was insufficient to resolve the dispersion and the intrinsic linewidth of the two-exciton modes associated with the two pairs of Kramers doublets in the j =3/2 manifold ( Fig. 2a ). Here we exploit the different orbital symmetries of the two-exciton modes to selectively probe each mode, and with the much improved energy resolution (≈30 meV) offered by RIXS after recent developments, reveal their full dynamics. Figure 1: Hole versus exciton propagation in an antiferromagnetic background. ( a ) A moving hole (blue square) leaves a string of excited spins behind; that is, every hopping motion of the hole generates a flipping of a spin relative to the ground state configuration. Black wavy lines indicate pairs of ‘misaligned’ spins. ( b ) An analogous exciton hopping. While the nature of the spin–orbit exciton (charge-neutral object) and the hole (charged particle) is quite different, they share in common that their hopping creates a string of flipped spins (or isospins in the case of exciton). See Fig. 2 for the description of the isospins and the spin–orbit excitons. Full size image Figure 2: RIXS spectra of Sr 2 IrO 4 . ( a ) The spin–orbital level scheme of the three Kramers pairs and their orbital shapes in Sr 2 IrO 4 . The three-fold degenerate orbital states of t 2g symmetry under the cubic crystal field splits into a j =1/2 doublet and a j =3/2 quartet in the presence of spin–orbit coupling. The spin–orbit entangled nature of these quantum states is illustrated with colours; orange (blue) represent spin up (down) projection. A tetragonal crystal field further splits the j =3/2 quartet into two Kramers doublets labelled as B and C; B (C) represents states with j z quantum numbers ±3/2 (±1/2). Spin–orbit exciton refers to an excitation of a hole from the j =1/2 manifold to the j =3/2 manifold. ( b ) Spectrum at q =( π /2, π /2) measured at three different X-ray incident angle ϕ of 8°, 45° and 82°, corresponding to three-dimensional q of (−3.5,3,25.5),", "role": "user" }, { "content": "(Phys.org) —When is an electron hole like a quasiparticle (QP)? More specifically, what happens when a single electron hole is doped into a two-dimensional quantum antiferromagnet? Quasiparticle phenomena in such a system are predicted by theory, but have eluded observation, complicating the understanding of electron behavior in high-temperature superconducting cuprates. A team of experimenters working at the U.S. Department of Energy's (DOE's) Advanced Photon Source at Argonne National Laboratory have taken a different approach to the problem with their recent observation of an excitonic quasiparticle in strontium iridate (Sr2IrO4), a quasi-two-dimensional, spin-1/2, antiferromagnetic Mott insulator. Their work was published in Nature Communications. Strontium iridate is a newly-discovered pseudospin-1/2 Heisenberg antiferromagnet in which superconductivity has also been predicted but not yet observed. The experimenters from Argonne National Laboratory and the Institute for Theoretical Solid State Physics and Max Planck Institute for Solid State Research (Germany) used resonant inelastic x-ray scattering (RIXS) at the X-ray Science Division 30-ID-B,C beamline of the Advanced Photon Source, a DOE Office of Science user facility. They carried out their studies utilizing the MERIX spectrometer, a medium-energy-resolution diffractometer for non-resonant and resonant inelastic x-ray scattering (RIXS) measurements of samples that had been prepared at the Argonne Materials Science Division. Earlier RIXS studies of Sr2IrO4 showed that the dispersions of an electron hole excited across spin-orbit coupling levels could be related to the QP problem. The investigators attempted to reflect the behavior of an electron hole in Sr2IrO4 by using an exciton analog. Using a theoretical model structured around the observation that the propagation of an orbital excitation through a Mott insulator such as Sr2IrO4 can be mapped on the motion of a single hole, the researchers employed a self-consistent Born approximation (SCBA) for comparison and interpretation of the RIXS data. They found an excellent agreement between the effective t-J model (used to calculate high-Tc states) calculated within the SCBA and the experimental spectra. Energy distribution curves showed a sharp exciton peak, which is both narrower than the sharpest peak measured in Sr2IrO4 by angle-resolved photoemission spectroscopy (ARPES) and smaller than the total bandwidth of about 112 meV, which reveals the exciton to be a QP. While this demonstrates that a coherent particle can propagate through a quantum antiferromagnet, it does not yet explain the lack of a QP with a single-hole excitation. The researchers attribute this to the charge-neutral nature of an exciton compared to the charged-particle character of a hole. Because a charged hole interacts much more strongly with the lattice structure and the inevitable impurities present in an insulator, it also tends to dampen or completely wash out QP phenomena, particularly in ARPES measurements. On the other hand, a charge-neutral exciton is not subject to these effects and thus can more readily reveal subtle QP dynamics that can elude experimenters. The work confirms that QPs can definitely be observed in Mott insulators and that these materials can display striking parallels with high-temperature cuprate superconductors. By showing that an exciton in a spin-1/2 antiferromagnet can display fundamentally similar dynamics to a charged hole doped into the same kind of system, the researchers have cast new light on a classic problem in condensed matter physics and opened a new pathway for the study of high-temperature superconductors. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In condensed matter systems, out of a large number of interacting degrees of freedom emerge weakly coupled quasiparticles (QPs), in terms of which most physical properties are described. The lack of identification of such QPs is a major barrier for understanding myriad exotic properties of correlated electrons, such as unconventional superconductivity and non-Fermi liquid behaviours. Here we report the observation of a composite particle in a quasi-two-dimensional spin–1/2 antiferromagnet Sr 2 IrO 4 —an exciton dressed with magnons—that propagates with the canonical characteristics of a QP: a finite QP residue and a lifetime longer than the hopping time scale. The dynamics of this charge-neutral excitation mirrors the fundamental process of the analogous one-hole propagation in the background of spins–1/2, and reveals the same intrinsic dynamics that is obscured for a single, charged-hole doped into two-dimensional cuprates. Introduction The dynamics of a single hole doped into a low-dimensional quantum antiferromagnet (AF) constitutes one of the classic unsolved problems, which has drawn much interest in the context of cuprate high-temperature superconductors 1 , 2 , 3 . In one picture, the single hole forms a coherent QP propagating in a medium of quantum-fluctuating spins, which strongly renormalizes the dispersion relations and the mutual interactions of the holes at finite doping. This spin–polaron picture is supported by numerical approaches, such as quantum Monte Carlo 4 , exact diagonalization 5 and self-consistent Born approximation (SCBA) 2 . In a contrasting picture, the notion of QP can break down due to various mechanism such as orthogonality catastrophe 6 , spin–charge separation 7 and/or localization effects 8 , reflecting the unconventional nature of two-dimensional (2D), strongly interacting fermions. To date, no evidence for a QP has been found in experiments 9 , 10 , 11 , 12 that probe the dynamics of a single hole doped into a 2D spin–1/2 quantum AFs. Motivated by the recent discovery of a new pseudospin–1/2 Heisenberg AF on a square lattice, Sr 2 IrO 4 (refs 13 , 14 , 15 , 16 , 17 , 18 ), we demonstrate a novel experimental approach using resonant inelastic X-ray scattering (RIXS), which is a rapidly evolving tool especially well suited for such 5 d transition-metal oxides, to address this longstanding problem. On the basis of its remarkable similarity to superconducting cuprates in structural 18 , electronic 13 and magnetic aspects 14 , 15 , 16 , superconductivity has been predicted in Sr 2 IrO 4 (ref. 19 ). Although the electron correlation strength in Sr 2 IrO 4 has been under much debate 20 , 21 , 22 , 23 , 24 , questioning the validity of classifying this compound as a Mott insulator, Sr 2 IrO 4 shares the same phenomenology that the hole spectral function as measured by angle-resolved photoemission spectroscopy (ARPES) lacks a legitimate QP 13 . This similarity suggests a common origin for the absence of a well-defined QP in the ARPES spectra for two distinct but similar classes of materials. As we shall see, however, Sr 2 IrO 4 supports a well-defined QP in another excitation channel, which RIXS is sensitive to and reflects the same dynamics as that of a hole, offering a novel route to studying elementary excitations in correlated oxides. In an earlier RIXS study of Sr 2 IrO 4 , excitations of a hole across the spin–orbit coupling split levels (from the j =1/2 manifold to the j =3/2 manifold) have been identified and it has been shown that their dispersions can be understood in close analogy to the single-hole problem 16 . Figure 1 depicts the hole-versus-exciton analogy: a ‘foreign’ object injected into a quantum Heisenberg AF, be it a hole or an exciton, creates a string of flipped spins along its hopping path. This analogy, in principle, suggests that the dynamics of a particle moving in a magnetic medium can also be studied using the exciton. However, the energy resolution of RIXS used in the earlier study (≈130 meV) was insufficient to resolve the dispersion and the intrinsic linewidth of the two-exciton modes associated with the two pairs of Kramers doublets in the j =3/2 manifold ( Fig. 2a ). Here we exploit the different orbital symmetries of the two-exciton modes to selectively probe each mode, and with the much improved energy resolution (≈30 meV) offered by RIXS after recent developments, reveal their full dynamics. Figure 1: Hole versus exciton propagation in an antiferromagnetic background. ( a ) A moving hole (blue square) leaves a string of excited spins behind; that is, every hopping motion of the hole generates a flipping of a spin relative to the ground state configuration. Black wavy lines indicate pairs of ‘misaligned’ spins. ( b ) An analogous exciton hopping. While the nature of the spin–orbit exciton (charge-neutral object) and the hole (charged particle) is quite different, they share in common that their hopping creates a string of flipped spins (or isospins in the case of exciton). See Fig. 2 for the description of the isospins and the spin–orbit excitons. Full size image Figure 2: RIXS spectra of Sr 2 IrO 4 . ( a ) The spin–orbital level scheme of the three Kramers pairs and their orbital shapes in Sr 2 IrO 4 . The three-fold degenerate orbital states of t 2g symmetry under the cubic crystal field splits into a j =1/2 doublet and a j =3/2 quartet in the presence of spin–orbit coupling. The spin–orbit entangled nature of these quantum states is illustrated with colours; orange (blue) represent spin up (down) projection. A tetragonal crystal field further splits the j =3/2 quartet into two Kramers doublets labelled as B and C; B (C) represents states with j z quantum numbers ±3/2 (±1/2). Spin–orbit exciton refers to an excitation of a hole from the j =1/2 manifold to the j =3/2 manifold. ( b ) Spectrum at q =( π /2, π /2) measured at three different X-ray incident angle ϕ of 8°, 45° and 82°, corresponding to three-dimensional q of (−3.5,3,25.5),<|im_end|> <|im_start|>assistant (Phys.org) —When is an electron hole like a quasiparticle (QP)? More specifically, what happens when a single electron hole is doped into a two-dimensional quantum antiferromagnet? Quasiparticle phenomena in such a system are predicted by theory, but have eluded observation, complicating the understanding of electron behavior in high-temperature superconducting cuprates. A team of experimenters working at the U.S. Department of Energy's (DOE's) Advanced Photon Source at Argonne National Laboratory have taken a different approach to the problem with their recent observation of an excitonic quasiparticle in strontium iridate (Sr2IrO4), a quasi-two-dimensional, spin-1/2, antiferromagnetic Mott insulator. Their work was published in Nature Communications. Strontium iridate is a newly-discovered pseudospin-1/2 Heisenberg antiferromagnet in which superconductivity has also been predicted but not yet observed. The experimenters from Argonne National Laboratory and the Institute for Theoretical Solid State Physics and Max Planck Institute for Solid State Research (Germany) used resonant inelastic x-ray scattering (RIXS) at the X-ray Science Division 30-ID-B,C beamline of the Advanced Photon Source, a DOE Office of Science user facility. They carried out their studies utilizing the MERIX spectrometer, a medium-energy-resolution diffractometer for non-resonant and resonant inelastic x-ray scattering (RIXS) measurements of samples that had been prepared at the Argonne Materials Science Division. Earlier RIXS studies of Sr2IrO4 showed that the dispersions of an electron hole excited across spin-orbit coupling levels could be related to the QP problem. The investigators attempted to reflect the behavior of an electron hole in Sr2IrO4 by using an exciton analog. Using a theoretical model structured around the observation that the propagation of an orbital excitation through a Mott insulator such as Sr2IrO4 can be mapped on the motion of a single hole, the researchers employed a self-consistent Born approximation (SCBA) for comparison and interpretation of the RIXS data. They found an excellent agreement between the effective t-J model (used to calculate high-Tc states) calculated within the SCBA and the experimental spectra. Energy distribution curves showed a sharp exciton peak, which is both narrower than the sharpest peak measured in Sr2IrO4 by angle-resolved photoemission spectroscopy (ARPES) and smaller than the total bandwidth of about 112 meV, which reveals the exciton to be a QP. While this demonstrates that a coherent particle can propagate through a quantum antiferromagnet, it does not yet explain the lack of a QP with a single-hole excitation. The researchers attribute this to the charge-neutral nature of an exciton compared to the charged-particle character of a hole. Because a charged hole interacts much more strongly with the lattice structure and the inevitable impurities present in an insulator, it also tends to dampen or completely wash out QP phenomena, particularly in ARPES measurements. On the other hand, a charge-neutral exciton is not subject to these effects and thus can more readily reveal subtle QP dynamics that can elude experimenters. The work confirms that QPs can definitely be observed in Mott insulators and that these materials can display striking parallels with high-temperature cuprate superconductors. By showing that an exciton in a spin-1/2 antiferromagnet can display fundamentally similar dynamics to a charged hole doped into the same kind of system, the researchers have cast new light on a classic problem in condensed matter physics and opened a new pathway for the study of high-temperature superconductors. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Coral growth anomalies (GAs) are tumor-like protrusions that are detrimental to coral health, affecting both the coral skeleton and soft tissues. These lesions are increasingly found throughout the tropics and are commonly associated with high human population density, yet little is known about the molecular pathology of the disease. Here, we investigate the metabolic impacts of GAs through 1 H nuclear magnetic resonance (NMR) metabolomics in Porites compressa tissues from a site of high disease prevalence (Coconut Island, Hawaii). We putatively identified 18 metabolites (8.1% of total annotated features) through complementary 1 H and 1 H– 13 C heteronuclear single quantum correlation NMR data that increase confidence in pathway analyses and may bolster future coral metabolite annotation efforts. Extract yield was elevated in both GA and unaffected (normal tissue from a diseased colony) compared to reference (normal tissue from GA-free colony) samples, potentially indicating elevated metabolic activity in GA-impacted colonies. Relatively high variation in metabolomic profiles among coral samples of the same treatment (i.e., inter-colony variation) confounded data interpretation, however, analyses of paired GA and unaffected samples identified 73 features that differed between these respective metabolome types. These features were largely annotated as unknowns, but 1-methylnicotinamide and trigonelline were found to be elevated in GA samples, while betaine, glycine, and histamine were lower in GA samples. Pathway analyses indicate decreased choline oxidation in GA samples, making this a pathway of interest for future targeted studies. Collectively, our results provide unique insights into GA pathophysiology by showing these lesions alter both the absolute and relative metabolism of affected colonies and by identifying features (metabolites and unknowns) and metabolic pathways of interest in GA pathophysiology going forward. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Coral reefs contain a disproportionately large amount of the ocean’s biodiversity and productivity, making them one of the most ecologically and economically important ecosystems in the world (Odum and Odum 1955 ; Moberg and Folke 1999 ). Nonetheless, the status of these ecosystems has declined in recent decades due to a combination of local and global challenges (Hughes et al. 2017 ). Increasing atmospheric carbon dioxide levels pose a ubiquitous threat to coral reefs due to the associated increase in oceanic temperatures and ocean acidification (Hoegh-Guldberg et al. 2007 ), while chemical pollution, eutrophication, fishing pressure, and other localized stressors also contribute to coral reef degradation (Knowlton 2001 ; van Dam et al. 2011 ). Coral disease occurrence is commonly linked to human activity (Green and Bruckner 2000 ) and is influenced by both local and global stressors, which may shift host–pathogen interactions in favor of disease (Lesser et al. 2007 ; Burge et al. 2014 ). Disease outbreaks can devastate impacted coral populations (e.g., Aronson and Precht 2001 ), and the rising prevalence and impact of coral diseases make them a substantial threat to coral reef health worldwide (Bruckner 2016 ). Coral diseases often share similar visual indicators, and any given disease may not originate from a single causative agent, thus complicating efforts to define disease pathology (Work and Aeby 2006 ; Lesser et al. 2007 ). However, emerging molecular techniques have the potential to improve diagnostic ability by investigating new aspects of coral biology as well as disease pathophysiology and etiology (Pollock et al. 2011 ). Coral growth anomalies (GAs) are generally characterized by irregular and accelerated growth of a less dense skeleton resulting in a tumor-like mass on a coral colony, with overlying tissues having fewer polyps, fewer endosymbiotic dinoflagellates (family Symbiodiniaceae), and reduced reproductive potential (Work et al. 2016 ). Histological descriptions of GAs have shown irregular polyp structure, thickened calicoblatic layer, and increased cell proliferation with suppressed apoptosis (Domart-Coulon et al. 2006 ; Yasuda and Hidaka 2012 ). These lesions affect many coral species and are common across the Indo-Pacific but less common in the Caribbean (Work et al. 2016 ). GAs do not typically lead directly to coral mortality, but their abnormal characteristics lower the fitness of impacted colonies and they therefore pose an ecological threat to coral populations where prevalence is high (Stimson 2011 ). Although the biological and ecological impacts of these lesions have been studied using a wide range of methods (e.g., Domart-Coulon et al. 2006 ; Burns and Takabayashi 2011 ; Kelly et al. 2016 ; Palmer and Baird 2018 ; Preston and Richards 2021 ), the cause and pathogenesis of GAs remain unknown. Early theorized causes include ultraviolet radiation (Coles and Seapy 1998 ; Stimson 2011 ) and pathogenic microorganisms (Kaczmarsky and Richardson 2007 ). More recent molecular investigations have produced contradictory results regarding the involvement of oncogenes in GA pathology (Spies and Takabayashi 2013 ; Zhang et al. 2017 ; Frazier et al. 2017 ). To date, conclusive evidence to support any of these hypotheses is lacking; however, the correlation between human population and GA prevalence (Aeby et al. 2011a , 2011b ) strongly indicates localized human activities influence GA formation. The development of molecular biology–omics techniques has facilitated the investigation of biological questions that were previously inaccessible (Joyce and Palsson 2006 ), and these techniques have recently emerged to supplement more traditional approaches in attempting to determine disease causative agents (Madsen 2005 ). One such molecular tool is metabolomics, a developing field dedicated to the study of low-molecular-weight compounds (here we refer specifically to the water-soluble polar metabolites) in biological samples under predetermined physiological conditions. These compounds are essential products and intermediates in biochemical pathways that fluctuate with gene expression and enzymatic activities, making the metabolome closely tied to the biochemical phenotype and thus excellent for closely monitoring organismal response to perturbations such as disease (Goodacre 2007 ; Viant 2008 ; Bundy et al. 2009 ). Targeted approaches are generally used in cases where specific, predetermined metabolites are of particular interest (Roberts et al. 2012 ). In other cases, an untargeted approach is common, where as many metabolites as possible are measured and biological interpretations are made based on the composition", "role": "user" }, { "content": "Coral reefs are a favorite spot for scuba divers and are among the world's most diverse ecosystems. For example, the Hawaiian coral reefs, known as the 'rainforests of the sea', host over 7,000 species of marine animals, fishes, birds and plants. But coral reefs are facing serious threats, including a number of diseases that have been linked to human activity. To understand the connection between human activity and a type of tumorlike disease called growth anomalies (GAs), researchers at the National Institute of Standards and Technology (NIST) have collaborated with the U.S Geological Survey (USGS) and the National Oceanic and Atmospheric Administration (NOAA) to use an emerging molecular profiling method to identify 18 small molecules that promise to help them better understand the series of molecular reactions that lead to the disease. GAs affect both the coral skeleton and its soft tissues. Scientists don't know the cause of the disease or how it spreads but have hypothesized that there is a strong correlation between GA prevalence in coral colonies and human population density nearby. Almost all types of corals are made of hundreds to millions of individual soft-bodied animals called polyps. The polyps secrete calcium carbonate to form a hard skeleton that lays the foundation for the coral colony. GAs affect corals through irregular and accelerated growth of their skeleton, causing it to be less dense and filled with holes. This results in a tumorlike mass in the skeleton of a coral colony with fewer polyps and a diminished ability to reproduce. Shallow water corals receive food like carbohydrates and oxygen as a byproduct of photosynthesis from the symbiotic relationship they have with zooxanthellae, photosynthetic algae that live inside coral tissues. GAs can lead to fewer symbiotic zooxanthellae and therefore less energy being absorbed from photosynthesis. Even though GAs do not typically directly lead to coral death, they do affect the overall health of coral colonies and can pose an ecological threat to coral populations. To analyze the disease, NIST researchers chose the coral species Porites compressa as their target sample. This coral species is known as the 'finger' or 'hump' coral and is part of the stony coral family, which is \"one of the important reef-building species in Hawaii,\" said NIST chemist Tracey Schock. \"They lay the foundation for the coral reef.\" P. compressa is found in shallow lagoons off the Hawaiian Islands, and the researchers obtained their coral samples from Kaneohe Bay, Oahu. The bay has been studied widely as a site affected by human activity such as sewage discharge and metal pollution. GAs have previously been observed in the coral species there. In order to analyze and study GAs in P. compressa, researchers turned to the field of metabolomics, which is the study of small molecules, such as those making up living organisms found in tissues, blood or urine. These small molecules, known as metabolites, are the intermediate and end products in a linked series of biochemical reactions known as molecular pathways in an organism. Some examples of such small molecules include sugars like glucose, amino acids, lipids and fatty acids. Their production can be influenced by genetic and environmental factors and can help researchers better understand the biochemical activity of tissue or cells. In this case, chemical analysis of metabolites provides significant information that helps researchers understand the physiology of the disease. Two different field images depicting the coral species Porites compressa, a reef building coral off of the coast of Hawaii. The corals are affected by growth anomalies (GAs), a disease that can cause tumor-like protrusions that affect both the coral skeleton and its soft tissue. The GAs are the \"larger protrusions\" on the corals. Credit: R. Day/NIST For their study, researchers sampled a coral colony that had both healthy and diseased tissue. They split up their samples so they could assess the healthy coral and diseased coral separately. They also had a separate adjacent sample that was free of diseased tissue. The samples were frozen in liquid nitrogen, and then freeze-dried for practical sample processing while maintaining metabolic integrity. The researchers then separated the diseased parts from the healthy colony using a hammer and stainless-steel chisel and collected the tissue from the skeleton with a brush. In one of the final stages of the sample preparation, they chemically extracted the metabolites from the coral tissue using a combination of methanol, water and chloroform. \"The method is novel for coral studies,\" said Schock. \"With metabolomics, it is critical to preserve the state of all metabolites in a sample at the time of collection. This requires halting all biochemical activity using liquid nitrogen and maintaining this state until chemical extraction of the metabolome. The complexity of a coral structure necessitates stringent collection and processing protocols.\" The researchers then produced a metabolomic analysis of the coral samples by using a reproducible profiling technique known as proton nuclear magnetic resonance (1H NMR). The 1H NMR technique exposes the coral extract to electromagnetic fields and measures the radio frequency signals released by the hydrogens in the sample. The various kinds of metabolites are revealed by their unique signals which inform of their chemical environment. NMR detects all signals from the magnetic nuclei within a sample, making it an unbiased \"all-in-one\" technique. Two-dimensional NMR experiments that can identify both hydrogens (1H) and their directly bound carbon (13C) atoms provide more chemical information, giving confidence in the accuracy of the identities of the various metabolites within a sample. The study identified 18 different metabolites and a new GA morphological form in P. compressa. The researchers found that GA tumors have distinct metabolite profiles compared with healthy areas of the same coral colony and detected specific metabolites and metabolic pathways that may be important for these profile differences. They also discovered that the loss of internal pH regulation is seemingly responsible for the hollow skeletons that are a characteristic of GAs. \"We have not only characterized new aspects of GA physiology, but have also discovered candidate pathways that provide a clear path forward for future research efforts aiming to further understand GA formation and coral metabolism, in general,\" said Schock. As studies of this type accumulate, the researchers envision a database that could pull together coral metabolite information from multiple coral species into an accessible location for all scientists. Collaborating with other researchers in different fields could increase understanding of the biological impacts of this disease on coral colonies. \"We are going to learn which species are tolerant and which species are sensitive to stresses, and the physiological adaptations or mechanisms of both types will be important to conservation efforts,\" said Schock. For now, the researchers hope these findings will be helpful for other scientists analyzing coral species and ultimately be beneficial for the coral reefs themselves, potentially aiding efforts to better preserve them. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Coral growth anomalies (GAs) are tumor-like protrusions that are detrimental to coral health, affecting both the coral skeleton and soft tissues. These lesions are increasingly found throughout the tropics and are commonly associated with high human population density, yet little is known about the molecular pathology of the disease. Here, we investigate the metabolic impacts of GAs through 1 H nuclear magnetic resonance (NMR) metabolomics in Porites compressa tissues from a site of high disease prevalence (Coconut Island, Hawaii). We putatively identified 18 metabolites (8.1% of total annotated features) through complementary 1 H and 1 H– 13 C heteronuclear single quantum correlation NMR data that increase confidence in pathway analyses and may bolster future coral metabolite annotation efforts. Extract yield was elevated in both GA and unaffected (normal tissue from a diseased colony) compared to reference (normal tissue from GA-free colony) samples, potentially indicating elevated metabolic activity in GA-impacted colonies. Relatively high variation in metabolomic profiles among coral samples of the same treatment (i.e., inter-colony variation) confounded data interpretation, however, analyses of paired GA and unaffected samples identified 73 features that differed between these respective metabolome types. These features were largely annotated as unknowns, but 1-methylnicotinamide and trigonelline were found to be elevated in GA samples, while betaine, glycine, and histamine were lower in GA samples. Pathway analyses indicate decreased choline oxidation in GA samples, making this a pathway of interest for future targeted studies. Collectively, our results provide unique insights into GA pathophysiology by showing these lesions alter both the absolute and relative metabolism of affected colonies and by identifying features (metabolites and unknowns) and metabolic pathways of interest in GA pathophysiology going forward. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Coral reefs contain a disproportionately large amount of the ocean’s biodiversity and productivity, making them one of the most ecologically and economically important ecosystems in the world (Odum and Odum 1955 ; Moberg and Folke 1999 ). Nonetheless, the status of these ecosystems has declined in recent decades due to a combination of local and global challenges (Hughes et al. 2017 ). Increasing atmospheric carbon dioxide levels pose a ubiquitous threat to coral reefs due to the associated increase in oceanic temperatures and ocean acidification (Hoegh-Guldberg et al. 2007 ), while chemical pollution, eutrophication, fishing pressure, and other localized stressors also contribute to coral reef degradation (Knowlton 2001 ; van Dam et al. 2011 ). Coral disease occurrence is commonly linked to human activity (Green and Bruckner 2000 ) and is influenced by both local and global stressors, which may shift host–pathogen interactions in favor of disease (Lesser et al. 2007 ; Burge et al. 2014 ). Disease outbreaks can devastate impacted coral populations (e.g., Aronson and Precht 2001 ), and the rising prevalence and impact of coral diseases make them a substantial threat to coral reef health worldwide (Bruckner 2016 ). Coral diseases often share similar visual indicators, and any given disease may not originate from a single causative agent, thus complicating efforts to define disease pathology (Work and Aeby 2006 ; Lesser et al. 2007 ). However, emerging molecular techniques have the potential to improve diagnostic ability by investigating new aspects of coral biology as well as disease pathophysiology and etiology (Pollock et al. 2011 ). Coral growth anomalies (GAs) are generally characterized by irregular and accelerated growth of a less dense skeleton resulting in a tumor-like mass on a coral colony, with overlying tissues having fewer polyps, fewer endosymbiotic dinoflagellates (family Symbiodiniaceae), and reduced reproductive potential (Work et al. 2016 ). Histological descriptions of GAs have shown irregular polyp structure, thickened calicoblatic layer, and increased cell proliferation with suppressed apoptosis (Domart-Coulon et al. 2006 ; Yasuda and Hidaka 2012 ). These lesions affect many coral species and are common across the Indo-Pacific but less common in the Caribbean (Work et al. 2016 ). GAs do not typically lead directly to coral mortality, but their abnormal characteristics lower the fitness of impacted colonies and they therefore pose an ecological threat to coral populations where prevalence is high (Stimson 2011 ). Although the biological and ecological impacts of these lesions have been studied using a wide range of methods (e.g., Domart-Coulon et al. 2006 ; Burns and Takabayashi 2011 ; Kelly et al. 2016 ; Palmer and Baird 2018 ; Preston and Richards 2021 ), the cause and pathogenesis of GAs remain unknown. Early theorized causes include ultraviolet radiation (Coles and Seapy 1998 ; Stimson 2011 ) and pathogenic microorganisms (Kaczmarsky and Richardson 2007 ). More recent molecular investigations have produced contradictory results regarding the involvement of oncogenes in GA pathology (Spies and Takabayashi 2013 ; Zhang et al. 2017 ; Frazier et al. 2017 ). To date, conclusive evidence to support any of these hypotheses is lacking; however, the correlation between human population and GA prevalence (Aeby et al. 2011a , 2011b ) strongly indicates localized human activities influence GA formation. The development of molecular biology–omics techniques has facilitated the investigation of biological questions that were previously inaccessible (Joyce and Palsson 2006 ), and these techniques have recently emerged to supplement more traditional approaches in attempting to determine disease causative agents (Madsen 2005 ). One such molecular tool is metabolomics, a developing field dedicated to the study of low-molecular-weight compounds (here we refer specifically to the water-soluble polar metabolites) in biological samples under predetermined physiological conditions. These compounds are essential products and intermediates in biochemical pathways that fluctuate with gene expression and enzymatic activities, making the metabolome closely tied to the biochemical phenotype and thus excellent for closely monitoring organismal response to perturbations such as disease (Goodacre 2007 ; Viant 2008 ; Bundy et al. 2009 ). Targeted approaches are generally used in cases where specific, predetermined metabolites are of particular interest (Roberts et al. 2012 ). In other cases, an untargeted approach is common, where as many metabolites as possible are measured and biological interpretations are made based on the composition<|im_end|> <|im_start|>assistant Coral reefs are a favorite spot for scuba divers and are among the world's most diverse ecosystems. For example, the Hawaiian coral reefs, known as the 'rainforests of the sea', host over 7,000 species of marine animals, fishes, birds and plants. But coral reefs are facing serious threats, including a number of diseases that have been linked to human activity. To understand the connection between human activity and a type of tumorlike disease called growth anomalies (GAs), researchers at the National Institute of Standards and Technology (NIST) have collaborated with the U.S Geological Survey (USGS) and the National Oceanic and Atmospheric Administration (NOAA) to use an emerging molecular profiling method to identify 18 small molecules that promise to help them better understand the series of molecular reactions that lead to the disease. GAs affect both the coral skeleton and its soft tissues. Scientists don't know the cause of the disease or how it spreads but have hypothesized that there is a strong correlation between GA prevalence in coral colonies and human population density nearby. Almost all types of corals are made of hundreds to millions of individual soft-bodied animals called polyps. The polyps secrete calcium carbonate to form a hard skeleton that lays the foundation for the coral colony. GAs affect corals through irregular and accelerated growth of their skeleton, causing it to be less dense and filled with holes. This results in a tumorlike mass in the skeleton of a coral colony with fewer polyps and a diminished ability to reproduce. Shallow water corals receive food like carbohydrates and oxygen as a byproduct of photosynthesis from the symbiotic relationship they have with zooxanthellae, photosynthetic algae that live inside coral tissues. GAs can lead to fewer symbiotic zooxanthellae and therefore less energy being absorbed from photosynthesis. Even though GAs do not typically directly lead to coral death, they do affect the overall health of coral colonies and can pose an ecological threat to coral populations. To analyze the disease, NIST researchers chose the coral species Porites compressa as their target sample. This coral species is known as the 'finger' or 'hump' coral and is part of the stony coral family, which is "one of the important reef-building species in Hawaii," said NIST chemist Tracey Schock. "They lay the foundation for the coral reef." P. compressa is found in shallow lagoons off the Hawaiian Islands, and the researchers obtained their coral samples from Kaneohe Bay, Oahu. The bay has been studied widely as a site affected by human activity such as sewage discharge and metal pollution. GAs have previously been observed in the coral species there. In order to analyze and study GAs in P. compressa, researchers turned to the field of metabolomics, which is the study of small molecules, such as those making up living organisms found in tissues, blood or urine. These small molecules, known as metabolites, are the intermediate and end products in a linked series of biochemical reactions known as molecular pathways in an organism. Some examples of such small molecules include sugars like glucose, amino acids, lipids and fatty acids. Their production can be influenced by genetic and environmental factors and can help researchers better understand the biochemical activity of tissue or cells. In this case, chemical analysis of metabolites provides significant information that helps researchers understand the physiology of the disease. Two different field images depicting the coral species Porites compressa, a reef building coral off of the coast of Hawaii. The corals are affected by growth anomalies (GAs), a disease that can cause tumor-like protrusions that affect both the coral skeleton and its soft tissue. The GAs are the "larger protrusions" on the corals. Credit: R. Day/NIST For their study, researchers sampled a coral colony that had both healthy and diseased tissue. They split up their samples so they could assess the healthy coral and diseased coral separately. They also had a separate adjacent sample that was free of diseased tissue. The samples were frozen in liquid nitrogen, and then freeze-dried for practical sample processing while maintaining metabolic integrity. The researchers then separated the diseased parts from the healthy colony using a hammer and stainless-steel chisel and collected the tissue from the skeleton with a brush. In one of the final stages of the sample preparation, they chemically extracted the metabolites from the coral tissue using a combination of methanol, water and chloroform. "The method is novel for coral studies," said Schock. "With metabolomics, it is critical to preserve the state of all metabolites in a sample at the time of collection. This requires halting all biochemical activity using liquid nitrogen and maintaining this state until chemical extraction of the metabolome. The complexity of a coral structure necessitates stringent collection and processing protocols." The researchers then produced a metabolomic analysis of the coral samples by using a reproducible profiling technique known as proton nuclear magnetic resonance (1H NMR). The 1H NMR technique exposes the coral extract to electromagnetic fields and measures the radio frequency signals released by the hydrogens in the sample. The various kinds of metabolites are revealed by their unique signals which inform of their chemical environment. NMR detects all signals from the magnetic nuclei within a sample, making it an unbiased "all-in-one" technique. Two-dimensional NMR experiments that can identify both hydrogens (1H) and their directly bound carbon (13C) atoms provide more chemical information, giving confidence in the accuracy of the identities of the various metabolites within a sample. The study identified 18 different metabolites and a new GA morphological form in P. compressa. The researchers found that GA tumors have distinct metabolite profiles compared with healthy areas of the same coral colony and detected specific metabolites and metabolic pathways that may be important for these profile differences. They also discovered that the loss of internal pH regulation is seemingly responsible for the hollow skeletons that are a characteristic of GAs. "We have not only characterized new aspects of GA physiology, but have also discovered candidate pathways that provide a clear path forward for future research efforts aiming to further understand GA formation and coral metabolism, in general," said Schock. As studies of this type accumulate, the researchers envision a database that could pull together coral metabolite information from multiple coral species into an accessible location for all scientists. Collaborating with other researchers in different fields could increase understanding of the biological impacts of this disease on coral colonies. "We are going to learn which species are tolerant and which species are sensitive to stresses, and the physiological adaptations or mechanisms of both types will be important to conservation efforts," said Schock. For now, the researchers hope these findings will be helpful for other scientists analyzing coral species and ultimately be beneficial for the coral reefs themselves, potentially aiding efforts to better preserve them. <|im_end|>

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292, 323, 87597, 17128, 320, 9173, 6157, 8, 311, 1005, 459, 24084, 31206, 56186, 1749, 311, 10765, 220, 972, 2678, 35715, 430, 11471, 311, 1520, 1124, 2731, 3619, 279, 4101, 315, 31206, 25481, 430, 3063, 311, 279, 8624, 13, 480, 2170, 7958, 2225, 279, 53103, 30535, 323, 1202, 8579, 39881, 13, 57116, 1541, 956, 1440, 279, 5353, 315, 279, 8624, 477, 1268, 433, 43653, 719, 617, 22601, 83979, 430, 1070, 374, 264, 3831, 26670, 1990, 27438, 38009, 304, 53103, 49028, 323, 3823, 7187, 17915, 14373, 13, 35403, 682, 4595, 315, 1867, 1147, 527, 1903, 315, 11758, 311, 11990, 315, 3927, 8579, 97397, 10099, 2663, 1499, 76299, 13, 578, 1499, 76299, 513, 9537, 35719, 84443, 311, 1376, 264, 2653, 30535, 430, 57622, 279, 16665, 369, 279, 53103, 42036, 13, 480, 2170, 7958, 1867, 1147, 1555, 42408, 323, 49858, 6650, 315, 872, 30535, 11, 14718, 433, 311, 387, 2753, 29050, 323, 10409, 449, 20349, 13, 1115, 3135, 304, 264, 36254, 4908, 3148, 304, 279, 30535, 315, 264, 53103, 42036, 449, 17162, 1499, 76299, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The solid–electrolyte interphase (SEI), a layer formed on the electrode surface, is essential for electrochemical reactions in batteries and critically governs the battery stability. Active materials, especially those with extremely high energy density, such as silicon (Si), often inevitably undergo a large volume swing upon ion insertion and extraction, raising a critical question as to how the SEI interactively responds to and evolves with the material and consequently controls the cycling stability of the battery. Here, by integrating sensitive elemental tomography, an advanced algorithm and cryogenic scanning transmission electron microscopy, we unveil, in three dimensions, a correlated structural and chemical evolution of Si and SEI. Corroborated with a chemomechanical model, we demonstrate progressive electrolyte permeation and SEI growth along the percolation channel of the nanovoids due to vacancy injection and condensation during the delithiation process. Consequently, the Si–SEI spatial configuration evolves from the classic ‘core–shell’ structure in the first few cycles to a ‘plum-pudding’ structure following extended cycling, featuring the engulfing of Si domains by the SEI, which leads to the disruption of electron conduction pathways and formation of dead Si, contributing to capacity loss. The spatially coupled interactive evolution model of SEI and active materials, in principle, applies to a broad class of high-capacity electrode materials, leading to a critical insight for remedying the fading of high-capacity electrodes. Main It has been almost two decades since the lithium-ion battery brought us the rechargeable world. The megatrend of electrification of our society, including the demand to power long-range electric vehicles, intelligent robots and powerful portable electronics and to improve the resiliency and reliability of electrical grids, has put continuous requirements on next-generation Li-ion batteries. Integration of new electrode materials, in terms of cycling stability, is often dictated by interaction between the materials and the associated working environment, which is manifested by an interlayer between the active material and the electrolyte 1 , 2 , that is, the SEI. Nevertheless, the understanding of how the SEI evolves during cycling and leads to capacity fading remains conjectural. For instance, due to its high gravimetric capacity, low voltage window (~0.01–1 V versus a Li/Li + electrode), low price and natural abundance, Si has been perceived by both the scientific community and industries as the most promising high-capacity anode material for practical application in next-generation Li-ion batteries 3 , 4 . Tremendous ingenious nanoscale engineering concepts have emerged in the past decade 5 , 6 , 7 , 8 , intending to tackle the barrier associated with the volume expansion of Si and consequently mitigating the capacity fading of Si-based anode materials 2 , 4 , 9 , 10 , 11 . However, large-scale application of Si as an anode for Li-ion batteries remains a challenge and requires a clear understanding of the underlying fading mechanism of the nanosized Si (refs. 4 , 5 , 12 ). It is generally conjectured that the capacity fading of Si originates in the intrinsic large volume changes and ensuing accumulation of the SEI with repeated cycling, as commonly anticipated for this class of materials. Typically, the volume change will lead to cracking of Si (ref. 13 ); crumpling, regeneration and accumulative growth of the SEI; and attendant loss of electrical contact 3 , 14 . This view appears to be self-consistent for explaining the capacity fading of Si with sizes larger than a critical dimension of typically 150 nm, but fails in reconciliation with the capacity fading of nanosized Si (refs. 3 , 15 ), wherein the material cracking issue is effectively attenuated by the reduced particle size 3 , 16 , 17 . Electrode-level failure aside 18 , the capacity fading of nanosized Si has been related, more or less hypothetically, to the thickening of the SEI layer on the material surface 2 , 19 , 20 , 21 , progressive loss of active materials such as Si and Li (refs. 22 , 23 ) and electrochemical–mechanical degradation 24 . However, key experimental evidence is still lacking on the dynamic evolution of SEI, both structural and chemical, in response to the large volume swing of electrodes during cycling. Current direct observations of the SEI are largely based on the two-dimensional projection imaging and energy dispersive X-ray spectroscopy (EDS) mapping of elements 20 , 25 , which are unable to correlate with the three-dimensional (3D) structural evolution of the nanosized Si. Electron tomography is a technique that retrieves the 3D structural information of nanoscale objects from a tilt series of two-dimensional projections 26 , a technique that has been pushed to image materials at the atomic level in three dimensions 27 . However, electron tomography on cycled electrode materials has been challenging due to the severe damage from the high electron dose necessary for electron tomography imaging. Inspired by the studies of structural biology 28 and cryogenic transmission electron microscopy (cryo-TEM) for Li dendrites 29 , 30 , we hold the sample at cryogenic temperature during preparation and imaging to minimize the sample damage from air and the imaging beam. Additionally, we employ an advanced reconstruction algorithm that enables capturing the tomography tilt series with a further reduced electron dose. These approaches preserve the lightweight materials encompassed by the SEI for the high-resolution electron tomography imaging of both the structure and chemical compositions, as detailed in the Methods . Herein, we integrate advanced EDS tomography, cryogenic scanning transmission electron microscopy (cryo-STEM) and chemomechanical modelling to show, explicitly in three dimensions, the correlated structural and chemical evolution of the SEI and Si. Specifically, we discover the progressive growth of the SEI towards the Si interior as the Si nanowires become porous with cycling. As such, the otherwise pure Si eventually evolves into a mixture of Si and SEI with a ‘plum-pudding’ structure. We reveal that the origin of such a structural evolution is rooted in the formation of voids due to vacancy condensation during the delithiation process. This discovery unravels beyond the fading mechanisms associated with the large volume change of Si—the intrinsic fading mechanism of the", "role": "user" }, { "content": "Silicon is a staple of the digital revolution, shunting loads of signals on a device that's likely just inches from your eyes at this very moment. Now, that same plentiful, cheap material is becoming a serious candidate for a big role in the burgeoning battery business. It's especially attractive because it's able to hold 10 times as much energy in an important part of a battery, the anode, than widely used graphite. But not so fast. While silicon has a swell reputation among scientists, the material itself swells when it's part of a battery. It swells so much that the anode flakes and cracks, causing the battery to lose its ability to hold a charge and ultimately to fail. Now scientists have witnessed the process for the first time, an important step toward making silicon a viable choice that could improve the cost, performance and charging speed of batteries for electric vehicles as well as cell phones, laptops, smart watches and other gadgets. \"Many people have imagined what might be happening but no one had actually demonstrated it before,\" said Chongmin Wang, a scientist at the Department of Energy's Pacific Northwest National Laboratory. Wang is a corresponding author of the paper recently published in Nature Nanotechnology. Of silicon anodes, peanut butter cups and packed airline passengers Lithium ions are the energy currency in a lithium-ion battery, traveling back and forth between two electrodes through liquid called electrolyte. When lithium ions enter an anode made of silicon, they muscle their way into the orderly structure, pushing the silicon atoms askew, like a stout airline passenger squeezing into the middle seat on a packed flight. This \"lithium squeeze\" makes the anode swell to three or four times its original size. When the lithium ions depart, things don't return to normal. Empty spaces known as vacancies remain. Displaced silicon atoms fill in many, but not all, of the vacancies, like passengers quickly taking back the empty space when the middle passenger heads for the restroom. But the lithium ions return, pushing their way in again. The process repeats as the lithium ions scoot back and forth between the anode and cathode, and the empty spaces in the silicon anode merge to form voids or gaps. These gaps translate to battery failure. Scientists have known about the process for years, but they hadn't before witnessed precisely how it results in battery failure. Some have attributed the failure to the loss of silicon and lithium. Others have blamed the thickening of a key component known as the solid-electrolyte interphase or SEI. The SEI is a delicate structure at the edge of the anode that is an important gateway between the anode and the liquid electrolyte. In its experiments, the team watched as the vacancies left by lithium ions in the silicon anode evolved into larger and larger gaps. Then they watched as the liquid electrolyte flowed into the gaps like tiny rivulets along a shoreline, infiltrating the silicon. This inflow allowed the SEI to develop in areas within the silicon where it shouldn't be, a molecular invader in a part of the battery where it doesn't belong. That created dead zones, destroying the ability of the silicon to store lithium and ruining the anode. Think of a peanut butter cup in pristine shape: The chocolate outside is distinct from the soft peanut butter inside. But if you hold it in your hand too long with too tight a grip, the outer shell softens and mixes with the soft chocolate inside. You're left with a single disordered mass whose structure is changed irreversibly. You no longer have a true peanut butter cup. Likewise, after the electrolyte and the SEI infiltrate the silicon, scientists no longer have a workable anode. A silicon anode after 100 cycles: The anode is barely recognizable as a silicon structure and is instead a mix of the silicon (green) and the fluorine (red) from the solid electrolyte interphase. Credit: Chongmin Wang | Pacific Northwest National Laboratory The team witnessed this process begin immediately after just one battery cycle. After 36 cycles, the battery's ability to hold a charge had fallen dramatically. After 100 cycles, the anode was ruined. Exploring the promise of silicon anodes Scientists are working on ways to protect the silicon from the electrolyte. Several groups, including scientists at PNNL, are developing coatings designed to act as gatekeepers, allowing lithium ions to go into and out of the anode while stopping other components of the electrolyte. Scientists from several institutions pooled their expertise to do the work. Scientists at Los Alamos National Laboratory created the silicon nanowires used in the study. PNNL scientists worked together with counterparts at Thermo Fisher Scientific to modify a cryogenic transmission electron microscope to reduce the damage from the electrons used for imaging. And Penn State University scientists developed an algorithm to simulate the molecular action between the liquid and the silicon. Altogether, the team used electrons to make ultra-high-resolution images of the process and then reconstructed the images in 3-D, similar to how physicians create a 3-D image of a patient's limb or organ. \"This work offers a clear roadmap for developing silicon as the anode for a high-capacity battery,\" said Wang. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The solid–electrolyte interphase (SEI), a layer formed on the electrode surface, is essential for electrochemical reactions in batteries and critically governs the battery stability. Active materials, especially those with extremely high energy density, such as silicon (Si), often inevitably undergo a large volume swing upon ion insertion and extraction, raising a critical question as to how the SEI interactively responds to and evolves with the material and consequently controls the cycling stability of the battery. Here, by integrating sensitive elemental tomography, an advanced algorithm and cryogenic scanning transmission electron microscopy, we unveil, in three dimensions, a correlated structural and chemical evolution of Si and SEI. Corroborated with a chemomechanical model, we demonstrate progressive electrolyte permeation and SEI growth along the percolation channel of the nanovoids due to vacancy injection and condensation during the delithiation process. Consequently, the Si–SEI spatial configuration evolves from the classic ‘core–shell’ structure in the first few cycles to a ‘plum-pudding’ structure following extended cycling, featuring the engulfing of Si domains by the SEI, which leads to the disruption of electron conduction pathways and formation of dead Si, contributing to capacity loss. The spatially coupled interactive evolution model of SEI and active materials, in principle, applies to a broad class of high-capacity electrode materials, leading to a critical insight for remedying the fading of high-capacity electrodes. Main It has been almost two decades since the lithium-ion battery brought us the rechargeable world. The megatrend of electrification of our society, including the demand to power long-range electric vehicles, intelligent robots and powerful portable electronics and to improve the resiliency and reliability of electrical grids, has put continuous requirements on next-generation Li-ion batteries. Integration of new electrode materials, in terms of cycling stability, is often dictated by interaction between the materials and the associated working environment, which is manifested by an interlayer between the active material and the electrolyte 1 , 2 , that is, the SEI. Nevertheless, the understanding of how the SEI evolves during cycling and leads to capacity fading remains conjectural. For instance, due to its high gravimetric capacity, low voltage window (~0.01–1 V versus a Li/Li + electrode), low price and natural abundance, Si has been perceived by both the scientific community and industries as the most promising high-capacity anode material for practical application in next-generation Li-ion batteries 3 , 4 . Tremendous ingenious nanoscale engineering concepts have emerged in the past decade 5 , 6 , 7 , 8 , intending to tackle the barrier associated with the volume expansion of Si and consequently mitigating the capacity fading of Si-based anode materials 2 , 4 , 9 , 10 , 11 . However, large-scale application of Si as an anode for Li-ion batteries remains a challenge and requires a clear understanding of the underlying fading mechanism of the nanosized Si (refs. 4 , 5 , 12 ). It is generally conjectured that the capacity fading of Si originates in the intrinsic large volume changes and ensuing accumulation of the SEI with repeated cycling, as commonly anticipated for this class of materials. Typically, the volume change will lead to cracking of Si (ref. 13 ); crumpling, regeneration and accumulative growth of the SEI; and attendant loss of electrical contact 3 , 14 . This view appears to be self-consistent for explaining the capacity fading of Si with sizes larger than a critical dimension of typically 150 nm, but fails in reconciliation with the capacity fading of nanosized Si (refs. 3 , 15 ), wherein the material cracking issue is effectively attenuated by the reduced particle size 3 , 16 , 17 . Electrode-level failure aside 18 , the capacity fading of nanosized Si has been related, more or less hypothetically, to the thickening of the SEI layer on the material surface 2 , 19 , 20 , 21 , progressive loss of active materials such as Si and Li (refs. 22 , 23 ) and electrochemical–mechanical degradation 24 . However, key experimental evidence is still lacking on the dynamic evolution of SEI, both structural and chemical, in response to the large volume swing of electrodes during cycling. Current direct observations of the SEI are largely based on the two-dimensional projection imaging and energy dispersive X-ray spectroscopy (EDS) mapping of elements 20 , 25 , which are unable to correlate with the three-dimensional (3D) structural evolution of the nanosized Si. Electron tomography is a technique that retrieves the 3D structural information of nanoscale objects from a tilt series of two-dimensional projections 26 , a technique that has been pushed to image materials at the atomic level in three dimensions 27 . However, electron tomography on cycled electrode materials has been challenging due to the severe damage from the high electron dose necessary for electron tomography imaging. Inspired by the studies of structural biology 28 and cryogenic transmission electron microscopy (cryo-TEM) for Li dendrites 29 , 30 , we hold the sample at cryogenic temperature during preparation and imaging to minimize the sample damage from air and the imaging beam. Additionally, we employ an advanced reconstruction algorithm that enables capturing the tomography tilt series with a further reduced electron dose. These approaches preserve the lightweight materials encompassed by the SEI for the high-resolution electron tomography imaging of both the structure and chemical compositions, as detailed in the Methods . Herein, we integrate advanced EDS tomography, cryogenic scanning transmission electron microscopy (cryo-STEM) and chemomechanical modelling to show, explicitly in three dimensions, the correlated structural and chemical evolution of the SEI and Si. Specifically, we discover the progressive growth of the SEI towards the Si interior as the Si nanowires become porous with cycling. As such, the otherwise pure Si eventually evolves into a mixture of Si and SEI with a ‘plum-pudding’ structure. We reveal that the origin of such a structural evolution is rooted in the formation of voids due to vacancy condensation during the delithiation process. This discovery unravels beyond the fading mechanisms associated with the large volume change of Si—the intrinsic fading mechanism of the<|im_end|> <|im_start|>assistant Silicon is a staple of the digital revolution, shunting loads of signals on a device that's likely just inches from your eyes at this very moment. Now, that same plentiful, cheap material is becoming a serious candidate for a big role in the burgeoning battery business. It's especially attractive because it's able to hold 10 times as much energy in an important part of a battery, the anode, than widely used graphite. But not so fast. While silicon has a swell reputation among scientists, the material itself swells when it's part of a battery. It swells so much that the anode flakes and cracks, causing the battery to lose its ability to hold a charge and ultimately to fail. Now scientists have witnessed the process for the first time, an important step toward making silicon a viable choice that could improve the cost, performance and charging speed of batteries for electric vehicles as well as cell phones, laptops, smart watches and other gadgets. "Many people have imagined what might be happening but no one had actually demonstrated it before," said Chongmin Wang, a scientist at the Department of Energy's Pacific Northwest National Laboratory. Wang is a corresponding author of the paper recently published in Nature Nanotechnology. Of silicon anodes, peanut butter cups and packed airline passengers Lithium ions are the energy currency in a lithium-ion battery, traveling back and forth between two electrodes through liquid called electrolyte. When lithium ions enter an anode made of silicon, they muscle their way into the orderly structure, pushing the silicon atoms askew, like a stout airline passenger squeezing into the middle seat on a packed flight. This "lithium squeeze" makes the anode swell to three or four times its original size. When the lithium ions depart, things don't return to normal. Empty spaces known as vacancies remain. Displaced silicon atoms fill in many, but not all, of the vacancies, like passengers quickly taking back the empty space when the middle passenger heads for the restroom. But the lithium ions return, pushing their way in again. The process repeats as the lithium ions scoot back and forth between the anode and cathode, and the empty spaces in the silicon anode merge to form voids or gaps. These gaps translate to battery failure. Scientists have known about the process for years, but they hadn't before witnessed precisely how it results in battery failure. Some have attributed the failure to the loss of silicon and lithium. Others have blamed the thickening of a key component known as the solid-electrolyte interphase or SEI. The SEI is a delicate structure at the edge of the anode that is an important gateway between the anode and the liquid electrolyte. In its experiments, the team watched as the vacancies left by lithium ions in the silicon anode evolved into larger and larger gaps. Then they watched as the liquid electrolyte flowed into the gaps like tiny rivulets along a shoreline, infiltrating the silicon. This inflow allowed the SEI to develop in areas within the silicon where it shouldn't be, a molecular invader in a part of the battery where it doesn't belong. That created dead zones, destroying the ability of the silicon to store lithium and ruining the anode. Think of a peanut butter cup in pristine shape: The chocolate outside is distinct from the soft peanut butter inside. But if you hold it in your hand too long with too tight a grip, the outer shell softens and mixes with the soft chocolate inside. You're left with a single disordered mass whose structure is changed irreversibly. You no longer have a true peanut butter cup. Likewise, after the electrolyte and the SEI infiltrate the silicon, scientists no longer have a workable anode. A silicon anode after 100 cycles: The anode is barely recognizable as a silicon structure and is instead a mix of the silicon (green) and the fluorine (red) from the solid electrolyte interphase. Credit: Chongmin Wang | Pacific Northwest National Laboratory The team witnessed this process begin immediately after just one battery cycle. After 36 cycles, the battery's ability to hold a charge had fallen dramatically. After 100 cycles, the anode was ruined. Exploring the promise of silicon anodes Scientists are working on ways to protect the silicon from the electrolyte. Several groups, including scientists at PNNL, are developing coatings designed to act as gatekeepers, allowing lithium ions to go into and out of the anode while stopping other components of the electrolyte. Scientists from several institutions pooled their expertise to do the work. Scientists at Los Alamos National Laboratory created the silicon nanowires used in the study. PNNL scientists worked together with counterparts at Thermo Fisher Scientific to modify a cryogenic transmission electron microscope to reduce the damage from the electrons used for imaging. And Penn State University scientists developed an algorithm to simulate the molecular action between the liquid and the silicon. Altogether, the team used electrons to make ultra-high-resolution images of the process and then reconstructed the images in 3-D, similar to how physicians create a 3-D image of a patient's limb or organ. "This work offers a clear roadmap for developing silicon as the anode for a high-capacity battery," said Wang. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Introduction Self-presentation and visual content-sharing apps Study 1 Hypotheses development Study 2 Table of contents Abstract Introduction Self-presentation and visual content-sharing apps Study 1 Hypotheses development Study 2 / Table of Contents Abstract Purpose The present research aims to examine selfie-marketing from a consumer behavior perspective. Creating and sharing selfies are gaining popularity among millennials. The authors seek to understand how this popularity relates to classic research on narcissism and self-concept and to determine the effectiveness of selfie-marketing in visual user-generated content. / Abstract__block Design/methodology/approach A mixed methods approach is used across two studies. Study 1’s qualitative exploration uses the grounded theory method by analyzing semi-structured interviews with millennials. The findings produce three research propositions. These propositions are further developed into testable hypotheses in Study 2’s quantitative investigation, featuring analysis of the variance of online survey data collected from millennials. / Abstract__block Findings The findings suggest that narcissism positively relates to millennials’ attitudes toward and intent to participate in selfie-marketing on visual content-sharing apps. Results also demonstrate that millennials seek to use selfies to present their self-concepts differently in various visual content-sharing environments. / Abstract__block Originality/value The present research is among the first to focus on the importance of self-presentation and narcissism in regard to consumers’ attitudes and behavioral responses toward selfie-marketing. For marketers, this underscores the importance of understanding the unique nature of user-generated visual content on social media. / Abstract__block / Abstract Keywords Self-concept Grounded theory Narcissism Selfie-marketing User-generated content Visual content-sharing apps Citation Fox, A.K. , Bacile, T.J. , Nakhata, C. and Weible, A. (2018), \"Selfie-marketing: exploring narcissism and self-concept in visual user-generated content on social media\", Journal of Consumer Marketing , Vol. 35 No. 1, pp. 11-21. Download as .RIS / Citation Publisher : Emerald Publishing Limited / Body Copyright © 2018, Emerald Publishing Limited / Citation Introduction The concept of a “selfie” is simple: a consumer takes a photo or video of himself or herself, shares it via social media and, then, waits for feedback. Approximately 93 million selfies are taken across the world each day ( Cohen, 2016 ), with nearly 40 per cent of millennials taking at least one selfie per day ( eMarketer, 2015 ). Indeed, selfies are an integral part of many consumers’ lives, especially for millennials. Due to this growing trend, some companies are increasingly devoting resources to selfie-focused marketing activities ( AdWeek, 2016 ), which encourage consumers to take and share selfies in relation to a brand. The authors hereafter refer to this concept as “selfie-marketing”, defined as user-generated selfies that are used by a company for marketing purposes. For example, Buffalo Wild Wings launched an Instagram campaign asking consumers to share selfies with the hashtag #fannerism while watching the World Cup at its restaurants ( Gibson, 2014 ). While the marketing academic literature is studying brand–consumer interactions on mobile devices and social media in general ( Bacile et al. , 2014 ; Hamilton et al. , 2016 ), it is important to examine the increasing trend of social networks featuring visual communication. Scholars outside of marketing, such as psychologists studying human interaction with computers, have made progress in this area. Bayer et al. (2016) examined visual-content sharing apps such as Instagram and Snapchat and how they differ from other social networking platforms in content formality and permanency, as well as unique social and emotional experiences. Moreover, Pittman and Reich (2016) suggested that people who share selfies on Instagram versus Snapchat may be attempting to express themselves differently, as social interactions on each platform may differ considerably. As such, consumers use self-presentation of selfies shared on visual content sharing apps as an impression management strategy ( Qiu et al. , 2015 ). However, this phenomenon is far less researched in a marketing context ( Lim and Lim, 2016 ), specifically as brands start to devote more resources to selfie-marketing campaigns. The present research begins to fill this void by exploring the interplay of selfies, self-presentation, narcissism and self-concept on two popular visual content-sharing apps: Instagram and Snapchat. The authors examine how millennials use selfies to present their self-concepts on visual content-sharing apps, in an effort to understand their attitudes and intention to participate in selfie-marketing. This research adds to the literature’s understanding of selfie-marketing and offers insights for marketers to plan and implement selfie-marketing initiatives. Self-presentation and visual content-sharing apps Goffman’s (1959) self-presentation theory posits that an individual develops a sense of self by creating an impression to showcase to others in face-to-face environments. In such social interactions, an individual controls which information to make available and how it should be made available, thereby forming one’s impression management strategy ( Leary and Kowalski, 1990 ). The prominence of self-presentation theory to marketers is immense and relates to several other consumer behavior theories. For example, the presentation of one’s self through the lens self-concept theory ( Sirgy, 1982 ) highlights the importance of consumers expressing an image or impression to others, such as through brand choice ( Onkvisit and Shaw, 1987 ). Despite the offline origin of self-presentation and related theories, researchers are expanding these purviews to online contexts. For instance, self-presentation is enhanced via computer-mediated-communication due to users exploiting technological aspects in certain online channels to manage their impressions ( Walther, 1996 ). This enables people to use features of computer-mediated-communication channels to control the exchange of social information and manage their self-presentations ( O’Sullivan, 2000 ). This idea of using channel attributes for “information control” ( Feaster, 2010 , p. 116) is paramount for users managing their self-presentations via different social media channels ( Krämer and Winter, 2008 ). The evolution of social media and front-facing camera technology now enables consumers to easily present themselves via a newer type of online environment: visual content-sharing apps. The photo- and video-editing features on visual content-sharing apps (e.g. Instagram and Snapchat) allow users to perform impression management by modifying their appearance to friends ( Qiu et al. , 2015 ). In addition, similar to how products have utilitarian and hedonic", "role": "user" }, { "content": "Who would have thought that millennials' polished selfies at the beach or #nofilter photos of themselves would influence how companies are marketing their products on various social media platforms? As it turns out, companies have caught onto selfie culture, now encouraging consumers to take and share personal \"selfies in relation to their brand.\" This trend, now coined as \"selfie-marketing,\" can be defined as \"user-generated selfies that are used by a company for marketing purposes.\" One University of Akron professor has been honored for her research paper on the subject. Dr. Alexa Fox, an assistant professor of marketing, received the Journal of Consumer Marketing's Outstanding Paper award in the 2019 Emerald Literati Awards for Excellence. Analyzing popularity of selfies The paper, titled \"Selfie-marketing: exploring narcissism and self-concept in visual user-generated content on social media,\" explains the research conducted by Fox in partnership with Todd J. Bacile of Loyola University New Orleans, Chinintorn Nakhata of Penn State Harrisburg and Aleshia Weible of Clarion University of Pennsylvania. Fox's research used two mixed-methods studies to analyze the popularity of selfies as it relates to classic research on narcissism and self-concept to help determine the effectiveness of selfie-marketing on photo-sharing social media apps like Snapchat and Instagram. The study defines narcissism as a personality trait \"characterized by a grandiose self-presentation motivated by the need to regulate self-esteem.\" The researchers' findings suggest that narcissism does in fact affect millennials' attitudes toward and intent to participate in selfie-marketing. Responding to environment The results also show that, due to ranging levels of narcissism, millennials use selfies to present self-concepts differently in various content-sharing apps. In other words, millennials present different versions of themselves based on the social media network's environment. For example, on Instagram, users may feel inclined to express their most ideal selves, posting photos where they feel they look their best and using filters to aid in doing so. On Snapchat, however, users may present a version of themselves that seems more authentic and every day. This is due to the less permanent nature of an app like Snapchat, where stories disappear after 24 hours, and direct messaging photos disappear after opening. \"Our research offers implications for what type of content resonates most on various social media platforms,\" explains Fox. \"For example, marketers of products designed to improve customers' lives in some way, like cosmetics, might benefit from using Instagram, whereas products designed with everyday life in mind, like coffee, might be more successful on Snapchat.\" Social media has changed the landscape of so many industries like marketing. Research like that conducted by Fox will allow marketers to get a leg up on the changing environment, providing a more thorough understanding of the consumer and opportunities for better strategy. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Introduction Self-presentation and visual content-sharing apps Study 1 Hypotheses development Study 2 Table of contents Abstract Introduction Self-presentation and visual content-sharing apps Study 1 Hypotheses development Study 2 / Table of Contents Abstract Purpose The present research aims to examine selfie-marketing from a consumer behavior perspective. Creating and sharing selfies are gaining popularity among millennials. The authors seek to understand how this popularity relates to classic research on narcissism and self-concept and to determine the effectiveness of selfie-marketing in visual user-generated content. / Abstract__block Design/methodology/approach A mixed methods approach is used across two studies. Study 1’s qualitative exploration uses the grounded theory method by analyzing semi-structured interviews with millennials. The findings produce three research propositions. These propositions are further developed into testable hypotheses in Study 2’s quantitative investigation, featuring analysis of the variance of online survey data collected from millennials. / Abstract__block Findings The findings suggest that narcissism positively relates to millennials’ attitudes toward and intent to participate in selfie-marketing on visual content-sharing apps. Results also demonstrate that millennials seek to use selfies to present their self-concepts differently in various visual content-sharing environments. / Abstract__block Originality/value The present research is among the first to focus on the importance of self-presentation and narcissism in regard to consumers’ attitudes and behavioral responses toward selfie-marketing. For marketers, this underscores the importance of understanding the unique nature of user-generated visual content on social media. / Abstract__block / Abstract Keywords Self-concept Grounded theory Narcissism Selfie-marketing User-generated content Visual content-sharing apps Citation Fox, A.K. , Bacile, T.J. , Nakhata, C. and Weible, A. (2018), "Selfie-marketing: exploring narcissism and self-concept in visual user-generated content on social media", Journal of Consumer Marketing , Vol. 35 No. 1, pp. 11-21. Download as .RIS / Citation Publisher : Emerald Publishing Limited / Body Copyright © 2018, Emerald Publishing Limited / Citation Introduction The concept of a “selfie” is simple: a consumer takes a photo or video of himself or herself, shares it via social media and, then, waits for feedback. Approximately 93 million selfies are taken across the world each day ( Cohen, 2016 ), with nearly 40 per cent of millennials taking at least one selfie per day ( eMarketer, 2015 ). Indeed, selfies are an integral part of many consumers’ lives, especially for millennials. Due to this growing trend, some companies are increasingly devoting resources to selfie-focused marketing activities ( AdWeek, 2016 ), which encourage consumers to take and share selfies in relation to a brand. The authors hereafter refer to this concept as “selfie-marketing”, defined as user-generated selfies that are used by a company for marketing purposes. For example, Buffalo Wild Wings launched an Instagram campaign asking consumers to share selfies with the hashtag #fannerism while watching the World Cup at its restaurants ( Gibson, 2014 ). While the marketing academic literature is studying brand–consumer interactions on mobile devices and social media in general ( Bacile et al. , 2014 ; Hamilton et al. , 2016 ), it is important to examine the increasing trend of social networks featuring visual communication. Scholars outside of marketing, such as psychologists studying human interaction with computers, have made progress in this area. Bayer et al. (2016) examined visual-content sharing apps such as Instagram and Snapchat and how they differ from other social networking platforms in content formality and permanency, as well as unique social and emotional experiences. Moreover, Pittman and Reich (2016) suggested that people who share selfies on Instagram versus Snapchat may be attempting to express themselves differently, as social interactions on each platform may differ considerably. As such, consumers use self-presentation of selfies shared on visual content sharing apps as an impression management strategy ( Qiu et al. , 2015 ). However, this phenomenon is far less researched in a marketing context ( Lim and Lim, 2016 ), specifically as brands start to devote more resources to selfie-marketing campaigns. The present research begins to fill this void by exploring the interplay of selfies, self-presentation, narcissism and self-concept on two popular visual content-sharing apps: Instagram and Snapchat. The authors examine how millennials use selfies to present their self-concepts on visual content-sharing apps, in an effort to understand their attitudes and intention to participate in selfie-marketing. This research adds to the literature’s understanding of selfie-marketing and offers insights for marketers to plan and implement selfie-marketing initiatives. Self-presentation and visual content-sharing apps Goffman’s (1959) self-presentation theory posits that an individual develops a sense of self by creating an impression to showcase to others in face-to-face environments. In such social interactions, an individual controls which information to make available and how it should be made available, thereby forming one’s impression management strategy ( Leary and Kowalski, 1990 ). The prominence of self-presentation theory to marketers is immense and relates to several other consumer behavior theories. For example, the presentation of one’s self through the lens self-concept theory ( Sirgy, 1982 ) highlights the importance of consumers expressing an image or impression to others, such as through brand choice ( Onkvisit and Shaw, 1987 ). Despite the offline origin of self-presentation and related theories, researchers are expanding these purviews to online contexts. For instance, self-presentation is enhanced via computer-mediated-communication due to users exploiting technological aspects in certain online channels to manage their impressions ( Walther, 1996 ). This enables people to use features of computer-mediated-communication channels to control the exchange of social information and manage their self-presentations ( O’Sullivan, 2000 ). This idea of using channel attributes for “information control” ( Feaster, 2010 , p. 116) is paramount for users managing their self-presentations via different social media channels ( Krämer and Winter, 2008 ). The evolution of social media and front-facing camera technology now enables consumers to easily present themselves via a newer type of online environment: visual content-sharing apps. The photo- and video-editing features on visual content-sharing apps (e.g. Instagram and Snapchat) allow users to perform impression management by modifying their appearance to friends ( Qiu et al. , 2015 ). In addition, similar to how products have utilitarian and hedonic<|im_end|> <|im_start|>assistant Who would have thought that millennials' polished selfies at the beach or #nofilter photos of themselves would influence how companies are marketing their products on various social media platforms? As it turns out, companies have caught onto selfie culture, now encouraging consumers to take and share personal "selfies in relation to their brand." This trend, now coined as "selfie-marketing," can be defined as "user-generated selfies that are used by a company for marketing purposes." One University of Akron professor has been honored for her research paper on the subject. Dr. Alexa Fox, an assistant professor of marketing, received the Journal of Consumer Marketing's Outstanding Paper award in the 2019 Emerald Literati Awards for Excellence. Analyzing popularity of selfies The paper, titled "Selfie-marketing: exploring narcissism and self-concept in visual user-generated content on social media," explains the research conducted by Fox in partnership with Todd J. Bacile of Loyola University New Orleans, Chinintorn Nakhata of Penn State Harrisburg and Aleshia Weible of Clarion University of Pennsylvania. Fox's research used two mixed-methods studies to analyze the popularity of selfies as it relates to classic research on narcissism and self-concept to help determine the effectiveness of selfie-marketing on photo-sharing social media apps like Snapchat and Instagram. The study defines narcissism as a personality trait "characterized by a grandiose self-presentation motivated by the need to regulate self-esteem." The researchers' findings suggest that narcissism does in fact affect millennials' attitudes toward and intent to participate in selfie-marketing. Responding to environment The results also show that, due to ranging levels of narcissism, millennials use selfies to present self-concepts differently in various content-sharing apps. In other words, millennials present different versions of themselves based on the social media network's environment. For example, on Instagram, users may feel inclined to express their most ideal selves, posting photos where they feel they look their best and using filters to aid in doing so. On Snapchat, however, users may present a version of themselves that seems more authentic and every day. This is due to the less permanent nature of an app like Snapchat, where stories disappear after 24 hours, and direct messaging photos disappear after opening. "Our research offers implications for what type of content resonates most on various social media platforms," explains Fox. "For example, marketers of products designed to improve customers' lives in some way, like cosmetics, might benefit from using Instagram, whereas products designed with everyday life in mind, like coffee, might be more successful on Snapchat." Social media has changed the landscape of so many industries like marketing. Research like that conducted by Fox will allow marketers to get a leg up on the changing environment, providing a more thorough understanding of the consumer and opportunities for better strategy. <|im_end|>

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1,948

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Bone is a natural composite of collagen protein and the mineral hydroxyapatite. The structure of bone is known to be important to its load-bearing characteristics, but relatively little is known about this structure or the mechanism that govern deformation at the molecular scale. Here we perform full-atomistic calculations of the three-dimensional molecular structure of a mineralized collagen protein matrix to try to better understand its mechanical characteristics under tensile loading at various mineral densities. We find that as the mineral density increases, the tensile modulus of the network increases monotonically and well beyond that of pure collagen fibrils. Our results suggest that the mineral crystals within this network bears up to four times the stress of the collagen fibrils, whereas the collagen is predominantly responsible for the material’s deformation response. These findings reveal the mechanism by which bone is able to achieve superior energy dissipation and fracture resistance characteristics beyond its individual constituents. Introduction Bone is a remarkable hierarchical biomaterial ( Fig. 1a ) that has two major constituents, soft collagen protein and much stiffer apatite mineral 1 , 2 . During the formation of bone, collagen molecules assemble into fibrils, which are mineralized via the formation of apatite crystals. Although larger-scale bone structures differentiate depending on bone type and species, the structure of mineralized fibrils is highly conserved across species and different types of bone, and hence act as the bone’s universal elementary building block 3 , 4 , 5 , 6 . The hierarchical structure of bone enables it to be a light-weight material that can carry large loads, and combines the toughness of inorganic material and the flexibility of protein-based tissues 7 , 8 , 9 , 10 , 11 , 12 . Previous studies based on mechanical models have uncovered key mechanistic features of bone as well, eluded to the role of mineral platelets in strengthening the material 13 , 14 , 15 , 16 , 17 , 18 . At the nanoscale, the interactions between collagen molecules and the mineral hydroxyapatite (HAP), and as well as the amount of mineral, are known to have a significant role in providing strength and toughness to the bone (or lack thereof, in disease states). In this paper we focus on the structure and mechanics of mineralized collagen fibrils, as it is universally found in many types of bone. Collagen–HAP composites are not only the basic building blocks of the human bone, but they are also amongst the most abundant class of biomineralized materials in the animal kingdom (found in the skeletal system, teeth or antler) 1 , 2 . Figure 1: Bone structure and model development. ( a ) Hierarchical structure of bone ranging from the macroscale skeleton to nanoscale collagen (green) and HAP (red). ( b ) Collagen microfibril model with 0% mineralization (inset shows the collagen triple-helix structure), 20% mineral content (inset shows a HAP unit cell) and 40% mineral content. The HAP crystals are arranged such that the c axis of crystal aligns with the fibril axis. Ca atoms plotted in green, OH groups plotted in red and white, and the tetrahedron structure visualizes the PO 4 group. The left three images in panel a taken from Launey et al . 65 Full size image Although the structure of bone and its mechanical properties have been well-studied, the knowledge about how collagen fibrils and HAP crystals interact at the molecular scale, and how they deform as an integrated system under external stress are not well understood. Developing a deeper understanding of the properties of bone from the level of its building blocks requires a thorough investigation of the interplay of the organic protein molecules with the mineral crystals. This, in turn, requires an atomistic-level investigation of the properties of the organic–inorganic interfaces 19 , 20 and its correlation with the overall mechanical behaviour. Several attempts have been made to develop a molecular model of bone, but those studies fell short to providing a full three-dimensional, chemically and structurally accurate model of the interactions of collagen with the mineral phase 21 , 22 , 23 , 24 . Coarse-grain models 25 of nascent bone showed that the mineral crystals provide additional strength and also increases the Young’s modulus and fracture strength. Although these models provided some insight into the mechanics of bone, they failed to capture atomic-scale mechanisms, did not reach higher mineralization levels, and did not allow for a direct comparison with experimental work (for example, in situ x-ray analysis of bone deformation 1 , 2 , 3 , 4 , 5 , 6 ). The coarse-grain description of nascent bone 25 is a highly simplified two-dimensional model and relies on empirically derived mechanical parameters, which were not directly derived from fundamental principles of chemical interactions. The model also neglected the details of the shape or distribution of the mineral platelets, which is likely to have an important impact on the mechanical properties of the material. In this paper we develop a three-dimensional, full-atomistic mineralized collagen microfibril model and perform tensile tests at various stress levels, to identify key deformation mechanisms. We find that as the mineral density increases, the tensile modulus increases successively, and is significantly larger than that of pure collagen fibrils. By comparing stress and strain fields associated with different mineral content and applied stress, we find that the mineral crystals carry about four times the stress compared with collagen, whereas the protein phase carries the bulk of deformation. These findings reveal the mechanism by which bone carries load at the nanoscale, where the district distribution of stress and strain between collagen and HAP enables a mechanism of great energy dissipation and resistance to fracture that overcomes the intrinsic limitations of the constituents and amplifies their superior properties. Results Mineralized microfibril model We apply an in silico mineralization scheme based on a Monte Carlo approach, and identify molecular structures of nascent bone for different mineral densities, from 0% (pure collagen microfibril, see Fig. 1b for model details) to 40% (highly mineralized", "role": "user" }, { "content": "Researchers working to design new materials that are durable, lightweight and environmentally sustainable are increasingly looking to natural composites, such as bone, for inspiration: Bone is strong and tough because its two constituent materials, soft collagen protein and stiff hydroxyapatite mineral, are arranged in complex hierarchical patterns that change at every scale of the composite, from the micro up to the macro. While researchers have come up with hierarchical structures in the design of new materials, going from a computer model to the production of physical artifacts has been a persistent challenge. This is because the hierarchical structures that give natural composites their strength are self-assembled through electrochemical reactions, a process not easily replicated in the lab. Now researchers at MIT have developed an approach that allows them to turn their designs into reality. In just a few hours, they can move directly from a multiscale computer model of a synthetic material to the creation of physical samples. In a paper published online June 17 in Advanced Functional Materials, associate professor Markus Buehler of the Department of Civil and Environmental Engineering and co-authors describe their approach. Using computer-optimized designs of soft and stiff polymers placed in geometric patterns that replicate nature's own patterns, and a 3-D printer that prints with two polymers at once, the team produced samples of synthetic materials that have fracture behavior similar to bone. One of the synthetics is 22 times more fracture-resistant than its strongest constituent material, a feat achieved by altering its hierarchical design. Two are stronger than one The collagen in bone is too soft and stretchy to serve as a structural material, and the mineral hydroxyapatite is brittle and prone to fracturing. Yet when the two combine, they form a remarkable composite capable of providing skeletal support for the human body. The hierarchical patterns help bone withstand fracturing by dissipating energy and distributing damage over a larger area, rather than letting the material fail at a single point. \"The geometric patterns we used in the synthetic materials are based on those seen in natural materials like bone or nacre, but also include new designs that do not exist in nature,\" says Buehler, who has done extensive research on the molecular structure and fracture behavior of biomaterials. His co-authors are graduate students Leon Dimas and Graham Bratzel, and Ido Eylon of the 3-D printer manufacturer Stratasys. \"As engineers we are no longer limited to the natural patterns. We can design our own, which may perform even better than the ones that already exist.\" The researchers created three synthetic composite materials, each of which is one-eighth inch thick and about 5-by-7 inches in size. The first sample simulates the mechanical properties of bone and nacre (also known as mother of pearl). This synthetic has a microscopic pattern that looks like a staggered brick-and-mortar wall: A soft black polymer works as the mortar, and a stiff blue polymer forms the bricks. Another composite simulates the mineral calcite, with an inverted brick-and-mortar pattern featuring soft bricks enclosed in stiff polymer cells. The third composite has a diamond pattern resembling snakeskin. This one was tailored specifically to improve upon one aspect of bone's ability to shift and spread damage. A step toward 'metamaterials' The team confirmed the accuracy of this approach by putting the samples through a series of tests to see if the new materials fracture in the same way as their computer-simulated counterparts. The samples passed the tests, validating the entire process and proving the efficacy and accuracy of the computer-optimized design. As predicted, the bonelike material proved to be the toughest overall. \"Most importantly, the experiments confirmed the computational prediction of the bonelike specimen exhibiting the largest fracture resistance,\" says Dimas, who is the first author of the paper. \"And we managed to manufacture a composite with a fracture resistance more than 20 times larger than its strongest constituent.\" According to Buehler, the process could be scaled up to provide a cost-effective means of manufacturing materials that consist of two or more constituents, arranged in patterns of any variation imaginable and tailored for specific functions in different parts of a structure. He hopes that eventually entire buildings might be printed with optimized materials that incorporate electrical circuits, plumbing and energy harvesting. \"The possibilities seem endless, as we are just beginning to push the limits of the kind of geometric features and material combinations we can print,\" Buehler says. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Bone is a natural composite of collagen protein and the mineral hydroxyapatite. The structure of bone is known to be important to its load-bearing characteristics, but relatively little is known about this structure or the mechanism that govern deformation at the molecular scale. Here we perform full-atomistic calculations of the three-dimensional molecular structure of a mineralized collagen protein matrix to try to better understand its mechanical characteristics under tensile loading at various mineral densities. We find that as the mineral density increases, the tensile modulus of the network increases monotonically and well beyond that of pure collagen fibrils. Our results suggest that the mineral crystals within this network bears up to four times the stress of the collagen fibrils, whereas the collagen is predominantly responsible for the material’s deformation response. These findings reveal the mechanism by which bone is able to achieve superior energy dissipation and fracture resistance characteristics beyond its individual constituents. Introduction Bone is a remarkable hierarchical biomaterial ( Fig. 1a ) that has two major constituents, soft collagen protein and much stiffer apatite mineral 1 , 2 . During the formation of bone, collagen molecules assemble into fibrils, which are mineralized via the formation of apatite crystals. Although larger-scale bone structures differentiate depending on bone type and species, the structure of mineralized fibrils is highly conserved across species and different types of bone, and hence act as the bone’s universal elementary building block 3 , 4 , 5 , 6 . The hierarchical structure of bone enables it to be a light-weight material that can carry large loads, and combines the toughness of inorganic material and the flexibility of protein-based tissues 7 , 8 , 9 , 10 , 11 , 12 . Previous studies based on mechanical models have uncovered key mechanistic features of bone as well, eluded to the role of mineral platelets in strengthening the material 13 , 14 , 15 , 16 , 17 , 18 . At the nanoscale, the interactions between collagen molecules and the mineral hydroxyapatite (HAP), and as well as the amount of mineral, are known to have a significant role in providing strength and toughness to the bone (or lack thereof, in disease states). In this paper we focus on the structure and mechanics of mineralized collagen fibrils, as it is universally found in many types of bone. Collagen–HAP composites are not only the basic building blocks of the human bone, but they are also amongst the most abundant class of biomineralized materials in the animal kingdom (found in the skeletal system, teeth or antler) 1 , 2 . Figure 1: Bone structure and model development. ( a ) Hierarchical structure of bone ranging from the macroscale skeleton to nanoscale collagen (green) and HAP (red). ( b ) Collagen microfibril model with 0% mineralization (inset shows the collagen triple-helix structure), 20% mineral content (inset shows a HAP unit cell) and 40% mineral content. The HAP crystals are arranged such that the c axis of crystal aligns with the fibril axis. Ca atoms plotted in green, OH groups plotted in red and white, and the tetrahedron structure visualizes the PO 4 group. The left three images in panel a taken from Launey et al . 65 Full size image Although the structure of bone and its mechanical properties have been well-studied, the knowledge about how collagen fibrils and HAP crystals interact at the molecular scale, and how they deform as an integrated system under external stress are not well understood. Developing a deeper understanding of the properties of bone from the level of its building blocks requires a thorough investigation of the interplay of the organic protein molecules with the mineral crystals. This, in turn, requires an atomistic-level investigation of the properties of the organic–inorganic interfaces 19 , 20 and its correlation with the overall mechanical behaviour. Several attempts have been made to develop a molecular model of bone, but those studies fell short to providing a full three-dimensional, chemically and structurally accurate model of the interactions of collagen with the mineral phase 21 , 22 , 23 , 24 . Coarse-grain models 25 of nascent bone showed that the mineral crystals provide additional strength and also increases the Young’s modulus and fracture strength. Although these models provided some insight into the mechanics of bone, they failed to capture atomic-scale mechanisms, did not reach higher mineralization levels, and did not allow for a direct comparison with experimental work (for example, in situ x-ray analysis of bone deformation 1 , 2 , 3 , 4 , 5 , 6 ). The coarse-grain description of nascent bone 25 is a highly simplified two-dimensional model and relies on empirically derived mechanical parameters, which were not directly derived from fundamental principles of chemical interactions. The model also neglected the details of the shape or distribution of the mineral platelets, which is likely to have an important impact on the mechanical properties of the material. In this paper we develop a three-dimensional, full-atomistic mineralized collagen microfibril model and perform tensile tests at various stress levels, to identify key deformation mechanisms. We find that as the mineral density increases, the tensile modulus increases successively, and is significantly larger than that of pure collagen fibrils. By comparing stress and strain fields associated with different mineral content and applied stress, we find that the mineral crystals carry about four times the stress compared with collagen, whereas the protein phase carries the bulk of deformation. These findings reveal the mechanism by which bone carries load at the nanoscale, where the district distribution of stress and strain between collagen and HAP enables a mechanism of great energy dissipation and resistance to fracture that overcomes the intrinsic limitations of the constituents and amplifies their superior properties. Results Mineralized microfibril model We apply an in silico mineralization scheme based on a Monte Carlo approach, and identify molecular structures of nascent bone for different mineral densities, from 0% (pure collagen microfibril, see Fig. 1b for model details) to 40% (highly mineralized<|im_end|> <|im_start|>assistant Researchers working to design new materials that are durable, lightweight and environmentally sustainable are increasingly looking to natural composites, such as bone, for inspiration: Bone is strong and tough because its two constituent materials, soft collagen protein and stiff hydroxyapatite mineral, are arranged in complex hierarchical patterns that change at every scale of the composite, from the micro up to the macro. While researchers have come up with hierarchical structures in the design of new materials, going from a computer model to the production of physical artifacts has been a persistent challenge. This is because the hierarchical structures that give natural composites their strength are self-assembled through electrochemical reactions, a process not easily replicated in the lab. Now researchers at MIT have developed an approach that allows them to turn their designs into reality. In just a few hours, they can move directly from a multiscale computer model of a synthetic material to the creation of physical samples. In a paper published online June 17 in Advanced Functional Materials, associate professor Markus Buehler of the Department of Civil and Environmental Engineering and co-authors describe their approach. Using computer-optimized designs of soft and stiff polymers placed in geometric patterns that replicate nature's own patterns, and a 3-D printer that prints with two polymers at once, the team produced samples of synthetic materials that have fracture behavior similar to bone. One of the synthetics is 22 times more fracture-resistant than its strongest constituent material, a feat achieved by altering its hierarchical design. Two are stronger than one The collagen in bone is too soft and stretchy to serve as a structural material, and the mineral hydroxyapatite is brittle and prone to fracturing. Yet when the two combine, they form a remarkable composite capable of providing skeletal support for the human body. The hierarchical patterns help bone withstand fracturing by dissipating energy and distributing damage over a larger area, rather than letting the material fail at a single point. "The geometric patterns we used in the synthetic materials are based on those seen in natural materials like bone or nacre, but also include new designs that do not exist in nature," says Buehler, who has done extensive research on the molecular structure and fracture behavior of biomaterials. His co-authors are graduate students Leon Dimas and Graham Bratzel, and Ido Eylon of the 3-D printer manufacturer Stratasys. "As engineers we are no longer limited to the natural patterns. We can design our own, which may perform even better than the ones that already exist." The researchers created three synthetic composite materials, each of which is one-eighth inch thick and about 5-by-7 inches in size. The first sample simulates the mechanical properties of bone and nacre (also known as mother of pearl). This synthetic has a microscopic pattern that looks like a staggered brick-and-mortar wall: A soft black polymer works as the mortar, and a stiff blue polymer forms the bricks. Another composite simulates the mineral calcite, with an inverted brick-and-mortar pattern featuring soft bricks enclosed in stiff polymer cells. The third composite has a diamond pattern resembling snakeskin. This one was tailored specifically to improve upon one aspect of bone's ability to shift and spread damage. A step toward 'metamaterials' The team confirmed the accuracy of this approach by putting the samples through a series of tests to see if the new materials fracture in the same way as their computer-simulated counterparts. The samples passed the tests, validating the entire process and proving the efficacy and accuracy of the computer-optimized design. As predicted, the bonelike material proved to be the toughest overall. "Most importantly, the experiments confirmed the computational prediction of the bonelike specimen exhibiting the largest fracture resistance," says Dimas, who is the first author of the paper. "And we managed to manufacture a composite with a fracture resistance more than 20 times larger than its strongest constituent." According to Buehler, the process could be scaled up to provide a cost-effective means of manufacturing materials that consist of two or more constituents, arranged in patterns of any variation imaginable and tailored for specific functions in different parts of a structure. He hopes that eventually entire buildings might be printed with optimized materials that incorporate electrical circuits, plumbing and energy harvesting. "The possibilities seem endless, as we are just beginning to push the limits of the kind of geometric features and material combinations we can print," Buehler says. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Upon detection of pathogen-associated molecular patterns, innate immune receptors initiate inflammatory responses. These receptors include cytoplasmic NOD-like receptors (NLRs) whose stimulation recruits and proteolytically activates caspase-1 within the inflammasome, a multiprotein complex. Caspase-1 mediates the production of interleukin-1 family cytokines (IL1FCs), leading to fever and inflammatory cell death (pyroptosis) 1 , 2 . Mutations that constitutively activate these pathways underlie several autoinflammatory diseases with diverse clinical features 3 . We describe a family with a previously unreported syndrome featuring neonatal-onset enterocolitis, periodic fever, and fatal or near-fatal episodes of autoinflammation. We show that the disease is caused by a de novo gain-of-function mutation in NLRC4 encoding a p.Val341Ala substitution in the HD1 domain of the protein that cosegregates with disease. Mutant NLRC4 causes constitutive IL1FC production and macrophage cell death. Infected macrophages from affected individuals are polarized toward pyroptosis and exhibit abnormal staining for inflammasome components. These findings identify and describe the cause of a life-threatening but treatable autoinflammatory disease that underscores the divergent roles of the NLRC4 inflammasome. Main Secretion of IL1FCs (IL-1 and IL-18) normally requires two signals. 'Signal 1', from membrane-spanning receptors (for example, Toll-like receptors), induces the expression of pro-IL1FCs 2 . 'Signal 2', from cytosolic detectors including NLRs, leads to procaspase-1 autoproteolysis and activation 1 . Cleaved caspase-1 converts pro-IL1FCs into their active forms 2 , 4 . One NLR, NLRC4, cooperates with NAIP to detect flagellin and components of the type 3 secretion system (TTSS), used by Salmonella typhimurium and Pseudomonas aeruginosa to infect host cells 5 , 6 . Upon ligand binding, NAIP and NLRC4 oligomerize and recruit the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) 7 , 8 . This macromolecular NLRC4 inflammasome (>1 μm in diameter) induces autoproteolysis of procaspase-1, with subsequent IL1FC secretion and pyroptosis 1 , 7 . Mutant mice that cannot colocalize ASC and cleaved caspase-1 lose the ability to produce IL1FCs yet retain pyroptosis 6 , 9 , 10 . The index case in our study ( Fig. 1a , III.3) presented at 1 week of life with secretory diarrhea and fever (38.8 °C); no infectious cause was identified. Markers of systemic inflammation were at elevated levels, including ferritin (4,840 ng/ml; normal range of 18–370 ng/ml) ( Fig. 1d ) and C-reactive protein ( Supplementary Table 1 ). The numbers of natural killer (NK) cells were reduced. Hypertriglyceridemia, hypofibrinoginemia, coagulopathy and pancytopenia developed, culminating in death on day 23 from diffuse alveolar hemorrhage. Autopsy found splenomegaly, numerous activated (CD163-positive) macrophages infiltrating the central nervous system ( Supplementary Fig. 1 ) and widespread bowel autolysis. Remaining intestinal tissue showed the presence of mixed inflammatory cells and villous blunting ( Fig. 1b , top). Figure 1: Kindred with a syndrome of infantile enterocolitis and autoinflammation caused by mutation of NLRC4 . ( a ) Kindred structure. Affected members are denoted by filled symbols. Protein alterations encoded at the NLRC4 locus are indicated. WT, wild type. ( b ) Hematoxylin and eosin staining of duodenal tissue obtained by autopsy (top; subject III.3) or biopsy (bottom; subject III.2) demonstrating villous blunting and the presence of intraepithelial lymphocytes. Original magnification, 200×; scale bars, 500 μm. ( c ) Hematoxylin and eosin staining of bone marrow from subject II.3 during an episode of acute autoinflammation demonstrating hemo- and myelophagocytosis. Original magnification, 1,000×; scale bar, 20 μm. ( d ) Elevated serum ferritin concentrations in three affected individuals. The immune-modulatory treatments used in subject II.3 (blue) are indicated. The institutional normal range is indicated in gray. t = 0 represents the birth date of subject III.3. The father (II.3) presented with acute illness at day 28. Subject III.2 has been interictal during laboratory assessments and without severe febrile episodes throughout the observed interval. IVIG, intravenous administration of immunoglobulin G. ( e ) Elevated plasma IL-18 levels in subjects II.3 and III.2. The normal range, indicated in gray, was determined by testing the plasma of 4 related (3 adult, 1 pediatric) and 18 unrelated (13 adult, 5 pediatric) healthy controls. Full size image Two days after the funeral for the index case, his 43-year-old father ( Fig. 1a , II.3) presented with fever (40.6 °C), acute respiratory distress syndrome, subarachnoid hemorrhage and hematochezia; disseminated intravascular coagulation and pancytopenia developed, with elevated levels of ferritin (29,200 ng/ml), IL-18 (11,934 pg/ml; normal range of 69–503 pg/ml), C-reactive protein and soluble IL-2R ( Supplementary Table 1 ). Bone marrow biopsy showed erythro- and myelophagocytosis ( Fig. 1c ). Ultrasonography showed splenomegaly. NK cell lymphopenia was prominent. As no infectious agent was isolated, high-dose intravenous immunoglobulin, dexamethasone and cyclosporine were instituted for immunosuppression. The father gradually improved and was discharged after 9 weeks, remaining on cyclosporine; serum ferritin levels normalized, but IL-18 levels remained markedly elevated ( Fig. 1d,e ). He subsequently reported a lifelong history of periodic fevers (>40 °C) provoked by physical and emotional stressors. During infancy, he had an extended hospitalization for fever, vomiting, non-bloody diarrhea and failure to thrive; no specific diagnosis was made. His gastrointestinal symptoms resolved by 1 year of age. In adulthood, erythematous plaques and joint pains accompanied fevers; sero-negative psoriatic arthritis was diagnosed. The father's family history included healthy parents and two additional offspring, one without illness and a 5-year-old half-brother (III.2) of the deceased infant (III.3) who also had periodic fevers (range of 38.9–40 °C) beginning on day 3 of life after circumcision. A more severe febrile episode associated with vomiting, non-hemolytic anemia and acute renal failure occurred at 6 weeks of age ( Supplementary Table 1 ). Later, his fevers were induced by overexertion and were accompanied by abdominal pain. A duodenal biopsy in the first year of life found villous blunting and the presence of intraepithelial lymphocytes ( Fig. 1b , bottom). The levels of inflammatory markers including ferritin (516–856 ng/ml), C-reactive protein, soluble IL-2R and plasma IL-18 (11,520–24,129 pg/ml) were persistently elevated ( Fig. 1d,e ). NK cells, normal in number, were dysfunctional as determined by chromium release assay ( Supplementary Table 1 ).", "role": "user" }, { "content": "(Medical Xpress)—Shortly after the death of his newborn son, 43-year-old Erik Drewniak was hospitalized with some of the same symptoms that killed the infant—high fever, severe respiratory distress, and hemorrhaging in the lungs, intestines, and brain. Infectious agents had been ruled out in both cases. Doctors at Yale-New Haven Hospital asked: Could the Fairfield man's condition be related to the mysterious illness that took his 23-day-old son? Researchers at the Yale School of Medicine have provided a definitive answer to the mystery. A genomic analysis of the Drewniak family published online Sept. 7 in the journal Nature Genetics reveals that Erik and his son—as well as another of Erik's sons—share a previously undescribed disease featuring dangerous spikes in temperature and inflammation. The study shows that the disease is caused by a mutation resulting in abnormal activation of a pathway normally triggered by bacterial invasion of cells. \"This is a great example of what we can do at Yale, seamlessly combining incisive clinical observation with genome sequencing, computational analysis, and biochemistry,\" said Richard Lifton, Sterling Professor of Genetics and co-senior author of the paper. Dr. Neil Romberg, assistant professor of pediatrics and first author of the study, first saw the infant boy at Yale-New Haven Hospital shortly before his death and recognized the signs of a primary inflammatory disease, which was a key to identifying the causative mutation. \"This study highlights the utility of genome sequencing in establishing a diagnosis for patients with unexplained illnesses,\" he said. The Yale researchers used high-throughput DNA sequencing at the Yale Center for Genome Analysis to determine the sequence of all 21,000 protein-coding genes in the genome in members of the family. Within six days, researchers had come up with a provisional diagnosis. Erik Drewniak had a new protein-altering mutation that was absent in his own parents and was transmitted to his sons. Armed with this knowledge, doctors devised a treatment plan that eventually led to Drewniak's release from the hospital. Biochemical analysis later comfirmed that the mutated protein caused activation of inflammation in the absence of infection. Markers of inflammation were chronically elevated in mutation carriers but not other family members. In retrospect, Drewniak noted that he suffered from a similar severe undiagnosed illness at birth and has subsequently had high fevers induced by stress or fatigue his entire life. \"It is tragic that we were unable to save the baby, but grateful that his illness led to diagnosis of his father and brother,\" added Dr. Barbara I. Kazmierczak, associate professor of medicine and co-senior author of the paper. \"Moreover, because there is an approved inhibitor of the inflammatory cascade caused by this mutation, this finding has therapeutic implications for other patients found to have this rare disease.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Upon detection of pathogen-associated molecular patterns, innate immune receptors initiate inflammatory responses. These receptors include cytoplasmic NOD-like receptors (NLRs) whose stimulation recruits and proteolytically activates caspase-1 within the inflammasome, a multiprotein complex. Caspase-1 mediates the production of interleukin-1 family cytokines (IL1FCs), leading to fever and inflammatory cell death (pyroptosis) 1 , 2 . Mutations that constitutively activate these pathways underlie several autoinflammatory diseases with diverse clinical features 3 . We describe a family with a previously unreported syndrome featuring neonatal-onset enterocolitis, periodic fever, and fatal or near-fatal episodes of autoinflammation. We show that the disease is caused by a de novo gain-of-function mutation in NLRC4 encoding a p.Val341Ala substitution in the HD1 domain of the protein that cosegregates with disease. Mutant NLRC4 causes constitutive IL1FC production and macrophage cell death. Infected macrophages from affected individuals are polarized toward pyroptosis and exhibit abnormal staining for inflammasome components. These findings identify and describe the cause of a life-threatening but treatable autoinflammatory disease that underscores the divergent roles of the NLRC4 inflammasome. Main Secretion of IL1FCs (IL-1 and IL-18) normally requires two signals. 'Signal 1', from membrane-spanning receptors (for example, Toll-like receptors), induces the expression of pro-IL1FCs 2 . 'Signal 2', from cytosolic detectors including NLRs, leads to procaspase-1 autoproteolysis and activation 1 . Cleaved caspase-1 converts pro-IL1FCs into their active forms 2 , 4 . One NLR, NLRC4, cooperates with NAIP to detect flagellin and components of the type 3 secretion system (TTSS), used by Salmonella typhimurium and Pseudomonas aeruginosa to infect host cells 5 , 6 . Upon ligand binding, NAIP and NLRC4 oligomerize and recruit the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) 7 , 8 . This macromolecular NLRC4 inflammasome (>1 μm in diameter) induces autoproteolysis of procaspase-1, with subsequent IL1FC secretion and pyroptosis 1 , 7 . Mutant mice that cannot colocalize ASC and cleaved caspase-1 lose the ability to produce IL1FCs yet retain pyroptosis 6 , 9 , 10 . The index case in our study ( Fig. 1a , III.3) presented at 1 week of life with secretory diarrhea and fever (38.8 °C); no infectious cause was identified. Markers of systemic inflammation were at elevated levels, including ferritin (4,840 ng/ml; normal range of 18–370 ng/ml) ( Fig. 1d ) and C-reactive protein ( Supplementary Table 1 ). The numbers of natural killer (NK) cells were reduced. Hypertriglyceridemia, hypofibrinoginemia, coagulopathy and pancytopenia developed, culminating in death on day 23 from diffuse alveolar hemorrhage. Autopsy found splenomegaly, numerous activated (CD163-positive) macrophages infiltrating the central nervous system ( Supplementary Fig. 1 ) and widespread bowel autolysis. Remaining intestinal tissue showed the presence of mixed inflammatory cells and villous blunting ( Fig. 1b , top). Figure 1: Kindred with a syndrome of infantile enterocolitis and autoinflammation caused by mutation of NLRC4 . ( a ) Kindred structure. Affected members are denoted by filled symbols. Protein alterations encoded at the NLRC4 locus are indicated. WT, wild type. ( b ) Hematoxylin and eosin staining of duodenal tissue obtained by autopsy (top; subject III.3) or biopsy (bottom; subject III.2) demonstrating villous blunting and the presence of intraepithelial lymphocytes. Original magnification, 200×; scale bars, 500 μm. ( c ) Hematoxylin and eosin staining of bone marrow from subject II.3 during an episode of acute autoinflammation demonstrating hemo- and myelophagocytosis. Original magnification, 1,000×; scale bar, 20 μm. ( d ) Elevated serum ferritin concentrations in three affected individuals. The immune-modulatory treatments used in subject II.3 (blue) are indicated. The institutional normal range is indicated in gray. t = 0 represents the birth date of subject III.3. The father (II.3) presented with acute illness at day 28. Subject III.2 has been interictal during laboratory assessments and without severe febrile episodes throughout the observed interval. IVIG, intravenous administration of immunoglobulin G. ( e ) Elevated plasma IL-18 levels in subjects II.3 and III.2. The normal range, indicated in gray, was determined by testing the plasma of 4 related (3 adult, 1 pediatric) and 18 unrelated (13 adult, 5 pediatric) healthy controls. Full size image Two days after the funeral for the index case, his 43-year-old father ( Fig. 1a , II.3) presented with fever (40.6 °C), acute respiratory distress syndrome, subarachnoid hemorrhage and hematochezia; disseminated intravascular coagulation and pancytopenia developed, with elevated levels of ferritin (29,200 ng/ml), IL-18 (11,934 pg/ml; normal range of 69–503 pg/ml), C-reactive protein and soluble IL-2R ( Supplementary Table 1 ). Bone marrow biopsy showed erythro- and myelophagocytosis ( Fig. 1c ). Ultrasonography showed splenomegaly. NK cell lymphopenia was prominent. As no infectious agent was isolated, high-dose intravenous immunoglobulin, dexamethasone and cyclosporine were instituted for immunosuppression. The father gradually improved and was discharged after 9 weeks, remaining on cyclosporine; serum ferritin levels normalized, but IL-18 levels remained markedly elevated ( Fig. 1d,e ). He subsequently reported a lifelong history of periodic fevers (>40 °C) provoked by physical and emotional stressors. During infancy, he had an extended hospitalization for fever, vomiting, non-bloody diarrhea and failure to thrive; no specific diagnosis was made. His gastrointestinal symptoms resolved by 1 year of age. In adulthood, erythematous plaques and joint pains accompanied fevers; sero-negative psoriatic arthritis was diagnosed. The father's family history included healthy parents and two additional offspring, one without illness and a 5-year-old half-brother (III.2) of the deceased infant (III.3) who also had periodic fevers (range of 38.9–40 °C) beginning on day 3 of life after circumcision. A more severe febrile episode associated with vomiting, non-hemolytic anemia and acute renal failure occurred at 6 weeks of age ( Supplementary Table 1 ). Later, his fevers were induced by overexertion and were accompanied by abdominal pain. A duodenal biopsy in the first year of life found villous blunting and the presence of intraepithelial lymphocytes ( Fig. 1b , bottom). The levels of inflammatory markers including ferritin (516–856 ng/ml), C-reactive protein, soluble IL-2R and plasma IL-18 (11,520–24,129 pg/ml) were persistently elevated ( Fig. 1d,e ). NK cells, normal in number, were dysfunctional as determined by chromium release assay ( Supplementary Table 1 ).<|im_end|> <|im_start|>assistant (Medical Xpress)—Shortly after the death of his newborn son, 43-year-old Erik Drewniak was hospitalized with some of the same symptoms that killed the infant—high fever, severe respiratory distress, and hemorrhaging in the lungs, intestines, and brain. Infectious agents had been ruled out in both cases. Doctors at Yale-New Haven Hospital asked: Could the Fairfield man's condition be related to the mysterious illness that took his 23-day-old son? Researchers at the Yale School of Medicine have provided a definitive answer to the mystery. A genomic analysis of the Drewniak family published online Sept. 7 in the journal Nature Genetics reveals that Erik and his son—as well as another of Erik's sons—share a previously undescribed disease featuring dangerous spikes in temperature and inflammation. The study shows that the disease is caused by a mutation resulting in abnormal activation of a pathway normally triggered by bacterial invasion of cells. "This is a great example of what we can do at Yale, seamlessly combining incisive clinical observation with genome sequencing, computational analysis, and biochemistry," said Richard Lifton, Sterling Professor of Genetics and co-senior author of the paper. Dr. Neil Romberg, assistant professor of pediatrics and first author of the study, first saw the infant boy at Yale-New Haven Hospital shortly before his death and recognized the signs of a primary inflammatory disease, which was a key to identifying the causative mutation. "This study highlights the utility of genome sequencing in establishing a diagnosis for patients with unexplained illnesses," he said. The Yale researchers used high-throughput DNA sequencing at the Yale Center for Genome Analysis to determine the sequence of all 21,000 protein-coding genes in the genome in members of the family. Within six days, researchers had come up with a provisional diagnosis. Erik Drewniak had a new protein-altering mutation that was absent in his own parents and was transmitted to his sons. Armed with this knowledge, doctors devised a treatment plan that eventually led to Drewniak's release from the hospital. Biochemical analysis later comfirmed that the mutated protein caused activation of inflammation in the absence of infection. Markers of inflammation were chronically elevated in mutation carriers but not other family members. In retrospect, Drewniak noted that he suffered from a similar severe undiagnosed illness at birth and has subsequently had high fevers induced by stress or fatigue his entire life. "It is tragic that we were unable to save the baby, but grateful that his illness led to diagnosis of his father and brother," added Dr. Barbara I. Kazmierczak, associate professor of medicine and co-senior author of the paper. "Moreover, because there is an approved inhibitor of the inflammatory cascade caused by this mutation, this finding has therapeutic implications for other patients found to have this rare disease." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Helium and carbon isotopic data from 12 springs along a ~400 km segment of the Denali fault system (Alaska, USA), inform mantle-to-surface connections of this enigmatic structure. Warm springs on the main strand, west of the 2002 M7.9 Denali fault earthquake rupture, have 3 He/ 4 He as high as 2.4 R C /R A (air-corrected 3 He/ 4 He relative to air ratio) indicating ~30% mantle He. Corresponding δ 13 C values are −9.1‰ to −7.8‰ (relative to Vienna Peedee belemnite), suggesting that the CO 2 at these western springs is partially mantle derived. At the eastern end of the 2002 rupture, Totschunda fault springs have 3 He/ 4 He of 0.65–0.99 R C /R A (~8%–12% mantle He), with δ13C values (~0‰) from carbonates. Results confirm the Denali fault system is a lithosphericscale feature tapping mantle volatiles. Springs along the 2002 rupture yield air-like 3 He/ 4 He of 1 R/R A and δ 13 C values from −9.2‰ to −3.4‰, interpreted as representing shallow groundwater circulation through shales and carbonates without mantle contributions. A thrust splay parallel to the rupture zone has air-like 3 He/ 4 He, whereas an along-strike high-angle normal splay yields 3 He/ 4 He of 1.3 R C /R A (~16% mantle He), implying that flow paths along the ruptured strand are disrupted in the upper 10 km of the fault zone. Because the Denali fault is a lithospheric-scale, transcurrent structure separating North America from independently moving southern Alaska, we suggest that it has characteristics of a transform boundary. The similarity of our results to helium isotope values at analogous tectonic settings suggest that without magmatism influence, there is a maximum mantle fluid flux through continental strike-slip faults. INTRODUCTION Active strike-slip faults have three-dimensional geometries that vary along strike and can facilitate deep fluid flow and mantle-to-crust connections, with implications for the seismic cycle (e.g., Vauchez et al., 2012 ; Norris and Toy, 2014 ). Conversely, ancient “dead” strike-slip faults have been seismically imaged as crustal-scale features offsetting the Moho ( Diaconescu et al., 1998 ), but it is unclear whether these maintain mantle fluid connections. Furthermore, strike-slip faults that penetrate to mantle depths can facilitate lithosphere-scale deformation and act as transform plate boundaries, but not all continental strike-slip faults share these characteristics ( Andrew et al., 2023 ). Isotopic signatures of gases in springs (e.g., 3 He/ 4 He, δ 13 C) along active faults are ideal for quantifying mantle-to-crust connections and testing geophysical and structural models for strike-slip fault systems (e.g., Kennedy et al., 1997 ; de Leeuw et al., 2010 ; Klemperer et al., 2013 ). Documenting the presence of persistent mantle-to-surface volatile flux has implications for how fluid pressure gradients may impact fault strength and seismicity along strike-slip faults ( Kennedy et al., 1997 ). The Denali fault (northwestern North America) is a long-lived (>10 7 yr), >2000-km-long dextral strike-slip system (e.g., Benowitz et al., 2022 ). Here we present 3 He/ 4 He and δ 13 C data from previously ( Richter et al., 1973 ) and newly identified thermal springs along the Denali fault system in Alaska (USA) ( Fig. 1 ). We sampled springs located along and outside of the rupture associated with the 2002 M7.9 Denali fault earthquake ( Eberhart-Phillips et al., 2003 ). Results clarify questions about the lithospherescale nature of the Denali fault, hydrologic connectivity of fault splays and the main strand, and possible hydrologic impacts from the 2002 earthquake. We suggest that similarities in the 3 He/ 4 He ratio of springs at analogous tectonic settings place constraints on the mantle fluid flux into continental strike-slip faults. GEOLOGIC SETTING Southern Alaska, composed primarily of the Wrangellia composite terrane ( Trop et al., 2020 ), is delineated by the Denali fault system to the north and east and by the Aleutian Trench to the south ( Fig. 1 ). The Denali fault is active, demonstrated by a M7.9 earthquake in 2002 that ruptured ~340 km of the Denali and Totschunda faults ( Fig. 2 ) ( Eberhart-Phillips et al., 2003 ). Geodetic data indicate that southern Alaska is moving westward and independent of North America (e.g., Elliott and Freymueller, 2020 ). Hence, further knowledge of the Denali fault system’s lithospheric-scale nature is critical to discerning its role in the northeastern Pacific plate transform system and whether southern Alaska comprises an independent tectonic plate. The Denali fault system can be divided into the primarily strike-slip Totschunda fault (e.g., Trop et al., 2022 ), the main strand of the Denali fault which becomes more transpressive east to west ( Regan et al., 2021 ), and the ancient strikeslip and now dominantly dip-slip Hines Creek fault ( Benowitz et al., 2022 ). Based on receiver functions, Brennan et al. (2011) concluded the active central Denali fault does not extend into the mantle nor offset the Moho but the Hines Creek fault offsets the Moho by ~10 km. Conversely, Allam et al. (2017) , using double difference tomography and receiver functions, concluded the active strand of the Denali and the Hines Creek and Totschunda faults all extend into the mantle with ~10 km Moho offsets. Pleistocene slip rates decrease east to west from ~13 to ~5 mm yr –1 along the Denali fault ( Fig. 1 ) ( Haeussler et al., 2017 ), which are compatible with Oligocene reconstructions of longterm slip decreasing east (~300 km) to west (~150 km) (e.g., Regan et al., 2021 ). Brocher et al. (2004) , based on aftershocks from the 2002 earthquake, inferred splay faults like the Granite Mountain and McCallum Creek thrusts connect to the Denali fault at depth ( Fig. 1 ), but it is not clear whether these faults are also hydrologically connected. Given that deep crustal fluid circulation, including mantle contributions, affects the strength of faults ( Kennedy et al., 1997 ; Lee et al., 2019 ), any variation in fluid flow along strike of the Denali fault and along splay faults would influence how the", "role": "user" }, { "content": "The 1,200-mile-long Denali Fault stretches in an upward arc from southwestern Alaska and the Bering Sea eastward to western Canada's Yukon Territory and British Columbia. The long-lived and active strike-slip fault system, which slices through Denali National Park and Preserve, is responsible for the formation of the Alaska Range. \"It's a big, sweeping fault and the source of a magnitude 7.9 earthquake in 2002, that ruptured more than 200 miles of the Denali Fault, along with the Totschunda Fault to the east, causing significant damage to remote villages and central Alaska's infrastructure,\" says Utah State University geochemist Dennis Newell. Understanding the restless fault's mantle-to-crust connections provides critical information for understanding the lithospheric-scale fault's seismic cycle, says Newell, associate professor in USU's Department of Geosciences. He and colleagues Jeff Benowitz, an Alaska-based geochronologist, Sean Regan of the University of Alaska Fairbanks, and doctoral candidate Coleman Hiett of USU, collected and analyzed helium and carbon isotopic data from springs along a nearly 250-mile segment of the fault and published their findings, \"Roadblocks and Speed Limits: Mantle-to-Surface Volatile Flux in the Lithospheric Scale Denali Fault, Alaska,\" in Geology. \"Active strike-slip faults like Denali have three-dimensional geometries with possible deep conduit connections below the Earth's surface,\" Newell says. \"But we don't know much about how and if these connections are maintained.\" To examine these possible deep connections, Newell and Regan sampled 12 springs along the Denali and Totschunda Faults, by way of helicopter and on foot, to the remote, mountainous regions of Alaska's interior. \"Helium-3, a rare isotope of helium gas, in springs is a good indicator of whether or not an area has a connection to the Earth's mantle,\" Newell says. \"Warm, bubbling springs west of the 2002 earthquake rupture, along the Cantwell segment of the Denali Fault, have a strong helium-3 signature, indicating intact connections to the mantle. In contrast, springs along the ruptured fault segment only have atmospheric gases, suggesting a 'roadblock' preventing the flow of mantle helium to the surface.\" These observations, he says, have implications for how groundwater pathways along the fault are changed by earthquakes, and the timescales on which they heal. \"The last major earthquake on the Cantwell segment was 400 years ago, and the helium data suggest those mantel connections have been reestablished,\" Newell says. \"These bubbling springs are indicative of the possibility of a future large destructive earthquake along the Denali Fault segment near Denali National Park, which receives some 600,000 visitors each summer.\" The geoscientists also seek data on how fast helium can move from the mantle to the crust along active faults. \"That's the 'speed limit' part of our research,\" Newell says. \"This is important as it reveals mantle-to-surface volatile flux and how fluid pressure gradients may impact fault strength and seismicity along the fault.\" The fault's mantle fluid flow rates fall in the range observed for the world's other major and active strike-slip faults that form plate boundaries, he says, including California's San Andreas Fault and Turkey's North Anatolian Fault Zone. These types of faults host large, devastating earthquakes, such as February 2023's deadly earthquake on the East Anatolia Fault, which caused widespread destruction in Turkey and Syria. \"Quantifying crust-to-mantle connections along major strike-slip faults is critical for understanding linkages between deep fluid flow, seismicity and fault healing,\" Newell says. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Helium and carbon isotopic data from 12 springs along a ~400 km segment of the Denali fault system (Alaska, USA), inform mantle-to-surface connections of this enigmatic structure. Warm springs on the main strand, west of the 2002 M7.9 Denali fault earthquake rupture, have 3 He/ 4 He as high as 2.4 R C /R A (air-corrected 3 He/ 4 He relative to air ratio) indicating ~30% mantle He. Corresponding δ 13 C values are −9.1‰ to −7.8‰ (relative to Vienna Peedee belemnite), suggesting that the CO 2 at these western springs is partially mantle derived. At the eastern end of the 2002 rupture, Totschunda fault springs have 3 He/ 4 He of 0.65–0.99 R C /R A (~8%–12% mantle He), with δ13C values (~0‰) from carbonates. Results confirm the Denali fault system is a lithosphericscale feature tapping mantle volatiles. Springs along the 2002 rupture yield air-like 3 He/ 4 He of 1 R/R A and δ 13 C values from −9.2‰ to −3.4‰, interpreted as representing shallow groundwater circulation through shales and carbonates without mantle contributions. A thrust splay parallel to the rupture zone has air-like 3 He/ 4 He, whereas an along-strike high-angle normal splay yields 3 He/ 4 He of 1.3 R C /R A (~16% mantle He), implying that flow paths along the ruptured strand are disrupted in the upper 10 km of the fault zone. Because the Denali fault is a lithospheric-scale, transcurrent structure separating North America from independently moving southern Alaska, we suggest that it has characteristics of a transform boundary. The similarity of our results to helium isotope values at analogous tectonic settings suggest that without magmatism influence, there is a maximum mantle fluid flux through continental strike-slip faults. INTRODUCTION Active strike-slip faults have three-dimensional geometries that vary along strike and can facilitate deep fluid flow and mantle-to-crust connections, with implications for the seismic cycle (e.g., Vauchez et al., 2012 ; Norris and Toy, 2014 ). Conversely, ancient “dead” strike-slip faults have been seismically imaged as crustal-scale features offsetting the Moho ( Diaconescu et al., 1998 ), but it is unclear whether these maintain mantle fluid connections. Furthermore, strike-slip faults that penetrate to mantle depths can facilitate lithosphere-scale deformation and act as transform plate boundaries, but not all continental strike-slip faults share these characteristics ( Andrew et al., 2023 ). Isotopic signatures of gases in springs (e.g., 3 He/ 4 He, δ 13 C) along active faults are ideal for quantifying mantle-to-crust connections and testing geophysical and structural models for strike-slip fault systems (e.g., Kennedy et al., 1997 ; de Leeuw et al., 2010 ; Klemperer et al., 2013 ). Documenting the presence of persistent mantle-to-surface volatile flux has implications for how fluid pressure gradients may impact fault strength and seismicity along strike-slip faults ( Kennedy et al., 1997 ). The Denali fault (northwestern North America) is a long-lived (>10 7 yr), >2000-km-long dextral strike-slip system (e.g., Benowitz et al., 2022 ). Here we present 3 He/ 4 He and δ 13 C data from previously ( Richter et al., 1973 ) and newly identified thermal springs along the Denali fault system in Alaska (USA) ( Fig. 1 ). We sampled springs located along and outside of the rupture associated with the 2002 M7.9 Denali fault earthquake ( Eberhart-Phillips et al., 2003 ). Results clarify questions about the lithospherescale nature of the Denali fault, hydrologic connectivity of fault splays and the main strand, and possible hydrologic impacts from the 2002 earthquake. We suggest that similarities in the 3 He/ 4 He ratio of springs at analogous tectonic settings place constraints on the mantle fluid flux into continental strike-slip faults. GEOLOGIC SETTING Southern Alaska, composed primarily of the Wrangellia composite terrane ( Trop et al., 2020 ), is delineated by the Denali fault system to the north and east and by the Aleutian Trench to the south ( Fig. 1 ). The Denali fault is active, demonstrated by a M7.9 earthquake in 2002 that ruptured ~340 km of the Denali and Totschunda faults ( Fig. 2 ) ( Eberhart-Phillips et al., 2003 ). Geodetic data indicate that southern Alaska is moving westward and independent of North America (e.g., Elliott and Freymueller, 2020 ). Hence, further knowledge of the Denali fault system’s lithospheric-scale nature is critical to discerning its role in the northeastern Pacific plate transform system and whether southern Alaska comprises an independent tectonic plate. The Denali fault system can be divided into the primarily strike-slip Totschunda fault (e.g., Trop et al., 2022 ), the main strand of the Denali fault which becomes more transpressive east to west ( Regan et al., 2021 ), and the ancient strikeslip and now dominantly dip-slip Hines Creek fault ( Benowitz et al., 2022 ). Based on receiver functions, Brennan et al. (2011) concluded the active central Denali fault does not extend into the mantle nor offset the Moho but the Hines Creek fault offsets the Moho by ~10 km. Conversely, Allam et al. (2017) , using double difference tomography and receiver functions, concluded the active strand of the Denali and the Hines Creek and Totschunda faults all extend into the mantle with ~10 km Moho offsets. Pleistocene slip rates decrease east to west from ~13 to ~5 mm yr –1 along the Denali fault ( Fig. 1 ) ( Haeussler et al., 2017 ), which are compatible with Oligocene reconstructions of longterm slip decreasing east (~300 km) to west (~150 km) (e.g., Regan et al., 2021 ). Brocher et al. (2004) , based on aftershocks from the 2002 earthquake, inferred splay faults like the Granite Mountain and McCallum Creek thrusts connect to the Denali fault at depth ( Fig. 1 ), but it is not clear whether these faults are also hydrologically connected. Given that deep crustal fluid circulation, including mantle contributions, affects the strength of faults ( Kennedy et al., 1997 ; Lee et al., 2019 ), any variation in fluid flow along strike of the Denali fault and along splay faults would influence how the<|im_end|> <|im_start|>assistant The 1,200-mile-long Denali Fault stretches in an upward arc from southwestern Alaska and the Bering Sea eastward to western Canada's Yukon Territory and British Columbia. The long-lived and active strike-slip fault system, which slices through Denali National Park and Preserve, is responsible for the formation of the Alaska Range. "It's a big, sweeping fault and the source of a magnitude 7.9 earthquake in 2002, that ruptured more than 200 miles of the Denali Fault, along with the Totschunda Fault to the east, causing significant damage to remote villages and central Alaska's infrastructure," says Utah State University geochemist Dennis Newell. Understanding the restless fault's mantle-to-crust connections provides critical information for understanding the lithospheric-scale fault's seismic cycle, says Newell, associate professor in USU's Department of Geosciences. He and colleagues Jeff Benowitz, an Alaska-based geochronologist, Sean Regan of the University of Alaska Fairbanks, and doctoral candidate Coleman Hiett of USU, collected and analyzed helium and carbon isotopic data from springs along a nearly 250-mile segment of the fault and published their findings, "Roadblocks and Speed Limits: Mantle-to-Surface Volatile Flux in the Lithospheric Scale Denali Fault, Alaska," in Geology. "Active strike-slip faults like Denali have three-dimensional geometries with possible deep conduit connections below the Earth's surface," Newell says. "But we don't know much about how and if these connections are maintained." To examine these possible deep connections, Newell and Regan sampled 12 springs along the Denali and Totschunda Faults, by way of helicopter and on foot, to the remote, mountainous regions of Alaska's interior. "Helium-3, a rare isotope of helium gas, in springs is a good indicator of whether or not an area has a connection to the Earth's mantle," Newell says. "Warm, bubbling springs west of the 2002 earthquake rupture, along the Cantwell segment of the Denali Fault, have a strong helium-3 signature, indicating intact connections to the mantle. In contrast, springs along the ruptured fault segment only have atmospheric gases, suggesting a 'roadblock' preventing the flow of mantle helium to the surface." These observations, he says, have implications for how groundwater pathways along the fault are changed by earthquakes, and the timescales on which they heal. "The last major earthquake on the Cantwell segment was 400 years ago, and the helium data suggest those mantel connections have been reestablished," Newell says. "These bubbling springs are indicative of the possibility of a future large destructive earthquake along the Denali Fault segment near Denali National Park, which receives some 600,000 visitors each summer." The geoscientists also seek data on how fast helium can move from the mantle to the crust along active faults. "That's the 'speed limit' part of our research," Newell says. "This is important as it reveals mantle-to-surface volatile flux and how fluid pressure gradients may impact fault strength and seismicity along the fault." The fault's mantle fluid flow rates fall in the range observed for the world's other major and active strike-slip faults that form plate boundaries, he says, including California's San Andreas Fault and Turkey's North Anatolian Fault Zone. These types of faults host large, devastating earthquakes, such as February 2023's deadly earthquake on the East Anatolia Fault, which caused widespread destruction in Turkey and Syria. "Quantifying crust-to-mantle connections along major strike-slip faults is critical for understanding linkages between deep fluid flow, seismicity and fault healing," Newell says. <|im_end|>

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331, 27990, 57790, 320, 23966, 13, 220, 17, 883, 320, 469, 655, 47489, 12, 92777, 3153, 1880, 453, 2637, 220, 1049, 18, 7609, 4323, 347, 5411, 828, 13519, 430, 18561, 28366, 374, 7366, 9909, 1637, 323, 9678, 315, 4892, 5270, 320, 68, 1326, 2637, 48644, 323, 7730, 1631, 84, 7218, 11, 220, 2366, 15, 7609, 32140, 11, 4726, 6677, 315, 279, 9973, 8115, 14867, 1887, 753, 46282, 24527, 11893, 13230, 7138, 374, 9200, 311, 42645, 287, 1202, 3560, 304, 279, 87244, 16867, 12235, 5276, 1887, 323, 3508, 18561, 28366, 41095, 459, 9678, 259, 440, 14338, 12235, 13, 578, 9973, 8115, 14867, 1887, 649, 387, 18255, 1139, 279, 15871, 13471, 1355, 34215, 350, 2469, 331, 27990, 14867, 320, 68, 1326, 2637, 350, 897, 1880, 453, 2637, 220, 2366, 17, 7026, 279, 1925, 42589, 315, 279, 9973, 8115, 14867, 902, 9221, 810, 1380, 69563, 11226, 311, 9909, 320, 3263, 276, 1880, 453, 2637, 220, 2366, 16, 7026, 323, 279, 14154, 23170, 34215, 323, 1457, 11358, 18007, 24522, 1355, 34215, 473, 1572, 24076, 14867, 320, 7505, 53431, 1880, 453, 2637, 220, 2366, 17, 7609, 20817, 389, 14291, 5865, 11, 59850, 1880, 453, 13, 320, 679, 16, 8, 20536, 279, 4642, 8792, 9973, 8115, 14867, 1587, 539, 13334, 1139, 279, 71532, 6463, 4445, 279, 20409, 78, 719, 279, 473, 1572, 24076, 14867, 36146, 279, 20409, 78, 555, 4056, 605, 13437, 13, 82671, 11, 2052, 309, 1880, 453, 13, 320, 679, 22, 8, 1174, 1701, 2033, 6811, 10390, 5814, 323, 14291, 5865, 11, 20536, 279, 4642, 42589, 315, 279, 9973, 8115, 323, 279, 473, 1572, 24076, 323, 350, 2469, 331, 27990, 57790, 682, 13334, 1139, 279, 71532, 449, 4056, 605, 13437, 20409, 78, 36146, 13, 33540, 380, 78782, 21818, 7969, 18979, 11226, 311, 9909, 505, 4056, 1032, 311, 4056, 20, 9653, 43438, 1389, 16, 3235, 279, 9973, 8115, 14867, 320, 23966, 13, 220, 16, 883, 320, 473, 6043, 1892, 1565, 1880, 453, 2637, 220, 679, 22, 7026, 902, 527, 18641, 449, 507, 7864, 78782, 16456, 20232, 315, 1317, 5098, 21818, 44649, 11226, 31857, 3101, 13437, 8, 311, 9909, 31857, 3965, 13437, 8, 320, 68, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Whether age-associated defects in T cells impact the immunogenicity and reactogenicity of mRNA vaccines remains unclear. Using a vaccinated cohort ( n = 216), we demonstrated that older adults (aged ≥65 years) had fewer vaccine-induced spike-specific CD4 + T cells including CXCR3 + circulating follicular helper T cells and the T H 1 subset of helper T cells after the first dose, which correlated with their lower peak IgG levels and fewer systemic adverse effects after the second dose, compared with younger adults. Moreover, spike-specific T H 1 cells in older adults expressed higher levels of programmed cell death protein 1, a negative regulator of T cell activation, which was associated with low spike-specific CD8 + T cell responses. Thus, an inefficient CD4 + T cell response after the first dose may reduce the production of helper T cytokines, even after the second dose, thereby lowering humoral and cellular immunity and reducing systemic reactogenicity. Therefore, enhancing CD4 + T cell response following the first dose is key to improving vaccine efficacy in older adults. Main Advanced age is the most important risk factor for severe coronavirus disease 2019 (COVID-19) outcomes 1 , 2 , 3 ; this may be largely due to the age-associated decline in immune competence. T cells are immune cells that belong to the adaptive immune system and play a central role in antigen-specific antibody response and cytotoxicity against virus-infected cells 4 . Despite their critical roles, the production of new T cells begins to decline during early life stages due to thymic involution and undergoes various qualitative and compositional changes and functional dysregulations with age 5 , 6 , 7 , 8 , 9 , 10 , 11 . Thus, older individuals are strongly recommended to receive vaccines; however, the benefits and efficacy of vaccination are limited, primarily due to the decreased effectiveness of adaptive immunity 12 , 13 , 14 . The newly developed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines are highly effective at preventing severe illness, as well as infection, at ~95% efficacy, even in participants aged ≥65 years 15 . However, spike-specific IgG levels and neutralizing antibody titers are significantly lower in older individuals 16 , 17 , 18 , 19 . Detailed immunological studies revealed that the mRNA vaccines elicit strong type 1 helper T (T H )1) cell and follicular helper T (T FH ) cell responses 20 , 21 . Importantly, older adults, especially individuals >80 years of age, showed fewer cytokine-positive CD4 + T cells after vaccination 16 , 19 . However, the detailed trajectory of T cell responses and how T H 1 and T FH cell responses are affected in older adults remains to be investigated. Considering the importance of T cells in vaccine responses, elucidating age-associated differences in T cell responses to mRNA vaccines is fundamental. Noticeable and severe adverse effects (AEs) are another characteristic of mRNA vaccines 22 . Notably, AEs are more frequent and more severe after the second dose 15 , which strongly suggests that AEs are a consequence of immunological memory. However, previous reports did not reach a consensus concerning the association between AEs and vaccine-induced immune reactions, likely due to the small cohorts and variations of the definition of AEs 23 , 24 , 25 , 26 , 27 . Moreover, most studies have examined the associations of AEs with the humoral immune response but not with T cell responses, which can result in the production of cytokines and thus cause systemic effects. In this study, we investigated these key questions by comparing the spike-specific T H 1 cell and T FH cell responses to two doses of mRNA vaccine between adults and older adults in a Japanese cohort of healthy individuals over 3 months after vaccination, including the priming and contraction phases. Furthermore, we explored the associations of spike-specific T cell responses with AEs. Our results provide an improved understanding of the mechanisms of age-related and individual differences in the effectiveness of mRNA vaccines and may be relevant for future vaccine strategies, especially for the highly vulnerable older population. Results Lower induction and early contraction of CD4 + T cell responses in older adults We studied 216 SARS-CoV-2-naïve Japanese donors comprising adults (aged <65 years; median age, 43 years; n = 107) and older adults (aged ≥ 65 years; median age, 71 years; n = 109) who met the eligibility criteria (see ‘ Study design ’ in the Methods ), having received two doses of BNT162b2 vaccine within around 3-week intervals (median, 21.0 d; range, 19.0 to 30.0 d), and were successfully followed up until 3 months after the first dose (Extended Data Fig. 1a,b and Table 1 ). Blood samples were obtained before the vaccination (Pre; median, −14 d (range, −29 to 0 d)), 2 weeks after the first dose (Post1; median, 11 d (range, 6–21 d)), 2 weeks after the second dose (Post2; median, 34 d (range, 30−39 d)) and 3 months after the first dose (3 mo; median, 93 d (range, 77–104 d; Extended Data Fig. 1a ). Donors were also followed up for medical conditions at each study visit. None of the donors tested positive for anti-SARS-CoV-2 nucleocapsid (N) protein IgM/IgG, which reflects the history of COVID-19 at enrollment (Table 1 ). Table 1 Participant characteristics at enrollment Full size table To quantify and characterize vaccine-induced T cell responses, we utilized activation-induced marker (AIM) and intracellular cytokine staining (ICS) assays (Extended Data Figs. 2 and 3 ) 20 , 21 , 28 , 29 , 30 , 31 , 32 . Peripheral blood mononuclear cells (PBMCs) were stimulated with overlapping peptide pools covering the complete sequence of the spike protein of SARS-CoV-2, which was used as a vaccine antigen. Markers used for flow cytometric analysis and the gating strategies are shown in Supplementary Table 1 and Extended Data Figs. 2 and 3 . The total number of CD4 + T cells in peripheral blood did not differ between adults and older adults", "role": "user" }, { "content": "The Yoko Hamazaki Laboratory at CiRA has reported that the slower onset of helper T-cell responses in the elderly after COVID-19 vaccinations is associated with lower antibody production, killer T cell activation, and frequency of adverse reactions. It is well known that immune functions generally decline with age (immunosenescence). However, it is not well understood how and to what extent aging impacts the responsiveness of T-cells—which play a central role in immune responses against viruses and cancer—to stimulation in vivo. In this study, the research team aimed to address these questions by taking advantage of the rare opportunity of a massive vaccination campaign, in which large groups of individuals are exposed to an identical antigen to stimulate their immune systems. A total of 216 healthy volunteers, approximately half adults (aged <65 years) and the other half from the elderly population (aged 65 years or older), all of whom were vaccinated against COVID-19 (Pfizer's BNT162b2), were recruited to the study. The Hamazaki group examined the T-cell responses of these individuals after vaccination and assessed how they correlated with antibody production and adverse reactions. The results showed that the helper T-cell response after vaccination in the elderly was characterized by slow onset but rapid contraction (waning of the immune response). In addition, vaccine-specific helper T-cells collected from the elderly expressed higher levels of PD-1 (programmed cell death-1), a protein that suppresses T-cell activation, suggesting that the response was more likely to be subdued. Regardless of age, they also found that individuals with a slower onset of the helper T-cell response had lower maximum antibody titers and killer T-cell activation, but were also less likely to experience systemic adverse reactions. These results suggest that the key to improving vaccine efficacy is to enhance the helper T-cell response and ensure sufficient cytokine production during the initial vaccination. Furthermore, it has become clear that there are not only age differences but also extremely large individual variations in the immune response induced by vaccines. These results may be useful for developing more effective vaccine formulations for the elderly and other people with declining immune functions, as well as adjusting vaccination schedules to better suit individual immune status. Additional data will be collected through long-term observation to determine whether there are any age-related differences in the maintenance of immune memory. Furthermore, a better understanding of the mechanisms underlying age and individual differences in the immune response will also help to improve other types of immunotherapies and to devise immune aging interventions (immune rejuvenation) in the future. The results of this study were published online in Nature Aging on January 12, 2023. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Whether age-associated defects in T cells impact the immunogenicity and reactogenicity of mRNA vaccines remains unclear. Using a vaccinated cohort ( n = 216), we demonstrated that older adults (aged ≥65 years) had fewer vaccine-induced spike-specific CD4 + T cells including CXCR3 + circulating follicular helper T cells and the T H 1 subset of helper T cells after the first dose, which correlated with their lower peak IgG levels and fewer systemic adverse effects after the second dose, compared with younger adults. Moreover, spike-specific T H 1 cells in older adults expressed higher levels of programmed cell death protein 1, a negative regulator of T cell activation, which was associated with low spike-specific CD8 + T cell responses. Thus, an inefficient CD4 + T cell response after the first dose may reduce the production of helper T cytokines, even after the second dose, thereby lowering humoral and cellular immunity and reducing systemic reactogenicity. Therefore, enhancing CD4 + T cell response following the first dose is key to improving vaccine efficacy in older adults. Main Advanced age is the most important risk factor for severe coronavirus disease 2019 (COVID-19) outcomes 1 , 2 , 3 ; this may be largely due to the age-associated decline in immune competence. T cells are immune cells that belong to the adaptive immune system and play a central role in antigen-specific antibody response and cytotoxicity against virus-infected cells 4 . Despite their critical roles, the production of new T cells begins to decline during early life stages due to thymic involution and undergoes various qualitative and compositional changes and functional dysregulations with age 5 , 6 , 7 , 8 , 9 , 10 , 11 . Thus, older individuals are strongly recommended to receive vaccines; however, the benefits and efficacy of vaccination are limited, primarily due to the decreased effectiveness of adaptive immunity 12 , 13 , 14 . The newly developed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines are highly effective at preventing severe illness, as well as infection, at ~95% efficacy, even in participants aged ≥65 years 15 . However, spike-specific IgG levels and neutralizing antibody titers are significantly lower in older individuals 16 , 17 , 18 , 19 . Detailed immunological studies revealed that the mRNA vaccines elicit strong type 1 helper T (T H )1) cell and follicular helper T (T FH ) cell responses 20 , 21 . Importantly, older adults, especially individuals >80 years of age, showed fewer cytokine-positive CD4 + T cells after vaccination 16 , 19 . However, the detailed trajectory of T cell responses and how T H 1 and T FH cell responses are affected in older adults remains to be investigated. Considering the importance of T cells in vaccine responses, elucidating age-associated differences in T cell responses to mRNA vaccines is fundamental. Noticeable and severe adverse effects (AEs) are another characteristic of mRNA vaccines 22 . Notably, AEs are more frequent and more severe after the second dose 15 , which strongly suggests that AEs are a consequence of immunological memory. However, previous reports did not reach a consensus concerning the association between AEs and vaccine-induced immune reactions, likely due to the small cohorts and variations of the definition of AEs 23 , 24 , 25 , 26 , 27 . Moreover, most studies have examined the associations of AEs with the humoral immune response but not with T cell responses, which can result in the production of cytokines and thus cause systemic effects. In this study, we investigated these key questions by comparing the spike-specific T H 1 cell and T FH cell responses to two doses of mRNA vaccine between adults and older adults in a Japanese cohort of healthy individuals over 3 months after vaccination, including the priming and contraction phases. Furthermore, we explored the associations of spike-specific T cell responses with AEs. Our results provide an improved understanding of the mechanisms of age-related and individual differences in the effectiveness of mRNA vaccines and may be relevant for future vaccine strategies, especially for the highly vulnerable older population. Results Lower induction and early contraction of CD4 + T cell responses in older adults We studied 216 SARS-CoV-2-naïve Japanese donors comprising adults (aged <65 years; median age, 43 years; n = 107) and older adults (aged ≥ 65 years; median age, 71 years; n = 109) who met the eligibility criteria (see ‘ Study design ’ in the Methods ), having received two doses of BNT162b2 vaccine within around 3-week intervals (median, 21.0 d; range, 19.0 to 30.0 d), and were successfully followed up until 3 months after the first dose (Extended Data Fig. 1a,b and Table 1 ). Blood samples were obtained before the vaccination (Pre; median, −14 d (range, −29 to 0 d)), 2 weeks after the first dose (Post1; median, 11 d (range, 6–21 d)), 2 weeks after the second dose (Post2; median, 34 d (range, 30−39 d)) and 3 months after the first dose (3 mo; median, 93 d (range, 77–104 d; Extended Data Fig. 1a ). Donors were also followed up for medical conditions at each study visit. None of the donors tested positive for anti-SARS-CoV-2 nucleocapsid (N) protein IgM/IgG, which reflects the history of COVID-19 at enrollment (Table 1 ). Table 1 Participant characteristics at enrollment Full size table To quantify and characterize vaccine-induced T cell responses, we utilized activation-induced marker (AIM) and intracellular cytokine staining (ICS) assays (Extended Data Figs. 2 and 3 ) 20 , 21 , 28 , 29 , 30 , 31 , 32 . Peripheral blood mononuclear cells (PBMCs) were stimulated with overlapping peptide pools covering the complete sequence of the spike protein of SARS-CoV-2, which was used as a vaccine antigen. Markers used for flow cytometric analysis and the gating strategies are shown in Supplementary Table 1 and Extended Data Figs. 2 and 3 . The total number of CD4 + T cells in peripheral blood did not differ between adults and older adults<|im_end|> <|im_start|>assistant The Yoko Hamazaki Laboratory at CiRA has reported that the slower onset of helper T-cell responses in the elderly after COVID-19 vaccinations is associated with lower antibody production, killer T cell activation, and frequency of adverse reactions. It is well known that immune functions generally decline with age (immunosenescence). However, it is not well understood how and to what extent aging impacts the responsiveness of T-cells—which play a central role in immune responses against viruses and cancer—to stimulation in vivo. In this study, the research team aimed to address these questions by taking advantage of the rare opportunity of a massive vaccination campaign, in which large groups of individuals are exposed to an identical antigen to stimulate their immune systems. A total of 216 healthy volunteers, approximately half adults (aged <65 years) and the other half from the elderly population (aged 65 years or older), all of whom were vaccinated against COVID-19 (Pfizer's BNT162b2), were recruited to the study. The Hamazaki group examined the T-cell responses of these individuals after vaccination and assessed how they correlated with antibody production and adverse reactions. The results showed that the helper T-cell response after vaccination in the elderly was characterized by slow onset but rapid contraction (waning of the immune response). In addition, vaccine-specific helper T-cells collected from the elderly expressed higher levels of PD-1 (programmed cell death-1), a protein that suppresses T-cell activation, suggesting that the response was more likely to be subdued. Regardless of age, they also found that individuals with a slower onset of the helper T-cell response had lower maximum antibody titers and killer T-cell activation, but were also less likely to experience systemic adverse reactions. These results suggest that the key to improving vaccine efficacy is to enhance the helper T-cell response and ensure sufficient cytokine production during the initial vaccination. Furthermore, it has become clear that there are not only age differences but also extremely large individual variations in the immune response induced by vaccines. These results may be useful for developing more effective vaccine formulations for the elderly and other people with declining immune functions, as well as adjusting vaccination schedules to better suit individual immune status. Additional data will be collected through long-term observation to determine whether there are any age-related differences in the maintenance of immune memory. Furthermore, a better understanding of the mechanisms underlying age and individual differences in the immune response will also help to improve other types of immunotherapies and to devise immune aging interventions (immune rejuvenation) in the future. The results of this study were published online in Nature Aging on January 12, 2023. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Since 2020, the COVID-19 pandemic has urged event holders to shift conferences online. Virtual and hybrid conferences are greener alternatives to in-person conferences, yet their environmental sustainability has not been fully assessed. Considering food, accommodation, preparation, execution, information and communication technology, and transportation, here we report comparative life cycle assessment results of in-person, virtual, and hybrid conferences and consider carbon footprint trade-offs between in-person participation and hybrid conferences. We find that transitioning from in-person to virtual conferencing can substantially reduce the carbon footprint by 94% and energy use by 90%. For the sake of maintaining more than 50% of in-person participation, carefully selected hubs for hybrid conferences have the potential to slash carbon footprint and energy use by two-thirds. Furthermore, switching the dietary type of future conferences to plant-based diets and improving energy efficiencies of the information and communication technology sector can further reduce the carbon footprint of virtual conferences. Introduction The rapid expansion of the global event industry over the last few decades has brought about tourism growth and socio-economic development and also exerted surprisingly large pressure on the goals to mitigate global climate change. In 2017, more than 1.5 billion participants across over 180 countries were involved in business events, contributing to $2.5 trillion of spending and supporting 26 million jobs 1 . In addition, the number of regular international events (≥50 participants) doubles every ten years, and the market size of the trillion-dollar events industry is expected to grow at a rate of 11.2% for this decade 2 , 3 . As the event industry proliferates, it also leads to substantial greenhouse gas (GHG) emissions. The carbon footprint per participant reaches up to 3000 kg CO 2 equivalent as reported by previous life cycle assessment (LCA) studies 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , suggesting that the annual carbon footprint for the global event industry are of the same order of magnitude as the yearly GHG emissions of the entire United States (U.S.), responsible for more than 10% of global CO 2 emissions 14 . To meet the Paris Agreement target 15 , the event organizers adopt sustainability measures 16 , and promotion towards the less carbon-intensive virtual conferences has never been discontinued in the past decade 8 , 17 , 18 , 19 , 20 . Since 2020, the COVID-19 pandemic has urged event holders to shift conferences online. Whether future conferences should return in-person, keep fully virtual, or evolve to a hybrid of both has been widely debated 19 . Common reasons against virtual conferences can be categorized as digital-meeting fatigue, loss of serendipitous hallway conversations, impersonal interactions, and challenging time zones 19 . By contrast, supporters of virtual conferences consider virtual interactions as a far more accessible, inclusive, and sustainable counterpart to the traditional in-person format 18 , 21 , 22 , 23 . As a compromise of the two, hybrid conferences may be a viable solution 24 , 25 . However, there is a minimal quantitative understanding of the environmental impacts from different modes of conferences. In order to understand the sustainability implications of future conferences and inform the policies, it is essential to quantify the environmental footprints of virtual, in-person, and hybrid conferences and also investigate the trade-offs between in-person interactions and the life cycle carbon footprint. Previous analysis on the travel emissions of in-person conferences and their virtual and multi-hub hybrid counterparts has been conducted 4 , but it neglected greenhouse gas emissions from the video-conferencing technology and auxiliary emissions from resource and energy consumptions other than transportation, such as conference planning and preparation, execution, catering, and accommodation during the conference. This simplification may overrate the benefits of virtual conferences and cause discriminating opposition to the in-person conferences. A recent study on the carbon footprint of virtual, in-person, and hybrid conferences accounted for the video-conferencing-related emissions, transportation, execution, catering, and accommodation 26 . However, it considered a single conference hub for both in-person and hybrid conferences and thus neglected the geographical effects of hub selection and participant assignment. Several studies attempted to quantify the environmental impacts from virtual and in-person conferences 5 , 6 , but none of them assessed the environmental sustainability of hybrid conferences. Thus, a critical gap exists in improving the understanding of life cycle environmental impacts of in-person, virtual, and hybrid conferences. In addition, the geographical effects of hub selection and participant assignment have not yet been investigated in the literature, to the best of our knowledge. To fill these knowledge gaps, the objective of this study is to quantify the life cycle environmental impacts of in-person, virtual, and hybrid conferences and to understand the trade-offs between in-person interactions and the carbon footprint of conferences. Here, we present holistic LCA results on the most concerning carbon footprint and cumulative energy demand (CED) of the in-person, virtual, and hybrid conferences to understand their impacts on climate change, as shown in Fig. 1 . In addition, a total of 17 ReCiPe midpoint indicators 27 , each of which represents a specific aspect of environmental concerns, are adopted to demonstrate the full-spectrum environmental impacts and to identify environmental hotspots. Following the ISO 14040 standard 28 , the LCA methodology is constituted by four phases, including goal and scope definition, life cycle inventory (LCI), life cycle impact assessment (LCIA), and interpretation. The four phases of this study are detailed in the Methods section. Hub selections and participant assignments are optimized using a facility location model to assess the potentials of mitigating carbon footprint for in-person conferences with multiple conference hubs. Participants of the 2020 American Center for Life Cycle Assessment virtual conference are used for this case study. We demonstrate that the carbon footprint can be lowered by 94% and CED by 90% when switching from in-person to virtual conferences. Furthermore, we consider two sets of scenarios for the hybrid conferences to investigate the trade-offs between in-person communication and carbon footprint. In particular, the Maximum Virtual Participation", "role": "user" }, { "content": "The COVID-19 global pandemic—unexpectedly—has shown humanity a new way to reduce climate change: Scrap in-person meetings and conventions. Moving a professional conference completely online reduces its carbon footprint by 94%, and shifting it to a hybrid model, with no more than half of conventioneers online, curtails the footprint to 67%, according to a new Cornell University-led study in Nature Communication. The annual carbon footprint for the global event and convention industry is on par with the yearly greenhouse gas emissions of the entire U.S., according to the new paper. \"We all go to conferences. We fly, we drive, we check in to a hotel, give a talk, meet people—and we're done,\" said senior author Fengqi You, professor in energy systems engineering at Cornell University and a senior faculty fellow at the Cornell Atkinson Center for Sustainability. \"But we looked at this problem comprehensively and behind the scenes, conventions generate a lot of carbon, consume a lot of energy, print a lot of paper, offer a lot of food—not to mention create municipal solid waste. Yet, video conferencing also requires energy and equipment use. Conference planning means a lot to consider.\" By studying the amount of carbon needed, adding regional conference hubs at the right locations and boosting virtual participation levels, carbon-reduction benefits can be achieved, You said. \"But environmental benefits become less prominent as the number of regional hubs increases\" he said. In 2017, more than 1.5 billion participants—from about 180 countries—traveled to attend conferences, according to the paper. The number of regular, international convention events—of more than 50 people—doubles every 10 years, and the convention industry's market size is expected to grow at a 11.2% rate over the next decade. The growth leads to substantial greenhouse gas emissions, said Yanqiu Tao, the first author of the paper and a doctoral student at You's Process-Energy-Environmental Systems Engineering (PEESE) lab. The carbon footprint per individual participant reaches up to 6,600 pounds of carbon dioxide equivalent, as reported by life cycle assessment studies. For in-person conferences, Tao and You suggest participants should reduce stopovers when booking flights. Hybrid and in-person meeting organizers should carefully select hubs and take transportation modes and distances into consideration. For virtual conferences, carbon-reduction opportunities include improving the energy efficiency of the information and communication technology sector and increasing the share of renewable energy in the power grids. \"There is a lot of interest and attention on climate change, so moving from in-person conferences to hybrid or remote events would be beneficial,\" You said. \"But we should also be cautious and optimize decisions in terms of selecting hubs and determining participant levels for hybrid meetings.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Since 2020, the COVID-19 pandemic has urged event holders to shift conferences online. Virtual and hybrid conferences are greener alternatives to in-person conferences, yet their environmental sustainability has not been fully assessed. Considering food, accommodation, preparation, execution, information and communication technology, and transportation, here we report comparative life cycle assessment results of in-person, virtual, and hybrid conferences and consider carbon footprint trade-offs between in-person participation and hybrid conferences. We find that transitioning from in-person to virtual conferencing can substantially reduce the carbon footprint by 94% and energy use by 90%. For the sake of maintaining more than 50% of in-person participation, carefully selected hubs for hybrid conferences have the potential to slash carbon footprint and energy use by two-thirds. Furthermore, switching the dietary type of future conferences to plant-based diets and improving energy efficiencies of the information and communication technology sector can further reduce the carbon footprint of virtual conferences. Introduction The rapid expansion of the global event industry over the last few decades has brought about tourism growth and socio-economic development and also exerted surprisingly large pressure on the goals to mitigate global climate change. In 2017, more than 1.5 billion participants across over 180 countries were involved in business events, contributing to $2.5 trillion of spending and supporting 26 million jobs 1 . In addition, the number of regular international events (≥50 participants) doubles every ten years, and the market size of the trillion-dollar events industry is expected to grow at a rate of 11.2% for this decade 2 , 3 . As the event industry proliferates, it also leads to substantial greenhouse gas (GHG) emissions. The carbon footprint per participant reaches up to 3000 kg CO 2 equivalent as reported by previous life cycle assessment (LCA) studies 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , suggesting that the annual carbon footprint for the global event industry are of the same order of magnitude as the yearly GHG emissions of the entire United States (U.S.), responsible for more than 10% of global CO 2 emissions 14 . To meet the Paris Agreement target 15 , the event organizers adopt sustainability measures 16 , and promotion towards the less carbon-intensive virtual conferences has never been discontinued in the past decade 8 , 17 , 18 , 19 , 20 . Since 2020, the COVID-19 pandemic has urged event holders to shift conferences online. Whether future conferences should return in-person, keep fully virtual, or evolve to a hybrid of both has been widely debated 19 . Common reasons against virtual conferences can be categorized as digital-meeting fatigue, loss of serendipitous hallway conversations, impersonal interactions, and challenging time zones 19 . By contrast, supporters of virtual conferences consider virtual interactions as a far more accessible, inclusive, and sustainable counterpart to the traditional in-person format 18 , 21 , 22 , 23 . As a compromise of the two, hybrid conferences may be a viable solution 24 , 25 . However, there is a minimal quantitative understanding of the environmental impacts from different modes of conferences. In order to understand the sustainability implications of future conferences and inform the policies, it is essential to quantify the environmental footprints of virtual, in-person, and hybrid conferences and also investigate the trade-offs between in-person interactions and the life cycle carbon footprint. Previous analysis on the travel emissions of in-person conferences and their virtual and multi-hub hybrid counterparts has been conducted 4 , but it neglected greenhouse gas emissions from the video-conferencing technology and auxiliary emissions from resource and energy consumptions other than transportation, such as conference planning and preparation, execution, catering, and accommodation during the conference. This simplification may overrate the benefits of virtual conferences and cause discriminating opposition to the in-person conferences. A recent study on the carbon footprint of virtual, in-person, and hybrid conferences accounted for the video-conferencing-related emissions, transportation, execution, catering, and accommodation 26 . However, it considered a single conference hub for both in-person and hybrid conferences and thus neglected the geographical effects of hub selection and participant assignment. Several studies attempted to quantify the environmental impacts from virtual and in-person conferences 5 , 6 , but none of them assessed the environmental sustainability of hybrid conferences. Thus, a critical gap exists in improving the understanding of life cycle environmental impacts of in-person, virtual, and hybrid conferences. In addition, the geographical effects of hub selection and participant assignment have not yet been investigated in the literature, to the best of our knowledge. To fill these knowledge gaps, the objective of this study is to quantify the life cycle environmental impacts of in-person, virtual, and hybrid conferences and to understand the trade-offs between in-person interactions and the carbon footprint of conferences. Here, we present holistic LCA results on the most concerning carbon footprint and cumulative energy demand (CED) of the in-person, virtual, and hybrid conferences to understand their impacts on climate change, as shown in Fig. 1 . In addition, a total of 17 ReCiPe midpoint indicators 27 , each of which represents a specific aspect of environmental concerns, are adopted to demonstrate the full-spectrum environmental impacts and to identify environmental hotspots. Following the ISO 14040 standard 28 , the LCA methodology is constituted by four phases, including goal and scope definition, life cycle inventory (LCI), life cycle impact assessment (LCIA), and interpretation. The four phases of this study are detailed in the Methods section. Hub selections and participant assignments are optimized using a facility location model to assess the potentials of mitigating carbon footprint for in-person conferences with multiple conference hubs. Participants of the 2020 American Center for Life Cycle Assessment virtual conference are used for this case study. We demonstrate that the carbon footprint can be lowered by 94% and CED by 90% when switching from in-person to virtual conferences. Furthermore, we consider two sets of scenarios for the hybrid conferences to investigate the trade-offs between in-person communication and carbon footprint. In particular, the Maximum Virtual Participation<|im_end|> <|im_start|>assistant The COVID-19 global pandemic—unexpectedly—has shown humanity a new way to reduce climate change: Scrap in-person meetings and conventions. Moving a professional conference completely online reduces its carbon footprint by 94%, and shifting it to a hybrid model, with no more than half of conventioneers online, curtails the footprint to 67%, according to a new Cornell University-led study in Nature Communication. The annual carbon footprint for the global event and convention industry is on par with the yearly greenhouse gas emissions of the entire U.S., according to the new paper. "We all go to conferences. We fly, we drive, we check in to a hotel, give a talk, meet people—and we're done," said senior author Fengqi You, professor in energy systems engineering at Cornell University and a senior faculty fellow at the Cornell Atkinson Center for Sustainability. "But we looked at this problem comprehensively and behind the scenes, conventions generate a lot of carbon, consume a lot of energy, print a lot of paper, offer a lot of food—not to mention create municipal solid waste. Yet, video conferencing also requires energy and equipment use. Conference planning means a lot to consider." By studying the amount of carbon needed, adding regional conference hubs at the right locations and boosting virtual participation levels, carbon-reduction benefits can be achieved, You said. "But environmental benefits become less prominent as the number of regional hubs increases" he said. In 2017, more than 1.5 billion participants—from about 180 countries—traveled to attend conferences, according to the paper. The number of regular, international convention events—of more than 50 people—doubles every 10 years, and the convention industry's market size is expected to grow at a 11.2% rate over the next decade. The growth leads to substantial greenhouse gas emissions, said Yanqiu Tao, the first author of the paper and a doctoral student at You's Process-Energy-Environmental Systems Engineering (PEESE) lab. The carbon footprint per individual participant reaches up to 6,600 pounds of carbon dioxide equivalent, as reported by life cycle assessment studies. For in-person conferences, Tao and You suggest participants should reduce stopovers when booking flights. Hybrid and in-person meeting organizers should carefully select hubs and take transportation modes and distances into consideration. For virtual conferences, carbon-reduction opportunities include improving the energy efficiency of the information and communication technology sector and increasing the share of renewable energy in the power grids. "There is a lot of interest and attention on climate change, so moving from in-person conferences to hybrid or remote events would be beneficial," You said. "But we should also be cautious and optimize decisions in terms of selecting hubs and determining participant levels for hybrid meetings." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Increased intake of dietary carbohydrate that is fermented in the colon by the microbiota has been reported to decrease body weight, although the mechanism remains unclear. Here we use in vivo 11 C-acetate and PET-CT scanning to show that colonic acetate crosses the blood–brain barrier and is taken up by the brain. Intraperitoneal acetate results in appetite suppression and hypothalamic neuronal activation patterning. We also show that acetate administration is associated with activation of acetyl-CoA carboxylase and changes in the expression profiles of regulatory neuropeptides that favour appetite suppression. Furthermore, we demonstrate through 13 C high-resolution magic-angle-spinning that 13 C acetate from fermentation of 13 C-labelled carbohydrate in the colon increases hypothalamic 13 C acetate above baseline levels. Hypothalamic 13 C acetate regionally increases the 13 C labelling of the glutamate–glutamine and GABA neuroglial cycles, with hypothalamic 13 C lactate reaching higher levels than the ‘remaining brain’. These observations suggest that acetate has a direct role in central appetite regulation. Introduction Obesity has reached epidemic proportions worldwide, with incidence rates above 20% in most western countries now representing a major public health burden 1 . This rise in obesity is fuelled by the mismatch between an inherited genetic predisposition for survival in environments where food supply is limited and the current obesogenic environment where reduced physical activity and excess energy intake prevails 2 . Modern food processing has resulted in the mass production of cheap, energy-dense foods that are generally high in refined sugars and fats but low in fibre 3 . It has been estimated that the Palaeolithic diet delivered >100 g per day of fibre, whereas current western intakes are only between 10 and 20 g per day 4 . Much of the fibre consumed in the Palaeolithic diet, unlike current fibre intake, would have been highly fermentable. There is a growing body of evidence that links fermentation of dietary carbohydrate (including fibre) by the colonic microbiota to positive effects on metabolism 5 . Observations by Cani et al. 6 demonstrated that rats exposed to a high-fat diet (HFD) with an increased fermentable carbohydrate (FC) component for 4 weeks had lower dietary energy intake, body weight and adiposity, suggesting that increased dietary FC leads to improved appetite and body weight regulation. FCs are thought to promote the release of the anorectic gut hormones peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) (ref. 7 ). However, FC-associated weight loss in human and rodent models have failed to consistently show increases in these anorectic hormones 8 . We have recently shown in mice that dietary FC supplementation is associated with reduced energy intake, body weight, adiposity and changes in hypothalamic neuronal activation patterns, all of which were independent of changes in circulating concentrations of GLP-1 (ref. 9 ). To better understand the mechanism behind the anorectic action of FC supplementation, we investigated the direct effects of the most abundant end product of colonic FC fermentation, the short-chain fatty acid (SCFA) acetate, on the control of appetite. We present herein that acetate derived from the colonic fermentation of FC acts to directly supress appetite through central hypothalamic mechanisms involving changes in transcellular neurotransmitter cycles. This, therefore, opens up new research directions into the promotion of acetate production by colonic microbiota and therapeutic strategies for the prevention and treatment of obesity. Results The effect of FCs on body weight We fed C57BL/6 mice with HFD supplemented with either the FC inulin (HF-I) or the poorly fermentable fibre cellulose (HF-C). After 8 weeks, mice fed the HF-I diet gained significantly less weight than those fed HF-C ( Fig. 1a ) and consumed significantly less food ( Fig. 1b ). SCFA analysis of the colonic content of the former animals demonstrated a significant increase in total SCFA concentrations and especially the most abundant SCFA, acetate ( Fig. 1c ). Although others have reported that FC supplementation leads to an increase in the anorectic hormones GLP-1 and PYY 6 , our group has recently reported that FC-rich diets increase manganese-enhanced MRI (MEMRI) signal in the hypothalamus, a proxy of neuronal activation, via a mechanism that appears to be independent of changes in GLP-1 (ref. 9 ). In support of this, infusion of anorectic gut hormones have previously been shown to suppress hypothalamic MEMRI signal 10 , thereby suggesting that any increase in signal seen following FC supplementation is not PYY or GLP-1 dependent. We therefore hypothesized that there was a direct effect of SCFAs on appetite regulation, namely by acetate, given it is the most abundant SCFA produced in the colon, and that it partially avoids hepatic clearance to reach micromolar concentrations in the peripheral circulation. Figure 1: FCs reduce food intake and increase faecal SCFA concentrations. ( a ) Body weight gain and ( b ) average weekly food intake of mice fed with either a HFD supplemented with the highly fermentable fibre inulin (HF-I) or a relatively non-fermentable fibre cellulose (HF-C). Body weight gain and average food intake significantly reduced in the HF-I group, ** P <0.01, ** P <0.05 based on two-sided, unpaired Student’s t -test( n =12 per group). ( c ) Total and acetate-only faecal SCFA concentrations obtained from HF-C and HF-I fed mice ** P <0.01 based on two-sided, unpaired Student’s t -test ( n =6 per group randomly selected from the n =24 cohort). ( d ) The biodistribution of carbon-11 ( 11 C) i.v. acetate as determined using PET scanning. Image depicts a fasted mouse following i.v. infusion. Image shows uptake in the brain, liver and heart. ( e – g ) Brain, liver and heart uptake of i.v. and colon infused 11 C-acetate as expressed as a percentage of the initial dose administered. No significant differences, when compared by GEE and Mann–Whitney U -test, were observed between i.v. administrations in the fed or fasted state, but there is a slower increase when the 11 C-acetate was colonically infused ( P <0.001; n =3–4 per group). Full size image The biodistribution of acetate and uptake in the", "role": "user" }, { "content": "(Medical Xpress)—New research has helped unpick a long-standing mystery about how dietary fibre supresses appetite. In a study led by Imperial College London and the Medical Research Council (MRC), an international team of researchers identified an anti-appetite molecule called acetate that is naturally released when we digest fibre in the gut. Once released, the acetate is transported to the brain where it produces a signal to tell us to stop eating. The research, published in Nature Communications, confirms the natural benefits of increasing the amount of fibre in our diets to control over-eating and could also help develop methods to reduce appetite. The study found that acetate reduces appetite when directly applied into the bloodstream, the colon or the brain. Dietary fibre is found in most plants and vegetables but tends to be at low levels in processed food. When fibre is digested by bacteria in our colon, it ferments and releases large amounts of acetate as a waste product. The study tracked the pathway of acetate from the colon to the brain and identified some of the mechanisms that enable it to influence appetite. lead author of the study Professor Gary Frost, from the Department of Medicine at Imperial College London, said: \"The average diet in Europe today contains about 15g of fibre per day. In stone-age times we ate about 100g per day, but now we favour low-fibre ready-made meals over vegetables, pulses and other sources of fibre. Unfortunately our digestive system has not yet evolved to deal with this modern diet and this mismatch contributes to the current obesity epidemic. Our research has shown that the release of acetate is central to how fibre supresses our appetite and this could help scientists to tackle overeating.\" The study analysed the effects of a form of dietary fibre called inulin which comes from chicory and sugar beets and is also added to cereal bars. Using a mouse model, researchers demonstrated that mice fed on a high-fat diet with added inulin ate less and gained less weight than mice fed on a high-fat diet with no inulin. Further analysis showed that the mice fed on a diet containing inulin had a high level of acetate in their guts. Using positron emission tomography (PET) scans, the researchers tracked the acetate through the body from the colon to the liver and the heart and showed that it eventually ended up in the hypothalamus region of the brain, which controls hunger. In collaboration with Consejo Superior de Investigaciones Científicas (CSIC) in Madrid, the researchers investigated the effects of acetate in the hypothalamus using a cutting-edge scanning technique called High Resolution Magic Angle Spinning. Professor Sebastian Cerdán from CSIC said: \"This complements the PET scans and allows us to follow the metabolism of acetate in the hypothalamus. From this we could clearly see that the acetate accumulates in the hypothalamus after fibre has been digested. The acetate then triggers a series of chemical events in the hypothalamus leading to the firing of pro-opiomelanocortin neurons, which are known to supress appetite.\" This is the first demonstration that acetate released from dietary fibre can affect the appetite response in the brain. The research also showed that when acetate was injected into the bloodstream, the colon or the brain it reduced the amount of food eaten by mice. Co-author on the study Professor Jimmy Bell, from the MRC Clinical Sciences Centre, said: \"It's exciting that we have started to really understand what lies behind fibre's natural ability to supress our appetite and identified acetate as essential to the process. In the context of the growing rates of obesity in western countries, the findings of the research could inform potential methods to prevent weight gain.\" Professor Gary Frost added: \"The major challenge is to develop an approach that will deliver the amount of acetate needed to supress appetite but in a form that is acceptable and safe for humans. Acetate is only active for a short amount of time in the body so if we focussed on a purely acetate-based product we would need to find a way to drip-feed it and mimic its slow release in the gut. \"Another option is to focus on the fibre and manipulate it so that it produces more acetate than normal and less fibre is needed to have the same effect, providing a more palatable and comfortable option than massively increasing the amount of fibre in our diet. Developing these approaches will be difficult but it's a good challenge to have and we're looking forward to researching possible ways of using acetate to address health issues around weight gain.\" Professor David Lomas, Chair of the MRC's Population and Systems Medicine Board, added: \"It's becoming increasingly clear that the interaction between the gut and the brain plays a key role in controlling how much food we eat. Being able to influence this relationship, for example using acetate to suppress appetite, may in future lead to new, non-surgical treatments for obesity.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Increased intake of dietary carbohydrate that is fermented in the colon by the microbiota has been reported to decrease body weight, although the mechanism remains unclear. Here we use in vivo 11 C-acetate and PET-CT scanning to show that colonic acetate crosses the blood–brain barrier and is taken up by the brain. Intraperitoneal acetate results in appetite suppression and hypothalamic neuronal activation patterning. We also show that acetate administration is associated with activation of acetyl-CoA carboxylase and changes in the expression profiles of regulatory neuropeptides that favour appetite suppression. Furthermore, we demonstrate through 13 C high-resolution magic-angle-spinning that 13 C acetate from fermentation of 13 C-labelled carbohydrate in the colon increases hypothalamic 13 C acetate above baseline levels. Hypothalamic 13 C acetate regionally increases the 13 C labelling of the glutamate–glutamine and GABA neuroglial cycles, with hypothalamic 13 C lactate reaching higher levels than the ‘remaining brain’. These observations suggest that acetate has a direct role in central appetite regulation. Introduction Obesity has reached epidemic proportions worldwide, with incidence rates above 20% in most western countries now representing a major public health burden 1 . This rise in obesity is fuelled by the mismatch between an inherited genetic predisposition for survival in environments where food supply is limited and the current obesogenic environment where reduced physical activity and excess energy intake prevails 2 . Modern food processing has resulted in the mass production of cheap, energy-dense foods that are generally high in refined sugars and fats but low in fibre 3 . It has been estimated that the Palaeolithic diet delivered >100 g per day of fibre, whereas current western intakes are only between 10 and 20 g per day 4 . Much of the fibre consumed in the Palaeolithic diet, unlike current fibre intake, would have been highly fermentable. There is a growing body of evidence that links fermentation of dietary carbohydrate (including fibre) by the colonic microbiota to positive effects on metabolism 5 . Observations by Cani et al. 6 demonstrated that rats exposed to a high-fat diet (HFD) with an increased fermentable carbohydrate (FC) component for 4 weeks had lower dietary energy intake, body weight and adiposity, suggesting that increased dietary FC leads to improved appetite and body weight regulation. FCs are thought to promote the release of the anorectic gut hormones peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) (ref. 7 ). However, FC-associated weight loss in human and rodent models have failed to consistently show increases in these anorectic hormones 8 . We have recently shown in mice that dietary FC supplementation is associated with reduced energy intake, body weight, adiposity and changes in hypothalamic neuronal activation patterns, all of which were independent of changes in circulating concentrations of GLP-1 (ref. 9 ). To better understand the mechanism behind the anorectic action of FC supplementation, we investigated the direct effects of the most abundant end product of colonic FC fermentation, the short-chain fatty acid (SCFA) acetate, on the control of appetite. We present herein that acetate derived from the colonic fermentation of FC acts to directly supress appetite through central hypothalamic mechanisms involving changes in transcellular neurotransmitter cycles. This, therefore, opens up new research directions into the promotion of acetate production by colonic microbiota and therapeutic strategies for the prevention and treatment of obesity. Results The effect of FCs on body weight We fed C57BL/6 mice with HFD supplemented with either the FC inulin (HF-I) or the poorly fermentable fibre cellulose (HF-C). After 8 weeks, mice fed the HF-I diet gained significantly less weight than those fed HF-C ( Fig. 1a ) and consumed significantly less food ( Fig. 1b ). SCFA analysis of the colonic content of the former animals demonstrated a significant increase in total SCFA concentrations and especially the most abundant SCFA, acetate ( Fig. 1c ). Although others have reported that FC supplementation leads to an increase in the anorectic hormones GLP-1 and PYY 6 , our group has recently reported that FC-rich diets increase manganese-enhanced MRI (MEMRI) signal in the hypothalamus, a proxy of neuronal activation, via a mechanism that appears to be independent of changes in GLP-1 (ref. 9 ). In support of this, infusion of anorectic gut hormones have previously been shown to suppress hypothalamic MEMRI signal 10 , thereby suggesting that any increase in signal seen following FC supplementation is not PYY or GLP-1 dependent. We therefore hypothesized that there was a direct effect of SCFAs on appetite regulation, namely by acetate, given it is the most abundant SCFA produced in the colon, and that it partially avoids hepatic clearance to reach micromolar concentrations in the peripheral circulation. Figure 1: FCs reduce food intake and increase faecal SCFA concentrations. ( a ) Body weight gain and ( b ) average weekly food intake of mice fed with either a HFD supplemented with the highly fermentable fibre inulin (HF-I) or a relatively non-fermentable fibre cellulose (HF-C). Body weight gain and average food intake significantly reduced in the HF-I group, ** P <0.01, ** P <0.05 based on two-sided, unpaired Student’s t -test( n =12 per group). ( c ) Total and acetate-only faecal SCFA concentrations obtained from HF-C and HF-I fed mice ** P <0.01 based on two-sided, unpaired Student’s t -test ( n =6 per group randomly selected from the n =24 cohort). ( d ) The biodistribution of carbon-11 ( 11 C) i.v. acetate as determined using PET scanning. Image depicts a fasted mouse following i.v. infusion. Image shows uptake in the brain, liver and heart. ( e – g ) Brain, liver and heart uptake of i.v. and colon infused 11 C-acetate as expressed as a percentage of the initial dose administered. No significant differences, when compared by GEE and Mann–Whitney U -test, were observed between i.v. administrations in the fed or fasted state, but there is a slower increase when the 11 C-acetate was colonically infused ( P <0.001; n =3–4 per group). Full size image The biodistribution of acetate and uptake in the<|im_end|> <|im_start|>assistant (Medical Xpress)—New research has helped unpick a long-standing mystery about how dietary fibre supresses appetite. In a study led by Imperial College London and the Medical Research Council (MRC), an international team of researchers identified an anti-appetite molecule called acetate that is naturally released when we digest fibre in the gut. Once released, the acetate is transported to the brain where it produces a signal to tell us to stop eating. The research, published in Nature Communications, confirms the natural benefits of increasing the amount of fibre in our diets to control over-eating and could also help develop methods to reduce appetite. The study found that acetate reduces appetite when directly applied into the bloodstream, the colon or the brain. Dietary fibre is found in most plants and vegetables but tends to be at low levels in processed food. When fibre is digested by bacteria in our colon, it ferments and releases large amounts of acetate as a waste product. The study tracked the pathway of acetate from the colon to the brain and identified some of the mechanisms that enable it to influence appetite. lead author of the study Professor Gary Frost, from the Department of Medicine at Imperial College London, said: "The average diet in Europe today contains about 15g of fibre per day. In stone-age times we ate about 100g per day, but now we favour low-fibre ready-made meals over vegetables, pulses and other sources of fibre. Unfortunately our digestive system has not yet evolved to deal with this modern diet and this mismatch contributes to the current obesity epidemic. Our research has shown that the release of acetate is central to how fibre supresses our appetite and this could help scientists to tackle overeating." The study analysed the effects of a form of dietary fibre called inulin which comes from chicory and sugar beets and is also added to cereal bars. Using a mouse model, researchers demonstrated that mice fed on a high-fat diet with added inulin ate less and gained less weight than mice fed on a high-fat diet with no inulin. Further analysis showed that the mice fed on a diet containing inulin had a high level of acetate in their guts. Using positron emission tomography (PET) scans, the researchers tracked the acetate through the body from the colon to the liver and the heart and showed that it eventually ended up in the hypothalamus region of the brain, which controls hunger. In collaboration with Consejo Superior de Investigaciones Científicas (CSIC) in Madrid, the researchers investigated the effects of acetate in the hypothalamus using a cutting-edge scanning technique called High Resolution Magic Angle Spinning. Professor Sebastian Cerdán from CSIC said: "This complements the PET scans and allows us to follow the metabolism of acetate in the hypothalamus. From this we could clearly see that the acetate accumulates in the hypothalamus after fibre has been digested. The acetate then triggers a series of chemical events in the hypothalamus leading to the firing of pro-opiomelanocortin neurons, which are known to supress appetite." This is the first demonstration that acetate released from dietary fibre can affect the appetite response in the brain. The research also showed that when acetate was injected into the bloodstream, the colon or the brain it reduced the amount of food eaten by mice. Co-author on the study Professor Jimmy Bell, from the MRC Clinical Sciences Centre, said: "It's exciting that we have started to really understand what lies behind fibre's natural ability to supress our appetite and identified acetate as essential to the process. In the context of the growing rates of obesity in western countries, the findings of the research could inform potential methods to prevent weight gain." Professor Gary Frost added: "The major challenge is to develop an approach that will deliver the amount of acetate needed to supress appetite but in a form that is acceptable and safe for humans. Acetate is only active for a short amount of time in the body so if we focussed on a purely acetate-based product we would need to find a way to drip-feed it and mimic its slow release in the gut. "Another option is to focus on the fibre and manipulate it so that it produces more acetate than normal and less fibre is needed to have the same effect, providing a more palatable and comfortable option than massively increasing the amount of fibre in our diet. Developing these approaches will be difficult but it's a good challenge to have and we're looking forward to researching possible ways of using acetate to address health issues around weight gain." Professor David Lomas, Chair of the MRC's Population and Systems Medicine Board, added: "It's becoming increasingly clear that the interaction between the gut and the brain plays a key role in controlling how much food we eat. Being able to influence this relationship, for example using acetate to suppress appetite, may in future lead to new, non-surgical treatments for obesity." <|im_end|>

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69575, 304, 279, 128257, 198, 128256, 78191, 198, 3269, 291, 950, 1630, 1911, 68850, 3648, 3495, 706, 9087, 22355, 875, 264, 1317, 56703, 23347, 922, 1268, 34625, 57525, 1043, 44357, 38575, 13, 763, 264, 4007, 6197, 555, 31013, 9304, 7295, 323, 279, 13235, 8483, 9251, 320, 44, 7532, 705, 459, 6625, 2128, 315, 12074, 11054, 459, 7294, 20624, 295, 635, 43030, 2663, 65802, 349, 430, 374, 18182, 6004, 994, 584, 21552, 57525, 304, 279, 18340, 13, 9843, 6004, 11, 279, 65802, 349, 374, 40460, 311, 279, 8271, 1405, 433, 19159, 264, 8450, 311, 3371, 603, 311, 3009, 12459, 13, 578, 3495, 11, 4756, 304, 22037, 26545, 11, 43496, 279, 5933, 7720, 315, 7859, 279, 3392, 315, 57525, 304, 1057, 41943, 311, 2585, 927, 5773, 1113, 323, 1436, 1101, 1520, 2274, 5528, 311, 8108, 38575, 13, 578, 4007, 1766, 430, 65802, 349, 26338, 38575, 994, 6089, 9435, 1139, 279, 100216, 11, 279, 15235, 477, 279, 8271, 13, 83808, 57525, 374, 1766, 304, 1455, 11012, 323, 24822, 719, 28335, 311, 387, 520, 3428, 5990, 304, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Although the etiology of obesity is not well-understood, genetic, environmental, and microbiome elements are recognized as contributors to this rising pandemic. It is well documented that Roux-en-Y gastric bypass (RYGB) surgery drastically alters the fecal microbiome, but data are sparse on temporal and spatial microbiome and metabolome changes, especially in human populations. We characterized the structure and function (through metabolites) of the microbial communities in the gut lumen and structure of microbial communities on mucosal surfaces in nine morbidly obese individuals before, 6 months, and 12 months after RYGB surgery. Moreover, using a comprehensive multi-omic approach, we compared this longitudinal cohort to a previously studied cross-sectional cohort ( n = 24). In addition to the expected weight reduction and improvement in obesity-related comorbidities after RYGB surgery, we observed that the impact of surgery was much greater on fecal communities in comparison to mucosal ones. The changes in the fecal microbiome were linked to increased concentrations of branched-chain fatty acids and an overall decrease in secondary bile acid concentrations. The microbiome and metabolome data sets for this longitudinal cohort strengthen our understanding of the persistent impact of RYGB on the gut microbiome and its metabolism. Our findings highlight the importance of changes in mucosal and fecal microbiomes after RYGB surgery. The spatial modifications in the microbiome after RYGB surgery corresponded to persistent changes in fecal fermentation and bile acid metabolism, both of which are associated with improved metabolic outcomes. Introduction Roux-en-Y gastric bypass (RYGB) is an effective treatment strategy for morbid obesity and its comorbidities, such as diabetes mellitus 1 . Although the precise mechanisms leading to its success remain unclear, RYGB alters hormonal response 2 , energy metabolism 2 , and bile acid circulation 3 towards weight loss outcomes. Additionally, an increasing number of studies have shown that RYGB alters gut microbiota in humans 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . The composition of the gut microbiota shifts promptly in humans as soon as 1–3 months after surgery 4 , 5 , 10 , and those changes have been reported to persist 12 months post-surgery 5 , 7 , 10 , 12 . Additionally, a number of studies 4 , 5 , 7 , 10 , 11 , 13 , 14 , 15 have evaluated the fecal microbiota after RYGB in longitudinal cohorts. Due to the invasiveness of mucosal microbiome sampling 16 , studies of the human gut microbiome in obesity and after RYGB have relied on fecal samples 4 , 5 , 7 , 8 , which underrepresent the mucosal communities that actively interact with host immune system and epithelial cells 17 . In healthy humans, composition of mucosal and fecal microbiota varies due to differences in local environments 16 , 18 . The composition of the mucosal microbiota can drastically change in humans during dysbiosis, such as in ulcerative colitis 19 , colorectal cancer 20 , and diabetes 21 but, to our knowledge, the mucosal microbiome after RYGB in humans has not been characterized longitudinally. After RYGB, the metabolic products of the gut microbiota exert beneficial effects on host metabolism 22 . For example, butyrate and propionate, which are known to induce satiety in animals 23 and humans 24 , were in greater concentrations in post-RYGB patients compared to nonsurgical controls 6 . RYGB surgery also increased bile acid concentrations in plasma 3 , 8 , 25 and this increase has been associated with weight loss in rats following RYGB 26 . An increase in propionate and bile acids after RYGB was associated with an increase in hormone peptide tyrosine tyrosine (PYY) in humans and, hence, resolution of diabetes 27 . Finally, RYGB increased the abundance of amino acid degradation products in feces 6 , 8 . However, these molecules in connection to microbiome have not been evaluated longitudinally in pre-surgical human populations. In this study, we characterized the temporal and spatial structures of the microbiome and metabolome in humans before and after RYGB surgery, using 16S rRNA amplicon gene sequencing, gas chromatography-mass spectrometry, liquid chromatography-mass spectrometry, and nuclear magnetic resonance spectroscopy. This longitudinal multi-omic approach revealed differences between mucosal and fecal microbial communities and in fecal metabolites in morbidly obese individuals before and after RYGB surgery. Furthermore, we demonstrated comparable findings from this longitudinal cohort to those of a cross-sectional one. Results and discussion RYGB surgery induced significant weight loss We studied the microbiome and metabolome of two cohorts: longitudinal and cross-sectional populations. For the longitudinal arm of the study, we recruited nine morbidly obese pre-RYGB participants (a tenth participant dropped out after baseline measurements) and monitored their weight loss and health outcomes 6 months (RYGB-6_mo) and 12 months (RYGB-12_mo) after RYGB surgery. The study design is presented in Fig. 1a , and participant characteristics are summarized in Table 1 . We also compared this longitudinal population to a previously studied cross-sectional RYGB cohort (RYGB-CS) ( n = 24) 6 . Fig. 1: Study design and weight loss after RYGB surgery. a Study design including number of participants and sample types collected longitudinally and cross-sectionally. b Body mass index (BMI) index of participants before the surgery (pre-RYGB), 6 months (RYGB-6_mo), and 12 months (RYGB-12_mo) after the surgery . c % Excess weight loss 12 months after the surgery, 6 months after the surgery, and 6–12 months after the surgery. The box plots represent minimum, maximum, median, first quartile and third quartile values. The gray shaded box around median of RYGB-CS represents median absolute deviation. Statistical significance between the groups was tested with Wilcoxon signed-rank test and p values were corrected using the Bonferroni method. ** p < 0.01. Full size image Table 1 Participant characteristics of the longitudinal cohort. Full size table Figure 1b, c shows the short- and longer-term effects of RYGB surgery on weight loss. Percent excess weight loss (%EWL) calculations, also shown in Fig. 1c , confirm that the participants achieved the greatest weight loss during the initial 6 months and maintained the weight", "role": "user" }, { "content": "Already considered a global epidemic, human obesity continues to be on the rise. According to the Centers for Disease Control, more than 40% of the U.S. population is considered obese. The gamut of adverse health effects associated with obesity is broad, including such devastating illnesses as type 2 diabetes, coronary artery disease, stroke, sleep apnea and certain forms of cancer. Patients often suffer depression, loss of mobility, social isolation and inability to work. With costs approaching $316 billion dollars annually in the U.S., understanding how to quell obesity will result not only in a healthier population, but could also help reduce runaway medical costs. Despite the looming need to address obesity, the causes are not well understood. Researchers generally agree that genetic and gut microbiome composition and activity are important factors in determining who is obese and who isn't. As interest and understanding of the human microbiome increases, researchers are increasingly looking to the gut for answers that can lead to new, more effective diagnostics and therapies. The trillions of microbes in the human gut perform a vast range of critical functions in the body and have even been implicated in mood and behavior. Among microbes' critical responsibilities are the micro-management of nutrients in the food we digest—one of the reasons for their central role in the regulation of body weight. In a new study, \"Temporospatial shifts in the human gut microbiome and metabolome after gastric bypass surgery,\" recently published in npj Biofilms and Microbiomes, ASU researcher Zehra Esra Ilhan, ASU Biodesign professor Rosa Krajmalnik-Brown—and researchers from Mayo Clinic and Pacific Northwest National Laboratory, have taken another step in understanding how the gut changes after gastric bypass surgery (also known as Roux-en-Y gastric bypass surgery). \"Our findings highlight the importance of changes in mucosal and fecal microbiomes that are reflected on gut metabolism after surgery,\" said Ilhan. The microbial changes after surgery corresponded to persistent changes in fecal fermentation and bile acid metabolism, both of which are associated with improved metabolic outcomes.\" In addition to the expected weight reduction and improvement in obesity-related comorbidities after gastric bypass surgery, the researchers observed that the impact of surgery is not limited to fecal communities; mucosal communities are altered as well. Changes in the microbiome were linked to increased concentrations of branched-chain fatty acids (amino acid fermentation products) and an overall decrease in primary and secondary bile acid concentrations in fecal samples. Bile is an alkaline fluid that aids digestion. \"Previous bariatric surgery-microbiome studies in humans relied largely on fecal samples because sampling through the intestinal mucosal membrane requires an invasive procedure,\" said Ilhan, lead researcher for the study. At the time of the study, Ilhan was a doctoral student in Krajmalnik-Brown's lab. She is currently conducting research at INRAE-French National Institute for Agriculture, Food and Environment. Bariatric surgery is an operation that causes people to lose weight by making changes to the digestive system. These changes are physiological and chemical and include gastric restriction, malabsorption, bile acid metabolism, and chemical signaling. \"The mucus membrane is a critically important site for host-microbe interactions. We understood that with fecal sampling, we had an underrepresented picture of how the mucosal communities actively interact with host immune system and epithelial cells,\" said Ilhan. (Epithelial cells are cells that line the surfaces of your body.) Although gastric bypass surgery has been successful for many patients suffering from morbid obesity, it is a serious, invasive procedure that is not without risk and expense. In addition, some patients regain the weight they have lost, perhaps because they lack the favorable microbes necessary for permanent weight loss. \"Understanding the microbial behavior in the gut could potentially lead to a creating a probiotic that could replace surgery—or an improved indicator to identify the best candidates for surgery and sustained weight loss,\" said Krajmalnik-Brown. In the longitudinal study, subjects provided fecal samples and rectal mucosal samples. The rectal mucosal samples were collected via un-sedated flexible sigmoidoscopy at baseline, and again at 12 months post-gastric bypass surgery. Researchers analyzed microbial DNA that was extracted from the fecal and mucosal samples. Fecal metabolites were analyzed using high-throughput metabolomics approaches. A tell-tale indicator of pathology in obese patients has been found in the gut, where a markedly lower diversity of microbial communities is observed. A high diversity of gut microbes is essential to good health. In 2009, Krajmalnik-Brown's research team showed for the first time that gastric bypass surgery produced profound changes in the composition of microbial communities in the gut. The gut flora of post-surgical gastric bypass patients showed a marked difference from obese and normal weight patients. In a 2017 study, the team took another step by comparing how microbes and the metabolome (the metabolome is the total number of metabolites present within an organism, cell or tissue) change after gastric bypass surgery and lap band surgery. The 2017 study demonstrated that gastric bypass surgery caused a dramatic reorganization of the gut, which increases microbial diversity. Changes in the gut microbiota related to lap band surgery (also known as laparoscopic adjustable gastric banding) were mild and accompanying weight loss was less pronounced. Earlier studies have demonstrated that fat is reduced and weight loss triggered when germ-free mice receive a fecal transplant from mice who had undergone gastric bypass surgery. Krajmalnik-Brown's team is currently working on a project funded by the National Institutes of Health in which the main goal is to quantify the contribution of the microbiome to the host energy balance. This project is intended to move the field from associations to causality and help identify how microbes and metabolites can fight obesity. Krajmalnik-Brown is a professor in the ASU School of Sustainable Engineering and Built Environment and faculty in the School of Life Sciences. At the Biodesign Institute, she practices as part of the Swette Center for Environmental Biotechnology. Krajmalnik-Brown is also known for her research into the role of the microbiome in those with autistic spectrum disorder. Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number R01DK090379 ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Although the etiology of obesity is not well-understood, genetic, environmental, and microbiome elements are recognized as contributors to this rising pandemic. It is well documented that Roux-en-Y gastric bypass (RYGB) surgery drastically alters the fecal microbiome, but data are sparse on temporal and spatial microbiome and metabolome changes, especially in human populations. We characterized the structure and function (through metabolites) of the microbial communities in the gut lumen and structure of microbial communities on mucosal surfaces in nine morbidly obese individuals before, 6 months, and 12 months after RYGB surgery. Moreover, using a comprehensive multi-omic approach, we compared this longitudinal cohort to a previously studied cross-sectional cohort ( n = 24). In addition to the expected weight reduction and improvement in obesity-related comorbidities after RYGB surgery, we observed that the impact of surgery was much greater on fecal communities in comparison to mucosal ones. The changes in the fecal microbiome were linked to increased concentrations of branched-chain fatty acids and an overall decrease in secondary bile acid concentrations. The microbiome and metabolome data sets for this longitudinal cohort strengthen our understanding of the persistent impact of RYGB on the gut microbiome and its metabolism. Our findings highlight the importance of changes in mucosal and fecal microbiomes after RYGB surgery. The spatial modifications in the microbiome after RYGB surgery corresponded to persistent changes in fecal fermentation and bile acid metabolism, both of which are associated with improved metabolic outcomes. Introduction Roux-en-Y gastric bypass (RYGB) is an effective treatment strategy for morbid obesity and its comorbidities, such as diabetes mellitus 1 . Although the precise mechanisms leading to its success remain unclear, RYGB alters hormonal response 2 , energy metabolism 2 , and bile acid circulation 3 towards weight loss outcomes. Additionally, an increasing number of studies have shown that RYGB alters gut microbiota in humans 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . The composition of the gut microbiota shifts promptly in humans as soon as 1–3 months after surgery 4 , 5 , 10 , and those changes have been reported to persist 12 months post-surgery 5 , 7 , 10 , 12 . Additionally, a number of studies 4 , 5 , 7 , 10 , 11 , 13 , 14 , 15 have evaluated the fecal microbiota after RYGB in longitudinal cohorts. Due to the invasiveness of mucosal microbiome sampling 16 , studies of the human gut microbiome in obesity and after RYGB have relied on fecal samples 4 , 5 , 7 , 8 , which underrepresent the mucosal communities that actively interact with host immune system and epithelial cells 17 . In healthy humans, composition of mucosal and fecal microbiota varies due to differences in local environments 16 , 18 . The composition of the mucosal microbiota can drastically change in humans during dysbiosis, such as in ulcerative colitis 19 , colorectal cancer 20 , and diabetes 21 but, to our knowledge, the mucosal microbiome after RYGB in humans has not been characterized longitudinally. After RYGB, the metabolic products of the gut microbiota exert beneficial effects on host metabolism 22 . For example, butyrate and propionate, which are known to induce satiety in animals 23 and humans 24 , were in greater concentrations in post-RYGB patients compared to nonsurgical controls 6 . RYGB surgery also increased bile acid concentrations in plasma 3 , 8 , 25 and this increase has been associated with weight loss in rats following RYGB 26 . An increase in propionate and bile acids after RYGB was associated with an increase in hormone peptide tyrosine tyrosine (PYY) in humans and, hence, resolution of diabetes 27 . Finally, RYGB increased the abundance of amino acid degradation products in feces 6 , 8 . However, these molecules in connection to microbiome have not been evaluated longitudinally in pre-surgical human populations. In this study, we characterized the temporal and spatial structures of the microbiome and metabolome in humans before and after RYGB surgery, using 16S rRNA amplicon gene sequencing, gas chromatography-mass spectrometry, liquid chromatography-mass spectrometry, and nuclear magnetic resonance spectroscopy. This longitudinal multi-omic approach revealed differences between mucosal and fecal microbial communities and in fecal metabolites in morbidly obese individuals before and after RYGB surgery. Furthermore, we demonstrated comparable findings from this longitudinal cohort to those of a cross-sectional one. Results and discussion RYGB surgery induced significant weight loss We studied the microbiome and metabolome of two cohorts: longitudinal and cross-sectional populations. For the longitudinal arm of the study, we recruited nine morbidly obese pre-RYGB participants (a tenth participant dropped out after baseline measurements) and monitored their weight loss and health outcomes 6 months (RYGB-6_mo) and 12 months (RYGB-12_mo) after RYGB surgery. The study design is presented in Fig. 1a , and participant characteristics are summarized in Table 1 . We also compared this longitudinal population to a previously studied cross-sectional RYGB cohort (RYGB-CS) ( n = 24) 6 . Fig. 1: Study design and weight loss after RYGB surgery. a Study design including number of participants and sample types collected longitudinally and cross-sectionally. b Body mass index (BMI) index of participants before the surgery (pre-RYGB), 6 months (RYGB-6_mo), and 12 months (RYGB-12_mo) after the surgery . c % Excess weight loss 12 months after the surgery, 6 months after the surgery, and 6–12 months after the surgery. The box plots represent minimum, maximum, median, first quartile and third quartile values. The gray shaded box around median of RYGB-CS represents median absolute deviation. Statistical significance between the groups was tested with Wilcoxon signed-rank test and p values were corrected using the Bonferroni method. ** p < 0.01. Full size image Table 1 Participant characteristics of the longitudinal cohort. Full size table Figure 1b, c shows the short- and longer-term effects of RYGB surgery on weight loss. Percent excess weight loss (%EWL) calculations, also shown in Fig. 1c , confirm that the participants achieved the greatest weight loss during the initial 6 months and maintained the weight<|im_end|> <|im_start|>assistant Already considered a global epidemic, human obesity continues to be on the rise. According to the Centers for Disease Control, more than 40% of the U.S. population is considered obese. The gamut of adverse health effects associated with obesity is broad, including such devastating illnesses as type 2 diabetes, coronary artery disease, stroke, sleep apnea and certain forms of cancer. Patients often suffer depression, loss of mobility, social isolation and inability to work. With costs approaching $316 billion dollars annually in the U.S., understanding how to quell obesity will result not only in a healthier population, but could also help reduce runaway medical costs. Despite the looming need to address obesity, the causes are not well understood. Researchers generally agree that genetic and gut microbiome composition and activity are important factors in determining who is obese and who isn't. As interest and understanding of the human microbiome increases, researchers are increasingly looking to the gut for answers that can lead to new, more effective diagnostics and therapies. The trillions of microbes in the human gut perform a vast range of critical functions in the body and have even been implicated in mood and behavior. Among microbes' critical responsibilities are the micro-management of nutrients in the food we digest—one of the reasons for their central role in the regulation of body weight. In a new study, "Temporospatial shifts in the human gut microbiome and metabolome after gastric bypass surgery," recently published in npj Biofilms and Microbiomes, ASU researcher Zehra Esra Ilhan, ASU Biodesign professor Rosa Krajmalnik-Brown—and researchers from Mayo Clinic and Pacific Northwest National Laboratory, have taken another step in understanding how the gut changes after gastric bypass surgery (also known as Roux-en-Y gastric bypass surgery). "Our findings highlight the importance of changes in mucosal and fecal microbiomes that are reflected on gut metabolism after surgery," said Ilhan. The microbial changes after surgery corresponded to persistent changes in fecal fermentation and bile acid metabolism, both of which are associated with improved metabolic outcomes." In addition to the expected weight reduction and improvement in obesity-related comorbidities after gastric bypass surgery, the researchers observed that the impact of surgery is not limited to fecal communities; mucosal communities are altered as well. Changes in the microbiome were linked to increased concentrations of branched-chain fatty acids (amino acid fermentation products) and an overall decrease in primary and secondary bile acid concentrations in fecal samples. Bile is an alkaline fluid that aids digestion. "Previous bariatric surgery-microbiome studies in humans relied largely on fecal samples because sampling through the intestinal mucosal membrane requires an invasive procedure," said Ilhan, lead researcher for the study. At the time of the study, Ilhan was a doctoral student in Krajmalnik-Brown's lab. She is currently conducting research at INRAE-French National Institute for Agriculture, Food and Environment. Bariatric surgery is an operation that causes people to lose weight by making changes to the digestive system. These changes are physiological and chemical and include gastric restriction, malabsorption, bile acid metabolism, and chemical signaling. "The mucus membrane is a critically important site for host-microbe interactions. We understood that with fecal sampling, we had an underrepresented picture of how the mucosal communities actively interact with host immune system and epithelial cells," said Ilhan. (Epithelial cells are cells that line the surfaces of your body.) Although gastric bypass surgery has been successful for many patients suffering from morbid obesity, it is a serious, invasive procedure that is not without risk and expense. In addition, some patients regain the weight they have lost, perhaps because they lack the favorable microbes necessary for permanent weight loss. "Understanding the microbial behavior in the gut could potentially lead to a creating a probiotic that could replace surgery—or an improved indicator to identify the best candidates for surgery and sustained weight loss," said Krajmalnik-Brown. In the longitudinal study, subjects provided fecal samples and rectal mucosal samples. The rectal mucosal samples were collected via un-sedated flexible sigmoidoscopy at baseline, and again at 12 months post-gastric bypass surgery. Researchers analyzed microbial DNA that was extracted from the fecal and mucosal samples. Fecal metabolites were analyzed using high-throughput metabolomics approaches. A tell-tale indicator of pathology in obese patients has been found in the gut, where a markedly lower diversity of microbial communities is observed. A high diversity of gut microbes is essential to good health. In 2009, Krajmalnik-Brown's research team showed for the first time that gastric bypass surgery produced profound changes in the composition of microbial communities in the gut. The gut flora of post-surgical gastric bypass patients showed a marked difference from obese and normal weight patients. In a 2017 study, the team took another step by comparing how microbes and the metabolome (the metabolome is the total number of metabolites present within an organism, cell or tissue) change after gastric bypass surgery and lap band surgery. The 2017 study demonstrated that gastric bypass surgery caused a dramatic reorganization of the gut, which increases microbial diversity. Changes in the gut microbiota related to lap band surgery (also known as laparoscopic adjustable gastric banding) were mild and accompanying weight loss was less pronounced. Earlier studies have demonstrated that fat is reduced and weight loss triggered when germ-free mice receive a fecal transplant from mice who had undergone gastric bypass surgery. Krajmalnik-Brown's team is currently working on a project funded by the National Institutes of Health in which the main goal is to quantify the contribution of the microbiome to the host energy balance. This project is intended to move the field from associations to causality and help identify how microbes and metabolites can fight obesity. Krajmalnik-Brown is a professor in the ASU School of Sustainable Engineering and Built Environment and faculty in the School of Life Sciences. At the Biodesign Institute, she practices as part of the Swette Center for Environmental Biotechnology. Krajmalnik-Brown is also known for her research into the role of the microbiome in those with autistic spectrum disorder. Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number R01DK090379 <|im_end|>

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2,729

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Several indigenous tribes around the world derive spiritual value from revering fauna and flora species. Species conservation is not a prime objective of such traditions but can be an unintended consequence. Conventional species conservation practices ignore this spiritual value and tribes are often evicted from protected areas. We use the existence value framework to develop a coupled ecological-economic model of the use and non-use, existence values of wildlife for a tribe that derives spiritual value from a wildlife population. We calibrate the model for the Biligiri Rangaswamy Temple (BRT) Tiger Reserve in India with the resident Soligas tribe who consider tigers as sacred and back out an existence value of tigers in this reserve from a tribe manager’s perspective. The model ascertains tiger population dynamics under several management scenarios. Steady-state convergence is observed under secure property rights for the Soligas. Scenarios in which they are evicted from the BRT reserve and lose their property rights yields localized tiger extinction. Finally, we generate a marginal existence value function and discuss the potential for using existence value estimates in guiding conservation policy. Working on a manuscript? Avoid the common mistakes 1 Introduction A fourth of animal and plant species are threatened with extinction (IUCN 2011) by direct threats such as overharvesting and indirect threats such as habitat loss and fragmentation (Ando and Langpap 2018 ). A similar share of carnivores is critically endangered, endangered, or vulnerable (Hilton-Taylor et al. 2009 ). Carnivores generate a variety of ecosystems services (ES): some of these are regulation ES whereby carnivores help stabilize ecosystems while others are provisioning (e.g., pelt) and cultural (e.g., recreation) ES. Some ES are derived through consumptive (e.g., trophy hunting) or non-consumptive use values (e.g., wildlife recreation). Others are derived through non-use values, such as existence values, and these are the least studied in part because they are the hardest to estimate. If non-use existence values are significant relative to use values, then public resource management decisions based on benefit–cost analyses that omit these values are not socially optimal and might lead to extinction (Alexander 2000 ). In addition, many of the ES that provide non-use values are public goods, and consequently, the conservation of the species providing them will be underprovided by private parties engaging in extractive use of the species, destruction of its habitat, or failing to maintain habitat health that is necessary for the survival of the species. Conservation policies aimed at correcting the market failure in species conservation include habitat conservation programs, policies to encourage habitat ecosystem health maintenance, and management of hunting (Ando and Langpap 2018 ). One of the most common habitat conservation policies consists of establishing protected areas. When the species of conservation interest coexists with indigenous communities, the enforcement of the protected status of the area often involves the expulsion and exclusion of these communities. The practice is controversial on human rights and ethical grounds, and its effectiveness has been mixed (Dowie 2009 ; Lele et al. 2010 ). Here, we use an ecological-economic model to show that this practice will fail to maximize the net social value derived from the resource and can be counterproductive: When communities derive existence value from the species, such as the value gained from worshiping tigers by local tribes in southwestern India, their expulsion and exclusion lead to species extinction. In contrast, securing their property rights leads to species survival. We use a case study of an indigenous tribe that worships tigers and estimate the existence values the tribe derives from worshipping the tiger. Conservationists have made claims that “tribal peoples are the best conservationists and guardians of the natural world” (Rust 2016 ). In some cases, such claims are supported by evidence. For example, the Soligas tribe in the Western Ghats of India reveres the wild Bengal tiger ( Panthera tigris ssp. tigris ) according to their customary spiritual beliefs. The NGO Survival International released data showing that the population of tigers in that region doubled between the years 2010 and 2014 and that the population growth rate was higher than the national average in India (Rust 2016 ). However, such claims and descriptive data might include confounding factors leading to this higher-than-average growth rate that might not be related to the co-existence of the species with the tribe. Moreover, there is no formal theoretical or empirical analysis in the conservation economics literature on the effect that existence values—which local populations derive from a species—have on the conservation status of that species. More generally, the literature on non-consumptive values in conservation tends to be limited to tourism use values (Skonhoft 1998 ). Although it is widely believed that non-consumptive public good values of endangered species may be considerable (Bulte and van Kooten 1999b ) and may well be greater than consumptive values (Swanson and Barbier 1992 ), no estimates of such values exist. This is in part because non-market valuation may not be appropriate to estimate the resource values of indigenous peoples who have socio-political structures and decision-making processes that are inconsistent with the referendum format of valuation surveys used to generate welfare estimates (Adamowicz et al. 1998 ). It is not surprising then that very few studies estimate existence values for endangered species as would be appropriate to do in the case of the spiritual values of the Bengal tiger. One notable exception is Zabel et al. ( 2011 ), a study that accounts for the existence values of tiger conservation in the case of co-existence with livestock. However, the existence values the authors consider represent values society at large might put on the knowledge that the species exists, which typically capture moral satisfaction, “warm glow” and ethical dimensions (Alpizar et al. 2003 ) but not spiritual values derived by the local populations from worshipping the tiger. Moreover, given the lack of functions that can be used to model such values, they focus on deriving a wide range of marginal existence values that guarantee interior solutions, as opposed to backing out existence value estimates as", "role": "user" }, { "content": "Spirituality isn't usually considered a factor in conservation efforts. But indigenous peoples who worship wildlife may be helping protect endangered species from extinction. The Soligas tribe in the Western Ghats of India reveres the Bengal tiger. Their coexistence in India's Biligiri Rangaswamy Temple Tiger Reserve has helped the tiger population flourish, says Shadi Atallah, a natural resource economist in the Department of Agricultural and Consumer Economics at University of Illinois. Atallah first learned about the Soligas from a BBC article that discussed how the tiger population doubled from 2010 to 2014, after the tribe obtained property rights to their ancestral land. \"The BBC article stated that the local tribe venerates the tiger and that worshiping relationship makes them the best conservationists,\" Atallah says. \"We could not find anything in the conservation economics literature that backs that claim. There was nothing that accounted for spirituality ecosystem service values.\" He and co-author Adrian Lopes wanted to investigate how the tribe's spiritual beliefs might make them effective conservation stewards. The researchers conducted a case study to assess spiritual value of the Bengal tiger for the Soligas tribe and show how such values can be harnessed as an economic tool for promoting sustainable wildlife conservation. Atallah and Lopes used bioeconomic modeling to estimate four different management scenarios: Whether or not the Soligas tribe had property rights to the land, and whether or not poaching fines were implemented for illegal harvesting of the tigers. Their results were clear: Tribal property rights were by far the best policy to protect the tigers. \"We observed that if you remove the property rights and poaching fines, the species goes to extinction in 49 years. Implementing poaching fines alone delays the extinction by nine years but does not prevent it,\" Atallah says. He suggests the tribe's veneration of the tiger makes them less likely to look for the quick reward of illegal poaching. There is little precedent for including spiritual values in economic models, Atallah notes. \"Putting a dollar value on spirituality is controversial,\" he says. \"But by leaving it out of economic calculations, we assume it has a value of zero.\" Bioeconomic models include biological information such as status and growth rate of a species and economic policies such as property rights and fines. They can also account for the values generated from wildlife ecotourism. But so far, they have not included wildlife spiritual values, Atallah states. \"If we can place a value on spiritual ecosystem services the way we do for ecotourism, we would not be under-accounting for those services when governments make policy decisions,\" he notes. Conservation efforts often consist of establishing protected areas by separating humans and wildlife. Such policies may involve expulsing indigenous communities and are controversial on ethical and humanitarian grounds. But Atallah and Lopes' research also provides an economic argument by showing that local tribes are, indeed, the best conservationists. The Indian Forest Rights Act grants indigenous tribes property rights to their ancestral lands; however, the tribes need to provide documentation for their claim to the land, and lack of proof has in some cases led to expulsion. \"Our research shows if a government has to decide which policy instrument to use, spending money in courts to secure the property rights of the local tribes is much more effective than spending money on catching and fining poachers,\" Atallah says. \"If you care about the survival of the species, securing the property rights of the tribes that venerate them is the best tool you can have,\" he concludes. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Several indigenous tribes around the world derive spiritual value from revering fauna and flora species. Species conservation is not a prime objective of such traditions but can be an unintended consequence. Conventional species conservation practices ignore this spiritual value and tribes are often evicted from protected areas. We use the existence value framework to develop a coupled ecological-economic model of the use and non-use, existence values of wildlife for a tribe that derives spiritual value from a wildlife population. We calibrate the model for the Biligiri Rangaswamy Temple (BRT) Tiger Reserve in India with the resident Soligas tribe who consider tigers as sacred and back out an existence value of tigers in this reserve from a tribe manager’s perspective. The model ascertains tiger population dynamics under several management scenarios. Steady-state convergence is observed under secure property rights for the Soligas. Scenarios in which they are evicted from the BRT reserve and lose their property rights yields localized tiger extinction. Finally, we generate a marginal existence value function and discuss the potential for using existence value estimates in guiding conservation policy. Working on a manuscript? Avoid the common mistakes 1 Introduction A fourth of animal and plant species are threatened with extinction (IUCN 2011) by direct threats such as overharvesting and indirect threats such as habitat loss and fragmentation (Ando and Langpap 2018 ). A similar share of carnivores is critically endangered, endangered, or vulnerable (Hilton-Taylor et al. 2009 ). Carnivores generate a variety of ecosystems services (ES): some of these are regulation ES whereby carnivores help stabilize ecosystems while others are provisioning (e.g., pelt) and cultural (e.g., recreation) ES. Some ES are derived through consumptive (e.g., trophy hunting) or non-consumptive use values (e.g., wildlife recreation). Others are derived through non-use values, such as existence values, and these are the least studied in part because they are the hardest to estimate. If non-use existence values are significant relative to use values, then public resource management decisions based on benefit–cost analyses that omit these values are not socially optimal and might lead to extinction (Alexander 2000 ). In addition, many of the ES that provide non-use values are public goods, and consequently, the conservation of the species providing them will be underprovided by private parties engaging in extractive use of the species, destruction of its habitat, or failing to maintain habitat health that is necessary for the survival of the species. Conservation policies aimed at correcting the market failure in species conservation include habitat conservation programs, policies to encourage habitat ecosystem health maintenance, and management of hunting (Ando and Langpap 2018 ). One of the most common habitat conservation policies consists of establishing protected areas. When the species of conservation interest coexists with indigenous communities, the enforcement of the protected status of the area often involves the expulsion and exclusion of these communities. The practice is controversial on human rights and ethical grounds, and its effectiveness has been mixed (Dowie 2009 ; Lele et al. 2010 ). Here, we use an ecological-economic model to show that this practice will fail to maximize the net social value derived from the resource and can be counterproductive: When communities derive existence value from the species, such as the value gained from worshiping tigers by local tribes in southwestern India, their expulsion and exclusion lead to species extinction. In contrast, securing their property rights leads to species survival. We use a case study of an indigenous tribe that worships tigers and estimate the existence values the tribe derives from worshipping the tiger. Conservationists have made claims that “tribal peoples are the best conservationists and guardians of the natural world” (Rust 2016 ). In some cases, such claims are supported by evidence. For example, the Soligas tribe in the Western Ghats of India reveres the wild Bengal tiger ( Panthera tigris ssp. tigris ) according to their customary spiritual beliefs. The NGO Survival International released data showing that the population of tigers in that region doubled between the years 2010 and 2014 and that the population growth rate was higher than the national average in India (Rust 2016 ). However, such claims and descriptive data might include confounding factors leading to this higher-than-average growth rate that might not be related to the co-existence of the species with the tribe. Moreover, there is no formal theoretical or empirical analysis in the conservation economics literature on the effect that existence values—which local populations derive from a species—have on the conservation status of that species. More generally, the literature on non-consumptive values in conservation tends to be limited to tourism use values (Skonhoft 1998 ). Although it is widely believed that non-consumptive public good values of endangered species may be considerable (Bulte and van Kooten 1999b ) and may well be greater than consumptive values (Swanson and Barbier 1992 ), no estimates of such values exist. This is in part because non-market valuation may not be appropriate to estimate the resource values of indigenous peoples who have socio-political structures and decision-making processes that are inconsistent with the referendum format of valuation surveys used to generate welfare estimates (Adamowicz et al. 1998 ). It is not surprising then that very few studies estimate existence values for endangered species as would be appropriate to do in the case of the spiritual values of the Bengal tiger. One notable exception is Zabel et al. ( 2011 ), a study that accounts for the existence values of tiger conservation in the case of co-existence with livestock. However, the existence values the authors consider represent values society at large might put on the knowledge that the species exists, which typically capture moral satisfaction, “warm glow” and ethical dimensions (Alpizar et al. 2003 ) but not spiritual values derived by the local populations from worshipping the tiger. Moreover, given the lack of functions that can be used to model such values, they focus on deriving a wide range of marginal existence values that guarantee interior solutions, as opposed to backing out existence value estimates as<|im_end|> <|im_start|>assistant Spirituality isn't usually considered a factor in conservation efforts. But indigenous peoples who worship wildlife may be helping protect endangered species from extinction. The Soligas tribe in the Western Ghats of India reveres the Bengal tiger. Their coexistence in India's Biligiri Rangaswamy Temple Tiger Reserve has helped the tiger population flourish, says Shadi Atallah, a natural resource economist in the Department of Agricultural and Consumer Economics at University of Illinois. Atallah first learned about the Soligas from a BBC article that discussed how the tiger population doubled from 2010 to 2014, after the tribe obtained property rights to their ancestral land. "The BBC article stated that the local tribe venerates the tiger and that worshiping relationship makes them the best conservationists," Atallah says. "We could not find anything in the conservation economics literature that backs that claim. There was nothing that accounted for spirituality ecosystem service values." He and co-author Adrian Lopes wanted to investigate how the tribe's spiritual beliefs might make them effective conservation stewards. The researchers conducted a case study to assess spiritual value of the Bengal tiger for the Soligas tribe and show how such values can be harnessed as an economic tool for promoting sustainable wildlife conservation. Atallah and Lopes used bioeconomic modeling to estimate four different management scenarios: Whether or not the Soligas tribe had property rights to the land, and whether or not poaching fines were implemented for illegal harvesting of the tigers. Their results were clear: Tribal property rights were by far the best policy to protect the tigers. "We observed that if you remove the property rights and poaching fines, the species goes to extinction in 49 years. Implementing poaching fines alone delays the extinction by nine years but does not prevent it," Atallah says. He suggests the tribe's veneration of the tiger makes them less likely to look for the quick reward of illegal poaching. There is little precedent for including spiritual values in economic models, Atallah notes. "Putting a dollar value on spirituality is controversial," he says. "But by leaving it out of economic calculations, we assume it has a value of zero." Bioeconomic models include biological information such as status and growth rate of a species and economic policies such as property rights and fines. They can also account for the values generated from wildlife ecotourism. But so far, they have not included wildlife spiritual values, Atallah states. "If we can place a value on spiritual ecosystem services the way we do for ecotourism, we would not be under-accounting for those services when governments make policy decisions," he notes. Conservation efforts often consist of establishing protected areas by separating humans and wildlife. Such policies may involve expulsing indigenous communities and are controversial on ethical and humanitarian grounds. But Atallah and Lopes' research also provides an economic argument by showing that local tribes are, indeed, the best conservationists. The Indian Forest Rights Act grants indigenous tribes property rights to their ancestral lands; however, the tribes need to provide documentation for their claim to the land, and lack of proof has in some cases led to expulsion. "Our research shows if a government has to decide which policy instrument to use, spending money in courts to secure the property rights of the local tribes is much more effective than spending money on catching and fining poachers," Atallah says. "If you care about the survival of the species, securing the property rights of the tribes that venerate them is the best tool you can have," he concludes. <|im_end|>

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13521, 37645, 323, 47142, 1291, 220, 2550, 17, 7026, 912, 17989, 315, 1778, 2819, 3073, 13, 1115, 374, 304, 961, 1606, 2536, 48831, 51262, 1253, 539, 387, 8475, 311, 16430, 279, 5211, 2819, 315, 39678, 32538, 889, 617, 41589, 55096, 32360, 14726, 323, 5597, 28846, 11618, 430, 527, 40240, 449, 279, 30798, 3645, 315, 51262, 32313, 1511, 311, 7068, 23460, 17989, 320, 38675, 363, 53322, 1880, 453, 13, 220, 2550, 23, 7609, 1102, 374, 539, 15206, 1243, 430, 1633, 2478, 7978, 16430, 14209, 2819, 369, 52356, 9606, 439, 1053, 387, 8475, 311, 656, 304, 279, 1162, 315, 279, 18330, 2819, 315, 279, 50120, 52835, 13, 3861, 28289, 4788, 374, 1901, 786, 1880, 453, 13, 320, 220, 679, 16, 7026, 264, 4007, 430, 9815, 369, 279, 14209, 2819, 315, 52835, 29711, 304, 279, 1162, 315, 1080, 10397, 81624, 449, 51876, 13, 4452, 11, 279, 14209, 2819, 279, 12283, 2980, 4097, 2819, 8396, 520, 3544, 2643, 2231, 389, 279, 6677, 430, 279, 9606, 6866, 11, 902, 11383, 12602, 16033, 24617, 11, 1054, 83697, 37066, 863, 323, 31308, 15696, 320, 2149, 79, 11403, 1880, 453, 13, 220, 1049, 18, 883, 719, 539, 18330, 2819, 14592, 555, 279, 2254, 22673, 505, 4191, 27606, 279, 52835, 13, 23674, 11, 2728, 279, 6996, 315, 5865, 430, 649, 387, 1511, 311, 1646, 1778, 2819, 11, 814, 5357, 389, 49189, 264, 7029, 2134, 315, 32873, 14209, 2819, 430, 15803, 15135, 10105, 11, 439, 16475, 311, 25695, 704, 14209, 907, 17989, 439, 128257, 198, 128256, 78191, 198, 87475, 10965, 4536, 956, 6118, 6646, 264, 8331, 304, 29711, 9045, 13, 2030, 39678, 32538, 889, 24863, 30405, 1253, 387, 10695, 6144, 52356, 9606, 505, 52609, 13, 578, 11730, 343, 300, 34671, 304, 279, 11104, 24855, 1900, 315, 6890, 36237, 288, 279, 50120, 52835, 13, 11205, 1080, 93772, 304, 6890, 596, 39158, 343, 21336, 432, 526, 300, 86, 27322, 19176, 36845, 25820, 706, 9087, 279, 52835, 7187, 67784, 11, 2795, 1443, 2836, 2468, 77578, 11, 264, 5933, 5211, 46215, 304, 279, 6011, 315, 60134, 323, 26262, 35300, 520, 3907, 315, 19174, 13, 2468, 77578, 1176, 9687, 922, 279, 11730, 343, 300, 505, 264, 18588, 4652, 430, 14407, 1268, 279, 52835, 7187, 35717, 505, 220, 679, 15, 311, 220, 679, 19, 11, 1306, 279, 34671, 12457, 3424, 3268, 311, 872, 78771, 4363, 13, 330, 791, 18588, 4652, 11224, 430, 279, 2254, 34671, 91231, 988, 279, 52835, 323, 430, 24863, 287, 5133, 3727, 1124, 279, 1888, 29711, 1705, 1359, 2468, 77578, 2795, 13, 330, 1687, 1436, 539, 1505, 4205, 304, 279, 29711, 28989, 17649, 430, 28678, 430, 3802, 13, 2684, 574, 4400, 430, 41853, 369, 75456, 26031, 2532, 2819, 1210, 1283, 323, 1080, 43802, 44692, 445, 19031, 4934, 311, 19874, 1268, 279, 34671, 596, 18330, 21463, 2643, 1304, 1124, 7524, 29711, 61443, 2402, 13, 578, 12074, 13375, 264, 1162, 4007, 311, 8720, 18330, 907, 315, 279, 50120, 52835, 369, 279, 11730, 343, 300, 34671, 323, 1501, 1268, 1778, 2819, 649, 387, 305, 1923, 22456, 439, 459, 7100, 5507, 369, 22923, 22556, 30405, 29711, 13, 2468, 77578, 323, 445, 19031, 1511, 17332, 49944, 34579, 311, 16430, 3116, 2204, 6373, 26350, 25, 13440, 477, 539, 279, 11730, 343, 300, 34671, 1047, 3424, 3268, 311, 279, 4363, 11, 323, 3508, 477, 539, 3273, 12092, 35018, 1051, 11798, 369, 12079, 66747, 315, 279, 259, 33214, 13, 11205, 3135, 1051, 2867, 25, 91212, 3424, 3268, 1051, 555, 3117, 279, 1888, 4947, 311, 6144, 279, 259, 33214, 13, 330, 1687, 13468, 430, 422, 499, 4148, 279, 3424, 3268, 323, 3273, 12092, 35018, 11, 279, 9606, 5900, 311, 52609, 304, 220, 2491, 1667, 13, 32175, 287, 3273, 12092, 35018, 7636, 32174, 279, 52609, 555, 11888, 1667, 719, 1587, 539, 5471, 433, 1359, 2468, 77578, 2795, 13, 1283, 13533, 279, 34671, 596, 348, 17699, 315, 279, 52835, 3727, 1124, 2753, 4461, 311, 1427, 369, 279, 4062, 11565, 315, 12079, 3273, 12092, 13, 2684, 374, 2697, 47891, 369, 2737, 18330, 2819, 304, 7100, 4211, 11, 2468, 77578, 8554, 13, 330, 99004, 264, 18160, 907, 389, 75456, 374, 20733, 1359, 568, 2795, 13, 330, 4071, 555, 9564, 433, 704, 315, 7100, 29217, 11, 584, 9855, 433, 706, 264, 907, 315, 7315, 1210, 24432, 49944, 4211, 2997, 24156, 2038, 1778, 439, 2704, 323, 6650, 4478, 315, 264, 9606, 323, 7100, 10396, 1778, 439, 3424, 3268, 323, 35018, 13, 2435, 649, 1101, 2759, 369, 279, 2819, 8066, 505, 30405, 12208, 354, 414, 2191, 13, 2030, 779, 3117, 11, 814, 617, 539, 5343, 30405, 18330, 2819, 11, 2468, 77578, 5415, 13, 330, 2746, 584, 649, 2035, 264, 907, 389, 18330, 26031, 3600, 279, 1648, 584, 656, 369, 12208, 354, 414, 2191, 11, 584, 1053, 539, 387, 1234, 51082, 287, 369, 1884, 3600, 994, 17047, 1304, 4947, 11429, 1359, 568, 8554, 13, 45435, 9045, 3629, 6824, 315, 31692, 2682, 5789, 555, 50545, 12966, 323, 30405, 13, 15483, 10396, 1253, 21736, 1367, 14630, 287, 39678, 10977, 323, 527, 20733, 389, 31308, 323, 38748, 21319, 13, 2030, 2468, 77578, 323, 445, 19031, 6, 3495, 1101, 5825, 459, 7100, 5811, 555, 9204, 430, 2254, 39503, 527, 11, 13118, 11, 279, 1888, 29711, 1705, 13, 578, 7904, 20585, 10734, 3298, 25076, 39678, 39503, 3424, 3268, 311, 872, 78771, 12098, 26, 4869, 11, 279, 39503, 1205, 311, 3493, 9904, 369, 872, 3802, 311, 279, 4363, 11, 323, 6996, 315, 11311, 706, 304, 1063, 5157, 6197, 311, 95989, 13, 330, 8140, 3495, 5039, 422, 264, 3109, 706, 311, 10491, 902, 4947, 14473, 311, 1005, 11, 10374, 3300, 304, 19359, 311, 9966, 279, 3424, 3268, 315, 279, 2254, 39503, 374, 1790, 810, 7524, 1109, 10374, 3300, 389, 34168, 323, 1913, 287, 3273, 27618, 1359, 2468, 77578, 2795, 13, 330, 2746, 499, 2512, 922, 279, 20237, 315, 279, 9606, 11, 41577, 279, 3424, 3268, 315, 279, 39503, 430, 348, 13523, 1124, 374, 279, 1888, 5507, 499, 649, 617, 1359, 568, 45537, 13, 220, 128257, 198 ]

2,016

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract It has been suggested that Iberian arrival in the Americas in 1492 and subsequent dramatic depopulation led to forest regrowth that had global impacts on atmospheric CO 2 concentrations and surface temperatures. Despite tropical forests representing the most important terrestrial carbon stock globally, systematic examination of historical afforestation in these habitats in the Neotropics is lacking. Additionally, there has been no assessment of similar depopulation–afforestation dynamics in other parts of the global tropics that were incorporated into the Spanish Empire. Here, we compile and semi-quantitatively analyse pollen records from the regions claimed by the Spanish in the Atlantic and Pacific to provide pan-tropical insights into European colonial impacts on forest dynamics. Our results suggest that periods of afforestation over the past millennium varied across space and time and depended on social, economic and biogeographic contexts. We argue that this reveals the unequal and divergent origins of the Anthropocene as a socio-political and biophysical process, highlighting the need for higher-resolution, targeted analyses to fully elucidate pre-colonial and colonial era human–tropical landscape interactions. Main The term Anthropocene—used to describe a new epoch in which human activity has become the dominant influence on Earth systems—has been vigorously debated in the natural and social sciences 1 , 2 , 3 since its popularization two decades ago 4 . Tropical forests, which cover only 14% of the Earth’s surface 5 but contain 68% of the global living carbon stock 6 and half of the Earth’s biodiversity 7 , are a central feature of this discussion 8 . Indeed, human-driven, habitat-scale reorganization of these systems (a conceivable scenario given contemporary climatic, fire and land use trajectories 9 ) is thought to pose an “existential threat to civilization” 10 . The search for the beginnings of the Anthropocene has, in geological circles, centred on the identification of a single golden spike 11 . Attempts to track this critical transition initially focused on the onset of industrial fossil fuel burning in the eighteenth and nineteenth centuries 4 , but today concentrate on the Great Acceleration in the 1960s 11 , 12 . However, there have been growing calls in the social sciences to search for the origins of the Anthropocene as a long-term process that extends back into the pre-industrial era 2 , 13 , 14 , based on the premise that early agricultural processes substantially impacted atmospheric greenhouse gas concentrations, including CO 2 levels 3 . This is particularly important within carbon-rich tropical forests where archaeological and palaeoecological research has revealed evidence for substantial human impacts on ecosystems, species distributions and soils over the past 45,000 years 15 . However, while there is increasing consensus that pre-industrial societies had large impacts on global ecosystems and biodiversity 16 , 17 , the exact scale and nature of anthropogenic alteration, particularly with respect to forest cover and CO 2 concentrations, remains to be elucidated. It has been proposed that contact between the so-called Old World and New World after 1492 ce as part of the expansion of the Spanish and Portuguese empires (termed the Columbian Exchange 18 ) resulted in the radical reorganization of life on Earth without geological precedent 18 , 19 . Not only did Iberian colonizers bring new crops, animals and ways of using the land to the tropics 18 , they also introduced lethal diseases from Eurasia. The ensuing pandemics, alongside starvation and murder, wiped out up to 90% of Indigenous populations in the Americas, with the impact of their lack of immunity compounded by colonial policies focused on urban relocation and enslavement 20 , 21 . Earth system scientists have argued that this Great Dying, and the abandonment of traditional land use now known to have been extensive across the Neotropics, was so widespread that it led to dramatic forest regrowth 22 , 23 . The latest estimates suggest that subsequent afforestation captured 7.4 PgC (3.5 ppm CO 2 equivalent) from the atmosphere, resulting in a CO 2 level drop recognizable in ice cores by 1610 ce and driving global cooling seen in the form of the Little Ice Age (LIA) 21 . Although the global impacts of this regional signal have been promoted as a potential golden spike for the Anthropocene and the scale of the Great Dying is historically well documented (noting that specific estimates remain debated), direct evaluation of consequential vegetation change and overhaul of land management in carbon-rich tropical forests following Iberian colonization has been limited. Research of this nature in the Americas has often been locally constrained (for example, ref. 24 ), while larger-scale analyses have focused on the synthesis of charcoal records to reveal population and land use change, including a sustained period of reduced biomass burning after ~500 calibrated years before the present (cal yr bp ) 21 , 25 , 26 . Assessment of ecosystem responses to these demographic and land use drivers has, to date, been qualitative, non-systematic and focused on a small number of datasets 21 . Homogenous, broad-scale ecological transitions in response to depopulation in the Neotropics thus remain more assumed than proven. Although Alfred Crosby, who coined the term Columbian Exchange 18 , discussed impacts at a global scale, recent framings of this phenomenon on tropical ecosystems and their Earth systems feedbacks have been almost entirely limited to the Atlantic sphere 21 . This is despite the fact that, following their arrival in the Philippine archipelago in the sixteenth century, the Spanish Empire (including Portuguese-claimed regions incorporated into the Spanish Empire between 1580 and 1640 ce during the short-lived Iberian Union) united Madrid, Mexico City and Manila into the first truly pan-tropical biological, cultural and economic system 27 (Fig. 1 ). Like their Neotropical counterparts, many societies living in Southeast Asia and parts of the Pacific had been part of extensive exchange systems that moved people, crops and ideas across vast areas 28 . Historical records and archaeology also show that the Spanish East Indies (including parts of Taiwan, Indonesia, Palau and Micronesia)—particularly those that were geographically isolated from Eurasia—witnessed large-scale", "role": "user" }, { "content": "A new study, published now in Nature Ecology and Evolution, draws on pollen records from tropical regions formerly claimed by the Spanish Empire in both the Atlantic and the Pacific to test the significance and extent of forest regrowth following widespread mortality among Indigenous populations after European contact in the 15th and 16th centuries. By analyzing microscopic pollen grains preserved in lake sediments, scientists are able to build up a picture as to how environments have changed over time. It is well documented that the arrival of Europeans in the Americas resulted in the spread of diseases including small pox, measles, typhus and cholera to Indigenous populations, many of whom were practicing sedentary agriculture. Archaeological and historical records indicate that this may have wiped out up to 90% of the Indigenous population, making it perhaps the most significant epidemiological disaster ever known. What is less known, however, is the impact of this so-called \"Great Dying\" on tropical landscapes that had, by this point, been managed by food producers and even urban dwellers for millennia. Researchers have recently argued in a widely popularized paper that the drastic reduction in Indigenous populations and the cessation of their land use in many tropical parts of the Neotropics, led to a dramatic regrowth of forest. So significant was this ecological change, the paper argues, that these new trees captured enough carbon to cause a recognizable dip in global atmospheric CO2 levels. This global atmospheric change is not only implicated in the Little Ice Age that caused lakes to freeze over in Europe, but has also been suggested as a potential start date for the Anthropocene. Nevertheless, existing assessments of forest regrowth are based on a limited number of environmental records and have been exclusively focused on the Americas. In the new study, the research team, comprised of palaeoecologists, archaeologists and historians, set out to empirically test the proposed link between colonization and forest regrowth by synthesizing and assessing long-term records of tropical vegetation change from across the Americas, as well as the often-overlooked Asian-Pacific domain of the Spanish Empire. Pollen grains from different plants have unique shapes and can be used to reconstruct ecosystem composition at different time points. Credit: R. Hamilton Their analysis paints a much more complex picture of colonial human-environment interactions. \"Though we were expecting a signal of forest regrowth following known Indigenous population decline, clear examples of this process were only seen in about one third of cases in both the Americas and in Pacific Asia. Changes in forest cover were, in fact, diverse,\" says Dr. Rebecca Hamilton, lead author of the study. The team attributes this complexity to the variable influence of climate, humans and geography across space and through time. \"Our results suggest that dense, wet forests and highland forests were less likely to show an afforestation signal following Spanish contact,\" continues Hamilton. The authors offer two possibilities for the apparent lack of forest growth. One is that these habitats were maintained by agro-forestry prior to colonization, meaning they had never been cleared of trees to begin with. Another possibility is that these landscapes were more difficult for Europeans to access, leading to the persistence of Indigenous populations well into the Spanish period, as is documented in historical records. By contrast, isolated, water limited ecosystems, particularly in the Pacific, showed clearer signals of forest regrowth. It is widely held that dense tropical forest encroached into open agricultural landscapes following the mass mortality of Indigenous farmers from introduced European disease. Credit: R. Hamilton In some cases, the imposition of European land-use policies, including consolidated settlement and population relocation, plantations and ranching, led to a lack of forest re-growth, or even deforestation. \"Future studies exploring the impact of European colonialism on tropical landscapes need to develop detailed archaeological, historical and palaeoecological insights into how different parts of the tropics and their populations resisted, shaped and were impacted by processes of colonialism from the 15th century onwards,\" concludes Hamilton. The authors' work has ramifications for the future conservation of tropical ecosystems, which requires a careful consideration of historic land-use, population dynamics, geography, ecology and climate. The study also cautions that perspectives on the Anthropocene that hinge on a single time point may be overly simplistic. As the project co-lead Dr. Patrick Roberts puts it, \"treating the Anthropocene solely as a recent, single 'spike' can have the outcome of suggesting that it is the logical product of all humanity.\" In fact, he argues, the work of the team and others in the tropics make it clear \"that the Anthropocene is a long-term, varied and unequal process in the tropics—something that needs to be highlighted to develop more just, sustainable approaches to these crucial landscapes moving forward.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract It has been suggested that Iberian arrival in the Americas in 1492 and subsequent dramatic depopulation led to forest regrowth that had global impacts on atmospheric CO 2 concentrations and surface temperatures. Despite tropical forests representing the most important terrestrial carbon stock globally, systematic examination of historical afforestation in these habitats in the Neotropics is lacking. Additionally, there has been no assessment of similar depopulation–afforestation dynamics in other parts of the global tropics that were incorporated into the Spanish Empire. Here, we compile and semi-quantitatively analyse pollen records from the regions claimed by the Spanish in the Atlantic and Pacific to provide pan-tropical insights into European colonial impacts on forest dynamics. Our results suggest that periods of afforestation over the past millennium varied across space and time and depended on social, economic and biogeographic contexts. We argue that this reveals the unequal and divergent origins of the Anthropocene as a socio-political and biophysical process, highlighting the need for higher-resolution, targeted analyses to fully elucidate pre-colonial and colonial era human–tropical landscape interactions. Main The term Anthropocene—used to describe a new epoch in which human activity has become the dominant influence on Earth systems—has been vigorously debated in the natural and social sciences 1 , 2 , 3 since its popularization two decades ago 4 . Tropical forests, which cover only 14% of the Earth’s surface 5 but contain 68% of the global living carbon stock 6 and half of the Earth’s biodiversity 7 , are a central feature of this discussion 8 . Indeed, human-driven, habitat-scale reorganization of these systems (a conceivable scenario given contemporary climatic, fire and land use trajectories 9 ) is thought to pose an “existential threat to civilization” 10 . The search for the beginnings of the Anthropocene has, in geological circles, centred on the identification of a single golden spike 11 . Attempts to track this critical transition initially focused on the onset of industrial fossil fuel burning in the eighteenth and nineteenth centuries 4 , but today concentrate on the Great Acceleration in the 1960s 11 , 12 . However, there have been growing calls in the social sciences to search for the origins of the Anthropocene as a long-term process that extends back into the pre-industrial era 2 , 13 , 14 , based on the premise that early agricultural processes substantially impacted atmospheric greenhouse gas concentrations, including CO 2 levels 3 . This is particularly important within carbon-rich tropical forests where archaeological and palaeoecological research has revealed evidence for substantial human impacts on ecosystems, species distributions and soils over the past 45,000 years 15 . However, while there is increasing consensus that pre-industrial societies had large impacts on global ecosystems and biodiversity 16 , 17 , the exact scale and nature of anthropogenic alteration, particularly with respect to forest cover and CO 2 concentrations, remains to be elucidated. It has been proposed that contact between the so-called Old World and New World after 1492 ce as part of the expansion of the Spanish and Portuguese empires (termed the Columbian Exchange 18 ) resulted in the radical reorganization of life on Earth without geological precedent 18 , 19 . Not only did Iberian colonizers bring new crops, animals and ways of using the land to the tropics 18 , they also introduced lethal diseases from Eurasia. The ensuing pandemics, alongside starvation and murder, wiped out up to 90% of Indigenous populations in the Americas, with the impact of their lack of immunity compounded by colonial policies focused on urban relocation and enslavement 20 , 21 . Earth system scientists have argued that this Great Dying, and the abandonment of traditional land use now known to have been extensive across the Neotropics, was so widespread that it led to dramatic forest regrowth 22 , 23 . The latest estimates suggest that subsequent afforestation captured 7.4 PgC (3.5 ppm CO 2 equivalent) from the atmosphere, resulting in a CO 2 level drop recognizable in ice cores by 1610 ce and driving global cooling seen in the form of the Little Ice Age (LIA) 21 . Although the global impacts of this regional signal have been promoted as a potential golden spike for the Anthropocene and the scale of the Great Dying is historically well documented (noting that specific estimates remain debated), direct evaluation of consequential vegetation change and overhaul of land management in carbon-rich tropical forests following Iberian colonization has been limited. Research of this nature in the Americas has often been locally constrained (for example, ref. 24 ), while larger-scale analyses have focused on the synthesis of charcoal records to reveal population and land use change, including a sustained period of reduced biomass burning after ~500 calibrated years before the present (cal yr bp ) 21 , 25 , 26 . Assessment of ecosystem responses to these demographic and land use drivers has, to date, been qualitative, non-systematic and focused on a small number of datasets 21 . Homogenous, broad-scale ecological transitions in response to depopulation in the Neotropics thus remain more assumed than proven. Although Alfred Crosby, who coined the term Columbian Exchange 18 , discussed impacts at a global scale, recent framings of this phenomenon on tropical ecosystems and their Earth systems feedbacks have been almost entirely limited to the Atlantic sphere 21 . This is despite the fact that, following their arrival in the Philippine archipelago in the sixteenth century, the Spanish Empire (including Portuguese-claimed regions incorporated into the Spanish Empire between 1580 and 1640 ce during the short-lived Iberian Union) united Madrid, Mexico City and Manila into the first truly pan-tropical biological, cultural and economic system 27 (Fig. 1 ). Like their Neotropical counterparts, many societies living in Southeast Asia and parts of the Pacific had been part of extensive exchange systems that moved people, crops and ideas across vast areas 28 . Historical records and archaeology also show that the Spanish East Indies (including parts of Taiwan, Indonesia, Palau and Micronesia)—particularly those that were geographically isolated from Eurasia—witnessed large-scale<|im_end|> <|im_start|>assistant A new study, published now in Nature Ecology and Evolution, draws on pollen records from tropical regions formerly claimed by the Spanish Empire in both the Atlantic and the Pacific to test the significance and extent of forest regrowth following widespread mortality among Indigenous populations after European contact in the 15th and 16th centuries. By analyzing microscopic pollen grains preserved in lake sediments, scientists are able to build up a picture as to how environments have changed over time. It is well documented that the arrival of Europeans in the Americas resulted in the spread of diseases including small pox, measles, typhus and cholera to Indigenous populations, many of whom were practicing sedentary agriculture. Archaeological and historical records indicate that this may have wiped out up to 90% of the Indigenous population, making it perhaps the most significant epidemiological disaster ever known. What is less known, however, is the impact of this so-called "Great Dying" on tropical landscapes that had, by this point, been managed by food producers and even urban dwellers for millennia. Researchers have recently argued in a widely popularized paper that the drastic reduction in Indigenous populations and the cessation of their land use in many tropical parts of the Neotropics, led to a dramatic regrowth of forest. So significant was this ecological change, the paper argues, that these new trees captured enough carbon to cause a recognizable dip in global atmospheric CO2 levels. This global atmospheric change is not only implicated in the Little Ice Age that caused lakes to freeze over in Europe, but has also been suggested as a potential start date for the Anthropocene. Nevertheless, existing assessments of forest regrowth are based on a limited number of environmental records and have been exclusively focused on the Americas. In the new study, the research team, comprised of palaeoecologists, archaeologists and historians, set out to empirically test the proposed link between colonization and forest regrowth by synthesizing and assessing long-term records of tropical vegetation change from across the Americas, as well as the often-overlooked Asian-Pacific domain of the Spanish Empire. Pollen grains from different plants have unique shapes and can be used to reconstruct ecosystem composition at different time points. Credit: R. Hamilton Their analysis paints a much more complex picture of colonial human-environment interactions. "Though we were expecting a signal of forest regrowth following known Indigenous population decline, clear examples of this process were only seen in about one third of cases in both the Americas and in Pacific Asia. Changes in forest cover were, in fact, diverse," says Dr. Rebecca Hamilton, lead author of the study. The team attributes this complexity to the variable influence of climate, humans and geography across space and through time. "Our results suggest that dense, wet forests and highland forests were less likely to show an afforestation signal following Spanish contact," continues Hamilton. The authors offer two possibilities for the apparent lack of forest growth. One is that these habitats were maintained by agro-forestry prior to colonization, meaning they had never been cleared of trees to begin with. Another possibility is that these landscapes were more difficult for Europeans to access, leading to the persistence of Indigenous populations well into the Spanish period, as is documented in historical records. By contrast, isolated, water limited ecosystems, particularly in the Pacific, showed clearer signals of forest regrowth. It is widely held that dense tropical forest encroached into open agricultural landscapes following the mass mortality of Indigenous farmers from introduced European disease. Credit: R. Hamilton In some cases, the imposition of European land-use policies, including consolidated settlement and population relocation, plantations and ranching, led to a lack of forest re-growth, or even deforestation. "Future studies exploring the impact of European colonialism on tropical landscapes need to develop detailed archaeological, historical and palaeoecological insights into how different parts of the tropics and their populations resisted, shaped and were impacted by processes of colonialism from the 15th century onwards," concludes Hamilton. The authors' work has ramifications for the future conservation of tropical ecosystems, which requires a careful consideration of historic land-use, population dynamics, geography, ecology and climate. The study also cautions that perspectives on the Anthropocene that hinge on a single time point may be overly simplistic. As the project co-lead Dr. Patrick Roberts puts it, "treating the Anthropocene solely as a recent, single 'spike' can have the outcome of suggesting that it is the logical product of all humanity." In fact, he argues, the work of the team and others in the tropics make it clear "that the Anthropocene is a long-term, varied and unequal process in the tropics—something that needs to be highlighted to develop more just, sustainable approaches to these crucial landscapes moving forward." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs) are deadly and common cancers. Recent genomic studies implicate multiple genetic pathways, including cell signaling, cell cycle and immune evasion, in their development. Here we analyze public data sets and uncover a previously unappreciated role of epigenome deregulation in the genesis of 13% of HPV-negative HNSCCs. Specifically, we identify novel recurrent mutations encoding p.Lys36Met (K36M) alterations in multiple H3 histone genes. histones. We further validate the presence of these alterations in multiple independent HNSCC data sets and show that, along with previously described NSD1 mutations, they correspond to a specific DNA methylation cluster. The K36M substitution and NSD1 defects converge on altering methylation of histone H3 at K36 (H3K36), subsequently blocking cellular differentiation and promoting oncogenesis. Our data further indicate limited redundancy for NSD family members in HPV-negative HNSCCs and suggest a potential role for impaired H3K36 methylation in their development. Further investigation of drugs targeting chromatin regulators is warranted in HPV-negative HNSCCs driven by aberrant H3K36 methylation. Main HNSCCs are a heterogeneous group of tumors that develop through chemically (as a result of tobacco and/or alcohol abuse) or virally induced carcinogenesis after infection with high-risk HPV 1 . They represent the seventh most frequent cancer worldwide, with ∼ 600,000 new cases per year 2 , and occur throughout the oral cavity, hypopharynx, oropharynx, nasopharynx or larynx. Tumors are often locally advanced, invading proximal structures at diagnosis, or show spread to cervical lymph nodes or distant metastases. Despite several advances and innovations in multimodality treatment, survival rates of locally advanced HNSCCs have not substantially improved, and the prognosis for relapsed or metastatic tumors remains dismal 3 . Several studies, including a recent comprehensive genomic profiling of a vast number of tumors by The Cancer Genome Atlas Project (TCGA), have shown that HPV-negative and HPV-positive HNSCCs represent distinct disease entities 4 , 5 , 6 . The latter, which arises mainly in the oropharynx (tonsils and base of tongue), is associated with a substantially improved outcome and harbors distinct molecular alterations 3 , 6 , 7 . The vast majority of HPV-negative tumors have loss-of-function TP53 mutations and CDKN2A inactivation. Integrated genomic and DNA methylation analyses indicate a high level of heterogeneity in this entity, with the presence of several molecular clusters seemingly enriched for specific genetic alterations 6 . These studies also identified frequent alterations in pathways involving growth factor receptors, RAS and PI3K signaling, the cell cycle, cell death and differentiation and/or oxidative stress, which have thus become the focus of current research efforts and targeted therapies in HNSCCs 3 , 4 , 5 , 6 , 8 , 9 , 10 , 11 , 12 , 13 . Interestingly, alterations in the gene encoding epigenetic modulator nuclear receptor-binding set domain protein 1 (NSD1) were recently identified in HPV-negative HNSCCs, but insights into whether or how these mutations could drive oncogenesis are lacking 6 , 12 . NSD1 is a member of the NSD family of mammalian histone methyltransferases, which are essential in development. NSD enzymes act as mono- and dimethyltransferases for H3K36 (ref. 14 ), and SETD2 mediates trimethylation of H3K36, a chromatin mark associated with active transcription, gene splicing and DNA damage repair. Notably, aberrant regulation of H3K36 methylation has been identified in several neoplasms and could potentially promote oncogenesis 15 , 16 , 17 , 18 , 19 , 20 . Germline hypomorphic NSD1 mutations lead to Sotos overgrowth syndrome, which is associated with a higher likelihood of cancer 21 . Somatic translocation and gain-of-function mutations involving NSD2 have been identified in leukemia and multiple myeloma, and NSD1 loss-of-function mutations have been described in lung cancers 22 . In acute myeloid leukemia (AML), the recurring t(5;11)(q35;p15.5) translocation fuses NSD1 to NUP98 (encoding nucleoporin-98) and leads to leukemogenesis through aberrant establishment of H3K36 methylation at specific genomic loci 16 . SETD2 mutations have also been described in a wide range of cancers 15 , 19 , 23 . Therefore, we reasoned that an abnormal epigenetic landscape, through alterations in the H3K36 methylation pathway, might constitute a mechanism in the development of HPV-negative HNSCCs. To investigate this, we performed an integrative analysis of existing genomic and DNA methylation data sets of HNSCCs to assess the functional impact of NSD1 alterations and investigated the presence of other genetic alterations affecting the post-translational modifications of histones including H3K36. We found an epigenetically distinct subgroup in HPV-negative HNSCCs, where the main genetic alterations converge to specifically disrupt H3K36 methylation, potentially driving oncogenesis. Results Reanalysis of the TCGA HNSCC data set To assess the prevalence and nature of the genetic alterations affecting the epigenome in HNSCCs, we analyzed available HNSCC data with reported results from next-generation sequencing and DNA methylation profiling 4 , 5 , 6 , 10 , 11 . The TCGA data set, the largest generated on HNSCCs, had DNA methylation data (Infinium HumanMethylation450 BeadChip arrays) available for 528 samples, whole-exome sequencing (WES) for 526 samples and RNA sequencing for 520 samples. A total of 518 samples were profiled on all three platforms ( Supplementary Fig. 1 ). We performed unsupervised hierarchical clustering of DNA methylation data ( Fig. 1 ) and identified a subgroup previously found to be enriched in NSD1 mutations. This subgroup comprised 61 samples, 44 of which carried damaging single nucleotide variants in NSD1 annotated in the initial TCGA analysis 6 ( Supplementary Fig. 2 and Supplementary Table 1 ). Upon closer inspection of the primary data, we found that other tumors within this cluster had more complex genomic events, including large chromosomal deletions encompassing this gene ( n = 2), focal deletions within NSD1 ( n = 2) and splicing defects ( n = 1). Analysis of RNA-seq data showed absent NSD1 transcripts in two samples with noninterpretable WES data. In one sample, no conclusion could be drawn on NSD1 mutational status, as only methylation data were available ( Supplementary Table 2 and Supplementary Fig. 3 ). Overall, the reanalysis indicated that 51/61 (84%)", "role": "user" }, { "content": "A team of researchers at the Research Institute of the McGill University Health Centre (RI-MUHC) has found an epigenetic modification that might be the cause of 15% of adult cancers of the throat linked to alcohol and tobacco use. This is a first in the field of epigenetics and the researchers are hopeful that the discovery can blaze a path in the development of new, targeted, more effective treatments that could arise over the next few years. \"This discovery was absolutely unexpected since it seemed highly improbable that the kind of alterations of the epigenome that we had previously found in other types of tumours in children and young adults could also target an epithelial tumour like throat cancer that occurs only in adults,\" explains Dr. Nada Jabado, a researcher at the RI-MUHC and one of the principal authors of the study published in Nature Genetics. Head and neck cancers, also called oropharyngeal cancers or throat cancer often have devastating consequences. Standard treatments involve surgery, radiotherapy or chemotherapy. Unfortunately, the side effects of these treatments are significant and relapses are common. That's why oncologists are searching to develop more effective treatments that will be less harmful and have fewer deleterious effects. The discovery of this epigenetic modification opens new treatment possibilities. In fact, some promising drug molecules are already on the market for other illnesses and could possibly be tested for head and neck cancers as well as other cancers like multiple myeloma and lung cancer. Dr. Jabado, who is also a pediatric hemato-oncologist, has hopes that this discover will have positive repercussions for pediatric cancers as well. \"Now that we've identified this cohort of patients, we can move quite quickly since in the case of adults, as opposed to children, there are more patients and lots of clinical trials. The medicines could then be tested on children afterward.\" About the discovery Dr. Jabado's work focuses on epigenetics in pediatric cancers, and more specifically on the mutations of histone H3. Histones are proteins that package the structure of our DNA and regulate the expression of our genes. For this group of researchers, collaboration between scientists and access to the vast genomic databases of patients around the world is essential. They were particularly intrigued by a 2015 publication by the Tumor Cancer Genome Atlas Consortium (TCGA) on head and neck cancer that mentioned one of the genes that regulates H3. \"We made use of the same data but took a completely different approach. Instead of concentrating on genetic mutations, we looked at the effect of these mutations on histone H3 proteins. That's when we discovered that the histone H3 protein was abnormal or incorrectly modified in about 15% of patients with head and neck cancer. The data were there, but this fact had gone unnoticed,\" explains Dr. Jacek Majewski, a researcher at McGill University and one of the principal authors of the study. \"It's crucial to have access to public data, because it allows us to advance faster and go further in our analyses. In our case, this discovery revealed a sub-group of patients who might benefit from a therapy that targets the epigenome. This could improve the treatment of more than one in five patients suffering from devastating oropharyngeal cancer,\" points out Dr. Jabado. \"We are currently collaborating with two big groups specializing in head and neck cancer with the goal of finding treatments.\" Epigenetics The body is composed of a large number of different types of cells (neurons, skin cells, fat cells, immune system cells, etc.) Even though they differ, all these cells have the same DNA or genome. Scientists have only recently discovered that their differences can be explained by epigenetics, i.e. what triggers activity in each cell. To illustrate her research, Dr. Jabado compares the genome to notes of music and our epigenetics to a musical score. \"Using the same scale, you can create many different melodies. Like a sheet of music that dictates which notes to play and in which order, epigenetics organizes and provides meaning to our genes. If an error makes its way into the score, there's going to be a problem with the music.\" Epigenetics can provide explanations for why environmental factors, like tobacco or alcohol, can induce changes in the expression of our genes without actually modifying our DNA. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs) are deadly and common cancers. Recent genomic studies implicate multiple genetic pathways, including cell signaling, cell cycle and immune evasion, in their development. Here we analyze public data sets and uncover a previously unappreciated role of epigenome deregulation in the genesis of 13% of HPV-negative HNSCCs. Specifically, we identify novel recurrent mutations encoding p.Lys36Met (K36M) alterations in multiple H3 histone genes. histones. We further validate the presence of these alterations in multiple independent HNSCC data sets and show that, along with previously described NSD1 mutations, they correspond to a specific DNA methylation cluster. The K36M substitution and NSD1 defects converge on altering methylation of histone H3 at K36 (H3K36), subsequently blocking cellular differentiation and promoting oncogenesis. Our data further indicate limited redundancy for NSD family members in HPV-negative HNSCCs and suggest a potential role for impaired H3K36 methylation in their development. Further investigation of drugs targeting chromatin regulators is warranted in HPV-negative HNSCCs driven by aberrant H3K36 methylation. Main HNSCCs are a heterogeneous group of tumors that develop through chemically (as a result of tobacco and/or alcohol abuse) or virally induced carcinogenesis after infection with high-risk HPV 1 . They represent the seventh most frequent cancer worldwide, with ∼ 600,000 new cases per year 2 , and occur throughout the oral cavity, hypopharynx, oropharynx, nasopharynx or larynx. Tumors are often locally advanced, invading proximal structures at diagnosis, or show spread to cervical lymph nodes or distant metastases. Despite several advances and innovations in multimodality treatment, survival rates of locally advanced HNSCCs have not substantially improved, and the prognosis for relapsed or metastatic tumors remains dismal 3 . Several studies, including a recent comprehensive genomic profiling of a vast number of tumors by The Cancer Genome Atlas Project (TCGA), have shown that HPV-negative and HPV-positive HNSCCs represent distinct disease entities 4 , 5 , 6 . The latter, which arises mainly in the oropharynx (tonsils and base of tongue), is associated with a substantially improved outcome and harbors distinct molecular alterations 3 , 6 , 7 . The vast majority of HPV-negative tumors have loss-of-function TP53 mutations and CDKN2A inactivation. Integrated genomic and DNA methylation analyses indicate a high level of heterogeneity in this entity, with the presence of several molecular clusters seemingly enriched for specific genetic alterations 6 . These studies also identified frequent alterations in pathways involving growth factor receptors, RAS and PI3K signaling, the cell cycle, cell death and differentiation and/or oxidative stress, which have thus become the focus of current research efforts and targeted therapies in HNSCCs 3 , 4 , 5 , 6 , 8 , 9 , 10 , 11 , 12 , 13 . Interestingly, alterations in the gene encoding epigenetic modulator nuclear receptor-binding set domain protein 1 (NSD1) were recently identified in HPV-negative HNSCCs, but insights into whether or how these mutations could drive oncogenesis are lacking 6 , 12 . NSD1 is a member of the NSD family of mammalian histone methyltransferases, which are essential in development. NSD enzymes act as mono- and dimethyltransferases for H3K36 (ref. 14 ), and SETD2 mediates trimethylation of H3K36, a chromatin mark associated with active transcription, gene splicing and DNA damage repair. Notably, aberrant regulation of H3K36 methylation has been identified in several neoplasms and could potentially promote oncogenesis 15 , 16 , 17 , 18 , 19 , 20 . Germline hypomorphic NSD1 mutations lead to Sotos overgrowth syndrome, which is associated with a higher likelihood of cancer 21 . Somatic translocation and gain-of-function mutations involving NSD2 have been identified in leukemia and multiple myeloma, and NSD1 loss-of-function mutations have been described in lung cancers 22 . In acute myeloid leukemia (AML), the recurring t(5;11)(q35;p15.5) translocation fuses NSD1 to NUP98 (encoding nucleoporin-98) and leads to leukemogenesis through aberrant establishment of H3K36 methylation at specific genomic loci 16 . SETD2 mutations have also been described in a wide range of cancers 15 , 19 , 23 . Therefore, we reasoned that an abnormal epigenetic landscape, through alterations in the H3K36 methylation pathway, might constitute a mechanism in the development of HPV-negative HNSCCs. To investigate this, we performed an integrative analysis of existing genomic and DNA methylation data sets of HNSCCs to assess the functional impact of NSD1 alterations and investigated the presence of other genetic alterations affecting the post-translational modifications of histones including H3K36. We found an epigenetically distinct subgroup in HPV-negative HNSCCs, where the main genetic alterations converge to specifically disrupt H3K36 methylation, potentially driving oncogenesis. Results Reanalysis of the TCGA HNSCC data set To assess the prevalence and nature of the genetic alterations affecting the epigenome in HNSCCs, we analyzed available HNSCC data with reported results from next-generation sequencing and DNA methylation profiling 4 , 5 , 6 , 10 , 11 . The TCGA data set, the largest generated on HNSCCs, had DNA methylation data (Infinium HumanMethylation450 BeadChip arrays) available for 528 samples, whole-exome sequencing (WES) for 526 samples and RNA sequencing for 520 samples. A total of 518 samples were profiled on all three platforms ( Supplementary Fig. 1 ). We performed unsupervised hierarchical clustering of DNA methylation data ( Fig. 1 ) and identified a subgroup previously found to be enriched in NSD1 mutations. This subgroup comprised 61 samples, 44 of which carried damaging single nucleotide variants in NSD1 annotated in the initial TCGA analysis 6 ( Supplementary Fig. 2 and Supplementary Table 1 ). Upon closer inspection of the primary data, we found that other tumors within this cluster had more complex genomic events, including large chromosomal deletions encompassing this gene ( n = 2), focal deletions within NSD1 ( n = 2) and splicing defects ( n = 1). Analysis of RNA-seq data showed absent NSD1 transcripts in two samples with noninterpretable WES data. In one sample, no conclusion could be drawn on NSD1 mutational status, as only methylation data were available ( Supplementary Table 2 and Supplementary Fig. 3 ). Overall, the reanalysis indicated that 51/61 (84%)<|im_end|> <|im_start|>assistant A team of researchers at the Research Institute of the McGill University Health Centre (RI-MUHC) has found an epigenetic modification that might be the cause of 15% of adult cancers of the throat linked to alcohol and tobacco use. This is a first in the field of epigenetics and the researchers are hopeful that the discovery can blaze a path in the development of new, targeted, more effective treatments that could arise over the next few years. "This discovery was absolutely unexpected since it seemed highly improbable that the kind of alterations of the epigenome that we had previously found in other types of tumours in children and young adults could also target an epithelial tumour like throat cancer that occurs only in adults," explains Dr. Nada Jabado, a researcher at the RI-MUHC and one of the principal authors of the study published in Nature Genetics. Head and neck cancers, also called oropharyngeal cancers or throat cancer often have devastating consequences. Standard treatments involve surgery, radiotherapy or chemotherapy. Unfortunately, the side effects of these treatments are significant and relapses are common. That's why oncologists are searching to develop more effective treatments that will be less harmful and have fewer deleterious effects. The discovery of this epigenetic modification opens new treatment possibilities. In fact, some promising drug molecules are already on the market for other illnesses and could possibly be tested for head and neck cancers as well as other cancers like multiple myeloma and lung cancer. Dr. Jabado, who is also a pediatric hemato-oncologist, has hopes that this discover will have positive repercussions for pediatric cancers as well. "Now that we've identified this cohort of patients, we can move quite quickly since in the case of adults, as opposed to children, there are more patients and lots of clinical trials. The medicines could then be tested on children afterward." About the discovery Dr. Jabado's work focuses on epigenetics in pediatric cancers, and more specifically on the mutations of histone H3. Histones are proteins that package the structure of our DNA and regulate the expression of our genes. For this group of researchers, collaboration between scientists and access to the vast genomic databases of patients around the world is essential. They were particularly intrigued by a 2015 publication by the Tumor Cancer Genome Atlas Consortium (TCGA) on head and neck cancer that mentioned one of the genes that regulates H3. "We made use of the same data but took a completely different approach. Instead of concentrating on genetic mutations, we looked at the effect of these mutations on histone H3 proteins. That's when we discovered that the histone H3 protein was abnormal or incorrectly modified in about 15% of patients with head and neck cancer. The data were there, but this fact had gone unnoticed," explains Dr. Jacek Majewski, a researcher at McGill University and one of the principal authors of the study. "It's crucial to have access to public data, because it allows us to advance faster and go further in our analyses. In our case, this discovery revealed a sub-group of patients who might benefit from a therapy that targets the epigenome. This could improve the treatment of more than one in five patients suffering from devastating oropharyngeal cancer," points out Dr. Jabado. "We are currently collaborating with two big groups specializing in head and neck cancer with the goal of finding treatments." Epigenetics The body is composed of a large number of different types of cells (neurons, skin cells, fat cells, immune system cells, etc.) Even though they differ, all these cells have the same DNA or genome. Scientists have only recently discovered that their differences can be explained by epigenetics, i.e. what triggers activity in each cell. To illustrate her research, Dr. Jabado compares the genome to notes of music and our epigenetics to a musical score. "Using the same scale, you can create many different melodies. Like a sheet of music that dictates which notes to play and in which order, epigenetics organizes and provides meaning to our genes. If an error makes its way into the score, there's going to be a problem with the music." Epigenetics can provide explanations for why environmental factors, like tobacco or alcohol, can induce changes in the expression of our genes without actually modifying our DNA. <|im_end|>

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2,413

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Some of the most unique and compelling survival strategies in the natural world are fixed in isolated species 1 . To date, molecular insight into these ancient adaptations has been limited, as classic experimental genetics has focused on interfertile individuals in populations 2 . Here we use a new mapping approach, which screens mutants in a sterile interspecific hybrid, to identify eight housekeeping genes that underlie the growth advantage of Saccharomyces cerevisiae over its distant relative Saccharomyces paradoxus at high temperature. Pro-thermotolerance alleles at these mapped loci were required for the adaptive trait in S. cerevisiae and sufficient for its partial reconstruction in S. paradoxus . The emerging picture is one in which S. cerevisiae improved the heat resistance of multiple components of the fundamental growth machinery in response to selective pressure. Our study lays the groundwork for the mapping of genotype to phenotype in clades of sister species across Eukarya. Main Geneticists since Mendel have sought to understand how and why wild individuals differ. Studies to this end routinely test for a relationship between genotype and phenotype via linkage or association 2 . These familiar approaches, though powerful in many contexts, have an important drawback—they can only be applied to interfertile members of the same species. This rules out any case in which an innovation in form or function evolved long ago and is now fixed in a reproductively isolated population. As organisms undergo selection over long timescales, their traits may be refined by processes quite different from those that happen early in adaptation 3 , 4 . We know little about these mechanisms in the wild, expressly because when the resulting lineages become reproductively incompatible, classic statistical-genetic methods cannot be used to analyze them 1 . To date, the field has advanced largely on the strength of candidate-based studies that implicate a single variant gene in an interspecific trait 5 , 6 , with the complete genetic architecture often remaining unknown. Against the backdrop of a few specialized introgression 7 , 8 , 9 , 10 and molecular-evolution 11 techniques available in the field, dissection of complex trait differences between species has remained a key challenge. Here we develop a new genetic mapping strategy, based on the reciprocal hemizygosity test 12 , 13 , and use it to identify the determinants of a difference in high-temperature growth between isolated Saccharomyces yeast species. We validate the contributions of the mapped loci to the thermotolerance trait, and we investigate their evolutionary history. At high temperature, the yeast Saccharomyces cerevisiae grows qualitatively better than other members of its clade 14 , 15 , 16 , including its closest relative, Saccharomyces paradoxus , from which it diverged ~5 million years ago 17 . In culture at 39 °C, S. cerevisiae doubled faster than S. paradoxus and accumulated more biomass over a time course, a compound trait that we call thermotolerance. The magnitude of differences in thermotolerance between species far exceeded that of strain variation within each species (Fig. 1 ), whereas no such effect was detectable at 28 °C (Supplementary Fig. 1 ). The failure by S. paradoxus to grow to high density at 39 °C was, at least in part, a product of reduced survival relative to that of S. cerevisiae , as cells of the former were largely unable to form colonies after heat treatment (Supplementary Fig. 2 ). In microscopy experiments, S. paradoxus cells were almost uniformly visible as large-budded dyads after 24 h at 39 °C (Supplementary Fig. 3 ), suggestive of defects late in the cell cycle as a proximal cause of death 18 . No such tendency was apparent in S. cerevisiae at high temperature, or in either species at 28 °C (Supplementary Fig. 3 ). Fig. 1: S. cerevisiae grows better at high temperature than S. paradoxus . a , Each point reports optical density (OD 600nm ) of the indicated wild isolate of S. cerevisiae (various shades of blue) or S. paradoxus (orange) over a time course of growth at 39 °C. Each solid line shows a logistic population growth model fit to the respective cell density measurements. b , Each bar reports mean efficiency ( n = 4 cultures) of the indicated strain at 39 °C, defined as the difference between cell density at 24 h of growth and that at the time of inoculation. * P = 3.78 × 10 −11 , two-sample, two-tailed t -test; individual measurements are reported as circles. Full size image We set out to dissect the genetic basis of S. cerevisiae thermotolerance, using a genomic implementation of the reciprocal hemizygote test 12 , 13 (Fig. 2a ). For this purpose, we first mated S. cerevisiae strain DBVPG1373, a soil isolate from the Netherlands, with S. paradoxus strain Z1, an English oak tree isolate. The resulting sterile hybrid had a thermotolerance phenotype between those of its purebred parents (Supplementary Fig. 4 ). In this hybrid background we generated hemizygote mutants using a plasmid-borne, selectable piggyBac transposon system 19 . We cultured the pool of mutants in bulk for approximately seven generations at 39 °C and, separately, at 28 °C. From cells in each culture we sequenced transposon insertion locations 20 as a readout of the genotypes and abundance of mutant hemizygote clones present in the selected sample. In these sequencing data, at each of 4,888 genes we detected transposon mutant clones in both species’ alleles in the hybrid (Supplementary Fig. 5 ), with transposon insertions distributed in a largely unbiased manner across the genome (Supplementary Fig. 6 ). For a given gene, we tabulated the abundances of mutants whose transposon insertion fell in the S. cerevisiae allele of the hybrid, after high-temperature selection relative to the 28 °C control, and we compared them to the abundance distribution of mutants in the S. paradoxus allele (Fig. 2a ). Any difference in abundance between these reciprocal hemizygote cohorts can be ascribed to variants between the retained alleles at the respective locus; we refer to the comparison as reciprocal hemizygosity", "role": "user" }, { "content": "Why do naked mole rats live up to 31 years, when distantly related lab mice are lucky to make it to four? How is the aquatic axolotl capable of regenerating limbs, jaws, spines and even brains when frogs can only regrow tails as tadpoles? How can these difference be exploited for the benefit of human health? Questions like these set up a classic starting point for genetics research. When a trait catches a geneticist's eye, the goal is always to find the DNA sequence differences that underlie it. But to date, the tools of the field have focused on individuals of a population—what makes one human different from another, for example, when we are all the same species. Trait differences between species have been essentially out of reach. Now researchers at the Buck Institute have broken through this roadblock by designing a method that pinpoints genetic causality for trait differences between closely related species. The research, published in Nature Genetics, lays the groundwork for the mapping of specific genes to specific traits in sister species throughout the plant and animal kingdoms. \"Think of all the amazing characteristics we see in organisms around us, from longevity and disease resistance to the spots on a butterfly,\" said Rachel Brem, Ph.D., associate professor at the Buck Institute for Research in Aging. \"We want to find the genes at the root of these traits, and in many cases, they'll be relevant for human health.\" As an example, Brem points out that there are mouse species with stark differences in longevity, immunity, susceptibility to cancer, and the ability to recover from brain injury, among others. \"Now we'll be able to find the genetic basis for those advantages and start comparing the findings with human genetics.\" Brem says the method is being utilized in multiple labs at the Buck, where the ultimate goal is to design drugs that mimic, in humans, the best that the natural world has to offer. The new method, which Brem says is straightforward and simple, was developed by genetically dissecting an ancient divergence in two species of yeast that differed in their tolerance to heat. In addition to research involving human health, Brem says the work has wide applicability to plant biology and agriculture, as well as climate change as scientists seek to understand how animals adapt to extreme environments. \"Evolutionary geneticists are interested in 'outliers' - plants and animals that developed unusual traits as they evolved to survive and thrive in new environments and conditions,\" said Brem. \"There's a lot left to be discovered and we're hoping that our work will provide a jump start to that process.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Some of the most unique and compelling survival strategies in the natural world are fixed in isolated species 1 . To date, molecular insight into these ancient adaptations has been limited, as classic experimental genetics has focused on interfertile individuals in populations 2 . Here we use a new mapping approach, which screens mutants in a sterile interspecific hybrid, to identify eight housekeeping genes that underlie the growth advantage of Saccharomyces cerevisiae over its distant relative Saccharomyces paradoxus at high temperature. Pro-thermotolerance alleles at these mapped loci were required for the adaptive trait in S. cerevisiae and sufficient for its partial reconstruction in S. paradoxus . The emerging picture is one in which S. cerevisiae improved the heat resistance of multiple components of the fundamental growth machinery in response to selective pressure. Our study lays the groundwork for the mapping of genotype to phenotype in clades of sister species across Eukarya. Main Geneticists since Mendel have sought to understand how and why wild individuals differ. Studies to this end routinely test for a relationship between genotype and phenotype via linkage or association 2 . These familiar approaches, though powerful in many contexts, have an important drawback—they can only be applied to interfertile members of the same species. This rules out any case in which an innovation in form or function evolved long ago and is now fixed in a reproductively isolated population. As organisms undergo selection over long timescales, their traits may be refined by processes quite different from those that happen early in adaptation 3 , 4 . We know little about these mechanisms in the wild, expressly because when the resulting lineages become reproductively incompatible, classic statistical-genetic methods cannot be used to analyze them 1 . To date, the field has advanced largely on the strength of candidate-based studies that implicate a single variant gene in an interspecific trait 5 , 6 , with the complete genetic architecture often remaining unknown. Against the backdrop of a few specialized introgression 7 , 8 , 9 , 10 and molecular-evolution 11 techniques available in the field, dissection of complex trait differences between species has remained a key challenge. Here we develop a new genetic mapping strategy, based on the reciprocal hemizygosity test 12 , 13 , and use it to identify the determinants of a difference in high-temperature growth between isolated Saccharomyces yeast species. We validate the contributions of the mapped loci to the thermotolerance trait, and we investigate their evolutionary history. At high temperature, the yeast Saccharomyces cerevisiae grows qualitatively better than other members of its clade 14 , 15 , 16 , including its closest relative, Saccharomyces paradoxus , from which it diverged ~5 million years ago 17 . In culture at 39 °C, S. cerevisiae doubled faster than S. paradoxus and accumulated more biomass over a time course, a compound trait that we call thermotolerance. The magnitude of differences in thermotolerance between species far exceeded that of strain variation within each species (Fig. 1 ), whereas no such effect was detectable at 28 °C (Supplementary Fig. 1 ). The failure by S. paradoxus to grow to high density at 39 °C was, at least in part, a product of reduced survival relative to that of S. cerevisiae , as cells of the former were largely unable to form colonies after heat treatment (Supplementary Fig. 2 ). In microscopy experiments, S. paradoxus cells were almost uniformly visible as large-budded dyads after 24 h at 39 °C (Supplementary Fig. 3 ), suggestive of defects late in the cell cycle as a proximal cause of death 18 . No such tendency was apparent in S. cerevisiae at high temperature, or in either species at 28 °C (Supplementary Fig. 3 ). Fig. 1: S. cerevisiae grows better at high temperature than S. paradoxus . a , Each point reports optical density (OD 600nm ) of the indicated wild isolate of S. cerevisiae (various shades of blue) or S. paradoxus (orange) over a time course of growth at 39 °C. Each solid line shows a logistic population growth model fit to the respective cell density measurements. b , Each bar reports mean efficiency ( n = 4 cultures) of the indicated strain at 39 °C, defined as the difference between cell density at 24 h of growth and that at the time of inoculation. * P = 3.78 × 10 −11 , two-sample, two-tailed t -test; individual measurements are reported as circles. Full size image We set out to dissect the genetic basis of S. cerevisiae thermotolerance, using a genomic implementation of the reciprocal hemizygote test 12 , 13 (Fig. 2a ). For this purpose, we first mated S. cerevisiae strain DBVPG1373, a soil isolate from the Netherlands, with S. paradoxus strain Z1, an English oak tree isolate. The resulting sterile hybrid had a thermotolerance phenotype between those of its purebred parents (Supplementary Fig. 4 ). In this hybrid background we generated hemizygote mutants using a plasmid-borne, selectable piggyBac transposon system 19 . We cultured the pool of mutants in bulk for approximately seven generations at 39 °C and, separately, at 28 °C. From cells in each culture we sequenced transposon insertion locations 20 as a readout of the genotypes and abundance of mutant hemizygote clones present in the selected sample. In these sequencing data, at each of 4,888 genes we detected transposon mutant clones in both species’ alleles in the hybrid (Supplementary Fig. 5 ), with transposon insertions distributed in a largely unbiased manner across the genome (Supplementary Fig. 6 ). For a given gene, we tabulated the abundances of mutants whose transposon insertion fell in the S. cerevisiae allele of the hybrid, after high-temperature selection relative to the 28 °C control, and we compared them to the abundance distribution of mutants in the S. paradoxus allele (Fig. 2a ). Any difference in abundance between these reciprocal hemizygote cohorts can be ascribed to variants between the retained alleles at the respective locus; we refer to the comparison as reciprocal hemizygosity<|im_end|> <|im_start|>assistant Why do naked mole rats live up to 31 years, when distantly related lab mice are lucky to make it to four? How is the aquatic axolotl capable of regenerating limbs, jaws, spines and even brains when frogs can only regrow tails as tadpoles? How can these difference be exploited for the benefit of human health? Questions like these set up a classic starting point for genetics research. When a trait catches a geneticist's eye, the goal is always to find the DNA sequence differences that underlie it. But to date, the tools of the field have focused on individuals of a population—what makes one human different from another, for example, when we are all the same species. Trait differences between species have been essentially out of reach. Now researchers at the Buck Institute have broken through this roadblock by designing a method that pinpoints genetic causality for trait differences between closely related species. The research, published in Nature Genetics, lays the groundwork for the mapping of specific genes to specific traits in sister species throughout the plant and animal kingdoms. "Think of all the amazing characteristics we see in organisms around us, from longevity and disease resistance to the spots on a butterfly," said Rachel Brem, Ph.D., associate professor at the Buck Institute for Research in Aging. "We want to find the genes at the root of these traits, and in many cases, they'll be relevant for human health." As an example, Brem points out that there are mouse species with stark differences in longevity, immunity, susceptibility to cancer, and the ability to recover from brain injury, among others. "Now we'll be able to find the genetic basis for those advantages and start comparing the findings with human genetics." Brem says the method is being utilized in multiple labs at the Buck, where the ultimate goal is to design drugs that mimic, in humans, the best that the natural world has to offer. The new method, which Brem says is straightforward and simple, was developed by genetically dissecting an ancient divergence in two species of yeast that differed in their tolerance to heat. In addition to research involving human health, Brem says the work has wide applicability to plant biology and agriculture, as well as climate change as scientists seek to understand how animals adapt to extreme environments. "Evolutionary geneticists are interested in 'outliers' - plants and animals that developed unusual traits as they evolved to survive and thrive in new environments and conditions," said Brem. "There's a lot left to be discovered and we're hoping that our work will provide a jump start to that process." <|im_end|>

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355, 311, 3139, 311, 1579, 17915, 520, 220, 2137, 37386, 34, 574, 11, 520, 3325, 304, 961, 11, 264, 2027, 315, 11293, 20237, 8844, 311, 430, 315, 328, 13, 28091, 2749, 73078, 1174, 439, 7917, 315, 279, 4846, 1051, 14090, 12153, 311, 1376, 49028, 1306, 8798, 6514, 320, 10254, 67082, 23966, 13, 220, 17, 7609, 763, 92914, 21896, 11, 328, 13, 52313, 355, 7917, 1051, 4661, 78909, 9621, 439, 3544, 1481, 86892, 14282, 7819, 1306, 220, 1187, 305, 520, 220, 2137, 37386, 34, 320, 10254, 67082, 23966, 13, 220, 18, 7026, 99578, 315, 42655, 3389, 304, 279, 2849, 11008, 439, 264, 22267, 2931, 5353, 315, 4648, 220, 972, 662, 2360, 1778, 31954, 574, 10186, 304, 328, 13, 28091, 2749, 73078, 520, 1579, 9499, 11, 477, 304, 3060, 9606, 520, 220, 1591, 37386, 34, 320, 10254, 67082, 23966, 13, 220, 18, 7609, 23966, 13, 220, 16, 25, 328, 13, 28091, 2749, 73078, 28815, 2731, 520, 1579, 9499, 1109, 328, 13, 52313, 355, 662, 264, 1174, 9062, 1486, 6821, 29393, 17915, 320, 2114, 220, 5067, 20211, 883, 315, 279, 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296, 660, 328, 13, 28091, 2749, 73078, 26800, 6078, 53, 11637, 10148, 18, 11, 264, 17614, 43223, 505, 279, 26746, 11, 449, 328, 13, 52313, 355, 26800, 1901, 16, 11, 459, 6498, 38971, 5021, 43223, 13, 578, 13239, 82743, 26038, 1047, 264, 30945, 354, 32761, 82423, 1990, 1884, 315, 1202, 10748, 91842, 6699, 320, 10254, 67082, 23966, 13, 220, 19, 7609, 763, 420, 26038, 4092, 584, 8066, 17728, 450, 49865, 1295, 88754, 1701, 264, 628, 10753, 307, 1481, 17334, 11, 82151, 24623, 4680, 33, 582, 1380, 981, 263, 1887, 220, 777, 662, 1226, 89948, 279, 7463, 315, 88754, 304, 20155, 369, 13489, 8254, 22540, 520, 220, 2137, 37386, 34, 323, 11, 26214, 11, 520, 220, 1591, 37386, 34, 13, 5659, 7917, 304, 1855, 7829, 584, 11506, 5886, 1380, 981, 263, 37027, 10687, 220, 508, 439, 264, 1373, 412, 315, 279, 4173, 22583, 323, 37492, 315, 61618, 17728, 450, 49865, 1295, 67007, 3118, 304, 279, 4183, 6205, 13, 763, 1521, 62119, 828, 11, 520, 1855, 315, 220, 19, 11, 12251, 21389, 584, 16914, 1380, 981, 263, 61618, 67007, 304, 2225, 9606, 529, 98260, 304, 279, 26038, 320, 10254, 67082, 23966, 13, 220, 20, 7026, 449, 1380, 981, 263, 5774, 919, 4332, 304, 264, 14090, 74315, 11827, 4028, 279, 33869, 320, 10254, 67082, 23966, 13, 220, 21, 7609, 1789, 264, 2728, 15207, 11, 584, 5769, 7913, 279, 23325, 3095, 315, 88754, 6832, 1380, 981, 263, 37027, 11299, 304, 279, 328, 13, 28091, 2749, 73078, 70510, 315, 279, 26038, 11, 1306, 1579, 12, 35658, 6727, 8844, 311, 279, 220, 1591, 37386, 34, 2585, 11, 323, 584, 7863, 1124, 311, 279, 37492, 8141, 315, 88754, 304, 279, 328, 13, 52313, 355, 70510, 320, 30035, 13, 220, 17, 64, 7609, 5884, 6811, 304, 37492, 1990, 1521, 87298, 17728, 450, 49865, 1295, 90388, 649, 387, 439, 17890, 311, 27103, 1990, 279, 35363, 98260, 520, 279, 20081, 79257, 26, 584, 8464, 311, 279, 12593, 439, 87298, 17728, 450, 49865, 22828, 128257, 198, 128256, 78191, 198, 10445, 656, 19557, 35751, 32510, 3974, 709, 311, 220, 2148, 1667, 11, 994, 1612, 18007, 5552, 10278, 24548, 527, 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57622, 279, 95844, 369, 279, 13021, 315, 3230, 21389, 311, 3230, 25022, 304, 13219, 9606, 6957, 279, 6136, 323, 10065, 96506, 13, 330, 39787, 315, 682, 279, 8056, 17910, 584, 1518, 304, 44304, 2212, 603, 11, 505, 58219, 323, 8624, 13957, 311, 279, 19300, 389, 264, 56269, 1359, 1071, 32532, 426, 1864, 11, 2405, 920, 2637, 22712, 14561, 520, 279, 27156, 10181, 369, 8483, 304, 77188, 13, 330, 1687, 1390, 311, 1505, 279, 21389, 520, 279, 3789, 315, 1521, 25022, 11, 323, 304, 1690, 5157, 11, 814, 3358, 387, 9959, 369, 3823, 2890, 1210, 1666, 459, 3187, 11, 426, 1864, 3585, 704, 430, 1070, 527, 8814, 9606, 449, 38246, 12062, 304, 58219, 11, 40368, 11, 88636, 311, 9572, 11, 323, 279, 5845, 311, 11993, 505, 8271, 11134, 11, 4315, 3885, 13, 330, 7184, 584, 3358, 387, 3025, 311, 1505, 279, 19465, 8197, 369, 1884, 22934, 323, 1212, 27393, 279, 14955, 449, 3823, 56104, 1210, 426, 1864, 2795, 279, 1749, 374, 1694, 34716, 304, 5361, 51048, 520, 279, 27156, 11, 1405, 279, 17139, 5915, 374, 311, 2955, 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1,909

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Differences in cortical morphology—in particular, cortical volume, thickness and surface area—have been reported in individuals with autism. However, it is unclear what aspects of genetic and transcriptomic variation are associated with these differences. Here we investigate the genetic correlates of global cortical thickness differences (ΔCT) in children with autism. We used Partial Least Squares Regression (PLSR) on structural MRI data from 548 children (166 with autism, 295 neurotypical children and 87 children with ADHD) and cortical gene expression data from the Allen Institute for Brain Science to identify genetic correlates of ΔCT in autism. We identify that these genes are enriched for synaptic transmission pathways and explain significant variation in ΔCT. These genes are also significantly enriched for genes dysregulated in the autism post-mortem cortex (Odd Ratio (OR) = 1.11, P corrected 10 −14 ), driven entirely by downregulated genes (OR = 1.87, P corrected 10 −15 ). We validated the enrichment for downregulated genes in two independent data sets: Validation 1 (OR = 1.44, P corrected = 0.004) and Validation 2 (OR = 1.30; P corrected = 0.001). We conclude that transcriptionally downregulated genes implicated in autism are robustly associated with global changes in cortical thickness variability in children with autism. Introduction Autism Spectrum Conditions (henceforth ‘autism’) are characterized by difficulties in social communication alongside unusually narrow interests and restrictive, repetitive behaviours, a resistance to unexpected change and sensory hypersensitivity [ 1 ]. In addition to behavioural and clinical differences, differences in cortical morphology between individuals with autism compared to typical controls have been reported [ 2 , 3 , 4 , 5 ]. While heterogeneous, recent studies have reported increased cortical volumes in the first years of life with autism compared to controls, with accelerated decline or arrest in growth in adolescents [ 3 , 4 ]. Changes in cortical volume may be attributed to changes in cortical thickness (CT), changes in surface area or both [ 3 ]. In support of this, studies have separately identified differences in both surface area [ 6 ] and CT [ 7 ] in children with autism. For example, Smith et al. [ 7 ] show that the developmentally accelerated gain in grey matter volume in autism is largely driven by the lack of typical age-related CT decrease ( ). Furthermore, earlier studies identified differential trajectories in CT development in autism [ 8 ] as well as CT differences in autism in specific brain regions [ 9 , 10 ]. In addition, Hardan et al. [ 11 ] found areas of increased CT in children with autism, predominantly in temporal and parietal lobules. In contrast however, Hadjikhani et al. [ 12 ] report a pattern of cortical thinning in adults with autism, mainly within the mirror neuron system. Both these studies point towards significant heterogeneity within findings that is at least partially related to differences in age. Despite significant heterogeneity in cortical morphology across autism imaging studies [ 13 ], recent studies have also indicated alterations in areas associated with higher cognition (e.g. language, social perception and self-referential processing) [ 7 , 14 ]. This has been supported by observed differences in cortical minicolumns in association areas in individuals with autism [ 15 ]. It is unclear what contributes to these differences in cortical morphology in individuals with autism. Genetic factors play a major role in the development of brain networks and volumes in typically developing individuals [ 16 , 17 , 18 ]. For instance, twin heritability of CT measures suggest modest to high heritability for most regions of the brain [ 19 ]. In parallel, the contribution of genetic factors for autism has been estimated between 50–90% [ 20 , 21 , 22 ]. Different classes of genetic variation have been associated with risk for autism. Several recent studies have identified a significant contribution of rare, de novo putative loss-of-function mutations for autism [ 23 , 24 , 25 , 26 , 27 ]. In addition, common genetic variants, cumulatively, account for approximately half of the total variance in risk for autism [ 20 ]. Studies have also identified genes dysregulated in the autism post-mortem cortex [ 28 , 29 , 30 ], enriched in processes such as synaptic transmission and astrocyte and microglial genes. These dysregulated genes may either represent causal mechanisms for risk or compensatory mechanisms as a result of upstream biological and cellular changes. Genes dysregulated in the autism post-mortem cortex are also enriched in specific gene co-expression modules identified using both adult [ 28 , 29 , 30 ] and fetal [ 31 ] cortical post-mortem samples. Despite considerable progress in understanding neuroanatomical and genetic risk for autism, several questions remain. Mechanistically, it is likely that genetic risk variants alter neuroanatomical structural and functional properties, contributing to behavioural and clinical phenotypes. Given the heterogeneity in autism imaging findings [ 13 ], it is pertinent to ask how genetic risk for autism is associated with variability in cortical morphology observed in individuals with autism. Thus, the goal of the present study was to identify molecular correlates of disease-related neuroanatomy irrespective of regional specific neuroanatomical differences that may not replicate well across studies [ 13 ]. Here, focusing on CT, we ask 3 specific questions: (Q1) Which genes and biological pathways are associated with in CT variability (ΔCT) in children with autism? (Q2) What is the spatial expression profile of genes associated with ΔCT? and (Q3) Are these genes enriched for three different classes of risk factors associated with autism: rare, de novo variants, common genetic variants and/or dysregulated genes in the post-mortem cortex? We address these questions by combining analysis of ΔCT in autism, as measured with MRI, with gene expression post-mortem data provided by the Allen Institute for Brain Science (AIBS; [ 32 , 33 ]). Methods Overview We first assessed differences in CT (ΔCT) across 308 cortical regions in individuals with autism by extracting CT estimates for 62 children with autism (cases) and 87 matched typically developing individuals (controls) from the ABIDE-I (Table", "role": "user" }, { "content": "A team of scientists at the University of Cambridge has discovered that specific genes are linked to individual differences in brain anatomy in autistic children. Previous studies have reported differences in brain structure of autistic individuals. However, until now, scientists have not known which genes are linked to these differences. The Cambridge team analysed magnetic resonance imaging (MRI) brain scans from more than 150 autistic children and compared them with MRI scans from similarly aged children but who did not have autism. They looked at variation in the thickness of the cortex, the outermost layer of the brain, and linked this to gene activity in the brain. They discovered a set of genes linked to differences in the thickness of the cortex between autistic kids and non-autistic children. Many of these genes are involved in how brain cells (or neurons) communicate with each other. Interestingly, many of the genes identified in this study have been shown to have lower gene activity at the molecular level in autistic post mortem brain tissue samples. The study was led by two postdoctoral scientists, Dr Rafael Romero-Garcia and Dr Richard Bethlehem, and Varun Warrier, a PhD student. The study is published in the journal Molecular Psychiatry and provides the first evidence linking differences in the autistic brain to genes with atypical gene activity in autistic brains. Dr Richard Bethlehem said: \"This takes us one step closer to understanding why the brains of people with and without autism may differ from one another. We have long known that autism itself is genetic, but by combining these different data sets (brain imaging and genetics) we can now identify more precisely which genes are linked to how the autistic brain may differ. In essence, we are beginning to link molecular and macroscopic levels of analysis to better understand the diversity and complexity of autism.\" Varun Warrier added: \"We now need to confirm these results using new genetic and brain scan data so as to understand how exactly gene activity and thickness of the cortex are linked in autism.\" \"The identification of genes linked to brain changes in autism is just the first step,\" said Dr Rafael Romero-Garcia. \"These promising findings reveal how important multidisciplinary approaches are if we want to better understand the molecular mechanisms underlying autism. The complexity of this condition requires a joint effort from a wide scientific community.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Differences in cortical morphology—in particular, cortical volume, thickness and surface area—have been reported in individuals with autism. However, it is unclear what aspects of genetic and transcriptomic variation are associated with these differences. Here we investigate the genetic correlates of global cortical thickness differences (ΔCT) in children with autism. We used Partial Least Squares Regression (PLSR) on structural MRI data from 548 children (166 with autism, 295 neurotypical children and 87 children with ADHD) and cortical gene expression data from the Allen Institute for Brain Science to identify genetic correlates of ΔCT in autism. We identify that these genes are enriched for synaptic transmission pathways and explain significant variation in ΔCT. These genes are also significantly enriched for genes dysregulated in the autism post-mortem cortex (Odd Ratio (OR) = 1.11, P corrected 10 −14 ), driven entirely by downregulated genes (OR = 1.87, P corrected 10 −15 ). We validated the enrichment for downregulated genes in two independent data sets: Validation 1 (OR = 1.44, P corrected = 0.004) and Validation 2 (OR = 1.30; P corrected = 0.001). We conclude that transcriptionally downregulated genes implicated in autism are robustly associated with global changes in cortical thickness variability in children with autism. Introduction Autism Spectrum Conditions (henceforth ‘autism’) are characterized by difficulties in social communication alongside unusually narrow interests and restrictive, repetitive behaviours, a resistance to unexpected change and sensory hypersensitivity [ 1 ]. In addition to behavioural and clinical differences, differences in cortical morphology between individuals with autism compared to typical controls have been reported [ 2 , 3 , 4 , 5 ]. While heterogeneous, recent studies have reported increased cortical volumes in the first years of life with autism compared to controls, with accelerated decline or arrest in growth in adolescents [ 3 , 4 ]. Changes in cortical volume may be attributed to changes in cortical thickness (CT), changes in surface area or both [ 3 ]. In support of this, studies have separately identified differences in both surface area [ 6 ] and CT [ 7 ] in children with autism. For example, Smith et al. [ 7 ] show that the developmentally accelerated gain in grey matter volume in autism is largely driven by the lack of typical age-related CT decrease ( ). Furthermore, earlier studies identified differential trajectories in CT development in autism [ 8 ] as well as CT differences in autism in specific brain regions [ 9 , 10 ]. In addition, Hardan et al. [ 11 ] found areas of increased CT in children with autism, predominantly in temporal and parietal lobules. In contrast however, Hadjikhani et al. [ 12 ] report a pattern of cortical thinning in adults with autism, mainly within the mirror neuron system. Both these studies point towards significant heterogeneity within findings that is at least partially related to differences in age. Despite significant heterogeneity in cortical morphology across autism imaging studies [ 13 ], recent studies have also indicated alterations in areas associated with higher cognition (e.g. language, social perception and self-referential processing) [ 7 , 14 ]. This has been supported by observed differences in cortical minicolumns in association areas in individuals with autism [ 15 ]. It is unclear what contributes to these differences in cortical morphology in individuals with autism. Genetic factors play a major role in the development of brain networks and volumes in typically developing individuals [ 16 , 17 , 18 ]. For instance, twin heritability of CT measures suggest modest to high heritability for most regions of the brain [ 19 ]. In parallel, the contribution of genetic factors for autism has been estimated between 50–90% [ 20 , 21 , 22 ]. Different classes of genetic variation have been associated with risk for autism. Several recent studies have identified a significant contribution of rare, de novo putative loss-of-function mutations for autism [ 23 , 24 , 25 , 26 , 27 ]. In addition, common genetic variants, cumulatively, account for approximately half of the total variance in risk for autism [ 20 ]. Studies have also identified genes dysregulated in the autism post-mortem cortex [ 28 , 29 , 30 ], enriched in processes such as synaptic transmission and astrocyte and microglial genes. These dysregulated genes may either represent causal mechanisms for risk or compensatory mechanisms as a result of upstream biological and cellular changes. Genes dysregulated in the autism post-mortem cortex are also enriched in specific gene co-expression modules identified using both adult [ 28 , 29 , 30 ] and fetal [ 31 ] cortical post-mortem samples. Despite considerable progress in understanding neuroanatomical and genetic risk for autism, several questions remain. Mechanistically, it is likely that genetic risk variants alter neuroanatomical structural and functional properties, contributing to behavioural and clinical phenotypes. Given the heterogeneity in autism imaging findings [ 13 ], it is pertinent to ask how genetic risk for autism is associated with variability in cortical morphology observed in individuals with autism. Thus, the goal of the present study was to identify molecular correlates of disease-related neuroanatomy irrespective of regional specific neuroanatomical differences that may not replicate well across studies [ 13 ]. Here, focusing on CT, we ask 3 specific questions: (Q1) Which genes and biological pathways are associated with in CT variability (ΔCT) in children with autism? (Q2) What is the spatial expression profile of genes associated with ΔCT? and (Q3) Are these genes enriched for three different classes of risk factors associated with autism: rare, de novo variants, common genetic variants and/or dysregulated genes in the post-mortem cortex? We address these questions by combining analysis of ΔCT in autism, as measured with MRI, with gene expression post-mortem data provided by the Allen Institute for Brain Science (AIBS; [ 32 , 33 ]). Methods Overview We first assessed differences in CT (ΔCT) across 308 cortical regions in individuals with autism by extracting CT estimates for 62 children with autism (cases) and 87 matched typically developing individuals (controls) from the ABIDE-I (Table<|im_end|> <|im_start|>assistant A team of scientists at the University of Cambridge has discovered that specific genes are linked to individual differences in brain anatomy in autistic children. Previous studies have reported differences in brain structure of autistic individuals. However, until now, scientists have not known which genes are linked to these differences. The Cambridge team analysed magnetic resonance imaging (MRI) brain scans from more than 150 autistic children and compared them with MRI scans from similarly aged children but who did not have autism. They looked at variation in the thickness of the cortex, the outermost layer of the brain, and linked this to gene activity in the brain. They discovered a set of genes linked to differences in the thickness of the cortex between autistic kids and non-autistic children. Many of these genes are involved in how brain cells (or neurons) communicate with each other. Interestingly, many of the genes identified in this study have been shown to have lower gene activity at the molecular level in autistic post mortem brain tissue samples. The study was led by two postdoctoral scientists, Dr Rafael Romero-Garcia and Dr Richard Bethlehem, and Varun Warrier, a PhD student. The study is published in the journal Molecular Psychiatry and provides the first evidence linking differences in the autistic brain to genes with atypical gene activity in autistic brains. Dr Richard Bethlehem said: "This takes us one step closer to understanding why the brains of people with and without autism may differ from one another. We have long known that autism itself is genetic, but by combining these different data sets (brain imaging and genetics) we can now identify more precisely which genes are linked to how the autistic brain may differ. In essence, we are beginning to link molecular and macroscopic levels of analysis to better understand the diversity and complexity of autism." Varun Warrier added: "We now need to confirm these results using new genetic and brain scan data so as to understand how exactly gene activity and thickness of the cortex are linked in autism." "The identification of genes linked to brain changes in autism is just the first step," said Dr Rafael Romero-Garcia. "These promising findings reveal how important multidisciplinary approaches are if we want to better understand the molecular mechanisms underlying autism. The complexity of this condition requires a joint effort from a wide scientific community." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics. Main Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for coronavirus disease 2019 (COVID-19), has caused morbidity and mortality at an unprecedented scale globally 1 . Scientific and clinical evidence is evolving on the subacute and long-term effects of COVID-19, which can affect multiple organ systems 2 . Early reports suggest residual effects of SARS-CoV-2 infection, such as fatigue, dyspnea, chest pain, cognitive disturbances, arthralgia and decline in quality of life 3 , 4 , 5 . Cellular damage, a robust innate immune response with inflammatory cytokine production, and a pro-coagulant state induced by SARS-CoV-2 infection may contribute to these sequelae 6 , 7 , 8 . Survivors of previous coronavirus infections, including the SARS epidemic of 2003 and the Middle East respiratory syndrome (MERS) outbreak of 2012, have demonstrated a similar constellation of persistent symptoms, reinforcing concern for clinically significant sequelae of COVID-19 (refs. 9 , 10 , 11 , 12 , 13 , 14 , 15 ). Systematic study of sequelae after recovery from acute COVID-19 is needed to develop an evidence-based multidisciplinary team approach for caring for these patients, and to inform research priorities. A comprehensive understanding of patient care needs beyond the acute phase will help in the development of infrastructure for COVID-19 clinics that will be equipped to provide integrated multispecialty care in the outpatient setting. While the definition of the post-acute COVID-19 timeline is evolving, it has been suggested to include persistence of symptoms or development of sequelae beyond 3 or 4 weeks from the onset of acute symptoms of COVID-19 (refs. 16 , 17 ), as replication-competent SARS-CoV-2 has not been isolated after 3 weeks 18 . For the purpose of this review, we defined post-acute COVID-19 as persistent symptoms and/or delayed or long-term complications of SARS-CoV-2 infection beyond 4 weeks from the onset of symptoms (Fig. 1 ). Based on recent literature, it is further divided into two categories: (1) subacute or ongoing symptomatic COVID-19, which includes symptoms and abnormalities present from 4–12 weeks beyond acute COVID-19; and (2) chronic or post-COVID-19 syndrome, which includes symptoms and abnormalities persisting or present beyond 12 weeks of the onset of acute COVID-19 and not attributable to alternative diagnoses 17 , 19 . Herein, we summarize the epidemiology and organ-specific sequelae of post-acute COVID-19 and address management considerations for the interdisciplinary comprehensive care of these patients in COVID-19 clinics (Box 1 and Fig. 2 ). Fig. 1: Timeline of post-acute COVID-19. Acute COVID-19 usually lasts until 4 weeks from the onset of symptoms, beyond which replication-competent SARS-CoV-2 has not been isolated. Post-acute COVID-19 is defined as persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. The common symptoms observed in post-acute COVID-19 are summarized. Full size image Fig. 2: Interdisciplinary management in COVID-19 clinics. Multidisciplinary collaboration is essential to provide integrated outpatient care to survivors of acute COVID-19 in COVID-19 clinics. Depending on resources, prioritization may be considered for those at high risk for post-acute COVID-19, defined as those with severe illness during acute COVID-19 and/or requirement for care in an ICU, advanced age and the presence of organ comorbidities (pre-existing respiratory disease, obesity, diabetes, hypertension, chronic cardiovascular disease, chronic kidney disease, post-organ transplant or active cancer). The pulmonary/cardiovascular management plan was adapted from a guidance document for patients hospitalized with COVID-19 pneumonia 76 . HRCT, high-resolution computed tomography; PE, pulmonary embolism. Full size image Box 1 Summary of post-acute COVID-19 by organ system Pulmonary Dyspnea, decreased exercise capacity and hypoxia are commonly persistent symptoms and signs Reduced diffusion capacity, restrictive pulmonary physiology, and ground-glass opacities and fibrotic changes on imaging have been noted at follow-up of COVID-19 survivors Assessment of progression or recovery of pulmonary disease and function may include home pulse oximetry, 6MWTs, PFTs, high-resolution computed tomography of the chest and computed tomography pulmonary angiogram as clinically appropriate Hematologic Thromboembolic events have been noted to be <5% in post-acute COVID-19 in retrospective studies The duration of the hyperinflammatory state induced by infection with SARS-CoV-2 is unknown Direct oral anticoagulants and low-molecular-weight heparin may be considered for extended thromboprophylaxis after risk–benefit discussion in patients with predisposing risk factors for immobility, persistently elevated d -dimer levels (greater than twice the upper limit of normal) and other high-risk comorbidities such as cancer Cardiovascular Persistent symptoms may include palpitations, dyspnea and chest pain Long-term sequelae may include increased cardiometabolic demand, myocardial fibrosis or scarring (detectable via cardiac MRI), arrhythmias, tachycardia and autonomic dysfunction Patients with cardiovascular complications during acute infection or those experiencing persistent cardiac symptoms may be monitored with serial clinical, echocardiogram and electrocardiogram follow-up Neuropsychiatric Persistent abnormalities may include fatigue, myalgia, headache, dysautonomia and cognitive impairment (brain fog) Anxiety, depression, sleep disturbances and PTSD have been reported in 30–40% of COVID-19 survivors, similar to survivors of other pathogenic coronaviruses The pathophysiology of neuropsychiatric complications is mechanistically diverse and entails immune dysregulation, inflammation,", "role": "user" }, { "content": "Physicians across the country have analyzed the emerging scientific data about the long-term effects of COVID-19, creating an initial knowledge base about the clinical experiences of so-called \"long-haulers\"—patients with COVID-19 who experience prolonged symptoms and/or the emergence of new ones well after the initial viral infection has resolved. A comprehensive review published today in Nature Medicine offers an initial glimpse of the multi-organ effects of long-term COVID-19 and suggests a framework for the care of COVID-19 long-haulers through dedicated, multidisciplinary clinics. \"It was important to respond to our patients' concerns and pay close attention to the symptoms they were experiencing beyond the acute phase of COVID-19,\" said Kartik Sehgal, MD, a lead author of the new study and a medical oncologist at Dana-Farber Cancer Institute and Brigham and Women's Hospital, and instructor in medicine at Harvard Medical School. \"While our knowledge in this area is still evolving and will continue to evolve over the next few years, we have provided a comprehensive resource for physicians caring for patients who have recovered from acute COVID-19 and scientists currently investigating the potential prolonged effects of COVID-19.\" Sehgal and his colleagues at hospitals affiliated with Harvard University and Columbia University worked at the frontlines of the pandemic last spring and have witnessed first-hand the myriad health effects that the responsible virus, known as SARS-CoV-2, can inflict. That includes the recognition that COVID-19 is not simply an illness of the lungs or respiratory tract but can also affect many other organ systems. Sehgal was among the co-authors of a study published last summer in Nature Medicine that summarized the vast constellation of multi-organ symptoms associated with the COVID-19. As the pandemic wore on, the team heard from their own patients as well as patient advocacy groups about surprisingly persistent symptoms—complications that extended for weeks, even months, beyond the initial infection. \"COVID-19 is the first infectious disease that I've come across that has such an effect on a wide variety of organs. It's changed my clinical practice. No matter what the patient comes in for, I now ask if they ever had COVID-19. It changes the possible range of diagnoses,\" added Elaine Y. Wan, MD, the Esther Aboodi Assistant Professor of Medicine in Cardiology and Cardiac Electrophysiology at Columbia University Vagelos College of Physicians and Surgeons and senior author of the study. These observations prompted the authors to undertake a comprehensive review of the published literature on long-term effects of COVID-19 so they could develop a better understanding of the condition themselves and share it with the physician and scientific community. They found that the most common symptoms of long COVID include fatigue, shortness of breath, brain fog, loss of sense of smell or taste, anxiety, depression, and post-traumatic stress disorder (PTSD). Based on the limited number of studies published to date, at least one-third of patients who required hospitalization for COVID-19 have experienced one of these long-term side effects. While there is much more work yet to be done, this finding is consistent with what has been found in the few studies of survivors of the SARS epidemic in 2003 as well as the MERS outbreak in 2012, which involved viruses that are closely related to SARS-CoV-2. \"The medical needs of patients with COVID-19 don't stop at the time of hospital discharge and they also don't necessarily stop after three to four weeks, even for those who didn't require hospitalization,\" said Sehgal. \"It is important for physicians to be aware of these possible symptoms and complications and to have resources available for early recognition to provide the best possible care.\" Because the symptoms of long COVID are not typically restricted to just one organ system, the researchers stress the importance of multidisciplinary care, such as a dedicated COVID-19 clinic that includes specialists with expertise in diverse areas of clinical medicine. \"It is important to not forget about the mental health effects of COVID-19 in these patients, while taking care of their physical symptoms,\" said Sehgal. Some academic medical centers have already established such an effort. In response to the clinical need and the emerging research findings, the Brigham Lung Center has recently established a COVID Recovery Center to coordinate and deliver multi-disciplinary care for patients with long-term symptoms after infection. Moving forward, Sehgal and his colleagues believe it will also be essential to develop mechanisms for appropriately sharing and pooling patient data across organizations and institutions, including from patient advocacy groups, which played a major role in highlighting the health struggles of long haulers. \"There are a lot of questions we'll need to answer,\" said Sehgal. \"The only way we can do that quickly is by systematically collecting and harnessing all of the data that's out there.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics. Main Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for coronavirus disease 2019 (COVID-19), has caused morbidity and mortality at an unprecedented scale globally 1 . Scientific and clinical evidence is evolving on the subacute and long-term effects of COVID-19, which can affect multiple organ systems 2 . Early reports suggest residual effects of SARS-CoV-2 infection, such as fatigue, dyspnea, chest pain, cognitive disturbances, arthralgia and decline in quality of life 3 , 4 , 5 . Cellular damage, a robust innate immune response with inflammatory cytokine production, and a pro-coagulant state induced by SARS-CoV-2 infection may contribute to these sequelae 6 , 7 , 8 . Survivors of previous coronavirus infections, including the SARS epidemic of 2003 and the Middle East respiratory syndrome (MERS) outbreak of 2012, have demonstrated a similar constellation of persistent symptoms, reinforcing concern for clinically significant sequelae of COVID-19 (refs. 9 , 10 , 11 , 12 , 13 , 14 , 15 ). Systematic study of sequelae after recovery from acute COVID-19 is needed to develop an evidence-based multidisciplinary team approach for caring for these patients, and to inform research priorities. A comprehensive understanding of patient care needs beyond the acute phase will help in the development of infrastructure for COVID-19 clinics that will be equipped to provide integrated multispecialty care in the outpatient setting. While the definition of the post-acute COVID-19 timeline is evolving, it has been suggested to include persistence of symptoms or development of sequelae beyond 3 or 4 weeks from the onset of acute symptoms of COVID-19 (refs. 16 , 17 ), as replication-competent SARS-CoV-2 has not been isolated after 3 weeks 18 . For the purpose of this review, we defined post-acute COVID-19 as persistent symptoms and/or delayed or long-term complications of SARS-CoV-2 infection beyond 4 weeks from the onset of symptoms (Fig. 1 ). Based on recent literature, it is further divided into two categories: (1) subacute or ongoing symptomatic COVID-19, which includes symptoms and abnormalities present from 4–12 weeks beyond acute COVID-19; and (2) chronic or post-COVID-19 syndrome, which includes symptoms and abnormalities persisting or present beyond 12 weeks of the onset of acute COVID-19 and not attributable to alternative diagnoses 17 , 19 . Herein, we summarize the epidemiology and organ-specific sequelae of post-acute COVID-19 and address management considerations for the interdisciplinary comprehensive care of these patients in COVID-19 clinics (Box 1 and Fig. 2 ). Fig. 1: Timeline of post-acute COVID-19. Acute COVID-19 usually lasts until 4 weeks from the onset of symptoms, beyond which replication-competent SARS-CoV-2 has not been isolated. Post-acute COVID-19 is defined as persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. The common symptoms observed in post-acute COVID-19 are summarized. Full size image Fig. 2: Interdisciplinary management in COVID-19 clinics. Multidisciplinary collaboration is essential to provide integrated outpatient care to survivors of acute COVID-19 in COVID-19 clinics. Depending on resources, prioritization may be considered for those at high risk for post-acute COVID-19, defined as those with severe illness during acute COVID-19 and/or requirement for care in an ICU, advanced age and the presence of organ comorbidities (pre-existing respiratory disease, obesity, diabetes, hypertension, chronic cardiovascular disease, chronic kidney disease, post-organ transplant or active cancer). The pulmonary/cardiovascular management plan was adapted from a guidance document for patients hospitalized with COVID-19 pneumonia 76 . HRCT, high-resolution computed tomography; PE, pulmonary embolism. Full size image Box 1 Summary of post-acute COVID-19 by organ system Pulmonary Dyspnea, decreased exercise capacity and hypoxia are commonly persistent symptoms and signs Reduced diffusion capacity, restrictive pulmonary physiology, and ground-glass opacities and fibrotic changes on imaging have been noted at follow-up of COVID-19 survivors Assessment of progression or recovery of pulmonary disease and function may include home pulse oximetry, 6MWTs, PFTs, high-resolution computed tomography of the chest and computed tomography pulmonary angiogram as clinically appropriate Hematologic Thromboembolic events have been noted to be <5% in post-acute COVID-19 in retrospective studies The duration of the hyperinflammatory state induced by infection with SARS-CoV-2 is unknown Direct oral anticoagulants and low-molecular-weight heparin may be considered for extended thromboprophylaxis after risk–benefit discussion in patients with predisposing risk factors for immobility, persistently elevated d -dimer levels (greater than twice the upper limit of normal) and other high-risk comorbidities such as cancer Cardiovascular Persistent symptoms may include palpitations, dyspnea and chest pain Long-term sequelae may include increased cardiometabolic demand, myocardial fibrosis or scarring (detectable via cardiac MRI), arrhythmias, tachycardia and autonomic dysfunction Patients with cardiovascular complications during acute infection or those experiencing persistent cardiac symptoms may be monitored with serial clinical, echocardiogram and electrocardiogram follow-up Neuropsychiatric Persistent abnormalities may include fatigue, myalgia, headache, dysautonomia and cognitive impairment (brain fog) Anxiety, depression, sleep disturbances and PTSD have been reported in 30–40% of COVID-19 survivors, similar to survivors of other pathogenic coronaviruses The pathophysiology of neuropsychiatric complications is mechanistically diverse and entails immune dysregulation, inflammation,<|im_end|> <|im_start|>assistant Physicians across the country have analyzed the emerging scientific data about the long-term effects of COVID-19, creating an initial knowledge base about the clinical experiences of so-called "long-haulers"—patients with COVID-19 who experience prolonged symptoms and/or the emergence of new ones well after the initial viral infection has resolved. A comprehensive review published today in Nature Medicine offers an initial glimpse of the multi-organ effects of long-term COVID-19 and suggests a framework for the care of COVID-19 long-haulers through dedicated, multidisciplinary clinics. "It was important to respond to our patients' concerns and pay close attention to the symptoms they were experiencing beyond the acute phase of COVID-19," said Kartik Sehgal, MD, a lead author of the new study and a medical oncologist at Dana-Farber Cancer Institute and Brigham and Women's Hospital, and instructor in medicine at Harvard Medical School. "While our knowledge in this area is still evolving and will continue to evolve over the next few years, we have provided a comprehensive resource for physicians caring for patients who have recovered from acute COVID-19 and scientists currently investigating the potential prolonged effects of COVID-19." Sehgal and his colleagues at hospitals affiliated with Harvard University and Columbia University worked at the frontlines of the pandemic last spring and have witnessed first-hand the myriad health effects that the responsible virus, known as SARS-CoV-2, can inflict. That includes the recognition that COVID-19 is not simply an illness of the lungs or respiratory tract but can also affect many other organ systems. Sehgal was among the co-authors of a study published last summer in Nature Medicine that summarized the vast constellation of multi-organ symptoms associated with the COVID-19. As the pandemic wore on, the team heard from their own patients as well as patient advocacy groups about surprisingly persistent symptoms—complications that extended for weeks, even months, beyond the initial infection. "COVID-19 is the first infectious disease that I've come across that has such an effect on a wide variety of organs. It's changed my clinical practice. No matter what the patient comes in for, I now ask if they ever had COVID-19. It changes the possible range of diagnoses," added Elaine Y. Wan, MD, the Esther Aboodi Assistant Professor of Medicine in Cardiology and Cardiac Electrophysiology at Columbia University Vagelos College of Physicians and Surgeons and senior author of the study. These observations prompted the authors to undertake a comprehensive review of the published literature on long-term effects of COVID-19 so they could develop a better understanding of the condition themselves and share it with the physician and scientific community. They found that the most common symptoms of long COVID include fatigue, shortness of breath, brain fog, loss of sense of smell or taste, anxiety, depression, and post-traumatic stress disorder (PTSD). Based on the limited number of studies published to date, at least one-third of patients who required hospitalization for COVID-19 have experienced one of these long-term side effects. While there is much more work yet to be done, this finding is consistent with what has been found in the few studies of survivors of the SARS epidemic in 2003 as well as the MERS outbreak in 2012, which involved viruses that are closely related to SARS-CoV-2. "The medical needs of patients with COVID-19 don't stop at the time of hospital discharge and they also don't necessarily stop after three to four weeks, even for those who didn't require hospitalization," said Sehgal. "It is important for physicians to be aware of these possible symptoms and complications and to have resources available for early recognition to provide the best possible care." Because the symptoms of long COVID are not typically restricted to just one organ system, the researchers stress the importance of multidisciplinary care, such as a dedicated COVID-19 clinic that includes specialists with expertise in diverse areas of clinical medicine. "It is important to not forget about the mental health effects of COVID-19 in these patients, while taking care of their physical symptoms," said Sehgal. Some academic medical centers have already established such an effort. In response to the clinical need and the emerging research findings, the Brigham Lung Center has recently established a COVID Recovery Center to coordinate and deliver multi-disciplinary care for patients with long-term symptoms after infection. Moving forward, Sehgal and his colleagues believe it will also be essential to develop mechanisms for appropriately sharing and pooling patient data across organizations and institutions, including from patient advocacy groups, which played a major role in highlighting the health struggles of long haulers. "There are a lot of questions we'll need to answer," said Sehgal. "The only way we can do that quickly is by systematically collecting and harnessing all of the data that's out there." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Volcanic ash layers are important markers for the chronostratigraphy of paleoclimate and paleoenvironmental archives at the southern tip of South America. However, this requires that tephras are well-dated. We report geochemical data from stalagmite MA1 formed in a non-karst cave near Mt. Burney volcano in southernmost Patagonia (~53°S). High-resolution LA-ICP-MS analyses, SEM imagery, EPMA data, and NanoSIMS enable to identify volcanogenic signals during the last 4.5 kyrs from sub-annual trace element variations and tephra particles in distinct laminae. Our new 230 Th/U-chronology of MA1 provides precise dating of tephra from Mt. Burney (MB) and, probably, Aguilera (A) at 4,216 +93 / −193 yrs BP (MB 2 ), 2,291 ± 33 yrs BP (MB 3 ), 853 +41 / −60 yrs BP (MB 4 ) and 2,978 +91 / −104 yrs BP (A 1 ). This unique high-resolution record holds potential to date further eruptions from Southern Andean volcanoes for the tephrochronology in this critical region, and potentially also large-volume explosive volcanism off South America. Introduction Severe and long-lasting impact on regional ecosystems from explosive volcanic eruptions and ash (tephra) fallout has been observed in fragile environments such as the super-humid South Patagonian Andes 1 , 2 . While geochemical fingerprinting links tephra glass shard compositions to their volcanic source and represents a valuable tool in tephrochronology 3 , the dating of distinct tephra layers enables a reconstruction of the regional history of volcanic activity and provides isochronous and stratigraphic marker horizons for the correlation of paleoenvironmental archives over large geographical areas 4 . Despite intensive research and rapid advances in the development of tephrochronological methods in the past few decades, the accurate identification of distinct tephra layers and the precise synchronization of single volcanic events recorded in geological archives from different depositional environments remains challenging 4 , 5 . In southernmost Patagonia, the ages of widespread Holocene tephra layers from Plinian eruptions from volcanoes of the Patagonian Andes 6 in the southern segment of the Southern (41.5–46°S) and the Austral (49–55°S) Volcanic Zones were mainly deduced from 14 C-dated materials of terrestrial outcrops, peat and marine/lacustrine sediment cores 3 , 5 , 7 , 8 . This tephrochronological framework constitutes the principal reference for the stratigraphy of most geological records used in paleoclimate/paleoenvironmental studies from this climatically unique and poorly explored region 9 . But accurate age constraints for sedimentary climate and environmental archives are particularly difficult to obtain because age uncertainties and problems with the correlation of tephra layers in regional soils and sediment or peat core archives are due to variable composition, unclear stratigraphy, and diverging chronologies based on 14 C-dated carbonates, bulk organic matter (OM) or single plant remains 3 , 4 . In particular, 14 C-dated components of soils and sediments can have age offsets of hundreds of years due to reservoir effects caused by, e.g., the re-sedimentation and bioturbation of older OM or carbonate dissolution 10 , 11 , which have serious implications for age models. Large errors in age determination of volcanic ash layers also occur from the interpolation of bracketing 14 C dates 4 and/or age constraints based on estimated sedimentation/peat accumulation rates 12 , 13 . Further challenges include the correct identification of the source volcano through the characteristic physical/textural properties as well as the mineralogical and geochemical composition of tephra pumice and glass shards 8 . Site-dependent, potentially intense weathering processes in acidic peatland ecosystems 14 can compromise geochemical fingerprinting methods for tephra correlation 3 . Chemical weathering over long periods strongly alters the composition of volcanic glass and embedded phenocrysts, leading to changes in the concentration of major and trace elements 15 , 16 , 17 . Despite their increasingly important role as high-resolution terrestrial archives for the reconstruction of past climate and environmental changes, only a few speleothem records have so far contributed to regional tephrochronologies worldwide 18 , 19 , 20 , 21 , 22 . This is due to the difficulty of detecting unequivocal volcanic signals in speleothems. Furthermore, speleothem layers containing tephra glass shards or even small pumice particles have — to our knowledge — not yet been documented. Paine et al. 23 , for example, emphasized that the site-specific hydrological regime and soil/vegetation perturbation may attenuate the chemical signals from explosive volcanism that are preserved in stalagmites. Moreover, chemical signals of volcanic ash deposition can outlast the actual eruptive events by millennia 1 . These effects contribute to complicate the identification of volcanic eruptions by the sole stalagmite trace element profiling. Nevertheless, speleothems can be very useful for such studies because 230 Th/U dating allows exceptionally accurate and precise dating and variations in chemical elements can be detected with up to (sub-) annual resolution. Therefore, speleothems have great potential for the high precision dating of volcanic events comparable to ice core tephra records 18 , 24 . Combined with stable isotope data (δ 18 O, δ 13 C) and trace element proxies, speleothem records enable both the dating of volcanic activity and the evaluation of possible environmental and climate impacts following the documented eruptions 18 , 19 , 20 , 21 . In this work, we analyze a non-karst speleothem (stalagmite MA1 25 ) to better constrain the Late Holocene tephrostratigraphy in southernmost Patagonia and provide evidence for soil–environmental changes related to tephra deposition under extreme climate conditions. This speleothem formed in a small cave ca. 40 km S of Mt. Burney volcano and recorded sub-annual trace element variations detected by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). These high-resolution compositional profiles were combined with a refined 230 Th/U-chronology age model constructed from published 25 and additional new 230 Th/U dates. Based on this improved age model, our new LA-ICP-MS data, and principal component analysis (PCA), we (i) detect and analyze pyroclastic particles incorporated into the stalagmite and (ii) correlate these particles to pristine tephra of Mt. Burney volcano by electron microprobe (EPMA) glass composition measurements. This allows (iii) to precisely date the MB 2 , MB 3 , and MB 4 tephra", "role": "user" }, { "content": "The soils and vegetation of Patagonia's fjord regions form a unique and highly sensitive ecosystem that is closely linked to marine ecosystems, sediment deposition and carbon storage in the ocean. A research team, including the University of Göttingen, has been working on reconstructing the climate history of this region in this extremely wet, rainy and inaccessible fjord and island zone of the Patagonian Andes in southern Chile. Due to its location, the area is a key region for understanding the history of the southern westerly wind belt within the global climate system. The results were published in the journal Communications Earth & Environment. The research, in collaboration with the University of Trier, is based on extensive soil analyses and, above all, the detailed geochemical analyses of a stalagmite that is around 4,500 years old, which was recovered from an almost inaccessible cave. \"This stalagmite is the southernmost limestone deposit of its kind ever found,\" says Professor Gerhard Wörner of the Geoscience Center at Göttingen University. \"Its fine and detailed stratification enables us to document the chemical composition of the stalagmite at high temporal resolution.\" Since the stalagmite formed over a long time from surface waters that seeped into the cave, this geological \"archive\" makes it possible to reconstruct the climate-driven chemical processes in the peaty soils at the Earth's surface above the cave. Field work on the glaciers of Patagonia. Credit: R Kilian It turns out that the transport of chemical compounds from the peatlands to the fjords in southern Patagonian fjords are particularly closely coupled with natural processes in the delicate soil ecosystems, which react highly sensitively to climate fluctuations and the input of volcanic ash from nearby active volcanoes. \"It was a surprise to discover actual remnants of volcanic dust from eruptions of nearby volcanoes in the soil. In fact, tiny volcanic particles were detected embedded in the stalagmite from the cave,\" Wörner explains. The effect of volcanic depositions can also be documented from geochemical anomalies in the stalagmite—such as the high presence of sulfur—and can even be attributed to individual volcanic eruptions by dating the stalagmite layers. These volcanic deposits are of fundamental importance for the chemical processes in the peatlands of Patagonia and have a particularly strong effect under the influence of the extreme precipitation in the region. \"These effects range from substantial destruction of vegetation after large eruptions to a possible fertilizing effect on the ocean as a result of nutrients released after smaller eruptions,\" Wörner adds. Section through the MA-1 stalagmite from Arevalo Cave showing the fine layering of limestone. These deposits are a geochemical archive of the changing environmental conditions at the Earth's surface over more than 4,000 years. Credit: R Kilian/G Wörner ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Volcanic ash layers are important markers for the chronostratigraphy of paleoclimate and paleoenvironmental archives at the southern tip of South America. However, this requires that tephras are well-dated. We report geochemical data from stalagmite MA1 formed in a non-karst cave near Mt. Burney volcano in southernmost Patagonia (~53°S). High-resolution LA-ICP-MS analyses, SEM imagery, EPMA data, and NanoSIMS enable to identify volcanogenic signals during the last 4.5 kyrs from sub-annual trace element variations and tephra particles in distinct laminae. Our new 230 Th/U-chronology of MA1 provides precise dating of tephra from Mt. Burney (MB) and, probably, Aguilera (A) at 4,216 +93 / −193 yrs BP (MB 2 ), 2,291 ± 33 yrs BP (MB 3 ), 853 +41 / −60 yrs BP (MB 4 ) and 2,978 +91 / −104 yrs BP (A 1 ). This unique high-resolution record holds potential to date further eruptions from Southern Andean volcanoes for the tephrochronology in this critical region, and potentially also large-volume explosive volcanism off South America. Introduction Severe and long-lasting impact on regional ecosystems from explosive volcanic eruptions and ash (tephra) fallout has been observed in fragile environments such as the super-humid South Patagonian Andes 1 , 2 . While geochemical fingerprinting links tephra glass shard compositions to their volcanic source and represents a valuable tool in tephrochronology 3 , the dating of distinct tephra layers enables a reconstruction of the regional history of volcanic activity and provides isochronous and stratigraphic marker horizons for the correlation of paleoenvironmental archives over large geographical areas 4 . Despite intensive research and rapid advances in the development of tephrochronological methods in the past few decades, the accurate identification of distinct tephra layers and the precise synchronization of single volcanic events recorded in geological archives from different depositional environments remains challenging 4 , 5 . In southernmost Patagonia, the ages of widespread Holocene tephra layers from Plinian eruptions from volcanoes of the Patagonian Andes 6 in the southern segment of the Southern (41.5–46°S) and the Austral (49–55°S) Volcanic Zones were mainly deduced from 14 C-dated materials of terrestrial outcrops, peat and marine/lacustrine sediment cores 3 , 5 , 7 , 8 . This tephrochronological framework constitutes the principal reference for the stratigraphy of most geological records used in paleoclimate/paleoenvironmental studies from this climatically unique and poorly explored region 9 . But accurate age constraints for sedimentary climate and environmental archives are particularly difficult to obtain because age uncertainties and problems with the correlation of tephra layers in regional soils and sediment or peat core archives are due to variable composition, unclear stratigraphy, and diverging chronologies based on 14 C-dated carbonates, bulk organic matter (OM) or single plant remains 3 , 4 . In particular, 14 C-dated components of soils and sediments can have age offsets of hundreds of years due to reservoir effects caused by, e.g., the re-sedimentation and bioturbation of older OM or carbonate dissolution 10 , 11 , which have serious implications for age models. Large errors in age determination of volcanic ash layers also occur from the interpolation of bracketing 14 C dates 4 and/or age constraints based on estimated sedimentation/peat accumulation rates 12 , 13 . Further challenges include the correct identification of the source volcano through the characteristic physical/textural properties as well as the mineralogical and geochemical composition of tephra pumice and glass shards 8 . Site-dependent, potentially intense weathering processes in acidic peatland ecosystems 14 can compromise geochemical fingerprinting methods for tephra correlation 3 . Chemical weathering over long periods strongly alters the composition of volcanic glass and embedded phenocrysts, leading to changes in the concentration of major and trace elements 15 , 16 , 17 . Despite their increasingly important role as high-resolution terrestrial archives for the reconstruction of past climate and environmental changes, only a few speleothem records have so far contributed to regional tephrochronologies worldwide 18 , 19 , 20 , 21 , 22 . This is due to the difficulty of detecting unequivocal volcanic signals in speleothems. Furthermore, speleothem layers containing tephra glass shards or even small pumice particles have — to our knowledge — not yet been documented. Paine et al. 23 , for example, emphasized that the site-specific hydrological regime and soil/vegetation perturbation may attenuate the chemical signals from explosive volcanism that are preserved in stalagmites. Moreover, chemical signals of volcanic ash deposition can outlast the actual eruptive events by millennia 1 . These effects contribute to complicate the identification of volcanic eruptions by the sole stalagmite trace element profiling. Nevertheless, speleothems can be very useful for such studies because 230 Th/U dating allows exceptionally accurate and precise dating and variations in chemical elements can be detected with up to (sub-) annual resolution. Therefore, speleothems have great potential for the high precision dating of volcanic events comparable to ice core tephra records 18 , 24 . Combined with stable isotope data (δ 18 O, δ 13 C) and trace element proxies, speleothem records enable both the dating of volcanic activity and the evaluation of possible environmental and climate impacts following the documented eruptions 18 , 19 , 20 , 21 . In this work, we analyze a non-karst speleothem (stalagmite MA1 25 ) to better constrain the Late Holocene tephrostratigraphy in southernmost Patagonia and provide evidence for soil–environmental changes related to tephra deposition under extreme climate conditions. This speleothem formed in a small cave ca. 40 km S of Mt. Burney volcano and recorded sub-annual trace element variations detected by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). These high-resolution compositional profiles were combined with a refined 230 Th/U-chronology age model constructed from published 25 and additional new 230 Th/U dates. Based on this improved age model, our new LA-ICP-MS data, and principal component analysis (PCA), we (i) detect and analyze pyroclastic particles incorporated into the stalagmite and (ii) correlate these particles to pristine tephra of Mt. Burney volcano by electron microprobe (EPMA) glass composition measurements. This allows (iii) to precisely date the MB 2 , MB 3 , and MB 4 tephra<|im_end|> <|im_start|>assistant The soils and vegetation of Patagonia's fjord regions form a unique and highly sensitive ecosystem that is closely linked to marine ecosystems, sediment deposition and carbon storage in the ocean. A research team, including the University of Göttingen, has been working on reconstructing the climate history of this region in this extremely wet, rainy and inaccessible fjord and island zone of the Patagonian Andes in southern Chile. Due to its location, the area is a key region for understanding the history of the southern westerly wind belt within the global climate system. The results were published in the journal Communications Earth & Environment. The research, in collaboration with the University of Trier, is based on extensive soil analyses and, above all, the detailed geochemical analyses of a stalagmite that is around 4,500 years old, which was recovered from an almost inaccessible cave. "This stalagmite is the southernmost limestone deposit of its kind ever found," says Professor Gerhard Wörner of the Geoscience Center at Göttingen University. "Its fine and detailed stratification enables us to document the chemical composition of the stalagmite at high temporal resolution." Since the stalagmite formed over a long time from surface waters that seeped into the cave, this geological "archive" makes it possible to reconstruct the climate-driven chemical processes in the peaty soils at the Earth's surface above the cave. Field work on the glaciers of Patagonia. Credit: R Kilian It turns out that the transport of chemical compounds from the peatlands to the fjords in southern Patagonian fjords are particularly closely coupled with natural processes in the delicate soil ecosystems, which react highly sensitively to climate fluctuations and the input of volcanic ash from nearby active volcanoes. "It was a surprise to discover actual remnants of volcanic dust from eruptions of nearby volcanoes in the soil. In fact, tiny volcanic particles were detected embedded in the stalagmite from the cave," Wörner explains. The effect of volcanic depositions can also be documented from geochemical anomalies in the stalagmite—such as the high presence of sulfur—and can even be attributed to individual volcanic eruptions by dating the stalagmite layers. These volcanic deposits are of fundamental importance for the chemical processes in the peatlands of Patagonia and have a particularly strong effect under the influence of the extreme precipitation in the region. "These effects range from substantial destruction of vegetation after large eruptions to a possible fertilizing effect on the ocean as a result of nutrients released after smaller eruptions," Wörner adds. Section through the MA-1 stalagmite from Arevalo Cave showing the fine layering of limestone. These deposits are a geochemical archive of the changing environmental conditions at the Earth's surface over more than 4,000 years. Credit: R Kilian/G Wörner <|im_end|>

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2,093

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Double-stranded DNA bacteriophages package their genome at high pressure inside a procapsid through the portal, an oligomeric ring protein located at a unique capsid vertex. Once the DNA has been packaged, the tail components assemble on the portal to render the mature infective virion. The tail tightly seals the ejection conduit until infection, when its interaction with the host membrane triggers the opening of the channel and the viral genome is delivered to the host cell. Using high-resolution cryo-electron microscopy and X-ray crystallography, here we describe various structures of the T7 bacteriophage portal and fiber-less tail complex, which suggest a possible mechanism for DNA retention and ejection: a portal closed conformation temporarily retains the genome before the tail is assembled, whereas an open portal is found in the tail. Moreover, a fold including a seven-bladed β-propeller domain is described for the nozzle tail protein. Introduction The order Caudovirales comprises the largest number of biological entities on Earth. They are bacterial viruses characterized by an icosahedral capsid, enclosing a double-stranded (ds) DNA, with a tail. These phages share a common assembly pathway of prohead formation and genome packaging with herpesviruses 1 , 2 , 3 . Mechanisms for DNA incorporation and ejection show a number of similarities based on the existence of a machinery built by several components, including the portal protein or head-to-tail connector, motor proteins that provide energy-dependent DNA translocation (terminases) 4 , and, in phages, the tail complex 5 . In the case of the Podoviridae family, bacteriophages have a short, non-contractile tail, which generally comprises an adaptor and a tubular nozzle or knob, with a plug to prevent DNA leakage. The other tail components are the fibers (or spikes), which are responsible mainly for bacterial receptor recognition 6 , 7 . Phage portal proteins are key viral components located in a single pentameric vertex of the capsid and they act as initiators of capsid assembly. They are also critical components of the DNA-packaging complex and are involved in tail assembly 1 , 2 , 8 . In spite of a lack of extensive sequence similarity, all portal structures solved to date for Caudovirales (phi29 9 , 10 ; SPP1 11 ; P22 12 ; T4 13 ) share common morphological features, including a conical channel along the longitudinal axis and a conspicuous ring made of 12 subunits 1 , 2 , 8 . DNA packaging into preformed proheads requires the interaction of the portal protein with the terminase, which generates forces involved in the processive translocation of dsDNA into the viral capsid, where it is stored at quasi-crystalline concentration 1 , 14 , 15 . Both in phages 16 , 17 , 18 and in herpesviruses 19 , the interaction of the packaging terminase occurs at a region of the portal protein that extends outside the capsid shell through the portal vertex. After completion of the packaging, the DNA stored inside the capsid undergoes considerable stress due to mechanical strain induced by bending, as well as extensive repulsive electrostatic interactions 20 , 21 , 22 . In phi29 and SPP1, the DNA interacts with positively charged residues in the central channel of the portal protein, which have been proposed to contribute to stabilize the DNA inside the capsid prior to tail assembly 9 , 22 , 23 . The DNA is permanently stabilized inside the capsid, after the release of the terminase, by the subsequent incorporation of a dodecameric adaptor complex and the rest of the tail machine 24 , 25 . In phage P22, the gp4 adaptor ring interacts at the outer tip of the portal protein, called the clip, and has a long C-terminal helix that extends onto the outer surface of the portal protein monomer–monomer interface 12 . Although the structure of the isolated adaptor protein of phage Sf6 (gp7) shows a very similar arrangement to that of P22 gp4 and other adaptor proteins 12 , 26 , it shows differences in the relative position of the first α-helix. These observations suggest that this conformational change might be related to the structure before and after assembly in the mature phage 26 . In phage T7, the formation of the tail starts by the assembly of the gp11 adaptor toroidal ring, after which protein gp12 assembles on the distal side of the adaptor to build the hexameric nozzle 27 . The interaction of the adaptor and the nozzle generates the six regions where the fibers (trimers of gp17) assemble to render the final functional viral particle 27 , 28 . Podoviridae nozzles present distinct conformations during DNA ejection. In T7, interaction of the fibers with the bacterial receptor triggers a conformational change by untwisting the nozzle monomers, which results in the opening of the channel required for DNA release 28 , 29 . Although the precise details and molecular mechanisms of DNA release are not fully known, similar conformational changes in the nozzle have also been characterized in phage P-SSP7, a relative of T7 30 . In P22, the tail machinery also undergoes conformational changes during bacterial adsorption 31 . Here we report a number of crystal and high-resolution cryo-electron microscopy (cryo-EM) structures of the T7 bacteriophage portal (gp8). The structures show two conformations—open and closed—of the portal and suggest a possible mechanism of the channel valve that regulates DNA passage. Moreover, we describe the atomic structure, determined by cryo-EM, of the 1.5 MDa T7 tail complex (gp8-gp11-gp12), thus characterizing the whole ejection channel. In particular, the tail nozzle (gp12) shows an unexpected fold with six β-propellers, which are essential to tightly close the channel gate in the mature phage. All these structures, associated with different states of the infection cycle, support a mechanism underlying DNA retention inside the capsid and its ejection during infection. Results Structure of the T7 bacteriophage portal Several X-ray data sets from various crystal forms of the T7 portal in its dodecameric (12mer) and tridecameric (13mer) forms were collected. Although the portal protein is always found as a dodecamer", "role": "user" }, { "content": "The Epstein-Barr virus is one of the most widespread human viruses. Part of the herpesvirus family, it causes glandular fever (infectious mononucleosis), cancer and autoimmune diseases. At present, there is no treatment for infections caused by this virus. In work recently published in Nature Communications, scientists from the Institute for Research in Biomedicine (IRB Barcelona) and the Molecular Biology Institute of Barcelona (IBMB-CSIC) in Spain used cryo-electron microscopy (cryo-EM) to reveal the structure of a key protein, known as a portal, in the Epstein-Barr virus. Similarities between herpesviruses and tailed bacteriophages (viruses that infect bacteria) suggest that these two types of organism may be related. In a second paper published in the same journal, the team solved the structure of the portal protein in bacteriophage T7, using a combination of cryo-EM and X-ray crystallography. These results allowed them to infer how the Epstein-Barr virus portal works and may help in the development of a treatment for this virus. In 2018, we brought you the news that high-resolution cryo-EM at eBIC had uncovered new information about a critical feature of the Herpes Simplex Virus. Cryo-EM has now worked its magic on the related Epstein-Barr virus, paving the way towards ways to defeat this untreatable virus. The herpesvirus family is enormous and includes eight human pathogens. The Epstein-Barr virus infects B-cells (a type of white blood cell) and also the epithelial cells that make up skin and also line the inside of the throat, blood vessels and organs. It causes glandular fever (infectious mononucleosis) and can cause several kinds of cancer and autoimmune diseases. All herpesviruses infect in a similar way. Once the virus has entered a cell and reached the nucleus, it releases its DNA. This DNA can lie dormant for many years until specific conditions trigger replication. When the virus replicates, the DNA is introduced into a new viral shell (capsid), forming a new virus capable of attacking other cells. The virus uses a protein called a portal for packaging its DNA into the viral capsid and to release it to the host cell during infection. As the portal plays a critical role in replication and infection, it makes an attractive target for the development of new anti-viral drugs. The portal: an open and shut case? The similarities between the capsid structure and viral DNA packaging mechanism of herpesviruses and tailed bacteriophages suggest that they may be related. Although researchers have been able to determine the structure of portal proteins from bacteriophages successfully, the study of herpesvirus portals has been more challenging. Scientists from the Institute for Research in Biomedicine (IRB Barcelona) and the Molecular Biology Institute of Barcelona (IBMB-CSIC) have now used cryo-EM at eBIC to reveal the structure of the portal protein in the Epstein-Barr virus at a resolution of 3.5 Å. In a second study, the same team used a combination of cryo-EM and X-ray crystallography to characterise the structure of the portal protein in bacteriophage T7. Their work illustrates the power of using these techniques in conjunction to solve challenging molecular structures. The bacteriophage also uses its portal to package its DNA inside a pro-capsid. The tail components then assemble on the portal to make an infectious virus. The ejection conduit remains tightly sealed until infection, when the channel opens to deliver the DNA to the host cell. All of the portals analysed to date for the Caudovirales family of bacteriophages share common structural features. In search of antivirals Miquel Coll is head of the Structural Biology of Protein & Nucleic Acid Complexes and Molecular Machines Lab at IRB Barcelona and a professor at IBMB-CSIC. He says; \"Understanding the structure of the portal protein could aid the design of inhibitors for the treatment of herpesvirus infections such as Epstein-Barr. As this protein is only found in herpesviruses, these inhibitors would be virus-specific and may be less toxic for humans.\" Cristina Machón and Montserrat Fàbrega, postdoctoral fellows at IRB Barcelona and IBMB-CSIC are first authors on both papers. They say that \"solving the structure of the portal protein of bacteriophage T7 has allowed us to infer how the portal from Epstein-Barr virus works.\" The drugs currently used to treat herpesvirus infections target the viral DNA polymerase. They are not very efficient, with serious side effects and the appearance of viral resistance after prolonged treatment. There is no specific treatment for the Epstein-Barr virus. Knowledge of the atomic structures of portal proteins will be extremely valuable, allowing the structure-driven design of compounds targeting their function—highly specific anti-virals that should cause fewer side effects. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Double-stranded DNA bacteriophages package their genome at high pressure inside a procapsid through the portal, an oligomeric ring protein located at a unique capsid vertex. Once the DNA has been packaged, the tail components assemble on the portal to render the mature infective virion. The tail tightly seals the ejection conduit until infection, when its interaction with the host membrane triggers the opening of the channel and the viral genome is delivered to the host cell. Using high-resolution cryo-electron microscopy and X-ray crystallography, here we describe various structures of the T7 bacteriophage portal and fiber-less tail complex, which suggest a possible mechanism for DNA retention and ejection: a portal closed conformation temporarily retains the genome before the tail is assembled, whereas an open portal is found in the tail. Moreover, a fold including a seven-bladed β-propeller domain is described for the nozzle tail protein. Introduction The order Caudovirales comprises the largest number of biological entities on Earth. They are bacterial viruses characterized by an icosahedral capsid, enclosing a double-stranded (ds) DNA, with a tail. These phages share a common assembly pathway of prohead formation and genome packaging with herpesviruses 1 , 2 , 3 . Mechanisms for DNA incorporation and ejection show a number of similarities based on the existence of a machinery built by several components, including the portal protein or head-to-tail connector, motor proteins that provide energy-dependent DNA translocation (terminases) 4 , and, in phages, the tail complex 5 . In the case of the Podoviridae family, bacteriophages have a short, non-contractile tail, which generally comprises an adaptor and a tubular nozzle or knob, with a plug to prevent DNA leakage. The other tail components are the fibers (or spikes), which are responsible mainly for bacterial receptor recognition 6 , 7 . Phage portal proteins are key viral components located in a single pentameric vertex of the capsid and they act as initiators of capsid assembly. They are also critical components of the DNA-packaging complex and are involved in tail assembly 1 , 2 , 8 . In spite of a lack of extensive sequence similarity, all portal structures solved to date for Caudovirales (phi29 9 , 10 ; SPP1 11 ; P22 12 ; T4 13 ) share common morphological features, including a conical channel along the longitudinal axis and a conspicuous ring made of 12 subunits 1 , 2 , 8 . DNA packaging into preformed proheads requires the interaction of the portal protein with the terminase, which generates forces involved in the processive translocation of dsDNA into the viral capsid, where it is stored at quasi-crystalline concentration 1 , 14 , 15 . Both in phages 16 , 17 , 18 and in herpesviruses 19 , the interaction of the packaging terminase occurs at a region of the portal protein that extends outside the capsid shell through the portal vertex. After completion of the packaging, the DNA stored inside the capsid undergoes considerable stress due to mechanical strain induced by bending, as well as extensive repulsive electrostatic interactions 20 , 21 , 22 . In phi29 and SPP1, the DNA interacts with positively charged residues in the central channel of the portal protein, which have been proposed to contribute to stabilize the DNA inside the capsid prior to tail assembly 9 , 22 , 23 . The DNA is permanently stabilized inside the capsid, after the release of the terminase, by the subsequent incorporation of a dodecameric adaptor complex and the rest of the tail machine 24 , 25 . In phage P22, the gp4 adaptor ring interacts at the outer tip of the portal protein, called the clip, and has a long C-terminal helix that extends onto the outer surface of the portal protein monomer–monomer interface 12 . Although the structure of the isolated adaptor protein of phage Sf6 (gp7) shows a very similar arrangement to that of P22 gp4 and other adaptor proteins 12 , 26 , it shows differences in the relative position of the first α-helix. These observations suggest that this conformational change might be related to the structure before and after assembly in the mature phage 26 . In phage T7, the formation of the tail starts by the assembly of the gp11 adaptor toroidal ring, after which protein gp12 assembles on the distal side of the adaptor to build the hexameric nozzle 27 . The interaction of the adaptor and the nozzle generates the six regions where the fibers (trimers of gp17) assemble to render the final functional viral particle 27 , 28 . Podoviridae nozzles present distinct conformations during DNA ejection. In T7, interaction of the fibers with the bacterial receptor triggers a conformational change by untwisting the nozzle monomers, which results in the opening of the channel required for DNA release 28 , 29 . Although the precise details and molecular mechanisms of DNA release are not fully known, similar conformational changes in the nozzle have also been characterized in phage P-SSP7, a relative of T7 30 . In P22, the tail machinery also undergoes conformational changes during bacterial adsorption 31 . Here we report a number of crystal and high-resolution cryo-electron microscopy (cryo-EM) structures of the T7 bacteriophage portal (gp8). The structures show two conformations—open and closed—of the portal and suggest a possible mechanism of the channel valve that regulates DNA passage. Moreover, we describe the atomic structure, determined by cryo-EM, of the 1.5 MDa T7 tail complex (gp8-gp11-gp12), thus characterizing the whole ejection channel. In particular, the tail nozzle (gp12) shows an unexpected fold with six β-propellers, which are essential to tightly close the channel gate in the mature phage. All these structures, associated with different states of the infection cycle, support a mechanism underlying DNA retention inside the capsid and its ejection during infection. Results Structure of the T7 bacteriophage portal Several X-ray data sets from various crystal forms of the T7 portal in its dodecameric (12mer) and tridecameric (13mer) forms were collected. Although the portal protein is always found as a dodecamer<|im_end|> <|im_start|>assistant The Epstein-Barr virus is one of the most widespread human viruses. Part of the herpesvirus family, it causes glandular fever (infectious mononucleosis), cancer and autoimmune diseases. At present, there is no treatment for infections caused by this virus. In work recently published in Nature Communications, scientists from the Institute for Research in Biomedicine (IRB Barcelona) and the Molecular Biology Institute of Barcelona (IBMB-CSIC) in Spain used cryo-electron microscopy (cryo-EM) to reveal the structure of a key protein, known as a portal, in the Epstein-Barr virus. Similarities between herpesviruses and tailed bacteriophages (viruses that infect bacteria) suggest that these two types of organism may be related. In a second paper published in the same journal, the team solved the structure of the portal protein in bacteriophage T7, using a combination of cryo-EM and X-ray crystallography. These results allowed them to infer how the Epstein-Barr virus portal works and may help in the development of a treatment for this virus. In 2018, we brought you the news that high-resolution cryo-EM at eBIC had uncovered new information about a critical feature of the Herpes Simplex Virus. Cryo-EM has now worked its magic on the related Epstein-Barr virus, paving the way towards ways to defeat this untreatable virus. The herpesvirus family is enormous and includes eight human pathogens. The Epstein-Barr virus infects B-cells (a type of white blood cell) and also the epithelial cells that make up skin and also line the inside of the throat, blood vessels and organs. It causes glandular fever (infectious mononucleosis) and can cause several kinds of cancer and autoimmune diseases. All herpesviruses infect in a similar way. Once the virus has entered a cell and reached the nucleus, it releases its DNA. This DNA can lie dormant for many years until specific conditions trigger replication. When the virus replicates, the DNA is introduced into a new viral shell (capsid), forming a new virus capable of attacking other cells. The virus uses a protein called a portal for packaging its DNA into the viral capsid and to release it to the host cell during infection. As the portal plays a critical role in replication and infection, it makes an attractive target for the development of new anti-viral drugs. The portal: an open and shut case? The similarities between the capsid structure and viral DNA packaging mechanism of herpesviruses and tailed bacteriophages suggest that they may be related. Although researchers have been able to determine the structure of portal proteins from bacteriophages successfully, the study of herpesvirus portals has been more challenging. Scientists from the Institute for Research in Biomedicine (IRB Barcelona) and the Molecular Biology Institute of Barcelona (IBMB-CSIC) have now used cryo-EM at eBIC to reveal the structure of the portal protein in the Epstein-Barr virus at a resolution of 3.5 Å. In a second study, the same team used a combination of cryo-EM and X-ray crystallography to characterise the structure of the portal protein in bacteriophage T7. Their work illustrates the power of using these techniques in conjunction to solve challenging molecular structures. The bacteriophage also uses its portal to package its DNA inside a pro-capsid. The tail components then assemble on the portal to make an infectious virus. The ejection conduit remains tightly sealed until infection, when the channel opens to deliver the DNA to the host cell. All of the portals analysed to date for the Caudovirales family of bacteriophages share common structural features. In search of antivirals Miquel Coll is head of the Structural Biology of Protein & Nucleic Acid Complexes and Molecular Machines Lab at IRB Barcelona and a professor at IBMB-CSIC. He says; "Understanding the structure of the portal protein could aid the design of inhibitors for the treatment of herpesvirus infections such as Epstein-Barr. As this protein is only found in herpesviruses, these inhibitors would be virus-specific and may be less toxic for humans." Cristina Machón and Montserrat Fàbrega, postdoctoral fellows at IRB Barcelona and IBMB-CSIC are first authors on both papers. They say that "solving the structure of the portal protein of bacteriophage T7 has allowed us to infer how the portal from Epstein-Barr virus works." The drugs currently used to treat herpesvirus infections target the viral DNA polymerase. They are not very efficient, with serious side effects and the appearance of viral resistance after prolonged treatment. There is no specific treatment for the Epstein-Barr virus. Knowledge of the atomic structures of portal proteins will be extremely valuable, allowing the structure-driven design of compounds targeting their function—highly specific anti-virals that should cause fewer side effects. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Household air pollution generated from the use of polluting cooking fuels and technologies is a major source of disease and environmental degradation in low- and middle-income countries. Using a novel modelling approach, we provide detailed global, regional and country estimates of the percentages and populations mainly using 6 fuel categories (electricity, gaseous fuels, kerosene, biomass, charcoal, coal) and overall polluting/clean fuel use – from 1990-2020 and with urban/rural disaggregation. Here we show that 53% of the global population mainly used polluting cooking fuels in 1990, dropping to 36% in 2020. In urban areas, gaseous fuels currently dominate, with a growing reliance on electricity; in rural populations, high levels of biomass use persist alongside increasing use of gaseous fuels. Future projections of observed trends suggest 31% will still mainly use polluting fuels in 2030, including over 1 billion people in Sub-Saharan African by 2025. Introduction For 3 billion people 1 living in low-income and middle-income countries (LMICs), the simple act of cooking is a major health and safety risk. The inefficient combustion of solid fuels (wood, coal, charcoal, dung, and crop waste) and kerosene in simple stoves and devices produces high levels of household air pollution (HAP). Chronic exposure to HAP increases the risk of noncommunicable disease including ischemic heart disease, stroke, chronic obstructive pulmonary disease, lung cancer, as well as pneumonia 2 . Overall, HAP exposure accounts for some 3.8 million premature deaths annually 3 . Use of open fires or poorly balanced pots is also a major cause of burns and scalds in LMICs, while kerosene and charcoal use in the home is a major source of poisonings from either ingestion or carbon monoxide exposure 2 . Households that rely on polluting energy systems frequently have to travel great distances to gather fuel—sometimes traveling hours each week—putting them at increased risk of musculoskeletal injury and violence 4 . Fuel collection is often tasked to women and children, perpetuating the negative socioeconomic and gender inequities of energy poverty by taking away time that could be spent on other activities likes schooling, income-generation, and socializing. 4 Polluting cooking practices are also an important cause of environmental degradation and climate change: the black carbon from cooking, heating and lighting is responsible for 25% of anthropogenic global black carbon emissions 5 , and around 30% of wood fuels harvested globally are unsustainable 6 . In recognition of these significant burdens, the global community has prioritized achieving universal access to clean cooking, enshrined in the 2030 Agenda for Sustainable Development 7 as one of three targets for Sustainable Development Goal (SDG) 7, to “ensure access to affordable, reliable, sustainable, and modern energy”. As part of its mandate to monitor and inform policy towards this goal, the World Health Organization (WHO) publishes estimates of exposure to HAP 8 and related disease burdens 3 . Historically, such estimates were calculated using the estimated population mainly using solid fuels 9 for cooking. However in 2014, the WHO published the first-ever normative guidelines on the fuels and technologies that can be considered “clean” for health 2 , which highlight the importance of stove and fuel performance in combination, while also recommending against or discouraging the use of certain fuels—notably unprocessed coal and kerosene, a liquid fuel previously considered clean that emits high levels of harmful pollution. Since then, tracking of “solid fuels” has been replaced with “polluting fuels and technologies”—where polluting fuels consists of unprocessed biomass (wood, crop residues, and dung), charcoal, coal, and kerosene (Fig. 1 ), and polluting technologies refers to those stoves with emission rates higher than the recommended rates included in WHO Guidelines. Meanwhile, estimates of the proportion of the population mainly using clean fuels and technologies—where clean fuels consists of gaseous fuels (liquified petroleum gas or LPG, natural gas, biogas), electricity, alcohol, and solar energy (Fig. 1 )—inform monitoring of progress towards universal access to clean cooking 1 . Acknowledging the very limited survey data on the technologies used for cooking, and the limited availability of truly clean-burning (for health) biomass stoves in LMICs, this analysis focuses only on the fuels used rather than stove technologies. Fig. 1: Cooking fuel categorization. Classification of cooking fuels within the scope of the global household energy model as clean or polluting. Full size image While the aggregate indicators “polluting fuel use” and “clean fuel use” are effective for summarizing and communicating the global extent of polluting cooking, and progress towards global goals, fuel-specific estimates are needed to optimally inform policies and decision-making on how to achieve the greatest reductions in HAP exposure as quickly as possible. These data in combination with local expert knowledge on challenges of affordability, availability, infrastructure, and cultural preferences are critical to maximizing the health benefits from the clean cooking transition. Fuel-specific estimates are also desirable to refine estimates of HAP exposure and health burdens at regional, country level, and sub-national levels, fully taking into account the varying harm and types of pollution associated with different fuels (notably, carbon monoxide is currently absent from burden of disease calculations 10 ). Using a new model based on individual/specific fuel categories 11 (detailed in “Methods” section), we report estimates of main cooking fuel use at country, regional, (SDG and WHO regions) and global levels, for each year from 1990 to 2020, with urban/rural disaggregation. We provide estimates of aggregate clean and polluting fuel use, and report for the first time estimates for six specific fuel categories: electricity, gaseous fuels, kerosene, unprocessed biomass, charcoal, and coal. For brevity, gaseous fuels and unprocessed biomass are from here onwards called “gas” and “biomass”, respectively. We also report future projections of all estimates up to 2030 representing a possible scenario, where trends seen in recent decades continue. We provide all estimates as Supplementary Data for download: Supplementary Data 1 contains estimates at country level; Supplementary Data 2 contains estimates at SDG region and global levels; and Supplementary Data 3 contains estimates at WHO region level. In this article, we will often refer to percentages or populations mainly", "role": "user" }, { "content": "In 2030, almost 1 in 3people around the world will still be mainly using polluting cooking fuels and technologies, a major source of disease and environmental destruction and devastation, new research warned. This rises to more than 4 in 5 in sub-Saharan Africa, where the number of people mainly using polluting fuels is growing at an alarming rate. A new study, carried out by U.K. researchers and the World Health Organization (WHO), has estimated that just under 3 billion people worldwide—including more than 1 billion in sub-Saharan Africa—will still mainly be using polluting fuels such as wood fuels and charcoal at the end of the decade. These dirty fuels are a source of major health risks as they produce high levels of household air pollution—chronic exposure to which increases the risk of heart disease, pneumonia, lung cancer and strokes, amongst others. While the overall percentage of the global population mainly using polluting cooking fuels has been steadily decreasing since 1990, this trend is already showing signs of stagnation. Six in in ten people in rural areas are still reliant on biomass fuels such as wood and charcoal. Reports by the WHO and others have attributed household air pollution from these fuels to millions of deaths per year—comparable to the death toll from outdoor air pollution. At the same time, fuel collection is often tasked to women and children, reducing opportunities for education, or income generation. Polluting fuels are also an important cause of environmental degradation and climate change, with the black carbon from residential biomass cooking estimate to account for 25 percent of anthropogenic global black carbon emissions each year. The researchers insist the pivotal new study shows that, although progress has been made, the quest to deliver universal access to clean cooking by 2030 is \"far off track.\" They believe that global leaders and policy makers need to make significant advancements, in the short-term future, to help combat the health and environmental risks of household air pollution. The study is published in Nature Communications on October 4, 2021. The lead author of the study, Dr. Oliver Stoner, who carried out the research at the University of Exeter but is now at the University of Glasgow said: \"Analyzing global trends suggests incremental progress in the direction of clean cooking fuels, but the simple reality is that there can be no global success while the number of people using polluting fuels in sub-Saharan Africa grows by 10s of millions every year.\" Heather Adair-Rohani, technical lead on Health and Energy in the Department of Environment, Climate Change and Health at the WHO headquarters in Geneva, and a senior author on the study, stressed the importance of tackling the root causes household air pollution, \"Accelerating access to clean cooking solutions must be a developmental priority. Ensuring the sustained adoption of clean cooking solutions can prevent disease and improve the livelihoods of the poorest populations as well as protect our climate.\" The crucial need to provide access to clean cooking globally was enshrined in the 2030 Agenda for Sustainable Development, adopted by all United Nations member states, as one of three targets for Sustainable Development Goal (SDG) 7, to \"ensure access to affordable, reliable, sustainable and modern energy.\" As part of its mandate to monitor and inform policy towards this goal, WHO publishes estimates of exposure to HAP and related disease burdens, which have traditionally examined use of polluting fuels as a group, without distinguishing between the different fuels used. For the new study, the researchers used sophisticated modeling combined with increasingly detailed household survey data to give a more accurate portrayal of the extent polluting cooking fuels are still used. The research provides comprehensive and reliable estimates for the use of six types of fuel—electricity, gaseous fuels, kerosene, biomass, charcoal, coal—as well as overall clean and polluting fuel use from 1990 to 2020, and subsequent predictions up until 2030. Together with the article, all estimates are published open access, to enable a new wave of research and policy aimed at tackling household air pollution. Among the research findings are: The absolute number of people using polluting fuels has deviated little from 3 billion over the last three decades. Projections show that 2.7 billion people—just under 1 in 3—will continue to mainly rely on polluting cooking fuels in 2030. Sub-Saharan Africa is now the largest regional population mainly using polluting fuels for cooking, expected to rise above 1 billion people in the next five years under a business-as-usual scenario. Charcoal has become the most popular fuel in urban sub-Saharan Africa. Dr. Stoner added: \"While our analysis already paints a bleak picture, we don't yet know the full extent to which the COVID-19 pandemic has threatened or even undone recent progress.\" \"Household cooking fuel estimates at global and country level for 1990 to 2030,\" is published in Nature Communications on October 4, 2021. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Household air pollution generated from the use of polluting cooking fuels and technologies is a major source of disease and environmental degradation in low- and middle-income countries. Using a novel modelling approach, we provide detailed global, regional and country estimates of the percentages and populations mainly using 6 fuel categories (electricity, gaseous fuels, kerosene, biomass, charcoal, coal) and overall polluting/clean fuel use – from 1990-2020 and with urban/rural disaggregation. Here we show that 53% of the global population mainly used polluting cooking fuels in 1990, dropping to 36% in 2020. In urban areas, gaseous fuels currently dominate, with a growing reliance on electricity; in rural populations, high levels of biomass use persist alongside increasing use of gaseous fuels. Future projections of observed trends suggest 31% will still mainly use polluting fuels in 2030, including over 1 billion people in Sub-Saharan African by 2025. Introduction For 3 billion people 1 living in low-income and middle-income countries (LMICs), the simple act of cooking is a major health and safety risk. The inefficient combustion of solid fuels (wood, coal, charcoal, dung, and crop waste) and kerosene in simple stoves and devices produces high levels of household air pollution (HAP). Chronic exposure to HAP increases the risk of noncommunicable disease including ischemic heart disease, stroke, chronic obstructive pulmonary disease, lung cancer, as well as pneumonia 2 . Overall, HAP exposure accounts for some 3.8 million premature deaths annually 3 . Use of open fires or poorly balanced pots is also a major cause of burns and scalds in LMICs, while kerosene and charcoal use in the home is a major source of poisonings from either ingestion or carbon monoxide exposure 2 . Households that rely on polluting energy systems frequently have to travel great distances to gather fuel—sometimes traveling hours each week—putting them at increased risk of musculoskeletal injury and violence 4 . Fuel collection is often tasked to women and children, perpetuating the negative socioeconomic and gender inequities of energy poverty by taking away time that could be spent on other activities likes schooling, income-generation, and socializing. 4 Polluting cooking practices are also an important cause of environmental degradation and climate change: the black carbon from cooking, heating and lighting is responsible for 25% of anthropogenic global black carbon emissions 5 , and around 30% of wood fuels harvested globally are unsustainable 6 . In recognition of these significant burdens, the global community has prioritized achieving universal access to clean cooking, enshrined in the 2030 Agenda for Sustainable Development 7 as one of three targets for Sustainable Development Goal (SDG) 7, to “ensure access to affordable, reliable, sustainable, and modern energy”. As part of its mandate to monitor and inform policy towards this goal, the World Health Organization (WHO) publishes estimates of exposure to HAP 8 and related disease burdens 3 . Historically, such estimates were calculated using the estimated population mainly using solid fuels 9 for cooking. However in 2014, the WHO published the first-ever normative guidelines on the fuels and technologies that can be considered “clean” for health 2 , which highlight the importance of stove and fuel performance in combination, while also recommending against or discouraging the use of certain fuels—notably unprocessed coal and kerosene, a liquid fuel previously considered clean that emits high levels of harmful pollution. Since then, tracking of “solid fuels” has been replaced with “polluting fuels and technologies”—where polluting fuels consists of unprocessed biomass (wood, crop residues, and dung), charcoal, coal, and kerosene (Fig. 1 ), and polluting technologies refers to those stoves with emission rates higher than the recommended rates included in WHO Guidelines. Meanwhile, estimates of the proportion of the population mainly using clean fuels and technologies—where clean fuels consists of gaseous fuels (liquified petroleum gas or LPG, natural gas, biogas), electricity, alcohol, and solar energy (Fig. 1 )—inform monitoring of progress towards universal access to clean cooking 1 . Acknowledging the very limited survey data on the technologies used for cooking, and the limited availability of truly clean-burning (for health) biomass stoves in LMICs, this analysis focuses only on the fuels used rather than stove technologies. Fig. 1: Cooking fuel categorization. Classification of cooking fuels within the scope of the global household energy model as clean or polluting. Full size image While the aggregate indicators “polluting fuel use” and “clean fuel use” are effective for summarizing and communicating the global extent of polluting cooking, and progress towards global goals, fuel-specific estimates are needed to optimally inform policies and decision-making on how to achieve the greatest reductions in HAP exposure as quickly as possible. These data in combination with local expert knowledge on challenges of affordability, availability, infrastructure, and cultural preferences are critical to maximizing the health benefits from the clean cooking transition. Fuel-specific estimates are also desirable to refine estimates of HAP exposure and health burdens at regional, country level, and sub-national levels, fully taking into account the varying harm and types of pollution associated with different fuels (notably, carbon monoxide is currently absent from burden of disease calculations 10 ). Using a new model based on individual/specific fuel categories 11 (detailed in “Methods” section), we report estimates of main cooking fuel use at country, regional, (SDG and WHO regions) and global levels, for each year from 1990 to 2020, with urban/rural disaggregation. We provide estimates of aggregate clean and polluting fuel use, and report for the first time estimates for six specific fuel categories: electricity, gaseous fuels, kerosene, unprocessed biomass, charcoal, and coal. For brevity, gaseous fuels and unprocessed biomass are from here onwards called “gas” and “biomass”, respectively. We also report future projections of all estimates up to 2030 representing a possible scenario, where trends seen in recent decades continue. We provide all estimates as Supplementary Data for download: Supplementary Data 1 contains estimates at country level; Supplementary Data 2 contains estimates at SDG region and global levels; and Supplementary Data 3 contains estimates at WHO region level. In this article, we will often refer to percentages or populations mainly<|im_end|> <|im_start|>assistant In 2030, almost 1 in 3people around the world will still be mainly using polluting cooking fuels and technologies, a major source of disease and environmental destruction and devastation, new research warned. This rises to more than 4 in 5 in sub-Saharan Africa, where the number of people mainly using polluting fuels is growing at an alarming rate. A new study, carried out by U.K. researchers and the World Health Organization (WHO), has estimated that just under 3 billion people worldwide—including more than 1 billion in sub-Saharan Africa—will still mainly be using polluting fuels such as wood fuels and charcoal at the end of the decade. These dirty fuels are a source of major health risks as they produce high levels of household air pollution—chronic exposure to which increases the risk of heart disease, pneumonia, lung cancer and strokes, amongst others. While the overall percentage of the global population mainly using polluting cooking fuels has been steadily decreasing since 1990, this trend is already showing signs of stagnation. Six in in ten people in rural areas are still reliant on biomass fuels such as wood and charcoal. Reports by the WHO and others have attributed household air pollution from these fuels to millions of deaths per year—comparable to the death toll from outdoor air pollution. At the same time, fuel collection is often tasked to women and children, reducing opportunities for education, or income generation. Polluting fuels are also an important cause of environmental degradation and climate change, with the black carbon from residential biomass cooking estimate to account for 25 percent of anthropogenic global black carbon emissions each year. The researchers insist the pivotal new study shows that, although progress has been made, the quest to deliver universal access to clean cooking by 2030 is "far off track." They believe that global leaders and policy makers need to make significant advancements, in the short-term future, to help combat the health and environmental risks of household air pollution. The study is published in Nature Communications on October 4, 2021. The lead author of the study, Dr. Oliver Stoner, who carried out the research at the University of Exeter but is now at the University of Glasgow said: "Analyzing global trends suggests incremental progress in the direction of clean cooking fuels, but the simple reality is that there can be no global success while the number of people using polluting fuels in sub-Saharan Africa grows by 10s of millions every year." Heather Adair-Rohani, technical lead on Health and Energy in the Department of Environment, Climate Change and Health at the WHO headquarters in Geneva, and a senior author on the study, stressed the importance of tackling the root causes household air pollution, "Accelerating access to clean cooking solutions must be a developmental priority. Ensuring the sustained adoption of clean cooking solutions can prevent disease and improve the livelihoods of the poorest populations as well as protect our climate." The crucial need to provide access to clean cooking globally was enshrined in the 2030 Agenda for Sustainable Development, adopted by all United Nations member states, as one of three targets for Sustainable Development Goal (SDG) 7, to "ensure access to affordable, reliable, sustainable and modern energy." As part of its mandate to monitor and inform policy towards this goal, WHO publishes estimates of exposure to HAP and related disease burdens, which have traditionally examined use of polluting fuels as a group, without distinguishing between the different fuels used. For the new study, the researchers used sophisticated modeling combined with increasingly detailed household survey data to give a more accurate portrayal of the extent polluting cooking fuels are still used. The research provides comprehensive and reliable estimates for the use of six types of fuel—electricity, gaseous fuels, kerosene, biomass, charcoal, coal—as well as overall clean and polluting fuel use from 1990 to 2020, and subsequent predictions up until 2030. Together with the article, all estimates are published open access, to enable a new wave of research and policy aimed at tackling household air pollution. Among the research findings are: The absolute number of people using polluting fuels has deviated little from 3 billion over the last three decades. Projections show that 2.7 billion people—just under 1 in 3—will continue to mainly rely on polluting cooking fuels in 2030. Sub-Saharan Africa is now the largest regional population mainly using polluting fuels for cooking, expected to rise above 1 billion people in the next five years under a business-as-usual scenario. Charcoal has become the most popular fuel in urban sub-Saharan Africa. Dr. Stoner added: "While our analysis already paints a bleak picture, we don't yet know the full extent to which the COVID-19 pandemic has threatened or even undone recent progress." "Household cooking fuel estimates at global and country level for 1990 to 2030," is published in Nature Communications on October 4, 2021. <|im_end|>

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7230, 10831, 10633, 1005, 11, 323, 1934, 369, 279, 1176, 892, 17989, 369, 4848, 3230, 10633, 11306, 25, 18200, 11, 342, 521, 788, 40373, 11, 597, 6398, 1994, 11, 653, 35122, 58758, 11, 61203, 11, 323, 11756, 13, 1789, 5395, 85, 488, 11, 342, 521, 788, 40373, 323, 653, 35122, 58758, 527, 505, 1618, 60525, 2663, 1054, 40625, 863, 323, 1054, 8385, 316, 395, 9520, 15947, 13, 1226, 1101, 1934, 3938, 41579, 315, 682, 17989, 709, 311, 220, 9639, 15, 14393, 264, 3284, 15398, 11, 1405, 18845, 3970, 304, 3293, 11026, 3136, 13, 1226, 3493, 682, 17989, 439, 99371, 2956, 369, 4232, 25, 99371, 2956, 220, 16, 5727, 17989, 520, 3224, 2237, 26, 99371, 2956, 220, 17, 5727, 17989, 520, 8189, 38, 5654, 323, 3728, 5990, 26, 323, 99371, 2956, 220, 18, 5727, 17989, 520, 40312, 5654, 2237, 13, 763, 420, 4652, 11, 584, 690, 3629, 8464, 311, 54208, 477, 22673, 14918, 128257, 198, 128256, 78191, 198, 644, 220, 9639, 15, 11, 4661, 220, 16, 304, 220, 18, 16455, 2212, 279, 1917, 690, 2103, 387, 14918, 1701, 7230, 10831, 17677, 40373, 323, 14645, 11, 264, 3682, 2592, 315, 8624, 323, 12434, 19814, 323, 83015, 11, 502, 3495, 19201, 13, 1115, 38268, 311, 810, 1109, 220, 19, 304, 220, 20, 304, 1207, 97519, 10384, 11, 1405, 279, 1396, 315, 1274, 14918, 1701, 7230, 10831, 40373, 374, 7982, 520, 459, 57376, 4478, 13, 362, 502, 4007, 11, 11953, 704, 555, 549, 11606, 13, 12074, 323, 279, 4435, 6401, 21021, 320, 78847, 705, 706, 13240, 430, 1120, 1234, 220, 18, 7239, 1274, 15603, 76070, 810, 1109, 220, 16, 7239, 304, 1207, 97519, 10384, 2345, 14724, 2103, 14918, 387, 1701, 7230, 10831, 40373, 1778, 439, 7732, 40373, 323, 61203, 520, 279, 842, 315, 279, 13515, 13, 4314, 19108, 40373, 527, 264, 2592, 315, 3682, 2890, 15635, 439, 814, 8356, 1579, 5990, 315, 14048, 3805, 25793, 2345, 7562, 292, 14675, 311, 902, 12992, 279, 5326, 315, 4851, 8624, 11, 69329, 11, 21271, 9572, 323, 53572, 11, 24059, 3885, 13, 6104, 279, 8244, 11668, 315, 279, 3728, 7187, 14918, 1701, 7230, 10831, 17677, 40373, 706, 1027, 43071, 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2,388

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Roquin and Regnase-1 proteins bind and post-transcriptionally regulate proinflammatory target messenger RNAs to maintain immune homeostasis. Either the sanroque mutation in Roquin-1 or loss of Regnase-1 cause systemic lupus erythematosus-like phenotypes. Analyzing mice with T cells that lack expression of Roquin-1, its paralog Roquin-2 and Regnase-1 proteins, we detect overlapping or unique phenotypes by comparing individual and combined inactivation. These comprised spontaneous activation, metabolic reprogramming and persistence of T cells leading to autoimmunity. Here, we define an interaction surface in Roquin-1 for binding to Regnase-1 that included the sanroque residue. Mutations in Roquin-1 impairing this interaction and cooperative regulation of targets induced T follicular helper cells, germinal center B cells and autoantibody formation. These mutations also improved the functionality of tumor-specific T cells by promoting their accumulation in the tumor and reducing expression of exhaustion markers. Our data reveal the physical interaction of Roquin-1 with Regnase-1 as a hub to control self-reactivity and effector functions in immune cell therapies. Main Post-transcriptional control of mRNA stability or translation through RNA-binding proteins (RBPs) represents an important level of gene regulation with crucial impact on immune cell fate decisions. This role becomes evident from combined genetic inactivation of alleles encoding for the Roquin-1 and Roquin-2 proteins with redundant functions in mice or in a human patient who developed a severe hyperinflammatory syndrome due to a homozygous nonsense mutation in the RC3H1 gene encoding ROQUIN-1 (refs. 1 , 2 , 3 ). Moreover, a single amino acid exchange (M199R), called sanroque mutation, in the murine Roquin-1 protein causes lupus-like autoimmunity. Regnase-1-deficient mice exhibit a comparable autoimmune phenotype with activated CD4 + and CD8 + T cells, accumulation of plasma cells, hypergammaglobulinemia and autoantibody production 4 , 5 . In response to T cell activation, Roquin-1, its paralog Roquin-2 and Regnase-1 are similarly regulated by MALT1-dependent proteolytic cleavage 5 , 6 . All three RBPs share a number of mRNA targets 3 , 5 , 6 , 7 , suggesting potential cooperation 6 , 8 . Roquin-1/2 proteins repress the expression of Regnase-1 (refs. 6 , 8 ). Mapping of binding sites of overexpressed Regnase-1 crosslinked to cellular mRNAs revealed the sequence determinants of Roquin-recognized stem loops of the constitutive decay element (CDE) 7 , 9 . Despite an extensive overlap in phenotypes and regulation of these RBPs, they have different functions. Roquin-1 interacts with components of the mRNA deadenylation and decapping machinery 9 , 10 , 11 , whereas Regnase-1 endonuclease cleaves target mRNAs 4 , 7 , 12 . Because Roquin-1 and Regnase-1 were found enriched in P bodies and at the endoplasmic reticulum (ER), respectively and differed in their requirements for regulation of reporter mRNAs, it was proposed that Roquin-1/2 and Regnase-1 proteins function in a compartmentalized manner independently of each other 7 , 13 . Owing to the prominent humoral autoimmunity occurring in mice with the sanroque mutation or Regnase-1 inactivation 4 , 14 and recapitulation of hallmark phenotypes by T cell-specific deletion of Roquin-1/2 or Regnase-1 (refs. 3 , 5 ), previous studies mostly focused on CD4 + helper T cells. Nevertheless, the ubiquitous expression of Roquin-1/2 and the prevalence of individual Regnase-1/2/3/4 paralogs suggest an importance of both RBP families in many types of cells and fate decisions 15 , 16 , 17 . More recently, inactivation of Regnase-1 in tumor-specific CD8 + T cells or chimeric antigen receptor (CAR)-T cells resulted in increased antitumor responses 18 , 19 , whereas an involvement of Roquin paralogs in CD8 + effector T cell responses has not yet been studied. In the context of defining tumor antigen-specific T cell antigen receptors (TCRs) or CARs, current efforts also try to modulate tumor-specific T cells. The aim is to bolster activation, prevent regulatory T (T reg ) cell-induced suppression, reprogram metabolism or break tumor-imposed exhaustion and make adoptive cell therapies (ACTs) efficient for different blood cancers as well as solid tumors. Here we explore how the interaction of Roquin-1 with Regnase-1 affects peripheral tolerance and how this program can be used in ACT. We show that both proteins bind to each other in a ternary complex on RNA. This interaction was important for the regulation of shared targets and controlled CD4 + and CD8 + T cell quiescence, metabolic programs, T cell activation, differentiation and effector functions. Weakening the physical interaction of Roquin-1 with Regnase-1 by introducing mutations into the mouse germline caused humoral autoimmunity but led to enhanced responses of cytotoxic T cells directed toward tumor-expressed antigens in the tumor setting. Results Roquin-1/2 and Regnase-1 maintain quiescence of T cells To address the functional relationship of Roquin-1/2 and Regnase-1 proteins we analyzed mice with T cell-specific deletion of the genes encoding Regnase-1 (ref. 20 ) ( Zc3h12a fl/fl ; Cd4- Cre, termed KO T ), Roquin-1 and Roquin-2 (refs. 3 , 21 ) ( Rc3h1 fl/fl ; Rc3h2 fl/fl ; Cd4- Cre, termed DKO T ) or a combination of all three genes ( Zc3h12a fl/fl ; Rc3h1 fl/fl ; Rc3h2 fl/fl ; Cd4- Cre, termed TKO T ). CD4 + and CD8 + T cells from all mutant mice showed a spontaneous reduction of naive T cells (CD62L + CD44 lo ) and an increase in effector memory T cells (CD62L – CD44 hi ) (Fig. 1a,b ). Accumulation of effector CD4 + and CD8 + T cells was not due to a reduction in T reg cells, which instead increased in frequencies in all knockout mice and also in numbers in KO T and TKO T mice (Fig. 1c,d ). Reconstituting lethally irradiated CD45.1/2 congenic mice with mixtures of wild-type (CD45.1) and TKO T (CD45.2) bone marrow (Extended Data Fig. 1a ) revealed that the increase in peripheral T reg cells (Fig. 1c,d ) was not cell intrinsic, as we found comparable frequencies of wild-type and TKO T T reg cells in mixed-bone-marrow chimeric mice that were increased compared to wild-type/wild-type chimeric mice (Extended Data Fig. 1b ). The increased T reg cell frequencies in TKO T but also", "role": "user" }, { "content": "Ludwig Maximilians University Munich (LMU) immunologists have discovered how mutations in Roquin-1 trigger autoimmunity, but can also improve the body's fight against cancer cells. With autoimmune diseases such as lupus erythematosus, severe inflammation occurs in different areas of the organism. The immune system mistakenly identifies the body's own structures as foreign and attacks them. Such disorders have various triggers, and only a handful of known mutations in individual genes lead to autoimmunity. These include the gene that codes for Roquin-1. The so-called sanroque mutation induces a lupus-like syndrome in mice. \"Such mutations teach us how our body protects itself against autoaggressive reactions of the immune system,\" explains Professor Vigo Heissmeyer, who is a researcher at the Institute for Immunology at LMU and the Molecular Immune Regulation Research Unit at Helmholtz Zentrum München. By means of functional investigations and mouse models, he and his team have now shown how the exchange of a single amino acid—such as the sanroque mutation in Roquin-1—leads to stronger autoimmunity. \"We think we've found a target structure that controls autoimmunity and which could even be suitable for enhancing anti-tumor responses,\" says Heissmeyer, outlining the key results of the experiments from his team. Roquin controls immunological processes Together with colleagues from the Helmholtz Zentrum München and LMU, he had previously elucidated molecular functions of Roquin-1. The protein plays a key role in the adaptive immune response by controlling the activation and differentiation of T cells via the regulation of gene expression. Interestingly, it had been suggested that the Regnase-1 protein works in the same way. \"What we didn't understand before was why the exchange of an amino acid in the sanroque mutation of Roquin-1 leads to a very similar form of autoimmunity as the loss of the gene encoding Regnase-1,\" says Heissmeyer. The research group has now been able to demonstrate that Roquin-1 binds directly to the Regnase-1 protein so as to efficiently control the expression of certain genes. Surprisingly, the amino acids involved in this binding were discovered to be in close spatial proximity to the amino acid that was altered in the sanroque mutant. This suggested that they represent an extended binding site. In the gene encoding Roquin-1 in mice, the researchers successfully used CRISPR-Cas technology to replace individual amino acids that are involved in the binding to Regnase-1 with other specific amino acids. During the protein biosynthesis, this produced Roquin-1 proteins that interacted much more weakly with Regnase-1. These novel mutations led to autoimmunity in the rodents.\" Our data shows that the physical interaction of Roquin-1 with Regnase-1 is of key importance when it comes to controlling the activity of immune cells,\" summarizes the LMU scientist. Enhancing immune responses as a therapeutic strategy Although the observed autoimmunity damages the organism and leads to illnesses, there could be benefits for cancer patients in an enhanced activation of immune cells that fight tumors. \"Mechanisms in T cells that our immune system has developed to prevent autoimmunity are actually used by the tumor to silence T cells,\" explains Heissmeyer. Accordingly, mice with the Roquin-1 gene mutations described above produced T cells that attacked malignant cells with greater vigor after transfer into tumor-bearing mice. This makes Roquin-1 an interesting target structure for oncology. Future research projects could seek to develop an inhibitor that reduces interactions between Roquin-1 and Regnase-1—and that activates immune cells. \"We expect that this will give a strong boost to the T cell response against tumors for a limited period of time,\" says Heissmeyer. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Roquin and Regnase-1 proteins bind and post-transcriptionally regulate proinflammatory target messenger RNAs to maintain immune homeostasis. Either the sanroque mutation in Roquin-1 or loss of Regnase-1 cause systemic lupus erythematosus-like phenotypes. Analyzing mice with T cells that lack expression of Roquin-1, its paralog Roquin-2 and Regnase-1 proteins, we detect overlapping or unique phenotypes by comparing individual and combined inactivation. These comprised spontaneous activation, metabolic reprogramming and persistence of T cells leading to autoimmunity. Here, we define an interaction surface in Roquin-1 for binding to Regnase-1 that included the sanroque residue. Mutations in Roquin-1 impairing this interaction and cooperative regulation of targets induced T follicular helper cells, germinal center B cells and autoantibody formation. These mutations also improved the functionality of tumor-specific T cells by promoting their accumulation in the tumor and reducing expression of exhaustion markers. Our data reveal the physical interaction of Roquin-1 with Regnase-1 as a hub to control self-reactivity and effector functions in immune cell therapies. Main Post-transcriptional control of mRNA stability or translation through RNA-binding proteins (RBPs) represents an important level of gene regulation with crucial impact on immune cell fate decisions. This role becomes evident from combined genetic inactivation of alleles encoding for the Roquin-1 and Roquin-2 proteins with redundant functions in mice or in a human patient who developed a severe hyperinflammatory syndrome due to a homozygous nonsense mutation in the RC3H1 gene encoding ROQUIN-1 (refs. 1 , 2 , 3 ). Moreover, a single amino acid exchange (M199R), called sanroque mutation, in the murine Roquin-1 protein causes lupus-like autoimmunity. Regnase-1-deficient mice exhibit a comparable autoimmune phenotype with activated CD4 + and CD8 + T cells, accumulation of plasma cells, hypergammaglobulinemia and autoantibody production 4 , 5 . In response to T cell activation, Roquin-1, its paralog Roquin-2 and Regnase-1 are similarly regulated by MALT1-dependent proteolytic cleavage 5 , 6 . All three RBPs share a number of mRNA targets 3 , 5 , 6 , 7 , suggesting potential cooperation 6 , 8 . Roquin-1/2 proteins repress the expression of Regnase-1 (refs. 6 , 8 ). Mapping of binding sites of overexpressed Regnase-1 crosslinked to cellular mRNAs revealed the sequence determinants of Roquin-recognized stem loops of the constitutive decay element (CDE) 7 , 9 . Despite an extensive overlap in phenotypes and regulation of these RBPs, they have different functions. Roquin-1 interacts with components of the mRNA deadenylation and decapping machinery 9 , 10 , 11 , whereas Regnase-1 endonuclease cleaves target mRNAs 4 , 7 , 12 . Because Roquin-1 and Regnase-1 were found enriched in P bodies and at the endoplasmic reticulum (ER), respectively and differed in their requirements for regulation of reporter mRNAs, it was proposed that Roquin-1/2 and Regnase-1 proteins function in a compartmentalized manner independently of each other 7 , 13 . Owing to the prominent humoral autoimmunity occurring in mice with the sanroque mutation or Regnase-1 inactivation 4 , 14 and recapitulation of hallmark phenotypes by T cell-specific deletion of Roquin-1/2 or Regnase-1 (refs. 3 , 5 ), previous studies mostly focused on CD4 + helper T cells. Nevertheless, the ubiquitous expression of Roquin-1/2 and the prevalence of individual Regnase-1/2/3/4 paralogs suggest an importance of both RBP families in many types of cells and fate decisions 15 , 16 , 17 . More recently, inactivation of Regnase-1 in tumor-specific CD8 + T cells or chimeric antigen receptor (CAR)-T cells resulted in increased antitumor responses 18 , 19 , whereas an involvement of Roquin paralogs in CD8 + effector T cell responses has not yet been studied. In the context of defining tumor antigen-specific T cell antigen receptors (TCRs) or CARs, current efforts also try to modulate tumor-specific T cells. The aim is to bolster activation, prevent regulatory T (T reg ) cell-induced suppression, reprogram metabolism or break tumor-imposed exhaustion and make adoptive cell therapies (ACTs) efficient for different blood cancers as well as solid tumors. Here we explore how the interaction of Roquin-1 with Regnase-1 affects peripheral tolerance and how this program can be used in ACT. We show that both proteins bind to each other in a ternary complex on RNA. This interaction was important for the regulation of shared targets and controlled CD4 + and CD8 + T cell quiescence, metabolic programs, T cell activation, differentiation and effector functions. Weakening the physical interaction of Roquin-1 with Regnase-1 by introducing mutations into the mouse germline caused humoral autoimmunity but led to enhanced responses of cytotoxic T cells directed toward tumor-expressed antigens in the tumor setting. Results Roquin-1/2 and Regnase-1 maintain quiescence of T cells To address the functional relationship of Roquin-1/2 and Regnase-1 proteins we analyzed mice with T cell-specific deletion of the genes encoding Regnase-1 (ref. 20 ) ( Zc3h12a fl/fl ; Cd4- Cre, termed KO T ), Roquin-1 and Roquin-2 (refs. 3 , 21 ) ( Rc3h1 fl/fl ; Rc3h2 fl/fl ; Cd4- Cre, termed DKO T ) or a combination of all three genes ( Zc3h12a fl/fl ; Rc3h1 fl/fl ; Rc3h2 fl/fl ; Cd4- Cre, termed TKO T ). CD4 + and CD8 + T cells from all mutant mice showed a spontaneous reduction of naive T cells (CD62L + CD44 lo ) and an increase in effector memory T cells (CD62L – CD44 hi ) (Fig. 1a,b ). Accumulation of effector CD4 + and CD8 + T cells was not due to a reduction in T reg cells, which instead increased in frequencies in all knockout mice and also in numbers in KO T and TKO T mice (Fig. 1c,d ). Reconstituting lethally irradiated CD45.1/2 congenic mice with mixtures of wild-type (CD45.1) and TKO T (CD45.2) bone marrow (Extended Data Fig. 1a ) revealed that the increase in peripheral T reg cells (Fig. 1c,d ) was not cell intrinsic, as we found comparable frequencies of wild-type and TKO T T reg cells in mixed-bone-marrow chimeric mice that were increased compared to wild-type/wild-type chimeric mice (Extended Data Fig. 1b ). The increased T reg cell frequencies in TKO T but also<|im_end|> <|im_start|>assistant Ludwig Maximilians University Munich (LMU) immunologists have discovered how mutations in Roquin-1 trigger autoimmunity, but can also improve the body's fight against cancer cells. With autoimmune diseases such as lupus erythematosus, severe inflammation occurs in different areas of the organism. The immune system mistakenly identifies the body's own structures as foreign and attacks them. Such disorders have various triggers, and only a handful of known mutations in individual genes lead to autoimmunity. These include the gene that codes for Roquin-1. The so-called sanroque mutation induces a lupus-like syndrome in mice. "Such mutations teach us how our body protects itself against autoaggressive reactions of the immune system," explains Professor Vigo Heissmeyer, who is a researcher at the Institute for Immunology at LMU and the Molecular Immune Regulation Research Unit at Helmholtz Zentrum München. By means of functional investigations and mouse models, he and his team have now shown how the exchange of a single amino acid—such as the sanroque mutation in Roquin-1—leads to stronger autoimmunity. "We think we've found a target structure that controls autoimmunity and which could even be suitable for enhancing anti-tumor responses," says Heissmeyer, outlining the key results of the experiments from his team. Roquin controls immunological processes Together with colleagues from the Helmholtz Zentrum München and LMU, he had previously elucidated molecular functions of Roquin-1. The protein plays a key role in the adaptive immune response by controlling the activation and differentiation of T cells via the regulation of gene expression. Interestingly, it had been suggested that the Regnase-1 protein works in the same way. "What we didn't understand before was why the exchange of an amino acid in the sanroque mutation of Roquin-1 leads to a very similar form of autoimmunity as the loss of the gene encoding Regnase-1," says Heissmeyer. The research group has now been able to demonstrate that Roquin-1 binds directly to the Regnase-1 protein so as to efficiently control the expression of certain genes. Surprisingly, the amino acids involved in this binding were discovered to be in close spatial proximity to the amino acid that was altered in the sanroque mutant. This suggested that they represent an extended binding site. In the gene encoding Roquin-1 in mice, the researchers successfully used CRISPR-Cas technology to replace individual amino acids that are involved in the binding to Regnase-1 with other specific amino acids. During the protein biosynthesis, this produced Roquin-1 proteins that interacted much more weakly with Regnase-1. These novel mutations led to autoimmunity in the rodents." Our data shows that the physical interaction of Roquin-1 with Regnase-1 is of key importance when it comes to controlling the activity of immune cells," summarizes the LMU scientist. Enhancing immune responses as a therapeutic strategy Although the observed autoimmunity damages the organism and leads to illnesses, there could be benefits for cancer patients in an enhanced activation of immune cells that fight tumors. "Mechanisms in T cells that our immune system has developed to prevent autoimmunity are actually used by the tumor to silence T cells," explains Heissmeyer. Accordingly, mice with the Roquin-1 gene mutations described above produced T cells that attacked malignant cells with greater vigor after transfer into tumor-bearing mice. This makes Roquin-1 an interesting target structure for oncology. Future research projects could seek to develop an inhibitor that reduces interactions between Roquin-1 and Regnase-1—and that activates immune cells. "We expect that this will give a strong boost to the T cell response against tumors for a limited period of time," says Heissmeyer. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Climate change is already exposing species to dangerous temperatures driving widespread population and geographical contractions. However, little is known about how these risks of thermal exposure will expand across species’ existing geographical ranges over time as climate change continues. Here, using geographical data for approximately 36,000 marine and terrestrial species and climate projections to 2100, we show that the area of each species’ geographical range at risk of thermal exposure will expand abruptly. On average, more than 50% of the increase in exposure projected for a species will occur in a single decade. This abruptness is partly due to the rapid pace of future projected warming but also because the greater area available at the warm end of thermal gradients constrains species to disproportionately occupy sites close to their upper thermal limit. These geographical constraints on the structure of species ranges operate both on land and in the ocean and mean that, even in the absence of amplifying ecological feedbacks, thermally sensitive species may be inherently vulnerable to sudden warming-driven collapse. With higher levels of warming, the number of species passing these thermal thresholds, and at risk of abrupt and widespread thermal exposure, increases, doubling from less than 15% to more than 30% between 1.5 °C and 2.5 °C of global warming. These results indicate that climate threats to thousands of species are expected to expand abruptly in the coming decades, thereby highlighting the urgency of mitigation and adaptation actions. Main Species are increasingly being exposed to dangerous temperatures, driving mass die-offs, and population declines and contractions at the warm edges of their geographical range 1 , 2 , 3 , 4 , 5 , 6 , 7 . As global warming continues, the area over which species are adversely impacted by thermal exposure will expand, increasing the risks of local and global extinctions 8 , 9 and disrupting the functioning and stability of the ecosystems these species form and on which society depends 10 . Critical to understanding and managing these climate risks is how the spatial footprint of thermal exposure will expand across a species’ geographical range over time. Because climate change will unfold over decades to centuries, the expansion in the area over which a species is at risk of thermal exposure may also be protracted 11 . A gradual spread of thermal risks would provide more time for species to adapt via dispersal 12 or evolution 13 , and more opportunity to implement conservation interventions and adaptation policies once the adverse effects of thermal exposure are first detected. While the gradual spread of risk could pose a potential challenge for existing vulnerability assessments, which typically consider population and range declines over much shorter time horizons (for example, a single decade 14 , 15 ), a greater concern is the possibility that future climate risks to species will expand suddenly, impacting widespread areas across a species’ geographical range almost simultaneously 16 , 17 , 18 . An abrupt expansion in the area of a species’ geographical range at risk of thermal exposure could overwhelm the ecological and evolutionary processes that might otherwise provide resilience to species and ecosystems under more gradual environmental change 19 , 20 , and would limit the capacity for timely conservation actions 21 . Determining whether there are thresholds of warming beyond which risks of thermal exposure to species rapidly expand, and predicting where and when these thresholds will be crossed, is essential for improved early warning systems to assist conservation and adaptation planning, and for informing international policy to mitigate climate change. To understand the risks to species from abrupt thermal exposure, we used global climate models to project the cumulative area of individual species existing geographical ranges that will be exposed to potentially dangerous temperatures up to 2100 (at approximately 100-km grid cell resolution; Methods ). Our analysis encompasses geographical data on 35,863 species from both terrestrial ( n = 31,790) and near-surface-marine ( n = 4,073) environments, including: mammals, amphibians, reptiles, birds, corals, cephalopods, reef fish, seagrasses and zooplankton (Extended Data Table 1 ). While species will be adversely impacted by exposure to multiple abiotic and biotic variables, we focus our analysis on temperature, which provides a universal driver of species distributions across both marine 22 and terrestrial 23 realms; thus, it is a logical starting point for understanding the spatiotemporal dynamics of climate change risks to species. We do not consider processes of evolutionary adaptation, changes in phenology and behaviour or dispersal to new locations. While these processes will determine the resilience of species to climate change, in this study we focus on the first key step of understanding the spatial and temporal dynamics of thermal exposure that will ultimately drive these biological responses. The adverse impacts of thermal exposure (for example, declines of fitness or increased mortality) are probably driven by the increasing intensity and frequency of extreme temperatures rather than changes in long-term climate averages 24 , 25 . In this study, we define thermal exposure as the year after which the annual maximum monthly air or sea-surface temperatures in a grid cell consistently (for at least 5 consecutive years) exceeds the most extreme monthly temperature experienced by a species across its geographical range over recent history (1850–2014), hereafter its ‘upper realized thermal limit’ 10 ( Methods ). We focus on an intermediate greenhouse gas (GHG) shared socioeconomic pathway (SSP) emission scenario (SSP2-4.5), corresponding to approximately 2.5 °C global warming by the end of the century, relative to the pre-industrial period (1850–1900). This is approximately the level of warming expected if countries meet the 2030 targets in their nationally determined contributions at the time of COP26 (ref. 26 ). We also explore how the dynamics of thermal exposure vary under both lower (SSP1-2.6) and higher (SSP5-8.5) GHG emission scenarios and thus global warming levels. We quantify how gradually or abruptly the spatial extent of thermal exposure is projected to expand over time using a moving window analysis to calculate the maximum percentage of grid cell exposure", "role": "user" }, { "content": "Climate change is likely to abruptly push species over tipping points as their geographic ranges reach unforeseen temperatures, finds a new study led by a UCL researcher. The new Nature Ecology & Evolution study predicts when and where climate change is likely to expose species across the globe to potentially dangerous temperatures. The research team from UCL, University of Cape Town, University of Connecticut and University at Buffalo analyzed data from more than 35,000 species of animals (including mammals, amphibians, reptiles, birds, corals, fish, cephalopods and plankton) and seagrasses from every continent and ocean basin, alongside climate projections running up to 2100. The researchers investigated when areas within each species' geographical range will cross a threshold of thermal exposure, defined as the first five consecutive years where temperatures consistently exceed the most extreme monthly temperature experienced by a species across its geographic range over recent history (1850–2014). Once the thermal exposure threshold is crossed, the animal is not necessarily going to die out, but there is no evidence that it is able to survive the higher temperatures—that is, the research projects that for many species there could be an abrupt loss of habitat due to future climate change. The researchers found a consistent trend that for many animals, the thermal exposure threshold will be crossed for much of their geographic range within the same decade. Lead author Dr. Alex Pigot (UCL Center for Biodiversity & Environment Research, UCL Biosciences) said, \"It is unlikely that climate change will gradually make environments more difficult for animals to survive in. Instead, for many animals, large swaths of their geographic range are likely to become unfamiliarly hot in a short span of time. \"While some animals may be able to survive these higher temperatures, many other animals will need to move to cooler regions or evolve to adapt, which they likely cannot do in such short timeframes. \"Our findings suggest that once we start to notice that a species is suffering under unfamiliar conditions, there may be very little time before most of its range becomes inhospitable, so it's important that we identify in advance which species may be at risk in coming decades.\" The researchers found that the extent of global warming makes a big difference: if the planet warms by 1.5°C, 15% of species they studied will be at risk of experiencing unfamiliarly hot temperatures across at least 30% of their existing geographic range in a single decade, but this doubles to 30% of species at 2.5°C of warming. Dr. Pigot added, \"Our study is yet another example of why we need to urgently reduce carbon emissions to mitigate the harmful effects climate change is having on animals and plants, and avoid a massive extinction crisis.\" The researchers hope that their study could help with targeting conservation efforts, as their data provides an early warning system showing when and where particular animals are likely to be at risk. Co-author Dr. Christopher Trisos (African Climate and Development Initiative, University of Cape Town) said, \"In the past we've had snapshots to show the impact of climate change, but here we are presenting the data more like a film, where you can see the changes unfold over time. This shows that for many species the risk is a bit like everything, everywhere, all at once. By animating this process, we hope to help direct conservation efforts before it's too late, while also showing the potentially catastrophic consequences of letting climate change continue unchecked.\" The researchers say that this pattern of abrupt exposure may be an inevitable feature of living on a round planet—because of the shape of the Earth, there is more area available to species in environments near the hot end of what they are used to, such as in low-lying areas or near the equator. A previous study by the same lead authors found that even if we stop climate change so that global temperatures peak and start to decline, the risks to biodiversity could persist for decades after. In another analysis similar to the current study, they found that many species facing unfamiliar temperatures will be living alongside other animals experiencing similar temperature shocks, which could pose grave risks to local ecosystem function. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Climate change is already exposing species to dangerous temperatures driving widespread population and geographical contractions. However, little is known about how these risks of thermal exposure will expand across species’ existing geographical ranges over time as climate change continues. Here, using geographical data for approximately 36,000 marine and terrestrial species and climate projections to 2100, we show that the area of each species’ geographical range at risk of thermal exposure will expand abruptly. On average, more than 50% of the increase in exposure projected for a species will occur in a single decade. This abruptness is partly due to the rapid pace of future projected warming but also because the greater area available at the warm end of thermal gradients constrains species to disproportionately occupy sites close to their upper thermal limit. These geographical constraints on the structure of species ranges operate both on land and in the ocean and mean that, even in the absence of amplifying ecological feedbacks, thermally sensitive species may be inherently vulnerable to sudden warming-driven collapse. With higher levels of warming, the number of species passing these thermal thresholds, and at risk of abrupt and widespread thermal exposure, increases, doubling from less than 15% to more than 30% between 1.5 °C and 2.5 °C of global warming. These results indicate that climate threats to thousands of species are expected to expand abruptly in the coming decades, thereby highlighting the urgency of mitigation and adaptation actions. Main Species are increasingly being exposed to dangerous temperatures, driving mass die-offs, and population declines and contractions at the warm edges of their geographical range 1 , 2 , 3 , 4 , 5 , 6 , 7 . As global warming continues, the area over which species are adversely impacted by thermal exposure will expand, increasing the risks of local and global extinctions 8 , 9 and disrupting the functioning and stability of the ecosystems these species form and on which society depends 10 . Critical to understanding and managing these climate risks is how the spatial footprint of thermal exposure will expand across a species’ geographical range over time. Because climate change will unfold over decades to centuries, the expansion in the area over which a species is at risk of thermal exposure may also be protracted 11 . A gradual spread of thermal risks would provide more time for species to adapt via dispersal 12 or evolution 13 , and more opportunity to implement conservation interventions and adaptation policies once the adverse effects of thermal exposure are first detected. While the gradual spread of risk could pose a potential challenge for existing vulnerability assessments, which typically consider population and range declines over much shorter time horizons (for example, a single decade 14 , 15 ), a greater concern is the possibility that future climate risks to species will expand suddenly, impacting widespread areas across a species’ geographical range almost simultaneously 16 , 17 , 18 . An abrupt expansion in the area of a species’ geographical range at risk of thermal exposure could overwhelm the ecological and evolutionary processes that might otherwise provide resilience to species and ecosystems under more gradual environmental change 19 , 20 , and would limit the capacity for timely conservation actions 21 . Determining whether there are thresholds of warming beyond which risks of thermal exposure to species rapidly expand, and predicting where and when these thresholds will be crossed, is essential for improved early warning systems to assist conservation and adaptation planning, and for informing international policy to mitigate climate change. To understand the risks to species from abrupt thermal exposure, we used global climate models to project the cumulative area of individual species existing geographical ranges that will be exposed to potentially dangerous temperatures up to 2100 (at approximately 100-km grid cell resolution; Methods ). Our analysis encompasses geographical data on 35,863 species from both terrestrial ( n = 31,790) and near-surface-marine ( n = 4,073) environments, including: mammals, amphibians, reptiles, birds, corals, cephalopods, reef fish, seagrasses and zooplankton (Extended Data Table 1 ). While species will be adversely impacted by exposure to multiple abiotic and biotic variables, we focus our analysis on temperature, which provides a universal driver of species distributions across both marine 22 and terrestrial 23 realms; thus, it is a logical starting point for understanding the spatiotemporal dynamics of climate change risks to species. We do not consider processes of evolutionary adaptation, changes in phenology and behaviour or dispersal to new locations. While these processes will determine the resilience of species to climate change, in this study we focus on the first key step of understanding the spatial and temporal dynamics of thermal exposure that will ultimately drive these biological responses. The adverse impacts of thermal exposure (for example, declines of fitness or increased mortality) are probably driven by the increasing intensity and frequency of extreme temperatures rather than changes in long-term climate averages 24 , 25 . In this study, we define thermal exposure as the year after which the annual maximum monthly air or sea-surface temperatures in a grid cell consistently (for at least 5 consecutive years) exceeds the most extreme monthly temperature experienced by a species across its geographical range over recent history (1850–2014), hereafter its ‘upper realized thermal limit’ 10 ( Methods ). We focus on an intermediate greenhouse gas (GHG) shared socioeconomic pathway (SSP) emission scenario (SSP2-4.5), corresponding to approximately 2.5 °C global warming by the end of the century, relative to the pre-industrial period (1850–1900). This is approximately the level of warming expected if countries meet the 2030 targets in their nationally determined contributions at the time of COP26 (ref. 26 ). We also explore how the dynamics of thermal exposure vary under both lower (SSP1-2.6) and higher (SSP5-8.5) GHG emission scenarios and thus global warming levels. We quantify how gradually or abruptly the spatial extent of thermal exposure is projected to expand over time using a moving window analysis to calculate the maximum percentage of grid cell exposure<|im_end|> <|im_start|>assistant Climate change is likely to abruptly push species over tipping points as their geographic ranges reach unforeseen temperatures, finds a new study led by a UCL researcher. The new Nature Ecology & Evolution study predicts when and where climate change is likely to expose species across the globe to potentially dangerous temperatures. The research team from UCL, University of Cape Town, University of Connecticut and University at Buffalo analyzed data from more than 35,000 species of animals (including mammals, amphibians, reptiles, birds, corals, fish, cephalopods and plankton) and seagrasses from every continent and ocean basin, alongside climate projections running up to 2100. The researchers investigated when areas within each species' geographical range will cross a threshold of thermal exposure, defined as the first five consecutive years where temperatures consistently exceed the most extreme monthly temperature experienced by a species across its geographic range over recent history (1850–2014). Once the thermal exposure threshold is crossed, the animal is not necessarily going to die out, but there is no evidence that it is able to survive the higher temperatures—that is, the research projects that for many species there could be an abrupt loss of habitat due to future climate change. The researchers found a consistent trend that for many animals, the thermal exposure threshold will be crossed for much of their geographic range within the same decade. Lead author Dr. Alex Pigot (UCL Center for Biodiversity & Environment Research, UCL Biosciences) said, "It is unlikely that climate change will gradually make environments more difficult for animals to survive in. Instead, for many animals, large swaths of their geographic range are likely to become unfamiliarly hot in a short span of time. "While some animals may be able to survive these higher temperatures, many other animals will need to move to cooler regions or evolve to adapt, which they likely cannot do in such short timeframes. "Our findings suggest that once we start to notice that a species is suffering under unfamiliar conditions, there may be very little time before most of its range becomes inhospitable, so it's important that we identify in advance which species may be at risk in coming decades." The researchers found that the extent of global warming makes a big difference: if the planet warms by 1.5°C, 15% of species they studied will be at risk of experiencing unfamiliarly hot temperatures across at least 30% of their existing geographic range in a single decade, but this doubles to 30% of species at 2.5°C of warming. Dr. Pigot added, "Our study is yet another example of why we need to urgently reduce carbon emissions to mitigate the harmful effects climate change is having on animals and plants, and avoid a massive extinction crisis." The researchers hope that their study could help with targeting conservation efforts, as their data provides an early warning system showing when and where particular animals are likely to be at risk. Co-author Dr. Christopher Trisos (African Climate and Development Initiative, University of Cape Town) said, "In the past we've had snapshots to show the impact of climate change, but here we are presenting the data more like a film, where you can see the changes unfold over time. This shows that for many species the risk is a bit like everything, everywhere, all at once. By animating this process, we hope to help direct conservation efforts before it's too late, while also showing the potentially catastrophic consequences of letting climate change continue unchecked." The researchers say that this pattern of abrupt exposure may be an inevitable feature of living on a round planet—because of the shape of the Earth, there is more area available to species in environments near the hot end of what they are used to, such as in low-lying areas or near the equator. A previous study by the same lead authors found that even if we stop climate change so that global temperatures peak and start to decline, the risks to biodiversity could persist for decades after. In another analysis similar to the current study, they found that many species facing unfamiliar temperatures will be living alongside other animals experiencing similar temperature shocks, which could pose grave risks to local ecosystem function. <|im_end|>

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2,112

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Mechanical stress acting in the Earth’s crust is a fundamental property that is important for a wide range of scientific and engineering applications. The orientation of maximum horizontal compressive stress can be estimated by inverting earthquake source mechanisms and measured directly from borehole-based measurements, but large regions of the continents have few or no observations. Here we present an approach to determine the orientation of maximum horizontal compressive stress by measuring stress-induced anisotropy of nonlinear susceptibility, which is the derivative of elastic modulus with respect to strain. Laboratory and Earth experiments show that nonlinear susceptibility is azimuthally dependent in an anisotropic stress field and is maximum in the orientation of maximum horizontal compressive stress. We observe this behavior in the Earth—in Oklahoma and New Mexico, U.S.A, where maximum nonlinear susceptibility coincides with the orientation of maximum horizontal compressive stress measured using traditional methods. Our measurements use empirical Green’s functions and solid-earth tides and can be applied at different temporal and spatial scales. Introduction Knowledge of the mechanical stress acting in the Earth’s crust and lithosphere is important for a wide range of geophysical studies and applications 1 , 2 , 3 , 4 including plate tectonics 5 , 6 , seismicity and faulting 7 , 8 , 9 , 10 , 11 , and subsurface fluid behavior 9 , 12 , 13 . The stress field is commonly represented as the orientation of the maximum horizontal compressive stress ( S Hmax ) 3 , 8 , 14 , 15 , 16 , and other information regarding the principal components is often not known, much less the full stress tensor. At regional to tectonic-plate scales (100 s to 1000 s of km), the orientation of S Hmax is influenced by lateral plate boundary forces, tractions along the bottom of the lithosphere, and gravitational potential 17 . At local scales (<100 km), the orientation of S Hmax may vary owing to heterogeneities in density and elasticity, slip-on faults 7 , 12 , and pore pressure 12 . The orientation of S Hmax is commonly estimated using borehole-based methods 18 , 19 , inverting earthquake focal mechanisms 20 , 21 , 22 , 23 , 24 , and less commonly by measuring the orientation of young, stress-sensitive geologic features 25 . Shear wave splitting and azimuthal seismic anisotropy are sometimes related to the stress field, but also reflect past deformation 26 . Borehole-based methods are high-cost, point measurements 27 , and are commonly applied in hydrocarbon-producing regions 8 . Interpreting earthquake focal mechanisms is limited to seismically active areas and requires an adequate monitoring network to produce high-quality, low-uncertainty source mechanisms. Because of limitations with these techniques, the stress field in broad regions of continental interiors is poorly constrained 15 . Rocks are heterogeneous materials with stress and strain-dependent elastic properties, and finite, nonzero relaxation times (slow dynamics) 28 , 29 , 30 . This is in contrast to ideal linear elasticity (Hooke’s Law), in which the elastic modulus is insensitive to strain, and the elastic response is instantaneous 31 . In individual rock samples, the relationship between stress, strain, and elasticity is complex 32 , 33 with mechanical damage and weak grain contacts being primarily responsible for nonlinear elastic behavior in brittle rocks 34 . Temperature, pressure, and the presence of fluids modulate the nonlinear behavior 34 , 35 . In the Earth, seismic velocities are commonly observed to be faster when rocks are compressed, usually interpreted as the closing of cracks and stiffening of internal contacts 36 , 37 , whereas they are typically slower after experiencing strong shaking, usually interpreted as the breaking or weakening of internal contacts 38 , 39 . After a dynamic disturbance, the material relaxes back to its original or a new metastable state via the process of slow dynamics 39 , 40 . Thus, rocks are metastable in their elastic behavior and strongly influenced by relatively weak external forces perturbing their material structure 35 , 38 , 39 . Rock samples in laboratory experiments exhibit anisotropic linear and nonlinear elastic properties when differential stress is applied 41 , 42 . In two dimensions, differential stress is the difference between the two principal stresses. To demonstrate this nonlinear effect, Nur and Simmons (1969) applied uniaxial stress to a cylinder of granite, normal to the cylinder axis, and measured the travel time of an elastic wave as a function of angle with respect to the uniaxial stress 42 . The pressure derivative of the wave modulus with respect to strain (called nonlinear susceptibility, NS) was strongest when the angle between the uniaxial stress and the propagation of the probe wave was zero, and weakest when the angle was 90 degrees (Fig. 1 ). The effect was greatest for compressional P-waves, and the nonlinear elastic behavior can be quantified by measuring it. Stress-induced anisotropy in linear elasticity is exhibited by the velocity being faster for P-waves traveling in the same orientation of the applied uniaxial stress, rather than perpendicular. Stress-induced anisotropy in nonlinear elasticity is exhibited by the stress derivative of P-wave velocity being higher in the same orientation as the applied uniaxial stress, rather than perpendicular. Owing to a modest uniaxial or differential stress (1 MPa), one can observe anisotropy in linear elasticity of a few percent, whereas one can observe anisotropy in nonlinear elasticity of 100 s of percent 41 , 42 . Hence, it is preferable to measure anisotropy in nonlinear elasticity to infer principal stress orientations, rather than anisotropy in linear elasticity, as is done with shear wave splitting and azimuthal anisotropy of surface or body waves. Fig. 1: Stress-induced anisotropy. Stress-induced anisotropy in nonlinear susceptibility with data from Nur and Simmons 42 . The vertical axis represents nonlinear susceptibility. The horizontal axis shows the angle between the orientation of the uniaxial stress and the orientation of propagation of the probe wave. Full size image In addition to a nonlinear response to quasi-static stress, rocks exhibit creep behavior when compressed 43 . In", "role": "user" }, { "content": "Scientists at Los Alamos National Laboratory have developed a method to determine the orientation of mechanical stress in the earth's crust without relying on data from earthquakes or drilling. This method is less expensive that current approaches, could have broad applicability in geophysics and provide insight into continental regions lacking historical geologic information. \"We utilized the nonlinear elastic behavior in rocks and applied a new technique to monitor the orientation of the maximum horizontal compressive stress in rocks in parts of Oklahoma and New Mexico,\" said Andrew Delorey of Los Alamos. \"The orientation of that maximum horizontal compressive stress reveals which fractures in the rock will be active.\" North-central Oklahoma was selected because induced seismic activity has been ongoing in the region after decades of injected wastewater from oil and gas operations. That seismic activity occurs on faults optimally oriented in the regional stress field. North-central New Mexico was selected to compare the results to a geologic setting straddling a continental rift separating the Colorado Plateau from a stable section of the earth's crust. The scientists determined that the earth exhibits stress-induced anisotropy of nonlinear susceptibility that is aligned with the maximum horizontal compressive stress in these two different geologic settings. Rocks become stiffer when compressed and softer when extended, but this effect isn't instantaneous. The rate is faster in the orientation where the ambient stress field is most compressive. By measuring this rate in different orientations, scientists can determine the orientation where ambient stress is most compressive. Determining the geophysical stress orientation, or the direction of maximum horizontal compressive stress, is usually determined by drilling narrow, deep boreholes. However, borehole drilling is expensive and only provides a single data point. Additionally for vast regions, the geophysical data simply hasn't been collected because it is too expensive. This method provides an alternative. Their approach could be essential for the oil and gas industry trying to avoid hazards and optimize production. In the case of hydro fracking, the fractures will open in the direction of the minimum horizontal compressive stress, which scientists can now determine before any drilling. \"Estimation of the orientation of stress in the Earth's crust without earthquake or borehole data,\" by Andrew A. Delorey, Christopher W. Johnson, and Paul A. Johnson and Götz Bokelmann of the University of Vienna was published in September in Nature's \"Communications Earth and Environment journal. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Mechanical stress acting in the Earth’s crust is a fundamental property that is important for a wide range of scientific and engineering applications. The orientation of maximum horizontal compressive stress can be estimated by inverting earthquake source mechanisms and measured directly from borehole-based measurements, but large regions of the continents have few or no observations. Here we present an approach to determine the orientation of maximum horizontal compressive stress by measuring stress-induced anisotropy of nonlinear susceptibility, which is the derivative of elastic modulus with respect to strain. Laboratory and Earth experiments show that nonlinear susceptibility is azimuthally dependent in an anisotropic stress field and is maximum in the orientation of maximum horizontal compressive stress. We observe this behavior in the Earth—in Oklahoma and New Mexico, U.S.A, where maximum nonlinear susceptibility coincides with the orientation of maximum horizontal compressive stress measured using traditional methods. Our measurements use empirical Green’s functions and solid-earth tides and can be applied at different temporal and spatial scales. Introduction Knowledge of the mechanical stress acting in the Earth’s crust and lithosphere is important for a wide range of geophysical studies and applications 1 , 2 , 3 , 4 including plate tectonics 5 , 6 , seismicity and faulting 7 , 8 , 9 , 10 , 11 , and subsurface fluid behavior 9 , 12 , 13 . The stress field is commonly represented as the orientation of the maximum horizontal compressive stress ( S Hmax ) 3 , 8 , 14 , 15 , 16 , and other information regarding the principal components is often not known, much less the full stress tensor. At regional to tectonic-plate scales (100 s to 1000 s of km), the orientation of S Hmax is influenced by lateral plate boundary forces, tractions along the bottom of the lithosphere, and gravitational potential 17 . At local scales (<100 km), the orientation of S Hmax may vary owing to heterogeneities in density and elasticity, slip-on faults 7 , 12 , and pore pressure 12 . The orientation of S Hmax is commonly estimated using borehole-based methods 18 , 19 , inverting earthquake focal mechanisms 20 , 21 , 22 , 23 , 24 , and less commonly by measuring the orientation of young, stress-sensitive geologic features 25 . Shear wave splitting and azimuthal seismic anisotropy are sometimes related to the stress field, but also reflect past deformation 26 . Borehole-based methods are high-cost, point measurements 27 , and are commonly applied in hydrocarbon-producing regions 8 . Interpreting earthquake focal mechanisms is limited to seismically active areas and requires an adequate monitoring network to produce high-quality, low-uncertainty source mechanisms. Because of limitations with these techniques, the stress field in broad regions of continental interiors is poorly constrained 15 . Rocks are heterogeneous materials with stress and strain-dependent elastic properties, and finite, nonzero relaxation times (slow dynamics) 28 , 29 , 30 . This is in contrast to ideal linear elasticity (Hooke’s Law), in which the elastic modulus is insensitive to strain, and the elastic response is instantaneous 31 . In individual rock samples, the relationship between stress, strain, and elasticity is complex 32 , 33 with mechanical damage and weak grain contacts being primarily responsible for nonlinear elastic behavior in brittle rocks 34 . Temperature, pressure, and the presence of fluids modulate the nonlinear behavior 34 , 35 . In the Earth, seismic velocities are commonly observed to be faster when rocks are compressed, usually interpreted as the closing of cracks and stiffening of internal contacts 36 , 37 , whereas they are typically slower after experiencing strong shaking, usually interpreted as the breaking or weakening of internal contacts 38 , 39 . After a dynamic disturbance, the material relaxes back to its original or a new metastable state via the process of slow dynamics 39 , 40 . Thus, rocks are metastable in their elastic behavior and strongly influenced by relatively weak external forces perturbing their material structure 35 , 38 , 39 . Rock samples in laboratory experiments exhibit anisotropic linear and nonlinear elastic properties when differential stress is applied 41 , 42 . In two dimensions, differential stress is the difference between the two principal stresses. To demonstrate this nonlinear effect, Nur and Simmons (1969) applied uniaxial stress to a cylinder of granite, normal to the cylinder axis, and measured the travel time of an elastic wave as a function of angle with respect to the uniaxial stress 42 . The pressure derivative of the wave modulus with respect to strain (called nonlinear susceptibility, NS) was strongest when the angle between the uniaxial stress and the propagation of the probe wave was zero, and weakest when the angle was 90 degrees (Fig. 1 ). The effect was greatest for compressional P-waves, and the nonlinear elastic behavior can be quantified by measuring it. Stress-induced anisotropy in linear elasticity is exhibited by the velocity being faster for P-waves traveling in the same orientation of the applied uniaxial stress, rather than perpendicular. Stress-induced anisotropy in nonlinear elasticity is exhibited by the stress derivative of P-wave velocity being higher in the same orientation as the applied uniaxial stress, rather than perpendicular. Owing to a modest uniaxial or differential stress (1 MPa), one can observe anisotropy in linear elasticity of a few percent, whereas one can observe anisotropy in nonlinear elasticity of 100 s of percent 41 , 42 . Hence, it is preferable to measure anisotropy in nonlinear elasticity to infer principal stress orientations, rather than anisotropy in linear elasticity, as is done with shear wave splitting and azimuthal anisotropy of surface or body waves. Fig. 1: Stress-induced anisotropy. Stress-induced anisotropy in nonlinear susceptibility with data from Nur and Simmons 42 . The vertical axis represents nonlinear susceptibility. The horizontal axis shows the angle between the orientation of the uniaxial stress and the orientation of propagation of the probe wave. Full size image In addition to a nonlinear response to quasi-static stress, rocks exhibit creep behavior when compressed 43 . In<|im_end|> <|im_start|>assistant Scientists at Los Alamos National Laboratory have developed a method to determine the orientation of mechanical stress in the earth's crust without relying on data from earthquakes or drilling. This method is less expensive that current approaches, could have broad applicability in geophysics and provide insight into continental regions lacking historical geologic information. "We utilized the nonlinear elastic behavior in rocks and applied a new technique to monitor the orientation of the maximum horizontal compressive stress in rocks in parts of Oklahoma and New Mexico," said Andrew Delorey of Los Alamos. "The orientation of that maximum horizontal compressive stress reveals which fractures in the rock will be active." North-central Oklahoma was selected because induced seismic activity has been ongoing in the region after decades of injected wastewater from oil and gas operations. That seismic activity occurs on faults optimally oriented in the regional stress field. North-central New Mexico was selected to compare the results to a geologic setting straddling a continental rift separating the Colorado Plateau from a stable section of the earth's crust. The scientists determined that the earth exhibits stress-induced anisotropy of nonlinear susceptibility that is aligned with the maximum horizontal compressive stress in these two different geologic settings. Rocks become stiffer when compressed and softer when extended, but this effect isn't instantaneous. The rate is faster in the orientation where the ambient stress field is most compressive. By measuring this rate in different orientations, scientists can determine the orientation where ambient stress is most compressive. Determining the geophysical stress orientation, or the direction of maximum horizontal compressive stress, is usually determined by drilling narrow, deep boreholes. However, borehole drilling is expensive and only provides a single data point. Additionally for vast regions, the geophysical data simply hasn't been collected because it is too expensive. This method provides an alternative. Their approach could be essential for the oil and gas industry trying to avoid hazards and optimize production. In the case of hydro fracking, the fractures will open in the direction of the minimum horizontal compressive stress, which scientists can now determine before any drilling. "Estimation of the orientation of stress in the Earth's crust without earthquake or borehole data," by Andrew A. Delorey, Christopher W. Johnson, and Paul A. Johnson and Götz Bokelmann of the University of Vienna was published in September in Nature's "Communications Earth and Environment journal. <|im_end|>

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1,805

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Mathematical models of social contagion that incorporate networks of human interactions have become increasingly popular, however, very few approaches have tackled the challenges of including complex and realistic properties of socio-technical systems. Here, we define a framework to characterize the dynamics of the Maki–Thompson rumour spreading model in structured populations, and analytically find a previously uncharacterized dynamical phase transition that separates the local and global contagion regimes. We validate our threshold prediction through extensive Monte Carlo simulations. Furthermore, we apply this framework in two real-world systems, the European commuting and transportation network and the Digital Bibliography and Library Project collaboration network. Our findings highlight the importance of the underlying population structure in understanding social contagion phenomena and have the potential to define new intervention strategies aimed at hindering or facilitating the diffusion of information in socio-technical systems. Main The mathematical modelling of contagion processes is crucial in gaining insight into a broad range of phenomena from the spreading of infectious diseases to social collective behaviour. While this avenue of research has a long tradition both in the biological and social sciences, in recent years there have been considerable advancements triggered by increasing computational power and data availability characterizing socio-technical systems. These advances are particularly evident in the area of infectious disease forecasting where current models now incorporate realistic mobility and interaction data of human populations 1 , 2 , 3 , 4 , 5 , 6 . Analogously, social contagion phenomena that were initially modelled using the same mathematical framework as epidemics 7 , 8 , 9 , 10 are now described by complex contagion models 11 , 12 , 13 aimed at specifically characterizing processes such as the establishment of shared social norms and beliefs 14 , 15 , 16 , the diffusion of knowledge and information 17 , 18 , and the emergence of political consensus 19 . These models consider complex factors such as reinforcement and threshold mechanisms 20 , 21 , 22 , 23 and the loss of interest mediated by social interactions 24 , 25 . Furthermore, many of these theoretical approaches have put networks at the centre of our understanding of social contagion phenomena and the information spreading process 8 , 12 , 17 , 26 , 27 , 28 , 29 , 30 , 31 , 32 . However, most theoretical and numerical work on the dynamics of social contagion focuses on highly stylized models, trading off the realistic features of human interactions for analytical transparency and computational efficiency. As a result, social contagion models able to integrate the effects of human mobility, community structure and time-varying behavioural patterns are largely unexplored. Here we consider the classic rumour spreading model 24 , 25 to study the effects of structured populations on the global diffusion of a rumour or piece of information. More specifically, we model the spatial structure of realistic populations and the behaviour of individuals in virtual social networks through a reaction–diffusion model in a metapopulation network and an activity-driven model with communities, respectively. We first identify analytically the necessary conditions for the social contagion to spread to a macroscopic fraction of the population. This analysis shows that although the rumour model is lacking any critical threshold, the population structure introduces a dynamical phase transition (global invasion threshold 33 ) that is a function of the interactions between subpopulations. We validate the analytical results with large-scale numerical simulations on synthetic networks with different topological structures. Additionally, we recover the global threshold of the contagion process in data-driven models of the European transportation network and the Digital Bibliography and Library Project (DBLP) collaboration network. Understanding how the social structure in both the physical and virtual worlds affects the emergence of contagion phenomena has the potential to indicate novel ways to utilize the network connectivity to develop efficient network-based interventions. The framework developed here opens a path to study the effects of communities and spatial structures in other complex contagion processes that can incorporate agent memory 34 and social reinforcement 22 , or introduce other heterogeneous features such as age-dependent contact patterns and socio-economic conditions 35 . Model definition Here we use a variant of the original rumour model 24 , known as the Maki–Thompson model 25 , to describe the spread of information through a population based on interactions between agents 36 . Similar to epidemic models, individuals can be classified into three compartments: ignorants, those who do not know the rumour; spreaders, those who know and are actively sharing the rumour; and stiflers, those who know the rumour but are no longer spreading it. The contagion process evolves through interactions between individuals in a population. If a spreader contacts an ignorant individual, with a probability λ , the ignorant will transition into a spreader. However, when a spreader contacts either a stifler or another spreader, with a probability α , the spreader will transition into a stifler. The stifling mechanism describes an individual’s tendency to become uninterested in the rumour once the appeared novelty of the information is lost. In homogeneously mixed populations, this feature does not allow the presence of a rumour threshold 24 , 37 , meaning that for any λ > 0 the rumour will always spread to a macroscopic proportion of the population (see Methods). We investigate the behaviour of this model on two types of structured populations that incorporate the complexity observed in socio-technical systems (Fig. 1 ). Rumour model in spatially structured populations We first consider a population where spatially defined groups of individuals (subpopulations) are coupled together by a mobility rate (Fig. 1a ) 32 , 38 . This structure, also called a metapopulation network, is used to model species persistence in ecosystems 39 , the evolution of populations 40 and the global spreading of infectious diseases 41 . Specifically, we consider a metapopulation network with V subpopulations, each with an average population size of \$\\overline{N}\$ individuals. Reaction–diffusion processes are used to characterize both the local interaction and global mobility dynamics. Individuals first react", "role": "user" }, { "content": "Think of all the false rumors that went viral about COVID-19—it got so bad, the World Health Organization called it an \"infodemic.\" Whether it is in hoaxes or a viral conspiracy theory, information travels fast these days. Just how fast and far information moves depends on who shares it, and where, from discussions on social media to conversations with fellow commuters on your way to work. So, how can our interactions and their infrastructures affect the spread of rumors and information? That's a question that researchers are beginning to answer with complex math models of social contagion, the concept that social behavior and ideas spread like a pathogen. \"The thing with social contagion is that it is like the threading of some type of behavior, or an idea, or information,\" says Jessica Davis, a third-year doctoral student at Northeastern's Network Science Institute. Davis recently led a study that uses mathematical equations to model the way rumors and information spread in different types of environments. In a paper published Monday in Nature Physics, Davis's team outlined a new way to incorporate into their calculations aspects of the way information is shared in the physical world—such as people's commute to work and the online groups they interact with—that might influence how information spreads. The model lays the groundwork for more realistic ways to study how information travels, Davis says. \"These models can be used to point out different structural, social, and other factors,\" she says, \"that aren't normally taken into account when you're thinking about how information spreads.\" Alessandro Vespignani, Sternberg Family Distinguished University Professor of physics, computer science, and health sciences, says the inclusion of such realistic features is essential to accurately model the way information spreads in real time. Vespignani, a co-author of the study, has also modeled the spread of the COVID-19 outbreak. \"The study opens the path to more realistic modeling of the diffusion of information and misinformation that takes into account the geographical and social structure of social networks,\" he says. The team's approach to modeling the way information spreads among people is based on similar efforts by Vespignani and other scientists to model how infectious diseases spread, and takes advantage of data already available from epidemiological studies. \"We have a lot more data in the world now, and we can use it to understand how things are spreading,\" Davis says. \"We have people who are using transportation networks, people using Google, Twitter, and other social media, to get an understanding of how a disease is spreading.\" Davis and her team also used a classic rumor propagation model as the basis of their model. That approach, known as the Maki-Thompson model, factors in people who spread, ignore, and refrain from spreading the rumor. All of those individuals mirror the function of infected, susceptible, and recovering people in models of disease and infection. In their study, the team tested how people's ability to move and travel in Europe could influence the spread of a rumor. Other tests included models constrained to online databases to simulate the way information permeates different academic disciplines. The idea is to calculate the tipping point at which rumors and information go viral. \"We write down a set of equations, and we can solve for this threshold,\" Davis says. \"It's a function of both the rumor model parameters, as well as the structure of this network.\" Those equations are what social contagion models need in order to be as insightful as they can be, Davis says. And, in the long run, it's what could set network scientists up to model the spread of information in the real world with more precision, including the roles that different groups of people play. \"Some types of information spreading in the teenage range might not affect the elderly population,\" Davis says. \"If we could understand who is being affected by that information, that could help us or help maybe social media sites monitor or get a better understanding of who's been impacted by this information.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Mathematical models of social contagion that incorporate networks of human interactions have become increasingly popular, however, very few approaches have tackled the challenges of including complex and realistic properties of socio-technical systems. Here, we define a framework to characterize the dynamics of the Maki–Thompson rumour spreading model in structured populations, and analytically find a previously uncharacterized dynamical phase transition that separates the local and global contagion regimes. We validate our threshold prediction through extensive Monte Carlo simulations. Furthermore, we apply this framework in two real-world systems, the European commuting and transportation network and the Digital Bibliography and Library Project collaboration network. Our findings highlight the importance of the underlying population structure in understanding social contagion phenomena and have the potential to define new intervention strategies aimed at hindering or facilitating the diffusion of information in socio-technical systems. Main The mathematical modelling of contagion processes is crucial in gaining insight into a broad range of phenomena from the spreading of infectious diseases to social collective behaviour. While this avenue of research has a long tradition both in the biological and social sciences, in recent years there have been considerable advancements triggered by increasing computational power and data availability characterizing socio-technical systems. These advances are particularly evident in the area of infectious disease forecasting where current models now incorporate realistic mobility and interaction data of human populations 1 , 2 , 3 , 4 , 5 , 6 . Analogously, social contagion phenomena that were initially modelled using the same mathematical framework as epidemics 7 , 8 , 9 , 10 are now described by complex contagion models 11 , 12 , 13 aimed at specifically characterizing processes such as the establishment of shared social norms and beliefs 14 , 15 , 16 , the diffusion of knowledge and information 17 , 18 , and the emergence of political consensus 19 . These models consider complex factors such as reinforcement and threshold mechanisms 20 , 21 , 22 , 23 and the loss of interest mediated by social interactions 24 , 25 . Furthermore, many of these theoretical approaches have put networks at the centre of our understanding of social contagion phenomena and the information spreading process 8 , 12 , 17 , 26 , 27 , 28 , 29 , 30 , 31 , 32 . However, most theoretical and numerical work on the dynamics of social contagion focuses on highly stylized models, trading off the realistic features of human interactions for analytical transparency and computational efficiency. As a result, social contagion models able to integrate the effects of human mobility, community structure and time-varying behavioural patterns are largely unexplored. Here we consider the classic rumour spreading model 24 , 25 to study the effects of structured populations on the global diffusion of a rumour or piece of information. More specifically, we model the spatial structure of realistic populations and the behaviour of individuals in virtual social networks through a reaction–diffusion model in a metapopulation network and an activity-driven model with communities, respectively. We first identify analytically the necessary conditions for the social contagion to spread to a macroscopic fraction of the population. This analysis shows that although the rumour model is lacking any critical threshold, the population structure introduces a dynamical phase transition (global invasion threshold 33 ) that is a function of the interactions between subpopulations. We validate the analytical results with large-scale numerical simulations on synthetic networks with different topological structures. Additionally, we recover the global threshold of the contagion process in data-driven models of the European transportation network and the Digital Bibliography and Library Project (DBLP) collaboration network. Understanding how the social structure in both the physical and virtual worlds affects the emergence of contagion phenomena has the potential to indicate novel ways to utilize the network connectivity to develop efficient network-based interventions. The framework developed here opens a path to study the effects of communities and spatial structures in other complex contagion processes that can incorporate agent memory 34 and social reinforcement 22 , or introduce other heterogeneous features such as age-dependent contact patterns and socio-economic conditions 35 . Model definition Here we use a variant of the original rumour model 24 , known as the Maki–Thompson model 25 , to describe the spread of information through a population based on interactions between agents 36 . Similar to epidemic models, individuals can be classified into three compartments: ignorants, those who do not know the rumour; spreaders, those who know and are actively sharing the rumour; and stiflers, those who know the rumour but are no longer spreading it. The contagion process evolves through interactions between individuals in a population. If a spreader contacts an ignorant individual, with a probability λ , the ignorant will transition into a spreader. However, when a spreader contacts either a stifler or another spreader, with a probability α , the spreader will transition into a stifler. The stifling mechanism describes an individual’s tendency to become uninterested in the rumour once the appeared novelty of the information is lost. In homogeneously mixed populations, this feature does not allow the presence of a rumour threshold 24 , 37 , meaning that for any λ > 0 the rumour will always spread to a macroscopic proportion of the population (see Methods). We investigate the behaviour of this model on two types of structured populations that incorporate the complexity observed in socio-technical systems (Fig. 1 ). Rumour model in spatially structured populations We first consider a population where spatially defined groups of individuals (subpopulations) are coupled together by a mobility rate (Fig. 1a ) 32 , 38 . This structure, also called a metapopulation network, is used to model species persistence in ecosystems 39 , the evolution of populations 40 and the global spreading of infectious diseases 41 . Specifically, we consider a metapopulation network with V subpopulations, each with an average population size of $\overline{N}$ individuals. Reaction–diffusion processes are used to characterize both the local interaction and global mobility dynamics. Individuals first react<|im_end|> <|im_start|>assistant Think of all the false rumors that went viral about COVID-19—it got so bad, the World Health Organization called it an "infodemic." Whether it is in hoaxes or a viral conspiracy theory, information travels fast these days. Just how fast and far information moves depends on who shares it, and where, from discussions on social media to conversations with fellow commuters on your way to work. So, how can our interactions and their infrastructures affect the spread of rumors and information? That's a question that researchers are beginning to answer with complex math models of social contagion, the concept that social behavior and ideas spread like a pathogen. "The thing with social contagion is that it is like the threading of some type of behavior, or an idea, or information," says Jessica Davis, a third-year doctoral student at Northeastern's Network Science Institute. Davis recently led a study that uses mathematical equations to model the way rumors and information spread in different types of environments. In a paper published Monday in Nature Physics, Davis's team outlined a new way to incorporate into their calculations aspects of the way information is shared in the physical world—such as people's commute to work and the online groups they interact with—that might influence how information spreads. The model lays the groundwork for more realistic ways to study how information travels, Davis says. "These models can be used to point out different structural, social, and other factors," she says, "that aren't normally taken into account when you're thinking about how information spreads." Alessandro Vespignani, Sternberg Family Distinguished University Professor of physics, computer science, and health sciences, says the inclusion of such realistic features is essential to accurately model the way information spreads in real time. Vespignani, a co-author of the study, has also modeled the spread of the COVID-19 outbreak. "The study opens the path to more realistic modeling of the diffusion of information and misinformation that takes into account the geographical and social structure of social networks," he says. The team's approach to modeling the way information spreads among people is based on similar efforts by Vespignani and other scientists to model how infectious diseases spread, and takes advantage of data already available from epidemiological studies. "We have a lot more data in the world now, and we can use it to understand how things are spreading," Davis says. "We have people who are using transportation networks, people using Google, Twitter, and other social media, to get an understanding of how a disease is spreading." Davis and her team also used a classic rumor propagation model as the basis of their model. That approach, known as the Maki-Thompson model, factors in people who spread, ignore, and refrain from spreading the rumor. All of those individuals mirror the function of infected, susceptible, and recovering people in models of disease and infection. In their study, the team tested how people's ability to move and travel in Europe could influence the spread of a rumor. Other tests included models constrained to online databases to simulate the way information permeates different academic disciplines. The idea is to calculate the tipping point at which rumors and information go viral. "We write down a set of equations, and we can solve for this threshold," Davis says. "It's a function of both the rumor model parameters, as well as the structure of this network." Those equations are what social contagion models need in order to be as insightful as they can be, Davis says. And, in the long run, it's what could set network scientists up to model the spread of information in the real world with more precision, including the roles that different groups of people play. "Some types of information spreading in the teenage range might not affect the elderly population," Davis says. "If we could understand who is being affected by that information, that could help us or help maybe social media sites monitor or get a better understanding of who's been impacted by this information." <|im_end|>

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2,081

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract For decades, researchers have sought to understand how the irreversibility of the surrounding world emerges from the seemingly time-symmetric, fundamental laws of physics. Quantum mechanics conjectured a clue that final irreversibility is set by the measurement procedure and that the time-reversal requires complex conjugation of the wave function, which is overly complex to spontaneously appear in nature. Building on this Landau-Wigner conjecture, it became possible to demonstrate that time-reversal is exponentially improbable in a virgin nature and to design an algorithm artificially reversing a time arrow for a given quantum state on the IBM quantum computer. However, the implemented arrow-of-time reversal embraced only the known states initially disentangled from the thermodynamic reservoir. Here we develop a procedure for reversing the temporal evolution of an arbitrary unknown quantum state. This opens the route for general universal algorithms sending temporal evolution of an arbitrary system backward in time. Introduction An origin of the arrow of time, the concept coined for expressing one-way direction of time, is inextricably associated with the Second Law of Thermodynamics 1 , which declares that entropy growth stems from the system’s energy dissipation to the environment 2 , 3 , 4 , 5 , 6 . Thermodynamic considerations 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , combined with the quantum mechanical hypothesis that irreversibility of the evolution of the physical system is related to measurement procedure 18 , 19 , and to the necessity of the anti-unitary complex conjugation of the wave function of the system for time reversal 20 , led to understanding that the energy dissipation can be treated in terms of the system’s entanglement with the environment 1 , 21 , 22 , 23 , 24 . The quantum mechanical approach to the origin of the entropy growth problem was crowned by finding that in a quantum system initially not correlated with an environment, the local violation of the second law can occur 25 . Extending then the solely quantum viewpoint on the arrow of time and elaborating on the implications of the Landau–Neumann–Wigner hypothesis 18 , 19 , 20 , enabled to quantify the complexity of reversing the evolution of the known quantum state and realize the reversal of the arrow of time on the IBM quantum computer 26 . In all these past studies, a thermodynamic reservoir at finite temperatures has been appearing as a high-entropy stochastic bath thermalizing a given quantum system and increasing thus its thermal disorder, hence entropy. We find that most unexpectedly, it is exactly the presence of the reservoir that makes it possible to prepare the high-temperature thermal states of an auxiliary quantum system governed by the same Hamiltonian \$\\hat{H}\$ as the Hamiltonian of a given system. This enables us to devise the operator of the backward-time evolution \$\\hat{U}=\\exp (i\\hat{H}t)\$ reversing the temporal dynamics of the given quantum system. The necessary requirement is that the dynamics of the both, auxiliary and given, systems were governed by the same Hamiltonian \$\\hat{H}\$ . The time-reversal protocol comprises the cyclic sequential process of quantum computation on the combined auxiliary and the given systems and the thermalization process of the auxiliary system. A universal time-reversal procedure of an unknown quantum state defined through the density matrix \$\\hat{\\rho }(t)\$ of a quantum system \${\\mathcal{S}}\$ will be described as a reversal of the temporal system evolution \$\\hat{\\rho }(t)\\to \\hat{\\rho }(0)=\\exp (i\\hat{H}t/\\hslash )\\hat{\\rho }(t)\\exp (-i\\hat{H}t/\\hslash )\$ returning it to system’s original state \$\\hat{\\rho }(0)\$ . Importantly, we need not know the quantum state of this system in order to implement the arrow of time reversal. A dramatic qualitative advance of the new protocol is that it eliminates the need of keeping an exponentially huge record of classical information about the values of the state amplitudes. Moreover, the crucial step compared with the protocol of time reversal of the known quantum state 26 is that we now lift the requirement that initially the evolving quantum system must be a pure uncorrelated state. Here, we develop a procedure where the initial state can be a mixed state and, therefore, include correlations due to system’s past interaction with the environment. Results Universal procedure The calculations are organized as follows. First, we describe how the time reversal of an unknown state can be implemented in a universal manner and estimate its computational complexity. Next, we outline a somewhat more resource-demanding procedure, where, however, one can relax the need of knowing the Hamiltonian \$\\hat{H}\$ . Then we show that if in addition to the quantum system \${\\mathcal{S}}\$ one is provided by an auxiliary system \${\\mathcal{A}}\$ , so that \$\\dim {\\mathcal{S}}=\\dim {\\mathcal{A}}\$ , whose dynamics is governed by the same Hamiltonian \$\\hat{H}\$ , one can devise \${\\hat{U}}^{\\dagger }(t)\$ without knowing an exact form of \$\\hat{H}\$ . Finally, we discuss how the partial knowledge on the state \$\\hat{\\rho }(t)\$ can reduce and optimize the complexity of the time-reversal procedure. The starting point of the reversal procedure is drawn from the observation of S. Lloyd et al. 27 that having an ancilla system in a state \$\\hat{\\sigma }\$ one can approximately construct a unitary operation \$\\exp (-i\\omega \\hat{\\sigma }\\delta t)\$ acting on a system \${\\mathcal{S}}\$ simulating its evolution under Hamiltonian \${\\hat{H}}_{a}=\\hslash \\omega \\hat{\\sigma }\$ during the infinitesimal time interval δ t . Here, ω refers to some arbitrary rate, which for a moment, we leave unspecified. Having N identical copies of ancillas, one generates a finite time evolution \$\\rho (t)\\to \\rho (t+\\tau )={e}^{-i\\omega \\tau \\hat{\\sigma }}\\hat{\\rho }(t){e}^{+i\\omega \\tau \\hat{\\sigma }}\$ over the time interval τ = N δ t with the accuracy ∝ ( ω τ ) 2 / N (see “Methods”). The first step of the time-reversal procedure is then constructing the density matrix \$\\hat{\\sigma }\$ . Consider the density operator defined by the given finite-dimensional Hamiltonian \$\\hat{H}\$ having the maximal eigenvalue \${\\epsilon }_{\\max }\$ : $$\\hat{\\sigma }=\\frac{1}{Z}\\left({\\mathbb{1}}{\\epsilon }_{\\max }-\\hat{H}\\right),$$ (1) where \$Z={\\epsilon }_{\\max }\\dim {\\mathcal{S}}-\\,{\\text{Tr}}\\,\\{\\hat{H}\\}\$ is the normalization factor. Then the Lloyd (LMR) procedure maps the", "role": "user" }, { "content": "Physicists have long sought to understand the irreversibility of the surrounding world and have credited its emergence to the time-symmetric, fundamental laws of physics. According to quantum mechanics, the final irreversibility of conceptual time reversal requires extremely intricate and implausible scenarios that are unlikely to spontaneously occur in nature. Physicists had previously shown that while time-reversibility is exponentially improbable in a natural environment—it is possible to design an algorithm to artificially reverse a time arrow to a known or given state within an IBM quantum computer. However, this version of the reversed arrow-of-time only embraced a known quantum state and is therefore compared to the quantum version of pressing rewind on a video to \"reverse the flow of time.\" In a new report now published in Communications Physics, Physicists A.V. Lebedev and V.M. Vinokur and colleagues in materials, physics and advanced engineering in the U.S. and Russia, built on their previous work to develop a technical method to reverse the temporal evolution of an arbitrary unknown quantum state. The technical work will open new routes for general universal algorithms to send the temporal evolution of an arbitrary system backward in time. This work only outlined the mathematical process of time reversal without experimental implementations. The arrow of time and developing a time-reversal protocol The arrow of time originates from expressing the direction of time in a singular route relative to the second law of thermodynamics, which implies that entropy growth stems from energy dissipation of the system to the environment. Scientists can therefore consider energy dissipation relative to the system's entanglement with the environment. Previous research solely focused on the quantum viewpoint of the arrow of time and on understanding the effects of the Landau-Neumann-Wigner hypothesis to quantify the complexity of reversing the arrow of time on an IBM quantum computer. In the present work, the scientists propose using a thermodynamic reservoir at finite temperatures to form a high-entropy stochastic bath to thermalize a given quantum system and experimentally increase thermal disorder or entropy in the system. However, experimentally, the IBM computers do not support thermalization, which forms the first step in the currently proposed cycle. In theory, the presence of the thermal reservoir unexpectedly made it possible to prepare high-temperature thermal states of an auxiliary (alternative) quantum system elsewhere, governed by the same Hamiltonian (an operator corresponding to the sum of kinetic energy and potential energies for all particles in the system). This allowed Lebedev and Vinokur to mathematically devise an operator of backward-time evolution to reverse the chronological dynamics in a given quantum system. Universal procedure and the auxiliary system The team defined the universal time-reversal process of an unknown quantum state using the density matrix of a quantum system (a mixed state); to describe reversal of the temporal system's evolution to return to its original state. The quantum state of the new system could remain unknown while implementing the arrow of time reversal. In contrast to the previous protocol of time reversal of a known quantum state, the initial state did not have to be of a purely uncorrelated state either and could remain in a mixed state and correlate to past interactions with the environment. The team noted reduced time-reversal complexity for a mixed high-entropy state in the system. Lebedev et al. drew upon the reversal procedure previously detailed by S. Lloyd, Mohseni and Rebentrost (LMR procedure) to construct or map the initial density matrix. The LMR procedure considered the combined arrangement of the system in question and an ancilla to accomplish reversible computation. The experimental system will be equipped with a thermodynamic bath to thermalize the ancilla and provide the desired state for reverse evolution. The hotter the system, the more chaotic it would become. By using a heat reservoir to expose the auxiliary system to an extremely high temperature, Lebedev et al. paradoxically aim to experimentally observe the primary system's cold and ordered past using the LMR formula. The authors reason that a universal time reversal algorithm can run a computation in reverse, without a specific quantum state to rewind to, as long as the algorithm facilitates time reversal to its point of origin. Computational complexity of the time-reversal procedure The work only outlined the mathematical analysis of time reversal without specifying experimental implementations. While exercising time reversal, the proposed system continued to maintain the forward evolution governed by its own Hamiltonian. The computational complexity of time reversal for an unknown quantum state was proportional to the square of the system's Hilbert space dimension (an abstract vector space). To accomplish this in practice, the experimental system will require a natural system that evolves under an unknown Hamiltonian alongside thermalization, which quantum computers do not support, paired with universal quantum gates to achieve time reversal. As a result, practical implementation of this work will require an upgrade to existing quantum computers to meet the outlined requirements. A route to upgrade the existing design of quantum chips Lebedev et al. therefore aim to upgrade the existing design of quantum chips to achieve a set of interacting qubits (quantum bits) that can thermalize on-demand in a high-temperature environment. To accomplish this, superconducting qubits can be coupled with a transmission line where high-temperature thermal radiation will be fed to set the qubits to a high-temperature state. Thereafter, they will require a second set of qubits that can store a quantum state similar to the original set of qubits. When the original set of qubits are then experimentally thermalized to implement the joint LMR evolution, subsequent qubits will be able to undergo time-reversed dynamics under the same Hamiltonian to reach the original state. If accurately implemented, the proposed mechanism will also facilitate error-correction of an upgraded quantum computer to confirm its correct function. Lebedev et al. envision implementing the procedure on emergent computers with on-demand thermalized qubits. In this way, Lebedev and Vinokur demonstrated the time reversal procedure of an unknown mixed quantum state. The process relies on performing the LMR protocol and the existence of an ancilla system, whose dynamics can be governed by the same Hamiltonian as the Hamiltonian of the reversed system. To accomplish the reversal procedure the LMR protocol will need to be applied sequentially to the joint state of the system and ancilla, prepared in a thermal state. The work developed a formula to highlight the number of cycles that should be repeated to reverse the state of a given system towards earlier states in the past. This number will depend on the system's complexity and how far back in time it is supposed to go. When implementing the time reversal protocol, the operation rate of the LMR procedure should be sufficiently high, to overrun the forward time evolution of the reversed system. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract For decades, researchers have sought to understand how the irreversibility of the surrounding world emerges from the seemingly time-symmetric, fundamental laws of physics. Quantum mechanics conjectured a clue that final irreversibility is set by the measurement procedure and that the time-reversal requires complex conjugation of the wave function, which is overly complex to spontaneously appear in nature. Building on this Landau-Wigner conjecture, it became possible to demonstrate that time-reversal is exponentially improbable in a virgin nature and to design an algorithm artificially reversing a time arrow for a given quantum state on the IBM quantum computer. However, the implemented arrow-of-time reversal embraced only the known states initially disentangled from the thermodynamic reservoir. Here we develop a procedure for reversing the temporal evolution of an arbitrary unknown quantum state. This opens the route for general universal algorithms sending temporal evolution of an arbitrary system backward in time. Introduction An origin of the arrow of time, the concept coined for expressing one-way direction of time, is inextricably associated with the Second Law of Thermodynamics 1 , which declares that entropy growth stems from the system’s energy dissipation to the environment 2 , 3 , 4 , 5 , 6 . Thermodynamic considerations 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , combined with the quantum mechanical hypothesis that irreversibility of the evolution of the physical system is related to measurement procedure 18 , 19 , and to the necessity of the anti-unitary complex conjugation of the wave function of the system for time reversal 20 , led to understanding that the energy dissipation can be treated in terms of the system’s entanglement with the environment 1 , 21 , 22 , 23 , 24 . The quantum mechanical approach to the origin of the entropy growth problem was crowned by finding that in a quantum system initially not correlated with an environment, the local violation of the second law can occur 25 . Extending then the solely quantum viewpoint on the arrow of time and elaborating on the implications of the Landau–Neumann–Wigner hypothesis 18 , 19 , 20 , enabled to quantify the complexity of reversing the evolution of the known quantum state and realize the reversal of the arrow of time on the IBM quantum computer 26 . In all these past studies, a thermodynamic reservoir at finite temperatures has been appearing as a high-entropy stochastic bath thermalizing a given quantum system and increasing thus its thermal disorder, hence entropy. We find that most unexpectedly, it is exactly the presence of the reservoir that makes it possible to prepare the high-temperature thermal states of an auxiliary quantum system governed by the same Hamiltonian $\hat{H}$ as the Hamiltonian of a given system. This enables us to devise the operator of the backward-time evolution $\hat{U}=\exp (i\hat{H}t)$ reversing the temporal dynamics of the given quantum system. The necessary requirement is that the dynamics of the both, auxiliary and given, systems were governed by the same Hamiltonian $\hat{H}$ . The time-reversal protocol comprises the cyclic sequential process of quantum computation on the combined auxiliary and the given systems and the thermalization process of the auxiliary system. A universal time-reversal procedure of an unknown quantum state defined through the density matrix $\hat{\rho }(t)$ of a quantum system ${\mathcal{S}}$ will be described as a reversal of the temporal system evolution $\hat{\rho }(t)\to \hat{\rho }(0)=\exp (i\hat{H}t/\hslash )\hat{\rho }(t)\exp (-i\hat{H}t/\hslash )$ returning it to system’s original state $\hat{\rho }(0)$ . Importantly, we need not know the quantum state of this system in order to implement the arrow of time reversal. A dramatic qualitative advance of the new protocol is that it eliminates the need of keeping an exponentially huge record of classical information about the values of the state amplitudes. Moreover, the crucial step compared with the protocol of time reversal of the known quantum state 26 is that we now lift the requirement that initially the evolving quantum system must be a pure uncorrelated state. Here, we develop a procedure where the initial state can be a mixed state and, therefore, include correlations due to system’s past interaction with the environment. Results Universal procedure The calculations are organized as follows. First, we describe how the time reversal of an unknown state can be implemented in a universal manner and estimate its computational complexity. Next, we outline a somewhat more resource-demanding procedure, where, however, one can relax the need of knowing the Hamiltonian $\hat{H}$ . Then we show that if in addition to the quantum system ${\mathcal{S}}$ one is provided by an auxiliary system ${\mathcal{A}}$ , so that $\dim {\mathcal{S}}=\dim {\mathcal{A}}$ , whose dynamics is governed by the same Hamiltonian $\hat{H}$ , one can devise ${\hat{U}}^{\dagger }(t)$ without knowing an exact form of $\hat{H}$ . Finally, we discuss how the partial knowledge on the state $\hat{\rho }(t)$ can reduce and optimize the complexity of the time-reversal procedure. The starting point of the reversal procedure is drawn from the observation of S. Lloyd et al. 27 that having an ancilla system in a state $\hat{\sigma }$ one can approximately construct a unitary operation $\exp (-i\omega \hat{\sigma }\delta t)$ acting on a system ${\mathcal{S}}$ simulating its evolution under Hamiltonian ${\hat{H}}_{a}=\hslash \omega \hat{\sigma }$ during the infinitesimal time interval δ t . Here, ω refers to some arbitrary rate, which for a moment, we leave unspecified. Having N identical copies of ancillas, one generates a finite time evolution $\rho (t)\to \rho (t+\tau )={e}^{-i\omega \tau \hat{\sigma }}\hat{\rho }(t){e}^{+i\omega \tau \hat{\sigma }}$ over the time interval τ = N δ t with the accuracy ∝ ( ω τ ) 2 / N (see “Methods”). The first step of the time-reversal procedure is then constructing the density matrix $\hat{\sigma }$ . Consider the density operator defined by the given finite-dimensional Hamiltonian $\hat{H}$ having the maximal eigenvalue ${\epsilon }_{\max }$ : $$\hat{\sigma }=\frac{1}{Z}\left({\mathbb{1}}{\epsilon }_{\max }-\hat{H}\right),$$ (1) where $Z={\epsilon }_{\max }\dim {\mathcal{S}}-\,{\text{Tr}}\,\{\hat{H}\}$ is the normalization factor. Then the Lloyd (LMR) procedure maps the<|im_end|> <|im_start|>assistant Physicists have long sought to understand the irreversibility of the surrounding world and have credited its emergence to the time-symmetric, fundamental laws of physics. According to quantum mechanics, the final irreversibility of conceptual time reversal requires extremely intricate and implausible scenarios that are unlikely to spontaneously occur in nature. Physicists had previously shown that while time-reversibility is exponentially improbable in a natural environment—it is possible to design an algorithm to artificially reverse a time arrow to a known or given state within an IBM quantum computer. However, this version of the reversed arrow-of-time only embraced a known quantum state and is therefore compared to the quantum version of pressing rewind on a video to "reverse the flow of time." In a new report now published in Communications Physics, Physicists A.V. Lebedev and V.M. Vinokur and colleagues in materials, physics and advanced engineering in the U.S. and Russia, built on their previous work to develop a technical method to reverse the temporal evolution of an arbitrary unknown quantum state. The technical work will open new routes for general universal algorithms to send the temporal evolution of an arbitrary system backward in time. This work only outlined the mathematical process of time reversal without experimental implementations. The arrow of time and developing a time-reversal protocol The arrow of time originates from expressing the direction of time in a singular route relative to the second law of thermodynamics, which implies that entropy growth stems from energy dissipation of the system to the environment. Scientists can therefore consider energy dissipation relative to the system's entanglement with the environment. Previous research solely focused on the quantum viewpoint of the arrow of time and on understanding the effects of the Landau-Neumann-Wigner hypothesis to quantify the complexity of reversing the arrow of time on an IBM quantum computer. In the present work, the scientists propose using a thermodynamic reservoir at finite temperatures to form a high-entropy stochastic bath to thermalize a given quantum system and experimentally increase thermal disorder or entropy in the system. However, experimentally, the IBM computers do not support thermalization, which forms the first step in the currently proposed cycle. In theory, the presence of the thermal reservoir unexpectedly made it possible to prepare high-temperature thermal states of an auxiliary (alternative) quantum system elsewhere, governed by the same Hamiltonian (an operator corresponding to the sum of kinetic energy and potential energies for all particles in the system). This allowed Lebedev and Vinokur to mathematically devise an operator of backward-time evolution to reverse the chronological dynamics in a given quantum system. Universal procedure and the auxiliary system The team defined the universal time-reversal process of an unknown quantum state using the density matrix of a quantum system (a mixed state); to describe reversal of the temporal system's evolution to return to its original state. The quantum state of the new system could remain unknown while implementing the arrow of time reversal. In contrast to the previous protocol of time reversal of a known quantum state, the initial state did not have to be of a purely uncorrelated state either and could remain in a mixed state and correlate to past interactions with the environment. The team noted reduced time-reversal complexity for a mixed high-entropy state in the system. Lebedev et al. drew upon the reversal procedure previously detailed by S. Lloyd, Mohseni and Rebentrost (LMR procedure) to construct or map the initial density matrix. The LMR procedure considered the combined arrangement of the system in question and an ancilla to accomplish reversible computation. The experimental system will be equipped with a thermodynamic bath to thermalize the ancilla and provide the desired state for reverse evolution. The hotter the system, the more chaotic it would become. By using a heat reservoir to expose the auxiliary system to an extremely high temperature, Lebedev et al. paradoxically aim to experimentally observe the primary system's cold and ordered past using the LMR formula. The authors reason that a universal time reversal algorithm can run a computation in reverse, without a specific quantum state to rewind to, as long as the algorithm facilitates time reversal to its point of origin. Computational complexity of the time-reversal procedure The work only outlined the mathematical analysis of time reversal without specifying experimental implementations. While exercising time reversal, the proposed system continued to maintain the forward evolution governed by its own Hamiltonian. The computational complexity of time reversal for an unknown quantum state was proportional to the square of the system's Hilbert space dimension (an abstract vector space). To accomplish this in practice, the experimental system will require a natural system that evolves under an unknown Hamiltonian alongside thermalization, which quantum computers do not support, paired with universal quantum gates to achieve time reversal. As a result, practical implementation of this work will require an upgrade to existing quantum computers to meet the outlined requirements. A route to upgrade the existing design of quantum chips Lebedev et al. therefore aim to upgrade the existing design of quantum chips to achieve a set of interacting qubits (quantum bits) that can thermalize on-demand in a high-temperature environment. To accomplish this, superconducting qubits can be coupled with a transmission line where high-temperature thermal radiation will be fed to set the qubits to a high-temperature state. Thereafter, they will require a second set of qubits that can store a quantum state similar to the original set of qubits. When the original set of qubits are then experimentally thermalized to implement the joint LMR evolution, subsequent qubits will be able to undergo time-reversed dynamics under the same Hamiltonian to reach the original state. If accurately implemented, the proposed mechanism will also facilitate error-correction of an upgraded quantum computer to confirm its correct function. Lebedev et al. envision implementing the procedure on emergent computers with on-demand thermalized qubits. In this way, Lebedev and Vinokur demonstrated the time reversal procedure of an unknown mixed quantum state. The process relies on performing the LMR protocol and the existence of an ancilla system, whose dynamics can be governed by the same Hamiltonian as the Hamiltonian of the reversed system. To accomplish the reversal procedure the LMR protocol will need to be applied sequentially to the joint state of the system and ancilla, prepared in a thermal state. The work developed a formula to highlight the number of cycles that should be repeated to reverse the state of a given system towards earlier states in the past. This number will depend on the system's complexity and how far back in time it is supposed to go. When implementing the time reversal protocol, the operation rate of the LMR procedure should be sufficiently high, to overrun the forward time evolution of the reversed system. <|im_end|>

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59214, 315, 279, 37015, 1887, 596, 15740, 311, 471, 311, 1202, 4113, 1614, 13, 578, 31228, 1614, 315, 279, 502, 1887, 1436, 7293, 9987, 1418, 25976, 279, 18404, 315, 892, 59214, 13, 763, 13168, 311, 279, 3766, 11766, 315, 892, 59214, 315, 264, 3967, 31228, 1614, 11, 279, 2926, 1614, 1550, 539, 617, 311, 387, 315, 264, 32227, 653, 6133, 9920, 1614, 3060, 323, 1436, 7293, 304, 264, 9709, 1614, 323, 81584, 311, 3347, 22639, 449, 279, 4676, 13, 578, 2128, 10555, 11293, 892, 5621, 3078, 278, 23965, 369, 264, 9709, 1579, 12, 50250, 1614, 304, 279, 1887, 13, 2009, 2788, 5230, 1880, 453, 13, 24465, 5304, 279, 59214, 10537, 8767, 11944, 555, 328, 13, 46296, 11, 20409, 12021, 72, 323, 52743, 306, 42602, 320, 11237, 49, 10537, 8, 311, 9429, 477, 2472, 279, 2926, 17915, 6303, 13, 578, 445, 18953, 10537, 6646, 279, 11093, 27204, 315, 279, 1887, 304, 3488, 323, 459, 46845, 6374, 311, 22829, 81193, 35547, 13, 578, 22772, 1887, 690, 387, 19167, 449, 264, 30945, 61002, 9061, 311, 29487, 553, 279, 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2,897

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract From a gym workout, to deciding whether to persevere at work, many activities require us to persist in deciding that rewards are ‘worth the effort’ even as we become fatigued. However, studies examining effort-based decisions typically assume that the willingness to work is static. Here, we use computational modelling on two effort-based tasks, one behavioural and one during fMRI. We show that two hidden states of fatigue fluctuate on a moment-to-moment basis on different timescales but both reduce the willingness to exert effort for reward. The value of one state increases after effort but is ‘recoverable’ by rests, whereas a second ‘unrecoverable’ state gradually increases with work. The BOLD response in separate medial and lateral frontal sub-regions covaried with these states when making effort-based decisions, while a distinct fronto-striatal system integrated fatigue with value. These results provide a computational framework for understanding the brain mechanisms of persistence and momentary fatigue. Introduction Most daily tasks require the exertion of effort over an extended period of time. From a workout at the gym to deciding whether to persist with a task at work, much of our activities require us to keep deciding whether the effort is ‘worth it’. However, declines in our willingness to work often co-occur with sensations of ‘fatigue’. Such sensations are a common debilitating symptom across many psychiatric and neurological disorders and have dramatic impacts on levels of daily activity 1 , 2 , 3 . Research has begun to provide a richer understanding of the computational and neural mechanisms underlying how people value, and decide, whether a given amount of effort is ‘worth it’ for a certain magnitude of reward 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 . However, implicitly such studies have not accounted for the effects of fatigue or have attempted to control for any of its potential effects. Yet, the willingness to work is not static 13 . Sometimes even though the objective difficulty of a task remains the same individuals give up or take a break 14 , 15 , 16 , 17 , 18 . What are the hidden internal states that change how we subjectively value effort over time and prevent us from persisting? Theories suggest that the willingness to work can be characterised by cost-benefit trade-offs, where the value of a reward is subjectively discounted by the effort required to obtain it. Theoretically, we are willing to work when we consider the value of a reward worth the effort we have to exert to obtain it 13 , 19 . Although a number of factors can influence such valuations, it has been argued that sensations of fatigue induced by the exertion of effort can lead to subsequent reductions in the willingness to work. Theoretically, as fatigue intensifies, it increases the devaluation of rewards by effort, leading to reductions in the willingness to persist with a task, with less rewarding and more effortful acts likely to be avoided 13 , 20 , 21 , 22 . In addition, time spent resting can have a restorative effect 18 , reducing fatigue and concomitantly increasing the willingness to exert effort to obtain rewards. Despite these claims being at the cornerstone of theoretical accounts, few studies have directly tested these tenets. Existing research has shown that higher levels of fatigue are related to a reduced willingness to exert effort for rewards 18 , 23 . But little work has examined the dynamic, moment-to-moment changes in how willing we are to decide that a reward is worth it for the effort 13 , 19 , 20 , 21 , 24 . Moreover, separate lines of evidence suggest that fatigue may be comprised of distinct components that operate on different timescales. There are short-term increases in fatigue during tasks, which can be reduced by short periods of rest ( recoverable fatigue ( RF )) 14 . In addition, there are also longer-term changes that occur after extended periods of exertion for which simply resting may not lead to restoration ( unrecoverable ) 25 . As they increase, both components putatively also increase the devaluation of rewards by effort. However, although these components have been examined separately, there has yet to be a formal framework that unifies them, quantifies dynamic changes in fatigue, and how fatigue shifts the value people attribute to exerting effort to obtain rewards on a moment-to-moment basis. Previous neurophysiological and neuroimaging accounts have highlighted a core system in the brain that processes the costs and benefits of engaging in effortful activities. Activity in sub-regions of the supplementary motor area (SMA)/anterior cingulate cortex (ACC), the middle frontal gyri (MFG), frontal pole (FP), and ventral striatum (VS) have been implicated in computing value and motivating the exertion of effort 4 , 5 , 7 , 26 , 27 , 28 , 29 , 30 , 31 , 32 . Evidence suggests that these regions also change their response with time on task 13 , 15 , 17 . However, it is unclear how this distributed system changes on a moment-to-moment basis, and how that might lead to changes in the value ascribed to exerting effort for reward. Do separate sub-regions within this network signal fatigue on different timescales and integrate this into computations of value? Here, we hypothesise that the brain regions outlined above, that have previously been linked to effort-based decision-making, covary differentially with RF, unrecoverable fatigue (UF), and the momentary value of working (fatigue-weighted value). To test this notion, we designed an effort-based decision-making task (Fig. 1 ) where participants had to exert physical effort (grip force) to obtain rewards (credits) whilst undergoing functional Magnetic Resonance Imaging (fMRI). On each trial of this task, they chose between a 5 s ‘rest’ (no effort, low reward [1 credit]) and 5 s of ‘work’ which varied in effort (30–48% of maximum grip strength) and reward (6–10 credits). Using a computational model combining previous cost-benefit valuation models with latent fatigue variables, we predicted how effort-based decisions", "role": "user" }, { "content": "How do we decide whether or not an activity which requires work is 'worth the effort'? Researchers at the University of Birmingham & University of Oxford have shown that the willingness to work is not static, and depends upon the fluctuating rhythms of fatigue. Fatigue—the feeling of exhaustion from doing effortful tasks—is something we all experience daily. It makes us lose motivation and want to take a break. Although scientists understand the mechanisms the brain uses to decide whether a given task is worth the effort, the influence of fatigue on this process is not yet well understood. The research team conducted a study to investigate the impact of fatigue on a person's decision to exert effort. They found that people were less likely to work and exert effort—even for a reward—if they were fatigued. The results are published in Nature Communications. Intriguingly, the researchers found that there were two different types of fatigue that were detected in distinct parts of the brain. In the first, fatigue is experienced as a short-term feeling, which can be overcome after a short rest. Over time, however, a second, longer term feeling builds up, stops people from wanting to work, and doesn't go away with short rests. \"We found that people's willingness to exert effort fluctuated moment by moment, but gradually declined as they repeated a task over time,\" says Tanja Müller, first author of the study, based at the University of Oxford. \"Such changes in the motivation to work seem to be related to fatigue—and sometimes make us decide not to persist.\" The team tested 36 young, healthy people on a computer-based task, where they were asked to exert physical effort to obtain differing amounts of monetary rewards. The participants completed more than 200 trials and in each, they were asked if they would prefer to 'work' – which involved squeezing a grip force device—and gain the higher rewards offered, or to rest and only earn a small reward. The team built a mathematical model to predict how much fatigue a person would be feeling at any point in the experiment, and how much that fatigue was influencing their decisions of whether to work or rest. While performing the task, the participants also underwent an MRI scan, which enabled the researchers to look for activity in the brain that matched the predictions of the model. They found areas of the brain's frontal cortex had activity that fluctuated in line with the predictions, while an area called the ventral striatum signalled how much fatigue was influencing people's motivation to keep working. \"This work provides new ways of studying and understanding fatigue, its effects on the brain, and on why it can change some people's motivation more than others\" says Dr. Matthew Apps, senior author of the study, based at the University of Birmingham's Centre for Human Brain Health. \"This helps begin to get to grips with something that affects many patients lives, as well as people while at work, school, and even elite athletes. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract From a gym workout, to deciding whether to persevere at work, many activities require us to persist in deciding that rewards are ‘worth the effort’ even as we become fatigued. However, studies examining effort-based decisions typically assume that the willingness to work is static. Here, we use computational modelling on two effort-based tasks, one behavioural and one during fMRI. We show that two hidden states of fatigue fluctuate on a moment-to-moment basis on different timescales but both reduce the willingness to exert effort for reward. The value of one state increases after effort but is ‘recoverable’ by rests, whereas a second ‘unrecoverable’ state gradually increases with work. The BOLD response in separate medial and lateral frontal sub-regions covaried with these states when making effort-based decisions, while a distinct fronto-striatal system integrated fatigue with value. These results provide a computational framework for understanding the brain mechanisms of persistence and momentary fatigue. Introduction Most daily tasks require the exertion of effort over an extended period of time. From a workout at the gym to deciding whether to persist with a task at work, much of our activities require us to keep deciding whether the effort is ‘worth it’. However, declines in our willingness to work often co-occur with sensations of ‘fatigue’. Such sensations are a common debilitating symptom across many psychiatric and neurological disorders and have dramatic impacts on levels of daily activity 1 , 2 , 3 . Research has begun to provide a richer understanding of the computational and neural mechanisms underlying how people value, and decide, whether a given amount of effort is ‘worth it’ for a certain magnitude of reward 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 . However, implicitly such studies have not accounted for the effects of fatigue or have attempted to control for any of its potential effects. Yet, the willingness to work is not static 13 . Sometimes even though the objective difficulty of a task remains the same individuals give up or take a break 14 , 15 , 16 , 17 , 18 . What are the hidden internal states that change how we subjectively value effort over time and prevent us from persisting? Theories suggest that the willingness to work can be characterised by cost-benefit trade-offs, where the value of a reward is subjectively discounted by the effort required to obtain it. Theoretically, we are willing to work when we consider the value of a reward worth the effort we have to exert to obtain it 13 , 19 . Although a number of factors can influence such valuations, it has been argued that sensations of fatigue induced by the exertion of effort can lead to subsequent reductions in the willingness to work. Theoretically, as fatigue intensifies, it increases the devaluation of rewards by effort, leading to reductions in the willingness to persist with a task, with less rewarding and more effortful acts likely to be avoided 13 , 20 , 21 , 22 . In addition, time spent resting can have a restorative effect 18 , reducing fatigue and concomitantly increasing the willingness to exert effort to obtain rewards. Despite these claims being at the cornerstone of theoretical accounts, few studies have directly tested these tenets. Existing research has shown that higher levels of fatigue are related to a reduced willingness to exert effort for rewards 18 , 23 . But little work has examined the dynamic, moment-to-moment changes in how willing we are to decide that a reward is worth it for the effort 13 , 19 , 20 , 21 , 24 . Moreover, separate lines of evidence suggest that fatigue may be comprised of distinct components that operate on different timescales. There are short-term increases in fatigue during tasks, which can be reduced by short periods of rest ( recoverable fatigue ( RF )) 14 . In addition, there are also longer-term changes that occur after extended periods of exertion for which simply resting may not lead to restoration ( unrecoverable ) 25 . As they increase, both components putatively also increase the devaluation of rewards by effort. However, although these components have been examined separately, there has yet to be a formal framework that unifies them, quantifies dynamic changes in fatigue, and how fatigue shifts the value people attribute to exerting effort to obtain rewards on a moment-to-moment basis. Previous neurophysiological and neuroimaging accounts have highlighted a core system in the brain that processes the costs and benefits of engaging in effortful activities. Activity in sub-regions of the supplementary motor area (SMA)/anterior cingulate cortex (ACC), the middle frontal gyri (MFG), frontal pole (FP), and ventral striatum (VS) have been implicated in computing value and motivating the exertion of effort 4 , 5 , 7 , 26 , 27 , 28 , 29 , 30 , 31 , 32 . Evidence suggests that these regions also change their response with time on task 13 , 15 , 17 . However, it is unclear how this distributed system changes on a moment-to-moment basis, and how that might lead to changes in the value ascribed to exerting effort for reward. Do separate sub-regions within this network signal fatigue on different timescales and integrate this into computations of value? Here, we hypothesise that the brain regions outlined above, that have previously been linked to effort-based decision-making, covary differentially with RF, unrecoverable fatigue (UF), and the momentary value of working (fatigue-weighted value). To test this notion, we designed an effort-based decision-making task (Fig. 1 ) where participants had to exert physical effort (grip force) to obtain rewards (credits) whilst undergoing functional Magnetic Resonance Imaging (fMRI). On each trial of this task, they chose between a 5 s ‘rest’ (no effort, low reward [1 credit]) and 5 s of ‘work’ which varied in effort (30–48% of maximum grip strength) and reward (6–10 credits). Using a computational model combining previous cost-benefit valuation models with latent fatigue variables, we predicted how effort-based decisions<|im_end|> <|im_start|>assistant How do we decide whether or not an activity which requires work is 'worth the effort'? Researchers at the University of Birmingham & University of Oxford have shown that the willingness to work is not static, and depends upon the fluctuating rhythms of fatigue. Fatigue—the feeling of exhaustion from doing effortful tasks—is something we all experience daily. It makes us lose motivation and want to take a break. Although scientists understand the mechanisms the brain uses to decide whether a given task is worth the effort, the influence of fatigue on this process is not yet well understood. The research team conducted a study to investigate the impact of fatigue on a person's decision to exert effort. They found that people were less likely to work and exert effort—even for a reward—if they were fatigued. The results are published in Nature Communications. Intriguingly, the researchers found that there were two different types of fatigue that were detected in distinct parts of the brain. In the first, fatigue is experienced as a short-term feeling, which can be overcome after a short rest. Over time, however, a second, longer term feeling builds up, stops people from wanting to work, and doesn't go away with short rests. "We found that people's willingness to exert effort fluctuated moment by moment, but gradually declined as they repeated a task over time," says Tanja Müller, first author of the study, based at the University of Oxford. "Such changes in the motivation to work seem to be related to fatigue—and sometimes make us decide not to persist." The team tested 36 young, healthy people on a computer-based task, where they were asked to exert physical effort to obtain differing amounts of monetary rewards. The participants completed more than 200 trials and in each, they were asked if they would prefer to 'work' – which involved squeezing a grip force device—and gain the higher rewards offered, or to rest and only earn a small reward. The team built a mathematical model to predict how much fatigue a person would be feeling at any point in the experiment, and how much that fatigue was influencing their decisions of whether to work or rest. While performing the task, the participants also underwent an MRI scan, which enabled the researchers to look for activity in the brain that matched the predictions of the model. They found areas of the brain's frontal cortex had activity that fluctuated in line with the predictions, while an area called the ventral striatum signalled how much fatigue was influencing people's motivation to keep working. "This work provides new ways of studying and understanding fatigue, its effects on the brain, and on why it can change some people's motivation more than others" says Dr. Matthew Apps, senior author of the study, based at the University of Birmingham's Centre for Human Brain Health. "This helps begin to get to grips with something that affects many patients lives, as well as people while at work, school, and even elite athletes. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Many tumors increase uptake and dependence on glucose, cystine or glutamine. These basic observations on cancer cell metabolism have opened multiple new diagnostic and therapeutic avenues in cancer research. Recent studies demonstrated that smoking could induce the expression of xCT (SLC7A11) in oral cancer cells, suggesting that overexpression of xCT may support lung tumor progression. We hypothesized that overexpression of xCT occurs in lung cancer cells to satisfy the metabolic requirements for growth and survival. Our results demonstrated that 1) xCT was highly expressed at the cytoplasmic membrane in non-small cell lung cancer (NSCLC), 2) the expression of xCT was correlated with advanced stage and predicted a worse 5-year survival, 3) targeting xCT transport activity in xCT overexpressing NSCLC cells with sulfasalazine decreased cell proliferation and invasion in vitro and in vivo and 4) increased dependence on glutamine was observed in xCT overexpressed normal airway epithelial cells. These results suggested that xCT regulate metabolic requirements during lung cancer progression and be a potential therapeutic target in NSCLC. Introduction Although many molecular targets have been identified to improve the treatment strategies in non-small cell lung cancer (NSCLC), 5-year overall survival rate for patients with NSCLC is still 16% [ 1 ]. A subgroup of tumors has been found to be driven by genetic alterations in NSCLC, such as EGFR mutations and ALK rearrangements. Tumors with these targetable oncogenic alterations tend to respond to EGFR or ALK inhibitors [ 2 , 3 , 4 ]. However, most responders ultimately develop drug resistance and tumor progression. The determinants of tumor progression complicated by the tremendous heterogeneity in molecular alterations in lung cancer are only partially understood. Thus, there is a pressing need for further our understanding of the molecular mechanisms of progression and for the pursuit of innovative therapeutic targets to improve the quality of care and survival of patients with NSCLC. Recent evidence suggests that metabolic changes, caused by oncogenic activation of signal transduction pathways and transcription factors such as MYC, satisfy the large biosynthetic requirements associated with cancer cell proliferation [ 5 , 6 , 7 , 8 ]. These metabolic changes include increased glucose consumption, lactate production, and glutamine dependency. xCT (SLC7A11) is a cystine/glutamate antiporter that imports cystine into the cells while exporting glutamate [ 9 , 10 ]. One molecule of cystine can then be converted into two molecules of cysteine, which is a committed step for glutathione (GSH) biosynthesis. GSH plays a necessary role in maintaining cancer cell function [ 11 ]. To quench reactive oxygen species (ROS), GSH is oxidized to GSH disulfide (GSSG), a reaction requiring nicotinamide adenine dinucleotide phosphate (NADPH). Thus, GSH appears as an exciting therapeutic target due to its role in ROS neutralization and detoxification of xenobiotics such as chemotherapeutics. Sulfasalazine (SASP), a FDA-approved drug, has been shown to be functional in the treatment of inflammatory bowel diseases such as rheumatic diseases, Crohn’s disease, and ulcerative colitis [ 12 ]. SASP shows inhibitory effects on xCT’s function by decreasing the supply of cystine, an essential step for GSH production [ 13 ]. Although high levels of ROS induce cell death and cellular damage, cancer cells tend to maintain a high concentration of GSH to optimize the appropriate redox balance [ 14 ]. Targeting xCT may therefore compromise cellular redox defense balance and prevent tumor growth [ 15 ]. To maintain the intracellular glutamate pool, cells overexpressing xCT consume more glutamine for glutamate synthesis, a process of glutamine addiction [ 16 ]. The dependency on glutamine for cell function is considered a hallmark of cancer metabolism [ 17 ]. Different isoforms of glutaminases (GLS), such as GAC and KGA, play major roles in modulating the intracellular glutamine/glutamate concentration [ 18 ]. The major function of GLS is to convert glutamine to glutamate with ammonia production. GLS, especially GLS1, is commonly considered as not only a biomarker of glutamine dependence but also a therapeutic target for many types of cancer [ 19 , 20 , 21 ]. Recently, higher xCT activity along with elevated intracellular levels of cystine has been shown to promote tumor survival [ 22 ] and to contribute to breast cancer progression [ 16 ]. Investigators have established the expression pattern of xCT in the NCI 60 cancer cell lines, which suggests that the expression of xCT could act as a predictor of cellular response to chemotherapy [ 23 , 24 ]. However, the role of this protein has not been studied in details in lung cancer. Therefore, we decided to conduct detailed functional studies to determine whether xCT may cause significant metabolic changes and reprogram the cells for cancer development. The specific goals of this study were: first, to evaluate the expression pattern of xCT protein in different lung cancer subtypes; second, to assess its relevance to the clinical outcomes in NSCLC; and finally, to establish the metabolic functional contribution of xCT in supporting cell growth and viability of lung cancer cells in vitro and in vivo. Results xCT is overexpressed and is correlated with worse survival in NSCLC patients To identify the abundance of xCT expression in NSCLC, we first examined mRNA expression of xCT in tumors including adenocarcinomas (ADC; N = 511), squamous cell carcinomas (SCC; N = 502) and normal lung tissues ( N = 109) from The Cancer Genome Atlas (TCGA) database ( ). Our results illustrated that xCT was significantly overexpressed in SCC and ADC compared with normal lung tissues ( p < 0.0001; Fig. 1a ). A cut-off value of mean + 2 SD for xCT in the control group was used to compare the mRNA level of xCT in TCGA lung cancer dataset. With these criteria, we demonstrated that 51% of ADCs (260/511) and 61% of SCC (306/502) were overexpressing the transcripts of xCT. Fig. 1 xCT is overexpressed in human NSCLC tumors and predicts worse overall survival. a The mRNA expression of xCT is significantly overexpressed in SCC and ADC compared with normal lung tissues in TCGA ( p < 0.001).", "role": "user" }, { "content": "An amino acid transporter named xCT may affect the growth and progression of non-small cell lung cancer, a discovery that may predict the five-year survival rate of patients suffering from this cancer, now at 16 percent, researchers at Georgia State University and Vanderbilt University Medical Center have concluded. The team, led by Xiangming Ji of Georgia State and Pierre Massion of Vanderbilt University Medical Center, published their findings in the current issue of Oncogene. xCT is an amino acid transporter, which carries the amino acid cystine into the cells and exports glutamate, a chemical that nerve cells use to send signals to other cells. It provides the key building blocks for glutathione (GSH) synthesis, which feeds cancer cell function and growth. The researchers used sulfasalazine, an anti-inflammatory drug often used to treat Crohn's disease, rheumatoid arthritis and related diseases, to reduce tumor formation by inhibiting the function of xCT. Previous studies published in cancer research journals show sulfasalazine's ability to affect xCT in other forms of cancer, including breast, bladder and small cell lung cancer. Researchers first examined xCT protein expression in non-small cell lung cancer cell lines and found larger quantities in the non-small cell lung cancer cells compared to normal lung tissue. By analyzing protein expression of patients from Vanderbilt-Ingram Cancer Center, the researchers found patients with higher xCT expression have a lower five-year cancer survival rate. On the positive side, the data show xCT as a therapeutic targeting candidate. Ji and Massion tested the cancer cells in the laboratory and in mice, discovering that targeting xCT genetically or therapeutically could reduce the tumor formation in vitro (in cell culture) and in vivo (in living organisms). They also found only cells with elevated xCT expression were more sensitive to glutamine withdrawal. The results show strong evidence that lowering xCT may improve survival rates for individuals with non-small cell lung cancer. \"In conclusion, our results demonstrate that xCT is a major regulator of metabolic reprogramming with overarching effects on glucose metabolism, glutamine dependency and intracellular GSH/GSSG redox balance. All these metabolic effects contribute to lung cancer development,\" Ji said. The expression of xCT is correlated with a poor prognosis in non-small cell lung cancer and represents a new opportunity to therapeutically target this biomarker in molecularly strati?ed non-small cell lung cancer patients. Further studies are needed to better understand the unwanted communication between xCT and other tumor-associated cell signaling pathways such as MYC, KRAS and NOTCH in the formation of lung cancer tumors. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Many tumors increase uptake and dependence on glucose, cystine or glutamine. These basic observations on cancer cell metabolism have opened multiple new diagnostic and therapeutic avenues in cancer research. Recent studies demonstrated that smoking could induce the expression of xCT (SLC7A11) in oral cancer cells, suggesting that overexpression of xCT may support lung tumor progression. We hypothesized that overexpression of xCT occurs in lung cancer cells to satisfy the metabolic requirements for growth and survival. Our results demonstrated that 1) xCT was highly expressed at the cytoplasmic membrane in non-small cell lung cancer (NSCLC), 2) the expression of xCT was correlated with advanced stage and predicted a worse 5-year survival, 3) targeting xCT transport activity in xCT overexpressing NSCLC cells with sulfasalazine decreased cell proliferation and invasion in vitro and in vivo and 4) increased dependence on glutamine was observed in xCT overexpressed normal airway epithelial cells. These results suggested that xCT regulate metabolic requirements during lung cancer progression and be a potential therapeutic target in NSCLC. Introduction Although many molecular targets have been identified to improve the treatment strategies in non-small cell lung cancer (NSCLC), 5-year overall survival rate for patients with NSCLC is still 16% [ 1 ]. A subgroup of tumors has been found to be driven by genetic alterations in NSCLC, such as EGFR mutations and ALK rearrangements. Tumors with these targetable oncogenic alterations tend to respond to EGFR or ALK inhibitors [ 2 , 3 , 4 ]. However, most responders ultimately develop drug resistance and tumor progression. The determinants of tumor progression complicated by the tremendous heterogeneity in molecular alterations in lung cancer are only partially understood. Thus, there is a pressing need for further our understanding of the molecular mechanisms of progression and for the pursuit of innovative therapeutic targets to improve the quality of care and survival of patients with NSCLC. Recent evidence suggests that metabolic changes, caused by oncogenic activation of signal transduction pathways and transcription factors such as MYC, satisfy the large biosynthetic requirements associated with cancer cell proliferation [ 5 , 6 , 7 , 8 ]. These metabolic changes include increased glucose consumption, lactate production, and glutamine dependency. xCT (SLC7A11) is a cystine/glutamate antiporter that imports cystine into the cells while exporting glutamate [ 9 , 10 ]. One molecule of cystine can then be converted into two molecules of cysteine, which is a committed step for glutathione (GSH) biosynthesis. GSH plays a necessary role in maintaining cancer cell function [ 11 ]. To quench reactive oxygen species (ROS), GSH is oxidized to GSH disulfide (GSSG), a reaction requiring nicotinamide adenine dinucleotide phosphate (NADPH). Thus, GSH appears as an exciting therapeutic target due to its role in ROS neutralization and detoxification of xenobiotics such as chemotherapeutics. Sulfasalazine (SASP), a FDA-approved drug, has been shown to be functional in the treatment of inflammatory bowel diseases such as rheumatic diseases, Crohn’s disease, and ulcerative colitis [ 12 ]. SASP shows inhibitory effects on xCT’s function by decreasing the supply of cystine, an essential step for GSH production [ 13 ]. Although high levels of ROS induce cell death and cellular damage, cancer cells tend to maintain a high concentration of GSH to optimize the appropriate redox balance [ 14 ]. Targeting xCT may therefore compromise cellular redox defense balance and prevent tumor growth [ 15 ]. To maintain the intracellular glutamate pool, cells overexpressing xCT consume more glutamine for glutamate synthesis, a process of glutamine addiction [ 16 ]. The dependency on glutamine for cell function is considered a hallmark of cancer metabolism [ 17 ]. Different isoforms of glutaminases (GLS), such as GAC and KGA, play major roles in modulating the intracellular glutamine/glutamate concentration [ 18 ]. The major function of GLS is to convert glutamine to glutamate with ammonia production. GLS, especially GLS1, is commonly considered as not only a biomarker of glutamine dependence but also a therapeutic target for many types of cancer [ 19 , 20 , 21 ]. Recently, higher xCT activity along with elevated intracellular levels of cystine has been shown to promote tumor survival [ 22 ] and to contribute to breast cancer progression [ 16 ]. Investigators have established the expression pattern of xCT in the NCI 60 cancer cell lines, which suggests that the expression of xCT could act as a predictor of cellular response to chemotherapy [ 23 , 24 ]. However, the role of this protein has not been studied in details in lung cancer. Therefore, we decided to conduct detailed functional studies to determine whether xCT may cause significant metabolic changes and reprogram the cells for cancer development. The specific goals of this study were: first, to evaluate the expression pattern of xCT protein in different lung cancer subtypes; second, to assess its relevance to the clinical outcomes in NSCLC; and finally, to establish the metabolic functional contribution of xCT in supporting cell growth and viability of lung cancer cells in vitro and in vivo. Results xCT is overexpressed and is correlated with worse survival in NSCLC patients To identify the abundance of xCT expression in NSCLC, we first examined mRNA expression of xCT in tumors including adenocarcinomas (ADC; N = 511), squamous cell carcinomas (SCC; N = 502) and normal lung tissues ( N = 109) from The Cancer Genome Atlas (TCGA) database ( ). Our results illustrated that xCT was significantly overexpressed in SCC and ADC compared with normal lung tissues ( p < 0.0001; Fig. 1a ). A cut-off value of mean + 2 SD for xCT in the control group was used to compare the mRNA level of xCT in TCGA lung cancer dataset. With these criteria, we demonstrated that 51% of ADCs (260/511) and 61% of SCC (306/502) were overexpressing the transcripts of xCT. Fig. 1 xCT is overexpressed in human NSCLC tumors and predicts worse overall survival. a The mRNA expression of xCT is significantly overexpressed in SCC and ADC compared with normal lung tissues in TCGA ( p < 0.001).<|im_end|> <|im_start|>assistant An amino acid transporter named xCT may affect the growth and progression of non-small cell lung cancer, a discovery that may predict the five-year survival rate of patients suffering from this cancer, now at 16 percent, researchers at Georgia State University and Vanderbilt University Medical Center have concluded. The team, led by Xiangming Ji of Georgia State and Pierre Massion of Vanderbilt University Medical Center, published their findings in the current issue of Oncogene. xCT is an amino acid transporter, which carries the amino acid cystine into the cells and exports glutamate, a chemical that nerve cells use to send signals to other cells. It provides the key building blocks for glutathione (GSH) synthesis, which feeds cancer cell function and growth. The researchers used sulfasalazine, an anti-inflammatory drug often used to treat Crohn's disease, rheumatoid arthritis and related diseases, to reduce tumor formation by inhibiting the function of xCT. Previous studies published in cancer research journals show sulfasalazine's ability to affect xCT in other forms of cancer, including breast, bladder and small cell lung cancer. Researchers first examined xCT protein expression in non-small cell lung cancer cell lines and found larger quantities in the non-small cell lung cancer cells compared to normal lung tissue. By analyzing protein expression of patients from Vanderbilt-Ingram Cancer Center, the researchers found patients with higher xCT expression have a lower five-year cancer survival rate. On the positive side, the data show xCT as a therapeutic targeting candidate. Ji and Massion tested the cancer cells in the laboratory and in mice, discovering that targeting xCT genetically or therapeutically could reduce the tumor formation in vitro (in cell culture) and in vivo (in living organisms). They also found only cells with elevated xCT expression were more sensitive to glutamine withdrawal. The results show strong evidence that lowering xCT may improve survival rates for individuals with non-small cell lung cancer. "In conclusion, our results demonstrate that xCT is a major regulator of metabolic reprogramming with overarching effects on glucose metabolism, glutamine dependency and intracellular GSH/GSSG redox balance. All these metabolic effects contribute to lung cancer development," Ji said. The expression of xCT is correlated with a poor prognosis in non-small cell lung cancer and represents a new opportunity to therapeutically target this biomarker in molecularly strati?ed non-small cell lung cancer patients. Further studies are needed to better understand the unwanted communication between xCT and other tumor-associated cell signaling pathways such as MYC, KRAS and NOTCH in the formation of lung cancer tumors. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Large-scale quantum networks promise to enable secure communication, distributed quantum computing, enhanced sensing and fundamental tests of quantum mechanics through the distribution of entanglement across nodes 1 , 2 , 3 , 4 , 5 , 6 , 7 . Moving beyond current two-node networks 8 , 9 , 10 , 11 , 12 , 13 requires the rate of entanglement generation between nodes to exceed the decoherence (loss) rate of the entanglement. If this criterion is met, intrinsically probabilistic entangling protocols can be used to provide deterministic remote entanglement at pre-specified times. Here we demonstrate this using diamond spin qubit nodes separated by two metres. We realize a fully heralded single-photon entanglement protocol that achieves entangling rates of up to 39 hertz, three orders of magnitude higher than previously demonstrated two-photon protocols on this platform 14 . At the same time, we suppress the decoherence rate of remote-entangled states to five hertz through dynamical decoupling. By combining these results with efficient charge-state control and mitigation of spectral diffusion, we deterministically deliver a fresh remote state with an average entanglement fidelity of more than 0.5 at every clock cycle of about 100 milliseconds without any pre- or post-selection. These results demonstrate a key building block for extended quantum networks and open the door to entanglement distribution across multiple remote nodes. Main The power of future quantum networks will derive from entanglement that is shared between the network nodes. Two critical parameters for the performance of such networks are the entanglement-generation rate r ent between nodes and the entangled-state decoherence rate r dec . Their ratio η link = r ent / r dec , which we term the quantum link efficiency 8 , 15 , quantifies how effectively entangled states can be preserved over the timescales necessary to generate them. Alternatively, the link efficiency determines the average number of entangled states that can be created within one entangled-state lifetime. A link efficiency of unity therefore represents a critical threshold above which entanglement can be generated faster than it is lost. Exceeding this threshold is central to allowing multiple entangled links to be created and maintained simultaneously, as is required for the distribution of many-body quantum states across a network 6 , 15 . Consider an elementary entanglement-delivery protocol that delivers states at pre-determined times. This can be achieved by making multiple attempts to generate entanglement and then protecting successfully generated entangled states from decoherence until the required delivery time (Fig. 1a , steps (1)–(3)). If we try to generate entanglement for a period t ent , then the cumulative probability of success will be \${p}_{{\\rm{succ}}}=1-{{\\rm{e}}}^{-{r}_{{\\rm{ent}}}{t}_{{\\rm{ent}}}}\$ . For a given p succ , the average fidelity F succ with respect to a maximally entangled state of the successfully generated states is solely determined by the quantum link efficiency η link (Methods). We plot F succ versus p succ for several values of η link in Fig. 1b . Fig. 1: Deterministic remote-entanglement delivery. a , Deterministic entanglement delivery guarantees the output of states with an average entanglement fidelity of more than 0.5 at pre-specified times. In our protocol, underlying this deterministic delivery is a probabilistic but heralded entanglement process. Repeated entangling attempts (dashed helical links) are made (1) and then, upon heralded success (2), the entangled state (solid helical link) is protected from decoherence (represented by the lock) until the specified delivery time (3). If no attempt at entanglement generation succeeds within one cycle, an unentangled state must be delivered (4). b , For the underlying entanglement-generation and state-preservation protocol (steps (1)–(3) in a ), the effectiveness of the trade-off between the average fidelity of the entangled state that is delivered and the success probability is determined by the quantum link efficiency η link . The dashed line represents the classical threshold of F = 0.5, above which a state is entangled. c , Maximum fidelity of deterministically delivered states as a function of η link . A critical threshold of η link ≈ 0.83 (vertical green line) must be surpassed to deliver an entangled state at every cycle on average. Full size image This protocol allows entangled states to be delivered at specified times, but with a finite probability of success. By delivering an unentangled state (state fidelity F unent ≤ 1/2) in cycles in which all entanglement-generation attempts failed, the protocol can be cast into a fully deterministic black box (Fig. 1a , step (4)). The states output from such a black box will have a fidelity of $${F}_{{\\rm{\\det }}}={p}_{{\\rm{succ}}}{F}_{{\\rm{succ}}}+(1-{p}_{{\\rm{succ}}}){F}_{{\\rm{unent}}}$$ (1) The maximum achievable fidelity \${F}_{{\\rm{\\det }}}^{{\\rm{\\max }}}\$ of this deterministic state-delivery protocol, found by optimizing p succ , is also determined only by the quantum link efficiency η link . For F unent = 1/4 (a fully mixed state), we find (Fig. 1c ) $${F}_{{\\rm{\\det }}}^{{\\rm{\\max }}}=\\frac{1}{4}\\left[1+3{\\eta }_{{\\rm{link}}}^{1/(1-{\\eta }_{{\\rm{link}}})}\\right]$$ (2) For η link greater than about 0.83, there exists a combination of p succ and F succ high enough to compensate for cycles in which entanglement is not heralded, enabling the deterministic delivery of states that are entangled on average \$\\left({F}_{{\\rm{\\det }}}^{{\\rm{\\max }}}\\ge 1/2\\right)\$ . Deterministic entanglement delivery is therefore a critical benchmark of the performance of a network, certifying that its quantum link efficiency is of order unity or higher. Furthermore, the ability to specify in advance the time at which entangled states are delivered may assist in designing multi-step quantum-information tasks such as entanglement routing 16 , 17 . However, so far, quantum link efficiencies of order unity or greater have remained out of reach for solid-state quantum networks. Quantum dots have been used to demonstrate kilohertz entanglement rates r ent , but decoherence rates r dec of tens of megahertz limit their quantum link efficiencies 18 , 19 η link to around 10 −4 . Nitrogen–vacancy (NV) centres—point defects in diamond with a long-lived electron spin and bright optical transitions—have been used to demonstrate entanglement rates r ent of tens of millihertz 10 , 14 and, in separate experiments, decoherence rates r dec of", "role": "user" }, { "content": "Researchers at QuTech in Delft have succeeded in generating quantum entanglement between two quantum chips faster than the entanglement is lost. Via a novel smart entanglement protocol and careful protection of the entanglement, the scientists led by Prof. Ronald Hanson are the first in the world to deliver such a quantum link on demand. This opens the door to connect multiple quantum nodes and create the very first quantum network in the world. Their results are published in Nature. By exploiting the power of quantum entanglement, it is theoretically possible to build a quantum internet invulnerable to eavesdropping. However, the realization of such a quantum network is a real challenge—it is necessary to create entanglement reliably on demand, and maintain it long enough to pass the entangled information to the next node. So far, this has been beyond the capabilities of quantum experiments. Scientists at QuTech in Delft have are now the first to experimentally generate entanglement over a distance of two metres in a fraction of a second, on demand, and theoretically maintain this entanglement long enough to enable entanglement to a third node. \"The challenge is now to be the first to create a network of multiple entangled nodes—the first version of a quantum internet,\" professor Hanson says. In 2015, Ronald Hanson's research group was the first to generate long-lived quantum entanglement over a long distance (1.3 kilometres), , allowing them to provide full experimental proof of quantum entanglement for the first time. This experiment is the basis of their current approach to developing a quantum internet. Distant single electrons on diamond chips are entangled using photons as mediators. However, this experiment has not had the necessary performance to create a real quantum network. Hanson says, \"In 2015, we managed to establish a connection once an hour, while the connection only remained active for a fraction of a second. It was impossible to add a third node, let alone multiple nodes, to the network.\" Researchers from QuTech in Delft working on the 'entanglement on demand' experiment'. From left to right: prof. Ronald Hanson, dr. Peter Humphreys and dr. Norbert Kalb, all from the group of prof Ronald Hanson of Delft University. Credit: TU Delft/Marieke de Lorijn The scientists have now made multiple innovative improvements to the experiment. First of all, they demonstrated a new entanglement method. This allows for the generation of entanglement 40 times a second between electrons at a distance of two metres. Co-author Peter Humphreys says, \"This is a thousand times faster than with the old method.\" In combination with a smart way of protecting the quantum link from external noise, the experiment has now surpassed a crucial threshold. For the first time, entanglement can be created faster than it is lost. Through technical improvements, the experimental setup is now always ready for entanglement-on-demand. Hanson says, \"Just like in the current internet, we always want to be online, the system has to entangle on each request.\" The scientists have achieved this by adding smart quality checks. Humphreys says, \"These checks only take a fraction of the total experimental time, while allowing us to ensure that our system is ready for entanglement, without any manual action.\" The researchers demonstrated last year that they were able to protect a quantum entangled link while a new connection was generated. By combining this and their new results, they are ready to create quantum networks with more than two nodes. The Delft scientists now plan to realize such a network between several quantum nodes. Hanson says, \"Together with partners such as KPN, we want to connect four cities in the Netherlands by 2020 via quantum entanglement. This will be the very first quantum internet in the world.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Large-scale quantum networks promise to enable secure communication, distributed quantum computing, enhanced sensing and fundamental tests of quantum mechanics through the distribution of entanglement across nodes 1 , 2 , 3 , 4 , 5 , 6 , 7 . Moving beyond current two-node networks 8 , 9 , 10 , 11 , 12 , 13 requires the rate of entanglement generation between nodes to exceed the decoherence (loss) rate of the entanglement. If this criterion is met, intrinsically probabilistic entangling protocols can be used to provide deterministic remote entanglement at pre-specified times. Here we demonstrate this using diamond spin qubit nodes separated by two metres. We realize a fully heralded single-photon entanglement protocol that achieves entangling rates of up to 39 hertz, three orders of magnitude higher than previously demonstrated two-photon protocols on this platform 14 . At the same time, we suppress the decoherence rate of remote-entangled states to five hertz through dynamical decoupling. By combining these results with efficient charge-state control and mitigation of spectral diffusion, we deterministically deliver a fresh remote state with an average entanglement fidelity of more than 0.5 at every clock cycle of about 100 milliseconds without any pre- or post-selection. These results demonstrate a key building block for extended quantum networks and open the door to entanglement distribution across multiple remote nodes. Main The power of future quantum networks will derive from entanglement that is shared between the network nodes. Two critical parameters for the performance of such networks are the entanglement-generation rate r ent between nodes and the entangled-state decoherence rate r dec . Their ratio η link = r ent / r dec , which we term the quantum link efficiency 8 , 15 , quantifies how effectively entangled states can be preserved over the timescales necessary to generate them. Alternatively, the link efficiency determines the average number of entangled states that can be created within one entangled-state lifetime. A link efficiency of unity therefore represents a critical threshold above which entanglement can be generated faster than it is lost. Exceeding this threshold is central to allowing multiple entangled links to be created and maintained simultaneously, as is required for the distribution of many-body quantum states across a network 6 , 15 . Consider an elementary entanglement-delivery protocol that delivers states at pre-determined times. This can be achieved by making multiple attempts to generate entanglement and then protecting successfully generated entangled states from decoherence until the required delivery time (Fig. 1a , steps (1)–(3)). If we try to generate entanglement for a period t ent , then the cumulative probability of success will be ${p}_{{\rm{succ}}}=1-{{\rm{e}}}^{-{r}_{{\rm{ent}}}{t}_{{\rm{ent}}}}$ . For a given p succ , the average fidelity F succ with respect to a maximally entangled state of the successfully generated states is solely determined by the quantum link efficiency η link (Methods). We plot F succ versus p succ for several values of η link in Fig. 1b . Fig. 1: Deterministic remote-entanglement delivery. a , Deterministic entanglement delivery guarantees the output of states with an average entanglement fidelity of more than 0.5 at pre-specified times. In our protocol, underlying this deterministic delivery is a probabilistic but heralded entanglement process. Repeated entangling attempts (dashed helical links) are made (1) and then, upon heralded success (2), the entangled state (solid helical link) is protected from decoherence (represented by the lock) until the specified delivery time (3). If no attempt at entanglement generation succeeds within one cycle, an unentangled state must be delivered (4). b , For the underlying entanglement-generation and state-preservation protocol (steps (1)–(3) in a ), the effectiveness of the trade-off between the average fidelity of the entangled state that is delivered and the success probability is determined by the quantum link efficiency η link . The dashed line represents the classical threshold of F = 0.5, above which a state is entangled. c , Maximum fidelity of deterministically delivered states as a function of η link . A critical threshold of η link ≈ 0.83 (vertical green line) must be surpassed to deliver an entangled state at every cycle on average. Full size image This protocol allows entangled states to be delivered at specified times, but with a finite probability of success. By delivering an unentangled state (state fidelity F unent ≤ 1/2) in cycles in which all entanglement-generation attempts failed, the protocol can be cast into a fully deterministic black box (Fig. 1a , step (4)). The states output from such a black box will have a fidelity of $${F}_{{\rm{\det }}}={p}_{{\rm{succ}}}{F}_{{\rm{succ}}}+(1-{p}_{{\rm{succ}}}){F}_{{\rm{unent}}}$$ (1) The maximum achievable fidelity ${F}_{{\rm{\det }}}^{{\rm{\max }}}$ of this deterministic state-delivery protocol, found by optimizing p succ , is also determined only by the quantum link efficiency η link . For F unent = 1/4 (a fully mixed state), we find (Fig. 1c ) $${F}_{{\rm{\det }}}^{{\rm{\max }}}=\frac{1}{4}\left[1+3{\eta }_{{\rm{link}}}^{1/(1-{\eta }_{{\rm{link}}})}\right]$$ (2) For η link greater than about 0.83, there exists a combination of p succ and F succ high enough to compensate for cycles in which entanglement is not heralded, enabling the deterministic delivery of states that are entangled on average $\left({F}_{{\rm{\det }}}^{{\rm{\max }}}\ge 1/2\right)$ . Deterministic entanglement delivery is therefore a critical benchmark of the performance of a network, certifying that its quantum link efficiency is of order unity or higher. Furthermore, the ability to specify in advance the time at which entangled states are delivered may assist in designing multi-step quantum-information tasks such as entanglement routing 16 , 17 . However, so far, quantum link efficiencies of order unity or greater have remained out of reach for solid-state quantum networks. Quantum dots have been used to demonstrate kilohertz entanglement rates r ent , but decoherence rates r dec of tens of megahertz limit their quantum link efficiencies 18 , 19 η link to around 10 −4 . Nitrogen–vacancy (NV) centres—point defects in diamond with a long-lived electron spin and bright optical transitions—have been used to demonstrate entanglement rates r ent of tens of millihertz 10 , 14 and, in separate experiments, decoherence rates r dec of<|im_end|> <|im_start|>assistant Researchers at QuTech in Delft have succeeded in generating quantum entanglement between two quantum chips faster than the entanglement is lost. Via a novel smart entanglement protocol and careful protection of the entanglement, the scientists led by Prof. Ronald Hanson are the first in the world to deliver such a quantum link on demand. This opens the door to connect multiple quantum nodes and create the very first quantum network in the world. Their results are published in Nature. By exploiting the power of quantum entanglement, it is theoretically possible to build a quantum internet invulnerable to eavesdropping. However, the realization of such a quantum network is a real challenge—it is necessary to create entanglement reliably on demand, and maintain it long enough to pass the entangled information to the next node. So far, this has been beyond the capabilities of quantum experiments. Scientists at QuTech in Delft have are now the first to experimentally generate entanglement over a distance of two metres in a fraction of a second, on demand, and theoretically maintain this entanglement long enough to enable entanglement to a third node. "The challenge is now to be the first to create a network of multiple entangled nodes—the first version of a quantum internet," professor Hanson says. In 2015, Ronald Hanson's research group was the first to generate long-lived quantum entanglement over a long distance (1.3 kilometres), , allowing them to provide full experimental proof of quantum entanglement for the first time. This experiment is the basis of their current approach to developing a quantum internet. Distant single electrons on diamond chips are entangled using photons as mediators. However, this experiment has not had the necessary performance to create a real quantum network. Hanson says, "In 2015, we managed to establish a connection once an hour, while the connection only remained active for a fraction of a second. It was impossible to add a third node, let alone multiple nodes, to the network." Researchers from QuTech in Delft working on the 'entanglement on demand' experiment'. From left to right: prof. Ronald Hanson, dr. Peter Humphreys and dr. Norbert Kalb, all from the group of prof Ronald Hanson of Delft University. Credit: TU Delft/Marieke de Lorijn The scientists have now made multiple innovative improvements to the experiment. First of all, they demonstrated a new entanglement method. This allows for the generation of entanglement 40 times a second between electrons at a distance of two metres. Co-author Peter Humphreys says, "This is a thousand times faster than with the old method." In combination with a smart way of protecting the quantum link from external noise, the experiment has now surpassed a crucial threshold. For the first time, entanglement can be created faster than it is lost. Through technical improvements, the experimental setup is now always ready for entanglement-on-demand. Hanson says, "Just like in the current internet, we always want to be online, the system has to entangle on each request." The scientists have achieved this by adding smart quality checks. Humphreys says, "These checks only take a fraction of the total experimental time, while allowing us to ensure that our system is ready for entanglement, without any manual action." The researchers demonstrated last year that they were able to protect a quantum entangled link while a new connection was generated. By combining this and their new results, they are ready to create quantum networks with more than two nodes. The Delft scientists now plan to realize such a network between several quantum nodes. Hanson says, "Together with partners such as KPN, we want to connect four cities in the Netherlands by 2020 via quantum entanglement. This will be the very first quantum internet in the world." <|im_end|>

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2,325

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Amyloid-β (Aβ) plaques, a hallmark of Alzheimer’s disease (AD), are surrounded by regions of neuronal and glial hyperactivity. We use in vivo two-photon and wide-field imaging of the glutamate sensor iGluSnFR to determine whether pathological changes in glutamate dynamics in the immediate vicinity of Aβ deposits in APPPS1 transgenic mice could alter neuronal activity in this microenvironment. In regions close to Aβ plaques chronic states of high spontaneous glutamate fluctuations are observed and the timing of glutamate responses evoked by sensory stimulation exhibit slower decay rates in two cortical brain areas. GLT-1 expression is reduced around Aβ plaques and upregulation of GLT-1 expression and activity by ceftriaxone partially restores glutamate dynamics to values in control regions. We conclude that the toxic microenvironment surrounding Aβ plaques results, at least partially, from enhanced glutamate levels and that pharmacologically increasing GLT-1 expression and activity may be a new target for early therapeutic intervention. Introduction Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and, with no cure available, it imposes a major burden on society. The pathological hallmarks of AD include the extracellular accumulation of amyloid plaques and intracellular protein inclusions known as neurofibrillary tangles 1 , 2 , 3 , 4 . Positron emission tomography imaging using Pittsburgh compound B has shown that cerebral Aβ plaque deposition is an early and predictive marker for the progression of preclinical to symptomatic AD 5 , 6 . Recent publications have revealed many interesting aspects of cell dysfunction in relation to Aβ deposits 7 , 8 , 9 , 10 , 11 , 12 . A current working hypothesis is that soluble Aβ adheres and combines with resident Aβ plaques leading to progressive plaque growth 13 , 14 . Although plaques consist of insoluble Aβ, each plaque may create a toxic microenvironment because soluble species continuously bind and unbind from its surface 7 , 8 . The toxic microenvironment hypothesis is supported by observations of neuronal dysfunction and decreased spine density in the immediate regions surrounding Aβ plaques 15 , 16 . Furthermore, hyperactive neurons, microglia and astrocytes with elevated intracellular calcium levels have been reported in the close proximity of Aβ plaques 9 , 10 , 12 , 17 , 18 . A shortcoming of the amyloid cascade hypothesis is that there are no clear connections between the onset of plaque deposition and the progression of cognitive impairment and neuronal loss 19 , 20 . In contrast, there are stronger correlations with the levels of soluble Aβ species 21 , 22 , 23 and cognitive impairment as well as neuronal loss. In this study we investigated whether changes in glutamate dynamics in the microenvironment surrounding Aβ deposits could contribute to neuronal dysfunction preceding the onset of neuronal death. This may establish an early link between Aβ toxicity and neuronal dysfunction. A genetically encoded fluorescent glutamate indicator, iGluSnFR, was used to detect the presence and time course of glutamate dynamics in vivo with two-photon and wide-field fluorescence microscopy 24 . It allows for unprecedented spatial and temporal resolution of local glutamate concentration on a subsecond timescale. Rapid glutamate uptake from the synaptic cleft, principally by the astrocyte glutamate transporter excitatory amino-acid transporter 2 (EAAT2 in humans or the homologue glutamate transporter 1 (GLT-1) in mice) 25 permits precise and fast synaptic transmission. Impairment of glutamate clearance in the extracellular space in AD 26 , 27 , 28 might underlie the reported upregulation of Ca 2+ signalling in neurons and astrocytes in the microenvironment of Aβ deposits and could contribute to excitotoxicity, which eventually leads to cell death. EAAT-2 activity has been reported to be significantly reduced in early stages of AD correlating well with cognitive decline in AD patients 29 . Moreover, studies of a heterozygous GLT-1 knockdown in an AD mouse model showed exacerbated cognitive decline further supporting the theory that dysfunction of the astrocyte glutamate transporter is involved in AD pathogenesis 30 , 31 . Recent in vitro results suggest that Aβ species are responsible for the loss of GLT-1 expression as a part of their toxicity to astrocytes 32 . Therefore, we treated APPPS1 mice with ceftriaxone to determine whether GLT-1 expression and/or transporter activity could be upregulated around plaques and whether this would restore normal glutamate dynamics in this region. Our results indicate that ceftriaxone helps to partially restore glutamate dynamics and chronically elevated levels of glutamate. Thus, it reduces the pathological impact of Aβ deposits and surrounding prefibrillary forms of Aβ. Results Wide-field imaging of glutamate dynamics We first ensured that changes in iGluSnFR fluorescence in mouse brains injected with iGluSnFR ( Fig. 1a ) were due to evoked synaptic release by examining the transient changes in fluorescent intensity evoked by visual or hindlimb stimulation (APPPS1 mice n =9; wild-type (WT) mice n =9). Figure 1b shows iGluSnFR expression in the hindlimb area of the somatosensory cortex. The complete cranial window ( Fig. 1c , ∼ 3.5 mm diameter) was used to analyse the stimulus-evoked signal. Wide-field imaging of the prestimulus baseline controls followed by the increase in iGluSnFR fluorescence on hindlimb stimulation and subsequent recovery to baseline levels is shown in Fig. 1d–f . The respective trace of the alterations in Δ F / F 0 shows a clear increase on stimulation of the hindlimb ( Fig. 1g , for video see Supplementary Video 1 ). Figure 1: Wide-field imaging of glutamate dynamics do not show significant changes. ( a ) Intracortical injection of AAV.hSynapsin.iGluSnFR in somatosensory cortex area coding for hindlimb ( n =9 transgene positive animals, 7 age-matched WT animals) followed by a cranial window surgery and mechanical hindlimb stimulation. Animals were head fixed and anaesthetized with isoflurane (1%) during imaging. ( b ) Pattern of iGluSnFR expression in the somatosensory cortex after viral injection. ( c ) The complete cranial window (3.5 mm diameter) was used for the analyses. A stimulus-locked response was detected on hindlimb stimulation ( e ) with baseline levels shown before and after stimulation ( d , f ). The respective trace", "role": "user" }, { "content": "New research from the Djavad Mowafaghian Centre for Brain Health at UBC has found a way to partially restore brain cell communication around areas damaged by plaques associated with Alzheimer's disease. The findings, published this week in Nature Communications, demonstrate a possible target and a potential drug treatment to reduce damage to the brain that occurs in the early stages of Alzheimer's disease. Using Ceftriaxone, an FDA-approved antibiotic used to treat bacterial infections, researchers were able to reduce synaptic disruption and clear the lines of neuronal communication in mice. Amyloid plaques of -amyloid deposits develop in brain regions of patients with Alzheimer's disease, These plaques are linked to the damage found in Alzheimer's disease because they prevent cell communication and are toxic to nerve cells. The researchers found that the brain areas around these plaques show high levels of glutamate, a signaling molecule essential to communication between brain cells, accompanying high levels of hyperactivity in glia, the brain's support cells. It's in this glutamate-rich environment that communication between neurons is changed or disrupted, causing neurons to die in the later stages of the disease. \"By imaging the glial cells and glutamate itself around the plaques, we were able to see that the cells were not able to 'remove' the glutamate accumulating in these brain areas. By using Ceftriaxone, we were able to up-regulate glutamate transport,\" explains Dr. MacVicar, principal investigator and professor of psychiatry. \"By restoring glutamate levels, we were able to mostly restore neuronal activity.\" The team's findings have implications for treatment of early symptoms of Alzheimer's disease. \"This dysfunction in cell communication occurs at a very early stage in the disease, before memory impairment is detectable,\" says Dr. Jasmin Hefendehl, a former Postdoctoral Fellow in Dr. MacVicar's lab and the lead author on the paper. \"This makes our discovery particularly interesting, as it opens a window for an early intervention strategy to possibly prevent or delay neuron and memory loss.\" Ceftriaxone is an antibiotic that is commonly administered before some types of surgery to prevent infections. Although a recent clinical trial failed to see improvements for treating amyotrophic lateral sclerosis (ALS), the researchers are hopeful about its potential for early intervention in treating Alzheimer's disease. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Amyloid-β (Aβ) plaques, a hallmark of Alzheimer’s disease (AD), are surrounded by regions of neuronal and glial hyperactivity. We use in vivo two-photon and wide-field imaging of the glutamate sensor iGluSnFR to determine whether pathological changes in glutamate dynamics in the immediate vicinity of Aβ deposits in APPPS1 transgenic mice could alter neuronal activity in this microenvironment. In regions close to Aβ plaques chronic states of high spontaneous glutamate fluctuations are observed and the timing of glutamate responses evoked by sensory stimulation exhibit slower decay rates in two cortical brain areas. GLT-1 expression is reduced around Aβ plaques and upregulation of GLT-1 expression and activity by ceftriaxone partially restores glutamate dynamics to values in control regions. We conclude that the toxic microenvironment surrounding Aβ plaques results, at least partially, from enhanced glutamate levels and that pharmacologically increasing GLT-1 expression and activity may be a new target for early therapeutic intervention. Introduction Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and, with no cure available, it imposes a major burden on society. The pathological hallmarks of AD include the extracellular accumulation of amyloid plaques and intracellular protein inclusions known as neurofibrillary tangles 1 , 2 , 3 , 4 . Positron emission tomography imaging using Pittsburgh compound B has shown that cerebral Aβ plaque deposition is an early and predictive marker for the progression of preclinical to symptomatic AD 5 , 6 . Recent publications have revealed many interesting aspects of cell dysfunction in relation to Aβ deposits 7 , 8 , 9 , 10 , 11 , 12 . A current working hypothesis is that soluble Aβ adheres and combines with resident Aβ plaques leading to progressive plaque growth 13 , 14 . Although plaques consist of insoluble Aβ, each plaque may create a toxic microenvironment because soluble species continuously bind and unbind from its surface 7 , 8 . The toxic microenvironment hypothesis is supported by observations of neuronal dysfunction and decreased spine density in the immediate regions surrounding Aβ plaques 15 , 16 . Furthermore, hyperactive neurons, microglia and astrocytes with elevated intracellular calcium levels have been reported in the close proximity of Aβ plaques 9 , 10 , 12 , 17 , 18 . A shortcoming of the amyloid cascade hypothesis is that there are no clear connections between the onset of plaque deposition and the progression of cognitive impairment and neuronal loss 19 , 20 . In contrast, there are stronger correlations with the levels of soluble Aβ species 21 , 22 , 23 and cognitive impairment as well as neuronal loss. In this study we investigated whether changes in glutamate dynamics in the microenvironment surrounding Aβ deposits could contribute to neuronal dysfunction preceding the onset of neuronal death. This may establish an early link between Aβ toxicity and neuronal dysfunction. A genetically encoded fluorescent glutamate indicator, iGluSnFR, was used to detect the presence and time course of glutamate dynamics in vivo with two-photon and wide-field fluorescence microscopy 24 . It allows for unprecedented spatial and temporal resolution of local glutamate concentration on a subsecond timescale. Rapid glutamate uptake from the synaptic cleft, principally by the astrocyte glutamate transporter excitatory amino-acid transporter 2 (EAAT2 in humans or the homologue glutamate transporter 1 (GLT-1) in mice) 25 permits precise and fast synaptic transmission. Impairment of glutamate clearance in the extracellular space in AD 26 , 27 , 28 might underlie the reported upregulation of Ca 2+ signalling in neurons and astrocytes in the microenvironment of Aβ deposits and could contribute to excitotoxicity, which eventually leads to cell death. EAAT-2 activity has been reported to be significantly reduced in early stages of AD correlating well with cognitive decline in AD patients 29 . Moreover, studies of a heterozygous GLT-1 knockdown in an AD mouse model showed exacerbated cognitive decline further supporting the theory that dysfunction of the astrocyte glutamate transporter is involved in AD pathogenesis 30 , 31 . Recent in vitro results suggest that Aβ species are responsible for the loss of GLT-1 expression as a part of their toxicity to astrocytes 32 . Therefore, we treated APPPS1 mice with ceftriaxone to determine whether GLT-1 expression and/or transporter activity could be upregulated around plaques and whether this would restore normal glutamate dynamics in this region. Our results indicate that ceftriaxone helps to partially restore glutamate dynamics and chronically elevated levels of glutamate. Thus, it reduces the pathological impact of Aβ deposits and surrounding prefibrillary forms of Aβ. Results Wide-field imaging of glutamate dynamics We first ensured that changes in iGluSnFR fluorescence in mouse brains injected with iGluSnFR ( Fig. 1a ) were due to evoked synaptic release by examining the transient changes in fluorescent intensity evoked by visual or hindlimb stimulation (APPPS1 mice n =9; wild-type (WT) mice n =9). Figure 1b shows iGluSnFR expression in the hindlimb area of the somatosensory cortex. The complete cranial window ( Fig. 1c , ∼ 3.5 mm diameter) was used to analyse the stimulus-evoked signal. Wide-field imaging of the prestimulus baseline controls followed by the increase in iGluSnFR fluorescence on hindlimb stimulation and subsequent recovery to baseline levels is shown in Fig. 1d–f . The respective trace of the alterations in Δ F / F 0 shows a clear increase on stimulation of the hindlimb ( Fig. 1g , for video see Supplementary Video 1 ). Figure 1: Wide-field imaging of glutamate dynamics do not show significant changes. ( a ) Intracortical injection of AAV.hSynapsin.iGluSnFR in somatosensory cortex area coding for hindlimb ( n =9 transgene positive animals, 7 age-matched WT animals) followed by a cranial window surgery and mechanical hindlimb stimulation. Animals were head fixed and anaesthetized with isoflurane (1%) during imaging. ( b ) Pattern of iGluSnFR expression in the somatosensory cortex after viral injection. ( c ) The complete cranial window (3.5 mm diameter) was used for the analyses. A stimulus-locked response was detected on hindlimb stimulation ( e ) with baseline levels shown before and after stimulation ( d , f ). The respective trace<|im_end|> <|im_start|>assistant New research from the Djavad Mowafaghian Centre for Brain Health at UBC has found a way to partially restore brain cell communication around areas damaged by plaques associated with Alzheimer's disease. The findings, published this week in Nature Communications, demonstrate a possible target and a potential drug treatment to reduce damage to the brain that occurs in the early stages of Alzheimer's disease. Using Ceftriaxone, an FDA-approved antibiotic used to treat bacterial infections, researchers were able to reduce synaptic disruption and clear the lines of neuronal communication in mice. Amyloid plaques of -amyloid deposits develop in brain regions of patients with Alzheimer's disease, These plaques are linked to the damage found in Alzheimer's disease because they prevent cell communication and are toxic to nerve cells. The researchers found that the brain areas around these plaques show high levels of glutamate, a signaling molecule essential to communication between brain cells, accompanying high levels of hyperactivity in glia, the brain's support cells. It's in this glutamate-rich environment that communication between neurons is changed or disrupted, causing neurons to die in the later stages of the disease. "By imaging the glial cells and glutamate itself around the plaques, we were able to see that the cells were not able to 'remove' the glutamate accumulating in these brain areas. By using Ceftriaxone, we were able to up-regulate glutamate transport," explains Dr. MacVicar, principal investigator and professor of psychiatry. "By restoring glutamate levels, we were able to mostly restore neuronal activity." The team's findings have implications for treatment of early symptoms of Alzheimer's disease. "This dysfunction in cell communication occurs at a very early stage in the disease, before memory impairment is detectable," says Dr. Jasmin Hefendehl, a former Postdoctoral Fellow in Dr. MacVicar's lab and the lead author on the paper. "This makes our discovery particularly interesting, as it opens a window for an early intervention strategy to possibly prevent or delay neuron and memory loss." Ceftriaxone is an antibiotic that is commonly administered before some types of surgery to prevent infections. Although a recent clinical trial failed to see improvements for treating amyotrophic lateral sclerosis (ALS), the researchers are hopeful about its potential for early intervention in treating Alzheimer's disease. <|im_end|>

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91357, 320, 47837, 705, 279, 12074, 527, 38650, 922, 1202, 4754, 369, 4216, 21623, 304, 27723, 44531, 596, 8624, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract 1. Introduction 2. Literature review 3. Research design and methodology 4. Results 5. Discussion 6. Conclusion Table of contents Abstract 1. Introduction 2. Literature review 3. Research design and methodology 4. Results 5. Discussion 6. Conclusion / Table of Contents Abstract Purpose Given the impending introduction of legislation requiring large Australian listed companies to make supply chain disclosures about modern slavery, the paper aims to reveal current voluntary practice. The purpose of this paper is to provide a benchmark for assessing the current engagement of large companies with modern slavery in Australia. / Abstract__block Design/methodology/approach Institutional theory provides the foundation for assessing current voluntary practice in relation to modern slavery disclosures by large Australian listed companies. Content analysis is used to identify quantity and quality of modern slavery disclosures of the top 100 companies listed on the Australian Stock Exchange. The contents of annual and standalone reports available on websites, as well as other online disclosures, are examined using terms associated with modern slavery identified from the literature. / Abstract__block Findings Evidence gathered about modern slavery disclosures by ASX 100 companies shows information in annual and standalone reports reveal far less than other disclosures on company websites. Overall, the volume and quality of disclosures are low and, where made, narrative. A wide range of themes on modern slavery are disclosed with bribery and corruption and human rights issues dominant. Although currently in line with institutional theory, as there appear to be mimetic processes encouraging disclosure, results support the idea that legislation is needed to encourage further engagement. / Abstract__block Research limitations/implications The paper provides a baseline of understanding about the volume and quality of modern slavery disclosures as a foundation for future research into the practices of Australian companies prior to the signalled introduction of legislation mandating reporting. It also identifies potential lines of research. The sample only examines large Australian listed companies which restricts generalisation from the results. / Abstract__block Originality/value This is the first academic research paper to examine quantity and quality of modern slavery disclosures of large Australian companies. Results add support for the introduction of legislation by government. / Abstract__block / Abstract Keywords Australia Sustainability Labour Modern slavery ASX 100 Listed company disclosure Citation Christ, K.L. , Rao, K.K. and Burritt, R.L. (2019), \"Accounting for modern slavery: an analysis of Australian listed company disclosures\", Accounting, Auditing & Accountability Journal , Vol. 32 No. 3, pp. 836-865. Download as .RIS / Citation Publisher : Emerald Publishing Limited / Body Copyright © 2019, Emerald Publishing Limited / Citation 1. Introduction Much has been written in recent years concerning the globalisation of business practices and the benefits provided by access to global markets. Driven by consumer desire for cheap goods, many business organisations have abandoned vertical integration in favour of horizontal business models that incorporate a variety of outsourcing and offshoring activities ( Stringer et al. , 2016 ). The argument is that by moving production in labour-intensive industries to countries that are less well developed and where labour is cheaper businesses can benefit from reduced costs while meeting customer demand for products and services and maintaining income ( Gold et al. , 2015 ). Although this proposition sounds good in theory, there is a dark side to the practice, and the pressure it puts on other organisations that keep labour “in house”, that the western world is only just beginning to acknowledge; it provides a fertile ground for a form of exploitation which has come to be known as modern slavery. Notwithstanding the fact that slavery has long been outlawed on a global scale, available evidence suggests there are more slaves in the world today than at any other time in human history ( Bales, 2009 ; Gold et al. , 2015 ). Modern slavery is an umbrella term used to describe a collection of practices which, in a business context, includes traditional slavery, bonded labour, human trafficking and forced labour ( Crane, 2013 ). At its core, modern slavery is “one of the most acute abuses of human rights in contemporary business practice” ( Crane, 2013 , p. 49), a form of economic exploitation which, according to the International Labour Organization (2017) , generates $150bn in illegal profits each year from forced labour in private enterprise alone. Although modern slavery incorporates sex trafficking and activities that relate to the domestic sector, business organisations and business-related supply chains are also prominent actors in this space ( Crane et al. , 2019 ). Indeed, it is now increasingly accepted that slavery-related practices are embedded in many of the goods that are consumed and used on a daily basis ( Bales, 2009 ; New, 2015 ). Until recently, it was relatively easy for business to turn a blind eye to inappropriate labour-related practices, or at least those that occurred at the relative comfort of arm’s-length in their overseas supply chains. However, there is a growing recognition that modern slavery is everywhere “[f]rom the construction of FIFA World Cup stadiums in Qatar to the cotton farms of Uzbekistan, from cattle ranches in Paraguay to fisheries in Thailand and the Philippines to agriculture in Italy, from sweatshops in Brazil and Argentina to berry pickers in Sweden. The production chains of clothes, food and services consumed globally are tainted with forced labour” ( Business and Human Rights Resource Centre, 2017 , p. 1). Few can now claim ignorance in relation to the modern slavery that exists in global business and domestic networks ( Johnson, 2013 ; LeBaron, 2014 ). The predominant response to this type of activity from governments around the world has been to legislate against slavery-related practices. One well-documented example is the UK Modern Slavery Act 2015 ( LeBaron and Rühmkorf, 2017 ). This type of legislation promotes transparency via the corporate reporting process as an appropriate way to address the issue ( New, 2015 ). Notwithstanding the fact some have questioned the efficacy of this approach, for example, see LeBaron (2014) and Crane et al. (2019) , to date", "role": "user" }, { "content": "New research from the University of South Australia finds that Australian businesses are ill-prepared for mandatory modern slavery reporting, with more than two-thirds of ASX 100 companies unable to produce a disclosure statement about potentially exploitative labour practices. It is a concerning finding given that initial reporting periods have already commenced requiring Australian businesses to deliver their first modern slavery statements by 31 December 2020. UniSA researchers Dr. Katherine Christ and Dr. Kathy Rao say that in order to meet the requirements of Australia's Modern Slavery Act, businesses must significantly ramp up their efforts to ensure they have the systems and procedures ready to report on modern slavery. \"Under federal legislation, businesses with turnovers of more than $100 million must declare what they're doing to eradicate slavery in their operations and supply chains, yet evidence shows the majority of Australian businesses are underprepared,\" Dr. Katherine Christ says. \"While a third of Australian businesses sampled in this research were able to produce a modern slavery statement, the volume and quality of their disclosures was low—typically narrative and descriptive of policy—plus there were many inconsistencies of where and how it was reported. \"The general nature of these disclosures just isn't enough. For Australian businesses to appropriately report on modern slavery, they must be able to produce systematic quantitative data with associated targets and finances.\" Modern slavery is the illegal and inappropriate labour practices that include human trafficking, forced labour, child labour, organ trafficking, sex exploitation, debt bondage and other slavery-like practices. Driven by consumer demand for cheap goods it is embedded within many of the products used by Australians every day, including 73 per cent of imported computers, mobile phones and laptops (representing an estimated US$7.0 billion) and 70 per cent of imported clothing and accessories (representing an estimated US$4.5 billion). Globally, more than 40 million people are trapped in modern slavery with nearly 25 million of these forced into slave labour. In Australia, 15,000 people are victims of modern slavery. This research is the first to consider the state of modern slavery disclosures within an Australian context, providing a useful benchmark against which the impact of Australia's Modern Slavery Act can be measured. Dr. Kathy Rao says that eradicating modern slavery requires commitment across all levels of Australian business. \"Modern slavery is a far-reaching and devastating issue, but the responsibility to eliminate it does not sit with business alone,\" Dr. Rao says. \"While all businesses have a responsibility to mitigate the risks of modern slavery, addressing modern slavery requires a joint and ongoing commitment from all parties including governments, business leaders and boards, suppliers, contractors, NGOs, researchers, professional bodies and the general public. \"Only through a committed process of ongoing and continuous improvement will we be able to ensure modern slavery is truly a thing of the past.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract 1. Introduction 2. Literature review 3. Research design and methodology 4. Results 5. Discussion 6. Conclusion Table of contents Abstract 1. Introduction 2. Literature review 3. Research design and methodology 4. Results 5. Discussion 6. Conclusion / Table of Contents Abstract Purpose Given the impending introduction of legislation requiring large Australian listed companies to make supply chain disclosures about modern slavery, the paper aims to reveal current voluntary practice. The purpose of this paper is to provide a benchmark for assessing the current engagement of large companies with modern slavery in Australia. / Abstract__block Design/methodology/approach Institutional theory provides the foundation for assessing current voluntary practice in relation to modern slavery disclosures by large Australian listed companies. Content analysis is used to identify quantity and quality of modern slavery disclosures of the top 100 companies listed on the Australian Stock Exchange. The contents of annual and standalone reports available on websites, as well as other online disclosures, are examined using terms associated with modern slavery identified from the literature. / Abstract__block Findings Evidence gathered about modern slavery disclosures by ASX 100 companies shows information in annual and standalone reports reveal far less than other disclosures on company websites. Overall, the volume and quality of disclosures are low and, where made, narrative. A wide range of themes on modern slavery are disclosed with bribery and corruption and human rights issues dominant. Although currently in line with institutional theory, as there appear to be mimetic processes encouraging disclosure, results support the idea that legislation is needed to encourage further engagement. / Abstract__block Research limitations/implications The paper provides a baseline of understanding about the volume and quality of modern slavery disclosures as a foundation for future research into the practices of Australian companies prior to the signalled introduction of legislation mandating reporting. It also identifies potential lines of research. The sample only examines large Australian listed companies which restricts generalisation from the results. / Abstract__block Originality/value This is the first academic research paper to examine quantity and quality of modern slavery disclosures of large Australian companies. Results add support for the introduction of legislation by government. / Abstract__block / Abstract Keywords Australia Sustainability Labour Modern slavery ASX 100 Listed company disclosure Citation Christ, K.L. , Rao, K.K. and Burritt, R.L. (2019), "Accounting for modern slavery: an analysis of Australian listed company disclosures", Accounting, Auditing & Accountability Journal , Vol. 32 No. 3, pp. 836-865. Download as .RIS / Citation Publisher : Emerald Publishing Limited / Body Copyright © 2019, Emerald Publishing Limited / Citation 1. Introduction Much has been written in recent years concerning the globalisation of business practices and the benefits provided by access to global markets. Driven by consumer desire for cheap goods, many business organisations have abandoned vertical integration in favour of horizontal business models that incorporate a variety of outsourcing and offshoring activities ( Stringer et al. , 2016 ). The argument is that by moving production in labour-intensive industries to countries that are less well developed and where labour is cheaper businesses can benefit from reduced costs while meeting customer demand for products and services and maintaining income ( Gold et al. , 2015 ). Although this proposition sounds good in theory, there is a dark side to the practice, and the pressure it puts on other organisations that keep labour “in house”, that the western world is only just beginning to acknowledge; it provides a fertile ground for a form of exploitation which has come to be known as modern slavery. Notwithstanding the fact that slavery has long been outlawed on a global scale, available evidence suggests there are more slaves in the world today than at any other time in human history ( Bales, 2009 ; Gold et al. , 2015 ). Modern slavery is an umbrella term used to describe a collection of practices which, in a business context, includes traditional slavery, bonded labour, human trafficking and forced labour ( Crane, 2013 ). At its core, modern slavery is “one of the most acute abuses of human rights in contemporary business practice” ( Crane, 2013 , p. 49), a form of economic exploitation which, according to the International Labour Organization (2017) , generates $150bn in illegal profits each year from forced labour in private enterprise alone. Although modern slavery incorporates sex trafficking and activities that relate to the domestic sector, business organisations and business-related supply chains are also prominent actors in this space ( Crane et al. , 2019 ). Indeed, it is now increasingly accepted that slavery-related practices are embedded in many of the goods that are consumed and used on a daily basis ( Bales, 2009 ; New, 2015 ). Until recently, it was relatively easy for business to turn a blind eye to inappropriate labour-related practices, or at least those that occurred at the relative comfort of arm’s-length in their overseas supply chains. However, there is a growing recognition that modern slavery is everywhere “[f]rom the construction of FIFA World Cup stadiums in Qatar to the cotton farms of Uzbekistan, from cattle ranches in Paraguay to fisheries in Thailand and the Philippines to agriculture in Italy, from sweatshops in Brazil and Argentina to berry pickers in Sweden. The production chains of clothes, food and services consumed globally are tainted with forced labour” ( Business and Human Rights Resource Centre, 2017 , p. 1). Few can now claim ignorance in relation to the modern slavery that exists in global business and domestic networks ( Johnson, 2013 ; LeBaron, 2014 ). The predominant response to this type of activity from governments around the world has been to legislate against slavery-related practices. One well-documented example is the UK Modern Slavery Act 2015 ( LeBaron and Rühmkorf, 2017 ). This type of legislation promotes transparency via the corporate reporting process as an appropriate way to address the issue ( New, 2015 ). Notwithstanding the fact some have questioned the efficacy of this approach, for example, see LeBaron (2014) and Crane et al. (2019) , to date<|im_end|> <|im_start|>assistant New research from the University of South Australia finds that Australian businesses are ill-prepared for mandatory modern slavery reporting, with more than two-thirds of ASX 100 companies unable to produce a disclosure statement about potentially exploitative labour practices. It is a concerning finding given that initial reporting periods have already commenced requiring Australian businesses to deliver their first modern slavery statements by 31 December 2020. UniSA researchers Dr. Katherine Christ and Dr. Kathy Rao say that in order to meet the requirements of Australia's Modern Slavery Act, businesses must significantly ramp up their efforts to ensure they have the systems and procedures ready to report on modern slavery. "Under federal legislation, businesses with turnovers of more than $100 million must declare what they're doing to eradicate slavery in their operations and supply chains, yet evidence shows the majority of Australian businesses are underprepared," Dr. Katherine Christ says. "While a third of Australian businesses sampled in this research were able to produce a modern slavery statement, the volume and quality of their disclosures was low—typically narrative and descriptive of policy—plus there were many inconsistencies of where and how it was reported. "The general nature of these disclosures just isn't enough. For Australian businesses to appropriately report on modern slavery, they must be able to produce systematic quantitative data with associated targets and finances." Modern slavery is the illegal and inappropriate labour practices that include human trafficking, forced labour, child labour, organ trafficking, sex exploitation, debt bondage and other slavery-like practices. Driven by consumer demand for cheap goods it is embedded within many of the products used by Australians every day, including 73 per cent of imported computers, mobile phones and laptops (representing an estimated US$7.0 billion) and 70 per cent of imported clothing and accessories (representing an estimated US$4.5 billion). Globally, more than 40 million people are trapped in modern slavery with nearly 25 million of these forced into slave labour. In Australia, 15,000 people are victims of modern slavery. This research is the first to consider the state of modern slavery disclosures within an Australian context, providing a useful benchmark against which the impact of Australia's Modern Slavery Act can be measured. Dr. Kathy Rao says that eradicating modern slavery requires commitment across all levels of Australian business. "Modern slavery is a far-reaching and devastating issue, but the responsibility to eliminate it does not sit with business alone," Dr. Rao says. "While all businesses have a responsibility to mitigate the risks of modern slavery, addressing modern slavery requires a joint and ongoing commitment from all parties including governments, business leaders and boards, suppliers, contractors, NGOs, researchers, professional bodies and the general public. "Only through a committed process of ongoing and continuous improvement will we be able to ensure modern slavery is truly a thing of the past." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract How do multiple stable states influence local and macroscale ecological patterns? Understanding how local feedbacks operate within heterogeneous coastal environments is essential to forecasting marsh persistence and loss in response to sea level rise, river impoundment, and other environmental changes. In coastal lagoons, feedbacks between open water, wind erosion, and stabilizing effects from wetland vegetation produce two states: open water with fringing marshes, and marsh-dominated basins. Unknown is whether, how, and at what scales these feedbacks affect distribution of marsh ecosystems in large, complex estuaries, where macroscale coastal and watershed characteristics control suspended sediment and wind energy. Using a multi-scale geospatial analysis spanning the Atlantic and Gulf coasts of the USA, we show that characteristics of estuaries (depth, shoreline complexity, land use, tidal range, latitude) and their watersheds (discharge) best predict wetland extent at broad spatial scales (~> 10 2 km 2 ). Bimodal distribution of wetland extent occurs at finer scales (~ 10 0 to 10 2 km 2 ) that correspond to the theoretical scale of wave erosion feedbacks. Local feedbacks are thus the mechanism that controls marsh dynamics, whereas coastal and watershed characteristics determine macroscale wetland distributions through their effects on these processes. In coastal marshes, and likely in other complex landscapes, the spatial extent of feedbacks shapes the scales at which local and macroscale processes control the distribution of alternative stable states. These findings help predict scales at which coastal wetlands will respond catastrophically or continuously to environmental change, and provide a basis for multi-scale strategies to protect and restore coastal wetland ecosystems. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Manuscript Highlights We evaluated coastal wetland patterns across eastern USA to understand drivers of persistence. Feedbacks between erosion and stabilizing vegetation control wetland extent at local scale. Feedbacks and macroscale drivers are primarily influential at different scales. Introduction How do alternative stable states influence ecological patterns over broad spatial scales? Alternative stable states can be expressed over whole ecosystems, such as lakes or sand dunes (Scheffer and others 1993 ; Hayden and others 1995 ; Scheffer and van Nes 2007 ), usually when such systems are relatively small, well-bounded, homogenous, and well-mixed systems. In most ecosystems, and especially over broad spatial scales, physical boundaries are less distinct (Schlesinger and others 1990 ; Staver and others 2011 ), and conditions are heterogeneous. This heterogeneity can disrupt or constrain feedbacks and thus alter or obscure the occurrence and distribution of alternative stable states. The relative influence of external drivers and self-organizing feedbacks may also vary with scale, with internal feedbacks shaping local patterns, but macroscale, physical drivers over-riding those effects at other scales or in particular locations (Sheffer and others 2013 ). In this study of coastal wetland distributions (Figure 1 A), our objective is to test whether alternative stable states are most clearly expressed at scales determined by spatial scales of feedback processes and landscape heterogeneity. Figure 1 Multi-scale patterns of wetland extent and their hypothesized drivers. Our study domain A spanned the Gulf and Atlantic coasts of the USA. At five spatial scales corresponding to USGS Hydrologic unit codes, we determined fraction of estuary occupied by wetlands and open water. The range of this characteristic is illustrated by the B Neuse River Estuary, NC, an example of fringing wetland and C the Satilla and Brunswick River Estuaries, GA, an example of extensive wetlands. At the same scales, we quantified estuarine and watershed characteristics, including relative volumes of river and tidal inflows ( D ; shown at HUC 4 scale along NC coastline), maximum depth ( E ; HUC 8), and shoreline complexity ( F ; HUC 12). Full size image Coastal wetlands are strongly connected to both upland watersheds and adjacent estuaries, whose alteration by human activity has caused wetland degradation and loss (Kennish 2001 ; Lotze and others 2006 ). Loss or alteration of coastal wetlands reduces the ecosystem services they provide, such as shoreline protection, fishery nurseries, nutrient filtration, and carbon sequestration (Zedler and Kercher 2005 ; McLeod and others 2011 ; Hansen and others 2018 ). Along coasts, alternative stable states of open water (Figure 1 B) and extensive, basin-filling marshes (Figure 1 C; Morris and others 2002 ; Marani and others 2007 ; Mariotti and Fagherazzi 2013 ) are thought to arise from a feedback between extent of tidal flat width and of open water (which influences fetch—the length of open water over which wind can blow to produce waves). The ratio of these morphological features, in turn, affects marsh building by vegetation (Redfield 1965 ; Mudd and others 2009 ) and wave erosion at wetland edges (van de Koppel and others 2005 ; Marani and others 2010 ; Mariotti and Fagherazzi 2013 ). Above a critical fetch, wave energy promotes rapid edge erosion, increasing open water extent and tidal flat width; below this critical fetch, marshes expand until the basin is filled. Critical fetch for a specific estuary depends on suspended sediment concentration (SSC) and rates of sea level rise (Mariotti and Fagherazzi 2013 ), and these factors should determine the spatial scales at which resulting states are most influential and apparent. Understanding how local, self-organizing feedbacks operate within heterogeneous coastal environments is essential to forecasting marsh persistence and loss in response to sea level rise, river impoundment, and other environmental changes. Among the macroscale factors that might influence marsh extent are coastal and near-shore morphology that control tidal dynamics and marine sediment inputs (Ardhuin and others 2003 ; Stone and others 2005 ); upland sediment inputs that differ depending on watershed size, terrestrial geology, and land use within the watershed (Mattheus and others 2009 ; Kirwan and others 2011 ; Tweel and Turner 2012 ); and climate-driven variation in vegetation productivity and phenology (Pennings and Bertness 2001 ; Osland and others 2013 , 2014 ). Distribution and covariation of these geophysical factors across multiple spatial scales creates a template within which local marsh building occurs. Shape, size, and depth of estuaries", "role": "user" }, { "content": "Sea-level rise, sediment starvation and other environmental woes pose increasing threats to coastal wetlands worldwide. But a massive new Duke University study could help stem these losses by giving scientists a broader understanding of which wetlands are most at risk, and why. The study, which assessed wetland distribution and resilience in hundreds of U.S. estuaries, found that it's all a matter of scale. \"At the local level, the persistence or loss of coastal marshes was invariably linked to feedbacks between two factors: erosion, which eats away at marsh edges, and vegetation, which stabilizes them,\" said Anna E. Braswell, a Ph.D. graduate of Duke's Nicholas School of the Environment, who conducted the research as part of her 2017 dissertation. \"But at broader spatial scales, other key drivers emerged, too.\" As the researchers took more of an estuary's surrounding geography into account, the depth, size, shape and latitude of the estuary became increasingly important predictors for determining the extent of wetlands it could support, Braswell said. The shape and orientation of the nearby coastline and the depth of near-shore waters mattered, too. And the amount of replenishing sediment being carried into the estuary by rivers or incoming tides became a key indicator of marshes' resilience to change. \"These macro-scale coastal and watershed characteristics accentuated or limited the stabilizing impacts of the local feedbacks,\" she said. \"But they weren't really evident until we took a few steps back and viewed the estuaries from broader spatial perspectives.\" \"What this tells us is that salt marshes everywhere probably have tipping points,\" said co-author James B. Heffernan, assistant professor of ecosystem ecology and ecohydrology at the Nicholas School. Researcher Anna Braswell samples soil from an estuary during her dissertation research on 'tipping points' for wetland preservation. Credit: Megan Fork \"Knowing what causes these tipping points to vary from location to location is an important step in identifying where we should expect marshes to be especially vulnerable to future change,\" he said. \"It also provides a framework for understanding where wetland restoration is likely or not likely to succeed.\" Coastal salt marshes provide a long list of ecosystem services that benefit humans, including shoreline protection, pollution filtration, flood prevention, fishery habitat and carbon sequestration. Braswell and Heffernan published their peer-reviewed findings Jan. 31 in the journal Ecosystems. Using existing geospatial data, they analyzed hundreds of estuaries on the U.S. Atlantic and Gulf coasts from Maine to Mexico to determine the fraction of each estuary that was occupied by wetlands and identify the factors that controlled the extent of the wetlands' spread and their resilience to change. Each site was analyzed at five different geographic scales—from macro-analyses that covered the entire estuary and its adjacent coastline and watersheds, to fine-scale analyses that zeroed in on what was happening in small, individual tributaries. \"Integrating data from five different scales allowed us to see patterns and linkages that we would have missed otherwise,\" said Braswell, who now works as a research scientist in the Earth Lab at the University of Colorado at Boulder. \"This information will be vital for future preservation and restoration efforts.\" Braswell and Heffernan used data from the National Wetlands Inventory and other publicly accessible sources to do their analyses. The five spatial scales they used—sub-region, basin, sub-basin, watershed and sub-watershed—correspond to standard U.S. Geological Survey hydrological units. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract How do multiple stable states influence local and macroscale ecological patterns? Understanding how local feedbacks operate within heterogeneous coastal environments is essential to forecasting marsh persistence and loss in response to sea level rise, river impoundment, and other environmental changes. In coastal lagoons, feedbacks between open water, wind erosion, and stabilizing effects from wetland vegetation produce two states: open water with fringing marshes, and marsh-dominated basins. Unknown is whether, how, and at what scales these feedbacks affect distribution of marsh ecosystems in large, complex estuaries, where macroscale coastal and watershed characteristics control suspended sediment and wind energy. Using a multi-scale geospatial analysis spanning the Atlantic and Gulf coasts of the USA, we show that characteristics of estuaries (depth, shoreline complexity, land use, tidal range, latitude) and their watersheds (discharge) best predict wetland extent at broad spatial scales (~> 10 2 km 2 ). Bimodal distribution of wetland extent occurs at finer scales (~ 10 0 to 10 2 km 2 ) that correspond to the theoretical scale of wave erosion feedbacks. Local feedbacks are thus the mechanism that controls marsh dynamics, whereas coastal and watershed characteristics determine macroscale wetland distributions through their effects on these processes. In coastal marshes, and likely in other complex landscapes, the spatial extent of feedbacks shapes the scales at which local and macroscale processes control the distribution of alternative stable states. These findings help predict scales at which coastal wetlands will respond catastrophically or continuously to environmental change, and provide a basis for multi-scale strategies to protect and restore coastal wetland ecosystems. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Manuscript Highlights We evaluated coastal wetland patterns across eastern USA to understand drivers of persistence. Feedbacks between erosion and stabilizing vegetation control wetland extent at local scale. Feedbacks and macroscale drivers are primarily influential at different scales. Introduction How do alternative stable states influence ecological patterns over broad spatial scales? Alternative stable states can be expressed over whole ecosystems, such as lakes or sand dunes (Scheffer and others 1993 ; Hayden and others 1995 ; Scheffer and van Nes 2007 ), usually when such systems are relatively small, well-bounded, homogenous, and well-mixed systems. In most ecosystems, and especially over broad spatial scales, physical boundaries are less distinct (Schlesinger and others 1990 ; Staver and others 2011 ), and conditions are heterogeneous. This heterogeneity can disrupt or constrain feedbacks and thus alter or obscure the occurrence and distribution of alternative stable states. The relative influence of external drivers and self-organizing feedbacks may also vary with scale, with internal feedbacks shaping local patterns, but macroscale, physical drivers over-riding those effects at other scales or in particular locations (Sheffer and others 2013 ). In this study of coastal wetland distributions (Figure 1 A), our objective is to test whether alternative stable states are most clearly expressed at scales determined by spatial scales of feedback processes and landscape heterogeneity. Figure 1 Multi-scale patterns of wetland extent and their hypothesized drivers. Our study domain A spanned the Gulf and Atlantic coasts of the USA. At five spatial scales corresponding to USGS Hydrologic unit codes, we determined fraction of estuary occupied by wetlands and open water. The range of this characteristic is illustrated by the B Neuse River Estuary, NC, an example of fringing wetland and C the Satilla and Brunswick River Estuaries, GA, an example of extensive wetlands. At the same scales, we quantified estuarine and watershed characteristics, including relative volumes of river and tidal inflows ( D ; shown at HUC 4 scale along NC coastline), maximum depth ( E ; HUC 8), and shoreline complexity ( F ; HUC 12). Full size image Coastal wetlands are strongly connected to both upland watersheds and adjacent estuaries, whose alteration by human activity has caused wetland degradation and loss (Kennish 2001 ; Lotze and others 2006 ). Loss or alteration of coastal wetlands reduces the ecosystem services they provide, such as shoreline protection, fishery nurseries, nutrient filtration, and carbon sequestration (Zedler and Kercher 2005 ; McLeod and others 2011 ; Hansen and others 2018 ). Along coasts, alternative stable states of open water (Figure 1 B) and extensive, basin-filling marshes (Figure 1 C; Morris and others 2002 ; Marani and others 2007 ; Mariotti and Fagherazzi 2013 ) are thought to arise from a feedback between extent of tidal flat width and of open water (which influences fetch—the length of open water over which wind can blow to produce waves). The ratio of these morphological features, in turn, affects marsh building by vegetation (Redfield 1965 ; Mudd and others 2009 ) and wave erosion at wetland edges (van de Koppel and others 2005 ; Marani and others 2010 ; Mariotti and Fagherazzi 2013 ). Above a critical fetch, wave energy promotes rapid edge erosion, increasing open water extent and tidal flat width; below this critical fetch, marshes expand until the basin is filled. Critical fetch for a specific estuary depends on suspended sediment concentration (SSC) and rates of sea level rise (Mariotti and Fagherazzi 2013 ), and these factors should determine the spatial scales at which resulting states are most influential and apparent. Understanding how local, self-organizing feedbacks operate within heterogeneous coastal environments is essential to forecasting marsh persistence and loss in response to sea level rise, river impoundment, and other environmental changes. Among the macroscale factors that might influence marsh extent are coastal and near-shore morphology that control tidal dynamics and marine sediment inputs (Ardhuin and others 2003 ; Stone and others 2005 ); upland sediment inputs that differ depending on watershed size, terrestrial geology, and land use within the watershed (Mattheus and others 2009 ; Kirwan and others 2011 ; Tweel and Turner 2012 ); and climate-driven variation in vegetation productivity and phenology (Pennings and Bertness 2001 ; Osland and others 2013 , 2014 ). Distribution and covariation of these geophysical factors across multiple spatial scales creates a template within which local marsh building occurs. Shape, size, and depth of estuaries<|im_end|> <|im_start|>assistant Sea-level rise, sediment starvation and other environmental woes pose increasing threats to coastal wetlands worldwide. But a massive new Duke University study could help stem these losses by giving scientists a broader understanding of which wetlands are most at risk, and why. The study, which assessed wetland distribution and resilience in hundreds of U.S. estuaries, found that it's all a matter of scale. "At the local level, the persistence or loss of coastal marshes was invariably linked to feedbacks between two factors: erosion, which eats away at marsh edges, and vegetation, which stabilizes them," said Anna E. Braswell, a Ph.D. graduate of Duke's Nicholas School of the Environment, who conducted the research as part of her 2017 dissertation. "But at broader spatial scales, other key drivers emerged, too." As the researchers took more of an estuary's surrounding geography into account, the depth, size, shape and latitude of the estuary became increasingly important predictors for determining the extent of wetlands it could support, Braswell said. The shape and orientation of the nearby coastline and the depth of near-shore waters mattered, too. And the amount of replenishing sediment being carried into the estuary by rivers or incoming tides became a key indicator of marshes' resilience to change. "These macro-scale coastal and watershed characteristics accentuated or limited the stabilizing impacts of the local feedbacks," she said. "But they weren't really evident until we took a few steps back and viewed the estuaries from broader spatial perspectives." "What this tells us is that salt marshes everywhere probably have tipping points," said co-author James B. Heffernan, assistant professor of ecosystem ecology and ecohydrology at the Nicholas School. Researcher Anna Braswell samples soil from an estuary during her dissertation research on 'tipping points' for wetland preservation. Credit: Megan Fork "Knowing what causes these tipping points to vary from location to location is an important step in identifying where we should expect marshes to be especially vulnerable to future change," he said. "It also provides a framework for understanding where wetland restoration is likely or not likely to succeed." Coastal salt marshes provide a long list of ecosystem services that benefit humans, including shoreline protection, pollution filtration, flood prevention, fishery habitat and carbon sequestration. Braswell and Heffernan published their peer-reviewed findings Jan. 31 in the journal Ecosystems. Using existing geospatial data, they analyzed hundreds of estuaries on the U.S. Atlantic and Gulf coasts from Maine to Mexico to determine the fraction of each estuary that was occupied by wetlands and identify the factors that controlled the extent of the wetlands' spread and their resilience to change. Each site was analyzed at five different geographic scales—from macro-analyses that covered the entire estuary and its adjacent coastline and watersheds, to fine-scale analyses that zeroed in on what was happening in small, individual tributaries. "Integrating data from five different scales allowed us to see patterns and linkages that we would have missed otherwise," said Braswell, who now works as a research scientist in the Earth Lab at the University of Colorado at Boulder. "This information will be vital for future preservation and restoration efforts." Braswell and Heffernan used data from the National Wetlands Inventory and other publicly accessible sources to do their analyses. The five spatial scales they used—sub-region, basin, sub-basin, watershed and sub-watershed—correspond to standard U.S. Geological Survey hydrological units. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Mechanical sources of nonlinear damping play a central role in modern physics, from solid-state physics to thermodynamics. The microscopic theory of mechanical dissipation suggests that nonlinear damping of a resonant mode can be strongly enhanced when it is coupled to a vibration mode that is close to twice its resonance frequency. To date, no experimental evidence of this enhancement has been realized. In this letter, we experimentally show that nanoresonators driven into parametric-direct internal resonance provide supporting evidence for the microscopic theory of nonlinear dissipation. By regulating the drive level, we tune the parametric resonance of a graphene nanodrum over a range of 40–70 MHz to reach successive two-to-one internal resonances, leading to a nearly two-fold increase of the nonlinear damping. Our study opens up a route towards utilizing modal interactions and parametric resonance to realize resonators with engineered nonlinear dissipation over wide frequency range. Introduction In nature, from macro- to nanoscale, dynamical systems evolve towards thermal equilibrium while exchanging energy with their surroundings. Dissipative mechanisms that mediate this equilibration convert energy from the dynamical system of interest to heat in an environmental bath. This process can be intricate, nonlinear, and in most cases hidden behind the veil of linear viscous damping, which is merely an approximation valid for small amplitude oscillations. In the last decade, nonlinear dissipation has attracted much attention with applications that span nanomechanics 1 , materials science 2 , biomechanics 3 , thermodynamics 4 , spintronics, 5 and quantum information 6 . It has been shown that the nonlinear dissipation process follows the empirical force model \${F}_{d}=-{\\tau }_{{\\rm{nl1}}}{x}^{2}\\dot{x}\$ where τ nl1 is the nonlinear damping coefficient, x is the displacement, and \$\\dot{x}\$ velocity. To date, the physical mechanism from which this empirical damping force originates has remained ambiguous, with a diverse range of phenomena being held responsible including viscoelasticity 7 , phonon–phonon interactions 8 , 9 , Akheizer relaxation 10 , and mode coupling 11 . The fact that nonlinear damping can stem from multiple origins simultaneously makes isolating one route from the others a daunting task, especially since the nonlinear damping coefficient τ nl1 is perceived to be a fixed parameter that unlike stiffness 12 , 13 , 14 , quality factor 15 , and nonlinear stiffness 16 , 17 , 18 , cannot be tuned easily. Amongst the different mechanisms that affect nonlinear damping, intermodal coupling is particularly interesting, as it can be enhanced near internal resonance (IR), a special condition at which the ratio of the resonance frequencies of the coupled modes is a rational number 19 . This phenomenon has frequently been observed in nano/micromechanical resonators 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 . At IR, modes can interact strongly even if their nonlinear coupling is relatively weak. Interestingly, IR is closely related to the effective stiffness of resonance modes, and can therefore be manipulated by careful engineering of the geometry of mechanical systems, their spring hardening nonlinearity 30 , 31 , and electrostatic spring softening 29 . IR also finds its route in the microscopic theory of dissipation proposed back in 1975, where it was hypothesized to lead to a significantly shorter relaxation time if there exists a resonance mode in the vicinity of twice the resonance frequency of the driven mode in the density of states 32 . Here, we demonstrate that nonlinear damping of graphene nanodrums can be strongly enhanced by parametric–direct IR, providing supporting evidence for the microscopic theory of nonlinear dissipation 10 , 32 . To achieve this, we bring the fundamental mode of the nanodrum into parametric resonance at twice its resonance frequency, allowing it to be tuned over a wide frequency range from 40 to 70 MHz. We extract the nonlinear damping as a function of the parametric drive level, and observe that it increases as much as 80% when the frequency shift of the parametric resonance brings it into IR with a higher mode. By comparing the characteristic dependence of the nonlinear damping coefficient on parametric drive to a theoretical model, we confirm that IR can be held accountable for the significant increase in nonlinear damping. Results Measurements Experiments are performed on a 10 nm thick multilayer graphene nanodrum with a diameter of 5 µm, which is transferred over a cavity etched in a layer of SiO 2 with a depth of 285 nm. A blue laser is used to thermomechanically actuate the membrane, where a red laser is being used to detect the motion, using interferometry (see “Methods” for details). A schematic of the setup is shown in Fig. 1 a. Fig. 1: Nonlinear dynamic response of a graphene nanodrum near 2:1 internal resonance. a Fabry–Pérot interferometry with thermomechanical actuation and microscope image of the graphene. Experiments are performed in vacuum at 10 −3 mbar. Red laser is used to detect the motion of the graphene drum and the blue laser is used to optothermally actuate it. BE beam expander, QWP quarter wave plate, PBS polarized beam splitter, PD photodiode, DM dichroic mirror, VNA vector network analyzer, \${{\\rm{V}}}_{a{c}_{in}}\$ analyzer port, \${{\\rm{V}}}_{{{\\rm{ac}}}_{{\\rm{out}}}}\$ excitation port. In the device schematic, Si and SiO 2 layers are represented by orange and blue colors, respectively. b Direct frequency response curve of the device (motion amplitude vs. drive frequency), showing multiple resonances (drive level = −12.6 dBm). The mode shapes are simulated by COMSOL. Resonance peaks are associated with \${f}_{m,n}^{(k)}\$ where m represents the number of nodal diameters, n nodal circles, and k = 1, 2 stand for the first and second asymmetric degenerate modes. Dashed line shows 2 f 0,1 , which is the drive frequency where the parametric resonance of mode f 0,1 is activated. c Parametric resonance curves (calibrated motion amplitude vs. drive frequency), driven at twice the detection frequency. As the parametric resonance curves approach the 2:1 internal resonance (IR), f SNB first locks to 2:1 IR frequency and consecutively saddle-node bifurcation surges to a higher frequency and amplitude. A SNB and", "role": "user" }, { "content": "Mechanical sources of dissipation play a key role in modern physics, with applications that span nanomechanics, biomechanics, materials science, and quantum computing. In clocks and other vibrating mechanisms, energy loss is usually proportional to the speed of the vibrating object. But in special circumstances, where one resonant frequency of the resonator is exactly twice as high as another resonant frequency, these losses suddenly become much greater, as additional energy is lost through the coupling between these modes of vibration. With support from the European Research Council (ERC), associate professor Farbod Alijani and Ata Keşkekler Ph.D. student in the department of precision and microsystems engineering at TU Delft, tuned the interaction between the vibrational states of a graphene nanodrum in such a way that one mode vibrates exactly twice as fast as another. In doing so, they also showed that with this mechanism it is possible to control the damping force via the coupling strength between the two vibration modes. Ata Keşkekler: \"Normally, the rate at which the sound of a guitar string decays is independent of how hard you pluck it. However, if we make an analogy between a nanoresonator and a guitar, in this work we find a mechanism which indicates that if you tune another string close to a note that is the first octave of the string that is played, the rate of decay becomes dependent on how hard you pluck it. The closer to the octave, the stronger is this dependency.\" As there have been few possibilities to influence the damping force in nanosystems until now, this research paves the way to exciting possibilities to better understand the origin of dissipation at the nanoscale and realize ultrasensitive controllable sensors. For this study, the researchers worked with colleagues from Ben Gurion University and the Kavli Institute of Nanoscience at TU Delft. This week, Nature communications published the results of this study. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Mechanical sources of nonlinear damping play a central role in modern physics, from solid-state physics to thermodynamics. The microscopic theory of mechanical dissipation suggests that nonlinear damping of a resonant mode can be strongly enhanced when it is coupled to a vibration mode that is close to twice its resonance frequency. To date, no experimental evidence of this enhancement has been realized. In this letter, we experimentally show that nanoresonators driven into parametric-direct internal resonance provide supporting evidence for the microscopic theory of nonlinear dissipation. By regulating the drive level, we tune the parametric resonance of a graphene nanodrum over a range of 40–70 MHz to reach successive two-to-one internal resonances, leading to a nearly two-fold increase of the nonlinear damping. Our study opens up a route towards utilizing modal interactions and parametric resonance to realize resonators with engineered nonlinear dissipation over wide frequency range. Introduction In nature, from macro- to nanoscale, dynamical systems evolve towards thermal equilibrium while exchanging energy with their surroundings. Dissipative mechanisms that mediate this equilibration convert energy from the dynamical system of interest to heat in an environmental bath. This process can be intricate, nonlinear, and in most cases hidden behind the veil of linear viscous damping, which is merely an approximation valid for small amplitude oscillations. In the last decade, nonlinear dissipation has attracted much attention with applications that span nanomechanics 1 , materials science 2 , biomechanics 3 , thermodynamics 4 , spintronics, 5 and quantum information 6 . It has been shown that the nonlinear dissipation process follows the empirical force model ${F}_{d}=-{\tau }_{{\rm{nl1}}}{x}^{2}\dot{x}$ where τ nl1 is the nonlinear damping coefficient, x is the displacement, and $\dot{x}$ velocity. To date, the physical mechanism from which this empirical damping force originates has remained ambiguous, with a diverse range of phenomena being held responsible including viscoelasticity 7 , phonon–phonon interactions 8 , 9 , Akheizer relaxation 10 , and mode coupling 11 . The fact that nonlinear damping can stem from multiple origins simultaneously makes isolating one route from the others a daunting task, especially since the nonlinear damping coefficient τ nl1 is perceived to be a fixed parameter that unlike stiffness 12 , 13 , 14 , quality factor 15 , and nonlinear stiffness 16 , 17 , 18 , cannot be tuned easily. Amongst the different mechanisms that affect nonlinear damping, intermodal coupling is particularly interesting, as it can be enhanced near internal resonance (IR), a special condition at which the ratio of the resonance frequencies of the coupled modes is a rational number 19 . This phenomenon has frequently been observed in nano/micromechanical resonators 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 . At IR, modes can interact strongly even if their nonlinear coupling is relatively weak. Interestingly, IR is closely related to the effective stiffness of resonance modes, and can therefore be manipulated by careful engineering of the geometry of mechanical systems, their spring hardening nonlinearity 30 , 31 , and electrostatic spring softening 29 . IR also finds its route in the microscopic theory of dissipation proposed back in 1975, where it was hypothesized to lead to a significantly shorter relaxation time if there exists a resonance mode in the vicinity of twice the resonance frequency of the driven mode in the density of states 32 . Here, we demonstrate that nonlinear damping of graphene nanodrums can be strongly enhanced by parametric–direct IR, providing supporting evidence for the microscopic theory of nonlinear dissipation 10 , 32 . To achieve this, we bring the fundamental mode of the nanodrum into parametric resonance at twice its resonance frequency, allowing it to be tuned over a wide frequency range from 40 to 70 MHz. We extract the nonlinear damping as a function of the parametric drive level, and observe that it increases as much as 80% when the frequency shift of the parametric resonance brings it into IR with a higher mode. By comparing the characteristic dependence of the nonlinear damping coefficient on parametric drive to a theoretical model, we confirm that IR can be held accountable for the significant increase in nonlinear damping. Results Measurements Experiments are performed on a 10 nm thick multilayer graphene nanodrum with a diameter of 5 µm, which is transferred over a cavity etched in a layer of SiO 2 with a depth of 285 nm. A blue laser is used to thermomechanically actuate the membrane, where a red laser is being used to detect the motion, using interferometry (see “Methods” for details). A schematic of the setup is shown in Fig. 1 a. Fig. 1: Nonlinear dynamic response of a graphene nanodrum near 2:1 internal resonance. a Fabry–Pérot interferometry with thermomechanical actuation and microscope image of the graphene. Experiments are performed in vacuum at 10 −3 mbar. Red laser is used to detect the motion of the graphene drum and the blue laser is used to optothermally actuate it. BE beam expander, QWP quarter wave plate, PBS polarized beam splitter, PD photodiode, DM dichroic mirror, VNA vector network analyzer, ${{\rm{V}}}_{a{c}_{in}}$ analyzer port, ${{\rm{V}}}_{{{\rm{ac}}}_{{\rm{out}}}}$ excitation port. In the device schematic, Si and SiO 2 layers are represented by orange and blue colors, respectively. b Direct frequency response curve of the device (motion amplitude vs. drive frequency), showing multiple resonances (drive level = −12.6 dBm). The mode shapes are simulated by COMSOL. Resonance peaks are associated with ${f}_{m,n}^{(k)}$ where m represents the number of nodal diameters, n nodal circles, and k = 1, 2 stand for the first and second asymmetric degenerate modes. Dashed line shows 2 f 0,1 , which is the drive frequency where the parametric resonance of mode f 0,1 is activated. c Parametric resonance curves (calibrated motion amplitude vs. drive frequency), driven at twice the detection frequency. As the parametric resonance curves approach the 2:1 internal resonance (IR), f SNB first locks to 2:1 IR frequency and consecutively saddle-node bifurcation surges to a higher frequency and amplitude. A SNB and<|im_end|> <|im_start|>assistant Mechanical sources of dissipation play a key role in modern physics, with applications that span nanomechanics, biomechanics, materials science, and quantum computing. In clocks and other vibrating mechanisms, energy loss is usually proportional to the speed of the vibrating object. But in special circumstances, where one resonant frequency of the resonator is exactly twice as high as another resonant frequency, these losses suddenly become much greater, as additional energy is lost through the coupling between these modes of vibration. With support from the European Research Council (ERC), associate professor Farbod Alijani and Ata Keşkekler Ph.D. student in the department of precision and microsystems engineering at TU Delft, tuned the interaction between the vibrational states of a graphene nanodrum in such a way that one mode vibrates exactly twice as fast as another. In doing so, they also showed that with this mechanism it is possible to control the damping force via the coupling strength between the two vibration modes. Ata Keşkekler: "Normally, the rate at which the sound of a guitar string decays is independent of how hard you pluck it. However, if we make an analogy between a nanoresonator and a guitar, in this work we find a mechanism which indicates that if you tune another string close to a note that is the first octave of the string that is played, the rate of decay becomes dependent on how hard you pluck it. The closer to the octave, the stronger is this dependency." As there have been few possibilities to influence the damping force in nanosystems until now, this research paves the way to exciting possibilities to better understand the origin of dissipation at the nanoscale and realize ultrasensitive controllable sensors. For this study, the researchers worked with colleagues from Ben Gurion University and the Kavli Institute of Nanoscience at TU Delft. This week, Nature communications published the results of this study. <|im_end|>

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311, 10383, 279, 84614, 5457, 304, 20622, 437, 95890, 3156, 1457, 11, 420, 3495, 281, 4798, 279, 1648, 311, 13548, 24525, 311, 2731, 3619, 279, 6371, 315, 14091, 49686, 520, 279, 20622, 437, 2296, 323, 13383, 8725, 13811, 19245, 687, 69855, 26148, 13, 1789, 420, 4007, 11, 279, 12074, 6575, 449, 18105, 505, 7505, 62033, 290, 3907, 323, 279, 735, 402, 747, 10181, 315, 33242, 24366, 1873, 520, 70514, 423, 491, 83, 13, 1115, 2046, 11, 22037, 17320, 4756, 279, 3135, 315, 420, 4007, 13, 220, 128257, 198 ]

1,833

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Peatlands are crucial sinks for atmospheric carbon but are critically threatened due to warming climates. Sphagnum (peat moss) species are keystone members of peatland communities where they actively engineer hyperacidic conditions, which improves their competitive advantage and accelerates ecosystem-level carbon sequestration. To dissect the molecular and physiological sources of this unique biology, we generated chromosome-scale genomes of two Sphagnum species: S. divinum and S. angustifolium . Sphagnum genomes show no gene colinearity with any other reference genome to date, demonstrating that Sphagnum represents an unsampled lineage of land plant evolution. The genomes also revealed an average recombination rate an order of magnitude higher than vascular land plants and short putative U/V sex chromosomes. These newly described sex chromosomes interact with autosomal loci that significantly impact growth across diverse pH conditions. This discovery demonstrates that the ability of Sphagnum to sequester carbon in acidic peat bogs is mediated by interactions between sex, autosomes and environment. Main Sphagnum (peat moss) is both an individual genus and an entire ecosystem. Sphagnum -dominated peatlands are estimated to cover ~3–5% of the Northern Hemisphere boreal zone, yet store ~30% of the total global terrestrial carbon pool 1 . Sphagnum grows most abundantly in bogs and fens, where they engineer peatland habitats through acidification (via cation exchange for nutrient uptake) and depletion of oxygen to promote their own persistence and dominance 2 . Within bogs, Sphagnum species display niche preferences, growing at different heights above the water table (‘hummock’ mounds and ‘hollow’ valleys) and pH levels. This community microtopography is characteristic of Sphagnum -dominated peatlands where species habitat is phylogenetically conserved such that closely related species occupy similar niches 3 , 4 which correlates with differences in growth, carbon sequestration and tissue decomposability. For these well-documented niche differences among species, Sphagnum and their bogs have long served as a model for studies of community assembly, stress physiology and carbon sequestration 5 , 6 ; efforts which have recently been bolstered by ecological genomics and biogeochemical experimental innovations 7 . In addition to species genetic differentiation, Sphagnum community assembly and within-species trait variation appear to be controlled in part by sex-ratio biases, where sexes are differentially adapted to local environments 8 . Sex, in haploid-dominant life-cycle bryophytes that have been examined, is determined by U/V (U, female; V, male) sex chromosomes that segregate 1:1 among spores during meiosis 9 . However, the mechanism for sex determination in Sphagnum has not yet been elucidated. While a balanced sex ratio is expected within any bryophyte habitat, skewed ratios are often observed (evidenced by either phenotypic or genotypic observations) 10 , particularly within stressful environments. These biases have important implications on effective population sizes and in extreme cases could result in population collapse 11 , 12 . Given that bryophyte sex ratios are influenced by extreme environments and Sphagnum engineers harsh, unfavourable conditions within bogs, Sphagnum comparative genomics provides a unique opportunity to investigate the underlying genetic components of bryophyte sex-determination and sex-ratio bias. To facilitate genetic analysis of carbon sequestration and stress responses in peatlands and understand how Sphagnum responds to environmental stress (both native and self-generated), we developed the first chromosome-scale, de novo genome assemblies for S. angustifolium (subgenus Cuspidata ) and S. divinum (subgenus Sphagnum ). Genome sequencing and genetic map construction enabled the discovery of a minuscule (~5 megabase (Mb)) sex chromosome (chr. 20; V chromosome) that is one-quarter the size of other chromosomes, shares conserved gene order (synteny) with autosome chr. 7 and is derived from ancient whole-genome rearrangements. To study how Sphagnum contends with abiotic stress encountered in peat bogs, reference genotypes were exposed to laboratory-simulated pH stress, finding that species endemic to hummock and hollow niches differentially respond to alkalinity and acidity through hormone expression and plasmodesmata-mediated cell transport. Investigation of the effect of pH stress on Sphagnum physiology in our F 1 -haploid pedigree population found that quantitative trait loci (QTLs) that impacted growth were dependent on U/V chromosome inheritance, providing a direct link between peatland environmental conditions, carbon sequestration and sex-ratio biases that are commonly observed in bryophytes. Results Sphagnum represents an uncharacterized lineage of plants Peat accumulation within bogs is primarily linked to growth, biomass deposition and low rates of decomposition. These traits, as well as niche and pH preferences among Sphagnum species are phylogenetically conserved. While tremendous variation exists across the five Sphagnum subgenera 13 based on previously explored phylogenetic relationships and niche evolution 3 , 14 , for reference genome sequencing we selected two haploid genotypes, one from the ancestral hummock clade: subgenus Sphagnum ( S. divinum ; recently reclassified within the S. magellanicum species complex 15 ) and the other from ancestral hollow clade: subgenus Cuspidata ( S. angustifolium ; previously S. fallax —misclassified at the time of collection; genotyped using marker data from ref. 16 ). Although Sphagnum diverged from other mosses millions of years ago (Ma), within the genus these references represent diverged lineages which diversified during the Miocene (7–20 Ma; ref. 17 ) and contain a large swath of Sphagnum functional ecological variation. Both were sequenced to ~70× consensus long read (CLR) PacBio coverage and assembled into highly contiguous chromosome sequences (Supplementary Table 1 ): the S. divinum and S. angustifolium genome assemblies were 439 Mb (contig N50: 17.5 Mb) and 395 Mb (contig N50: 17.4 Mb) in size, respectively. This is consistent with k -mer based genome size estimates for each reference of 424 and 367 Mb, respectively. Chromosomes were scaffolded for S. angustifolium from a high-density genetic map consisting of 2,990 genetic markers in 20 linkage groups (chromosomes 1–20). Gene content, order and orientation were then projected onto the S. divinum assembly to separately order contigs into 20 chromosomes. Each genome was also annotated with a combination of RNA-seq evidence-based and ab initio gene models, finding 25,227 primary gene models in S. divinum and 25,100 in S. angustifolium . Comparison of chromosomes between S. divinium and S. angustifolium showed that, despite their divergence, high collinearity between genomes is maintained (Fig. 1a", "role": "user" }, { "content": "A quest to understand how Sphagnum mosses facilitate the storage of vast amounts of carbon in peatlands led scientists to a surprising discovery: The plants have sex-based differences that appear to impact the carbon-storing process. The insight can help researchers better understand how the mosses tolerate stressful environments, including those of a warming climate. The research team co-led by the Department of Energy's Oak Ridge National Laboratory sequenced the genome of two key species of Sphagnum, the mossy plants that dominate peatlands and store about one-third of the world's soil carbon despite covering just 3%–5% of Earth's land surface. Sphagnum mosses are known as the chief engineer of long-term carbon storage in peat, helping keep the bogs wet, acidifying the environment and slowing down plant decay, which in turn retains carbon in the soil. Sphagnum, living and dead, likely store more carbon than any other genus of plant. These unique, soggy peat bogs are under threat, however, from rising temperatures that could dry them and hamper their ability to absorb and retain carbon. In fact, research at the DOE Spruce and Peatland Responses Under Changing Environments, or SPRUCE, whole-ecosystem manipulation experiment in northern Minnesota has revealed that warming conditions result in peat bogs turning from carbon accumulators into carbon emitters. To better comprehend the genetics at play in peat carbon cycling, scientists at ORNL teamed with researchers from the HudsonAlpha Institute for Biotechnology; the DOE Joint Genome Institute, or JGI, a DOE Office of Science user facility at Lawrence Berkeley National Laboratory; Duke University and others to sequence the complete genome of two Sphagnum species—S. divinum and S. angustifolium—present at the SPRUCE site. ORNL scientists also created a pedigree population of the mosses to link genes with Sphagnum traits. The research revealed tiny chromosomes that determine whether the plant is male or female. Scientists also found that these sex-determining chromosomes interact with other chromosomes to regulate plant responses to stress. The result, as described in Nature Plants, is important not just to the mosses' survival, but to their role in accumulating and holding carbon over time. \"We know that the climate is changing, and it's changing rapidly at high latitudes,\" said Bryan Piatkowski, an evolutionary biologist and distinguished staff fellow at ORNL who began working on the project in 2018 at Duke. \"Basically, the growth rate of these Sphagnum species is influenced by both plant genotype and the environment in a manner that depends on the sex of the plant.\" The discovery could lead to scientific solutions to help Sphagnum survive a changing climate. \"These genomes are coming from the plants that are largely responsible for storing carbon in these ecosystems,\" Piatkowski said. \"Knowledge of their genetics can provide us with insights to help peatlands continue being the carbon sinks they have been for thousands of years, instead of net sources of greenhouse gases like carbon dioxide and methane as the climate warms.\" \"The presence of the sex chromosome together with interactions with non-sex chromosomes and environmental conditions influence the plant's ability to survive and adapt to harsh conditions,\" said Dave Weston, a molecular plant biologist who led ORNL's efforts. \"Understanding those contributions to Sphagnum survival and reproduction will be super important in understanding how resilient this ecosystem is to changing climatic conditions, which cascades to their ability to sequester carbon for long-term storage.\" The research is a good example of linking genes to ecosystem function and emphasizing the importance of ecological genomics in advancing biology questions, Weston said. Piatkowski said the pedigree analysis on the moss species enables new insights into how Sphagnum relates to symbiotic microbes—how relationships with bacteria, for instance, might help plants survive under warmer scenarios in the future. \"The genetic resources developed as part of this project are now allowing our team to investigate the benefits of the plant microbiome under stress at the molecular level. It's an exciting area of research not possible without these genomes.\" The sequencing work and much of the comparative genomics and quantitative genetics was led by HudsonAlpha and JGI, while Duke focused on plant taxonomy, population genetics and plant collections. ORNL conducted the experimentation, performed analysis of the mosses' evolutionary history, collected plant material, performed nucleotide extractions for genome sequencing and developed the pedigree populations that enabled gene-to-trait linkages. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Peatlands are crucial sinks for atmospheric carbon but are critically threatened due to warming climates. Sphagnum (peat moss) species are keystone members of peatland communities where they actively engineer hyperacidic conditions, which improves their competitive advantage and accelerates ecosystem-level carbon sequestration. To dissect the molecular and physiological sources of this unique biology, we generated chromosome-scale genomes of two Sphagnum species: S. divinum and S. angustifolium . Sphagnum genomes show no gene colinearity with any other reference genome to date, demonstrating that Sphagnum represents an unsampled lineage of land plant evolution. The genomes also revealed an average recombination rate an order of magnitude higher than vascular land plants and short putative U/V sex chromosomes. These newly described sex chromosomes interact with autosomal loci that significantly impact growth across diverse pH conditions. This discovery demonstrates that the ability of Sphagnum to sequester carbon in acidic peat bogs is mediated by interactions between sex, autosomes and environment. Main Sphagnum (peat moss) is both an individual genus and an entire ecosystem. Sphagnum -dominated peatlands are estimated to cover ~3–5% of the Northern Hemisphere boreal zone, yet store ~30% of the total global terrestrial carbon pool 1 . Sphagnum grows most abundantly in bogs and fens, where they engineer peatland habitats through acidification (via cation exchange for nutrient uptake) and depletion of oxygen to promote their own persistence and dominance 2 . Within bogs, Sphagnum species display niche preferences, growing at different heights above the water table (‘hummock’ mounds and ‘hollow’ valleys) and pH levels. This community microtopography is characteristic of Sphagnum -dominated peatlands where species habitat is phylogenetically conserved such that closely related species occupy similar niches 3 , 4 which correlates with differences in growth, carbon sequestration and tissue decomposability. For these well-documented niche differences among species, Sphagnum and their bogs have long served as a model for studies of community assembly, stress physiology and carbon sequestration 5 , 6 ; efforts which have recently been bolstered by ecological genomics and biogeochemical experimental innovations 7 . In addition to species genetic differentiation, Sphagnum community assembly and within-species trait variation appear to be controlled in part by sex-ratio biases, where sexes are differentially adapted to local environments 8 . Sex, in haploid-dominant life-cycle bryophytes that have been examined, is determined by U/V (U, female; V, male) sex chromosomes that segregate 1:1 among spores during meiosis 9 . However, the mechanism for sex determination in Sphagnum has not yet been elucidated. While a balanced sex ratio is expected within any bryophyte habitat, skewed ratios are often observed (evidenced by either phenotypic or genotypic observations) 10 , particularly within stressful environments. These biases have important implications on effective population sizes and in extreme cases could result in population collapse 11 , 12 . Given that bryophyte sex ratios are influenced by extreme environments and Sphagnum engineers harsh, unfavourable conditions within bogs, Sphagnum comparative genomics provides a unique opportunity to investigate the underlying genetic components of bryophyte sex-determination and sex-ratio bias. To facilitate genetic analysis of carbon sequestration and stress responses in peatlands and understand how Sphagnum responds to environmental stress (both native and self-generated), we developed the first chromosome-scale, de novo genome assemblies for S. angustifolium (subgenus Cuspidata ) and S. divinum (subgenus Sphagnum ). Genome sequencing and genetic map construction enabled the discovery of a minuscule (~5 megabase (Mb)) sex chromosome (chr. 20; V chromosome) that is one-quarter the size of other chromosomes, shares conserved gene order (synteny) with autosome chr. 7 and is derived from ancient whole-genome rearrangements. To study how Sphagnum contends with abiotic stress encountered in peat bogs, reference genotypes were exposed to laboratory-simulated pH stress, finding that species endemic to hummock and hollow niches differentially respond to alkalinity and acidity through hormone expression and plasmodesmata-mediated cell transport. Investigation of the effect of pH stress on Sphagnum physiology in our F 1 -haploid pedigree population found that quantitative trait loci (QTLs) that impacted growth were dependent on U/V chromosome inheritance, providing a direct link between peatland environmental conditions, carbon sequestration and sex-ratio biases that are commonly observed in bryophytes. Results Sphagnum represents an uncharacterized lineage of plants Peat accumulation within bogs is primarily linked to growth, biomass deposition and low rates of decomposition. These traits, as well as niche and pH preferences among Sphagnum species are phylogenetically conserved. While tremendous variation exists across the five Sphagnum subgenera 13 based on previously explored phylogenetic relationships and niche evolution 3 , 14 , for reference genome sequencing we selected two haploid genotypes, one from the ancestral hummock clade: subgenus Sphagnum ( S. divinum ; recently reclassified within the S. magellanicum species complex 15 ) and the other from ancestral hollow clade: subgenus Cuspidata ( S. angustifolium ; previously S. fallax —misclassified at the time of collection; genotyped using marker data from ref. 16 ). Although Sphagnum diverged from other mosses millions of years ago (Ma), within the genus these references represent diverged lineages which diversified during the Miocene (7–20 Ma; ref. 17 ) and contain a large swath of Sphagnum functional ecological variation. Both were sequenced to ~70× consensus long read (CLR) PacBio coverage and assembled into highly contiguous chromosome sequences (Supplementary Table 1 ): the S. divinum and S. angustifolium genome assemblies were 439 Mb (contig N50: 17.5 Mb) and 395 Mb (contig N50: 17.4 Mb) in size, respectively. This is consistent with k -mer based genome size estimates for each reference of 424 and 367 Mb, respectively. Chromosomes were scaffolded for S. angustifolium from a high-density genetic map consisting of 2,990 genetic markers in 20 linkage groups (chromosomes 1–20). Gene content, order and orientation were then projected onto the S. divinum assembly to separately order contigs into 20 chromosomes. Each genome was also annotated with a combination of RNA-seq evidence-based and ab initio gene models, finding 25,227 primary gene models in S. divinum and 25,100 in S. angustifolium . Comparison of chromosomes between S. divinium and S. angustifolium showed that, despite their divergence, high collinearity between genomes is maintained (Fig. 1a<|im_end|> <|im_start|>assistant A quest to understand how Sphagnum mosses facilitate the storage of vast amounts of carbon in peatlands led scientists to a surprising discovery: The plants have sex-based differences that appear to impact the carbon-storing process. The insight can help researchers better understand how the mosses tolerate stressful environments, including those of a warming climate. The research team co-led by the Department of Energy's Oak Ridge National Laboratory sequenced the genome of two key species of Sphagnum, the mossy plants that dominate peatlands and store about one-third of the world's soil carbon despite covering just 3%–5% of Earth's land surface. Sphagnum mosses are known as the chief engineer of long-term carbon storage in peat, helping keep the bogs wet, acidifying the environment and slowing down plant decay, which in turn retains carbon in the soil. Sphagnum, living and dead, likely store more carbon than any other genus of plant. These unique, soggy peat bogs are under threat, however, from rising temperatures that could dry them and hamper their ability to absorb and retain carbon. In fact, research at the DOE Spruce and Peatland Responses Under Changing Environments, or SPRUCE, whole-ecosystem manipulation experiment in northern Minnesota has revealed that warming conditions result in peat bogs turning from carbon accumulators into carbon emitters. To better comprehend the genetics at play in peat carbon cycling, scientists at ORNL teamed with researchers from the HudsonAlpha Institute for Biotechnology; the DOE Joint Genome Institute, or JGI, a DOE Office of Science user facility at Lawrence Berkeley National Laboratory; Duke University and others to sequence the complete genome of two Sphagnum species—S. divinum and S. angustifolium—present at the SPRUCE site. ORNL scientists also created a pedigree population of the mosses to link genes with Sphagnum traits. The research revealed tiny chromosomes that determine whether the plant is male or female. Scientists also found that these sex-determining chromosomes interact with other chromosomes to regulate plant responses to stress. The result, as described in Nature Plants, is important not just to the mosses' survival, but to their role in accumulating and holding carbon over time. "We know that the climate is changing, and it's changing rapidly at high latitudes," said Bryan Piatkowski, an evolutionary biologist and distinguished staff fellow at ORNL who began working on the project in 2018 at Duke. "Basically, the growth rate of these Sphagnum species is influenced by both plant genotype and the environment in a manner that depends on the sex of the plant." The discovery could lead to scientific solutions to help Sphagnum survive a changing climate. "These genomes are coming from the plants that are largely responsible for storing carbon in these ecosystems," Piatkowski said. "Knowledge of their genetics can provide us with insights to help peatlands continue being the carbon sinks they have been for thousands of years, instead of net sources of greenhouse gases like carbon dioxide and methane as the climate warms." "The presence of the sex chromosome together with interactions with non-sex chromosomes and environmental conditions influence the plant's ability to survive and adapt to harsh conditions," said Dave Weston, a molecular plant biologist who led ORNL's efforts. "Understanding those contributions to Sphagnum survival and reproduction will be super important in understanding how resilient this ecosystem is to changing climatic conditions, which cascades to their ability to sequester carbon for long-term storage." The research is a good example of linking genes to ecosystem function and emphasizing the importance of ecological genomics in advancing biology questions, Weston said. Piatkowski said the pedigree analysis on the moss species enables new insights into how Sphagnum relates to symbiotic microbes—how relationships with bacteria, for instance, might help plants survive under warmer scenarios in the future. "The genetic resources developed as part of this project are now allowing our team to investigate the benefits of the plant microbiome under stress at the molecular level. It's an exciting area of research not possible without these genomes." The sequencing work and much of the comparative genomics and quantitative genetics was led by HudsonAlpha and JGI, while Duke focused on plant taxonomy, population genetics and plant collections. ORNL conducted the experimentation, performed analysis of the mosses' evolutionary history, collected plant material, performed nucleotide extractions for genome sequencing and developed the pedigree populations that enabled gene-to-trait linkages. <|im_end|>

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764, 351, 2470, 11105, 459, 653, 19740, 1534, 65009, 315, 11012, 5250, 266, 46835, 2949, 293, 27403, 374, 15871, 10815, 311, 6650, 11, 58758, 65374, 323, 3428, 7969, 315, 66266, 13, 4314, 25022, 11, 439, 1664, 439, 35149, 323, 37143, 19882, 4315, 328, 764, 351, 2470, 9606, 527, 37555, 86945, 37774, 1615, 2841, 13, 6104, 28040, 23851, 6866, 4028, 279, 4330, 328, 764, 351, 2470, 1207, 7642, 64, 220, 1032, 3196, 389, 8767, 36131, 37555, 86945, 5411, 12135, 323, 35149, 15740, 220, 18, 1174, 220, 975, 1174, 369, 5905, 33869, 62119, 584, 4183, 1403, 46900, 52196, 4173, 22583, 11, 832, 505, 279, 78771, 2854, 17127, 1206, 1037, 25, 1207, 106842, 328, 764, 351, 2470, 320, 328, 13, 3512, 258, 372, 2652, 6051, 312, 65974, 2949, 279, 328, 13, 4983, 616, 32370, 372, 9606, 6485, 220, 868, 883, 323, 279, 1023, 505, 78771, 42902, 1206, 1037, 25, 1207, 106842, 356, 355, 10629, 460, 320, 328, 13, 6590, 592, 333, 337, 2411, 2652, 8767, 328, 13, 4498, 710, 2001, 34965, 65974, 520, 279, 892, 315, 4526, 26, 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11, 15947, 13, 35318, 58375, 1051, 85552, 291, 369, 328, 13, 6590, 592, 333, 337, 2411, 505, 264, 1579, 89131, 19465, 2472, 31706, 315, 220, 17, 11, 19146, 19465, 24915, 304, 220, 508, 72541, 5315, 320, 41484, 58375, 220, 16, 4235, 508, 570, 24983, 2262, 11, 2015, 323, 17140, 1051, 1243, 28448, 8800, 279, 328, 13, 3512, 258, 372, 14956, 311, 26214, 2015, 687, 14801, 1139, 220, 508, 83181, 13, 9062, 33869, 574, 1101, 63951, 449, 264, 10824, 315, 41214, 7962, 80, 6029, 6108, 323, 671, 3003, 822, 15207, 4211, 11, 9455, 220, 914, 11, 14206, 6156, 15207, 4211, 304, 328, 13, 3512, 258, 372, 323, 220, 914, 11, 1041, 304, 328, 13, 6590, 592, 333, 337, 2411, 662, 43551, 315, 83181, 1990, 328, 13, 3512, 64990, 323, 328, 13, 6590, 592, 333, 337, 2411, 8710, 430, 11, 8994, 872, 82258, 11, 1579, 4631, 483, 10981, 1990, 85381, 374, 18908, 320, 30035, 13, 220, 16, 64, 128257, 198, 128256, 78191, 198, 32, 2271, 311, 3619, 1268, 328, 764, 351, 2470, 78343, 288, 28696, 279, 5942, 315, 13057, 15055, 315, 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2,481

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In band-like semiconductors, charge carriers form a thermal energy distribution rapidly after optical excitation. In hybrid perovskites, the cooling of such thermal carrier distributions occurs on timescales of about 300 fs via carrier-phonon scattering. However, the initial build-up of the thermal distribution proved difficult to resolve with pump–probe techniques due to the requirement of high resolution, both in time and pump energy. Here, we use two-dimensional electronic spectroscopy with sub-10 fs resolution to directly observe the carrier interactions that lead to a thermal carrier distribution. We find that thermalization occurs dominantly via carrier-carrier scattering under the investigated fluences and report the dependence of carrier scattering rates on excess energy and carrier density. We extract characteristic carrier thermalization times from below 10 to 85 fs. These values allow for mobilities of 500 cm 2 V −1 s −1 at carrier densities lower than 2 × 10 19 cm −3 and limit the time for carrier extraction in hot carrier solar cells. Introduction Hybrid perovskite semiconductors have attracted strong scientific interest for optoelectronic applications. Simple and low-cost solution-based fabrication techniques can be used to obtain poly-crystalline thin films 1 , 2 , 3 , as well as single crystals 4 and colloidal nanostructures 5 . Reports on sharp absorption onsets, long carrier lifetimes and high photoluminescence quantum efficiencies 4 , 6 , 7 , 8 , 9 , 10 , 11 highlight the semiconducting quality of these materials. Despite the current drive for higher optoelectronic device efficiencies and stabilities, little information exists about the fundamental non-equilibrium interactions of photo-excited charge carriers in these semiconductors, which define, for example, the fundamental limits of charge transport. Photo-excitation of a semiconductor with free band continuum states leads to an electron population in the conduction band. Initially, the excitations are in a superposition of ground and excited states. Over the dephasing time these coherences are lost and a pure population is left. However, after light absorption this carrier population is not in thermodynamic equilibrium immediately, as the energy of the excited carriers matches that of the absorbed light. The spectrum of the excitation pulse and the selection rules of the semiconductor determine the initial energetic distribution of the carrier population, which can lead to the observation of a “spectral hole” in the absorption spectrum for narrowband excitation 12 , 13 . Ultrafast scattering processes, such as carrier-carrier or carrier-optical-phonon scattering, lead to a broadening of the energetic distribution of the carrier population 14 , 15 , 16 , which can eventually be described by an equilibrium carrier temperature higher than the lattice temperature. This process of exchange of energy among charge carriers is called thermalization. Subsequently, a cooling of the carriers occurs through carrier-phonon and carrier-impurity scattering processes, bringing the carriers and lattice to thermodynamic equilibrium 14 . The carrier thermalization and cooling processes after light absorption depend on the properties of the excited charge carriers and the band structure of the semiconductor. In optoelectronic applications, the carrier scattering rates determine the fundamental limits of carrier transport and electronic coherence. For the prototypical semiconductor GaAs, studies of thermalization dynamics reported timescales ranging from 100 fs to 4 ps 12 , 15 , 17 , and provided insights into dephasing times 12 , band structure 15 and carrier-carrier scattering processes 18 , which affect subsequent carrier cooling and recombination processes. In hybrid perovskites, ultrafast transient absorption spectroscopy has been used to study the carrier cooling process, which was found to occur on 100 s of femtoseconds timescales 19 , 20 , 21 , 22 , with a strong contribution from a hot phonon effect at high fluences 23 . The thermalization process, on the other hand, has not yet been experimentally resolved and is expected to occur on much faster timescales 14 , 15 , 16 . To resolve ultrafast thermalization dynamics, the time evolution of the time-dependent energy distribution of an initial population excited at a well-defined energy needs to be tracked 24 . The necessary femtosecond time resolution requires the use of ultrashort, broadband light pulses, which compromises the desired high resolution in excitation energy. Two-dimensional electronic spectroscopy (2DES) is an extension of traditional transient absorption techniques that achieves both conditions simultaneously 25 by using a Fourier transform (FT) approach. In 2DES, two pump pulses are used instead of one, with the time delay between them (labeled t 1 ) being scanned with interferometric precision for a fixed delay between the second pump and the probe (the waiting time, labeled t 2 ). Taking the FT of the nonlinear optical signal over t 1 provides the excitation frequency axis, with a resolution that is only limited by the t 1 scanning range. Here, we report 2DES experiments on lead-iodide hybrid perovskites using thin films of the prototypical material CH 3 NH 3 PbI 3 . We extract thermalization time constants in the range of below 10–85 fs, depending on carrier density and excess energy and find that the main thermalization process is carrier-carrier scattering. Results Pump–probe experiment with sub-10 fs pulses We prepare thin films of CH 3 NH 3 PbI 3 on 170 μm thick glass substrates. Figure 1a shows the absorption spectrum of the samples with a bandgap around 760 nm (1.63 eV), which contains contributions from an excitonic transition near the bandgap and free carrier absorption towards shorter wavelengths 26 . Fig. 1 Pump–probe spectroscopy of lead iodide perovskite. a Absorption spectrum of lead iodide perovskite and broadband laser spectrum used for the degenerate pump–probe and 2D electronic spectroscopy (2DES) experiments. The pump spectrum overlaps with the free band continuum as well as the excitonic transition of perovskite. b Pump–probe spectroscopy of perovskite: Δ T / T spectrum as a function of probe wavelength and pump–probe delay (excitation density: 2 × 10 18 cm −3 ). The broadband nature of the short pump pulses makes the observation of a non-thermalized distribution and thermalization difficult in pump–probe experiments. Inset: Pump–probe dynamics at 745 nm probe wavelength. The signal rises over two distinct", "role": "user" }, { "content": "Researchers have quantified the astonishingly high speeds at which future solar cells would have to operate in order to stretch what are presently seen as natural limits on their energy conversion efficiency. The study, which investigated photovoltaic devices based on a type of materials called perovskites, suggests that these could achieve unprecedented levels of super-efficiency. But to do so, they will need to turn sunlight into electrons and then extract these as electrical charge within just quadrillionths of a second – a few \"femtoseconds\", to give them their scientific name. Moving electrons at this ultrafast rate would enable the creation of \"hot carrier\" cells. These are solar cells which can generate electricity more efficiently by making use of the added kinetic energy that electrons have for a brief moment just after they are created, while they are moving at high speed. The amount of electrical energy that can be extracted from a hot carrier cell, relative to the amount of light absorbed, could potentially match or even break an energy efficiency rate of 30%. In rough terms, this is the maximum energy efficiency that solar cells can conceivably achieve – although standard silicon cells typically have efficiencies closer to 20% in practice. Despite the minuscule fractions of time involved, the authors of the new paper say that it is possible that perovskites could ultimately push this efficiency barrier. The study, published in the journal Nature Communications, was carried out by academics in Italy and the UK. The British team involved researchers in the Cavendish Laboratory's Optoelectronics research group of Professor Sir Richard Friend, a Fellow of St John's College, Cambridge. The Italian team are based at the Politecnico di Milano in the group of Professor Guilio Cerullo. Johannes Richter, a PhD student in the Optoelectronics group and the paper's lead author, said: \"The timescale that we calculated is now the time limit that we have to operate within if we want to create super-efficient, hot carrier solar devices. We would need to get electrons out before this tiny amount of time elapses.\" \"We are talking about doing this extremely quickly, but it's not impossible that it could happen. Perovskite cells are very thin and this gives us hope, because the distance that the electrons have to cover is therefore very short.\" Perovskites are a class of materials which could before long replace silicon as the material of choice for many photovoltaic devices. Although perovskite solar cells have only been developed within the past few years, they are already almost as energy-efficient as silicon. Partly because they are considerably thinner, they are much cheaper to make. While silicon cells are about a millimetre thick, perovskite equivalents have a thickness of approximately one micrometre, about 100 times thinner than a human hair. They are also very flexible, meaning that in addition to being used to power buildings and machines, perovskite cells could eventually be incorporated into things like tents, or even clothing. In the new study, the researchers wanted to know for how long the electrons produced by these cells retain their highest possible levels of energy. When sunlight hits the cell, light particles (or photons), are converted into electrons. These can be drawn out through an electrode to harvest electrical charge. For a brief moment after they are created, the electrons are moving very quickly. However, they then start to collide, and lose energy. Electrons which retain their speed, prior to collision, are known as \"hot\" and their added kinetic energy means that they have the potential to produce more charge. \"Imagine if you had a pool table and each ball was moving at the same speed,\" Richter explained. \"After a certain amount of time, they are going to hit each other, which causes them to slow down and change direction. We wanted to know how long we have to extract the electrons before this happens.\" The Cambridge team took advantage of a method developed by their colleagues in Milan called two dimensional spectroscopy. This involves pumping light from two lasers on to samples of lead iodide perovskite cell in order to simulate sunlight, and then using a third \"probe\" laser to measure how much light is being absorbed. Once the electrons have collided and slowed down, and are thus starting to take up space in the cell, the amount of light being absorbed changes. The time it took for this to happen in the study effectively allowed the researchers to establish how much time is available to extract electrons while they are still \"hot\". The study found that electron collision events started to happen between 10 and 100 femtoseconds after light was initially absorbed by the cell. To maximise energy efficiency, the electrons would thus need to reach the electrode in as little as 10 quadrillionths of a second. The researchers are nonetheless optimistic that this might be possible. As well as taking advantage of the intrinsic thinness of perovskite, they believe that nanostructures could be created within the cells to reduce further the distance that the electrons need to travel. \"That approach is just an idea for now, but it is the sort of thing that we would require in order to overcome the very small timescales that we have measured,\" Richter added. The paper, \"Ultrafast carrier thermalization in lead iodide perovskite probed with two-dimensional electronic spectroscopy,\" is published in Nature Communications. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In band-like semiconductors, charge carriers form a thermal energy distribution rapidly after optical excitation. In hybrid perovskites, the cooling of such thermal carrier distributions occurs on timescales of about 300 fs via carrier-phonon scattering. However, the initial build-up of the thermal distribution proved difficult to resolve with pump–probe techniques due to the requirement of high resolution, both in time and pump energy. Here, we use two-dimensional electronic spectroscopy with sub-10 fs resolution to directly observe the carrier interactions that lead to a thermal carrier distribution. We find that thermalization occurs dominantly via carrier-carrier scattering under the investigated fluences and report the dependence of carrier scattering rates on excess energy and carrier density. We extract characteristic carrier thermalization times from below 10 to 85 fs. These values allow for mobilities of 500 cm 2 V −1 s −1 at carrier densities lower than 2 × 10 19 cm −3 and limit the time for carrier extraction in hot carrier solar cells. Introduction Hybrid perovskite semiconductors have attracted strong scientific interest for optoelectronic applications. Simple and low-cost solution-based fabrication techniques can be used to obtain poly-crystalline thin films 1 , 2 , 3 , as well as single crystals 4 and colloidal nanostructures 5 . Reports on sharp absorption onsets, long carrier lifetimes and high photoluminescence quantum efficiencies 4 , 6 , 7 , 8 , 9 , 10 , 11 highlight the semiconducting quality of these materials. Despite the current drive for higher optoelectronic device efficiencies and stabilities, little information exists about the fundamental non-equilibrium interactions of photo-excited charge carriers in these semiconductors, which define, for example, the fundamental limits of charge transport. Photo-excitation of a semiconductor with free band continuum states leads to an electron population in the conduction band. Initially, the excitations are in a superposition of ground and excited states. Over the dephasing time these coherences are lost and a pure population is left. However, after light absorption this carrier population is not in thermodynamic equilibrium immediately, as the energy of the excited carriers matches that of the absorbed light. The spectrum of the excitation pulse and the selection rules of the semiconductor determine the initial energetic distribution of the carrier population, which can lead to the observation of a “spectral hole” in the absorption spectrum for narrowband excitation 12 , 13 . Ultrafast scattering processes, such as carrier-carrier or carrier-optical-phonon scattering, lead to a broadening of the energetic distribution of the carrier population 14 , 15 , 16 , which can eventually be described by an equilibrium carrier temperature higher than the lattice temperature. This process of exchange of energy among charge carriers is called thermalization. Subsequently, a cooling of the carriers occurs through carrier-phonon and carrier-impurity scattering processes, bringing the carriers and lattice to thermodynamic equilibrium 14 . The carrier thermalization and cooling processes after light absorption depend on the properties of the excited charge carriers and the band structure of the semiconductor. In optoelectronic applications, the carrier scattering rates determine the fundamental limits of carrier transport and electronic coherence. For the prototypical semiconductor GaAs, studies of thermalization dynamics reported timescales ranging from 100 fs to 4 ps 12 , 15 , 17 , and provided insights into dephasing times 12 , band structure 15 and carrier-carrier scattering processes 18 , which affect subsequent carrier cooling and recombination processes. In hybrid perovskites, ultrafast transient absorption spectroscopy has been used to study the carrier cooling process, which was found to occur on 100 s of femtoseconds timescales 19 , 20 , 21 , 22 , with a strong contribution from a hot phonon effect at high fluences 23 . The thermalization process, on the other hand, has not yet been experimentally resolved and is expected to occur on much faster timescales 14 , 15 , 16 . To resolve ultrafast thermalization dynamics, the time evolution of the time-dependent energy distribution of an initial population excited at a well-defined energy needs to be tracked 24 . The necessary femtosecond time resolution requires the use of ultrashort, broadband light pulses, which compromises the desired high resolution in excitation energy. Two-dimensional electronic spectroscopy (2DES) is an extension of traditional transient absorption techniques that achieves both conditions simultaneously 25 by using a Fourier transform (FT) approach. In 2DES, two pump pulses are used instead of one, with the time delay between them (labeled t 1 ) being scanned with interferometric precision for a fixed delay between the second pump and the probe (the waiting time, labeled t 2 ). Taking the FT of the nonlinear optical signal over t 1 provides the excitation frequency axis, with a resolution that is only limited by the t 1 scanning range. Here, we report 2DES experiments on lead-iodide hybrid perovskites using thin films of the prototypical material CH 3 NH 3 PbI 3 . We extract thermalization time constants in the range of below 10–85 fs, depending on carrier density and excess energy and find that the main thermalization process is carrier-carrier scattering. Results Pump–probe experiment with sub-10 fs pulses We prepare thin films of CH 3 NH 3 PbI 3 on 170 μm thick glass substrates. Figure 1a shows the absorption spectrum of the samples with a bandgap around 760 nm (1.63 eV), which contains contributions from an excitonic transition near the bandgap and free carrier absorption towards shorter wavelengths 26 . Fig. 1 Pump–probe spectroscopy of lead iodide perovskite. a Absorption spectrum of lead iodide perovskite and broadband laser spectrum used for the degenerate pump–probe and 2D electronic spectroscopy (2DES) experiments. The pump spectrum overlaps with the free band continuum as well as the excitonic transition of perovskite. b Pump–probe spectroscopy of perovskite: Δ T / T spectrum as a function of probe wavelength and pump–probe delay (excitation density: 2 × 10 18 cm −3 ). The broadband nature of the short pump pulses makes the observation of a non-thermalized distribution and thermalization difficult in pump–probe experiments. Inset: Pump–probe dynamics at 745 nm probe wavelength. The signal rises over two distinct<|im_end|> <|im_start|>assistant Researchers have quantified the astonishingly high speeds at which future solar cells would have to operate in order to stretch what are presently seen as natural limits on their energy conversion efficiency. The study, which investigated photovoltaic devices based on a type of materials called perovskites, suggests that these could achieve unprecedented levels of super-efficiency. But to do so, they will need to turn sunlight into electrons and then extract these as electrical charge within just quadrillionths of a second – a few "femtoseconds", to give them their scientific name. Moving electrons at this ultrafast rate would enable the creation of "hot carrier" cells. These are solar cells which can generate electricity more efficiently by making use of the added kinetic energy that electrons have for a brief moment just after they are created, while they are moving at high speed. The amount of electrical energy that can be extracted from a hot carrier cell, relative to the amount of light absorbed, could potentially match or even break an energy efficiency rate of 30%. In rough terms, this is the maximum energy efficiency that solar cells can conceivably achieve – although standard silicon cells typically have efficiencies closer to 20% in practice. Despite the minuscule fractions of time involved, the authors of the new paper say that it is possible that perovskites could ultimately push this efficiency barrier. The study, published in the journal Nature Communications, was carried out by academics in Italy and the UK. The British team involved researchers in the Cavendish Laboratory's Optoelectronics research group of Professor Sir Richard Friend, a Fellow of St John's College, Cambridge. The Italian team are based at the Politecnico di Milano in the group of Professor Guilio Cerullo. Johannes Richter, a PhD student in the Optoelectronics group and the paper's lead author, said: "The timescale that we calculated is now the time limit that we have to operate within if we want to create super-efficient, hot carrier solar devices. We would need to get electrons out before this tiny amount of time elapses." "We are talking about doing this extremely quickly, but it's not impossible that it could happen. Perovskite cells are very thin and this gives us hope, because the distance that the electrons have to cover is therefore very short." Perovskites are a class of materials which could before long replace silicon as the material of choice for many photovoltaic devices. Although perovskite solar cells have only been developed within the past few years, they are already almost as energy-efficient as silicon. Partly because they are considerably thinner, they are much cheaper to make. While silicon cells are about a millimetre thick, perovskite equivalents have a thickness of approximately one micrometre, about 100 times thinner than a human hair. They are also very flexible, meaning that in addition to being used to power buildings and machines, perovskite cells could eventually be incorporated into things like tents, or even clothing. In the new study, the researchers wanted to know for how long the electrons produced by these cells retain their highest possible levels of energy. When sunlight hits the cell, light particles (or photons), are converted into electrons. These can be drawn out through an electrode to harvest electrical charge. For a brief moment after they are created, the electrons are moving very quickly. However, they then start to collide, and lose energy. Electrons which retain their speed, prior to collision, are known as "hot" and their added kinetic energy means that they have the potential to produce more charge. "Imagine if you had a pool table and each ball was moving at the same speed," Richter explained. "After a certain amount of time, they are going to hit each other, which causes them to slow down and change direction. We wanted to know how long we have to extract the electrons before this happens." The Cambridge team took advantage of a method developed by their colleagues in Milan called two dimensional spectroscopy. This involves pumping light from two lasers on to samples of lead iodide perovskite cell in order to simulate sunlight, and then using a third "probe" laser to measure how much light is being absorbed. Once the electrons have collided and slowed down, and are thus starting to take up space in the cell, the amount of light being absorbed changes. The time it took for this to happen in the study effectively allowed the researchers to establish how much time is available to extract electrons while they are still "hot". The study found that electron collision events started to happen between 10 and 100 femtoseconds after light was initially absorbed by the cell. To maximise energy efficiency, the electrons would thus need to reach the electrode in as little as 10 quadrillionths of a second. The researchers are nonetheless optimistic that this might be possible. As well as taking advantage of the intrinsic thinness of perovskite, they believe that nanostructures could be created within the cells to reduce further the distance that the electrons need to travel. "That approach is just an idea for now, but it is the sort of thing that we would require in order to overcome the very small timescales that we have measured," Richter added. The paper, "Ultrafast carrier thermalization in lead iodide perovskite probed with two-dimensional electronic spectroscopy," is published in Nature Communications. <|im_end|>

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2,492

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Oxytocin (OT) is a great facilitator of social life but, although its effects on socially relevant brain regions have been extensively studied, OT neuron activity during actual social interactions remains unexplored. Most OT neurons are magnocellular neurons, which simultaneously project to the pituitary and forebrain regions involved in social behaviors. In the present study, we show that a much smaller population of OT neurons, parvocellular neurons that do not project to the pituitary but synapse onto magnocellular neurons, is preferentially activated by somatosensory stimuli. This activation is transmitted to the larger population of magnocellular neurons, which consequently show coordinated increases in their activity during social interactions between virgin female rats. Selectively activating these parvocellular neurons promotes social motivation, whereas inhibiting them reduces social interactions. Thus, parvocellular OT neurons receive particular inputs to control social behavior by coordinating the responses of the much larger population of magnocellular OT neurons. Main The hypothalamic neuropeptide OT promotes various types of social behavior 1 , 2 , 3 . OT is mainly synthesized in neurons of the paraventricular nuclei (PVN) and supraoptic nuclei (SON) of the hypothalamus. The vast majority of these neurons project to the posterior pituitary, where OT is secreted into the blood for essential physiological effects, such as suckling-induced milk letdown and regulation of uterine contractions during birth 4 . In parallel, these neurons project axonal collaterals to forebrain regions 5 that express OT receptors (OTRs), including the central nucleus of the amygdala, nucleus accumbens, lateral septum, hippocampus and medial prefrontal cortex 6 , 7 . Studies employing microdialysis to measure OT concentrations within socially relevant brain regions revealed that OT is released in the bed nucleus of the stria terminalis, lateral septum and central nucleus of the amygdala during social investigation of a conspecific 2 , 8 , 9 . However, to date, no direct measurement of OT neuron activity during actual social interaction of freely moving conspecifics has been performed, although it was recently reported that social approach triggers calcium release in PVN OT neurons in immobilized, head-fixed male mice 10 . Several studies suggest that female–female interactions are predominantly mediated via somatosensory inputs 11 , 12 , whereas other interactions such as male–male, male–female or parental contact may rely on other sensory modalities. However, whether these sensory stimulations can activate OT neurons is unknown because, to date, there has been no direct recording of activity from identified OT neurons during actual social behavior. In an attempt to address these points, in the present study, we performed ex vivo and in vivo manipulation of OT neuron activity primarily in the PVN—the main source of OT in the brain 5 —to decipher their involvement in the modulation of social interaction in freely moving female rats. Results PVN OT neurons are activated on social interaction To identify OT neurons electrophysiologically, we injected a recombinant adeno-associated virus (rAAV-OTp-ChR2-mCherry) bilaterally into the PVN to induce expression of the light-sensitive ion channel Channelrhodopsin-2 (ChR2) under the control of the OT promoter 5 , 13 . This resulted in 90.4% of ChR2-expressing neurons being OT positive, showing the high specificity of the infection in the PVN (Extended Data Fig. 1a ). We then recorded individual neurons in the PVN using implanted tetrodes combined with an optic fiber to identify the OT neurons by their electrophysiological response to blue-laser pulses, similar to methods described previously 14 . In total, we recorded 90 neurons in 10 adult female rats at the diestrus phase of the ovarian cycle, while monitoring the behavior of the rats and their ultrasonic vocalizations during both open field (OF) exploration and free social interactions (FSIs) (Fig. 1a,b ). Of these neurons, 15 (in 5 animals) were stringently identified as single OT neurons (Extended Data Fig. 1e ). In the OF arena, the patterns of spiking activity of these neurons (Fig. 1d and Extended Data Fig. 2d ) were indistinguishable from those of OT neurons observed under basal conditions in anesthetized rats, because these neurons displayed typical OT neuron characteristics 15 . Specifically, they all display a low rate of tonic firing (~1 Hz) with a low index of dispersion of spikes (<1), and a distribution of interspike intervals consistent with random spike generation subject to a prolonged relative refractory period. In contrast, during episodes of FSI with an unfamiliar conspecific, the same neurons fired at a higher rate (mean increase 1.5 ± 0.4 spikes s −1 , P = 0.001, n = 15; Fig. 1c,d ) and more irregularly; the second-by-second firing rates showed a high index of dispersion, reflecting the prominent occurrence of clusters of spikes (Fig. 1d and Extended Data Fig. 1n ). Fig. 1: In vivo recording of individual OT neurons in the PVN. a , Setup for recordings of behavior, ultrasonic vocalizations and neural activity. b , Video-tracking and electrophysiological recording from a rat alone in the OF arena (top) and during FSI (bottom): animal movement path (blue line), location of prominent OT cell activity (colored dots), heatmap of time spent by the rat in different locations. c , Example firing rate of four identified OT neurons recorded simultaneously during FSI. Red bars indicate periods of social interaction. d , Average firing rate of 15 OT neurons from 5 rats: OF baseline 1.1 ± 0.4 Hz, not socially interacting (not-SI) 1.6 ± 0.3 Hz and SI 2.6 ± 0.2 Hz (OF not-SI, P = 0.07; OF SI, P = 0.001; not-SI SI, P = 0.03; one-way ANOVA). Average index of dispersion on 1-s time bins of 15 OT neurons: OF 0.9 ± 0.2, not-SI 1.4 ± 0.3, SI 3.4 ± 0.4 (OF not-SI, P = 0.16; OF SI, P = 0.0004; not-SI SI, P = 0.001; one-way ANOVA). Average pairwise Pearson’s correlation of spiking activity (1-s time bins) of 17 OT neuron pairs recorded in OF and SI ( P = 0.005, unpaired, two-sided Student’s t -test). e , Frames of recorded videos (top) of experimental rats that were placed either alone (OF), or with a mesh between", "role": "user" }, { "content": "The sense of touch can significantly affect how animals and humans perceive the world around them, enriching their experiences and allowing them to gather more information about their surroundings and other living organisms. Although touch is a crucial aspect of perceptual experience, in philosophical, psychological and neuroscientific research it has often been overshadowed by vision. Researchers at the Central Institute of Mental Health, University of Heidelberg, CNRS, University of Strasbourg, and other institutes in Europe, Israel and the US have recently carried out a fascinating study investigating how social touch can affect communication between female animals. Their paper, published in Nature Neuroscience, shows that in female rats, social touch promotes communication through the activation of parvocellular oxytocin neurons. \"From the softest caress to the harshest blow, touch lies at the heart of our sensory experience of the world and shapes the way we perceive it, especially during intimate interactions with other humans,\" Valery Grinevich, one of the researchers who carried out the study, told Medical Xpress. \"During evolution, vertebrates developed a plethora of sophisticated sensory systems, which represented a clear evolutionary advantage and entailed that higher mammals were able to discriminate between pain, moderate and gentle forms of touch.\" Social touch is crucial for intimacy and can also contribute to the formation of trust-based relationships between most mammals. Different types of touch, ranging from gentle touch, to grooming and caressing behaviors can be commonly observed among several classes of mammals, including rodents, felines, canines and primates. The chemicals in the brain produced by social touch can play a part in establishing and maintaining social hierarchies within groups of animals. In their study, Grinevich and his colleagues specifically focused on a chemical that is particularly crucial for establishing these relationships: the neuropeptide oxytocin. \"Oxytocin not only facilitates birth and lactation, but actively fine-tunes the brain to modulate emotions, sexual intercourse, pair bonding and parental behavior,\" Alexandre Charlet, another researcher involved in the study, told Medical Xpress. \"However, how, exactly, oxytocin promotes these prosocial behaviors and what triggers the actual release of the neuropeptide remained a mystery. This is the key question addressed in our paper.\" Grinevich, Charlet and their colleagues used a variety of modern neuroscience techniques to monitor and manipulate the activity of oxytocin neurons in freely moving female rats. Remarkably, they were the first research group to ever collect electrophysiological recordings of individual oxytocin cells and their populations. The researchers also periodically activated and inhibited a specific subset of oxytocin neurons, known as parvocellular neurons, using pharmacogenetic techniques. This allowed them to specifically examine the unique contributions of this small population of oxytocin neurons to inter-female communication. \"We also used viral vector-based tracer methods to visualize oxytocin neurons and establish their connectivity,\" Grinevich explained. \"Finally, we monitored social communication between females and males in which the activity of oxytocin neurons was enhanced or silenced.\" The results gathered by Grinevich, Charlet and their colleagues suggest that parvocellular oxytocin neurons play a key role in touch-based communication between female rats. More specifically, these neurons are responsible for translating sensory signals picked up by an animal's body into various types of social interactions. \"Our results provide fundamentally new insights into how the neuropeptide orchestrates social behavior,\" Charlet said. \"Furthermore, they support a vision of oxytocin as a powerful agent to treat mental disorders: A combination of sensory body stimulation (for example, via huddling or massage) and intranasal oxytocin administration might synergistically mitigate socio-emotional alterations in humans afflicted with mental diseases, such as autism spectrum disorder and posttraumatic stress disorder.\" While the researchers specifically conducted their study on virgin female rats, the findings they collected could also be applicable to other mammals, including humans. In the future, their work could thus pave the way toward the development of new forms of therapy for mental health disorders that integrate soothing forms of social touch. \"In our recent study, we focused on social behavior of unfamiliar female rats,\" Grinevich said. \"In the future, we plan to study whether the same oxytocin-ergic mechanisms underlie other types of social behavior, such as pair bond and parental behavior. Following translational aspect, we are interested in investigating whether the activity of the oxytocin system (particularly the parvocellular magnocellular oxytocin neuron pathway) is affected in animal models of mental diseases, mimicking human's autism spectrum disorder and posttraumatic stress disorder.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Oxytocin (OT) is a great facilitator of social life but, although its effects on socially relevant brain regions have been extensively studied, OT neuron activity during actual social interactions remains unexplored. Most OT neurons are magnocellular neurons, which simultaneously project to the pituitary and forebrain regions involved in social behaviors. In the present study, we show that a much smaller population of OT neurons, parvocellular neurons that do not project to the pituitary but synapse onto magnocellular neurons, is preferentially activated by somatosensory stimuli. This activation is transmitted to the larger population of magnocellular neurons, which consequently show coordinated increases in their activity during social interactions between virgin female rats. Selectively activating these parvocellular neurons promotes social motivation, whereas inhibiting them reduces social interactions. Thus, parvocellular OT neurons receive particular inputs to control social behavior by coordinating the responses of the much larger population of magnocellular OT neurons. Main The hypothalamic neuropeptide OT promotes various types of social behavior 1 , 2 , 3 . OT is mainly synthesized in neurons of the paraventricular nuclei (PVN) and supraoptic nuclei (SON) of the hypothalamus. The vast majority of these neurons project to the posterior pituitary, where OT is secreted into the blood for essential physiological effects, such as suckling-induced milk letdown and regulation of uterine contractions during birth 4 . In parallel, these neurons project axonal collaterals to forebrain regions 5 that express OT receptors (OTRs), including the central nucleus of the amygdala, nucleus accumbens, lateral septum, hippocampus and medial prefrontal cortex 6 , 7 . Studies employing microdialysis to measure OT concentrations within socially relevant brain regions revealed that OT is released in the bed nucleus of the stria terminalis, lateral septum and central nucleus of the amygdala during social investigation of a conspecific 2 , 8 , 9 . However, to date, no direct measurement of OT neuron activity during actual social interaction of freely moving conspecifics has been performed, although it was recently reported that social approach triggers calcium release in PVN OT neurons in immobilized, head-fixed male mice 10 . Several studies suggest that female–female interactions are predominantly mediated via somatosensory inputs 11 , 12 , whereas other interactions such as male–male, male–female or parental contact may rely on other sensory modalities. However, whether these sensory stimulations can activate OT neurons is unknown because, to date, there has been no direct recording of activity from identified OT neurons during actual social behavior. In an attempt to address these points, in the present study, we performed ex vivo and in vivo manipulation of OT neuron activity primarily in the PVN—the main source of OT in the brain 5 —to decipher their involvement in the modulation of social interaction in freely moving female rats. Results PVN OT neurons are activated on social interaction To identify OT neurons electrophysiologically, we injected a recombinant adeno-associated virus (rAAV-OTp-ChR2-mCherry) bilaterally into the PVN to induce expression of the light-sensitive ion channel Channelrhodopsin-2 (ChR2) under the control of the OT promoter 5 , 13 . This resulted in 90.4% of ChR2-expressing neurons being OT positive, showing the high specificity of the infection in the PVN (Extended Data Fig. 1a ). We then recorded individual neurons in the PVN using implanted tetrodes combined with an optic fiber to identify the OT neurons by their electrophysiological response to blue-laser pulses, similar to methods described previously 14 . In total, we recorded 90 neurons in 10 adult female rats at the diestrus phase of the ovarian cycle, while monitoring the behavior of the rats and their ultrasonic vocalizations during both open field (OF) exploration and free social interactions (FSIs) (Fig. 1a,b ). Of these neurons, 15 (in 5 animals) were stringently identified as single OT neurons (Extended Data Fig. 1e ). In the OF arena, the patterns of spiking activity of these neurons (Fig. 1d and Extended Data Fig. 2d ) were indistinguishable from those of OT neurons observed under basal conditions in anesthetized rats, because these neurons displayed typical OT neuron characteristics 15 . Specifically, they all display a low rate of tonic firing (~1 Hz) with a low index of dispersion of spikes (<1), and a distribution of interspike intervals consistent with random spike generation subject to a prolonged relative refractory period. In contrast, during episodes of FSI with an unfamiliar conspecific, the same neurons fired at a higher rate (mean increase 1.5 ± 0.4 spikes s −1 , P = 0.001, n = 15; Fig. 1c,d ) and more irregularly; the second-by-second firing rates showed a high index of dispersion, reflecting the prominent occurrence of clusters of spikes (Fig. 1d and Extended Data Fig. 1n ). Fig. 1: In vivo recording of individual OT neurons in the PVN. a , Setup for recordings of behavior, ultrasonic vocalizations and neural activity. b , Video-tracking and electrophysiological recording from a rat alone in the OF arena (top) and during FSI (bottom): animal movement path (blue line), location of prominent OT cell activity (colored dots), heatmap of time spent by the rat in different locations. c , Example firing rate of four identified OT neurons recorded simultaneously during FSI. Red bars indicate periods of social interaction. d , Average firing rate of 15 OT neurons from 5 rats: OF baseline 1.1 ± 0.4 Hz, not socially interacting (not-SI) 1.6 ± 0.3 Hz and SI 2.6 ± 0.2 Hz (OF not-SI, P = 0.07; OF SI, P = 0.001; not-SI SI, P = 0.03; one-way ANOVA). Average index of dispersion on 1-s time bins of 15 OT neurons: OF 0.9 ± 0.2, not-SI 1.4 ± 0.3, SI 3.4 ± 0.4 (OF not-SI, P = 0.16; OF SI, P = 0.0004; not-SI SI, P = 0.001; one-way ANOVA). Average pairwise Pearson’s correlation of spiking activity (1-s time bins) of 17 OT neuron pairs recorded in OF and SI ( P = 0.005, unpaired, two-sided Student’s t -test). e , Frames of recorded videos (top) of experimental rats that were placed either alone (OF), or with a mesh between<|im_end|> <|im_start|>assistant The sense of touch can significantly affect how animals and humans perceive the world around them, enriching their experiences and allowing them to gather more information about their surroundings and other living organisms. Although touch is a crucial aspect of perceptual experience, in philosophical, psychological and neuroscientific research it has often been overshadowed by vision. Researchers at the Central Institute of Mental Health, University of Heidelberg, CNRS, University of Strasbourg, and other institutes in Europe, Israel and the US have recently carried out a fascinating study investigating how social touch can affect communication between female animals. Their paper, published in Nature Neuroscience, shows that in female rats, social touch promotes communication through the activation of parvocellular oxytocin neurons. "From the softest caress to the harshest blow, touch lies at the heart of our sensory experience of the world and shapes the way we perceive it, especially during intimate interactions with other humans," Valery Grinevich, one of the researchers who carried out the study, told Medical Xpress. "During evolution, vertebrates developed a plethora of sophisticated sensory systems, which represented a clear evolutionary advantage and entailed that higher mammals were able to discriminate between pain, moderate and gentle forms of touch." Social touch is crucial for intimacy and can also contribute to the formation of trust-based relationships between most mammals. Different types of touch, ranging from gentle touch, to grooming and caressing behaviors can be commonly observed among several classes of mammals, including rodents, felines, canines and primates. The chemicals in the brain produced by social touch can play a part in establishing and maintaining social hierarchies within groups of animals. In their study, Grinevich and his colleagues specifically focused on a chemical that is particularly crucial for establishing these relationships: the neuropeptide oxytocin. "Oxytocin not only facilitates birth and lactation, but actively fine-tunes the brain to modulate emotions, sexual intercourse, pair bonding and parental behavior," Alexandre Charlet, another researcher involved in the study, told Medical Xpress. "However, how, exactly, oxytocin promotes these prosocial behaviors and what triggers the actual release of the neuropeptide remained a mystery. This is the key question addressed in our paper." Grinevich, Charlet and their colleagues used a variety of modern neuroscience techniques to monitor and manipulate the activity of oxytocin neurons in freely moving female rats. Remarkably, they were the first research group to ever collect electrophysiological recordings of individual oxytocin cells and their populations. The researchers also periodically activated and inhibited a specific subset of oxytocin neurons, known as parvocellular neurons, using pharmacogenetic techniques. This allowed them to specifically examine the unique contributions of this small population of oxytocin neurons to inter-female communication. "We also used viral vector-based tracer methods to visualize oxytocin neurons and establish their connectivity," Grinevich explained. "Finally, we monitored social communication between females and males in which the activity of oxytocin neurons was enhanced or silenced." The results gathered by Grinevich, Charlet and their colleagues suggest that parvocellular oxytocin neurons play a key role in touch-based communication between female rats. More specifically, these neurons are responsible for translating sensory signals picked up by an animal's body into various types of social interactions. "Our results provide fundamentally new insights into how the neuropeptide orchestrates social behavior," Charlet said. "Furthermore, they support a vision of oxytocin as a powerful agent to treat mental disorders: A combination of sensory body stimulation (for example, via huddling or massage) and intranasal oxytocin administration might synergistically mitigate socio-emotional alterations in humans afflicted with mental diseases, such as autism spectrum disorder and posttraumatic stress disorder." While the researchers specifically conducted their study on virgin female rats, the findings they collected could also be applicable to other mammals, including humans. In the future, their work could thus pave the way toward the development of new forms of therapy for mental health disorders that integrate soothing forms of social touch. "In our recent study, we focused on social behavior of unfamiliar female rats," Grinevich said. "In the future, we plan to study whether the same oxytocin-ergic mechanisms underlie other types of social behavior, such as pair bond and parental behavior. Following translational aspect, we are interested in investigating whether the activity of the oxytocin system (particularly the parvocellular magnocellular oxytocin neuron pathway) is affected in animal models of mental diseases, mimicking human's autism spectrum disorder and posttraumatic stress disorder." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Atomic clocks, which lock the frequency of an oscillator to the extremely stable quantized energy levels of atoms, are essential for navigation applications such as deep space exploration 1 and global navigation satellite systems 2 , and are useful tools with which to address questions in fundamental physics 3 , 4 , 5 , 6 . Such satellite systems use precise measurement of signal propagation times determined by atomic clocks, together with propagation speed, to calculate position. Although space atomic clocks with low instability are an enabling technology for global navigation, they have not yet been applied to deep space navigation and have seen only limited application to space-based fundamental physics, owing to performance constraints imposed by the rigours of space operation 7 . Methods of electromagnetically trapping and cooling ions have revolutionized atomic clock performance 8 , 9 , 10 , 11 , 12 , 13 . Terrestrial trapped-ion clocks operating in the optical domain have achieved orders-of-magnitude improvements in performance over their predecessors and have become a key component in national metrology laboratory research programmes 13 , but transporting this new technology into space has remained challenging. Here we show the results from a trapped-ion atomic clock operating in space. On the ground, NASA’s Deep Space Atomic Clock demonstrated a short-term fractional frequency stability of 1.5 × 10 −13 / τ 1/2 (where τ is the averaging time) 14 . Launched in 2019, the clock has operated for more than 12 months in space and demonstrated there a long-term stability of 3 × 10 −15 at 23 days (no drift removal), and an estimated drift of 3.0(0.7) × 10 −16 per day. Each of these exceeds current space clock performance by up to an order of magnitude 15 , 16 , 17 . The Deep Space Atomic Clock is particularly amenable to the space environment because of its low sensitivity to variations in radiation, temperature and magnetic fields. This level of space clock performance will enable one-way navigation in which signal delay times are measured in situ, making near-real-time navigation of deep space probes possible 18 . Main All space clocks in use today employ atomic beams or gas cells to confine atoms 15 , 16 , 17 . These clocks have short-term stabilities ranging from 1 × 10 −12 / τ 1/2 to 10 × 10 −12 / τ 1/2 , whereas long-term (greater than a day) stability, usually characterized by drift, is between 1 × 10 −15 and 10 × 10 −15 per day. Long-term clock autonomy, highly desirable for deep space and global navigation satellite system (GNSS) applications 19 , is limited by drift, which in cell clocks is usually caused by wall collisions. Trapped-ion clocks 20 solve this by electromagnetically confining atoms, thereby eliminating wall collisions. Recently, a different type of beam clock was demonstrated in space with an inferred short-term stability of 3 × 10 −13 / τ 1/2 (ref. 21 ), but no long-term stability was reported. Because of the advantages to clock performance provided by atom trapping, many primary atomic clocks used in national metrology laboratories use some form of trapping 12 , 13 . Motivated by the low instability of trapped-ion clocks and by their potentially very small size, NASA’s Jet Propulsion Laboratory (JPL) embarked on a series of mercury ion clock development projects aimed at ultimately producing a space-qualified version. Demonstrations in the laboratory achieved a stability of 2 × 10 −14 / τ 1/2 (ref. 10 ) and drifts as low as 2.7 × 10 −17 per day (no drift removal) 11 . The approach followed at JPL did not use lasers, cryogenics or microwave cavities, enabling the technology to be robust and relatively small, and to consume less than 50 W of power 10 , 22 , 23 , 24 . Following this success, in 2011 NASA’s Space Technology Mission Directorate initiated the Deep Space Atomic Clock (DSAC) mission to demonstrate a trapped-ion atomic clock in space with the goal of 2 × 10 −13 / τ 1/2 short-term stability and a non-drift-removed 3 × 10 −15 stability at one day. This technology demonstration mission is designed to address the unique needs of deep space navigation 25 , but given the clock’s low size, mass and power, it is also well suited for GNSS applications in Earth orbit. The DSAC payload, consisting of a trapped-ion clock and its 1 × 10 −13 class ultrastable local oscillator (LO) together with a Global Positioning System (GPS) receiver to aid comparisons with clocks on the ground, was launched in June 2019 aboard the General Atomics' Orbital Test Bed spacecraft into a 720-km, 100-min Earth orbit (Fig. 1 ) and first powered on in space in August 2019. The 2-year DSAC mission is designed to demonstrate clock operability, characterize performance of the technology in space and carry out several navigation experiments to demonstrate its utility in that domain. Fig. 1: The Deep Space Atomic Clock launch. Left to right: the DSAC clock (credit: JPL); the DSAC instrument, including GPS receiver and ultrastable oscillator (USO), integrated in the spacecraft payload (credit: General Atomics); and the launch of Space-X Falcon Heavy STP-2 carrying DSAC into space (credit: NASA). Full size image DSAC trapped-ion clock The DSAC ion clock, payload configuration and ground testing, as well as its navigational uses and some scientific applications, have been previously described 14 , 26 . Here we summarize these and then focus on results obtained after launch. At the heart of the DSAC clock are two linear radiofrequency Paul ion traps 27 , 28 , one having four rods (the quadrupole or load trap), the other having sixteen rods (the multipole trap). Figure 2 shows a schematic cross-section of the vacuum chamber, revealing the traps. A radiofrequency voltage is applied across alternating trap rod pairs, with the field strength decreasing linearly towards the trap axis. Ions seek the weakest field and are thereby trapped in the centre. The other two images in Fig. 2 show contour", "role": "user" }, { "content": "Spacecraft that venture beyond our Moon rely on communication with ground stations on Earth to figure out where they are and where they're going. NASA's Deep Space Atomic Clock is working toward giving those far-flung explorers more autonomy when navigating. In a new paper published today in the journal Nature, the mission reports progress in their work to improve the ability of space-based atomic clocks to measure time consistently over long periods. Known as stability, this feature also impacts the operation of GPS satellites that help people navigate on Earth, so this work also has the potential to increase the autonomy of next-generation GPS spacecraft. To calculate the trajectory of a distant spacecraft, engineers send signals from the spacecraft to Earth and back. They use refrigerator-size atomic clocks on the ground to log the timing of those signals, which is essential for precisely measuring the spacecraft's position. But for robots on Mars or more distant destinations, waiting for the signals to make the trip can quickly add up to tens of minutes or even hours. If those spacecraft carried atomic clocks, they could calculate their own position and direction, but the clocks would have to be highly stable. GPS satellites carry atomic clocks to help us get to our destinations on Earth, but those clocks require updates several times a day to maintain the necessary level of stability. Deep space missions would require more stable space-based clocks. Managed by NASA's Jet Propulsion Laboratory in Southern California, the Deep Space Atomic Clock has been operating aboard General Atomic's Orbital Test Bed spacecraft since June 2019. The new study reports that the mission team has set a new record for long-term atomic clock stability in space, reaching more than 10 times the stability of current space-based atomic clocks, including those on GPS satellites. When every nanosecond counts All atomic clocks have some degree of instability that leads to an offset in the clock's time versus the actual time. If not corrected, the offset, while miniscule, increases rapidly, and with spacecraft navigation, even a tiny offset could have drastic effects. One of the key goals of the Deep Space Atomic Clock mission was to measure the clock's stability over longer and longer periods, to see how it changes with time. In the new paper, the team reports a level of stability that leads to a time deviation of less than four nanoseconds after more than 20 days of operation. \"As a general rule, an uncertainty of one nanosecond in time corresponds to a distance uncertainty of about one foot,\" said Eric Burt, an atomic clock physicist for the mission at JPL and co-author of the new paper. \"Some GPS clocks must be updated several times a day to maintain this level of stability, and that means GPS is highly dependent on communication with the ground. The Deep Space Atomic Clock pushes this out to a week or more, thus potentially giving an application like GPS much more autonomy.\" The stability and subsequent time delay reported in the new paper is about five times better than what the team reported in the spring of 2020. This does not represent an improvement in the clock itself, but in the team's measurement of the clock's stability. Longer operating periods and almost a full year of additional data made it possible to improve the precision of their measurement. The Deep Space Atomic Clock mission will conclude in August, but NASA announced that work on this technology continues: the Deep Space Atomic Clock-2, an improved version of the cutting-edge timekeeper, will fly on the VERITAS (short for Venus Emissivity, Radio Science, InSAR, Topography, and Spectroscopy) mission to Venus. Like its predecessor, the new space clock is a technology demonstration, meaning its goal is to advance in-space capabilities by developing instruments, hardware, software, or the like that doesn't currently exist. Built by JPL and funded by NASA's Space Technology Mission Directorate (STMD), the ultra-precise clock signal generated with this technology could help enable autonomous spacecraft navigation and enhance radio science observations on future missions. \"NASA's selection of Deep Space Atomic Clock-2 on VERITAS speaks to this technology's promise,\" said Todd Ely, Deep Space Atomic Clock principal investigator and project manager at JPL. \"On VERITAS, we aim to put this next generation space clock through its paces and demonstrate its potential for deep space navigation and science.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Atomic clocks, which lock the frequency of an oscillator to the extremely stable quantized energy levels of atoms, are essential for navigation applications such as deep space exploration 1 and global navigation satellite systems 2 , and are useful tools with which to address questions in fundamental physics 3 , 4 , 5 , 6 . Such satellite systems use precise measurement of signal propagation times determined by atomic clocks, together with propagation speed, to calculate position. Although space atomic clocks with low instability are an enabling technology for global navigation, they have not yet been applied to deep space navigation and have seen only limited application to space-based fundamental physics, owing to performance constraints imposed by the rigours of space operation 7 . Methods of electromagnetically trapping and cooling ions have revolutionized atomic clock performance 8 , 9 , 10 , 11 , 12 , 13 . Terrestrial trapped-ion clocks operating in the optical domain have achieved orders-of-magnitude improvements in performance over their predecessors and have become a key component in national metrology laboratory research programmes 13 , but transporting this new technology into space has remained challenging. Here we show the results from a trapped-ion atomic clock operating in space. On the ground, NASA’s Deep Space Atomic Clock demonstrated a short-term fractional frequency stability of 1.5 × 10 −13 / τ 1/2 (where τ is the averaging time) 14 . Launched in 2019, the clock has operated for more than 12 months in space and demonstrated there a long-term stability of 3 × 10 −15 at 23 days (no drift removal), and an estimated drift of 3.0(0.7) × 10 −16 per day. Each of these exceeds current space clock performance by up to an order of magnitude 15 , 16 , 17 . The Deep Space Atomic Clock is particularly amenable to the space environment because of its low sensitivity to variations in radiation, temperature and magnetic fields. This level of space clock performance will enable one-way navigation in which signal delay times are measured in situ, making near-real-time navigation of deep space probes possible 18 . Main All space clocks in use today employ atomic beams or gas cells to confine atoms 15 , 16 , 17 . These clocks have short-term stabilities ranging from 1 × 10 −12 / τ 1/2 to 10 × 10 −12 / τ 1/2 , whereas long-term (greater than a day) stability, usually characterized by drift, is between 1 × 10 −15 and 10 × 10 −15 per day. Long-term clock autonomy, highly desirable for deep space and global navigation satellite system (GNSS) applications 19 , is limited by drift, which in cell clocks is usually caused by wall collisions. Trapped-ion clocks 20 solve this by electromagnetically confining atoms, thereby eliminating wall collisions. Recently, a different type of beam clock was demonstrated in space with an inferred short-term stability of 3 × 10 −13 / τ 1/2 (ref. 21 ), but no long-term stability was reported. Because of the advantages to clock performance provided by atom trapping, many primary atomic clocks used in national metrology laboratories use some form of trapping 12 , 13 . Motivated by the low instability of trapped-ion clocks and by their potentially very small size, NASA’s Jet Propulsion Laboratory (JPL) embarked on a series of mercury ion clock development projects aimed at ultimately producing a space-qualified version. Demonstrations in the laboratory achieved a stability of 2 × 10 −14 / τ 1/2 (ref. 10 ) and drifts as low as 2.7 × 10 −17 per day (no drift removal) 11 . The approach followed at JPL did not use lasers, cryogenics or microwave cavities, enabling the technology to be robust and relatively small, and to consume less than 50 W of power 10 , 22 , 23 , 24 . Following this success, in 2011 NASA’s Space Technology Mission Directorate initiated the Deep Space Atomic Clock (DSAC) mission to demonstrate a trapped-ion atomic clock in space with the goal of 2 × 10 −13 / τ 1/2 short-term stability and a non-drift-removed 3 × 10 −15 stability at one day. This technology demonstration mission is designed to address the unique needs of deep space navigation 25 , but given the clock’s low size, mass and power, it is also well suited for GNSS applications in Earth orbit. The DSAC payload, consisting of a trapped-ion clock and its 1 × 10 −13 class ultrastable local oscillator (LO) together with a Global Positioning System (GPS) receiver to aid comparisons with clocks on the ground, was launched in June 2019 aboard the General Atomics' Orbital Test Bed spacecraft into a 720-km, 100-min Earth orbit (Fig. 1 ) and first powered on in space in August 2019. The 2-year DSAC mission is designed to demonstrate clock operability, characterize performance of the technology in space and carry out several navigation experiments to demonstrate its utility in that domain. Fig. 1: The Deep Space Atomic Clock launch. Left to right: the DSAC clock (credit: JPL); the DSAC instrument, including GPS receiver and ultrastable oscillator (USO), integrated in the spacecraft payload (credit: General Atomics); and the launch of Space-X Falcon Heavy STP-2 carrying DSAC into space (credit: NASA). Full size image DSAC trapped-ion clock The DSAC ion clock, payload configuration and ground testing, as well as its navigational uses and some scientific applications, have been previously described 14 , 26 . Here we summarize these and then focus on results obtained after launch. At the heart of the DSAC clock are two linear radiofrequency Paul ion traps 27 , 28 , one having four rods (the quadrupole or load trap), the other having sixteen rods (the multipole trap). Figure 2 shows a schematic cross-section of the vacuum chamber, revealing the traps. A radiofrequency voltage is applied across alternating trap rod pairs, with the field strength decreasing linearly towards the trap axis. Ions seek the weakest field and are thereby trapped in the centre. The other two images in Fig. 2 show contour<|im_end|> <|im_start|>assistant Spacecraft that venture beyond our Moon rely on communication with ground stations on Earth to figure out where they are and where they're going. NASA's Deep Space Atomic Clock is working toward giving those far-flung explorers more autonomy when navigating. In a new paper published today in the journal Nature, the mission reports progress in their work to improve the ability of space-based atomic clocks to measure time consistently over long periods. Known as stability, this feature also impacts the operation of GPS satellites that help people navigate on Earth, so this work also has the potential to increase the autonomy of next-generation GPS spacecraft. To calculate the trajectory of a distant spacecraft, engineers send signals from the spacecraft to Earth and back. They use refrigerator-size atomic clocks on the ground to log the timing of those signals, which is essential for precisely measuring the spacecraft's position. But for robots on Mars or more distant destinations, waiting for the signals to make the trip can quickly add up to tens of minutes or even hours. If those spacecraft carried atomic clocks, they could calculate their own position and direction, but the clocks would have to be highly stable. GPS satellites carry atomic clocks to help us get to our destinations on Earth, but those clocks require updates several times a day to maintain the necessary level of stability. Deep space missions would require more stable space-based clocks. Managed by NASA's Jet Propulsion Laboratory in Southern California, the Deep Space Atomic Clock has been operating aboard General Atomic's Orbital Test Bed spacecraft since June 2019. The new study reports that the mission team has set a new record for long-term atomic clock stability in space, reaching more than 10 times the stability of current space-based atomic clocks, including those on GPS satellites. When every nanosecond counts All atomic clocks have some degree of instability that leads to an offset in the clock's time versus the actual time. If not corrected, the offset, while miniscule, increases rapidly, and with spacecraft navigation, even a tiny offset could have drastic effects. One of the key goals of the Deep Space Atomic Clock mission was to measure the clock's stability over longer and longer periods, to see how it changes with time. In the new paper, the team reports a level of stability that leads to a time deviation of less than four nanoseconds after more than 20 days of operation. "As a general rule, an uncertainty of one nanosecond in time corresponds to a distance uncertainty of about one foot," said Eric Burt, an atomic clock physicist for the mission at JPL and co-author of the new paper. "Some GPS clocks must be updated several times a day to maintain this level of stability, and that means GPS is highly dependent on communication with the ground. The Deep Space Atomic Clock pushes this out to a week or more, thus potentially giving an application like GPS much more autonomy." The stability and subsequent time delay reported in the new paper is about five times better than what the team reported in the spring of 2020. This does not represent an improvement in the clock itself, but in the team's measurement of the clock's stability. Longer operating periods and almost a full year of additional data made it possible to improve the precision of their measurement. The Deep Space Atomic Clock mission will conclude in August, but NASA announced that work on this technology continues: the Deep Space Atomic Clock-2, an improved version of the cutting-edge timekeeper, will fly on the VERITAS (short for Venus Emissivity, Radio Science, InSAR, Topography, and Spectroscopy) mission to Venus. Like its predecessor, the new space clock is a technology demonstration, meaning its goal is to advance in-space capabilities by developing instruments, hardware, software, or the like that doesn't currently exist. Built by JPL and funded by NASA's Space Technology Mission Directorate (STMD), the ultra-precise clock signal generated with this technology could help enable autonomous spacecraft navigation and enhance radio science observations on future missions. "NASA's selection of Deep Space Atomic Clock-2 on VERITAS speaks to this technology's promise," said Todd Ely, Deep Space Atomic Clock principal investigator and project manager at JPL. "On VERITAS, we aim to put this next generation space clock through its paces and demonstrate its potential for deep space navigation and science." <|im_end|>

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2,230

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Kombucha, a fermented tea beverage with an acidic and effervescent taste, is composed of a multispecies microbial ecosystem with complex interactions that are characterized by both cooperation and conflict. In kombucha, a complex community of bacteria and yeast initiates the fermentation of a starter tea (usually black or green tea with sugar), producing a biofilm that covers the liquid over several weeks. This happens through several fermentative phases that are characterized by cooperation and competition among the microbes within the kombucha solution. Yeast produce invertase as a public good that enables both yeast and bacteria to metabolize sugars. Bacteria produce a surface biofilm which may act as a public good providing protection from invaders, storage for resources, and greater access to oxygen for microbes embedded within it. The ethanol and acid produced during the fermentative process (by yeast and bacteria, respectively) may also help to protect the system from invasion by microbial competitors from the environment. Thus, kombucha can serve as a model system for addressing important questions about the evolution of cooperation and conflict in diverse multispecies systems. Further, it has the potential to be artificially selected to specialize it for particular human uses, including the development of antimicrobial ecosystems and novel materials. Finally, kombucha is easily-propagated, non-toxic, and inexpensive, making it an excellent system for scientific inquiry and citizen science. Cite this as May A, Narayanan S, Alcock J, Varsani A, Maley C, Aktipis A. 2019 . Kombucha: a novel model system for cooperation and conflict in a complex multi-species microbial ecosystem . PeerJ 7 : e7565 Main article text Introduction Kombucha is a traditional tea beverage fermented by a symbiotic community of acetic acid bacteria (AAB) ( Acetobacteraceae ) and osmophilic yeast ( De Filippis et al., 2018 ). While the origins of the beverage are uncertain, records of the drink are found in early 19th century Russia ( Dufresne & Farnworth, 2000 ). There is variation on the specifics of kombucha fermentation, but the typical process proceeds as follows: black or green tea is brewed for at least 5 min, supplemented with sucrose (5–10% (w/v)), cooled to room temperature (20 °C), and then inoculated with kombucha liquid (usually 10–20% (v/v)) from a previous batch ( Jayabalan et al., 2014 ). A mature bacterial cellulose (BC) biofilm from a previously brewed kombucha culture (often called a “mother” or SCOBY, for Symbiotic Community of Bacteria and Yeast) is typically placed on top of the solution and allowed to ferment for 10–14 days. The presence of a carbon source in the solution, typically sucrose, initiates a cascade of metabolic processes that generates a carbonated and slightly acidic drink at the end of the primary fermentation cycle. One of the more striking aspects of the system is the floating cellulose pellicle that forms in tandem with fermentation; this biofilm is produced by the bacteria and encapsulates a microbial community within it ( Marsh et al., 2014 ). The dominant bacterial genus in the system is Komagataeibacter (formerly Gluconacetobacter , and prior to that, Acetobacter , Yamada et al., 2012 ) ( Marsh et al., 2014 ; Chakravorty et al., 2016 ) with numerous species identified within various kombucha cultures. These include Komagataeibacter xylinus ( Reva et al., 2015 ; De Filippis et al., 2018 ), Komagataeibacter intermedius ( Dos Santos et al., 2015 ; Reva et al., 2015 ; Gaggìa et al., 2019 ), Komagataeibacter rhaeticus ( Machado et al., 2016 ; Semjonovs et al., 2017 ; Gaggìa et al., 2019 ), Komagataeibacter saccharivorans ( Reva et al., 2015 ; De Filippis et al., 2018 ), and Komagataeibacter kombuchae ( Reva et al., 2015 ). Another AAB genus often found in kombucha cultures is Gluconobacter ( Reva et al., 2015 ; Chakravorty et al., 2016 ; Gaggìa et al., 2019 ). The yeast species in the system are even more variable, and can include yeast in the genera Zygosaccharomyces, Candida, Torulaspora, Pichia, Brettanomyces/Dekkera, Schizosaccharomyces , and Saccharomyces ( Mayser et al., 1995 ; Teoh, Heard & Cox, 2004 ; Marsh et al., 2014 ; Jayabalan et al., 2014 ; Reva et al., 2015 ). The microbial profiles of kombucha seem to vary partly based on geographical origin ( Mayser et al., 1995 ; Marsh et al., 2014 ), and the composition of the kombucha changes over time as it progresses through fermentation ( Marsh et al., 2014 ). This process involves the enzymatic cleavage of sucrose and the subsequent processing of its monomer components into ethanol, acids, cellulose, and carbon dioxide ( Jayabalan et al., 2014 ; Chakravorty et al., 2016 ). Brewed kombucha has antimicrobial properties that persist even with neutralization of the solution to pH 7 and thermal denaturation at 80 °C for 30 min ( Sreeramulu, Zhu & Knol, 2000 ). In this manuscript, we describe the potential uses of kombucha as a model system for studying cooperative and competitive interactions, and we also discuss the potential human uses of kombucha and kombucha-generated biofilms for nutrition, human health and industrial applications. Survey methodology This review was assembled via electronic searches on various platforms, including Google Scholar, Web of Science, and PubMed. In order to gain a background understanding of kombucha as a scientific model, searches were focused on the terminology adjacent to it and other fermented foods: “kombucha”, “kombucha tea,” “tea fungus,” “fermented tea,” “fermentation,” “SCOBY,” “biofilm,” “pellicle,” Examples of other fermented foods were examined as well, particularly those already used as model systems, such as sourdough and yogurt. Further development of the literature collection used keywords associated with microbial ecology and social interactions between microbes, such as: “cooperation,” “conflict,” “symbiosis,” “syntrophy,” “cheater.” Searches evolved to include aspects of the four phases of development known to occur during kombucha fermentation: invertase production, ethanol fermentation, ethanol oxidation and acidification, and biofilm formation; many of these sources primarily used other organism models as references. Each of these sources provided a wealth of data far beyond the scope of this paper, and thus were culled down to focus on", "role": "user" }, { "content": "In today's health-conscious community, kombucha is all the rave. Its appeal comes from its accessibility and alleged health benefits, which range from introducing probiotics to killing deleterious bacteria in the human body. But as is the case for many things in science, there is more to kombucha than meets the eye—literally. The microscopic microbes inhabiting this fermented concoction could offer insight into how microbial communities interact, more specifically on how symbiotic relationships form within complex microbial models. Athena Aktipis, an assistant professor in the Department of Psychology and associate faculty in the Biodesign Center for Biocomputing, Security and Society, was a fan of kombucha herself, before delving deeper. \"Honestly, I started working on kombucha because I really liked the taste of it. I started brewing it in my kitchen for my own consumption. After brewing it for a couple of months, I would come home from work and just stare at it, asking, 'how do you work.' Being a scientist, I got on google scholar to learn more, but I didn't find much.\" In response to this, Aktipis teamed up with other researchers to take all the pieces of the puzzle she had found in pre-existing literature and put them together see the bigger picture on how kombucha operates and how the different species of microbes interact and cooperate within. Alexander May, a prior researcher in Aktipis's lab, led the efforts to expand on this knowledge in a review paper published in PeerJ (The Journal of Life and Environmental Sciences). Arvind Varsani, an associate professor in the Biodesign Center for Fundamental and Applied Microbiomics and associate faculty in the Biodesign Center for Mechanisms of Evolution, and Carlo Maley, faculty in the School of Life Sciences and an associate professor in the Biodesign Center for Biocomputing, Security and Society, served as collaborators on the review paper. The paper deconstructed each component of the microbial system, offering insight into how the microbes interact and what resources they utilize as a by-product of the fermentative processes used for making kombucha. \"We think kombucha is important as a model system because it's an easy-to-grow microbial community that can potentially answer interesting questions about cooperation between different species,\" May said. \"Microbes (including the bacteria and yeast in kombucha) actually have a lot of complex social behaviors that scientists are only really starting to learn about. We think that by understanding what's going on at the small scale, we can get clues as to what happens at the larger scale and see if the same patterns even hold true in human societies. People have been eating fermented foods like kombucha for centuries, but it's only recently that scientists have started digging into the systems themselves to understand how and why they can benefit humans.\" Kombucha is made by first introducing sucrose to black or green tea, followed by the addition of kombucha liquid from a previous batch. A biofilm, also from a previous batch of kombucha, is then placed on top of the liquid, and the concoction is allowed to ferment for 10 to 14 days. Although this may seem nothing more than a straightforward recipe for making a tasty refreshment, these fermentative steps actually sustain a wide variety of microbes, illustrating various ecological concepts we usually only see in real-time with non-microscopic organisms. For example, the yeast found in the kombucha liquid produces invertase, an enzyme that bacteria and yeast use to metabolize sugars, as a public good. Similarly, bacteria produce a biofilm at the top of the batch that protects microbes from outside invaders, provides oxygen and offers space for the storage of resources. Ethanol and acid, the by-products of fermentation, also keep invaders at bay. However, there are many systems that have various microbial species at play, so why pick kombucha to illustrate these relationships? \"There is an ease of management that comes from it (because it is easy to make), but it also has a sort of complexity because it contains so many species, and in that way, it is similar to a microbial system you would see in nature,\" Aktipis said. \"It is at this really nice boundary between simplicity and complexity.\" Kombucha has proven to be an efficient way to study interspecies interactions on the microbial scale, but it has much more to offer. From this study, Aktipis and collaborators are working on using kombucha as a model to develop interventions for bettering human health. It has been recently brought into light how important the human microbiome is—the balance of microbes in our bodies, which we have co-evolved with since the dawn of humankind, is pivotal to human health. Throwing that balance off could have significant adverse effects, but treating humans with microbes could restore that balance. \"Right now, we are trying to develop kombucha as a system that could allow us to create new antimicrobial products, which are based on multiple species,\" Aktipis said. \"Whereas drugs are used to kill organisms, we want to ask, 'how can we cultivate a diverse microbial community that can outcompete pathogens.'\" To do this, researchers are taking kombucha and introducing new invaders or removing some chemical or microbial component. \"We are trying to figure out which parts of cooperation in kombucha are most important,\" Aktipis said. \"This paper is the tip of the iceberg of a whole research program we are designing.\" These researchers are the first to look into kombucha as a model system—Aktipis says this is a good reminder to be aware of the world around and to never stop asking 'why.' \"There is this tendency in science to only look at things that are already being studied. A lot of what we did with this kombucha project is coming back to the importance of observation, observing the natural world. I think that's been a little bit lost, and it's also much more fun to be aware of your world and to try to understand it.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Kombucha, a fermented tea beverage with an acidic and effervescent taste, is composed of a multispecies microbial ecosystem with complex interactions that are characterized by both cooperation and conflict. In kombucha, a complex community of bacteria and yeast initiates the fermentation of a starter tea (usually black or green tea with sugar), producing a biofilm that covers the liquid over several weeks. This happens through several fermentative phases that are characterized by cooperation and competition among the microbes within the kombucha solution. Yeast produce invertase as a public good that enables both yeast and bacteria to metabolize sugars. Bacteria produce a surface biofilm which may act as a public good providing protection from invaders, storage for resources, and greater access to oxygen for microbes embedded within it. The ethanol and acid produced during the fermentative process (by yeast and bacteria, respectively) may also help to protect the system from invasion by microbial competitors from the environment. Thus, kombucha can serve as a model system for addressing important questions about the evolution of cooperation and conflict in diverse multispecies systems. Further, it has the potential to be artificially selected to specialize it for particular human uses, including the development of antimicrobial ecosystems and novel materials. Finally, kombucha is easily-propagated, non-toxic, and inexpensive, making it an excellent system for scientific inquiry and citizen science. Cite this as May A, Narayanan S, Alcock J, Varsani A, Maley C, Aktipis A. 2019 . Kombucha: a novel model system for cooperation and conflict in a complex multi-species microbial ecosystem . PeerJ 7 : e7565 Main article text Introduction Kombucha is a traditional tea beverage fermented by a symbiotic community of acetic acid bacteria (AAB) ( Acetobacteraceae ) and osmophilic yeast ( De Filippis et al., 2018 ). While the origins of the beverage are uncertain, records of the drink are found in early 19th century Russia ( Dufresne & Farnworth, 2000 ). There is variation on the specifics of kombucha fermentation, but the typical process proceeds as follows: black or green tea is brewed for at least 5 min, supplemented with sucrose (5–10% (w/v)), cooled to room temperature (20 °C), and then inoculated with kombucha liquid (usually 10–20% (v/v)) from a previous batch ( Jayabalan et al., 2014 ). A mature bacterial cellulose (BC) biofilm from a previously brewed kombucha culture (often called a “mother” or SCOBY, for Symbiotic Community of Bacteria and Yeast) is typically placed on top of the solution and allowed to ferment for 10–14 days. The presence of a carbon source in the solution, typically sucrose, initiates a cascade of metabolic processes that generates a carbonated and slightly acidic drink at the end of the primary fermentation cycle. One of the more striking aspects of the system is the floating cellulose pellicle that forms in tandem with fermentation; this biofilm is produced by the bacteria and encapsulates a microbial community within it ( Marsh et al., 2014 ). The dominant bacterial genus in the system is Komagataeibacter (formerly Gluconacetobacter , and prior to that, Acetobacter , Yamada et al., 2012 ) ( Marsh et al., 2014 ; Chakravorty et al., 2016 ) with numerous species identified within various kombucha cultures. These include Komagataeibacter xylinus ( Reva et al., 2015 ; De Filippis et al., 2018 ), Komagataeibacter intermedius ( Dos Santos et al., 2015 ; Reva et al., 2015 ; Gaggìa et al., 2019 ), Komagataeibacter rhaeticus ( Machado et al., 2016 ; Semjonovs et al., 2017 ; Gaggìa et al., 2019 ), Komagataeibacter saccharivorans ( Reva et al., 2015 ; De Filippis et al., 2018 ), and Komagataeibacter kombuchae ( Reva et al., 2015 ). Another AAB genus often found in kombucha cultures is Gluconobacter ( Reva et al., 2015 ; Chakravorty et al., 2016 ; Gaggìa et al., 2019 ). The yeast species in the system are even more variable, and can include yeast in the genera Zygosaccharomyces, Candida, Torulaspora, Pichia, Brettanomyces/Dekkera, Schizosaccharomyces , and Saccharomyces ( Mayser et al., 1995 ; Teoh, Heard & Cox, 2004 ; Marsh et al., 2014 ; Jayabalan et al., 2014 ; Reva et al., 2015 ). The microbial profiles of kombucha seem to vary partly based on geographical origin ( Mayser et al., 1995 ; Marsh et al., 2014 ), and the composition of the kombucha changes over time as it progresses through fermentation ( Marsh et al., 2014 ). This process involves the enzymatic cleavage of sucrose and the subsequent processing of its monomer components into ethanol, acids, cellulose, and carbon dioxide ( Jayabalan et al., 2014 ; Chakravorty et al., 2016 ). Brewed kombucha has antimicrobial properties that persist even with neutralization of the solution to pH 7 and thermal denaturation at 80 °C for 30 min ( Sreeramulu, Zhu & Knol, 2000 ). In this manuscript, we describe the potential uses of kombucha as a model system for studying cooperative and competitive interactions, and we also discuss the potential human uses of kombucha and kombucha-generated biofilms for nutrition, human health and industrial applications. Survey methodology This review was assembled via electronic searches on various platforms, including Google Scholar, Web of Science, and PubMed. In order to gain a background understanding of kombucha as a scientific model, searches were focused on the terminology adjacent to it and other fermented foods: “kombucha”, “kombucha tea,” “tea fungus,” “fermented tea,” “fermentation,” “SCOBY,” “biofilm,” “pellicle,” Examples of other fermented foods were examined as well, particularly those already used as model systems, such as sourdough and yogurt. Further development of the literature collection used keywords associated with microbial ecology and social interactions between microbes, such as: “cooperation,” “conflict,” “symbiosis,” “syntrophy,” “cheater.” Searches evolved to include aspects of the four phases of development known to occur during kombucha fermentation: invertase production, ethanol fermentation, ethanol oxidation and acidification, and biofilm formation; many of these sources primarily used other organism models as references. Each of these sources provided a wealth of data far beyond the scope of this paper, and thus were culled down to focus on<|im_end|> <|im_start|>assistant In today's health-conscious community, kombucha is all the rave. Its appeal comes from its accessibility and alleged health benefits, which range from introducing probiotics to killing deleterious bacteria in the human body. But as is the case for many things in science, there is more to kombucha than meets the eye—literally. The microscopic microbes inhabiting this fermented concoction could offer insight into how microbial communities interact, more specifically on how symbiotic relationships form within complex microbial models. Athena Aktipis, an assistant professor in the Department of Psychology and associate faculty in the Biodesign Center for Biocomputing, Security and Society, was a fan of kombucha herself, before delving deeper. "Honestly, I started working on kombucha because I really liked the taste of it. I started brewing it in my kitchen for my own consumption. After brewing it for a couple of months, I would come home from work and just stare at it, asking, 'how do you work.' Being a scientist, I got on google scholar to learn more, but I didn't find much." In response to this, Aktipis teamed up with other researchers to take all the pieces of the puzzle she had found in pre-existing literature and put them together see the bigger picture on how kombucha operates and how the different species of microbes interact and cooperate within. Alexander May, a prior researcher in Aktipis's lab, led the efforts to expand on this knowledge in a review paper published in PeerJ (The Journal of Life and Environmental Sciences). Arvind Varsani, an associate professor in the Biodesign Center for Fundamental and Applied Microbiomics and associate faculty in the Biodesign Center for Mechanisms of Evolution, and Carlo Maley, faculty in the School of Life Sciences and an associate professor in the Biodesign Center for Biocomputing, Security and Society, served as collaborators on the review paper. The paper deconstructed each component of the microbial system, offering insight into how the microbes interact and what resources they utilize as a by-product of the fermentative processes used for making kombucha. "We think kombucha is important as a model system because it's an easy-to-grow microbial community that can potentially answer interesting questions about cooperation between different species," May said. "Microbes (including the bacteria and yeast in kombucha) actually have a lot of complex social behaviors that scientists are only really starting to learn about. We think that by understanding what's going on at the small scale, we can get clues as to what happens at the larger scale and see if the same patterns even hold true in human societies. People have been eating fermented foods like kombucha for centuries, but it's only recently that scientists have started digging into the systems themselves to understand how and why they can benefit humans." Kombucha is made by first introducing sucrose to black or green tea, followed by the addition of kombucha liquid from a previous batch. A biofilm, also from a previous batch of kombucha, is then placed on top of the liquid, and the concoction is allowed to ferment for 10 to 14 days. Although this may seem nothing more than a straightforward recipe for making a tasty refreshment, these fermentative steps actually sustain a wide variety of microbes, illustrating various ecological concepts we usually only see in real-time with non-microscopic organisms. For example, the yeast found in the kombucha liquid produces invertase, an enzyme that bacteria and yeast use to metabolize sugars, as a public good. Similarly, bacteria produce a biofilm at the top of the batch that protects microbes from outside invaders, provides oxygen and offers space for the storage of resources. Ethanol and acid, the by-products of fermentation, also keep invaders at bay. However, there are many systems that have various microbial species at play, so why pick kombucha to illustrate these relationships? "There is an ease of management that comes from it (because it is easy to make), but it also has a sort of complexity because it contains so many species, and in that way, it is similar to a microbial system you would see in nature," Aktipis said. "It is at this really nice boundary between simplicity and complexity." Kombucha has proven to be an efficient way to study interspecies interactions on the microbial scale, but it has much more to offer. From this study, Aktipis and collaborators are working on using kombucha as a model to develop interventions for bettering human health. It has been recently brought into light how important the human microbiome is—the balance of microbes in our bodies, which we have co-evolved with since the dawn of humankind, is pivotal to human health. Throwing that balance off could have significant adverse effects, but treating humans with microbes could restore that balance. "Right now, we are trying to develop kombucha as a system that could allow us to create new antimicrobial products, which are based on multiple species," Aktipis said. "Whereas drugs are used to kill organisms, we want to ask, 'how can we cultivate a diverse microbial community that can outcompete pathogens.'" To do this, researchers are taking kombucha and introducing new invaders or removing some chemical or microbial component. "We are trying to figure out which parts of cooperation in kombucha are most important," Aktipis said. "This paper is the tip of the iceberg of a whole research program we are designing." These researchers are the first to look into kombucha as a model system—Aktipis says this is a good reminder to be aware of the world around and to never stop asking 'why.' "There is this tendency in science to only look at things that are already being studied. A lot of what we did with this kombucha project is coming back to the importance of observation, observing the natural world. I think that's been a little bit lost, and it's also much more fun to be aware of your world and to try to understand it." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Gas fermentation is one of the promising bioprocesses to convert CO 2 or syngas to important chemicals. Thermophilic gas fermentation of volatile chemicals has the potential for the development of consolidated bioprocesses that can simultaneously separate products during fermentation. This study reports the production of acetone from CO 2 and H 2 , CO, or syngas by introducing the acetone production pathway using acetyl–coenzyme A (Ac-CoA) and acetate produced via the Wood–Ljungdahl pathway in Moorella thermoacetica . Reducing the carbon flux from Ac-CoA to acetate through genetic engineering successfully enhanced acetone productivity, which varied on the basis of the gas composition. The highest acetone productivity was obtained with CO–H 2 , while autotrophic growth collapsed with CO 2 –H 2 . By adding H 2 to CO, the acetone productivity from the same amount of carbon source increased compared to CO gas only, and the maximum specific acetone production rate also increased from 0.04 to 0.09 g-acetone/g-dry cell/h. Our development of the engineered thermophilic acetogen M. thermoacetica , which grows at a temperature higher than the boiling point of acetone (58 °C), would pave the way for developing a consolidated process with simplified and cost-effective recovery via condensation following gas fermentation. Introduction Metabolic engineering of thermophilic microorganisms has several benefits compared to mesophilic microorganisms, such as a lower contamination risk, less energy required for cooling the fermentation system, and a faster production rate due to the advantageous thermodynamics (Sonnleitner and Fiechter 1983 ). One potential application is bioreactive distillation, which involves simultaneously fermenting volatile chemicals and collecting them by distillation (Zeldes et al. 2018 ). The bioreactive distillation has fewer steps and a lower cost of purification of target chemicals compared to the conventional fermentation processes. In addition, maintenance of the low concentration of fermentation products prevents the exposure of the chemicals to bacteria that inhibits bacterial growth and metabolism. Acetone is a volatile chemical used as an industrial solvent and a precursor of important downstream products (Anbarasan et al. 2012 ; Peters et al. 2015 ). Currently, industrial acetone production depends on petrochemical phenol production via the cumene process. Although the cumene process is cost-effective and widely used, it has the risk of shortage of nonrenewable fossil feedstock. Therefore, there is a demand for an alternative process, and acetone production by bioconversion from renewable feedstock is one option. Historically, acetone production by bioconversion has been studied as acetone-butanol-ethanol (ABE) fermentation. However, the focus is on alcohol production, and much effort is made for inhibiting acetone production as a by-product (Jiang et al. 2009 ; Luo et al. 2016 ; Xu et al. 2015 ). Metabolic engineering enables the development of acetone-producing strains such as Escherichia coli as the host (Bermejo et al. 1998 ). A few studies have reported thermophilic acetone fermentation from carbohydrates (Shaw et al. 2015 ; Straub et al. 2020 ). In addition, metabolic engineering of Synechocystis sp. PCC 6803, Acetobacterium woodii , and Clostridium ljungdahlii makes acetone production possible from CO 2 or CO gas as the carbon source (Banerjee et al. 2014 ; Hoffmeister et al. 2016 ; Zhou et al. 2012 ) by mesophilic organisms. CO 2 fixation by mixotrophy improves conversion of organic compounds to acetone, as shown by an engineered strain of C. ljungdahlii (Jones et al. 2016 ). Among the various bioconversion applications, gas fermentation utilizing anaerobic acetogenic bacteria (acetogen) is attracting increasing attention. Gas fermentation is economically and environmentally friendly because inexpensive gaseous waste feedstock, such as steel mill waste gas or syngas primarily comprising CO and H 2 , can be used (Claassens et al. 2016 ; Durre and Eikmanns 2015 ; Liew et al. 2016 ). Whereas practical applications still demand higher productivity and cost-effective processes, the combination of bioreactive distillation as the purification process with gas fermentation can reduce waste and cost, in addition to engineering the metabolism of acetogens. The economic feasibility of acetone production from syngas by bioreactive distillation has been evaluated using hypothetical systems with engineered thermophilic strains of Moorella thermoacetica (Redl et al. 2017 ). The bioreactive distillation also has advantages to remove acetone that has inhibitory effect on the cell growth and could maintain high cell density without need to replace culture medium if appropriate bioreactors are used. However, the detailed metabolic design and construction of the thermophilic strains for gas fermentation, their availability, and, therefore, experimental data to support the system are missing. This study genetically engineered the thermophilic homoacetogen M. thermoacetica to produce acetone from gaseous substrates at high temperature. We also developed a strategy to increase the carbon flux to acetone by genetic engineering and evaluated the productivity from CO 2 –H 2 , CO and CO–H 2 as a model syngas. To our knowledge, this is the first study to provide strains for thermophilic gas fermentation of acetone. Materials and methods Bacterial strains and growth conditions We used M. thermoacetica ATCC 39073 and its derivatives in this study (Table 1 ). Modified ATCC1754 PETC medium comprising 1.0 g of NH 4 Cl, 0.1 g of KCl, 0.2 g of MgSO 4 ·7H 2 O, 0.8 g of NaCl, 0.1 g of KH 2 PO 4 , 0.02 g of CaCl 2 ·2H 2 O, 2.0 g of NaHCO 3 , 10 mL of trace elements, 10 mL of Wolfe’s vitamin solution (Tanner 1989 ), and 1.0 mg of resazurin/L of deionized water was used as the basal medium (Tanner et al. 1993 ). The pH was adjusted to 6.9. The medium was prepared anaerobically by boiling and cooling under a N 2 –CO 2 (80:20) mixed-gas atmosphere. After cooling, the medium was dispensed to 125-mL serum bottles under a N 2 –CO 2 mixed-gas atmosphere. The serum bottles were crimp-sealed and autoclaved. Table 1 Strains and plasmids used in this study Full size table Before starting culture, we added yeast extract and l -cysteine·HCl·H 2 O to reach a final concentration of 1.0 and 1.2 g/L, respectively. 2.0 g/L of fructose was added for routine cultivation", "role": "user" }, { "content": "Acetone, a volatile solvent used for everything from removing nail polish and cleaning textiles to manufacturing plastics, could get a sustainability boost from a new strain of bacteria engineered by a research team based in Japan. They published the details of the heat-loving, acetone-producing bacteria called Moorella thermoacetica on April 23 in AMB Express. Acetone is typically produced through the widely used cumene method, which is cost-effective but not sustainable. The process, developed in 1942, involves converting two non-renewable resources into acetone and phenol, another chemical that helps manufacture a number of materials, including plastics. More environmentally friendly options exist—including gas fermentation, a bioprocess that converts carbon dioxide, monoxide and hydrogen into chemicals and fuels—but they tend to be cumbersome and costly, according to Yutaka Nakashimada, professor in the Graduate School of Integrated Sciences for Life, Hiroshima University, who led the research. One of the major expenses is the downstream processing, which involves separating out the desired chemicals from the other materials. \"We thought the key is a simultaneous separation of the product from the ongoing fermentation,\" Nakashimada said. \"Our choice was to produce volatile chemicals by using a group of bacteria thriving at high temperatures.\" The bacteria, M. thermoacetica, eat the gaseous feedstocks of hydrogen, carbon dioxide and monoxide—which can be procured from renewable resources—to produce acetone. Since they grow at a temperature higher than the boiling point of acetone, the acetone produced is a gas that evaporates and can be distilled as the bacteria make it. It streamlines the traditional system into a simultaneous process. \"Our development of the engineered bacteria could pave the way for developing a consolidated process with simplified and cost-effective recovery via condensation following gas fermentation on a large scale suitable for industrial production,\" said paper co-first author Junya Kato, specially appointed assistant professor in the Graduate School of Integrated Sciences for Life, Hiroshima University. To develop this productive bacteria strain, the researchers genetically engineered bacteria with modified metabolism processes. \"To our knowledge, this is the first study to provide strains of bacteria that thrive at high temperatures for gas fermentation of acetone,\" Kato said. \"Although further study would be needed to improve the productivity for realization of the industrial applications, the gas fermentation process can be simpler and more cost-effective than before.\" The researchers plan to scale their work and study the productivity of their bacteria in industrial conditions. \"We may need to genetically engineer the metabolism of the strain further,\" Nakashimada said. \"Our ultimate goal is the industrialization of the gas fermentation of the 'gas-to-gas' process that is simpler and lower-cost.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Gas fermentation is one of the promising bioprocesses to convert CO 2 or syngas to important chemicals. Thermophilic gas fermentation of volatile chemicals has the potential for the development of consolidated bioprocesses that can simultaneously separate products during fermentation. This study reports the production of acetone from CO 2 and H 2 , CO, or syngas by introducing the acetone production pathway using acetyl–coenzyme A (Ac-CoA) and acetate produced via the Wood–Ljungdahl pathway in Moorella thermoacetica . Reducing the carbon flux from Ac-CoA to acetate through genetic engineering successfully enhanced acetone productivity, which varied on the basis of the gas composition. The highest acetone productivity was obtained with CO–H 2 , while autotrophic growth collapsed with CO 2 –H 2 . By adding H 2 to CO, the acetone productivity from the same amount of carbon source increased compared to CO gas only, and the maximum specific acetone production rate also increased from 0.04 to 0.09 g-acetone/g-dry cell/h. Our development of the engineered thermophilic acetogen M. thermoacetica , which grows at a temperature higher than the boiling point of acetone (58 °C), would pave the way for developing a consolidated process with simplified and cost-effective recovery via condensation following gas fermentation. Introduction Metabolic engineering of thermophilic microorganisms has several benefits compared to mesophilic microorganisms, such as a lower contamination risk, less energy required for cooling the fermentation system, and a faster production rate due to the advantageous thermodynamics (Sonnleitner and Fiechter 1983 ). One potential application is bioreactive distillation, which involves simultaneously fermenting volatile chemicals and collecting them by distillation (Zeldes et al. 2018 ). The bioreactive distillation has fewer steps and a lower cost of purification of target chemicals compared to the conventional fermentation processes. In addition, maintenance of the low concentration of fermentation products prevents the exposure of the chemicals to bacteria that inhibits bacterial growth and metabolism. Acetone is a volatile chemical used as an industrial solvent and a precursor of important downstream products (Anbarasan et al. 2012 ; Peters et al. 2015 ). Currently, industrial acetone production depends on petrochemical phenol production via the cumene process. Although the cumene process is cost-effective and widely used, it has the risk of shortage of nonrenewable fossil feedstock. Therefore, there is a demand for an alternative process, and acetone production by bioconversion from renewable feedstock is one option. Historically, acetone production by bioconversion has been studied as acetone-butanol-ethanol (ABE) fermentation. However, the focus is on alcohol production, and much effort is made for inhibiting acetone production as a by-product (Jiang et al. 2009 ; Luo et al. 2016 ; Xu et al. 2015 ). Metabolic engineering enables the development of acetone-producing strains such as Escherichia coli as the host (Bermejo et al. 1998 ). A few studies have reported thermophilic acetone fermentation from carbohydrates (Shaw et al. 2015 ; Straub et al. 2020 ). In addition, metabolic engineering of Synechocystis sp. PCC 6803, Acetobacterium woodii , and Clostridium ljungdahlii makes acetone production possible from CO 2 or CO gas as the carbon source (Banerjee et al. 2014 ; Hoffmeister et al. 2016 ; Zhou et al. 2012 ) by mesophilic organisms. CO 2 fixation by mixotrophy improves conversion of organic compounds to acetone, as shown by an engineered strain of C. ljungdahlii (Jones et al. 2016 ). Among the various bioconversion applications, gas fermentation utilizing anaerobic acetogenic bacteria (acetogen) is attracting increasing attention. Gas fermentation is economically and environmentally friendly because inexpensive gaseous waste feedstock, such as steel mill waste gas or syngas primarily comprising CO and H 2 , can be used (Claassens et al. 2016 ; Durre and Eikmanns 2015 ; Liew et al. 2016 ). Whereas practical applications still demand higher productivity and cost-effective processes, the combination of bioreactive distillation as the purification process with gas fermentation can reduce waste and cost, in addition to engineering the metabolism of acetogens. The economic feasibility of acetone production from syngas by bioreactive distillation has been evaluated using hypothetical systems with engineered thermophilic strains of Moorella thermoacetica (Redl et al. 2017 ). The bioreactive distillation also has advantages to remove acetone that has inhibitory effect on the cell growth and could maintain high cell density without need to replace culture medium if appropriate bioreactors are used. However, the detailed metabolic design and construction of the thermophilic strains for gas fermentation, their availability, and, therefore, experimental data to support the system are missing. This study genetically engineered the thermophilic homoacetogen M. thermoacetica to produce acetone from gaseous substrates at high temperature. We also developed a strategy to increase the carbon flux to acetone by genetic engineering and evaluated the productivity from CO 2 –H 2 , CO and CO–H 2 as a model syngas. To our knowledge, this is the first study to provide strains for thermophilic gas fermentation of acetone. Materials and methods Bacterial strains and growth conditions We used M. thermoacetica ATCC 39073 and its derivatives in this study (Table 1 ). Modified ATCC1754 PETC medium comprising 1.0 g of NH 4 Cl, 0.1 g of KCl, 0.2 g of MgSO 4 ·7H 2 O, 0.8 g of NaCl, 0.1 g of KH 2 PO 4 , 0.02 g of CaCl 2 ·2H 2 O, 2.0 g of NaHCO 3 , 10 mL of trace elements, 10 mL of Wolfe’s vitamin solution (Tanner 1989 ), and 1.0 mg of resazurin/L of deionized water was used as the basal medium (Tanner et al. 1993 ). The pH was adjusted to 6.9. The medium was prepared anaerobically by boiling and cooling under a N 2 –CO 2 (80:20) mixed-gas atmosphere. After cooling, the medium was dispensed to 125-mL serum bottles under a N 2 –CO 2 mixed-gas atmosphere. The serum bottles were crimp-sealed and autoclaved. Table 1 Strains and plasmids used in this study Full size table Before starting culture, we added yeast extract and l -cysteine·HCl·H 2 O to reach a final concentration of 1.0 and 1.2 g/L, respectively. 2.0 g/L of fructose was added for routine cultivation<|im_end|> <|im_start|>assistant Acetone, a volatile solvent used for everything from removing nail polish and cleaning textiles to manufacturing plastics, could get a sustainability boost from a new strain of bacteria engineered by a research team based in Japan. They published the details of the heat-loving, acetone-producing bacteria called Moorella thermoacetica on April 23 in AMB Express. Acetone is typically produced through the widely used cumene method, which is cost-effective but not sustainable. The process, developed in 1942, involves converting two non-renewable resources into acetone and phenol, another chemical that helps manufacture a number of materials, including plastics. More environmentally friendly options exist—including gas fermentation, a bioprocess that converts carbon dioxide, monoxide and hydrogen into chemicals and fuels—but they tend to be cumbersome and costly, according to Yutaka Nakashimada, professor in the Graduate School of Integrated Sciences for Life, Hiroshima University, who led the research. One of the major expenses is the downstream processing, which involves separating out the desired chemicals from the other materials. "We thought the key is a simultaneous separation of the product from the ongoing fermentation," Nakashimada said. "Our choice was to produce volatile chemicals by using a group of bacteria thriving at high temperatures." The bacteria, M. thermoacetica, eat the gaseous feedstocks of hydrogen, carbon dioxide and monoxide—which can be procured from renewable resources—to produce acetone. Since they grow at a temperature higher than the boiling point of acetone, the acetone produced is a gas that evaporates and can be distilled as the bacteria make it. It streamlines the traditional system into a simultaneous process. "Our development of the engineered bacteria could pave the way for developing a consolidated process with simplified and cost-effective recovery via condensation following gas fermentation on a large scale suitable for industrial production," said paper co-first author Junya Kato, specially appointed assistant professor in the Graduate School of Integrated Sciences for Life, Hiroshima University. To develop this productive bacteria strain, the researchers genetically engineered bacteria with modified metabolism processes. "To our knowledge, this is the first study to provide strains of bacteria that thrive at high temperatures for gas fermentation of acetone," Kato said. "Although further study would be needed to improve the productivity for realization of the industrial applications, the gas fermentation process can be simpler and more cost-effective than before." The researchers plan to scale their work and study the productivity of their bacteria in industrial conditions. "We may need to genetically engineer the metabolism of the strain further," Nakashimada said. "Our ultimate goal is the industrialization of the gas fermentation of the 'gas-to-gas' process that is simpler and lower-cost." <|im_end|>

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2,101

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract We evaluated the influence of impurities in the vacuum chamber used for the fabrication of organic light-emitting diodes on the lifetime of the fabricated devices and found a correlation between lifetime and the device fabrication time. The contact angle of the ITO substrates stored the chamber under vacuum were used to evaluate chamber cleanliness. Liquid chromatography-mass spectrometry was performed on Si wafers stored in the vacuum chamber before device fabrication to examine the impurities in the chamber. Surprisingly, despite the chamber and evaporation sources being at room temperature, a variety of materials were detected, including previously deposited materials and plasticizers from the vacuum chamber components. We show that the impurities, and not differences in water content, in the chamber were the source of lifetime variations even when the duration of exposure to impurities only varied before and after deposition of the emitter layer. These results suggest that the impurities floating in the vacuum chamber significantly impact lifetime values and reproducibility. Introduction Advances in carbon-based semiconductors have organic electronics close to realizing a wide variety of lightweight, low-cost, flexible, and energy-efficient devices including light-emitting diodes, solar cells, and transistors that will have an enormous impact on our daily lives. Organic light-emitting diodes (OLEDs), the most advanced of these technologies, already form the basis for a new generation of commercially viable smart phone displays and large-screen televisions 1 and are being developed for flexible lighting and display panels, which cannot be realized with inorganic LED or LCD technology 2 , 3 . Although progress has been rapid regarding many facets of the performance, processing, and development of organic electronics, difficulty obtaining reproducible operational lifetimes for organic devices fabricated with the same structure and materials, even when made in the same laboratory, is a problem that continues to mystify researchers. Here we show that small amounts of impurities floating in the chamber used to fabricate vacuum-deposited OLEDs are a source of large variations in operational lifetime even when the time spent in the chamber differs by only a short amount. Our results suggest that reproducible and long lifetimes can be obtained in OLEDs and other organic devices that include a vacuum-deposition step, such as solar cells and transistors, without the use of ultra-high vacuum chambers by controlling the device fabrication and cleanliness of the chamber. Furthermore, the strong influence of miniscule amounts of impurities on lifetime found here highlights a major challenge facing organic devices fabricated by spin-coating, inkjet, and other printing methods, for which elimination of impurities is more difficult. Practical OLEDs rely on organic materials with high electroluminescence efficiencies and good stability under electrical operation. Internal quantum efficiencies ( η int ) of 100% have already been achieved through the development of second-generation emitter materials based on phosphorescence 4 and, more recently, third-generation emitters based on thermally-activated delayed fluorescence (TADF), with TADF emitters eliminating the need for the rare metals used in phosphorescent materials 5 , 6 . A long lifetime is also critical for commercial OLEDs, so research to develop durable device structures, reduce driving current by improving light out-coupling efficiency 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , and understand degradation mechanisms is in progress worldwide 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 . The lifetime of OLEDs, which combine a large number of organic materials, must be evaluated with good reproducibility to advance this area, but experimentally measured lifetimes often vary depending on conditions related to things such as the vacuum chamber, location, date, and operator. The difference between lifetimes measured for devices fabricated in academic laboratories and for those being mass produced can be particularly large. However, very few studies discuss why lifetimes for OLEDs fabricated with the same structure and materials can vary so widely. The degradation mechanisms affecting the lifetime of OLEDs can be either intrinsic or extrinsic. Degradation mechanisms intrinsic to the organic materials or device structure include interfacial degradation such as the organic/cathode or organic/anode interface 17 , 18 , trap formation 19 , and polaron-exciton interactions 20 . Chemical reactions and Joule heating have also been reported to cause bulk degradation 21 , 22 , 23 . Thus, researchers have been actively developing materials and device structures to prevent such intrinsic degradation. Impurities on the indium tin oxide (ITO) substrate surface are one source of extrinsic degradation that can lower lifetime, and the characteristics and lifetime of OLEDs can be improved by exposure to UV or O 2 plasma, which decompose organic impurities on the ITO surface 26 , 27 , 28 . Contamination from the outgassing of sealing resin 29 and halogen impurities in the organic material 30 , 31 are another two sources of degradation that have been identified. Furthermore, residual water in the vacuum chamber during fabrication 24 , 25 , which particularly affects the interface between the hole transport layer and the emission layer, has been shown to reduce lifetime by participating in degradation-inducing electrochemical reactions with the organic materials. However, the influence of impurities other that water in the deposition chamber is still poorly studied even though the possibility of such impurities being in the chamber is high. Impurities in the vacuum chamber can arise from a variety of sources that are often overlooked. Although the development oil-free vacuum pumps eliminated oil pollution as a problem, many key components of the vacuum chamber still require vacuum grease, which can outgas when heated such as by the evaporation sources, and residual traces of the oil used during the processing the stainless steel parts of a chamber can also be released in vacuum 32 , 33 , 34 . Most chambers rely on some polymer-based parts such as O-rings and insulating resins, which have outgassing rates much higher than those of metal components, and such polymer materials can outgas unreacted components ( e.g. , plasticizers and curing agents),", "role": "user" }, { "content": "Reproducibility is a necessity for science but has often eluded researchers studying the lifetime of organic light-emitting diodes (OLEDs). Recent research from Japan sheds new light on why: impurities present in the vacuum chamber during fabrication but in amounts so small that they are easily overlooked. Organic light-emitting diodes use a stack of organic layers to convert electricity into light, and these organic layers are most commonly fabricated by heating source materials in vacuum to evaporate and deposit them onto a lower temperature substrate. While issues affecting the efficiency of OLEDs are already well understood, a complete picture of exactly how and why OLEDs degrade and lose brightness over time is still missing. Complicating matters is that devices fabricated with seemingly the same procedures and conditions but by different research groups often degrade at vastly different rates even when the initial performance is the same. Unable to attribute these reproducibility issues to known sources such as the amount of residual water in the chamber and the purity of the starting materials, a report published online in Scientific Reports on December 13, 2016, adds a new piece to the puzzle by focusing on the analysis of the environment in the vacuum chamber. \"Although we often idealize vacuums as being clean environments, we detected many impurities floating in the vacuum even when the deposition chamber is at room temperature,\" says lead author Hiroshi Fujimoto, chief researcher at Fukuoka i3-Center for Organic Photonics and Electronics Research (i3-OPERA) and visiting associate professor of Kyushu University. Because of these impurities in the deposition chamber, the researchers found that the time until an OLED under operation dims by a given amount because of degradation, known as the lifetime, sharply increased for OLEDs that spent a shorter time in the deposition chamber during fabrication. This trend remained even after considering changes in residual water and source material purity, indicating the importance of controlling and minimizing the device fabrication time, a rarely discussed parameter. Research partners at Sumika Chemical Analysis Service Ltd. (SCAS) confirmed an increase of accumulated impurities with time by analyzing the materials that deposited on extremely clean silicon wafers that were stored in the deposition chamber when OLED materials were not being evaporated. Using a technique called liquid chromatography-mass spectrometry, the researchers found that many of the impurities could be traced to previously deposited materials and plasticizers from the vacuum chamber components. \"Really small amounts of these impurities get incorporated into the fabricated devices and are causing large changes in the lifetime,\" says Professor Chihaya Adachi, director of Kyushu University's Center for Organic Photonics and Electronics Research (OPERA), which also took part in the study. In fact, the new results suggest that the impurities amount to less than even a single molecular layer. To improve lifetime reproducibility, a practice often adopted in industry is the use of dedicated deposition chambers for specific materials, but this can be difficult in academic labs, where often only a limited number of deposition systems are available for testing a wide variety of new materials. In these cases, deposition chamber design and cleaning in addition to control of the deposition time are especially important. \"This is an excellent reminder of just how careful we need to be to do good, reproducible science,\" comments Professor Adachi. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract We evaluated the influence of impurities in the vacuum chamber used for the fabrication of organic light-emitting diodes on the lifetime of the fabricated devices and found a correlation between lifetime and the device fabrication time. The contact angle of the ITO substrates stored the chamber under vacuum were used to evaluate chamber cleanliness. Liquid chromatography-mass spectrometry was performed on Si wafers stored in the vacuum chamber before device fabrication to examine the impurities in the chamber. Surprisingly, despite the chamber and evaporation sources being at room temperature, a variety of materials were detected, including previously deposited materials and plasticizers from the vacuum chamber components. We show that the impurities, and not differences in water content, in the chamber were the source of lifetime variations even when the duration of exposure to impurities only varied before and after deposition of the emitter layer. These results suggest that the impurities floating in the vacuum chamber significantly impact lifetime values and reproducibility. Introduction Advances in carbon-based semiconductors have organic electronics close to realizing a wide variety of lightweight, low-cost, flexible, and energy-efficient devices including light-emitting diodes, solar cells, and transistors that will have an enormous impact on our daily lives. Organic light-emitting diodes (OLEDs), the most advanced of these technologies, already form the basis for a new generation of commercially viable smart phone displays and large-screen televisions 1 and are being developed for flexible lighting and display panels, which cannot be realized with inorganic LED or LCD technology 2 , 3 . Although progress has been rapid regarding many facets of the performance, processing, and development of organic electronics, difficulty obtaining reproducible operational lifetimes for organic devices fabricated with the same structure and materials, even when made in the same laboratory, is a problem that continues to mystify researchers. Here we show that small amounts of impurities floating in the chamber used to fabricate vacuum-deposited OLEDs are a source of large variations in operational lifetime even when the time spent in the chamber differs by only a short amount. Our results suggest that reproducible and long lifetimes can be obtained in OLEDs and other organic devices that include a vacuum-deposition step, such as solar cells and transistors, without the use of ultra-high vacuum chambers by controlling the device fabrication and cleanliness of the chamber. Furthermore, the strong influence of miniscule amounts of impurities on lifetime found here highlights a major challenge facing organic devices fabricated by spin-coating, inkjet, and other printing methods, for which elimination of impurities is more difficult. Practical OLEDs rely on organic materials with high electroluminescence efficiencies and good stability under electrical operation. Internal quantum efficiencies ( η int ) of 100% have already been achieved through the development of second-generation emitter materials based on phosphorescence 4 and, more recently, third-generation emitters based on thermally-activated delayed fluorescence (TADF), with TADF emitters eliminating the need for the rare metals used in phosphorescent materials 5 , 6 . A long lifetime is also critical for commercial OLEDs, so research to develop durable device structures, reduce driving current by improving light out-coupling efficiency 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , and understand degradation mechanisms is in progress worldwide 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 . The lifetime of OLEDs, which combine a large number of organic materials, must be evaluated with good reproducibility to advance this area, but experimentally measured lifetimes often vary depending on conditions related to things such as the vacuum chamber, location, date, and operator. The difference between lifetimes measured for devices fabricated in academic laboratories and for those being mass produced can be particularly large. However, very few studies discuss why lifetimes for OLEDs fabricated with the same structure and materials can vary so widely. The degradation mechanisms affecting the lifetime of OLEDs can be either intrinsic or extrinsic. Degradation mechanisms intrinsic to the organic materials or device structure include interfacial degradation such as the organic/cathode or organic/anode interface 17 , 18 , trap formation 19 , and polaron-exciton interactions 20 . Chemical reactions and Joule heating have also been reported to cause bulk degradation 21 , 22 , 23 . Thus, researchers have been actively developing materials and device structures to prevent such intrinsic degradation. Impurities on the indium tin oxide (ITO) substrate surface are one source of extrinsic degradation that can lower lifetime, and the characteristics and lifetime of OLEDs can be improved by exposure to UV or O 2 plasma, which decompose organic impurities on the ITO surface 26 , 27 , 28 . Contamination from the outgassing of sealing resin 29 and halogen impurities in the organic material 30 , 31 are another two sources of degradation that have been identified. Furthermore, residual water in the vacuum chamber during fabrication 24 , 25 , which particularly affects the interface between the hole transport layer and the emission layer, has been shown to reduce lifetime by participating in degradation-inducing electrochemical reactions with the organic materials. However, the influence of impurities other that water in the deposition chamber is still poorly studied even though the possibility of such impurities being in the chamber is high. Impurities in the vacuum chamber can arise from a variety of sources that are often overlooked. Although the development oil-free vacuum pumps eliminated oil pollution as a problem, many key components of the vacuum chamber still require vacuum grease, which can outgas when heated such as by the evaporation sources, and residual traces of the oil used during the processing the stainless steel parts of a chamber can also be released in vacuum 32 , 33 , 34 . Most chambers rely on some polymer-based parts such as O-rings and insulating resins, which have outgassing rates much higher than those of metal components, and such polymer materials can outgas unreacted components ( e.g. , plasticizers and curing agents),<|im_end|> <|im_start|>assistant Reproducibility is a necessity for science but has often eluded researchers studying the lifetime of organic light-emitting diodes (OLEDs). Recent research from Japan sheds new light on why: impurities present in the vacuum chamber during fabrication but in amounts so small that they are easily overlooked. Organic light-emitting diodes use a stack of organic layers to convert electricity into light, and these organic layers are most commonly fabricated by heating source materials in vacuum to evaporate and deposit them onto a lower temperature substrate. While issues affecting the efficiency of OLEDs are already well understood, a complete picture of exactly how and why OLEDs degrade and lose brightness over time is still missing. Complicating matters is that devices fabricated with seemingly the same procedures and conditions but by different research groups often degrade at vastly different rates even when the initial performance is the same. Unable to attribute these reproducibility issues to known sources such as the amount of residual water in the chamber and the purity of the starting materials, a report published online in Scientific Reports on December 13, 2016, adds a new piece to the puzzle by focusing on the analysis of the environment in the vacuum chamber. "Although we often idealize vacuums as being clean environments, we detected many impurities floating in the vacuum even when the deposition chamber is at room temperature," says lead author Hiroshi Fujimoto, chief researcher at Fukuoka i3-Center for Organic Photonics and Electronics Research (i3-OPERA) and visiting associate professor of Kyushu University. Because of these impurities in the deposition chamber, the researchers found that the time until an OLED under operation dims by a given amount because of degradation, known as the lifetime, sharply increased for OLEDs that spent a shorter time in the deposition chamber during fabrication. This trend remained even after considering changes in residual water and source material purity, indicating the importance of controlling and minimizing the device fabrication time, a rarely discussed parameter. Research partners at Sumika Chemical Analysis Service Ltd. (SCAS) confirmed an increase of accumulated impurities with time by analyzing the materials that deposited on extremely clean silicon wafers that were stored in the deposition chamber when OLED materials were not being evaporated. Using a technique called liquid chromatography-mass spectrometry, the researchers found that many of the impurities could be traced to previously deposited materials and plasticizers from the vacuum chamber components. "Really small amounts of these impurities get incorporated into the fabricated devices and are causing large changes in the lifetime," says Professor Chihaya Adachi, director of Kyushu University's Center for Organic Photonics and Electronics Research (OPERA), which also took part in the study. In fact, the new results suggest that the impurities amount to less than even a single molecular layer. To improve lifetime reproducibility, a practice often adopted in industry is the use of dedicated deposition chambers for specific materials, but this can be difficult in academic labs, where often only a limited number of deposition systems are available for testing a wide variety of new materials. In these cases, deposition chamber design and cleaning in addition to control of the deposition time are especially important. "This is an excellent reminder of just how careful we need to be to do good, reproducible science," comments Professor Adachi. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract We investigate theoretically thermal and electrical conductances for the system consisting of a quantum dot (QD) connected both to a pair of Majorana fermions residing at the edges of a Kitaev wire and two metallic leads. We demonstrate that both quantities reveal pronounced resonances, whose positions can be controlled by tuning of an asymmetry of the couplings of the QD and a pair of MFs. Similar behavior is revealed for the thermopower, Wiedemann-Franz law and dimensionless thermoelectric figure of merit. The considered geometry can thus be used as a tuner of heat and charge transport assisted by MFs. Introduction Majorana fermions (MFs) are particles that are equivalent to their antiparticles. The corresponding concept was first proposed in the domain of high-energy physics, but later on existence of the elementary excitations of this type was predicted for certain condensed matter systems. Particularly, MFs emerge as quasiparticle excitations characterized by zero-energy modes 1 , 2 appearing at the edges of the 1D Kitaev wire 3 , 4 , 5 , 6 , 7 . Kitaev model is used to describe the emerging phenomena of p -wave and spinless topological superconductivity. Kitaev topological phase can be experimentally achieved in the geometry consisting of a semiconducting nanowire with spin-orbit interaction put in contact with s -wave superconducting material and placed in external magnetic field 8 , 9 . Other condensed matter systems were also proposed as candidates for the observation of MFs. They include ferromagnetic chains placed on top of superconductors with spin-orbit interaction 10 , 11 , fractional quantum Hall state with filling factor ν = 5/2 12 , three-dimensional topological insulators 13 and superconducting vortices 14 , 15 , 16 . MFs residing at the opposite edges of a Kitaev wire are elements of a robust nonlocal qubit which appears to be immune to the environment decoherence. This attracted the interest of the researchers working in the domain of quantum information and transport, as systems with MFs 17 , 18 , 19 can be in principle used as building blocks for the next generation of nanodevices 20 , 21 , including current switches 20 and quantum memory elements 21 . At the same time, similar systems were proposed as thermoelectric nanodevices 22 , 23 , 24 , 25 . In this work, following the proposals of thermoelectric detection of MF states 22 , 23 , 24 , 25 , we explore theoretically zero-bias thermal and electrical transport through one particular geometry consisting of an individual QD coupled both to a pair of MFs and metallic leads as shown in the Fig. 1(a) . The MFs reside at the edges of a topological U-shaped Kitaev wire, similar to the case of ref. 19 . The QD coupling to the MFs is considered to be asymmetric, while coupling to the metallic leads is symmetric, and MFs are supposed to overlap with each other. The results of our calculations clearly show that thermoelectric conductance, thermopower, Wiedemann-Franz law 26 and dimensionless thermoelectric figure of merit (ZT) as function of the QD electron energy demonstrate resonant behavior. Moreover, the position of the resonance can be tuned by changing the coupling amplitudes between the QD and the MFs, which allows the system to operate as a tuner of heat and charge assisted by MFs. Figure 1 ( a ) The sketch of the geometry we consider. Topological U-shaped Kitaev wire with a pair of MFs η A and η B is placed in contact with a QD, which is connected as well to two metallic reservoirs. The coupling of the QD to the MFs is asymmetric and is characterized by tunneling matrix elements λ A and λ B , while coupling to the metallic leads is symmetric and is characterized by the tunneling matrix element V . ε 2 denotes the coupling between two MF states. ( b ) Equivalent auxiliary setup (Kitaev dimer) resulting from the mapping of the original system onto the system with nonlocal fermion residing in QD 2 . t is tunneling matrix element between the QDs 1 and 2, Δ is the binding energy of the Cooper pair delocalized between them. Full size image Model For theoretical treatment of the setup depicted in the Fig. 1(a) , we use the Hamiltonian proposed by Liu and Baranger 27 : $$\\begin{array}{rcl} {\\mathcal H} & = & \\sum _{\\alpha k}{\\varepsilon }_{k}{c}_{\\alpha k}^{\\dagger }{c}_{\\alpha k}+{\\varepsilon }_{1}{d}_{1}^{\\dagger }{d}_{1}+V\\,\\sum _{\\alpha k}({c}_{\\alpha k}^{\\dagger }{d}_{1}+{\\rm{H}}.{\\rm{c}}\\mathrm{.)}\\\\ & & +{\\lambda }_{A}({d}_{1}-{d}_{1}^{\\dagger }){\\eta }_{A}+{\\lambda }_{B}({d}_{1}+{d}_{1}^{\\dagger }){\\eta }_{B}+i{\\varepsilon }_{2}{\\eta }_{A}{\\eta }_{B},\\end{array}$$ (1) where the electrons in the leads α = H , C (for hot and cold reservoirs, respectively) are described by the operators \${c}_{\\alpha k}^{\\dagger }\$ ( c αk ) for the creation (annihilation) of an electron in a quantum state labeled by the wave number k and energy ε k . For the QD \${d}_{1}^{\\dagger }\$ ( d 1 ) creates (annihilates) an electron in the state with the energy ε 1 . The energies of both electrons in the leads and QD are counted from the chemical potential μ (we consider only the limit of small source-drain bias, thus assuming that chemical potential is the same everywhere). V stands for the hybridization between the QD and the leads. The asymmetric coupling between the QD and MFs at the edges of the topological U-shaped Kitaev wire is described by the complex tunneling amplitudes λ A and λ B . Introduction of an asymmetry in the couplings can account for the presence of the magnetic flux which can be introduced via Peierls phase shift 27 . ε 2 stands for the overlap between the MFs. Without loss of generality, we can put: \${\\lambda }_{A}=\\frac{(t+{\\rm{\\Delta }})}{\\sqrt{2}}\$ and \${\\lambda }_{B}=i\\frac{({\\rm{\\Delta }}-t)}{\\sqrt{2}}\$ , respectively for the left \$({\\eta }_{A}={\\eta }_{A}^{\\dagger })\$ and right \$({\\eta }_{B}={\\eta }_{B}^{\\dagger })\$ MFs, and introduce an auxiliary nonlocal fermion \${d}_{2}=\\tfrac{1}{\\sqrt{2}}({\\eta }_{A}+i{\\eta }_{B})\$ 20 , 21 . The expressions for \${\\lambda }_{A}=|{\\lambda }_{A}|{e}^{i{\\varphi }_{A}}\$ and \${\\lambda }_{B}=|{\\lambda }_{B}|{e}^{i{\\varphi }_{B}}\$ constitute a convenient gauge for our problem. We put ϕ A = 0", "role": "user" }, { "content": "In March 1938, the young Italian physicist Ettore Majorana disappeared mysteriously, leaving his country's scientific community shaken. The episode remains unexplained, despite Leonardo Scascia's attempt to unravel the enigma in his book The Disappearance of Majorana (1975). Majorana, whom Enrico Fermi called a genius of Isaac Newton's stature, vanished a year after making his main contribution to science. In 1937, when he was only 30, Majorana hypothesized a particle that is its own anti-particle and suggested that it might be the neutrino, whose existence had recently been predicted by Fermi and Wolfgang Pauli. Eight decades later, Majorana fermions, or simply majoranas, are among the objects most studied by physicists. In addition to neutrinos—whose nature, whether or not they are majoranas, is one of the investigative goals of the mega-experiment Dune—another class not of fundamental particles but of quasi-particles or apparent particles has been investigated in the field of condensed matter. These Majorana quasi-particles can emerge as excitations in topological superconductors. A new study by Ph.D. student Luciano Henrique Siliano Ricco and his supervisor Antonio Carlos Ferreira Seridonio and others, was conducted on the Ilha Solteira campus of São Paulo State University (UNESP) in Brazil and published in Scientific Reports. Credit: FAPESP \"We propose a theoretical device that acts as a thermoelectric tuner—a tuner of heat and charge—assisted by Majorana fermions,\" Seridonio said. The device consists of a quantum dot (QD), represented in figure A by the symbol ε1. QDs are often called \"artificial atoms.\" In this case, the QD is located between two metallic leads at different temperatures. The temperature difference allows thermal energy to flow across the QD. A quasi-one-dimensional superconducting wire—called a Kitaev wire after Russian physicist Alexei Kitaev, currently a professor at the California Institute of Technology (Caltech) in the U.S.—is connected to the QD. In this study, the Kitaev wire was ring- or U-shaped and had two majoranas (η1 and η2) at its edges. The majoranas emerge as excitations characterized by zero-energy modes. Credit: FAPESP \"When the QD is coupled to only one side of the wire, the system behaves resonantly with regard to electrical and thermal conductance. In other words, it behaves like a thermoelectric filter,\" Seridonio said. \"I should stress that this behavior as a filter for thermal and electrical energy occurs when the two majoranas 'see' each other via the wire, but only one of them 'sees' the QD in the connection.\" Another possibility investigated by the researchers involved making the QD \"see\" the two majoranas at the same time by connecting it to both ends of the Kitaev wire. \"By making the QD 'see' more of η1 or η2, i.e., by varying the system's asymmetry, we can use the artificial atom as a tuner, where the thermal or electrical energy that flows through it is redshifted or blueshifted,\" Seridonio said (see figure B). This theoretical paper, he added, is expected to contribute to the development of thermoelectric devices based on Majorana fermions. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract We investigate theoretically thermal and electrical conductances for the system consisting of a quantum dot (QD) connected both to a pair of Majorana fermions residing at the edges of a Kitaev wire and two metallic leads. We demonstrate that both quantities reveal pronounced resonances, whose positions can be controlled by tuning of an asymmetry of the couplings of the QD and a pair of MFs. Similar behavior is revealed for the thermopower, Wiedemann-Franz law and dimensionless thermoelectric figure of merit. The considered geometry can thus be used as a tuner of heat and charge transport assisted by MFs. Introduction Majorana fermions (MFs) are particles that are equivalent to their antiparticles. The corresponding concept was first proposed in the domain of high-energy physics, but later on existence of the elementary excitations of this type was predicted for certain condensed matter systems. Particularly, MFs emerge as quasiparticle excitations characterized by zero-energy modes 1 , 2 appearing at the edges of the 1D Kitaev wire 3 , 4 , 5 , 6 , 7 . Kitaev model is used to describe the emerging phenomena of p -wave and spinless topological superconductivity. Kitaev topological phase can be experimentally achieved in the geometry consisting of a semiconducting nanowire with spin-orbit interaction put in contact with s -wave superconducting material and placed in external magnetic field 8 , 9 . Other condensed matter systems were also proposed as candidates for the observation of MFs. They include ferromagnetic chains placed on top of superconductors with spin-orbit interaction 10 , 11 , fractional quantum Hall state with filling factor ν = 5/2 12 , three-dimensional topological insulators 13 and superconducting vortices 14 , 15 , 16 . MFs residing at the opposite edges of a Kitaev wire are elements of a robust nonlocal qubit which appears to be immune to the environment decoherence. This attracted the interest of the researchers working in the domain of quantum information and transport, as systems with MFs 17 , 18 , 19 can be in principle used as building blocks for the next generation of nanodevices 20 , 21 , including current switches 20 and quantum memory elements 21 . At the same time, similar systems were proposed as thermoelectric nanodevices 22 , 23 , 24 , 25 . In this work, following the proposals of thermoelectric detection of MF states 22 , 23 , 24 , 25 , we explore theoretically zero-bias thermal and electrical transport through one particular geometry consisting of an individual QD coupled both to a pair of MFs and metallic leads as shown in the Fig. 1(a) . The MFs reside at the edges of a topological U-shaped Kitaev wire, similar to the case of ref. 19 . The QD coupling to the MFs is considered to be asymmetric, while coupling to the metallic leads is symmetric, and MFs are supposed to overlap with each other. The results of our calculations clearly show that thermoelectric conductance, thermopower, Wiedemann-Franz law 26 and dimensionless thermoelectric figure of merit (ZT) as function of the QD electron energy demonstrate resonant behavior. Moreover, the position of the resonance can be tuned by changing the coupling amplitudes between the QD and the MFs, which allows the system to operate as a tuner of heat and charge assisted by MFs. Figure 1 ( a ) The sketch of the geometry we consider. Topological U-shaped Kitaev wire with a pair of MFs η A and η B is placed in contact with a QD, which is connected as well to two metallic reservoirs. The coupling of the QD to the MFs is asymmetric and is characterized by tunneling matrix elements λ A and λ B , while coupling to the metallic leads is symmetric and is characterized by the tunneling matrix element V . ε 2 denotes the coupling between two MF states. ( b ) Equivalent auxiliary setup (Kitaev dimer) resulting from the mapping of the original system onto the system with nonlocal fermion residing in QD 2 . t is tunneling matrix element between the QDs 1 and 2, Δ is the binding energy of the Cooper pair delocalized between them. Full size image Model For theoretical treatment of the setup depicted in the Fig. 1(a) , we use the Hamiltonian proposed by Liu and Baranger 27 : $$\begin{array}{rcl} {\mathcal H} & = & \sum _{\alpha k}{\varepsilon }_{k}{c}_{\alpha k}^{\dagger }{c}_{\alpha k}+{\varepsilon }_{1}{d}_{1}^{\dagger }{d}_{1}+V\,\sum _{\alpha k}({c}_{\alpha k}^{\dagger }{d}_{1}+{\rm{H}}.{\rm{c}}\mathrm{.)}\\ & & +{\lambda }_{A}({d}_{1}-{d}_{1}^{\dagger }){\eta }_{A}+{\lambda }_{B}({d}_{1}+{d}_{1}^{\dagger }){\eta }_{B}+i{\varepsilon }_{2}{\eta }_{A}{\eta }_{B},\end{array}$$ (1) where the electrons in the leads α = H , C (for hot and cold reservoirs, respectively) are described by the operators ${c}_{\alpha k}^{\dagger }$ ( c αk ) for the creation (annihilation) of an electron in a quantum state labeled by the wave number k and energy ε k . For the QD ${d}_{1}^{\dagger }$ ( d 1 ) creates (annihilates) an electron in the state with the energy ε 1 . The energies of both electrons in the leads and QD are counted from the chemical potential μ (we consider only the limit of small source-drain bias, thus assuming that chemical potential is the same everywhere). V stands for the hybridization between the QD and the leads. The asymmetric coupling between the QD and MFs at the edges of the topological U-shaped Kitaev wire is described by the complex tunneling amplitudes λ A and λ B . Introduction of an asymmetry in the couplings can account for the presence of the magnetic flux which can be introduced via Peierls phase shift 27 . ε 2 stands for the overlap between the MFs. Without loss of generality, we can put: ${\lambda }_{A}=\frac{(t+{\rm{\Delta }})}{\sqrt{2}}$ and ${\lambda }_{B}=i\frac{({\rm{\Delta }}-t)}{\sqrt{2}}$ , respectively for the left $({\eta }_{A}={\eta }_{A}^{\dagger })$ and right $({\eta }_{B}={\eta }_{B}^{\dagger })$ MFs, and introduce an auxiliary nonlocal fermion ${d}_{2}=\tfrac{1}{\sqrt{2}}({\eta }_{A}+i{\eta }_{B})$ 20 , 21 . The expressions for ${\lambda }_{A}=|{\lambda }_{A}|{e}^{i{\varphi }_{A}}$ and ${\lambda }_{B}=|{\lambda }_{B}|{e}^{i{\varphi }_{B}}$ constitute a convenient gauge for our problem. We put ϕ A = 0<|im_end|> <|im_start|>assistant In March 1938, the young Italian physicist Ettore Majorana disappeared mysteriously, leaving his country's scientific community shaken. The episode remains unexplained, despite Leonardo Scascia's attempt to unravel the enigma in his book The Disappearance of Majorana (1975). Majorana, whom Enrico Fermi called a genius of Isaac Newton's stature, vanished a year after making his main contribution to science. In 1937, when he was only 30, Majorana hypothesized a particle that is its own anti-particle and suggested that it might be the neutrino, whose existence had recently been predicted by Fermi and Wolfgang Pauli. Eight decades later, Majorana fermions, or simply majoranas, are among the objects most studied by physicists. In addition to neutrinos—whose nature, whether or not they are majoranas, is one of the investigative goals of the mega-experiment Dune—another class not of fundamental particles but of quasi-particles or apparent particles has been investigated in the field of condensed matter. These Majorana quasi-particles can emerge as excitations in topological superconductors. A new study by Ph.D. student Luciano Henrique Siliano Ricco and his supervisor Antonio Carlos Ferreira Seridonio and others, was conducted on the Ilha Solteira campus of São Paulo State University (UNESP) in Brazil and published in Scientific Reports. Credit: FAPESP "We propose a theoretical device that acts as a thermoelectric tuner—a tuner of heat and charge—assisted by Majorana fermions," Seridonio said. The device consists of a quantum dot (QD), represented in figure A by the symbol ε1. QDs are often called "artificial atoms." In this case, the QD is located between two metallic leads at different temperatures. The temperature difference allows thermal energy to flow across the QD. A quasi-one-dimensional superconducting wire—called a Kitaev wire after Russian physicist Alexei Kitaev, currently a professor at the California Institute of Technology (Caltech) in the U.S.—is connected to the QD. In this study, the Kitaev wire was ring- or U-shaped and had two majoranas (η1 and η2) at its edges. The majoranas emerge as excitations characterized by zero-energy modes. Credit: FAPESP "When the QD is coupled to only one side of the wire, the system behaves resonantly with regard to electrical and thermal conductance. In other words, it behaves like a thermoelectric filter," Seridonio said. "I should stress that this behavior as a filter for thermal and electrical energy occurs when the two majoranas 'see' each other via the wire, but only one of them 'sees' the QD in the connection." Another possibility investigated by the researchers involved making the QD "see" the two majoranas at the same time by connecting it to both ends of the Kitaev wire. "By making the QD 'see' more of η1 or η2, i.e., by varying the system's asymmetry, we can use the artificial atom as a tuner, where the thermal or electrical energy that flows through it is redshifted or blueshifted," Seridonio said (see figure B). This theoretical paper, he added, is expected to contribute to the development of thermoelectric devices based on Majorana fermions. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Weather extremes have harmful impacts on communities around Lake Victoria, where thousands of fishermen die every year because of intense night-time thunderstorms. Yet how these thunderstorms will evolve in a future warmer climate is still unknown. Here we show that Lake Victoria is projected to be a hotspot of future extreme precipitation intensification by using new satellite-based observations, a high-resolution climate projection for the African Great Lakes and coarser-scale ensemble projections. Land precipitation on the previous day exerts a control on night-time occurrence of extremes on the lake by enhancing atmospheric convergence (74%) and moisture availability (26%). The future increase in extremes over Lake Victoria is about twice as large relative to surrounding land under a high-emission scenario, as only over-lake moisture advection is high enough to sustain Clausius–Clapeyron scaling. Our results highlight a major hazard associated with climate change over East Africa and underline the need for high-resolution projections to assess local climate change. Introduction Severe thunderstorms and associated high waves represent a constant threat to the 200,000 fishermen operating on Lake Victoria 1 , 2 . The International Red Cross assumes that 3,000–5,000 fishermen die every year on the lake 2 , by which it substantially contributes to the global death toll from natural disasters. Each perished fisherman leaves on average eight relatives without an income, underlining the vulnerability of East African fishing communities to these natural hazards 1 , 2 , 3 . Despite the long-known bad reputation of Lake Victoria 4 , the understanding of the drivers of these extreme thunderstorms remains limited 5 . Moreover, anthropogenic climate change may significantly affect these hazardous weather systems. In many parts of the world, future climate simulations project an intensification of precipitation extremes and associated weather conditions 6 , 7 , 8 , 9 , 10 , 11 , but the potential future changes in extremes over Lake Victoria are still unknown. In this study, we use a unique combination of state-of-the-art satellite remote sensing, a high-resolution regional climate model and coarser-scale ensemble simulations to project changes in extreme precipitation over Lake Victoria. We project a strong and robust increase in precipitation extremes over Lake Victoria and show that this increase is about double over the lake compared with surrounding land. Although the occurrence of extreme precipitation in the present-day climate is mostly controlled by atmospheric dynamics, its future intensification can be entirely attributed to the advection of more humid air over the lake. Results Satellite data analysis Satellite observations enable the recognition of severe weather by detecting overshooting tops (OTs), that is, dome-like protrusions atop a cumulonimbus anvil induced by intense updrafts 12 , 13 . OTs mark the presence of vigorous thunderstorms and are tightly linked to severe weather reports 12 , 13 , 14 , 15 . By applying an OT detection algorithm to Meteosat Second Generation observations (Methods), we establish a new severe thunderstorm climatology for East Africa. The results reveal a marked imprint of Lake Victoria on the diurnal thunderstorm cycle and confirm its status as one of the most convectively active regions on Earth 5 , 13 , 16 , 17 , 18 ( Fig. 1 ). From 2005 to 2013, 73% of all 1,400,000 OT pixels detected over the lake occurred at night (22:00 to 9:00 UTC ), in contrast to the surrounding land where afternoon storms dominate (72% of all 4,200,000 OT pixels during 9:00 to 16:00 UTC ). Local evaporation and mesoscale circulation have been identified as key drivers of the present-day diurnal cycle of precipitation over Lake Victoria 5 , 17 , 18 , 19 , 20 , 21 , but so far it is not known how mean and extreme precipitation over this lake respond to a temperature increase induced by anthropogenic greenhouse gas emissions. To address this question, we performed a high resolution ( ∼ 7 km grid spacing), coupled lake–land–atmosphere climate projection for the African Great Lakes region with the regional climate model COSMO-CLM 2 , and analysed coarser-scale ensemble projections from the Coordinated Regional climate Downscaling Experiment (CORDEX) for the end of the century under a high-emission scenario (RCP8.5; Methods, Supplementary Fig. 1 and Supplementary Table 1 ). Figure 1: Lake imprint on severe thunderstorm occurrence. ( a , b ) Satellite-based overshooting tops (OT) detections during 2005–2013 over the Lake Victoria region (red square in the inset panel), from 9:00 to 15:00 UTC and from 00:00 to 9:00 UTC , respectively, as derived from the Spinning Enhanced Visible and Infrared Imager (SEVIRI; Methods). Full size image Extreme precipitation projections The projections show a contrasting change of mean and extreme precipitation over Lake Victoria ( Fig. 2 ; Supplementary Fig. 2 ), with mean precipitation decreasing while the intensity of extreme precipitation increases. Moreover, by the end of the century the increase in extremes (precipitation above the 99th percentile) is 2.4±0.1 times higher over the lake than over its surrounding land in the high-resolution projection (1.8±1.0 times in the CORDEX ensemble). Today convection initiates in the eastern part of the lake and intensifies while being advected westwards along the trade winds 4 , 5 . In the future, storms are projected to release extreme precipitation more in the eastern part of the lake, leading to an eastward shift of intense precipitation ( Fig. 2a,b ). Figure 2: Projected end-of-century changes in extreme precipitation over Lake Victoria. ( a ) Night-time 99th percentile precipitation ( P 99%,night , 00:00 to 9:00 UTC ) and ( b ) its projected future change from the high-resolution COSMO-CLM 2 model. ( c , d ) 24 h Lake (blue bars) and surrounding land (red bars) binned precipitation change (P bin) from COSMO-CLM 2 and the ensemble mean of nine CORDEX-Africa members, respectively. The red rectangle in Supplementary Fig. 1 includes the land pixels considered as surrounding land. All changes are between time periods 1981–2010 and 2071–2100 under RCP8.5. Full size image In contrast to the increase in extremes, the annual mean precipitation projected by the high-resolution model", "role": "user" }, { "content": "Lake Victoria in East Africa will become a hotspot for hazardous thunderstorms due to climate change. This is shown by an international study published in Nature Communications on the 23rd of September. Stef Lhermitte (TU Delft) analysed the differences between storms during the day (which occur mainly over land) and during the night (occur mainly over the lake). Lake Victoria is divided among Uganda, Kenya, and Tanzania. With a surface close to 70,000 km2, it is the biggest lake in Africa. The lake is also a notoriously dangerous place for the 200,000 people who go fishing there at night. The International Red Cross estimates that between 3,000 and 5,000 fishermen per year lose their lives in violent storms on the lake. Difference between day and night That Lake Victoria can be so stormy at night is related to the circulation in the atmosphere above the enormous water surface, explains Lhermitte, who was working for KU Leuven (Belgium) during the time of the research. During the day, a breeze develops that flows from the cool water towards the warm land. At night, the opposite occurs: the land breeze flows away from the cooling land towards the warmer lake. As the lake is shaped like a circle, these land breezes from all directions converge above the lake. Add evaporation to this cocktail and you get a lot of storms, rain, wind, and waves. Satellite observations The scientists were able to provide scientific evidence for this pattern in collaboration with American space agency NASA. Thanks to new NASA satellite products they were able to map the number of hazardous thunderstorms and their locations in East Africa – every 15 minutes for a period ranging from 2005 to 2013. During the day, most storms rage over the surrounding land, especially the typical afternoon thunderstorms that are caused by local upsurges of warm air. At night, these storms concentrate over Lake Victoria. The new NASA satellite observations clearly show the day-and-night rhythm of the climate above and around Lake Victoria (day image on the left, night image on the right). The darker the image, the more storms were counted there between 2005 and 2013. Credit: Delft University of Technology Hotspot for night-time storms To predict the impact of climate change on this process, the team, led by Wim Thiery (KU Leuven and ETH Zurich) also ran climate simulations using an advanced computer model: \"If we start from a business-as-usual scenario, whereby the emission of greenhouse gases continues to increase, the extreme amounts of rainfall over Lake Victoria will increase by twice as much as the rainfall over the surrounding land. As a result, the lake will become a hotspot for night-time storms. Superstorms that only occur once every 15 years today will occur almost every year by the end of the century.\" Warning system The scientists plan to do further research to optimize existing warning systems for local fishermen. The results make it possible to better predict extreme storms over the lake and to reduce the vulnerability of the local fishermen. In the meantime, a prototype of a new warning system has been developed. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Weather extremes have harmful impacts on communities around Lake Victoria, where thousands of fishermen die every year because of intense night-time thunderstorms. Yet how these thunderstorms will evolve in a future warmer climate is still unknown. Here we show that Lake Victoria is projected to be a hotspot of future extreme precipitation intensification by using new satellite-based observations, a high-resolution climate projection for the African Great Lakes and coarser-scale ensemble projections. Land precipitation on the previous day exerts a control on night-time occurrence of extremes on the lake by enhancing atmospheric convergence (74%) and moisture availability (26%). The future increase in extremes over Lake Victoria is about twice as large relative to surrounding land under a high-emission scenario, as only over-lake moisture advection is high enough to sustain Clausius–Clapeyron scaling. Our results highlight a major hazard associated with climate change over East Africa and underline the need for high-resolution projections to assess local climate change. Introduction Severe thunderstorms and associated high waves represent a constant threat to the 200,000 fishermen operating on Lake Victoria 1 , 2 . The International Red Cross assumes that 3,000–5,000 fishermen die every year on the lake 2 , by which it substantially contributes to the global death toll from natural disasters. Each perished fisherman leaves on average eight relatives without an income, underlining the vulnerability of East African fishing communities to these natural hazards 1 , 2 , 3 . Despite the long-known bad reputation of Lake Victoria 4 , the understanding of the drivers of these extreme thunderstorms remains limited 5 . Moreover, anthropogenic climate change may significantly affect these hazardous weather systems. In many parts of the world, future climate simulations project an intensification of precipitation extremes and associated weather conditions 6 , 7 , 8 , 9 , 10 , 11 , but the potential future changes in extremes over Lake Victoria are still unknown. In this study, we use a unique combination of state-of-the-art satellite remote sensing, a high-resolution regional climate model and coarser-scale ensemble simulations to project changes in extreme precipitation over Lake Victoria. We project a strong and robust increase in precipitation extremes over Lake Victoria and show that this increase is about double over the lake compared with surrounding land. Although the occurrence of extreme precipitation in the present-day climate is mostly controlled by atmospheric dynamics, its future intensification can be entirely attributed to the advection of more humid air over the lake. Results Satellite data analysis Satellite observations enable the recognition of severe weather by detecting overshooting tops (OTs), that is, dome-like protrusions atop a cumulonimbus anvil induced by intense updrafts 12 , 13 . OTs mark the presence of vigorous thunderstorms and are tightly linked to severe weather reports 12 , 13 , 14 , 15 . By applying an OT detection algorithm to Meteosat Second Generation observations (Methods), we establish a new severe thunderstorm climatology for East Africa. The results reveal a marked imprint of Lake Victoria on the diurnal thunderstorm cycle and confirm its status as one of the most convectively active regions on Earth 5 , 13 , 16 , 17 , 18 ( Fig. 1 ). From 2005 to 2013, 73% of all 1,400,000 OT pixels detected over the lake occurred at night (22:00 to 9:00 UTC ), in contrast to the surrounding land where afternoon storms dominate (72% of all 4,200,000 OT pixels during 9:00 to 16:00 UTC ). Local evaporation and mesoscale circulation have been identified as key drivers of the present-day diurnal cycle of precipitation over Lake Victoria 5 , 17 , 18 , 19 , 20 , 21 , but so far it is not known how mean and extreme precipitation over this lake respond to a temperature increase induced by anthropogenic greenhouse gas emissions. To address this question, we performed a high resolution ( ∼ 7 km grid spacing), coupled lake–land–atmosphere climate projection for the African Great Lakes region with the regional climate model COSMO-CLM 2 , and analysed coarser-scale ensemble projections from the Coordinated Regional climate Downscaling Experiment (CORDEX) for the end of the century under a high-emission scenario (RCP8.5; Methods, Supplementary Fig. 1 and Supplementary Table 1 ). Figure 1: Lake imprint on severe thunderstorm occurrence. ( a , b ) Satellite-based overshooting tops (OT) detections during 2005–2013 over the Lake Victoria region (red square in the inset panel), from 9:00 to 15:00 UTC and from 00:00 to 9:00 UTC , respectively, as derived from the Spinning Enhanced Visible and Infrared Imager (SEVIRI; Methods). Full size image Extreme precipitation projections The projections show a contrasting change of mean and extreme precipitation over Lake Victoria ( Fig. 2 ; Supplementary Fig. 2 ), with mean precipitation decreasing while the intensity of extreme precipitation increases. Moreover, by the end of the century the increase in extremes (precipitation above the 99th percentile) is 2.4±0.1 times higher over the lake than over its surrounding land in the high-resolution projection (1.8±1.0 times in the CORDEX ensemble). Today convection initiates in the eastern part of the lake and intensifies while being advected westwards along the trade winds 4 , 5 . In the future, storms are projected to release extreme precipitation more in the eastern part of the lake, leading to an eastward shift of intense precipitation ( Fig. 2a,b ). Figure 2: Projected end-of-century changes in extreme precipitation over Lake Victoria. ( a ) Night-time 99th percentile precipitation ( P 99%,night , 00:00 to 9:00 UTC ) and ( b ) its projected future change from the high-resolution COSMO-CLM 2 model. ( c , d ) 24 h Lake (blue bars) and surrounding land (red bars) binned precipitation change (P bin) from COSMO-CLM 2 and the ensemble mean of nine CORDEX-Africa members, respectively. The red rectangle in Supplementary Fig. 1 includes the land pixels considered as surrounding land. All changes are between time periods 1981–2010 and 2071–2100 under RCP8.5. Full size image In contrast to the increase in extremes, the annual mean precipitation projected by the high-resolution model<|im_end|> <|im_start|>assistant Lake Victoria in East Africa will become a hotspot for hazardous thunderstorms due to climate change. This is shown by an international study published in Nature Communications on the 23rd of September. Stef Lhermitte (TU Delft) analysed the differences between storms during the day (which occur mainly over land) and during the night (occur mainly over the lake). Lake Victoria is divided among Uganda, Kenya, and Tanzania. With a surface close to 70,000 km2, it is the biggest lake in Africa. The lake is also a notoriously dangerous place for the 200,000 people who go fishing there at night. The International Red Cross estimates that between 3,000 and 5,000 fishermen per year lose their lives in violent storms on the lake. Difference between day and night That Lake Victoria can be so stormy at night is related to the circulation in the atmosphere above the enormous water surface, explains Lhermitte, who was working for KU Leuven (Belgium) during the time of the research. During the day, a breeze develops that flows from the cool water towards the warm land. At night, the opposite occurs: the land breeze flows away from the cooling land towards the warmer lake. As the lake is shaped like a circle, these land breezes from all directions converge above the lake. Add evaporation to this cocktail and you get a lot of storms, rain, wind, and waves. Satellite observations The scientists were able to provide scientific evidence for this pattern in collaboration with American space agency NASA. Thanks to new NASA satellite products they were able to map the number of hazardous thunderstorms and their locations in East Africa – every 15 minutes for a period ranging from 2005 to 2013. During the day, most storms rage over the surrounding land, especially the typical afternoon thunderstorms that are caused by local upsurges of warm air. At night, these storms concentrate over Lake Victoria. The new NASA satellite observations clearly show the day-and-night rhythm of the climate above and around Lake Victoria (day image on the left, night image on the right). The darker the image, the more storms were counted there between 2005 and 2013. Credit: Delft University of Technology Hotspot for night-time storms To predict the impact of climate change on this process, the team, led by Wim Thiery (KU Leuven and ETH Zurich) also ran climate simulations using an advanced computer model: "If we start from a business-as-usual scenario, whereby the emission of greenhouse gases continues to increase, the extreme amounts of rainfall over Lake Victoria will increase by twice as much as the rainfall over the surrounding land. As a result, the lake will become a hotspot for night-time storms. Superstorms that only occur once every 15 years today will occur almost every year by the end of the century." Warning system The scientists plan to do further research to optimize existing warning systems for local fishermen. The results make it possible to better predict extreme storms over the lake and to reduce the vulnerability of the local fishermen. In the meantime, a prototype of a new warning system has been developed. <|im_end|>

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2,030

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The mid-depth ocean circulation is critically linked to actual changes in the long-term global climate system. However, in the past few decades, predictions based on ocean circulation models highlight the lack of data, knowledge, and long-term implications in climate change assessment. Here, using 842,421 observations produced by Argo floats from 2001-2020, and Lagrangian simulations, we show that only 3.8% of the mid-depth oceans, including part of the equatorial Pacific Ocean and the Antarctic Circumpolar Current, can be regarded as accurately modelled, while other regions exhibit significant underestimations in mean current velocity. Knowledge of ocean circulation is generally more complete in the low-latitude oceans but is especially poor in high latitude regions. Accordingly, we propose improvements in forecasting, model representation of stochasticity, and enhancement of observations of ocean currents. The study demonstrates that knowledge and model representations of global circulation are substantially compromised by inaccuracies of significant magnitude and direction, with important implications for modelled predictions of currents, temperature, carbon dioxide sequestration, and sea-level rise trends. Introduction The oceans, covering more than 70% of the earth’s surface and containing 95% of all water, critically modulate climate change through carbon dioxide sequestration and by absorbing excess heat 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . Dynamically, the large-scale ocean circulation plays a key role in the Earth’s climate system by redistributing the heat of the ocean 12 , 13 . Stratification arises through the processes of vertical mixing, one of the products of which is the mid-depth ocean near 1000 m between variable waters near the surface and stable waters at greater depth 14 . Interactions between surface currents and thermohaline currents inject changes into the mid-depth ocean near 1000 m. In turn, mid-depth ocean circulation has a significant impact on the global ocean as a whole by altering the physical characteristics of ocean waters 15 , 16 , 17 , 18 that play a fundamental role in the longer-term evolution of Earth’s climate system. However, knowledge of mid-depth ocean circulation is hampered by the lack of direct observations and novel methods are therefore needed to improve data, modeling accuracy in order to resolve the mechanism of mid-depth ocean circulation and related processes. In the past two decades, over 4000 floats from the Argo program provided more than two million profiles of water column properties from the upper 2000-m depth of the global ocean 10 , 19 , 20 . These enable the construction of satellite-tracked sea-surface profiles and cycles for direct estimation of mid-depth ocean velocities, and spatio-temporal circulation patterns from regional to global scales 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 . Argo velocities derived in this manner are Lagrangian, whereas ocean circulation models are Eulerian, resulting in systematic biases of current velocity when the coordinates are transformed 34 , 35 , 36 . Based on simulated Argo experiments 37 it has been suggested that Argo floats accelerate near strong mean flows due to the eddy‐mean flow interaction effect, although other potential biases and their implications for models remain highly uncertain. Using comprehensive and quantitative methods, we present here the detailed assessment and validation of global ocean circulation model skills near 1000 m depth. Results Sparse well-modelled mid-depth ocean Lagrangian velocities near 1,000 m depth for all the earth’s oceans were computed and multiple accuracy indicators were used to compare Argo float velocities with simulated velocities from global circulation models. The assessment is based on 842,421 Argo float observation displacements over 20 years, together with float simulation experiments. The goal is to map the areas of the oceans that are more reliably modelled and classify them in terms of how much is known about spatial variations in mid-ocean circulation. Global 1000-m ocean velocities were obtained from three eddy-permitting and daily-mean ocean general circulation models, including ECCO2 (Estimating the Circulation and Climate of the Ocean model, Phase II), OFES (the Ocean General Circulation Model for the Earth Simulator) and CMEMS GLORYS12 (Global Ocean Reanalysis and Simulations), and Argo velocities were acquired from the ANDRO dataset. Indicators of differences (see Supplementary Materials for details) comprise: DOD (Difference of Direction); DOV (Difference of Velocity); PDOV (Percentage of Velocity Difference); SD (Separation Distance); SS (Skill Score based on the cumulative simulated separation distance normalized by the cumulative observed displacement). We describe the distribution of each of these statistics before presenting the results of cluster analysis to reveal the linkages between indicators and overall spatial patterns of the clusters. Fig. 1 shows the global spatial distribution of the well-modelled areas, defined as areas where DOD is less than 30° and PDOV is less than 50%. The two most critical indicators are adopted, and the effect of parameter thresholds on the results can be seen in Supplementary Table 1 . Overall, only 1.3–3.8% of the global oceans are considered to have a robust or reliable prediction of the 1000-m depth circulation and hence, improved velocity field magnitude and direction data are needed for more than 96% of the global ocean. This deficiency therefore calls into question the reliability of predictions of the long-term implications of mid-depth ocean circulation changes. Meanwhile, several regions are better modelled, including the Antarctic Circumpolar Current and the equatorial Pacific Ocean, which is the largest spatially continuous well-modelled area that enables more reliable estimates of ocean current dynamics in the 1000-m layer. Fig. 1: Global distribution of well-modelled areas for models, 1.415% for ECCO2(a), 1.325% for OFES(b), and 3.843% for CMEMS(c). The well-modelled areas are highlighted by blue dots. Full size image Spatial patterns of widespread global disparities The global distribution of DOD in Fig. 2 shows that DOD in at least 81.1% of the oceans exceeds 45° or more (as shown by the most accurate model CMEMS), meaning that accurate simulation of circulation direction at 1000-m is lacking in more than four-fifths of the global oceans.", "role": "user" }, { "content": "Ocean motion plays a key role in the Earth's energy and climate systems. In recent decades, ocean science has made great strides in providing general estimates of large-scale ocean motion. However, there are still many dynamic mechanisms that are not fully understood or resolved. Prof. Su Fenzhen's team at the Institute of Geographic Sciences and Natural Resources Research of the Chinese Academy of Sciences and their collaborators found that humans know less than 5% of the ocean currents at depths of 1,000 meters below the sea surface, with important implications for modeled predictions of climate change and carbon sequestration. Their findings were published in Nature Communications. The researchers used a displacement dataset of 842,421 observations produced from Argo floats from 2001 to 2020. Lagrangian velocities were computed near 1,000-meter depth, and several accuracy indicators were used to compare Argo float velocities with simulated values from global circulation models. Results showed that only 3.8% of the mid-depth oceans can be considered as accurately modeled. \"An important finding that circulation energy in almost all of the world's oceans is underestimated. This is probably due to the poor resolution of high-frequency dynamics in ocean circulation models and the inadequacy of current solutions to sub-grid processes,\" said Prof. Su. \"In the future, we expect to develop ocean circulation models that could more faithfully represent observed ocean currents through more intensive and qualified observations, more productive parameterization, finer model resolution, and in-depth theoretical analysis,\" he said. The study highlights the nature and extent of the mismatch between scientific knowledge and the actual ocean environment. It can help guide recommendations for more intensive observational and more accurate predictions to reduce the large and significant biases between models and observations. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The mid-depth ocean circulation is critically linked to actual changes in the long-term global climate system. However, in the past few decades, predictions based on ocean circulation models highlight the lack of data, knowledge, and long-term implications in climate change assessment. Here, using 842,421 observations produced by Argo floats from 2001-2020, and Lagrangian simulations, we show that only 3.8% of the mid-depth oceans, including part of the equatorial Pacific Ocean and the Antarctic Circumpolar Current, can be regarded as accurately modelled, while other regions exhibit significant underestimations in mean current velocity. Knowledge of ocean circulation is generally more complete in the low-latitude oceans but is especially poor in high latitude regions. Accordingly, we propose improvements in forecasting, model representation of stochasticity, and enhancement of observations of ocean currents. The study demonstrates that knowledge and model representations of global circulation are substantially compromised by inaccuracies of significant magnitude and direction, with important implications for modelled predictions of currents, temperature, carbon dioxide sequestration, and sea-level rise trends. Introduction The oceans, covering more than 70% of the earth’s surface and containing 95% of all water, critically modulate climate change through carbon dioxide sequestration and by absorbing excess heat 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . Dynamically, the large-scale ocean circulation plays a key role in the Earth’s climate system by redistributing the heat of the ocean 12 , 13 . Stratification arises through the processes of vertical mixing, one of the products of which is the mid-depth ocean near 1000 m between variable waters near the surface and stable waters at greater depth 14 . Interactions between surface currents and thermohaline currents inject changes into the mid-depth ocean near 1000 m. In turn, mid-depth ocean circulation has a significant impact on the global ocean as a whole by altering the physical characteristics of ocean waters 15 , 16 , 17 , 18 that play a fundamental role in the longer-term evolution of Earth’s climate system. However, knowledge of mid-depth ocean circulation is hampered by the lack of direct observations and novel methods are therefore needed to improve data, modeling accuracy in order to resolve the mechanism of mid-depth ocean circulation and related processes. In the past two decades, over 4000 floats from the Argo program provided more than two million profiles of water column properties from the upper 2000-m depth of the global ocean 10 , 19 , 20 . These enable the construction of satellite-tracked sea-surface profiles and cycles for direct estimation of mid-depth ocean velocities, and spatio-temporal circulation patterns from regional to global scales 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 . Argo velocities derived in this manner are Lagrangian, whereas ocean circulation models are Eulerian, resulting in systematic biases of current velocity when the coordinates are transformed 34 , 35 , 36 . Based on simulated Argo experiments 37 it has been suggested that Argo floats accelerate near strong mean flows due to the eddy‐mean flow interaction effect, although other potential biases and their implications for models remain highly uncertain. Using comprehensive and quantitative methods, we present here the detailed assessment and validation of global ocean circulation model skills near 1000 m depth. Results Sparse well-modelled mid-depth ocean Lagrangian velocities near 1,000 m depth for all the earth’s oceans were computed and multiple accuracy indicators were used to compare Argo float velocities with simulated velocities from global circulation models. The assessment is based on 842,421 Argo float observation displacements over 20 years, together with float simulation experiments. The goal is to map the areas of the oceans that are more reliably modelled and classify them in terms of how much is known about spatial variations in mid-ocean circulation. Global 1000-m ocean velocities were obtained from three eddy-permitting and daily-mean ocean general circulation models, including ECCO2 (Estimating the Circulation and Climate of the Ocean model, Phase II), OFES (the Ocean General Circulation Model for the Earth Simulator) and CMEMS GLORYS12 (Global Ocean Reanalysis and Simulations), and Argo velocities were acquired from the ANDRO dataset. Indicators of differences (see Supplementary Materials for details) comprise: DOD (Difference of Direction); DOV (Difference of Velocity); PDOV (Percentage of Velocity Difference); SD (Separation Distance); SS (Skill Score based on the cumulative simulated separation distance normalized by the cumulative observed displacement). We describe the distribution of each of these statistics before presenting the results of cluster analysis to reveal the linkages between indicators and overall spatial patterns of the clusters. Fig. 1 shows the global spatial distribution of the well-modelled areas, defined as areas where DOD is less than 30° and PDOV is less than 50%. The two most critical indicators are adopted, and the effect of parameter thresholds on the results can be seen in Supplementary Table 1 . Overall, only 1.3–3.8% of the global oceans are considered to have a robust or reliable prediction of the 1000-m depth circulation and hence, improved velocity field magnitude and direction data are needed for more than 96% of the global ocean. This deficiency therefore calls into question the reliability of predictions of the long-term implications of mid-depth ocean circulation changes. Meanwhile, several regions are better modelled, including the Antarctic Circumpolar Current and the equatorial Pacific Ocean, which is the largest spatially continuous well-modelled area that enables more reliable estimates of ocean current dynamics in the 1000-m layer. Fig. 1: Global distribution of well-modelled areas for models, 1.415% for ECCO2(a), 1.325% for OFES(b), and 3.843% for CMEMS(c). The well-modelled areas are highlighted by blue dots. Full size image Spatial patterns of widespread global disparities The global distribution of DOD in Fig. 2 shows that DOD in at least 81.1% of the oceans exceeds 45° or more (as shown by the most accurate model CMEMS), meaning that accurate simulation of circulation direction at 1000-m is lacking in more than four-fifths of the global oceans.<|im_end|> <|im_start|>assistant Ocean motion plays a key role in the Earth's energy and climate systems. In recent decades, ocean science has made great strides in providing general estimates of large-scale ocean motion. However, there are still many dynamic mechanisms that are not fully understood or resolved. Prof. Su Fenzhen's team at the Institute of Geographic Sciences and Natural Resources Research of the Chinese Academy of Sciences and their collaborators found that humans know less than 5% of the ocean currents at depths of 1,000 meters below the sea surface, with important implications for modeled predictions of climate change and carbon sequestration. Their findings were published in Nature Communications. The researchers used a displacement dataset of 842,421 observations produced from Argo floats from 2001 to 2020. Lagrangian velocities were computed near 1,000-meter depth, and several accuracy indicators were used to compare Argo float velocities with simulated values from global circulation models. Results showed that only 3.8% of the mid-depth oceans can be considered as accurately modeled. "An important finding that circulation energy in almost all of the world's oceans is underestimated. This is probably due to the poor resolution of high-frequency dynamics in ocean circulation models and the inadequacy of current solutions to sub-grid processes," said Prof. Su. "In the future, we expect to develop ocean circulation models that could more faithfully represent observed ocean currents through more intensive and qualified observations, more productive parameterization, finer model resolution, and in-depth theoretical analysis," he said. The study highlights the nature and extent of the mismatch between scientific knowledge and the actual ocean environment. It can help guide recommendations for more intensive observational and more accurate predictions to reduce the large and significant biases between models and observations. <|im_end|>

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1,727

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Metabolic syndrome is characterized by a constellation of comorbidities that predispose individuals to an increased risk of developing cardiovascular pathologies as well as type 2 diabetes mellitus 1 . The gut microbiota is a new key contributor involved in the onset of obesity-related disorders 2 . In humans, studies have provided evidence for a negative correlation between Akkermansia muciniphila abundance and overweight, obesity, untreated type 2 diabetes mellitus or hypertension 3 , 4 , 5 , 6 , 7 , 8 . Since the administration of A. muciniphila has never been investigated in humans, we conducted a randomized, double-blind, placebo-controlled pilot study in overweight/obese insulin-resistant volunteers; 40 were enrolled and 32 completed the trial. The primary end points were safety, tolerability and metabolic parameters (that is, insulin resistance, circulating lipids, visceral adiposity and body mass). Secondary outcomes were gut barrier function (that is, plasma lipopolysaccharides) and gut microbiota composition. In this single-center study, we demonstrated that daily oral supplementation of 10 10 A. muciniphila bacteria either live or pasteurized for three months was safe and well tolerated. Compared to placebo, pasteurized A. muciniphila improved insulin sensitivity (+28.62 ± 7.02%, P = 0.002), and reduced insulinemia (−34.08 ± 7.12%, P = 0.006) and plasma total cholesterol (−8.68 ± 2.38%, P = 0.02). Pasteurized A. muciniphila supplementation slightly decreased body weight (−2.27 ± 0.92 kg, P = 0.091) compared to the placebo group, and fat mass (−1.37 ± 0.82 kg, P = 0.092) and hip circumference (−2.63 ± 1.14 cm, P = 0.091) compared to baseline. After three months of supplementation, A. muciniphila reduced the levels of the relevant blood markers for liver dysfunction and inflammation while the overall gut microbiome structure was unaffected. In conclusion, this proof-of-concept study (clinical trial no. NCT02637115 ) shows that the intervention was safe and well tolerated and that supplementation with A. muciniphila improves several metabolic parameters. Main To overcome the worldwide evolution of cardiometabolic diseases, research has increasingly focused its attention on interventions that target the gut microbiota 2 . Among commensal bacteria residing in the intestine, Akkermansia muciniphila has attracted growing interest for its health-promoting effects 9 . In rodents, treatment with A. muciniphila reduces obesity and related disorders, such as glucose intolerance, insulin resistance, steatosis and gut permeability 10 , 11 , 12 . Recently, in rodents, we serendipitously discovered that pasteurization of A. muciniphila enhances its beneficial properties on adiposity, insulin resistance and glucose tolerance 11 . However, translational evaluation of A. muciniphila for human investigation was hampered by the need for animal-derived compounds in the growth medium used to culture this bacterium. We circumvented this major issue by developing a synthetic medium compatible with human administration 11 . The main objectives of this exploratory study were (1) to evaluate the feasibility, safety and tolerance of A. muciniphila supplementation, and (2) to explore for the first time the metabolic effects of A. muciniphila supplementation in humans. The study was designed as an exploratory and proof-of-concept study for a first supplementation in humans. The primary outcomes were safety, tolerability (that is, hepatic and renal function, inflammation) and metabolic parameters (that is, insulin resistance, circulating lipids, visceral adiposity and body mass index (BMI)). The secondary outcomes were gut barrier function (that is, plasma lipopolysaccharides (LPS)/metabolic endotoxemia), gut microbiota composition and metabolites. In 2017, the first reported preliminary human data from this study obtained using 5 volunteers per group suggested that treatment with either placebo, two doses of live A. muciniphila (low dose of 10 9 bacteria per day or high dose of 10 10 bacteria per day) or pasteurized A. muciniphila (10 10 bacteria per day) was safe in individuals with excess body weight; no changes in safety parameters or reported adverse events were observed after 15 d of daily administration 11 . In this study, we further extended this randomized, double-blind, placebo-controlled proof-of-concept and feasibility study using daily oral administration of A. muciniphila for 3 months, either live or pasteurized and compared their effects at the highest dose tested, that is, at 10 10 bacteria per day, in individuals exhibiting excess body weight (overweight or obese), insulin resistance and metabolic syndrome. Individuals were enrolled and underwent randomization to receive either a placebo, live A. muciniphila (10 10 bacteria per day) or pasteurized A. muciniphila (10 10 bacteria per day) as a supplement for 3 months, with the specific advice to keep to their normal dietary intake and physical activity during the study period (see flow chart in Extended Data Fig. 1 ). Although participants were randomized, we found that before starting supplementation (that is, at T0), participants receiving pasteurized cells exhibited significantly higher levels of insulin and lower insulin sensitivity than those in the placebo group (Supplementary Table 1 ). In the interest of safety, an early visit was scheduled 15 d after the start of supplementation. We found that both safety and tolerability were similar between the two groups receiving the different forms of A. muciniphila compared to the placebo group (Supplementary Tables 2 and 3 ), except for a higher white blood cell count (WBC) in the placebo and treated groups (Supplementary Table 2 ). We further followed safety and tolerability parameters until three months after the start of supplementation and did not observe any adverse events (Supplementary Tables 4 and 5 ). In addition, compliance was higher than 99% in all groups (Supplementary Table 5 ). After 3 months, the placebo group exhibited a significant increase of fasting plasma insulin ( P < 0.05, T3 versus T0; Fig. 1a ), contrary to participants receiving both forms of A. muciniphila where reduced plasma insulin levels (approximately 30%) were observed compared to the placebo group (Fig. 1a ). This effect was significant between the pasteurized A. muciniphila and placebo groups (Fig. 1a ). Fasting glycemia was not affected (Fig. 1b ); however, participants were not highly hyperglycemic at baseline (Supplementary Table 1 ). Fig. 1: Changes in parameters related to glucose metabolism and WBC. a , Insulinemia. b , Glycemia. c", "role": "user" }, { "content": "In 2007, Patrice Cani (FNRS-WELBIO researcher) and his team at the Louvain Drug Research Institute of University of Louvain, in close collaboration with Willem de Vos, professor at UWageningen, discovered the beneficial effects of intestinal bacteria, Akkermansia muciniphila, able to moderate the development of obesity and type 2 diabetes, in mice. In 2017, the team discovered (still in the mouse) that the use of a pasteurized form of Akkermansia leads to an even greater protection than the living bacterium regarding various cardiovascular disease risk factors such as insulin resistance, hypercholesterolemia, or the storage of fat in adipose tissue. Following these discoveries, the UCLouvain team, in collaboration with the Cliniques Universitaires Saint-Luc, developed a clinical study in order to administer the bacteria to humans. For this, it was necessary to develop the capacity to produce the bacterium in large quantity and to make sure that the tests would be without risk for the participants. The UCLouvain researchers administered Akkermansia to overweight or obese volunteers, all displaying insulin resistance (pre-diabetes type 2) and metabolic syndrome, in other words, having several elevated risk factors for cardiovascular diseases. The volunteers were randomly divided into 3 groups (placebo, live bacteria and pasteurized bacteria) and were asked not to change their dietary habits or their physical activity. Akkermansia was provided as a nutritional supplement. The primary goal of this UCLouvain study was to demonstrate the feasibility of daily ingesting Akkermansia for 3 months, without risk. Clara Depommier and Amandine Everard, UCLouvain researchers, observed excellent compliance (the supplements were easy to ingest) and tolerance (there were no side effects) in the groups taking live or pasteurized bacteria. The conclusions are clear: The tests in humans confirm what had already been observed in mice. Ingestion of the (pasteurized) bacterium prevented the deterioration of the health status of the subjects (pre-diabetes, cardiovascular risks). Even better, the researchers observed a decrease in inflammation markers in the liver, a slight decrease in the body weight of the subjects (2.3 kg on average) as well as a lowering of cholesterol levels. In contrast, the metabolic parameters (insulin resistance or hypercholesterolemia) in placebo subjects continued to deteriorate over time. Who does it benefit? According to the WHO, one in three people die every day from cardiovascular disease worldwide. In Western countries, one in two people is overweight and has increased cardiovascular risks. This research of the UCLouvain would limit these risks and therefore potentially have an impact (limit the effects) on half of the population, if properly used. In conclusion, this pilot study demonstrates the feasibility of administrating (pasteurized) Akkermansia bacteria to humans in the form of a food supplement and reports encouraging results on the effectiveness of the Akkermansia-based dietary supplements to reduce cardio-metabolic risk factors. These results pave the way for a large-scale study, to confirm/elaborate these first results, but also endorse the commercialization of the bacteria as food supplements, by 2021. The study is published in Nature Medicine. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Metabolic syndrome is characterized by a constellation of comorbidities that predispose individuals to an increased risk of developing cardiovascular pathologies as well as type 2 diabetes mellitus 1 . The gut microbiota is a new key contributor involved in the onset of obesity-related disorders 2 . In humans, studies have provided evidence for a negative correlation between Akkermansia muciniphila abundance and overweight, obesity, untreated type 2 diabetes mellitus or hypertension 3 , 4 , 5 , 6 , 7 , 8 . Since the administration of A. muciniphila has never been investigated in humans, we conducted a randomized, double-blind, placebo-controlled pilot study in overweight/obese insulin-resistant volunteers; 40 were enrolled and 32 completed the trial. The primary end points were safety, tolerability and metabolic parameters (that is, insulin resistance, circulating lipids, visceral adiposity and body mass). Secondary outcomes were gut barrier function (that is, plasma lipopolysaccharides) and gut microbiota composition. In this single-center study, we demonstrated that daily oral supplementation of 10 10 A. muciniphila bacteria either live or pasteurized for three months was safe and well tolerated. Compared to placebo, pasteurized A. muciniphila improved insulin sensitivity (+28.62 ± 7.02%, P = 0.002), and reduced insulinemia (−34.08 ± 7.12%, P = 0.006) and plasma total cholesterol (−8.68 ± 2.38%, P = 0.02). Pasteurized A. muciniphila supplementation slightly decreased body weight (−2.27 ± 0.92 kg, P = 0.091) compared to the placebo group, and fat mass (−1.37 ± 0.82 kg, P = 0.092) and hip circumference (−2.63 ± 1.14 cm, P = 0.091) compared to baseline. After three months of supplementation, A. muciniphila reduced the levels of the relevant blood markers for liver dysfunction and inflammation while the overall gut microbiome structure was unaffected. In conclusion, this proof-of-concept study (clinical trial no. NCT02637115 ) shows that the intervention was safe and well tolerated and that supplementation with A. muciniphila improves several metabolic parameters. Main To overcome the worldwide evolution of cardiometabolic diseases, research has increasingly focused its attention on interventions that target the gut microbiota 2 . Among commensal bacteria residing in the intestine, Akkermansia muciniphila has attracted growing interest for its health-promoting effects 9 . In rodents, treatment with A. muciniphila reduces obesity and related disorders, such as glucose intolerance, insulin resistance, steatosis and gut permeability 10 , 11 , 12 . Recently, in rodents, we serendipitously discovered that pasteurization of A. muciniphila enhances its beneficial properties on adiposity, insulin resistance and glucose tolerance 11 . However, translational evaluation of A. muciniphila for human investigation was hampered by the need for animal-derived compounds in the growth medium used to culture this bacterium. We circumvented this major issue by developing a synthetic medium compatible with human administration 11 . The main objectives of this exploratory study were (1) to evaluate the feasibility, safety and tolerance of A. muciniphila supplementation, and (2) to explore for the first time the metabolic effects of A. muciniphila supplementation in humans. The study was designed as an exploratory and proof-of-concept study for a first supplementation in humans. The primary outcomes were safety, tolerability (that is, hepatic and renal function, inflammation) and metabolic parameters (that is, insulin resistance, circulating lipids, visceral adiposity and body mass index (BMI)). The secondary outcomes were gut barrier function (that is, plasma lipopolysaccharides (LPS)/metabolic endotoxemia), gut microbiota composition and metabolites. In 2017, the first reported preliminary human data from this study obtained using 5 volunteers per group suggested that treatment with either placebo, two doses of live A. muciniphila (low dose of 10 9 bacteria per day or high dose of 10 10 bacteria per day) or pasteurized A. muciniphila (10 10 bacteria per day) was safe in individuals with excess body weight; no changes in safety parameters or reported adverse events were observed after 15 d of daily administration 11 . In this study, we further extended this randomized, double-blind, placebo-controlled proof-of-concept and feasibility study using daily oral administration of A. muciniphila for 3 months, either live or pasteurized and compared their effects at the highest dose tested, that is, at 10 10 bacteria per day, in individuals exhibiting excess body weight (overweight or obese), insulin resistance and metabolic syndrome. Individuals were enrolled and underwent randomization to receive either a placebo, live A. muciniphila (10 10 bacteria per day) or pasteurized A. muciniphila (10 10 bacteria per day) as a supplement for 3 months, with the specific advice to keep to their normal dietary intake and physical activity during the study period (see flow chart in Extended Data Fig. 1 ). Although participants were randomized, we found that before starting supplementation (that is, at T0), participants receiving pasteurized cells exhibited significantly higher levels of insulin and lower insulin sensitivity than those in the placebo group (Supplementary Table 1 ). In the interest of safety, an early visit was scheduled 15 d after the start of supplementation. We found that both safety and tolerability were similar between the two groups receiving the different forms of A. muciniphila compared to the placebo group (Supplementary Tables 2 and 3 ), except for a higher white blood cell count (WBC) in the placebo and treated groups (Supplementary Table 2 ). We further followed safety and tolerability parameters until three months after the start of supplementation and did not observe any adverse events (Supplementary Tables 4 and 5 ). In addition, compliance was higher than 99% in all groups (Supplementary Table 5 ). After 3 months, the placebo group exhibited a significant increase of fasting plasma insulin ( P < 0.05, T3 versus T0; Fig. 1a ), contrary to participants receiving both forms of A. muciniphila where reduced plasma insulin levels (approximately 30%) were observed compared to the placebo group (Fig. 1a ). This effect was significant between the pasteurized A. muciniphila and placebo groups (Fig. 1a ). Fasting glycemia was not affected (Fig. 1b ); however, participants were not highly hyperglycemic at baseline (Supplementary Table 1 ). Fig. 1: Changes in parameters related to glucose metabolism and WBC. a , Insulinemia. b , Glycemia. c<|im_end|> <|im_start|>assistant In 2007, Patrice Cani (FNRS-WELBIO researcher) and his team at the Louvain Drug Research Institute of University of Louvain, in close collaboration with Willem de Vos, professor at UWageningen, discovered the beneficial effects of intestinal bacteria, Akkermansia muciniphila, able to moderate the development of obesity and type 2 diabetes, in mice. In 2017, the team discovered (still in the mouse) that the use of a pasteurized form of Akkermansia leads to an even greater protection than the living bacterium regarding various cardiovascular disease risk factors such as insulin resistance, hypercholesterolemia, or the storage of fat in adipose tissue. Following these discoveries, the UCLouvain team, in collaboration with the Cliniques Universitaires Saint-Luc, developed a clinical study in order to administer the bacteria to humans. For this, it was necessary to develop the capacity to produce the bacterium in large quantity and to make sure that the tests would be without risk for the participants. The UCLouvain researchers administered Akkermansia to overweight or obese volunteers, all displaying insulin resistance (pre-diabetes type 2) and metabolic syndrome, in other words, having several elevated risk factors for cardiovascular diseases. The volunteers were randomly divided into 3 groups (placebo, live bacteria and pasteurized bacteria) and were asked not to change their dietary habits or their physical activity. Akkermansia was provided as a nutritional supplement. The primary goal of this UCLouvain study was to demonstrate the feasibility of daily ingesting Akkermansia for 3 months, without risk. Clara Depommier and Amandine Everard, UCLouvain researchers, observed excellent compliance (the supplements were easy to ingest) and tolerance (there were no side effects) in the groups taking live or pasteurized bacteria. The conclusions are clear: The tests in humans confirm what had already been observed in mice. Ingestion of the (pasteurized) bacterium prevented the deterioration of the health status of the subjects (pre-diabetes, cardiovascular risks). Even better, the researchers observed a decrease in inflammation markers in the liver, a slight decrease in the body weight of the subjects (2.3 kg on average) as well as a lowering of cholesterol levels. In contrast, the metabolic parameters (insulin resistance or hypercholesterolemia) in placebo subjects continued to deteriorate over time. Who does it benefit? According to the WHO, one in three people die every day from cardiovascular disease worldwide. In Western countries, one in two people is overweight and has increased cardiovascular risks. This research of the UCLouvain would limit these risks and therefore potentially have an impact (limit the effects) on half of the population, if properly used. In conclusion, this pilot study demonstrates the feasibility of administrating (pasteurized) Akkermansia bacteria to humans in the form of a food supplement and reports encouraging results on the effectiveness of the Akkermansia-based dietary supplements to reduce cardio-metabolic risk factors. These results pave the way for a large-scale study, to confirm/elaborate these first results, but also endorse the commercialization of the bacteria as food supplements, by 2021. The study is published in Nature Medicine. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that overlap in their clinical presentation, pathology and genetic origin. Autoimmune disorders are also overrepresented in both ALS and FTD, but this remains an unexplained epidemiologic observation 1 , 2 , 3 . Expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial ALS and FTD (C9-ALS/FTD), and lead to both repeat-containing RNA and dipeptide accumulation, coupled with decreased C9orf72 protein expression in brain and peripheral blood cells 4 , 5 , 6 . Here we show in mice that loss of C9orf72 from myeloid cells alone is sufficient to recapitulate the age-dependent lymphoid hypertrophy and autoinflammation seen in animals with a complete knockout of C9orf72 . Dendritic cells isolated from C9orf72 −/− mice show marked early activation of the type I interferon response, and C9orf72 −/− myeloid cells are selectively hyperresponsive to activators of the stimulator of interferon genes (STING) protein—a key regulator of the innate immune response to cytosolic DNA. Degradation of STING through the autolysosomal pathway is diminished in C9orf72 −/− myeloid cells, and blocking STING suppresses hyperactive type I interferon responses in C9orf72 −/− immune cells as well as splenomegaly and inflammation in C9orf72 −/− mice. Moreover, mice lacking one or both copies of C9orf72 are more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune diseases seen in people with C9-ALS/FTD. Finally, blood-derived macrophages, whole blood and brain tissue from patients with C9-ALS/FTD all show an elevated type I interferon signature compared with samples from people with sporadic ALS/FTD; this increased interferon response can be suppressed with a STING inhibitor. Collectively, our results suggest that patients with C9-ALS/FTD have an altered immunophenotype because their reduced levels of C9orf72 cannot suppress the inflammation mediated by the induction of type I interferons by STING. Main C9orf72 -knockout mice demonstrate hyperplasia of lymphoid organs and age-related systemic inflammation; however, depending on their environment, they range from having no tissue injury and a normal lifespan 7 , to autoantibody production with renal injury 8 and fatal spontaneous autoimmune disease 9 . In the immune system, C9orf72 is most highly expressed in myeloid cells, especially dendritic cells (DCs) 7 . DCs are antigen-presenting cells of the innate immune system that regulate the adaptive immune response, playing an important part in autoimmunity and cancer immunity 10 , 11 . To assess the effect of loss of C9orf72 on DCs, we analysed the activation state of splenic DCs from C9orf72 −/− mice at 8 weeks, when minimal inflammation and lymphoid hyperplasia are present, and at 8 months, when the mice have pronounced markers of systemic inflammation (Extended Data Fig. 1 ). Although the development of DC subtypes was normal in C9orf72 −/− mice (Extended Data Fig. 1a ), we observed increased expression of the costimulatory molecule CD86 on CD11b DCs, becoming more prominent with age (Fig. 1a, b ). DCs are crucial for regulating T cell homeostasis, activation and tolerance, and T cells were reported to be activated in aged C9orf72 −/− mice 8 . We found that T cell development in the thymus was normal in C9orf72 −/− mice (Extended Data Fig. 1f ), but that numbers of memory and effector memory CD4 and CD8 T cells were increased even at 8 weeks, and became more pronounced with age (Fig. 1c, d ). Fig. 1: DC development and T-cell activation in young and aged C9orf72 − /− mice. a , b , Mean fluorescent intensity (MFI) of CD86 in CD11c + splenic DCs from young ( a ; n = 5) and aged ( b ; n = 6) mice. C9, C9orf72 . c , d , Flow cytometric analysis of naive (CD62L + ), memory (CD62L + CD44 + ) and effector memory (CD44 + ) CD4 T cells and CD8 T cells from 8-week-old ( c ; n = 5) and 8-month-old ( d ; n = 6) mice. e , Left, gross images of splenomegaly in C9orf72 - Cx3cr1 Cre mice at 5 months. Right, spleen weights (in milligrams) normalized to body weight (in grams) at 5 months ( n = 7). f , C9orf72-Cx3cr1 Cre mice have decreased numbers of naive CD4 and CD8 T cells, but increased numbers of CD4 memory and CD8 effector memory T cells ( n = 7). g , GSEA of significantly upregulated pathways in CD8 T cells and CD4 T cells of C9orf72-Cx3cr1 Cre mice versus at 3 months (false discovery rate (FDR) less than 0.05) ( n = 4). h , i , Transcripts per million (TPM) values from RNA-seq, showing non-cell-autonomous elevation of ISGs in CD8 T cells (wild-type, n = 4; C9 −/− , n = 3; C9orf72 fl/fl ; Cx3CR1 Cre , n = 3) and CD4 T cells (wild-type, n = 4; C9 −/− , n = 3; C9orf72 fl/fl ; Cx3CR1 Cre , n = 4) in C9orf72-Cx3cr1 Cre mice. a – d , f , One-way analysis of variance (ANOVA). e , Unpaired, two-tailed Student’s t -test. h , i , Two-way ANOVA. a – f , h , i , Data shown as means ± s.e.m. Each dot represents one mouse. Source data Full size image Given that C9orf72 is also expressed at low levels in lymphocytes, we crossed mice containing a C9orf72 conditional null allele ( C9orf72 fl/fl ) 12 to two different myeloid-specific Cre driver lines, Cx3cr1 Cre and LysM Cre , to determine whether the phenotype was cell autonomous to myeloid cells. The loss of C9orf72 selectively in myeloid populations (primarily monocytes, tissue macrophages and DCs 13 ) in C9orf72 fl/fl ; Cx3cr1 Cre mice completely recapitulated the splenomegaly, altered expression of costimulatory molecules in DCs, and T-cell activation seen in C9orf72 complete-knockout mice (Fig. 1e, f and Extended Data Fig. 2c, d ). Similar findings were observed with C9orf72 fl/fl ; LyzM Cre mice (Extended Data Fig. 3 ), although to a milder degree, potentially because the LyzM Cre", "role": "user" }, { "content": "A study published today in the journal Nature could help explain why certain people who develop amyotrophic lateral sclerosis (ALS), a deadly neurological disorder also known as Lou Gehrig's disease, are prone to autoimmune diseases. ALS, which has no known cure, causes progressive degeneration of nerve cells in the spinal cord and brain. About 5,000 people are diagnosed with the disease each year. The new research, led by Cedars-Sinai investigators, focuses on a mutation that decreases expression of a gene called C9orf72, the most common known cause of inherited ALS. Investigators found that this mutation, found in about 10% of patients with ALS, causes the stimulator of interferon genes (STING) protein, a critical sensor of viral infections in the immune system, to become hyperactive. This hyperactivity led to increased production of interferons. Interferons are key for fighting viral infections, but constant, uncontrolled production of interferons can lead to systemic inflammation and development of autoimmune diseases. \"These findings support that patients with C9orf72 mutations have a fundamentally different set point of their immune system, with increased propensity to autoimmune diseases, and probably altered responses to viruses and other pathogens in the environment,\" said Robert Baloh, MD, Ph.D., professor of Neurology and director of the Cedars-Sinai Center for Neural Science and Medicine. Baloh is the corresponding author of the study, available online today and in the Sept. 3 print edition of the journal. The C9orf72 mutation, which is believed to have originated in Northern Europe about 1,500 years ago and then spread as a result of Viking travels and wars, is also associated with frontotemporal lobar degeneration, a type of dementia that can accompany ALS. For the study, investigators examined the brain tissue of laboratory mice with the C9orf72 mutation and and also blood and brain tissue from ALS patients who carried the gene. Results included: Immune cells isolated from the laboratory mice showed early spontaneous activation. In addition, a certain type of immune cell, called myeloid cells, had increased production of the interferons in response to activation of the STING protein.Tissues from ALS patients with the genetic mutation and frontotemporal lobar degeneration showed an elevated immune response compared with samples from patients with a different type of ALS. Taken together, those findings suggested that ALS patients with the genetic mutation and frontotemporal lobar degeneration have an altered immune system because their reduced levels of C9orf72 cannot suppress the inflammation caused by the hyperactive STING protein, the investigators said. \"These results give us critical insights into the interplay of the immune system and neurodegenerative disease,\" said Nancy Sicotte, MD, chair of the Department of Neurology at Cedars-Sinai and the Women's Guild Distinguished Chair in Neurology. \"They have implications not only for ALS and frontotemporal lobar degeneration, but for other autoimmune and degenerative disorders affecting the nervous system.\" Interestingly, the investigators also found that mice with the C9orf72 mutation were more resistant to certain cancers, possibly as a byproduct of a hyperactive immune system. A similar decreased incidence of cancers has also been reported in ALS patients, but the reason remains a mystery. \"This study ties together research about a really important immune pathway and the genetics of ALS, linking neurodegeneration, autoimmune diseases and cancer,\" Baloh said. Baloh's Neurodegenerative Diseases Laboratory is now studying how this gene mutation and heightened autoimmune response is linked to neurodegeneration. He said that understanding these connections may help investigators lay the groundwork for developing therapies for ALS. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that overlap in their clinical presentation, pathology and genetic origin. Autoimmune disorders are also overrepresented in both ALS and FTD, but this remains an unexplained epidemiologic observation 1 , 2 , 3 . Expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial ALS and FTD (C9-ALS/FTD), and lead to both repeat-containing RNA and dipeptide accumulation, coupled with decreased C9orf72 protein expression in brain and peripheral blood cells 4 , 5 , 6 . Here we show in mice that loss of C9orf72 from myeloid cells alone is sufficient to recapitulate the age-dependent lymphoid hypertrophy and autoinflammation seen in animals with a complete knockout of C9orf72 . Dendritic cells isolated from C9orf72 −/− mice show marked early activation of the type I interferon response, and C9orf72 −/− myeloid cells are selectively hyperresponsive to activators of the stimulator of interferon genes (STING) protein—a key regulator of the innate immune response to cytosolic DNA. Degradation of STING through the autolysosomal pathway is diminished in C9orf72 −/− myeloid cells, and blocking STING suppresses hyperactive type I interferon responses in C9orf72 −/− immune cells as well as splenomegaly and inflammation in C9orf72 −/− mice. Moreover, mice lacking one or both copies of C9orf72 are more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune diseases seen in people with C9-ALS/FTD. Finally, blood-derived macrophages, whole blood and brain tissue from patients with C9-ALS/FTD all show an elevated type I interferon signature compared with samples from people with sporadic ALS/FTD; this increased interferon response can be suppressed with a STING inhibitor. Collectively, our results suggest that patients with C9-ALS/FTD have an altered immunophenotype because their reduced levels of C9orf72 cannot suppress the inflammation mediated by the induction of type I interferons by STING. Main C9orf72 -knockout mice demonstrate hyperplasia of lymphoid organs and age-related systemic inflammation; however, depending on their environment, they range from having no tissue injury and a normal lifespan 7 , to autoantibody production with renal injury 8 and fatal spontaneous autoimmune disease 9 . In the immune system, C9orf72 is most highly expressed in myeloid cells, especially dendritic cells (DCs) 7 . DCs are antigen-presenting cells of the innate immune system that regulate the adaptive immune response, playing an important part in autoimmunity and cancer immunity 10 , 11 . To assess the effect of loss of C9orf72 on DCs, we analysed the activation state of splenic DCs from C9orf72 −/− mice at 8 weeks, when minimal inflammation and lymphoid hyperplasia are present, and at 8 months, when the mice have pronounced markers of systemic inflammation (Extended Data Fig. 1 ). Although the development of DC subtypes was normal in C9orf72 −/− mice (Extended Data Fig. 1a ), we observed increased expression of the costimulatory molecule CD86 on CD11b DCs, becoming more prominent with age (Fig. 1a, b ). DCs are crucial for regulating T cell homeostasis, activation and tolerance, and T cells were reported to be activated in aged C9orf72 −/− mice 8 . We found that T cell development in the thymus was normal in C9orf72 −/− mice (Extended Data Fig. 1f ), but that numbers of memory and effector memory CD4 and CD8 T cells were increased even at 8 weeks, and became more pronounced with age (Fig. 1c, d ). Fig. 1: DC development and T-cell activation in young and aged C9orf72 − /− mice. a , b , Mean fluorescent intensity (MFI) of CD86 in CD11c + splenic DCs from young ( a ; n = 5) and aged ( b ; n = 6) mice. C9, C9orf72 . c , d , Flow cytometric analysis of naive (CD62L + ), memory (CD62L + CD44 + ) and effector memory (CD44 + ) CD4 T cells and CD8 T cells from 8-week-old ( c ; n = 5) and 8-month-old ( d ; n = 6) mice. e , Left, gross images of splenomegaly in C9orf72 - Cx3cr1 Cre mice at 5 months. Right, spleen weights (in milligrams) normalized to body weight (in grams) at 5 months ( n = 7). f , C9orf72-Cx3cr1 Cre mice have decreased numbers of naive CD4 and CD8 T cells, but increased numbers of CD4 memory and CD8 effector memory T cells ( n = 7). g , GSEA of significantly upregulated pathways in CD8 T cells and CD4 T cells of C9orf72-Cx3cr1 Cre mice versus at 3 months (false discovery rate (FDR) less than 0.05) ( n = 4). h , i , Transcripts per million (TPM) values from RNA-seq, showing non-cell-autonomous elevation of ISGs in CD8 T cells (wild-type, n = 4; C9 −/− , n = 3; C9orf72 fl/fl ; Cx3CR1 Cre , n = 3) and CD4 T cells (wild-type, n = 4; C9 −/− , n = 3; C9orf72 fl/fl ; Cx3CR1 Cre , n = 4) in C9orf72-Cx3cr1 Cre mice. a – d , f , One-way analysis of variance (ANOVA). e , Unpaired, two-tailed Student’s t -test. h , i , Two-way ANOVA. a – f , h , i , Data shown as means ± s.e.m. Each dot represents one mouse. Source data Full size image Given that C9orf72 is also expressed at low levels in lymphocytes, we crossed mice containing a C9orf72 conditional null allele ( C9orf72 fl/fl ) 12 to two different myeloid-specific Cre driver lines, Cx3cr1 Cre and LysM Cre , to determine whether the phenotype was cell autonomous to myeloid cells. The loss of C9orf72 selectively in myeloid populations (primarily monocytes, tissue macrophages and DCs 13 ) in C9orf72 fl/fl ; Cx3cr1 Cre mice completely recapitulated the splenomegaly, altered expression of costimulatory molecules in DCs, and T-cell activation seen in C9orf72 complete-knockout mice (Fig. 1e, f and Extended Data Fig. 2c, d ). Similar findings were observed with C9orf72 fl/fl ; LyzM Cre mice (Extended Data Fig. 3 ), although to a milder degree, potentially because the LyzM Cre<|im_end|> <|im_start|>assistant A study published today in the journal Nature could help explain why certain people who develop amyotrophic lateral sclerosis (ALS), a deadly neurological disorder also known as Lou Gehrig's disease, are prone to autoimmune diseases. ALS, which has no known cure, causes progressive degeneration of nerve cells in the spinal cord and brain. About 5,000 people are diagnosed with the disease each year. The new research, led by Cedars-Sinai investigators, focuses on a mutation that decreases expression of a gene called C9orf72, the most common known cause of inherited ALS. Investigators found that this mutation, found in about 10% of patients with ALS, causes the stimulator of interferon genes (STING) protein, a critical sensor of viral infections in the immune system, to become hyperactive. This hyperactivity led to increased production of interferons. Interferons are key for fighting viral infections, but constant, uncontrolled production of interferons can lead to systemic inflammation and development of autoimmune diseases. "These findings support that patients with C9orf72 mutations have a fundamentally different set point of their immune system, with increased propensity to autoimmune diseases, and probably altered responses to viruses and other pathogens in the environment," said Robert Baloh, MD, Ph.D., professor of Neurology and director of the Cedars-Sinai Center for Neural Science and Medicine. Baloh is the corresponding author of the study, available online today and in the Sept. 3 print edition of the journal. The C9orf72 mutation, which is believed to have originated in Northern Europe about 1,500 years ago and then spread as a result of Viking travels and wars, is also associated with frontotemporal lobar degeneration, a type of dementia that can accompany ALS. For the study, investigators examined the brain tissue of laboratory mice with the C9orf72 mutation and and also blood and brain tissue from ALS patients who carried the gene. Results included: Immune cells isolated from the laboratory mice showed early spontaneous activation. In addition, a certain type of immune cell, called myeloid cells, had increased production of the interferons in response to activation of the STING protein.Tissues from ALS patients with the genetic mutation and frontotemporal lobar degeneration showed an elevated immune response compared with samples from patients with a different type of ALS. Taken together, those findings suggested that ALS patients with the genetic mutation and frontotemporal lobar degeneration have an altered immune system because their reduced levels of C9orf72 cannot suppress the inflammation caused by the hyperactive STING protein, the investigators said. "These results give us critical insights into the interplay of the immune system and neurodegenerative disease," said Nancy Sicotte, MD, chair of the Department of Neurology at Cedars-Sinai and the Women's Guild Distinguished Chair in Neurology. "They have implications not only for ALS and frontotemporal lobar degeneration, but for other autoimmune and degenerative disorders affecting the nervous system." Interestingly, the investigators also found that mice with the C9orf72 mutation were more resistant to certain cancers, possibly as a byproduct of a hyperactive immune system. A similar decreased incidence of cancers has also been reported in ALS patients, but the reason remains a mystery. "This study ties together research about a really important immune pathway and the genetics of ALS, linking neurodegeneration, autoimmune diseases and cancer," Baloh said. Baloh's Neurodegenerative Diseases Laboratory is now studying how this gene mutation and heightened autoimmune response is linked to neurodegeneration. He said that understanding these connections may help investigators lay the groundwork for developing therapies for ALS. <|im_end|>

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555, 279, 17508, 3104, 4015, 1753, 13128, 11, 279, 26453, 1071, 13, 330, 9673, 3135, 3041, 603, 9200, 26793, 1139, 279, 958, 1387, 315, 279, 22852, 1887, 323, 18247, 451, 7642, 1413, 8624, 1359, 1071, 35336, 56954, 51111, 11, 14306, 11, 10716, 315, 279, 6011, 315, 32359, 36781, 520, 79613, 1590, 6354, 258, 2192, 323, 279, 11215, 596, 33592, 423, 80382, 16478, 304, 32359, 36781, 13, 330, 7009, 617, 25127, 539, 1193, 369, 39523, 323, 4156, 354, 3342, 10020, 326, 32493, 5367, 17699, 11, 719, 369, 1023, 88191, 323, 5367, 75989, 24673, 28987, 279, 23418, 1887, 1210, 58603, 11, 279, 26453, 1101, 1766, 430, 24548, 449, 279, 356, 24, 33942, 5332, 27472, 1051, 810, 31785, 311, 3738, 51423, 11, 11000, 439, 264, 555, 3107, 315, 264, 17508, 3104, 22852, 1887, 13, 362, 4528, 25983, 39775, 315, 51423, 706, 1101, 1027, 5068, 304, 39523, 6978, 11, 719, 279, 2944, 8625, 264, 23347, 13, 330, 2028, 4007, 20405, 3871, 3495, 922, 264, 2216, 3062, 22852, 38970, 323, 279, 56104, 315, 39523, 11, 31799, 18247, 451, 81157, 11, 88191, 19338, 323, 9572, 1359, 19984, 2319, 1071, 13, 19984, 2319, 596, 32359, 451, 7642, 1413, 70674, 32184, 374, 1457, 21630, 1268, 420, 15207, 27472, 323, 60487, 88191, 2077, 374, 10815, 311, 18247, 451, 81157, 13, 1283, 1071, 430, 8830, 1521, 13537, 1253, 1520, 26453, 11203, 279, 95844, 369, 11469, 52312, 369, 39523, 13, 220, 128257, 198 ]

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