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 articular release of the metacarpophalangeal joint produces a typical cracking sound, resulting in what is commonly referred to as the cracking of knuckles. Despite over sixty years of research, the source of the knuckle cracking sound continues to be debated due to inconclusive experimental evidence as a result of limitations in the temporal resolution of non-invasive physiological imaging techniques. To support the available experimental data and shed light onto the source of the cracking sound, we have developed a mathematical model of the events leading to the generation of the sound. The model resolves the dynamics of a collapsing cavitation bubble in the synovial fluid inside a metacarpophalangeal joint during an articular release. The acoustic signature from the resulting bubble dynamics is shown to be consistent in both magnitude and dominant frequency with experimental measurements in the literature and with our own experiments, thus lending support for cavitation bubble collapse as the source of the cracking sound. Finally, the model also shows that only a partial collapse of the bubble is needed to replicate the experimentally observed acoustic spectra, thus allowing for bubbles to persist following the generation of sound as has been reported in recent experiments. Introduction Some can and some cannot, but in any case knuckle cracking is very common. Knuckle cracking, the sound accompanying the articular release of the metacarpophalangeal (MCP) joint, has attracted the attention of researchers since the early 1900’s. Some of the earliest comprehensive studies on cracking of the MCP joint established that all joints cannot be cracked and that joints once cracked cannot be cracked again for approximately 20 minutes 1 . These observations have been confirmed by a number of studies over the years 2 , 3 , 4 , 5 ; however, interestingly the source of the cracking sound during articular release continues to be debated 4 . During articular release, the articulating surfaces (in this case the metacarpal and the proximal phalange) spring apart rapidly past the normal physiological range 6 . Roston and Wheeler hypothesized that this rapid motion of joints sets up vibrations in tissues leading to the cracking sound 1 . Mennel, on the other hand, ascribed the sound to the sudden tightening of the fibrous capsule about the joint during articular release 7 . However in 1971, Unsworth and co-workers through extensive experiments concluded cavitation and the subsequent collapse of cavitation bubbles in the synovial fluid as the source of the cracking sound 2 . Cavitation as the source of the cracking sound was widely accepted for over 40 years 3 , 6 , until Kawchuk and co-workers challenged this view recently by providing new evidence for the persistence of gas bubbles in the synovial fluid long after the cracking sounds were observed 4 . They hypothesized that tribonucleation-mediated sudden growth of bubbles and not their collapse was responsible for the sound. The recent hypothesis of tribonucleation-mediated cavity inception as the source of the cracking sounds cannot explain the observed magnitude of the sounds 4 , suggesting the need for more detailed studies to resolve the origin of sounds during knuckle cracking. Experimental resolution to this problem is limited by the temporal resolution of available imaging techniques such as radiography (discrete) 1 , 2 , cineradiography (120 fps) 5 and MRI (3.2 fps) 4 . Even today the capability of physiologically safe cineradiography (~100 fps) 8 and MRI (80–100 fps) 9 are far below 1200 fps, the minimum temporal resolution required to resolve the high speed dynamics of knuckle cracking as suggested by Watson et al . 5 , thus highlighting the need for numerical and theoretical approaches. The only study in this direction was conducted by Kanagawa and Taira, where they used the Rayleigh-Plesset equation to resolve the dynamics of cavitation bubbles subjected to impulsive and periodic forcing by an external pressure field 10 . Their results showed that cavitation bubbles under impulsive forcing can produce sharp sounds, highlighting the importance of bubble dynamics and underscoring the potential of numerical and theoretical approaches for understanding knuckle cracking. In this manuscript, we develop a physiologically consistent mathematical model that can explain the generation of sounds accompanying knuckle cracking and thus aid in resolving the debate over the source of the sound. The model accounts for the dynamics of cavitation bubble collapse in the synovial fluid, as the presence of bubbles in the joint during knuckle cracking is unambiguously supported by virtually all researchers 1 , 2 , 4 , 5 , 10 despite their differences on the origin of the sound. The cavitation bubble is assumed to originate due to the low pressure generated by tribonucleation and to subsequently evolve as the synovial fluid pressure changes inside a 2D approximated MCP joint. The acoustic waveforms and spectra generated by the collapsing bubble are shown to be consistent with our experimental recordings of knuckle cracking acoustics. Hence, this study establishes that the acoustic signature of cavitation bubble collapse is consistent with experimentally observed sounds, thus lending support for cavitation bubble collapse as a potential source of the sound. It also demonstrates the potential of detailed numerical and theoretical studies in cracking the enigma of the knuckle cracking sounds. Modelling We model the sounds accompanying knuckle cracking by resolving the acoustic signature of cavitation bubbles inside the joint during articular release. For developing the model, the joint is assumed to be axisymmetric, thus simplifying the solution of the governing equations. The governing equations themselves describe three important phenomena: (1) the generation of transient low pressures during tribonucleation, (2) the dynamics of a newly formed cavitation bubble in the time-varying ambient pressure field, and (3) the simultaneous acoustic pressure field generated by the bubble. 2D Approximation of the MCP Joint Geometric studies of the metacarpal head and the base of the proximal phalange of the MCP joint (Fig. 1a ) have demonstrated that the geometry can be approximated by two spherical surfaces 2 , 11 . Exploiting the geometric symmetry, the joint can be approximated in two", "role": "user" }, { "content": "It has puzzled scientists for over 100 years but now they appear to have cracked it: what, exactly, is it that causes that wince-inducing sound when you pop your knuckles? Love it or loathe it, knuckle-cracking is very common. Earlier studies have established that not all joints can be cracked, and that—for that those that can—the act can't be repeated for another 20 minutes. But the source of the sound remained a mystery. And \"popping\", it turns out, is exactly what it is, researchers said on Thursday after finding that the distinctive cracking sound was caused by the collapse of microscopic bubbles of joint fluid in the hand. Using a mathematical model alongside a geometrical representation of the joint, experts from Paris' Ecole Polytechnique and Stanford University in the United States simulated the events leading up to the crack. \"The sound that is generated when one cracks his or her knuckles is due to the partial collapse of a cavitation bubble that's in the fluid in the joint,\" explained Abdul Barakat, a professor at the Ecole Polytechnique. \"It could be multiple bubbles, but we showed that the collapse of a single bubble is sufficient to give you the signature sound you get,\" he told AFP by phone. Although experts had initially linked the sound to the collapse of knuckle bubbles back in 1971, their findings were thrown into question after further studies showed there were still bubbles left in the fluid after the knuckles had been cracked. But the mathematical model appears to resolve this apparent contradiction by showing the sound can be produced by partial collapse, the researchers said. Earlier studies using ultrasound had reached a similar conclusion linking the sound to changes in pressure in the joint fluid. A 2015 paper suggesting it was actually the formation of a bubble rather than its collapse which caused the distinctive crack. \"We wanted to look at it mathematically because all the previous work was based on observation or imaging, so we tried to build a mathematical model that described the physical phenomena that governed this,\" Barakat said. \"We showed that the collapse gave you the right signature sound.\" Although it may not settle the debate once and for all, the research is sure to trigger a spontaneous bout of knuckle-popping. \"After publishing this paper, my daughter tried it out and now she cracks her knuckles,\" said Barakat, himself a knuckle-cracker. So far, knuckle-cracking has not been shown to be beneficial or harmful. Contrary to popular belief, medics say it does not cause arthritis. ", "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 articular release of the metacarpophalangeal joint produces a typical cracking sound, resulting in what is commonly referred to as the cracking of knuckles. Despite over sixty years of research, the source of the knuckle cracking sound continues to be debated due to inconclusive experimental evidence as a result of limitations in the temporal resolution of non-invasive physiological imaging techniques. To support the available experimental data and shed light onto the source of the cracking sound, we have developed a mathematical model of the events leading to the generation of the sound. The model resolves the dynamics of a collapsing cavitation bubble in the synovial fluid inside a metacarpophalangeal joint during an articular release. The acoustic signature from the resulting bubble dynamics is shown to be consistent in both magnitude and dominant frequency with experimental measurements in the literature and with our own experiments, thus lending support for cavitation bubble collapse as the source of the cracking sound. Finally, the model also shows that only a partial collapse of the bubble is needed to replicate the experimentally observed acoustic spectra, thus allowing for bubbles to persist following the generation of sound as has been reported in recent experiments. Introduction Some can and some cannot, but in any case knuckle cracking is very common. Knuckle cracking, the sound accompanying the articular release of the metacarpophalangeal (MCP) joint, has attracted the attention of researchers since the early 1900’s. Some of the earliest comprehensive studies on cracking of the MCP joint established that all joints cannot be cracked and that joints once cracked cannot be cracked again for approximately 20 minutes 1 . These observations have been confirmed by a number of studies over the years 2 , 3 , 4 , 5 ; however, interestingly the source of the cracking sound during articular release continues to be debated 4 . During articular release, the articulating surfaces (in this case the metacarpal and the proximal phalange) spring apart rapidly past the normal physiological range 6 . Roston and Wheeler hypothesized that this rapid motion of joints sets up vibrations in tissues leading to the cracking sound 1 . Mennel, on the other hand, ascribed the sound to the sudden tightening of the fibrous capsule about the joint during articular release 7 . However in 1971, Unsworth and co-workers through extensive experiments concluded cavitation and the subsequent collapse of cavitation bubbles in the synovial fluid as the source of the cracking sound 2 . Cavitation as the source of the cracking sound was widely accepted for over 40 years 3 , 6 , until Kawchuk and co-workers challenged this view recently by providing new evidence for the persistence of gas bubbles in the synovial fluid long after the cracking sounds were observed 4 . They hypothesized that tribonucleation-mediated sudden growth of bubbles and not their collapse was responsible for the sound. The recent hypothesis of tribonucleation-mediated cavity inception as the source of the cracking sounds cannot explain the observed magnitude of the sounds 4 , suggesting the need for more detailed studies to resolve the origin of sounds during knuckle cracking. Experimental resolution to this problem is limited by the temporal resolution of available imaging techniques such as radiography (discrete) 1 , 2 , cineradiography (120 fps) 5 and MRI (3.2 fps) 4 . Even today the capability of physiologically safe cineradiography (~100 fps) 8 and MRI (80–100 fps) 9 are far below 1200 fps, the minimum temporal resolution required to resolve the high speed dynamics of knuckle cracking as suggested by Watson et al . 5 , thus highlighting the need for numerical and theoretical approaches. The only study in this direction was conducted by Kanagawa and Taira, where they used the Rayleigh-Plesset equation to resolve the dynamics of cavitation bubbles subjected to impulsive and periodic forcing by an external pressure field 10 . Their results showed that cavitation bubbles under impulsive forcing can produce sharp sounds, highlighting the importance of bubble dynamics and underscoring the potential of numerical and theoretical approaches for understanding knuckle cracking. In this manuscript, we develop a physiologically consistent mathematical model that can explain the generation of sounds accompanying knuckle cracking and thus aid in resolving the debate over the source of the sound. The model accounts for the dynamics of cavitation bubble collapse in the synovial fluid, as the presence of bubbles in the joint during knuckle cracking is unambiguously supported by virtually all researchers 1 , 2 , 4 , 5 , 10 despite their differences on the origin of the sound. The cavitation bubble is assumed to originate due to the low pressure generated by tribonucleation and to subsequently evolve as the synovial fluid pressure changes inside a 2D approximated MCP joint. The acoustic waveforms and spectra generated by the collapsing bubble are shown to be consistent with our experimental recordings of knuckle cracking acoustics. Hence, this study establishes that the acoustic signature of cavitation bubble collapse is consistent with experimentally observed sounds, thus lending support for cavitation bubble collapse as a potential source of the sound. It also demonstrates the potential of detailed numerical and theoretical studies in cracking the enigma of the knuckle cracking sounds. Modelling We model the sounds accompanying knuckle cracking by resolving the acoustic signature of cavitation bubbles inside the joint during articular release. For developing the model, the joint is assumed to be axisymmetric, thus simplifying the solution of the governing equations. The governing equations themselves describe three important phenomena: (1) the generation of transient low pressures during tribonucleation, (2) the dynamics of a newly formed cavitation bubble in the time-varying ambient pressure field, and (3) the simultaneous acoustic pressure field generated by the bubble. 2D Approximation of the MCP Joint Geometric studies of the metacarpal head and the base of the proximal phalange of the MCP joint (Fig. 1a ) have demonstrated that the geometry can be approximated by two spherical surfaces 2 , 11 . Exploiting the geometric symmetry, the joint can be approximated in two<|im_end|> <|im_start|>assistant It has puzzled scientists for over 100 years but now they appear to have cracked it: what, exactly, is it that causes that wince-inducing sound when you pop your knuckles? Love it or loathe it, knuckle-cracking is very common. Earlier studies have established that not all joints can be cracked, and that—for that those that can—the act can't be repeated for another 20 minutes. But the source of the sound remained a mystery. And "popping", it turns out, is exactly what it is, researchers said on Thursday after finding that the distinctive cracking sound was caused by the collapse of microscopic bubbles of joint fluid in the hand. Using a mathematical model alongside a geometrical representation of the joint, experts from Paris' Ecole Polytechnique and Stanford University in the United States simulated the events leading up to the crack. "The sound that is generated when one cracks his or her knuckles is due to the partial collapse of a cavitation bubble that's in the fluid in the joint," explained Abdul Barakat, a professor at the Ecole Polytechnique. "It could be multiple bubbles, but we showed that the collapse of a single bubble is sufficient to give you the signature sound you get," he told AFP by phone. Although experts had initially linked the sound to the collapse of knuckle bubbles back in 1971, their findings were thrown into question after further studies showed there were still bubbles left in the fluid after the knuckles had been cracked. But the mathematical model appears to resolve this apparent contradiction by showing the sound can be produced by partial collapse, the researchers said. Earlier studies using ultrasound had reached a similar conclusion linking the sound to changes in pressure in the joint fluid. A 2015 paper suggesting it was actually the formation of a bubble rather than its collapse which caused the distinctive crack. "We wanted to look at it mathematically because all the previous work was based on observation or imaging, so we tried to build a mathematical model that described the physical phenomena that governed this," Barakat said. "We showed that the collapse gave you the right signature sound." Although it may not settle the debate once and for all, the research is sure to trigger a spontaneous bout of knuckle-popping. "After publishing this paper, my daughter tried it out and now she cracks her knuckles," said Barakat, himself a knuckle-cracker. So far, knuckle-cracking has not been shown to be beneficial or harmful. Contrary to popular belief, medics say it does not cause arthritis. <|im_end|>

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1,826

[ { "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 Monitoring and ensuring the integrity of data within the clinical trial process is currently not always feasible with the current research system. We propose a blockchain-based system to make data collected in the clinical trial process immutable, traceable, and potentially more trustworthy. We use raw data from a real completed clinical trial, simulate the trial onto a proof of concept web portal service, and test its resilience to data tampering. We also assess its prospects to provide a traceable and useful audit trail of trial data for regulators, and a flexible service for all members within the clinical trials network. We also improve the way adverse events are currently reported. In conclusion, we advocate that this service could offer an improvement in clinical trial data management, and could bolster trust in the clinical research process and the ease at which regulators can oversee trials. Introduction Clinical trial networks often involve many parties and sites, and a large flow of information and confidential data. With the involvement of more parties, more exchanges, and trials being conducted far from sponsoring institutions comes the opportunity for human-induced error, whether it is unintentional or malicious. In a survey of authors of clinical drug trials, 17% of them reported that they were personally aware of intentional fabrication in research 1 . Although it is obviously not possible to calculate the actual rate or impact of fraud, there is evidence that some misconduct and alteration of data is happening in scientific and medical research 2 , potentially including clinical trials. In addition, current clinical trials are executed with many manual processes that could be prone to error. Enforcing Good Clinical Practice guidelines set forth by the International Council for Harmonization of Requirements for Pharmaceuticals for Human Use (ICH) has been a challenge for regulators of trials, and process improvement is an active area of research 3 . For regulators of trials such as the Food and Drug Administration (FDA), auditing of data are challenging, and real-time oversight of a trial is lacking as there is no easy and secure way of accessing or viewing the complex network of data transactions as they occur. There can be a lack of transparency and traceability of data, lack of real-time access to results as they are made, and potentially a risk of data tampering 3 . The ability to easily trace data back to the original source can be limited 4 , and the FDA has identified this lack of traceability as one of their top data issues to address 5 . Blockchain is a new software development methodology involving a unique data structure that has garnered increased attention due to the seminal paper that outlined Bitcoin (bitcoin.org) 6 . The technology provides a data structure that ensure a secure and unfalsifiable transaction history. This is accomplished primarily through the use of cryptographic hashing, which has properties and use cases in many domains ranging from internet security to banking. A hash function is a function that maps data of variable length data to a fixed-length digest. Any change to the input data result in an unpredictable change in the hash. In this implementation, each new block added to the chain includes a hash of the previous block. If the previous block is later changed, the subsequent hash would no longer be valid. In addition, blockchains are designed to be append only, and are thus immutable by design, providing a guarantee of safeguarded data. This yields a verifiable and tamper proof history of all transactions since its beginning 6 . We propose a solution to the challenges in the current clinical trials system by using blockchain technology, coupled with changes in methodology for the management of clinical trials. Due to the innate need of clinical trials to have a centralized authority, such as through the regulator, a completely decentralized blockchain infrastructure as used in Bitcoin might not be appropriate. Instead, we borrow ideas and repurpose the methodology to work with clinical trial management, and demonstrate the feasibility with a new prototype web portal. Blockchain has already been proposed for use in various healthcare settings 7 , with potential applications in medical record management, claims processing, health supply chain management, and integration of geospatial data in various data modalities 8 . Work has already begun in seeing how clinical trial management can be improved with blockchain technologies 9 , 10 . Moreover, certain aspects relevant to the clinical trial process, such as patient recruiting and IRB (Institutional Review Board) enforcement of human subject regulations via smart contracts, have been described at a high level in the literature 11 . We improve upon previous work by implementing a web-based portal accessible to all parties with a real clinical trial dataset, facilitating and verifying patient and clinical investigator interaction, integrating version control into the blockchain, expediting adverse event reporting, and testing malicious attacks to data integrity with real world clinical data. Results Network protocol We modeled a prototype phase II clinical trial. Upon approval of the study protocol and initiation of phase II, we propose a future regulator could instantiate a private blockchain and registers all participating parties in the portal providing authenticated and controlled web-based and API (application programming interface) access to the blockchain. All parties would be required to use the portal service for any and all exchange of information related to the trial, and only the information present on the blockchain would be used for review when considering approval of the treatment. The network and representative transactions are illustrated in Fig. 1 . Fig. 1 The idealized clinical trial network in the context of a blockchain-based record system. The various transactions (along each arrow) and key participants (boxed) within a clinical trial are shown Full size image For new patient recruitment and consent acquisition by the clinical site, we propose that an Interactive Voice Response System (IVRS) generates unique verification codes for each subject to give to the trial investigator at the clinical site, and posts encrypted decoding keys", "role": "user" }, { "content": "UC San Francisco researchers have created a proof-of-concept method for ensuring the integrity of clinical trials data with blockchain. The system creates an immutable audit trail that makes it easy to spot any tampering with results—such as making the treatment look more effective or diminishing side effects. \"Everyone is talking about how blockchain is going to revolutionize many of the data challenges in medicine, and here is one use that finally might make sense,\" said Atul Butte, MD, Ph.D., who is the Priscilla Chan and Mark Zuckerberg Distinguished Professor and director of the Bakar Computational Health Sciences Institute at UCSF. \"We think it could someday be useful for pharma companies running clinical trials.\" The research was published February 22 in Nature Communications. Blockchain technology utilizes an old computer science technique known as hashing, which creates a unique digital signature for each so-called block of data. The hashes accumulate sequentially, as new data is entered or changed, with each block depending on the last. The resulting \"blockchain\" creates an audit trail for regulators that is easy to decipher and validate, even without looking at the actual data. Daniel Wong, a Ph.D. candidate in Biological and Medical Informatics at UCSF, built the system to operate through a web portal, so that each time new data is entered on a given trial participant, the sender, receiver, timestamp, and file attachment containing the data, along with the hash of the previous block of data pertaining to that patient, is recorded onto a new block, with its own distinct signature. Unlike the decentralized nature of most blockchain applications, this clinical trial prototype depends on having a regulator with centralized authority, such as the U.S. Food and Drug Administration, to operate the web portal, register all parties, and keep a ledger of the blockchain's hashes. Data, including adverse events, would be reported to the regulatory agency in real time, which may provide a boost to the safety and efficiency of clinical trials. While the prototype makes allowances for data entry or other errors to be corrected, new data can only be appended to the existing chain, without erasing what was there before. \"It makes it really obvious when someone's changing something,\" Wong said. \"You can see who put their hands on it, who made it, who changed it, and who received it.\" Wong tested the system with a small subset of data from a real, previously run phase II trial included in ImmPort, a repository of open clinical trial data funded by the National Institutes of Allergy and Infectious Diseases (NIAID) that is managed by Butte's lab and collaborators. After entering the original data, he logged in as the trial sponsor and tried to erase adverse events that had been reported for two patients in their case report forms. Instead of deleting those reports, however, the system appended his changes to the original data, making it clear who had tried to corrupt the forms, when it was done, and what had been changed. Wong also tried corrupting the data stored from an earlier point in the trial, when patients were assigned to different treatment arms—drug or placebo—to make it look as though they had been given a different medication plan. But the blockchain ledger pinpointed exactly what had changed and when. A prototype system like this reduces risks, but does not completely protect data from tampering. Even within a system enabled with this type of blockchain technology, the authors pointed out, it is still possible that those seeing patients at the point of care could enter wrong or incorrect data at the outset. But blockchain technology could enable trials to be conducted under challenging conditions, or open doors to data exchanges that are more secure, more efficient, and more transparent for both researchers and the general public. \"A system built upon our prototype could be developed to enable oversight of international clinical trials, for example,\" Butte said. \"And it could be expanded to provide more access to raw data for research scientists, the way we do with ImmPort, or deliver trial results to the public.\" ", "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 Monitoring and ensuring the integrity of data within the clinical trial process is currently not always feasible with the current research system. We propose a blockchain-based system to make data collected in the clinical trial process immutable, traceable, and potentially more trustworthy. We use raw data from a real completed clinical trial, simulate the trial onto a proof of concept web portal service, and test its resilience to data tampering. We also assess its prospects to provide a traceable and useful audit trail of trial data for regulators, and a flexible service for all members within the clinical trials network. We also improve the way adverse events are currently reported. In conclusion, we advocate that this service could offer an improvement in clinical trial data management, and could bolster trust in the clinical research process and the ease at which regulators can oversee trials. Introduction Clinical trial networks often involve many parties and sites, and a large flow of information and confidential data. With the involvement of more parties, more exchanges, and trials being conducted far from sponsoring institutions comes the opportunity for human-induced error, whether it is unintentional or malicious. In a survey of authors of clinical drug trials, 17% of them reported that they were personally aware of intentional fabrication in research 1 . Although it is obviously not possible to calculate the actual rate or impact of fraud, there is evidence that some misconduct and alteration of data is happening in scientific and medical research 2 , potentially including clinical trials. In addition, current clinical trials are executed with many manual processes that could be prone to error. Enforcing Good Clinical Practice guidelines set forth by the International Council for Harmonization of Requirements for Pharmaceuticals for Human Use (ICH) has been a challenge for regulators of trials, and process improvement is an active area of research 3 . For regulators of trials such as the Food and Drug Administration (FDA), auditing of data are challenging, and real-time oversight of a trial is lacking as there is no easy and secure way of accessing or viewing the complex network of data transactions as they occur. There can be a lack of transparency and traceability of data, lack of real-time access to results as they are made, and potentially a risk of data tampering 3 . The ability to easily trace data back to the original source can be limited 4 , and the FDA has identified this lack of traceability as one of their top data issues to address 5 . Blockchain is a new software development methodology involving a unique data structure that has garnered increased attention due to the seminal paper that outlined Bitcoin (bitcoin.org) 6 . The technology provides a data structure that ensure a secure and unfalsifiable transaction history. This is accomplished primarily through the use of cryptographic hashing, which has properties and use cases in many domains ranging from internet security to banking. A hash function is a function that maps data of variable length data to a fixed-length digest. Any change to the input data result in an unpredictable change in the hash. In this implementation, each new block added to the chain includes a hash of the previous block. If the previous block is later changed, the subsequent hash would no longer be valid. In addition, blockchains are designed to be append only, and are thus immutable by design, providing a guarantee of safeguarded data. This yields a verifiable and tamper proof history of all transactions since its beginning 6 . We propose a solution to the challenges in the current clinical trials system by using blockchain technology, coupled with changes in methodology for the management of clinical trials. Due to the innate need of clinical trials to have a centralized authority, such as through the regulator, a completely decentralized blockchain infrastructure as used in Bitcoin might not be appropriate. Instead, we borrow ideas and repurpose the methodology to work with clinical trial management, and demonstrate the feasibility with a new prototype web portal. Blockchain has already been proposed for use in various healthcare settings 7 , with potential applications in medical record management, claims processing, health supply chain management, and integration of geospatial data in various data modalities 8 . Work has already begun in seeing how clinical trial management can be improved with blockchain technologies 9 , 10 . Moreover, certain aspects relevant to the clinical trial process, such as patient recruiting and IRB (Institutional Review Board) enforcement of human subject regulations via smart contracts, have been described at a high level in the literature 11 . We improve upon previous work by implementing a web-based portal accessible to all parties with a real clinical trial dataset, facilitating and verifying patient and clinical investigator interaction, integrating version control into the blockchain, expediting adverse event reporting, and testing malicious attacks to data integrity with real world clinical data. Results Network protocol We modeled a prototype phase II clinical trial. Upon approval of the study protocol and initiation of phase II, we propose a future regulator could instantiate a private blockchain and registers all participating parties in the portal providing authenticated and controlled web-based and API (application programming interface) access to the blockchain. All parties would be required to use the portal service for any and all exchange of information related to the trial, and only the information present on the blockchain would be used for review when considering approval of the treatment. The network and representative transactions are illustrated in Fig. 1 . Fig. 1 The idealized clinical trial network in the context of a blockchain-based record system. The various transactions (along each arrow) and key participants (boxed) within a clinical trial are shown Full size image For new patient recruitment and consent acquisition by the clinical site, we propose that an Interactive Voice Response System (IVRS) generates unique verification codes for each subject to give to the trial investigator at the clinical site, and posts encrypted decoding keys<|im_end|> <|im_start|>assistant UC San Francisco researchers have created a proof-of-concept method for ensuring the integrity of clinical trials data with blockchain. The system creates an immutable audit trail that makes it easy to spot any tampering with results—such as making the treatment look more effective or diminishing side effects. "Everyone is talking about how blockchain is going to revolutionize many of the data challenges in medicine, and here is one use that finally might make sense," said Atul Butte, MD, Ph.D., who is the Priscilla Chan and Mark Zuckerberg Distinguished Professor and director of the Bakar Computational Health Sciences Institute at UCSF. "We think it could someday be useful for pharma companies running clinical trials." The research was published February 22 in Nature Communications. Blockchain technology utilizes an old computer science technique known as hashing, which creates a unique digital signature for each so-called block of data. The hashes accumulate sequentially, as new data is entered or changed, with each block depending on the last. The resulting "blockchain" creates an audit trail for regulators that is easy to decipher and validate, even without looking at the actual data. Daniel Wong, a Ph.D. candidate in Biological and Medical Informatics at UCSF, built the system to operate through a web portal, so that each time new data is entered on a given trial participant, the sender, receiver, timestamp, and file attachment containing the data, along with the hash of the previous block of data pertaining to that patient, is recorded onto a new block, with its own distinct signature. Unlike the decentralized nature of most blockchain applications, this clinical trial prototype depends on having a regulator with centralized authority, such as the U.S. Food and Drug Administration, to operate the web portal, register all parties, and keep a ledger of the blockchain's hashes. Data, including adverse events, would be reported to the regulatory agency in real time, which may provide a boost to the safety and efficiency of clinical trials. While the prototype makes allowances for data entry or other errors to be corrected, new data can only be appended to the existing chain, without erasing what was there before. "It makes it really obvious when someone's changing something," Wong said. "You can see who put their hands on it, who made it, who changed it, and who received it." Wong tested the system with a small subset of data from a real, previously run phase II trial included in ImmPort, a repository of open clinical trial data funded by the National Institutes of Allergy and Infectious Diseases (NIAID) that is managed by Butte's lab and collaborators. After entering the original data, he logged in as the trial sponsor and tried to erase adverse events that had been reported for two patients in their case report forms. Instead of deleting those reports, however, the system appended his changes to the original data, making it clear who had tried to corrupt the forms, when it was done, and what had been changed. Wong also tried corrupting the data stored from an earlier point in the trial, when patients were assigned to different treatment arms—drug or placebo—to make it look as though they had been given a different medication plan. But the blockchain ledger pinpointed exactly what had changed and when. A prototype system like this reduces risks, but does not completely protect data from tampering. Even within a system enabled with this type of blockchain technology, the authors pointed out, it is still possible that those seeing patients at the point of care could enter wrong or incorrect data at the outset. But blockchain technology could enable trials to be conducted under challenging conditions, or open doors to data exchanges that are more secure, more efficient, and more transparent for both researchers and the general public. "A system built upon our prototype could be developed to enable oversight of international clinical trials, for example," Butte said. "And it could be expanded to provide more access to raw data for research scientists, the way we do with ImmPort, or deliver trial results to the public." <|im_end|>

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1,987

[ { "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 is concern that the stresses of inducing pluripotency may lead to deleterious DNA mutations in induced pluripotent stem cell (iPSC) lines, which would compromise their use for cell therapies. Here we report comparative genomic analysis of nine isogenic iPSC lines generated using three reprogramming methods: integrating retroviral vectors, non-integrating Sendai virus and synthetic mRNAs. We used whole-genome sequencing and de novo genome mapping to identify single-nucleotide variants, insertions and deletions, and structural variants. Our results show a moderate number of variants in the iPSCs that were not evident in the parental fibroblasts, which may result from reprogramming. There were only small differences in the total numbers and types of variants among different reprogramming methods. Most importantly, a thorough genomic analysis showed that the variants were generally benign. We conclude that the process of reprogramming is unlikely to introduce variants that would make the cells inappropriate for therapy. Introduction Cell replacement therapies using cells derived from human pluripotent stem cells (embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs)) have been approved for clinical trials for macular degeneration, spinal cord injury and type-1 diabetes. The limited data available to date indicate that there are no adverse events in patients receiving these cells 1 . However, there continues to be discussion about the theoretical chance that these transplanted cells may develop into tumours or cause other pathologies. The discussion has come to focus on iPSCs, largely due to concerns that the massive epigenetic remodelling that occurs during reprogramming might cause genomic mutations that could make the cells tumorigenic. These concerns have led multiple groups to study the genomic integrity of iPSCs using methods that include single-nucleotide polymorphism (SNP) genotyping 1 , 2 , CGH 3 , karyotyping 4 and exome sequencing 5 (reviewed in refs 6 , 7 ). In each case, the focus has been exclusively on a single type of genomic alteration, rather than considering the combined effects of single-nucleotide variants (SNVs), structural variants (SVs) and copy-number variations. Further, detailed comparative genomic analyses of iPSC lines that have been generated via distinct reprogramming methodologies have yet to be reported. In this study, we assessed genome-wide mutation rates from replicate isogenic cell lines generated by three distinct methods. We used integrating viral (retrovirus), non-integrating viral (Sendai virus) and non-integrating non-viral (messenger RNA (mRNA)) reprogramming strategies to introduce exogenous expression of POU5F1 , SOX2 , KLF4 and MYC in separate fractions of a single fibroblast population ( Fig. 1a ). Three clonal lines were established from iPSCs generated by each method and determined to be pluripotent by standard measures. To detect SNVs, SVs and copy-number variations within each line and the parental fibroblast population, we generated whole-genome sequencing data for each iPSC line and the parental fibroblasts at an average read depth of 39-fold, with 93.7% of the autosomal genome covered by at least 10 reads. In addition, to assess chromosomal rearrangements and large SVs with high resolution, we performed whole-genome mapping using the recently developed Irys Technology (BioNano Genomics, San Diego, CA). We detected subtle differences in the numbers of variants depending on the method, but rarely found mutations in genes that have any known association with increased cancer risk. We conclude that mutations that have been reported in iPSC cultures are unlikely to be caused by their reprogramming, but instead are probably due to the well-known selective pressures that occur when hPSCs are expanded in culture. Figure 1: Experimental and computational design for identifying variants caused by reprogramming. ( a ) Diagram describing the derivation of three biological replicates of each three reprogramming methods: retrovirus, Sendai virus and non-integrating mRNA. ( b ) Kernel density estimation for VAF and coverage for a constituent sample from each reprogramming method: M1 (mRNA), R1 (retrovirus) and S1 (Sendai virus). For R1 and S1, there are denser clusters near 40 × coverage and 40–60% VAF than the M1 sample, which indicates they had a higher mutational load during initial doublings. However, it should be noted that all these samples also contained several subclonal variants that are not considered in further analyses. The histograms are intended to aid the readers in interpreting the results of the kernel density estimations. ( c ) Flow diagram detailing the filtering strategy employed to arrive at high-confidence set of SNVs unique to each reprogrammed cell line using MuTect and HaplotypeCaller. Full size image Results Identification of single-nucleotide variants To characterize the mutational burden in iPSCs, we identified SNVs that were unique to each iPSC cell line by integrating results from HaplotypeCaller 8 and MuTect 9 , as described in the Methods section. For variant calling with HaplotypeCaller, we treated all 10 samples (the parent fibroblast population and three biological replicates for each reprogramming method) as part of a single population using the multisample option. This pipeline was tuned for the identification of recurrent variations in population studies, and therefore enabled us to have higher specificity in classifying reprogramming-induced mutations by accounting for mosaicism in the parental fibroblast population. To gain a more sensitive assessment of the SNV landscape across the iPSC samples, we also called variants using MuTect, wherein each iPSC line was compared with the parental fibroblast population in an analogous manner to which tumour samples are compared with normal tissue in oncogenomic studies ( Fig. 1c ; Supplementary Fig. 1 ). Taken together, the results from these two distinct variant calling pipelines gave us higher confidence in our ability to identify true variants through the moderation of type I and type II errors, respectively. The identified set of putative unique variants was split into three groups according to our confidence in the variant calls: Variant Set 1 was called unique by both MuTect and HaplotypeCaller; Variant Set 2 had coverage between 20–60 × , and allele frequency distribution between 0.4 and 0.6 but was called only by MuTect, and Variant Set 3 comprised those with allele frequencies between 0.2–0.4 and 30–50 × coverage. Variant validation by quantitative PCR from each of these three groups", "role": "user" }, { "content": "A new study led by scientists at The Scripps Research Institute (TSRI) and the J. Craig Venter Institute (JCVI) shows that the act of creating pluripotent stem cells for clinical use is unlikely to pass on cancer-causing mutations to patients. The research, published February 19, 2016 in the journal Nature Communications, is an important step in assessing patient safety in the rapidly developing field of stem cell therapies. The new study focused on the safety of using induced pluripotent stem cells (iPSCs) in human patients. Because iPSCs can differentiate into any kind of cell in the body, they hold potential for repairing damage from injuries or diseases such as Parkinson's and multiple sclerosis. \"We wanted to know whether reprogramming cells would make the cells prone to mutations,\" said Jeanne Loring, professor of developmental neurobiology at TSRI and co-leader of the new study with Nicholas J. Schork, professor and director of human biology at JCVI. \"The answer is 'no.'\" \"The safety of patients comes first, and our study is one of the first to address the safety concerns about iPSC-based cell replacement strategies and hopefully will spark further interest,\" added Schork. To make an iPSC, scientists must reprogram an adult cell, such as a skin cell, to express a different set of genes, which can be accomplished using viruses as delivery vehicles or with molecules called messenger RNAs (mRNAs). The researchers looked at three popular methods of iPSC production (integrating retroviral vectors, non-integrating Sendai virus and synthetic mRNAs), assessing each for the potential to trigger cancer-causing mutations. While the researchers noted some minor alterations in the iPSCs, none of the methods led to significant mutations. The researchers repeated the experiments two more times and again found no significant risk. \"The methods we're using to make pluripotent stem cells are safe,\" said Loring. The scientists do warn that even though iPSCs don't gain cancer-causing mutations during reprogramming, potentially harmful mutations can accumulate later on as iPSCs multiply in lab cultures. Loring said scientists must analyze their cells for these mutations before using them in therapies. \"We need to move on to developing these cells for clinical applications,\" said Loring. \"The quality control we're recommending is to use genomic methods to thoroughly characterize the cells before you put them into people.\" ", "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 is concern that the stresses of inducing pluripotency may lead to deleterious DNA mutations in induced pluripotent stem cell (iPSC) lines, which would compromise their use for cell therapies. Here we report comparative genomic analysis of nine isogenic iPSC lines generated using three reprogramming methods: integrating retroviral vectors, non-integrating Sendai virus and synthetic mRNAs. We used whole-genome sequencing and de novo genome mapping to identify single-nucleotide variants, insertions and deletions, and structural variants. Our results show a moderate number of variants in the iPSCs that were not evident in the parental fibroblasts, which may result from reprogramming. There were only small differences in the total numbers and types of variants among different reprogramming methods. Most importantly, a thorough genomic analysis showed that the variants were generally benign. We conclude that the process of reprogramming is unlikely to introduce variants that would make the cells inappropriate for therapy. Introduction Cell replacement therapies using cells derived from human pluripotent stem cells (embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs)) have been approved for clinical trials for macular degeneration, spinal cord injury and type-1 diabetes. The limited data available to date indicate that there are no adverse events in patients receiving these cells 1 . However, there continues to be discussion about the theoretical chance that these transplanted cells may develop into tumours or cause other pathologies. The discussion has come to focus on iPSCs, largely due to concerns that the massive epigenetic remodelling that occurs during reprogramming might cause genomic mutations that could make the cells tumorigenic. These concerns have led multiple groups to study the genomic integrity of iPSCs using methods that include single-nucleotide polymorphism (SNP) genotyping 1 , 2 , CGH 3 , karyotyping 4 and exome sequencing 5 (reviewed in refs 6 , 7 ). In each case, the focus has been exclusively on a single type of genomic alteration, rather than considering the combined effects of single-nucleotide variants (SNVs), structural variants (SVs) and copy-number variations. Further, detailed comparative genomic analyses of iPSC lines that have been generated via distinct reprogramming methodologies have yet to be reported. In this study, we assessed genome-wide mutation rates from replicate isogenic cell lines generated by three distinct methods. We used integrating viral (retrovirus), non-integrating viral (Sendai virus) and non-integrating non-viral (messenger RNA (mRNA)) reprogramming strategies to introduce exogenous expression of POU5F1 , SOX2 , KLF4 and MYC in separate fractions of a single fibroblast population ( Fig. 1a ). Three clonal lines were established from iPSCs generated by each method and determined to be pluripotent by standard measures. To detect SNVs, SVs and copy-number variations within each line and the parental fibroblast population, we generated whole-genome sequencing data for each iPSC line and the parental fibroblasts at an average read depth of 39-fold, with 93.7% of the autosomal genome covered by at least 10 reads. In addition, to assess chromosomal rearrangements and large SVs with high resolution, we performed whole-genome mapping using the recently developed Irys Technology (BioNano Genomics, San Diego, CA). We detected subtle differences in the numbers of variants depending on the method, but rarely found mutations in genes that have any known association with increased cancer risk. We conclude that mutations that have been reported in iPSC cultures are unlikely to be caused by their reprogramming, but instead are probably due to the well-known selective pressures that occur when hPSCs are expanded in culture. Figure 1: Experimental and computational design for identifying variants caused by reprogramming. ( a ) Diagram describing the derivation of three biological replicates of each three reprogramming methods: retrovirus, Sendai virus and non-integrating mRNA. ( b ) Kernel density estimation for VAF and coverage for a constituent sample from each reprogramming method: M1 (mRNA), R1 (retrovirus) and S1 (Sendai virus). For R1 and S1, there are denser clusters near 40 × coverage and 40–60% VAF than the M1 sample, which indicates they had a higher mutational load during initial doublings. However, it should be noted that all these samples also contained several subclonal variants that are not considered in further analyses. The histograms are intended to aid the readers in interpreting the results of the kernel density estimations. ( c ) Flow diagram detailing the filtering strategy employed to arrive at high-confidence set of SNVs unique to each reprogrammed cell line using MuTect and HaplotypeCaller. Full size image Results Identification of single-nucleotide variants To characterize the mutational burden in iPSCs, we identified SNVs that were unique to each iPSC cell line by integrating results from HaplotypeCaller 8 and MuTect 9 , as described in the Methods section. For variant calling with HaplotypeCaller, we treated all 10 samples (the parent fibroblast population and three biological replicates for each reprogramming method) as part of a single population using the multisample option. This pipeline was tuned for the identification of recurrent variations in population studies, and therefore enabled us to have higher specificity in classifying reprogramming-induced mutations by accounting for mosaicism in the parental fibroblast population. To gain a more sensitive assessment of the SNV landscape across the iPSC samples, we also called variants using MuTect, wherein each iPSC line was compared with the parental fibroblast population in an analogous manner to which tumour samples are compared with normal tissue in oncogenomic studies ( Fig. 1c ; Supplementary Fig. 1 ). Taken together, the results from these two distinct variant calling pipelines gave us higher confidence in our ability to identify true variants through the moderation of type I and type II errors, respectively. The identified set of putative unique variants was split into three groups according to our confidence in the variant calls: Variant Set 1 was called unique by both MuTect and HaplotypeCaller; Variant Set 2 had coverage between 20–60 × , and allele frequency distribution between 0.4 and 0.6 but was called only by MuTect, and Variant Set 3 comprised those with allele frequencies between 0.2–0.4 and 30–50 × coverage. Variant validation by quantitative PCR from each of these three groups<|im_end|> <|im_start|>assistant A new study led by scientists at The Scripps Research Institute (TSRI) and the J. Craig Venter Institute (JCVI) shows that the act of creating pluripotent stem cells for clinical use is unlikely to pass on cancer-causing mutations to patients. The research, published February 19, 2016 in the journal Nature Communications, is an important step in assessing patient safety in the rapidly developing field of stem cell therapies. The new study focused on the safety of using induced pluripotent stem cells (iPSCs) in human patients. Because iPSCs can differentiate into any kind of cell in the body, they hold potential for repairing damage from injuries or diseases such as Parkinson's and multiple sclerosis. "We wanted to know whether reprogramming cells would make the cells prone to mutations," said Jeanne Loring, professor of developmental neurobiology at TSRI and co-leader of the new study with Nicholas J. Schork, professor and director of human biology at JCVI. "The answer is 'no.'" "The safety of patients comes first, and our study is one of the first to address the safety concerns about iPSC-based cell replacement strategies and hopefully will spark further interest," added Schork. To make an iPSC, scientists must reprogram an adult cell, such as a skin cell, to express a different set of genes, which can be accomplished using viruses as delivery vehicles or with molecules called messenger RNAs (mRNAs). The researchers looked at three popular methods of iPSC production (integrating retroviral vectors, non-integrating Sendai virus and synthetic mRNAs), assessing each for the potential to trigger cancer-causing mutations. While the researchers noted some minor alterations in the iPSCs, none of the methods led to significant mutations. The researchers repeated the experiments two more times and again found no significant risk. "The methods we're using to make pluripotent stem cells are safe," said Loring. The scientists do warn that even though iPSCs don't gain cancer-causing mutations during reprogramming, potentially harmful mutations can accumulate later on as iPSCs multiply in lab cultures. Loring said scientists must analyze their cells for these mutations before using them in therapies. "We need to move on to developing these cells for clinical applications," said Loring. "The quality control we're recommending is to use genomic methods to thoroughly characterize the cells before you put them into people." <|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 report Fourier transform infrared spectro-microtomography, a nondestructive three-dimensional imaging approach that reveals the distribution of distinctive chemical compositions throughout an intact biological or materials sample. The method combines mid-infrared absorption contrast with computed tomographic data acquisition and reconstruction to enhance chemical and morphological localization by determining a complete infrared spectrum for every voxel (millions of spectra determined per sample). Main Synchrotron-based infrared (IR) beamlines provide high–spatial resolution spectroscopy enabling a variety of studies in living cells 1 , in biological tissues 2 , 3 and even of oil-degrading microbes from the recent oil spill in the Gulf of Mexico 4 . Two-dimensional (2D) IR spectromicroscopy has recently become substantially faster via the use of focal plane array (FPA) detectors, which are available at a specialized synchrotron IR beamline called Infrared Environmental Imaging (IRENI) developed at the Synchrotron Radiation Center (SRC) facility 5 . We now use the rapid 2D spectral image acquisition capability of IRENI to measure a large number of projected transmission images as a sample is rotated. For each wavelength, a full 3D representation of the sample is reconstructed via computed tomography algorithms. We produce 4D reconstructions: three spatial dimensions plus a full mid-IR spectral dimension. This method, Fourier transform infrared (FTIR) spectro-microtomography, provides rich spectral information and chemical fingerprinting, including 3D distributions of these signatures throughout the sample. 3D imaging approaches are necessary to study essential cellular functions—such as architecture, mechanical and biochemical triggers, and cell-cell communications—within living tissues 6 . Typical 3D imaging methods use fluorescence and magnetic resonance, requiring labels or contrast agents. To take spectral imaging into the third dimension, others have used confocal depth profiling 7 , 8 and serial sample sectioning 9 , both of which result in a stack of 2D spectral images. Surface-enhanced spatially offset Raman has also recently been used 10 to penetrate deeper into tissues. FTIR spectro-microtomography offers an alternative involving low-energy IR photons that do not affect living systems 11 , and it does not require artificial labels, contrast agents or sectioning. This new method greatly enhances the capabilities of both FTIR spectroscopy and tomography by creating a 'full-color' spectro-microtomogram in which colors are assigned by specific chemical identifications or spectral changes. Each voxel contains a complete spectrum, thus providing a wealth of information for advanced spectral segregation techniques such as clustering, neural networks and principal-component analysis. Colocated chemical fingerprints and morphology in 3D reveal internal composition and structure, as demonstrated here with examples from biology, geology, plant sciences, natural minerals and polymers. Computed tomography is a well-established approach 12 used to reconstruct cross-sectional slices through an object from the transmitted projection images taken as a function of angle around a single axis of rotation. These slices can be stacked to produce a 3D image of the object, which can then be visualized by one of several methods, including volume rendering or digital slicing through the sample along any arbitrary plane. Multiple-energy X-ray tomography can be performed at synchrotron tomography beamlines that can be tuned to, for example, above and below an X-ray absorption edge 13 , or multiple elements can be measured by X-ray fluorescence 14 . But, to our knowledge, wide-ranging spectral tomography, particularly that using the power of the mid-IR fingerprint region, has not been shown before. To make FTIR spectro-microtomography possible, we developed a motorized sample mount capable of precisely rotating a sample on a pin mount while holding it at the focus of an IR microscope. Data collection of 2D spectral transmission images as a function of sample angle was automated, and we modified computed tomography reconstruction algorithms to make them spectrally aware, meaning to allow the reconstruction of integrated absorption intensities of specified spectral regions with and without baseline subtractions, differences between spectral regions and full reconstructions for every wave number measured, which are reassembled into a complete spectrum for every voxel (Online Methods ). Elucidating the 3D molecular architecture of plant cell walls is a challenging problem in plant biology. Although general aspects of cell-wall assembly and synthesis are becoming clear 15 , the detailed 3D molecular structure remains poorly understood. A critical step in converting biomass to liquid biofuels and other industrial products is the deconstruction of recalcitrant lignified cell walls; a better understanding of microscale structures and chemical compositions will enhance basic understanding of plant cell walls and will help improve lignocellulose conversion efficiency. Zinnia elegans tracheary elements (individual components of the xylem vascular tissue) comprise a single homogeneous cell type with a known model of Zinnia cell-wall architecture 16 and can be cultivated and isolated in the laboratory 17 . We measured and reconstructed a single Z. elegans cell inside a MiTeGen polyimide microloop using FTIR spectro-microtomography ( Fig. 1 and Supplementary Video 1 ). Tomographic reconstructions were performed for every wave number such that the reconstructed spectrum of any voxel was extracted by assembling the reconstructed absorbances for that voxel's coordinates. The morphology of the tracheary element and its parallel secondary–cell wall thickenings containing strands of crystalline cellulose microfibrils interspersed with hemicellulose and lignin can be seen when reconstructing the OH-absorption spectral region. Figure 1: FTIR spectro-microtomographic imaging of Zinnia . Top, perspective view of a tomographic reconstruction of a Z. elegans tracheary element inside a polyimide microloop holder. The red color shows the reconstruction of the integrated intensity from the 2,356.7–2,376.0 cm −1 spectral region, where only the sharp edges of the microloop are visualized. The blue-green colors show the reconstruction of the 3,317–3,340 cm −1 spectral region associated with OH stretching, highlighting the parallel secondary cell wall thickenings. Reconstructions of this sample were performed at all 816 individual wavelengths measured. Bottom, the intensity of one voxel in the stem of the microloop was reassembled to extract the spectrum of one 1.1 × 1.1 × 1.1 μm 3 voxel showing a polyimide spectrum with quantitative absorbance matching the volume of the voxel (see Online Methods ). Scale bar, 20 μm. Full size image Populus is a genus of fast-growing deciduous trees cultivated worldwide", "role": "user" }, { "content": "An iconic moment in the history of Hollywood movie magic was born in the 1939 film The Wizard of Oz when Judy Garland as Dorothy Gale stepped out of the black and white world of Kansas into the rainbow colored world of Oz. An iconic moment in the history of infrared imaging may have been born with the announcement of the first technique to offer full color IR tomography. A collaboration between researchers at the U.S. Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of Wisconsin-Milwaukee (UWM) has combined Fourier Transform Infrared (FTIR) spectroscopy with computed tomography (CT-scans) to create a non-destructive 3D imaging technique that provides molecular-level chemical information of unprecedented detail on biological and other specimens with no need to stain or alter the specimen. \"The notion of having the colors in a 3D reconstructed image being tied to real chemistry is powerful,\" says Michael Martin, an infrared imaging expert at Berkeley Lab's Advanced Light Source, a DOE national user facility. \"We've all seen pretty 3D renderings of medical scans with colors, for example bone-colored bones, but that's simply an artistic choice. Now we can spectrally identify the specific types of minerals within a piece of bone and assign a color to each type within the 3D reconstructed image.\" Martin is one of two corresponding authors of a paper describing this research in the journal Nature Methods titled \"3D Spectral Imaging with Synchrotron Fourier Transform Infrared Spectro-microtomography.\" The other corresponding author is UWM physicist Carol Hirschmugl, Director of the Laboratory for Dynamics and Structure at Surfaces and a principal investigator with UW-Madison's Synchrotron Radiation Center (SRC). Every individual type of molecule absorbs infrared (IR) light at specific wavelengths that are as characteristic as a human fingerprint. IR spectroscopy can be used to identify the chemical constituents of a sample and the application of the Fourier-transform algorithm allows all IR fingerprints to be simultaneously recorded. FTIR spectroscopy is especially valuable for imaging proteins and other biological samples because it is non-destructive and can be performed without altering the sample. Martin and Hirschmugl and their colleagues have combined FTIR with computed tomography, the technique for reconstructing 3D images out of multiple cross-sectional slices, to achieve what is believed to be the first demonstration of FTIR spectro-microtomography. Spectro-microtomographic images of a human hair show absorptions of protein (red) and phospholipid (blue-green). Center, the medulla is observed to have little protein. Bottom, the medulla has higher concentrations of phospholipids. \"FTIR spectro-microtomography involves low-energy IR photons that do not affect living systems and do not require artificial labels, contrast agents or sectioning,\" Hirschmugl says. \"It greatly enhances the capabilities of both FTIR spectroscopy and CT by creating a full-color spectro-microtomogram in which each voxel contains a complete spectrum (millions of spectra per sample) that provides a wealth of information for advanced spectral segregation techniques such as clustering, neural networks and principal-component analysis.\" The success of FTIR spectro-microtomography was enabled by the speed with which 2D FTIR images can be obtained at the SRC's Infrared Environmental Imaging (IRENI) beamline. The SRC is a synchrotron radiation facility that provides infrared, ultra violet, and soft X-ray light for scientific research. IRENI offers one the nation's highest performance IR imaging beamlines through the use of unique focal plane array detectors. \"With capabilities such as those at IRENI, we can obtain hundreds of 2D spectral images as a sample is rotated,\" Martin says. \"For each wavelength, we can then reconstruct a full 3D representation of the sample via computed tomography algorithms.\" Martin, Hirschmugl and their colleagues developed a motorized sample mount that precisely rotates the sample while holding it at the focus of an IR microscope. Data col¬lection of 2D spectral transmission images as a function of sample angle is automated, and the computed tomography algorithms allow full reconstructions for every wavelength measured that are then reassembled into a complete spectrum for every voxel. \"We've been able to do a lot of exciting science with 2D FTIR imaging at the diffraction limit using synchrotron infrared beamlines, and it's very exciting to now be able to expand this to true 3D spectroscopic imaging,\" Martin says. \"While the most immediate applications will be in biomedical imaging, I think full color FTIR spectro-microtomography will also be applicable to imaging 3D structures in biofuels, plants, rocks, algae, soils, agriculture and possibly even studies of art history where different layers of paints could be revealed.\" The Berkeley Lab and UW researchers have already successfully applied FTIR spectro-microtomography to obtain 3D images of the molecular architecture of the cell walls in a flowering plant – zinnia - and in a woody plant - poplar. A better understanding of the chemical composition and architecture of plant cell walls is critical to the ultimate success of making biofuels from plant biomass. The collaboration also applied FTIR spectro-microtomography to study human hair, which has a distinctive biochemical construction, and an intact grouping of pluripotent mouse stem cells. \"The hair study showed that spectral reconstructions can be done on larger fully hydrated biological samples and that we can spectrally identify a fully buried portion of the sample,\" Hirschmugl says. \"The mouse study shows that our technique has promise not only for stem cell screening without the use of dyes or probes, but also for promoting a better understanding of the biochemical structure of differentiating stem cells in their microenvironment.\" The collaborators are continuing to improve the efficiency by which they can collect and analyze FTIR spectro-microtomography with new advances being incorporated at IRENI and at IR beamline 5.4 of Berkeley Lab's Advanced Light Source (ALS), a project being overseen by Martin. The work at the ALS is being done in collaboration with Berkeley Lab's National Energy Research Scientific Computing Center (NERSC). ", "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 report Fourier transform infrared spectro-microtomography, a nondestructive three-dimensional imaging approach that reveals the distribution of distinctive chemical compositions throughout an intact biological or materials sample. The method combines mid-infrared absorption contrast with computed tomographic data acquisition and reconstruction to enhance chemical and morphological localization by determining a complete infrared spectrum for every voxel (millions of spectra determined per sample). Main Synchrotron-based infrared (IR) beamlines provide high–spatial resolution spectroscopy enabling a variety of studies in living cells 1 , in biological tissues 2 , 3 and even of oil-degrading microbes from the recent oil spill in the Gulf of Mexico 4 . Two-dimensional (2D) IR spectromicroscopy has recently become substantially faster via the use of focal plane array (FPA) detectors, which are available at a specialized synchrotron IR beamline called Infrared Environmental Imaging (IRENI) developed at the Synchrotron Radiation Center (SRC) facility 5 . We now use the rapid 2D spectral image acquisition capability of IRENI to measure a large number of projected transmission images as a sample is rotated. For each wavelength, a full 3D representation of the sample is reconstructed via computed tomography algorithms. We produce 4D reconstructions: three spatial dimensions plus a full mid-IR spectral dimension. This method, Fourier transform infrared (FTIR) spectro-microtomography, provides rich spectral information and chemical fingerprinting, including 3D distributions of these signatures throughout the sample. 3D imaging approaches are necessary to study essential cellular functions—such as architecture, mechanical and biochemical triggers, and cell-cell communications—within living tissues 6 . Typical 3D imaging methods use fluorescence and magnetic resonance, requiring labels or contrast agents. To take spectral imaging into the third dimension, others have used confocal depth profiling 7 , 8 and serial sample sectioning 9 , both of which result in a stack of 2D spectral images. Surface-enhanced spatially offset Raman has also recently been used 10 to penetrate deeper into tissues. FTIR spectro-microtomography offers an alternative involving low-energy IR photons that do not affect living systems 11 , and it does not require artificial labels, contrast agents or sectioning. This new method greatly enhances the capabilities of both FTIR spectroscopy and tomography by creating a 'full-color' spectro-microtomogram in which colors are assigned by specific chemical identifications or spectral changes. Each voxel contains a complete spectrum, thus providing a wealth of information for advanced spectral segregation techniques such as clustering, neural networks and principal-component analysis. Colocated chemical fingerprints and morphology in 3D reveal internal composition and structure, as demonstrated here with examples from biology, geology, plant sciences, natural minerals and polymers. Computed tomography is a well-established approach 12 used to reconstruct cross-sectional slices through an object from the transmitted projection images taken as a function of angle around a single axis of rotation. These slices can be stacked to produce a 3D image of the object, which can then be visualized by one of several methods, including volume rendering or digital slicing through the sample along any arbitrary plane. Multiple-energy X-ray tomography can be performed at synchrotron tomography beamlines that can be tuned to, for example, above and below an X-ray absorption edge 13 , or multiple elements can be measured by X-ray fluorescence 14 . But, to our knowledge, wide-ranging spectral tomography, particularly that using the power of the mid-IR fingerprint region, has not been shown before. To make FTIR spectro-microtomography possible, we developed a motorized sample mount capable of precisely rotating a sample on a pin mount while holding it at the focus of an IR microscope. Data collection of 2D spectral transmission images as a function of sample angle was automated, and we modified computed tomography reconstruction algorithms to make them spectrally aware, meaning to allow the reconstruction of integrated absorption intensities of specified spectral regions with and without baseline subtractions, differences between spectral regions and full reconstructions for every wave number measured, which are reassembled into a complete spectrum for every voxel (Online Methods ). Elucidating the 3D molecular architecture of plant cell walls is a challenging problem in plant biology. Although general aspects of cell-wall assembly and synthesis are becoming clear 15 , the detailed 3D molecular structure remains poorly understood. A critical step in converting biomass to liquid biofuels and other industrial products is the deconstruction of recalcitrant lignified cell walls; a better understanding of microscale structures and chemical compositions will enhance basic understanding of plant cell walls and will help improve lignocellulose conversion efficiency. Zinnia elegans tracheary elements (individual components of the xylem vascular tissue) comprise a single homogeneous cell type with a known model of Zinnia cell-wall architecture 16 and can be cultivated and isolated in the laboratory 17 . We measured and reconstructed a single Z. elegans cell inside a MiTeGen polyimide microloop using FTIR spectro-microtomography ( Fig. 1 and Supplementary Video 1 ). Tomographic reconstructions were performed for every wave number such that the reconstructed spectrum of any voxel was extracted by assembling the reconstructed absorbances for that voxel's coordinates. The morphology of the tracheary element and its parallel secondary–cell wall thickenings containing strands of crystalline cellulose microfibrils interspersed with hemicellulose and lignin can be seen when reconstructing the OH-absorption spectral region. Figure 1: FTIR spectro-microtomographic imaging of Zinnia . Top, perspective view of a tomographic reconstruction of a Z. elegans tracheary element inside a polyimide microloop holder. The red color shows the reconstruction of the integrated intensity from the 2,356.7–2,376.0 cm −1 spectral region, where only the sharp edges of the microloop are visualized. The blue-green colors show the reconstruction of the 3,317–3,340 cm −1 spectral region associated with OH stretching, highlighting the parallel secondary cell wall thickenings. Reconstructions of this sample were performed at all 816 individual wavelengths measured. Bottom, the intensity of one voxel in the stem of the microloop was reassembled to extract the spectrum of one 1.1 × 1.1 × 1.1 μm 3 voxel showing a polyimide spectrum with quantitative absorbance matching the volume of the voxel (see Online Methods ). Scale bar, 20 μm. Full size image Populus is a genus of fast-growing deciduous trees cultivated worldwide<|im_end|> <|im_start|>assistant An iconic moment in the history of Hollywood movie magic was born in the 1939 film The Wizard of Oz when Judy Garland as Dorothy Gale stepped out of the black and white world of Kansas into the rainbow colored world of Oz. An iconic moment in the history of infrared imaging may have been born with the announcement of the first technique to offer full color IR tomography. A collaboration between researchers at the U.S. Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of Wisconsin-Milwaukee (UWM) has combined Fourier Transform Infrared (FTIR) spectroscopy with computed tomography (CT-scans) to create a non-destructive 3D imaging technique that provides molecular-level chemical information of unprecedented detail on biological and other specimens with no need to stain or alter the specimen. "The notion of having the colors in a 3D reconstructed image being tied to real chemistry is powerful," says Michael Martin, an infrared imaging expert at Berkeley Lab's Advanced Light Source, a DOE national user facility. "We've all seen pretty 3D renderings of medical scans with colors, for example bone-colored bones, but that's simply an artistic choice. Now we can spectrally identify the specific types of minerals within a piece of bone and assign a color to each type within the 3D reconstructed image." Martin is one of two corresponding authors of a paper describing this research in the journal Nature Methods titled "3D Spectral Imaging with Synchrotron Fourier Transform Infrared Spectro-microtomography." The other corresponding author is UWM physicist Carol Hirschmugl, Director of the Laboratory for Dynamics and Structure at Surfaces and a principal investigator with UW-Madison's Synchrotron Radiation Center (SRC). Every individual type of molecule absorbs infrared (IR) light at specific wavelengths that are as characteristic as a human fingerprint. IR spectroscopy can be used to identify the chemical constituents of a sample and the application of the Fourier-transform algorithm allows all IR fingerprints to be simultaneously recorded. FTIR spectroscopy is especially valuable for imaging proteins and other biological samples because it is non-destructive and can be performed without altering the sample. Martin and Hirschmugl and their colleagues have combined FTIR with computed tomography, the technique for reconstructing 3D images out of multiple cross-sectional slices, to achieve what is believed to be the first demonstration of FTIR spectro-microtomography. Spectro-microtomographic images of a human hair show absorptions of protein (red) and phospholipid (blue-green). Center, the medulla is observed to have little protein. Bottom, the medulla has higher concentrations of phospholipids. "FTIR spectro-microtomography involves low-energy IR photons that do not affect living systems and do not require artificial labels, contrast agents or sectioning," Hirschmugl says. "It greatly enhances the capabilities of both FTIR spectroscopy and CT by creating a full-color spectro-microtomogram in which each voxel contains a complete spectrum (millions of spectra per sample) that provides a wealth of information for advanced spectral segregation techniques such as clustering, neural networks and principal-component analysis." The success of FTIR spectro-microtomography was enabled by the speed with which 2D FTIR images can be obtained at the SRC's Infrared Environmental Imaging (IRENI) beamline. The SRC is a synchrotron radiation facility that provides infrared, ultra violet, and soft X-ray light for scientific research. IRENI offers one the nation's highest performance IR imaging beamlines through the use of unique focal plane array detectors. "With capabilities such as those at IRENI, we can obtain hundreds of 2D spectral images as a sample is rotated," Martin says. "For each wavelength, we can then reconstruct a full 3D representation of the sample via computed tomography algorithms." Martin, Hirschmugl and their colleagues developed a motorized sample mount that precisely rotates the sample while holding it at the focus of an IR microscope. Data col¬lection of 2D spectral transmission images as a function of sample angle is automated, and the computed tomography algorithms allow full reconstructions for every wavelength measured that are then reassembled into a complete spectrum for every voxel. "We've been able to do a lot of exciting science with 2D FTIR imaging at the diffraction limit using synchrotron infrared beamlines, and it's very exciting to now be able to expand this to true 3D spectroscopic imaging," Martin says. "While the most immediate applications will be in biomedical imaging, I think full color FTIR spectro-microtomography will also be applicable to imaging 3D structures in biofuels, plants, rocks, algae, soils, agriculture and possibly even studies of art history where different layers of paints could be revealed." The Berkeley Lab and UW researchers have already successfully applied FTIR spectro-microtomography to obtain 3D images of the molecular architecture of the cell walls in a flowering plant – zinnia - and in a woody plant - poplar. A better understanding of the chemical composition and architecture of plant cell walls is critical to the ultimate success of making biofuels from plant biomass. The collaboration also applied FTIR spectro-microtomography to study human hair, which has a distinctive biochemical construction, and an intact grouping of pluripotent mouse stem cells. "The hair study showed that spectral reconstructions can be done on larger fully hydrated biological samples and that we can spectrally identify a fully buried portion of the sample," Hirschmugl says. "The mouse study shows that our technique has promise not only for stem cell screening without the use of dyes or probes, but also for promoting a better understanding of the biochemical structure of differentiating stem cells in their microenvironment." The collaborators are continuing to improve the efficiency by which they can collect and analyze FTIR spectro-microtomography with new advances being incorporated at IRENI and at IR beamline 5.4 of Berkeley Lab's Advanced Light Source (ALS), a project being overseen by Martin. The work at the ALS is being done in collaboration with Berkeley Lab's National Energy Research Scientific Computing Center (NERSC). <|im_end|>

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2,688

[ { "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 The soil dwelling saprotrophic non-pathogenic fungus Fusarium venenatum , routinely used in the commercial fermentation industry, is phylogenetically closely related to the globally important cereal and non-cereal infecting pathogen F. graminearum . This study aimed to sequence, assemble and annotate the F. venenatum (strain A3/5) genome, and compare this genome with F. graminearum . Results Using shotgun sequencing, a 38,660,329 bp F. venenatum genome was assembled into four chromosomes, and a 78,618 bp mitochondrial genome. In comparison to F. graminearum , the predicted gene count of 13,946 was slightly lower. The F. venenatum centromeres were found to be 25% smaller compared to F. graminearum . Chromosome length was 2.8% greater in F. venenatum, primarily due to an increased abundance of repetitive elements and transposons, but not transposon diversity. On chromosome 3 a major sequence rearrangement was found, but its overall gene content was relatively unchanged. Unlike homothallic F. graminearum , heterothallic F. venenatum possessed the MAT1–1 type locus, but lacked the MAT1–2 locus. The F. venenatum genome has the type A trichothecene mycotoxin TRI5 cluster, whereas F. graminearum has type B. From the F. venenatum gene set, 786 predicted proteins were species-specific versus NCBI. The annotated F. venenatum genome was predicted to possess more genes coding for hydrolytic enzymes and species - specific genes involved in the breakdown of polysaccharides than F. graminearum . Comparison of the two genomes reduced the previously defined F. graminearum- specific gene set from 741 to 692 genes. A comparison of the F. graminearum versus F. venenatum proteomes identified 15 putative secondary metabolite gene clusters (SMC), 109 secreted proteins and 38 candidate effectors not found in F. venenatum . Five of the 15 F. graminearum-specific SMCs that were either absent or highly divergent in the F. venenatum genome showed increased in planta expression. In addition, two predicted F. graminearum transcription factors previously shown to be required for fungal virulence on wheat plants were absent or exhibited high sequence divergence. Conclusions This study identifies differences between the F. venenatum and F. graminearum genomes that may contribute to contrasting lifestyles, and highlights the repertoire of F. graminearum -specific candidate genes and SMCs potentially required for pathogenesis. Background The genus Fusarium contains numerous destructive and toxigenic filamentous ascomycete fungi that pose a current, and growing threat, to plant, animal, human and ecosystem health. Prominent plant diseases caused by Fusaria include, Fusarium head blight (FHB) of cereals [ 1 , 2 ], sudden death syndrome of soybeans [ 3 ], and vascular wilts of numerous important crops, such as banana, tomato and oil palm [ 4 ]. The negative impact of Fusarium -induced yield losses is compounded by the contamination of the crop with various mycotoxins, making the harvest unsuitable for human or animal consumption. Additionally, Fusaria can cause opportunistic, and life-threatening, infections of immunocompromised humans [ 5 ]. Other Fusaria are non-pathogenic and have a saprophytic or endophytic lifestyle [ 6 ]. The close phylogenetic relationships but diverse array of fungal lifestyles present within Fusaria are ideal for the identification of the genetic factors contributing to the occupancy of various biological and environmental niches, and the evolution of different lifestyles. Fusarium head blight disease, also known as Fusarium head scab in the United States and elsewhere, is caused by up to 17 related Fusarium species and occurs on all small grain cereals throughout the globe. Within Europe, the USA, China, Brazil and elsewhere, the main causal organism on wheat, barley and maize crops is F. graminearum. FHB is the number one floral disease affecting wheat crops and is a serious health hazard, due to direct crop losses and the contamination of the grain with type B trichothecene mycotoxins, such as deoxynivalenol (DON) and nivalenol [ 1 , 2 ]. Altered agronomic practices have failed to reduce inoculum levels, while fungicides only provide modest crop protection, and fully FHB-resistant wheat and barley cultivars have not been realised. Consequently, new approaches to control FHB are needed to improve grain yield, quality and safety. At present, F. graminearum is known to secrete a cocktail of enzymatic and non-enzymatic proteinaceous virulence factors in combination with host and non-host specific, toxic and non-toxic, metabolites into the plant tissue to manipulate the host and to obtain nutrition [ 7 ]. The independent loss of the secretion of i) the DON mycotoxin [ 8 ], ii) the iron scavenging triacetylfusarinine C (TAFC) siderophore [ 9 ], or iii) the Fgl1 lipase [ 10 ], results in a dramatic reduction in virulence, demonstrating that each secreted biologically active compound is required for full infection. Other unknown fungal compounds, metabolites and proteins potentially contribute to the establishment of infection and disease progression. Recent advancements have improved the understanding of the infection biology of F. graminearum in wheat [ 11 , 12 ], fungal virulence factor requirements [ 8 , 9 , 10 , 13 ] and some of the underlying plant resistance mechanisms [ 14 ]. However, an increased understanding of the evolution of F. graminearum as a pathogen of cereals may accelerate the rate of discovery of additional virulence determinants, and assist in the development of novel crop protection strategies. Fusarium venenatum A3/5 is a ubiquitous saprophytic, soil-dwelling fungus, which was initially misclassified as Fusarium graminearum A3/5, prior to the utilisation of molecular phylogenetic techniques [ 15 ]. In the 1980’s, F. venenatum was developed as a protein-rich alternative to meat, which was low in fat and high in dietary fibre, and subsequently commercialised under the name Quorn® [ 16 , 17 , 18 ]. The production of Quorn, involves fungal biomass accumulation in fermenters under specific growth conditions, which is then heated, mixed with egg albumin or potato starch, and rolled into meat-like fibres. To date, Quorn remains the only fungal-derived protein source (myco-protein) that is commercially available and approved for human consumption, throughout the world. Industrially, F. venenatum has also been widely used as a biological system for the production of recombinant proteins, including trypsin, lipases, phytases and xylanases [ 19 ,", "role": "user" }, { "content": "Genetic differences between two very similar fungi, one that led to Quorn, the proprietary meat substitute, and another that ranks among the world's most damaging crop pathogens, have exposed the significant features that dictate the pair's very different lifestyles. While the manufacturer of Quorn cultivates strains of Fusarium venenatum via fermentation into a mycoprotein dough for human consumption, farmers try to fight off Fusarium graminearum as this pervasive fungal pathogen invades multiple crops and threatens global food security. Researchers have now pinpointed several significant differences between the fungal pair that seem to turn F. graminearum nasty, features that promise targets for controlling disease. The findings, by a team from Rothamsted Research, are reported today in the journal, BMC Genomics. The team discovered, for instance, that F. venenatum does not contain some clusters of genes that produce subsidiary compounds, or secondary metabolites, which are produced by F. graminearum during successful wheat infection. \"Using improved computer software, we have enhanced gene predictions and secondary metabolite gene cluster predictions in both species to a level not found in most other filamentous fungal species,\" says Robert King, the team's lead bioinformatician at Rothamsted. Emphasising the importance of the findings, King notes: \"All this improved data is immediately available in the public domain via ENSEMBL [a genome database]. In the medium term, it should be possible to achieve a resilient control strategy for this globally important, cereal-infecting pathogen.\" The team also confirmed differences in mating strategies, notably that the pathogenic fungus can mate with itself, which influences gene transfer between generations and genome repair mechanisms, whereas the Quorn fungus would need to find a mate. And they found that key areas in chromosomes, the centromeric regions, are 25% smaller in the benign fungus, for reasons unknown but that offer \"an excellent starting point for follow-up investigations\", notes Kim Hammond-Kosack, a molecular plant pathologist at Rothamsted and leader of the research team. \"This is an important and fascinating piece of work that shows the many differences between F. venenatum and the plant pathogen F. graminearum at a number of different levels,\" says Rob Johnson, Science Manager and Fermentation Specialist at Quorn Foods. \"Despite the close relationship revealed by the sequencing,\" continues Johnson, \"the differences in lifestyle are written deep into the genomes of these fungi, with the saprophytic F. venenatum showing a range of genes devoted to breakdown of organic matter, whereas the F. graminearum contains unique genes for secondary metabolites and more devoted to its pathogenic nature.\" Johnson adds: \"The confirmation of the non-pathogenic nature of the species used to make Quorn and understanding of the genetics revealed by these data will make this paper one that Quorn will return to many times as we improve our process and grow our business.\" In separate research, also funded at Rothamsted by the Biotechnology and Biological Sciences Research Council, the team has been unravelling the pan-genome of F. graminearum, a reference genome that includes the genetic make-up of the pathogen and also those of its various strains. \"We can now immediately identify which of the newly predicted secondary metabolite gene clusters and small secreted protein effector sequences are found in all pathogenic strains of F. graminearum,\" says Hammond-Kosack. \"These sequences then become the targets for a far narrower set of follow-up gene function studies in F. graminearum by reverse genetic experimentation to pinpoint the genes essential for the disease-causing abilities of this pathogen.\" Hammond-Kosack concludes: \"Starting from the fundamental new knowledge gained from these studies, a sustainable discover and disease control pipeline has begun to be created.\" ", "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 The soil dwelling saprotrophic non-pathogenic fungus Fusarium venenatum , routinely used in the commercial fermentation industry, is phylogenetically closely related to the globally important cereal and non-cereal infecting pathogen F. graminearum . This study aimed to sequence, assemble and annotate the F. venenatum (strain A3/5) genome, and compare this genome with F. graminearum . Results Using shotgun sequencing, a 38,660,329 bp F. venenatum genome was assembled into four chromosomes, and a 78,618 bp mitochondrial genome. In comparison to F. graminearum , the predicted gene count of 13,946 was slightly lower. The F. venenatum centromeres were found to be 25% smaller compared to F. graminearum . Chromosome length was 2.8% greater in F. venenatum, primarily due to an increased abundance of repetitive elements and transposons, but not transposon diversity. On chromosome 3 a major sequence rearrangement was found, but its overall gene content was relatively unchanged. Unlike homothallic F. graminearum , heterothallic F. venenatum possessed the MAT1–1 type locus, but lacked the MAT1–2 locus. The F. venenatum genome has the type A trichothecene mycotoxin TRI5 cluster, whereas F. graminearum has type B. From the F. venenatum gene set, 786 predicted proteins were species-specific versus NCBI. The annotated F. venenatum genome was predicted to possess more genes coding for hydrolytic enzymes and species - specific genes involved in the breakdown of polysaccharides than F. graminearum . Comparison of the two genomes reduced the previously defined F. graminearum- specific gene set from 741 to 692 genes. A comparison of the F. graminearum versus F. venenatum proteomes identified 15 putative secondary metabolite gene clusters (SMC), 109 secreted proteins and 38 candidate effectors not found in F. venenatum . Five of the 15 F. graminearum-specific SMCs that were either absent or highly divergent in the F. venenatum genome showed increased in planta expression. In addition, two predicted F. graminearum transcription factors previously shown to be required for fungal virulence on wheat plants were absent or exhibited high sequence divergence. Conclusions This study identifies differences between the F. venenatum and F. graminearum genomes that may contribute to contrasting lifestyles, and highlights the repertoire of F. graminearum -specific candidate genes and SMCs potentially required for pathogenesis. Background The genus Fusarium contains numerous destructive and toxigenic filamentous ascomycete fungi that pose a current, and growing threat, to plant, animal, human and ecosystem health. Prominent plant diseases caused by Fusaria include, Fusarium head blight (FHB) of cereals [ 1 , 2 ], sudden death syndrome of soybeans [ 3 ], and vascular wilts of numerous important crops, such as banana, tomato and oil palm [ 4 ]. The negative impact of Fusarium -induced yield losses is compounded by the contamination of the crop with various mycotoxins, making the harvest unsuitable for human or animal consumption. Additionally, Fusaria can cause opportunistic, and life-threatening, infections of immunocompromised humans [ 5 ]. Other Fusaria are non-pathogenic and have a saprophytic or endophytic lifestyle [ 6 ]. The close phylogenetic relationships but diverse array of fungal lifestyles present within Fusaria are ideal for the identification of the genetic factors contributing to the occupancy of various biological and environmental niches, and the evolution of different lifestyles. Fusarium head blight disease, also known as Fusarium head scab in the United States and elsewhere, is caused by up to 17 related Fusarium species and occurs on all small grain cereals throughout the globe. Within Europe, the USA, China, Brazil and elsewhere, the main causal organism on wheat, barley and maize crops is F. graminearum. FHB is the number one floral disease affecting wheat crops and is a serious health hazard, due to direct crop losses and the contamination of the grain with type B trichothecene mycotoxins, such as deoxynivalenol (DON) and nivalenol [ 1 , 2 ]. Altered agronomic practices have failed to reduce inoculum levels, while fungicides only provide modest crop protection, and fully FHB-resistant wheat and barley cultivars have not been realised. Consequently, new approaches to control FHB are needed to improve grain yield, quality and safety. At present, F. graminearum is known to secrete a cocktail of enzymatic and non-enzymatic proteinaceous virulence factors in combination with host and non-host specific, toxic and non-toxic, metabolites into the plant tissue to manipulate the host and to obtain nutrition [ 7 ]. The independent loss of the secretion of i) the DON mycotoxin [ 8 ], ii) the iron scavenging triacetylfusarinine C (TAFC) siderophore [ 9 ], or iii) the Fgl1 lipase [ 10 ], results in a dramatic reduction in virulence, demonstrating that each secreted biologically active compound is required for full infection. Other unknown fungal compounds, metabolites and proteins potentially contribute to the establishment of infection and disease progression. Recent advancements have improved the understanding of the infection biology of F. graminearum in wheat [ 11 , 12 ], fungal virulence factor requirements [ 8 , 9 , 10 , 13 ] and some of the underlying plant resistance mechanisms [ 14 ]. However, an increased understanding of the evolution of F. graminearum as a pathogen of cereals may accelerate the rate of discovery of additional virulence determinants, and assist in the development of novel crop protection strategies. Fusarium venenatum A3/5 is a ubiquitous saprophytic, soil-dwelling fungus, which was initially misclassified as Fusarium graminearum A3/5, prior to the utilisation of molecular phylogenetic techniques [ 15 ]. In the 1980’s, F. venenatum was developed as a protein-rich alternative to meat, which was low in fat and high in dietary fibre, and subsequently commercialised under the name Quorn® [ 16 , 17 , 18 ]. The production of Quorn, involves fungal biomass accumulation in fermenters under specific growth conditions, which is then heated, mixed with egg albumin or potato starch, and rolled into meat-like fibres. To date, Quorn remains the only fungal-derived protein source (myco-protein) that is commercially available and approved for human consumption, throughout the world. Industrially, F. venenatum has also been widely used as a biological system for the production of recombinant proteins, including trypsin, lipases, phytases and xylanases [ 19 ,<|im_end|> <|im_start|>assistant Genetic differences between two very similar fungi, one that led to Quorn, the proprietary meat substitute, and another that ranks among the world's most damaging crop pathogens, have exposed the significant features that dictate the pair's very different lifestyles. While the manufacturer of Quorn cultivates strains of Fusarium venenatum via fermentation into a mycoprotein dough for human consumption, farmers try to fight off Fusarium graminearum as this pervasive fungal pathogen invades multiple crops and threatens global food security. Researchers have now pinpointed several significant differences between the fungal pair that seem to turn F. graminearum nasty, features that promise targets for controlling disease. The findings, by a team from Rothamsted Research, are reported today in the journal, BMC Genomics. The team discovered, for instance, that F. venenatum does not contain some clusters of genes that produce subsidiary compounds, or secondary metabolites, which are produced by F. graminearum during successful wheat infection. "Using improved computer software, we have enhanced gene predictions and secondary metabolite gene cluster predictions in both species to a level not found in most other filamentous fungal species," says Robert King, the team's lead bioinformatician at Rothamsted. Emphasising the importance of the findings, King notes: "All this improved data is immediately available in the public domain via ENSEMBL [a genome database]. In the medium term, it should be possible to achieve a resilient control strategy for this globally important, cereal-infecting pathogen." The team also confirmed differences in mating strategies, notably that the pathogenic fungus can mate with itself, which influences gene transfer between generations and genome repair mechanisms, whereas the Quorn fungus would need to find a mate. And they found that key areas in chromosomes, the centromeric regions, are 25% smaller in the benign fungus, for reasons unknown but that offer "an excellent starting point for follow-up investigations", notes Kim Hammond-Kosack, a molecular plant pathologist at Rothamsted and leader of the research team. "This is an important and fascinating piece of work that shows the many differences between F. venenatum and the plant pathogen F. graminearum at a number of different levels," says Rob Johnson, Science Manager and Fermentation Specialist at Quorn Foods. "Despite the close relationship revealed by the sequencing," continues Johnson, "the differences in lifestyle are written deep into the genomes of these fungi, with the saprophytic F. venenatum showing a range of genes devoted to breakdown of organic matter, whereas the F. graminearum contains unique genes for secondary metabolites and more devoted to its pathogenic nature." Johnson adds: "The confirmation of the non-pathogenic nature of the species used to make Quorn and understanding of the genetics revealed by these data will make this paper one that Quorn will return to many times as we improve our process and grow our business." In separate research, also funded at Rothamsted by the Biotechnology and Biological Sciences Research Council, the team has been unravelling the pan-genome of F. graminearum, a reference genome that includes the genetic make-up of the pathogen and also those of its various strains. "We can now immediately identify which of the newly predicted secondary metabolite gene clusters and small secreted protein effector sequences are found in all pathogenic strains of F. graminearum," says Hammond-Kosack. "These sequences then become the targets for a far narrower set of follow-up gene function studies in F. graminearum by reverse genetic experimentation to pinpoint the genes essential for the disease-causing abilities of this pathogen." Hammond-Kosack concludes: "Starting from the fundamental new knowledge gained from these studies, a sustainable discover and disease control pipeline has begun to be created." <|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 Sea ice primary production is considered a valuable energy source for Arctic marine food webs, yet the extent remains unclear through existing methods. Here we quantify ice algal carbon signatures using unique lipid biomarkers in over 2300 samples from 155 species including invertebrates, fish, seabirds, and marine mammals collected across the Arctic shelves. Ice algal carbon signatures were present within 96% of the organisms investigated, collected year-round from January to December, suggesting continuous utilization of this resource despite its lower proportion to pelagic production. These results emphasize the importance of benthic retention of ice algal carbon that is available to consumers year-round. Finally, we suggest that shifts in the phenology, distribution and biomass of sea ice primary production anticipated with declining seasonal sea ice will disrupt sympagic-pelagic-benthic coupling and consequently the structure and the functioning of the food web which is critical for Indigenous Peoples, commercial fisheries, and global biodiversity. Introduction Arctic marine food webs are classically viewed as being supported by two ecologically distinct types of primary production, effected in temporal sequence by ice-associated (sympagic) algae in spring and (pelagic) phytoplankton in summer. Each source contributes energy to the ecosystem with varying intensity, community composition, and nutritional quality 1 , 2 , with phytoplankton typically far more degraded than sea ice algae when it reaches the seafloor. Additionally, the early timing of ice algal blooms and high concentrations of polyunsaturated fatty acids make this a vital resource for many primary consumers in the spring 3 . These two microalgae communities display inherent similarities resulting from their dominance by photosynthetic diatoms 4 . However, until recently, the ability to differentiate and measure these two distinct carbon sources with other methods (e.g. stable isotopes and fatty acids) was somewhat limited in certainty owing to the lack of a specific biomarker for sea ice algae. With the steady decline of sea ice and projections of a seasonally ice-free Arctic Ocean within this century 5 , understanding how this ecosystem is responding to ongoing climate change is of critical importance. Numerous species have evolved with the seasonal extremes of the Arctic, timing their migrations, foraging, and reproduction with the phenology of ice-associated blooms 3 . The loss of seasonal sea ice will likely not only affect the primary consumers of this resource but could also drive cascading effects within the food web, including impacting coastal ecosystem resources on which Indigenous Peoples rely. The consequences to these Arctic organisms’ life-history events and their ability to adapt to an alteration in the sea-ice primary production is uncertain 6 , 7 . Here, we trace source-specific highly branched isoprenoid (HBI) diatom lipid biomarkers 8 , 9 to undertake the most comprehensive and quantitative spatial and temporal assessment of carbon partitioning within the Arctic marine ecosystem to date. Since certain HBI lipids are only synthesized by a minority of sea ice diatom species 10 , 11 , 12 , while other HBIs are produced by a similar proportion of phytoplankton species 13 , 14 , these proxies now make it possible to differentiate between carbon derived from these two sources in the consumers 9 . We combined HBI biomarker values from sea ice- and phytoplankton-carbon sources into a single index, termed “H-Print” 8 , 9 . Based on a previously established calibration 8 , we were then able to convert H-Print values into estimates of sea-ice particulate organic carbon (iPOC) directly consumed by animals 8 , 15 or transferred to higher trophic organisms. So far, this approach has resulted in comparable findings of carbon sources, examples including fatty acid markers 16 , 17 , 18 , bulk stable isotopes 19 , 20 and compound-specific stable isotope analysis of amino acids (CSIA-AA) 21 , 22 and CSIA of fatty acids (CSIA- FA) 17 , 23 , 24 . Stable isotope analysis of carbon for the primary ice-associated HBI, IP 25 , has also confirmed sea ice origins 25 . These multi-proxy approaches further validate the use of iPOC values as quantitative predictors of ice-algal carbon in Arctic food webs 26 . For example, iPOC and CSIA of a source amino acid (phenylalanine) in Atlantic walrus tissues were significantly positively correlated, where high iPOC values were associated with more enriched 13 C typical of sea-ice algae 21 . By quantifying the sea-ice algal HBI contribution (relative to phytoplankton) throughout food chains of the marine ecosystem, spanning several marginal seas and coastal areas of the Arctic, including both Pacific and Atlantic-influenced sectors, we reveal striking year-round consumption of sea ice-associated primary production. In doing so, we consider how the potential future decrease and redistribution of this carbon source will likely have dramatic consequences requiring a concerted conservation approach to mitigate this rapid biodiversity change. Results and discussion Spatial and seasonal distribution of sea ice organic carbon across organisms To reveal the importance of sea-ice organic carbon for the Arctic ecosystem, we conducted the most comprehensive synthesis to date of previously published HBI results, including additional novel biomarker data, from Arctic fauna. Our study gathers over 2300 individuals, representing 156 species, collected from approximately 60 sites across the pan-Arctic shelf ecosystems 27 and extending from the sub- to the high-Arctic (55 − 82°N; Fig. 1 ). Obtained between 1982 and 2019, sampling occurred throughout the year from January to December. Owing to spatiotemporal variation in sampling in terms of numbers of species and taxonomic groups collected each year, it was not possible to examine inter-annual variability in sea ice carbon source use in relation to environmental metrics. Although this analysis does not address changes over time as a result of declining sea ice, sea-ice carbon was shown to be utilized year-round by organisms from all taxa (benthic and ice-associated invertebrates, zooplankton, fish, seabirds, and marine mammals) and habitats (benthic, sympagic or pelagic) throughout the nearly four decades of observations. Fig. 1: Sample collection map. Locations where animals were sampled throughout the marginal seas of the Arctic region, spanning January to December between 1982 and 2019. Magenta line represents the median", "role": "user" }, { "content": "Sea ice algae is an essential resource for the survival of many species living in the Arctic. Traces of ice algae have been found in many animal groups from tiny filter-feeding shrimp to large predators like whales, revealing the critical importance of algae and the sea ice on which it grows to the fragile Arctic ecosystem. Plunged into constant darkness for several months of the year, the Arctic is a harsh environment where only those adapted to the extreme conditions are able to survive. When sunlight finally returns to the region for a few months in early spring, algae blooms appear across vast areas on the bottom of the sea ice. Arctic sea ice algae are among the best-adapted organisms on the planet to photosynthesize in low light levels, enabling them to survive in places where little else can grow. A new study published in Nature Communications has now examined the extent to which animals in the Arctic rely on the algae as a food source, as its decline could have cascading effects across Arctic food webs. To do this, researchers sampled 2,300 animals from 155 species, including invertebrates, fish, seabirds and marine mammals collected from across the Arctic shelves. They tested these specimens for a unique molecule produced by the algae to trace its presence throughout the food chain. They found traces of the algae in 96% of the studied organisms and, despite the algae blooms only occurring in the spring months, found traces in species collected year-round from January to December. Dr. Chelsea Koch, a scientist at the Museum and lead author of the study, says, \"Despite sea ice algae blooms only occurring during this limited window in the early spring, it has pretty far-reaching impacts.\" \"Much of the algae gets stored on the sea floor because as sea ice starts to melt and break apart each year, the algae are released into the water column and sinks rapidly without much degradation.\" There are diverse communities of animals such as sponges, crabs and worms that live on the sea floor which can feed directly on this resource throughout the year. Other animals, like diving seabirds, walruses and seals, then eat those animals, providing this year-round transfer of sea ice carbon into the food web to fuel the ecosystem. \"We think this might be one way in which Arctic environments can thrive despite having several months of little to no sunlight and no productivity,\" explains Chelsea. \"These ice algae reserves are available to keep things going.\" How were traces of algae detected in animals? Arctic sea ice algae are primarily comprised of diatoms, which are photosynthesizing algae found in almost every aquatic environment. Certain species of diatoms produce a type of lipid called highly branched isoprenoids (HBIs). Researchers found that HBIs appear not only in the tissues of animals that have eaten the algae, but also in animals that had eaten those animals. Therefore, these lipids could be used as a biomarker to trace their presence in species across the food web. Animals collected between 1982 and 2019 were tested for these HBIs. Older samples were obtained from frozen specimens in museum collections or other management organizations and communities, where the biomarker could still be extracted from tissues. The research team found the algae was essential for the majority of species across the Arctic food web throughout the year. \"It was surprising to see it so widespread and just see the vastness of it presented in this way,\" says Chelsea. \"Other methods have been used to look at sea ice algae that mostly agree with our findings. So this adds another piece of evidence to show it's important for Arctic marine food webs.\" What will happen to sea ice algae in the future? The climate crisis is driving a rapid change in the Arctic. Current projections show that sea ice will decline significantly, with seasonal periods of an ice-free Arctic Ocean likely within this century. Over the past few decades observations have shown that sea ice is already thinning. While initially this will enhance the potential habitat for sea ice algal growth in the short term as more light can penetrate the ice, changes to the distribution of sea ice could cause problems. Many organisms on the sea floor that eat the falling algae are relatively immobile and perhaps unlikely to move quickly enough to new areas covered by ice. In the long term, as the sea ice rapidly melts, we could see fewer algal blooms on shallow shelf systems in the Arctic. Therefore, the loss of sea ice will likely have cascading effects within the food web and impact coastal ecosystem resources on which Indigenous Peoples rely. The researchers also noted how different populations of species might be impacted in different ways. \"For this study, multiple researchers contributed datasets and we looked at everything broadly. However, there were a lot of interesting nuances that came out within certain species,\" explains Chelsea. \"For example, we saw a population of beluga whales with higher sea ice carbon and one with lower sea ice carbon. We realized that the former population tends to stick around in icy waters, while the latter migrate further south to go foraging.\" \"We also saw similar patterns when looking at the Pacific walrus and the Atlantic walrus sub-species. These populations have different migratory behavior and proximity to sea ice throughout the year, so we saw differences in their sea ice carbon values to match.\" \"It raises more questions to explore within that data about what might be happening at a species or population level and how their life cycles might depend on sea ice in one location but not so much in another.\" ", "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 Sea ice primary production is considered a valuable energy source for Arctic marine food webs, yet the extent remains unclear through existing methods. Here we quantify ice algal carbon signatures using unique lipid biomarkers in over 2300 samples from 155 species including invertebrates, fish, seabirds, and marine mammals collected across the Arctic shelves. Ice algal carbon signatures were present within 96% of the organisms investigated, collected year-round from January to December, suggesting continuous utilization of this resource despite its lower proportion to pelagic production. These results emphasize the importance of benthic retention of ice algal carbon that is available to consumers year-round. Finally, we suggest that shifts in the phenology, distribution and biomass of sea ice primary production anticipated with declining seasonal sea ice will disrupt sympagic-pelagic-benthic coupling and consequently the structure and the functioning of the food web which is critical for Indigenous Peoples, commercial fisheries, and global biodiversity. Introduction Arctic marine food webs are classically viewed as being supported by two ecologically distinct types of primary production, effected in temporal sequence by ice-associated (sympagic) algae in spring and (pelagic) phytoplankton in summer. Each source contributes energy to the ecosystem with varying intensity, community composition, and nutritional quality 1 , 2 , with phytoplankton typically far more degraded than sea ice algae when it reaches the seafloor. Additionally, the early timing of ice algal blooms and high concentrations of polyunsaturated fatty acids make this a vital resource for many primary consumers in the spring 3 . These two microalgae communities display inherent similarities resulting from their dominance by photosynthetic diatoms 4 . However, until recently, the ability to differentiate and measure these two distinct carbon sources with other methods (e.g. stable isotopes and fatty acids) was somewhat limited in certainty owing to the lack of a specific biomarker for sea ice algae. With the steady decline of sea ice and projections of a seasonally ice-free Arctic Ocean within this century 5 , understanding how this ecosystem is responding to ongoing climate change is of critical importance. Numerous species have evolved with the seasonal extremes of the Arctic, timing their migrations, foraging, and reproduction with the phenology of ice-associated blooms 3 . The loss of seasonal sea ice will likely not only affect the primary consumers of this resource but could also drive cascading effects within the food web, including impacting coastal ecosystem resources on which Indigenous Peoples rely. The consequences to these Arctic organisms’ life-history events and their ability to adapt to an alteration in the sea-ice primary production is uncertain 6 , 7 . Here, we trace source-specific highly branched isoprenoid (HBI) diatom lipid biomarkers 8 , 9 to undertake the most comprehensive and quantitative spatial and temporal assessment of carbon partitioning within the Arctic marine ecosystem to date. Since certain HBI lipids are only synthesized by a minority of sea ice diatom species 10 , 11 , 12 , while other HBIs are produced by a similar proportion of phytoplankton species 13 , 14 , these proxies now make it possible to differentiate between carbon derived from these two sources in the consumers 9 . We combined HBI biomarker values from sea ice- and phytoplankton-carbon sources into a single index, termed “H-Print” 8 , 9 . Based on a previously established calibration 8 , we were then able to convert H-Print values into estimates of sea-ice particulate organic carbon (iPOC) directly consumed by animals 8 , 15 or transferred to higher trophic organisms. So far, this approach has resulted in comparable findings of carbon sources, examples including fatty acid markers 16 , 17 , 18 , bulk stable isotopes 19 , 20 and compound-specific stable isotope analysis of amino acids (CSIA-AA) 21 , 22 and CSIA of fatty acids (CSIA- FA) 17 , 23 , 24 . Stable isotope analysis of carbon for the primary ice-associated HBI, IP 25 , has also confirmed sea ice origins 25 . These multi-proxy approaches further validate the use of iPOC values as quantitative predictors of ice-algal carbon in Arctic food webs 26 . For example, iPOC and CSIA of a source amino acid (phenylalanine) in Atlantic walrus tissues were significantly positively correlated, where high iPOC values were associated with more enriched 13 C typical of sea-ice algae 21 . By quantifying the sea-ice algal HBI contribution (relative to phytoplankton) throughout food chains of the marine ecosystem, spanning several marginal seas and coastal areas of the Arctic, including both Pacific and Atlantic-influenced sectors, we reveal striking year-round consumption of sea ice-associated primary production. In doing so, we consider how the potential future decrease and redistribution of this carbon source will likely have dramatic consequences requiring a concerted conservation approach to mitigate this rapid biodiversity change. Results and discussion Spatial and seasonal distribution of sea ice organic carbon across organisms To reveal the importance of sea-ice organic carbon for the Arctic ecosystem, we conducted the most comprehensive synthesis to date of previously published HBI results, including additional novel biomarker data, from Arctic fauna. Our study gathers over 2300 individuals, representing 156 species, collected from approximately 60 sites across the pan-Arctic shelf ecosystems 27 and extending from the sub- to the high-Arctic (55 − 82°N; Fig. 1 ). Obtained between 1982 and 2019, sampling occurred throughout the year from January to December. Owing to spatiotemporal variation in sampling in terms of numbers of species and taxonomic groups collected each year, it was not possible to examine inter-annual variability in sea ice carbon source use in relation to environmental metrics. Although this analysis does not address changes over time as a result of declining sea ice, sea-ice carbon was shown to be utilized year-round by organisms from all taxa (benthic and ice-associated invertebrates, zooplankton, fish, seabirds, and marine mammals) and habitats (benthic, sympagic or pelagic) throughout the nearly four decades of observations. Fig. 1: Sample collection map. Locations where animals were sampled throughout the marginal seas of the Arctic region, spanning January to December between 1982 and 2019. Magenta line represents the median<|im_end|> <|im_start|>assistant Sea ice algae is an essential resource for the survival of many species living in the Arctic. Traces of ice algae have been found in many animal groups from tiny filter-feeding shrimp to large predators like whales, revealing the critical importance of algae and the sea ice on which it grows to the fragile Arctic ecosystem. Plunged into constant darkness for several months of the year, the Arctic is a harsh environment where only those adapted to the extreme conditions are able to survive. When sunlight finally returns to the region for a few months in early spring, algae blooms appear across vast areas on the bottom of the sea ice. Arctic sea ice algae are among the best-adapted organisms on the planet to photosynthesize in low light levels, enabling them to survive in places where little else can grow. A new study published in Nature Communications has now examined the extent to which animals in the Arctic rely on the algae as a food source, as its decline could have cascading effects across Arctic food webs. To do this, researchers sampled 2,300 animals from 155 species, including invertebrates, fish, seabirds and marine mammals collected from across the Arctic shelves. They tested these specimens for a unique molecule produced by the algae to trace its presence throughout the food chain. They found traces of the algae in 96% of the studied organisms and, despite the algae blooms only occurring in the spring months, found traces in species collected year-round from January to December. Dr. Chelsea Koch, a scientist at the Museum and lead author of the study, says, "Despite sea ice algae blooms only occurring during this limited window in the early spring, it has pretty far-reaching impacts." "Much of the algae gets stored on the sea floor because as sea ice starts to melt and break apart each year, the algae are released into the water column and sinks rapidly without much degradation." There are diverse communities of animals such as sponges, crabs and worms that live on the sea floor which can feed directly on this resource throughout the year. Other animals, like diving seabirds, walruses and seals, then eat those animals, providing this year-round transfer of sea ice carbon into the food web to fuel the ecosystem. "We think this might be one way in which Arctic environments can thrive despite having several months of little to no sunlight and no productivity," explains Chelsea. "These ice algae reserves are available to keep things going." How were traces of algae detected in animals? Arctic sea ice algae are primarily comprised of diatoms, which are photosynthesizing algae found in almost every aquatic environment. Certain species of diatoms produce a type of lipid called highly branched isoprenoids (HBIs). Researchers found that HBIs appear not only in the tissues of animals that have eaten the algae, but also in animals that had eaten those animals. Therefore, these lipids could be used as a biomarker to trace their presence in species across the food web. Animals collected between 1982 and 2019 were tested for these HBIs. Older samples were obtained from frozen specimens in museum collections or other management organizations and communities, where the biomarker could still be extracted from tissues. The research team found the algae was essential for the majority of species across the Arctic food web throughout the year. "It was surprising to see it so widespread and just see the vastness of it presented in this way," says Chelsea. "Other methods have been used to look at sea ice algae that mostly agree with our findings. So this adds another piece of evidence to show it's important for Arctic marine food webs." What will happen to sea ice algae in the future? The climate crisis is driving a rapid change in the Arctic. Current projections show that sea ice will decline significantly, with seasonal periods of an ice-free Arctic Ocean likely within this century. Over the past few decades observations have shown that sea ice is already thinning. While initially this will enhance the potential habitat for sea ice algal growth in the short term as more light can penetrate the ice, changes to the distribution of sea ice could cause problems. Many organisms on the sea floor that eat the falling algae are relatively immobile and perhaps unlikely to move quickly enough to new areas covered by ice. In the long term, as the sea ice rapidly melts, we could see fewer algal blooms on shallow shelf systems in the Arctic. Therefore, the loss of sea ice will likely have cascading effects within the food web and impact coastal ecosystem resources on which Indigenous Peoples rely. The researchers also noted how different populations of species might be impacted in different ways. "For this study, multiple researchers contributed datasets and we looked at everything broadly. However, there were a lot of interesting nuances that came out within certain species," explains Chelsea. "For example, we saw a population of beluga whales with higher sea ice carbon and one with lower sea ice carbon. We realized that the former population tends to stick around in icy waters, while the latter migrate further south to go foraging." "We also saw similar patterns when looking at the Pacific walrus and the Atlantic walrus sub-species. These populations have different migratory behavior and proximity to sea ice throughout the year, so we saw differences in their sea ice carbon values to match." "It raises more questions to explore within that data about what might be happening at a species or population level and how their life cycles might depend on sea ice in one location but not so much in another." <|im_end|>

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2,467

[ { "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 Compound MHW-OAX events, during which marine heatwaves (MHWs) co-occur with ocean acidity extreme (OAX) events, can have larger impacts on marine ecosystems than the individual extremes. Using monthly open-ocean observations over the period 1982–2019, we show that globally 1.8 in 100 months (or about one out of five present-day MHW months) are compound MHW-OAX event months under a present-day baseline, almost twice as many as expected for 90th percentile extreme event exceedances if MHWs and OAX events were statistically independent. Compound MHW-OAX events are most likely in the subtropics (2.7 in 100 months; 10°−40° latitude) and less likely in the equatorial Pacific and the mid-to-high latitudes (0.7 in 100 months; >40° latitude). The likelihood pattern results from opposing effects of temperature and dissolved inorganic carbon on [H + ]. The likelihood is higher where the positive effect on [H + ] from increased temperatures during MHWs outweighs the negative effect on [H + ] from co-occurring decreases in dissolved inorganic carbon. Daily model output from a large-ensemble simulation of an Earth system model is analyzed to assess changes in the MHW-OAX likelihood under climate change. The projected long-term mean warming and acidification trends have the largest effect on the number of MHW-OAX days per year, increasing it from 12 to 265 days per year at 2 °C global warming relative to a fixed pre-industrial baseline. Even when long-term trends are removed, an increase in [H + ] variability leads to a 60% increase in the number of MHW-OAX days under 2 °C global warming. These projected increases may cause severe impacts on marine ecosystems. Introduction Anthropogenic climate change has led to an increase in frequency and intensity of ocean extreme events, such as marine heatwaves 1 , 2 , 3 , 4 , 5 , 6 , 7 and ocean acidity extremes 8 , 9 , a trend that is projected to continue over the 21st century 3 , 9 . The predominantly harmful impacts of such individual extreme events on marine ecosystems 10 , 11 , 12 may become more severe when two extreme events occur together 13 , 14 , 15 . These so-called compound events 16 , 17 have been vastly studied on land 18 , 19 , whereas marine compound events, such as compound MHW-OAX events (events of unusually high temperature and hydrogen ion concentration, [H + ]), are just starting to receive more attention 20 , 21 . The impact of compound MHW-OAX events on marine biota may exceed the impact from individual MHW or OAX events since co-occurring extremes can interact synergistically 22 . For example, the combination of high temperature and acidity conditions negatively impacted pteropods across cellular, physiological, and population levels in the California Current System in 2016 13 , 15 , and some of the devastating impacts of the Northeast Pacific 2013–2015 MHW 23 may have been amplified by the co-occurring extreme OA conditions 21 . Such rare observations and modeling studies of MHW-OAX events in the ocean are further corroborated by laboratory experiments showing synergistic negative effects on calcification, reproduction, and survival 24 , and trends towards lower survival, growth, and development 25 for many species under compound MHW-OAX conditions compared to single extreme conditions, and by mesocosm experiments showing shifts in community structure 26 , 27 . The likelihood of compound MHW-OAX event occurrence is influenced by a complex interplay of direct and indirect effects of high temperatures on [H + ] during MHWs. While hot temperatures directly lead to increases in [H + ] via changes in the carbonate chemistry equilibrium 28 , they can also modulate [H + ] indirectly via changes in dissolved inorganic carbon (C T ) 21 . These indirect changes of [H + ] during MHWs include a reduction of the CO 2 solubility in surface waters 29 and an associated net release of oceanic CO 2 to the atmosphere that reduces C T and [H + ] 30 , an increase in upper ocean thermal stratification 5 resulting in suppressed mixing of surface waters with carbon-rich subsurface waters and hence a reduction in surface ocean C T and [H + ] 31 , as well as changes in organic matter production that reduce C T and [H + ] if production increases 31 . The knowledge on compound MHW-OAX events and their drivers is currently very limited due to a lack of direct observations. However, novel observational-based data products 9 , 32 , 33 and large-ensemble simulations of comprehensive Earth System Models (ESMs) 34 , 35 permit us now to study compound MHW-OAX events globally. Here, we characterize patterns, identify drivers, and assess future changes of compound MHW-OAX events using (i) global monthly gridded observation-based sea surface temperature (SST) 33 and surface [H + ] data 9 from 1982 to 2019, (ii) time-series data of temperature and [H + ] from fifteen ocean stations with either approximately monthly or 3-hourly measurement frequency collected between 1983 and 2020, and (iii) output from 30 ensemble members of the Earth System Model GFDL ESM2M 36 , 37 at daily-mean resolution covering the period from 1861 to 2100 (see “Methods”). The analysis is restricted to the open ocean, since the high variability and locally important processes in coastal oceans, such as riverine fluxes or shelf and coastal dynamics, are neither captured by the gridded observation-based product 32 , 38 nor by the GFDL ESM2M model 37 . Extreme events in SST and [H + ] are defined with respect to seasonally varying 90th percentiles (see Methods). The percentile thresholds are determined from the shortest available timestep, i.e., monthly for observations and daily for the model output. In this study, compound MHW and OAX events are multivariate compound events 19 during which both extreme hot temperature and high acidity conditions co-occur in space and time. We refer to them simply as “compound MHW-OAX events”. We here quantify the number of MHW-OAX months per year (for the observation-based data) and the number of MHW-OAX days per year", "role": "user" }, { "content": "It's not just the land that is groaning under the heat—the ocean is also suffering from heatwaves. In the Mediterranean Sea along the Italian and Spanish coasts, for example, water temperatures are currently up to 5 °C higher than the long-term average at this time of year. Scientists have investigated marine heatwaves for a few years now—for example at the University of Bern. However, relatively little is known about how marine heatwaves co-occur with other extreme events in the ocean. Such events are known as compound events and considered to be a major risk of climate change. While the processes that lead to extreme events on land, such as floods, forest fires, heatwaves, or droughts and how they interact with each other have been intensively studied in the past, the finding that ocean weather and climate extreme events can also occur in combination is relatively new. A group of researchers at the Oeschger Center for Climate Change Research, led by Thomas Frölicher, has now investigated whether marine heatwaves co-occur in combination with extreme events in other potential marine ecosystem stressors. In addition to heat, potential stressors also include high acidity levels in the ocean. \"For the first time, we have quantified the frequency of compound events in which marine heatwaves happen together with extreme acidity\", says Friedrich Burger, postdoctoral researcher and first author of the study just published in the journal Nature Communications. Extreme events of high ocean acidity are occurrences where the proton concentration in seawater is higher than normal. Compound events especially frequent in the subtropical oceans The main finding of the study, which is based on monthly observations from the surface open ocean from 1982 to 2019, is that marine heatwaves and extreme ocean acidity events occur relatively often together. This means that the negative impacts of past marine heatwaves were potentially exacerbated by extreme acidic conditions. \"We can show,\" says ocean modeler Friedrich Burger, \"that these compound events are most common in the subtropical oceans, but comparably rare in the high latitudes and tropical Pacific.\" The co-occurrence of marine heatwaves and ocean acidity extremes in regions such as the subtropical oceans is caused by an increase in acidity at higher temperatures. However, if the temperature increase causes also other effects, such as less mixing of relatively more acidic subsurface water with surface water, a heatwave can also reduce acidity and thus decrease the frequency of compound events. This happens in the Southern Ocean or the tropical Pacific. \"To determine the relative frequency of combined extreme events, it is crucial to understand the effects of heatwaves on the circulation, biology, and chemistry of the respective ocean region\" says Jens Terhaar, co-author of the study. Compound events in the ocean are increasing strongly As a result of climate change and continuing CO2 emissions, extreme events such as marine heatwaves and ocean acidity extremes will continue to increase in frequency, and so will compound marine heatwave and ocean acidity extreme events. Earth system model simulations conducted by the Bern researchers show that the number of days in which marine heatwaves and high acidity events co-occur increases 22-fold at a global warming of 2 °C compared to pre-industrial conditions. \"This large projected increase may have severe impacts on marine ecosystems,\" said Thomas Frölicher, co-author. A team led by Frölicher had already shown the impact of marine heatwaves in a 2018 Nature study. The conclusion was that ocean heatwaves can irreversibly damage ecosystems and may pose a threat to fisheries. Although there is evidence that marine organisms can be further harmed by the concurrence of warm and acidic seawater conditions, still relatively little is known about the biological effects of co-occurrences of marine heatwaves and ocean acidity extremes. ", "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 Compound MHW-OAX events, during which marine heatwaves (MHWs) co-occur with ocean acidity extreme (OAX) events, can have larger impacts on marine ecosystems than the individual extremes. Using monthly open-ocean observations over the period 1982–2019, we show that globally 1.8 in 100 months (or about one out of five present-day MHW months) are compound MHW-OAX event months under a present-day baseline, almost twice as many as expected for 90th percentile extreme event exceedances if MHWs and OAX events were statistically independent. Compound MHW-OAX events are most likely in the subtropics (2.7 in 100 months; 10°−40° latitude) and less likely in the equatorial Pacific and the mid-to-high latitudes (0.7 in 100 months; >40° latitude). The likelihood pattern results from opposing effects of temperature and dissolved inorganic carbon on [H + ]. The likelihood is higher where the positive effect on [H + ] from increased temperatures during MHWs outweighs the negative effect on [H + ] from co-occurring decreases in dissolved inorganic carbon. Daily model output from a large-ensemble simulation of an Earth system model is analyzed to assess changes in the MHW-OAX likelihood under climate change. The projected long-term mean warming and acidification trends have the largest effect on the number of MHW-OAX days per year, increasing it from 12 to 265 days per year at 2 °C global warming relative to a fixed pre-industrial baseline. Even when long-term trends are removed, an increase in [H + ] variability leads to a 60% increase in the number of MHW-OAX days under 2 °C global warming. These projected increases may cause severe impacts on marine ecosystems. Introduction Anthropogenic climate change has led to an increase in frequency and intensity of ocean extreme events, such as marine heatwaves 1 , 2 , 3 , 4 , 5 , 6 , 7 and ocean acidity extremes 8 , 9 , a trend that is projected to continue over the 21st century 3 , 9 . The predominantly harmful impacts of such individual extreme events on marine ecosystems 10 , 11 , 12 may become more severe when two extreme events occur together 13 , 14 , 15 . These so-called compound events 16 , 17 have been vastly studied on land 18 , 19 , whereas marine compound events, such as compound MHW-OAX events (events of unusually high temperature and hydrogen ion concentration, [H + ]), are just starting to receive more attention 20 , 21 . The impact of compound MHW-OAX events on marine biota may exceed the impact from individual MHW or OAX events since co-occurring extremes can interact synergistically 22 . For example, the combination of high temperature and acidity conditions negatively impacted pteropods across cellular, physiological, and population levels in the California Current System in 2016 13 , 15 , and some of the devastating impacts of the Northeast Pacific 2013–2015 MHW 23 may have been amplified by the co-occurring extreme OA conditions 21 . Such rare observations and modeling studies of MHW-OAX events in the ocean are further corroborated by laboratory experiments showing synergistic negative effects on calcification, reproduction, and survival 24 , and trends towards lower survival, growth, and development 25 for many species under compound MHW-OAX conditions compared to single extreme conditions, and by mesocosm experiments showing shifts in community structure 26 , 27 . The likelihood of compound MHW-OAX event occurrence is influenced by a complex interplay of direct and indirect effects of high temperatures on [H + ] during MHWs. While hot temperatures directly lead to increases in [H + ] via changes in the carbonate chemistry equilibrium 28 , they can also modulate [H + ] indirectly via changes in dissolved inorganic carbon (C T ) 21 . These indirect changes of [H + ] during MHWs include a reduction of the CO 2 solubility in surface waters 29 and an associated net release of oceanic CO 2 to the atmosphere that reduces C T and [H + ] 30 , an increase in upper ocean thermal stratification 5 resulting in suppressed mixing of surface waters with carbon-rich subsurface waters and hence a reduction in surface ocean C T and [H + ] 31 , as well as changes in organic matter production that reduce C T and [H + ] if production increases 31 . The knowledge on compound MHW-OAX events and their drivers is currently very limited due to a lack of direct observations. However, novel observational-based data products 9 , 32 , 33 and large-ensemble simulations of comprehensive Earth System Models (ESMs) 34 , 35 permit us now to study compound MHW-OAX events globally. Here, we characterize patterns, identify drivers, and assess future changes of compound MHW-OAX events using (i) global monthly gridded observation-based sea surface temperature (SST) 33 and surface [H + ] data 9 from 1982 to 2019, (ii) time-series data of temperature and [H + ] from fifteen ocean stations with either approximately monthly or 3-hourly measurement frequency collected between 1983 and 2020, and (iii) output from 30 ensemble members of the Earth System Model GFDL ESM2M 36 , 37 at daily-mean resolution covering the period from 1861 to 2100 (see “Methods”). The analysis is restricted to the open ocean, since the high variability and locally important processes in coastal oceans, such as riverine fluxes or shelf and coastal dynamics, are neither captured by the gridded observation-based product 32 , 38 nor by the GFDL ESM2M model 37 . Extreme events in SST and [H + ] are defined with respect to seasonally varying 90th percentiles (see Methods). The percentile thresholds are determined from the shortest available timestep, i.e., monthly for observations and daily for the model output. In this study, compound MHW and OAX events are multivariate compound events 19 during which both extreme hot temperature and high acidity conditions co-occur in space and time. We refer to them simply as “compound MHW-OAX events”. We here quantify the number of MHW-OAX months per year (for the observation-based data) and the number of MHW-OAX days per year<|im_end|> <|im_start|>assistant It's not just the land that is groaning under the heat—the ocean is also suffering from heatwaves. In the Mediterranean Sea along the Italian and Spanish coasts, for example, water temperatures are currently up to 5 °C higher than the long-term average at this time of year. Scientists have investigated marine heatwaves for a few years now—for example at the University of Bern. However, relatively little is known about how marine heatwaves co-occur with other extreme events in the ocean. Such events are known as compound events and considered to be a major risk of climate change. While the processes that lead to extreme events on land, such as floods, forest fires, heatwaves, or droughts and how they interact with each other have been intensively studied in the past, the finding that ocean weather and climate extreme events can also occur in combination is relatively new. A group of researchers at the Oeschger Center for Climate Change Research, led by Thomas Frölicher, has now investigated whether marine heatwaves co-occur in combination with extreme events in other potential marine ecosystem stressors. In addition to heat, potential stressors also include high acidity levels in the ocean. "For the first time, we have quantified the frequency of compound events in which marine heatwaves happen together with extreme acidity", says Friedrich Burger, postdoctoral researcher and first author of the study just published in the journal Nature Communications. Extreme events of high ocean acidity are occurrences where the proton concentration in seawater is higher than normal. Compound events especially frequent in the subtropical oceans The main finding of the study, which is based on monthly observations from the surface open ocean from 1982 to 2019, is that marine heatwaves and extreme ocean acidity events occur relatively often together. This means that the negative impacts of past marine heatwaves were potentially exacerbated by extreme acidic conditions. "We can show," says ocean modeler Friedrich Burger, "that these compound events are most common in the subtropical oceans, but comparably rare in the high latitudes and tropical Pacific." The co-occurrence of marine heatwaves and ocean acidity extremes in regions such as the subtropical oceans is caused by an increase in acidity at higher temperatures. However, if the temperature increase causes also other effects, such as less mixing of relatively more acidic subsurface water with surface water, a heatwave can also reduce acidity and thus decrease the frequency of compound events. This happens in the Southern Ocean or the tropical Pacific. "To determine the relative frequency of combined extreme events, it is crucial to understand the effects of heatwaves on the circulation, biology, and chemistry of the respective ocean region" says Jens Terhaar, co-author of the study. Compound events in the ocean are increasing strongly As a result of climate change and continuing CO2 emissions, extreme events such as marine heatwaves and ocean acidity extremes will continue to increase in frequency, and so will compound marine heatwave and ocean acidity extreme events. Earth system model simulations conducted by the Bern researchers show that the number of days in which marine heatwaves and high acidity events co-occur increases 22-fold at a global warming of 2 °C compared to pre-industrial conditions. "This large projected increase may have severe impacts on marine ecosystems," said Thomas Frölicher, co-author. A team led by Frölicher had already shown the impact of marine heatwaves in a 2018 Nature study. The conclusion was that ocean heatwaves can irreversibly damage ecosystems and may pose a threat to fisheries. Although there is evidence that marine organisms can be further harmed by the concurrence of warm and acidic seawater conditions, still relatively little is known about the biological effects of co-occurrences of marine heatwaves and ocean acidity extremes. <|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 A traditional approach to investigate the genetic basis of complex diseases is to identify genes with a global change in expression between diseased and healthy individuals. However, population heterogeneity may undermine the effort to uncover genes with significant but individual contribution to the spectrum of disease phenotypes within a population. Here we investigate individual changes of gene expression when inducing hypertrophy and heart failure in 100 + strains of genetically distinct mice from the Hybrid Mouse Diversity Panel (HMDP). We find that genes whose expression fold-change correlates in a statistically significant way with the severity of the disease are either up or down-regulated across strains, and therefore missed by a traditional population-wide analysis of differential gene expression. Furthermore, those “fold-change” genes are enriched in human cardiac disease genes and form a dense co-regulated module strongly interacting with the cardiac hypertrophic signaling network in the human interactome. We validate our approach by showing that the knockdown of Hes1 , predicted as a strong candidate, induces a dramatic reduction of hypertrophy by 80–90% in neonatal rat ventricular myocytes. Our results demonstrate that individualized approaches are crucial to identify genes underlying complex diseases as well as to develop personalized therapies. Introduction Contrary to “Mendelian” diseases where causality can be traced back to strong effects of a single gene, common diseases result from modest effects of many interacting genes. 1 Understanding which genes are involved and how they affect diseases is a major challenge for designing appropriate therapies. Heart failure (HF) is a well-studied example of a genetically complex disease involving multiple processes that eventually lead to a common phenotype of abnormal ventricular function and cardiac hypertrophy. 2 Numerous studies have attempted to pinpoint differentially expressed genes (DEGs) to find biomarkers for the prognosis of the disease and the design of appropriate drugs, 3 as well as explore underlying affected signaling pathways. 4 Such studies typically compare the average gene expression between samples in healthy and diseased states, such as non-failing vs failing hearts in murine, 5 canine, 6 or human samples (see 7 for a broad review). Genes are ranked by the strength of their differential expression, and top ranking genes are further investigated for pathway enrichment and biomarker potential. However, because of the different genetic backgrounds of the surveyed individuals, as well as different severities of HF, those studies show very limited overlap of DEGs. While separate studies typically identify tens to hundreds of DEGs, not a single DEG is common to all studies. 7 Moreover, it is unclear whether the healthy state is itself a well-defined unique state. In particular, several studies have shown that, due to compensatory mechanisms involved in homeostasis, different combinations of ion channel conductances in neurons and cardiac cells can lead to a normal electrophysiological phenotype, e.g., a similar bursting pattern of motor neurons or a similar cardiac action potential and calcium transient. 8 , 9 This has led to the concept that genetically distinct individuals represent different “Good Enough Solutions” corresponding to distinct gene expression patterns underlying a healthy phenotype. Different combinations of gene expression in a healthy state resulting from genetic variations would be expected to yield different DEGs in a diseased state. Thus, small numbers of DEGs that are only shared by a subset of individuals, and would be missed by a standard population-wide DEG analysis, could in principle have a causal role. Identifying these genes remains a central challenge in personalized medicine. 10 , 11 In order to explore the variability of individual trajectories leading to hypertrophy and HF, we leverage the Hybrid Mouse Diversity Panel (HMDP), a model system consisting of >100 genetically diverse strains of mice that we described previously 12 , 13 (see Methods). Gene expression and phenotypic data are acquired before and 3 weeks after implantation of a pump delivering isoproterenol (ISO). This pathological stressor induces a global response characterized mainly by cardiac hypertrophy along with more marginal changes in chamber dilation and contractile function at the population level. 12 As a result, we primarily focus on the identification of genes relevant for cardiac hypertrophy. Expression data is collected at the whole heart level and the Total Heart Weight is used to quantify the degree of cardiac hypertrophy. Importantly, the severity of the hypertrophic response is highly variable among strains, ranging from almost no hypertrophy to up to an 80% increase of heart mass. Our study is directed at understanding why certain individuals are more susceptible to or protected against cardiac hypertrophy due to their genetic backgrounds. Because mice from the same strains are isogenic and renewable, the HMDP offers the possibility to analyze differential gene expression and phenotype change in a unique setting where subjects in the control population can be matched to a subject with the same genetic background in the treated population. In that setup, one can correlate the stressor-related gene expression change with the corresponding phenotype change (in our case, heart mass increase) while controlling for genetic background, thereby disentangling intra-strain (stressor-induced) and inter-strain (genetics-induced) variations. In the specific case of HF onto which we focus here, such data could not be obtained in human studies where heart tissue biopsies are extracted from either healthy donor hearts or explanted hearts of late stage HF patients in a genetically diverse population. 14 One would indeed require a population of identical twins in which one twin for each pair of twins is a heart donor and the other twin is a late stage HF patient. As such, gene expression data obtained from those biopsies can only be used to perform a population-level differential gene expression analysis. In contrast, here we identify relevant genes by correlating strain-specific temporal changes of gene expression, i.e., differential expression between a post-ISO mouse and another pre-ISO mouse from the same strain, with the corresponding strain-specific changes of phenotype, i.e., ratio of heart mass between the post- and pre-ISO mice of the same strain. Concretely (see Methods), we calculate the Pearson coefficient of correlation \$C_j\$ between the strain-specific fold-change of expression of", "role": "user" }, { "content": "One in four deaths in the United States each year are due to heart disease, according to the Centers for Disease Control and Prevention. It's the leading killer of both men and women, but the disease's genetic complexity makes it difficult to treat. In a paper published in npj Systems Biology and Applications, Northeastern physics professor Alain Karma and his colleagues describe their discovery of 36 previously unknown genes implicated in heart failure. The team confirmed that one of those genes plays a causal role in cardiac hypertrophy—abnormal thickening of the heart muscle—which can lead to heart failure. \"This is an exciting direction for personalized medicine, and also for identifying genes and therapeutic targets for complex diseases that involve many genes,\" Karma said. The ultimate goal is to create personalized therapeutic drugs to reverse heart disease. Researchers are probably still a decade away from achieving that sort of tailored therapy, Karma said. But companies interested in developing such drugs can use the method he and his colleagues developed and the genes they identified to get a step closer. The framework described in the paper can also be used to predict whether individuals suffering from a particular disease will respond to a given drug treatment, said lead author Marc Santolini, a postdoctoral research associate at Northeastern's Center for Complex Network Research. \"The method can predict beforehand whether a patient should be prescribed a different drug using just a simple blood test. This would save time and accelerate the therapy,\" Santolini said. \"In general, this research highlights the importance of personalized approaches to uncover novel disease genes and better understand disease processes.\" The traditional approach to finding genes related to heart disease works like this: Researchers take donated hearts from people who died unexpectedly but were previously healthy. They analyze the gene expression—that is, the amount of messenger RNA and proteins—produced by the genes of healthy hearts and compare it with the gene expression of sick hearts explanted from end-stage heart failure patients undergoing heart transplant. \"You see a different gene expression profile,\" Karma said. For example, if a gene found in the sick hearts expresses twice the amount of RNA as it did in the healthy hearts, it might be relevant to the disease. But so far, Karma said this method hasn't been very successful in finding important genes. His team took an entirely different approach—using the Hybrid Mouse Diversity Panel, a collection of 100 genetically different strains of mice that can be used to analyze the genetic and environmental factors underlying complex traits. Within each strain, the mice are inbred, making them all identical twins on a genetic level. Researchers took two mice from the same strain and gave one of them a stressor drug that induces heart failure. They then compared the stressed mouse's gene expression with its non-stressed twin. Since the mice have the same genome, they were able to pinpoint individual genes that changed expression as a direct result of the heart stressor. The researchers identified 36 such genes. Many of these genes were previously unknown to be implicated in heart failure. Karma said one of them is known as a transcription factor, meaning it controls the expression of many other genes. The researchers confirmed the gene's role by using molecular biology techniques to silence it and observe the resulting changes of expression. They found the transcription factor gene was directly connected to a whole network of proteins known to play a role in cardiac hypertrophy. One of the genes Karma found, called RFFL, was previously known to researchers to be implicated in other cardiac processes. However, it was not known to be related to hypertrophy, said Gideon Koren, a physician and director of the Cardiovascular Research Center at Rhode Island Hospital & the Cardiovascular Institute. Koren has been studying RFFL in his lab for the past two years. \"All of the sudden, this study reveals the gene is important for the hypertrophic trait,\" Koren said. \"We now think that RFFL is an important node that can cross-talk with cardiac hypertrophy failure and cardiac excitation.\" Cardiac excitation is the process that enables the chambers of the heart to contract and relax. \"That was something that we wouldn't have explored, given what we knew about RFFL,\" Koren added. As a next step, Karma said the new method could be tested on human stem cells, which have the same genetic code as the person they came from and can be induced to have similar gene expression patterns as heart cells. \"When you are comparing two populations of cells from the same person—one that has been controlled and one that has been under the effect of a drug or stressor—you can compare the change of gene expression in a personalized way,\" Karma 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 traditional approach to investigate the genetic basis of complex diseases is to identify genes with a global change in expression between diseased and healthy individuals. However, population heterogeneity may undermine the effort to uncover genes with significant but individual contribution to the spectrum of disease phenotypes within a population. Here we investigate individual changes of gene expression when inducing hypertrophy and heart failure in 100 + strains of genetically distinct mice from the Hybrid Mouse Diversity Panel (HMDP). We find that genes whose expression fold-change correlates in a statistically significant way with the severity of the disease are either up or down-regulated across strains, and therefore missed by a traditional population-wide analysis of differential gene expression. Furthermore, those “fold-change” genes are enriched in human cardiac disease genes and form a dense co-regulated module strongly interacting with the cardiac hypertrophic signaling network in the human interactome. We validate our approach by showing that the knockdown of Hes1 , predicted as a strong candidate, induces a dramatic reduction of hypertrophy by 80–90% in neonatal rat ventricular myocytes. Our results demonstrate that individualized approaches are crucial to identify genes underlying complex diseases as well as to develop personalized therapies. Introduction Contrary to “Mendelian” diseases where causality can be traced back to strong effects of a single gene, common diseases result from modest effects of many interacting genes. 1 Understanding which genes are involved and how they affect diseases is a major challenge for designing appropriate therapies. Heart failure (HF) is a well-studied example of a genetically complex disease involving multiple processes that eventually lead to a common phenotype of abnormal ventricular function and cardiac hypertrophy. 2 Numerous studies have attempted to pinpoint differentially expressed genes (DEGs) to find biomarkers for the prognosis of the disease and the design of appropriate drugs, 3 as well as explore underlying affected signaling pathways. 4 Such studies typically compare the average gene expression between samples in healthy and diseased states, such as non-failing vs failing hearts in murine, 5 canine, 6 or human samples (see 7 for a broad review). Genes are ranked by the strength of their differential expression, and top ranking genes are further investigated for pathway enrichment and biomarker potential. However, because of the different genetic backgrounds of the surveyed individuals, as well as different severities of HF, those studies show very limited overlap of DEGs. While separate studies typically identify tens to hundreds of DEGs, not a single DEG is common to all studies. 7 Moreover, it is unclear whether the healthy state is itself a well-defined unique state. In particular, several studies have shown that, due to compensatory mechanisms involved in homeostasis, different combinations of ion channel conductances in neurons and cardiac cells can lead to a normal electrophysiological phenotype, e.g., a similar bursting pattern of motor neurons or a similar cardiac action potential and calcium transient. 8 , 9 This has led to the concept that genetically distinct individuals represent different “Good Enough Solutions” corresponding to distinct gene expression patterns underlying a healthy phenotype. Different combinations of gene expression in a healthy state resulting from genetic variations would be expected to yield different DEGs in a diseased state. Thus, small numbers of DEGs that are only shared by a subset of individuals, and would be missed by a standard population-wide DEG analysis, could in principle have a causal role. Identifying these genes remains a central challenge in personalized medicine. 10 , 11 In order to explore the variability of individual trajectories leading to hypertrophy and HF, we leverage the Hybrid Mouse Diversity Panel (HMDP), a model system consisting of >100 genetically diverse strains of mice that we described previously 12 , 13 (see Methods). Gene expression and phenotypic data are acquired before and 3 weeks after implantation of a pump delivering isoproterenol (ISO). This pathological stressor induces a global response characterized mainly by cardiac hypertrophy along with more marginal changes in chamber dilation and contractile function at the population level. 12 As a result, we primarily focus on the identification of genes relevant for cardiac hypertrophy. Expression data is collected at the whole heart level and the Total Heart Weight is used to quantify the degree of cardiac hypertrophy. Importantly, the severity of the hypertrophic response is highly variable among strains, ranging from almost no hypertrophy to up to an 80% increase of heart mass. Our study is directed at understanding why certain individuals are more susceptible to or protected against cardiac hypertrophy due to their genetic backgrounds. Because mice from the same strains are isogenic and renewable, the HMDP offers the possibility to analyze differential gene expression and phenotype change in a unique setting where subjects in the control population can be matched to a subject with the same genetic background in the treated population. In that setup, one can correlate the stressor-related gene expression change with the corresponding phenotype change (in our case, heart mass increase) while controlling for genetic background, thereby disentangling intra-strain (stressor-induced) and inter-strain (genetics-induced) variations. In the specific case of HF onto which we focus here, such data could not be obtained in human studies where heart tissue biopsies are extracted from either healthy donor hearts or explanted hearts of late stage HF patients in a genetically diverse population. 14 One would indeed require a population of identical twins in which one twin for each pair of twins is a heart donor and the other twin is a late stage HF patient. As such, gene expression data obtained from those biopsies can only be used to perform a population-level differential gene expression analysis. In contrast, here we identify relevant genes by correlating strain-specific temporal changes of gene expression, i.e., differential expression between a post-ISO mouse and another pre-ISO mouse from the same strain, with the corresponding strain-specific changes of phenotype, i.e., ratio of heart mass between the post- and pre-ISO mice of the same strain. Concretely (see Methods), we calculate the Pearson coefficient of correlation $C_j$ between the strain-specific fold-change of expression of<|im_end|> <|im_start|>assistant One in four deaths in the United States each year are due to heart disease, according to the Centers for Disease Control and Prevention. It's the leading killer of both men and women, but the disease's genetic complexity makes it difficult to treat. In a paper published in npj Systems Biology and Applications, Northeastern physics professor Alain Karma and his colleagues describe their discovery of 36 previously unknown genes implicated in heart failure. The team confirmed that one of those genes plays a causal role in cardiac hypertrophy—abnormal thickening of the heart muscle—which can lead to heart failure. "This is an exciting direction for personalized medicine, and also for identifying genes and therapeutic targets for complex diseases that involve many genes," Karma said. The ultimate goal is to create personalized therapeutic drugs to reverse heart disease. Researchers are probably still a decade away from achieving that sort of tailored therapy, Karma said. But companies interested in developing such drugs can use the method he and his colleagues developed and the genes they identified to get a step closer. The framework described in the paper can also be used to predict whether individuals suffering from a particular disease will respond to a given drug treatment, said lead author Marc Santolini, a postdoctoral research associate at Northeastern's Center for Complex Network Research. "The method can predict beforehand whether a patient should be prescribed a different drug using just a simple blood test. This would save time and accelerate the therapy," Santolini said. "In general, this research highlights the importance of personalized approaches to uncover novel disease genes and better understand disease processes." The traditional approach to finding genes related to heart disease works like this: Researchers take donated hearts from people who died unexpectedly but were previously healthy. They analyze the gene expression—that is, the amount of messenger RNA and proteins—produced by the genes of healthy hearts and compare it with the gene expression of sick hearts explanted from end-stage heart failure patients undergoing heart transplant. "You see a different gene expression profile," Karma said. For example, if a gene found in the sick hearts expresses twice the amount of RNA as it did in the healthy hearts, it might be relevant to the disease. But so far, Karma said this method hasn't been very successful in finding important genes. His team took an entirely different approach—using the Hybrid Mouse Diversity Panel, a collection of 100 genetically different strains of mice that can be used to analyze the genetic and environmental factors underlying complex traits. Within each strain, the mice are inbred, making them all identical twins on a genetic level. Researchers took two mice from the same strain and gave one of them a stressor drug that induces heart failure. They then compared the stressed mouse's gene expression with its non-stressed twin. Since the mice have the same genome, they were able to pinpoint individual genes that changed expression as a direct result of the heart stressor. The researchers identified 36 such genes. Many of these genes were previously unknown to be implicated in heart failure. Karma said one of them is known as a transcription factor, meaning it controls the expression of many other genes. The researchers confirmed the gene's role by using molecular biology techniques to silence it and observe the resulting changes of expression. They found the transcription factor gene was directly connected to a whole network of proteins known to play a role in cardiac hypertrophy. One of the genes Karma found, called RFFL, was previously known to researchers to be implicated in other cardiac processes. However, it was not known to be related to hypertrophy, said Gideon Koren, a physician and director of the Cardiovascular Research Center at Rhode Island Hospital & the Cardiovascular Institute. Koren has been studying RFFL in his lab for the past two years. "All of the sudden, this study reveals the gene is important for the hypertrophic trait," Koren said. "We now think that RFFL is an important node that can cross-talk with cardiac hypertrophy failure and cardiac excitation." Cardiac excitation is the process that enables the chambers of the heart to contract and relax. "That was something that we wouldn't have explored, given what we knew about RFFL," Koren added. As a next step, Karma said the new method could be tested on human stem cells, which have the same genetic code as the person they came from and can be induced to have similar gene expression patterns as heart cells. "When you are comparing two populations of cells from the same person—one that has been controlled and one that has been under the effect of a drug or stressor—you can compare the change of gene expression in a personalized way," Karma 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 Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large samples are necessary to detect these risk loci. Here we present results from the largest BD GWAS to date by investigating 2.3 million single-nucleotide polymorphisms (SNPs) in a sample of 24,025 patients and controls. We detect 56 genome-wide significant SNPs in five chromosomal regions including previously reported risk loci ANK3 , ODZ4 and TRANK1, as well as the risk locus ADCY2 (5p15.31) and a region between MIR2113 and POU3F2 (6q16.1). ADCY2 is a key enzyme in cAMP signalling and our finding provides new insights into the biological mechanisms involved in the development of BD. Introduction Bipolar disorder (BD) is a severe disorder of mood, characterized by recurrent episodes of mania and depression, which affect thought, perception, emotion and social behaviour. With a lifetime prevalence of 1% in the general population, BD is a common condition. The World Health Organisation classifies BD as one of the top 10 leading causes of the global burden of disease for the age group of 15–44-year-old people. Formal and molecular genetic data strongly suggest that BD is a multifactorial disease 1 . This means that many genetic and environmental factors influence the risk of disease. The heritability estimates for BD range between 60 and 80% 2 . This suggests a substantial involvement of genetic factors in the development of the disease, but the particular factors underlying the pathophysiology and aetiology of BD are still largely unknown. Since the first genome-wide association study (GWAS) of BD 3 in 2007, a handful of risk loci have been identified through some larger GWAS, which replicated in adequately sized follow-up studies 4 , 5 , notably ANK3 , NCAN , CACNA1C and ODZ4. These first genes provide valuable insights into the molecular mechanisms involved in BD and form a basis for future exploration of the molecular pathomechanisms and possibly drug targets. The genetic risk variants at these loci show unprecedented statistical support, but explain only a smaller fraction of BD’s heritability. However, this is in line with results of recent studies that provide evidence for a strong polygenic component in BD, suggesting the presence of a large number of additional risk loci, each mediating small disease susceptibility 6 , 7 . Motivated by this and the successes of GWAS for non-psychiatric phenotypes, a big step forward was taken through a recent large BD GWAS by the multi-national Psychiatric Genomics Consortium Bipolar Disorder Working Group (PGC-BD) 7 . We have previously published a GWAS of BD using a German sample (named Germany I) 8 that was thereafter included in the GWAS of the PGC-BD 7 and another subsequent BD GWAS 9 . Here we generate new and so far unpublished genome-wide SNP data from 2,266 clinically well-characterized patients with BD ( ∼ 76% BD type I) and 5,028 ethnically matched controls, derived from the MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia) consortium. The samples originate from four European countries, Canada and Australia. To increase power for detection of risk variants with small genetic effect, we combine and jointly analyse our MooDS samples with the 7,481 patients and 9,250 controls from the aforementioned PGC-BD study (MooDS-PGC). We find strong evidence for common risk variants at three known loci ( ANK3 , ODZ4 and TRANK1 ) and identify two risk loci ( ADCY2 and the region between MIR2113 and POU3F2 ), which have not been implicated in BD before. Results Association analyses A total of 2,267,487 imputed SNPs from 9,747 patients and 14,278 controls ( Table 1 ) passed our stringent quality control (QC) and association analysis of autosomal SNPs was performed using a fixed-effects meta-analysis (Methods). Sex chromosomes were not analysed because the published PGC data do not contain the respective information. To adequately correct for inflation of P values due to varying sizes of the MooDS and PGC samples, we adjusted the P values of the MooDS-PGC analysis ( P GC ) using a standardized λ factor for genomic control (GC), which was 1.018 (Methods, Fig. 1 ). A P value plot showing an overview of the genome-wide association results is provided in Fig. 2a . Table 1 Phenotypic data for patients with bipolar disorder and controls following QC. Full size table Figure 1: Quantile–quantile plot of the MooDS-PGC GWAS of BD. A quantile–quantile (QQ) plot displays the relationship between the experimentally observed P values (vertical axis) to the expected P values of a null distribution (horizontal axis). The grey area represents the 95% concentration band. QQ plots are commonly used for graphical illustration of the effect of a QC on GWAS data. The dashed line (bold) indicates the threshold for genome-wide significance ( P GC =5 × 10 −8 ). Here we show the effect of a standardised λ factor for GC on the 2,267,487 autosomal P values from the fixed-effects meta-analysis (blue curve) in the last step of our QC procedure (Methods). After the application, a systematic adjustment of P values ( P GC , black curve) can be seen, suggesting that this QC step counteracts an inflation of P values by varying sample sizes in the MooDS and PGC data. Full size image Figure 2: Association results for the MooDS-PGC GWAS and the two new risk loci for BD. ( a ) Manhattan plot for all analysed SNPs, ( b , c ) regional association plots for the SNPs analysed at ADCY2 (5p15.31) and MIR2113 - POU3F2 (6q16.1). Regional association plots were drawn using SNAP 54 and data for LD (red) and recombination frequency (blue line) from the 1000 Genomes Project. Full size image The MooDS-PGC GWAS revealed 56 SNPs reaching genome-wide significance at five genomic loci, three of which had been described before ( ANK3 , ODZ4", "role": "user" }, { "content": "First on top of the world and then in the depths of despair – this is what the extreme mood changes for people with bipolar disorder are like. Under the direction of scientists from the University of Bonn Hospital, the Central Institute of Mental Health of Mannheim and the University of Basel Hospital, an international collaboration of researchers discovered two new gene regions which are connected with the prevalent disease. In addition, they were able to confirm three additional suspect genes. In this unparalleled worldwide study, the scientists are utilizing unprecedented numbers of patients. The results are now being published in the renowned journal Nature Communications. Throughout the course of their lives, about one percent of the population suffers from bipolar disorder, also known as manic-depressive disorder. The patients undergo a veritable rollercoaster of emotions: During extreme shifts, they experience manic phases with delusions of grandeur, increased drive and a decreased need for sleep as well as depressive episodes with a severely depressed mood to the point of suicidal thoughts. The causes of the disease are not yet fully understood, however in addition to psychosocial triggers, genetic factors play a large role. \"There is no one gene that has a significant effect on the development of bipolar disorder,\" says Prof. Dr. Markus M. Nöthen, Director of the Institute of Human Genetics of the University of Bonn Hospital. \"Many different genes are evidently involved and these genes work together with environmental factors in a complex way.\" Scale of the investigation is unparalleled worldwide In recent years, scientists at the Institute of Human Genetics were already involved in decoding several genes associated with bipolar disorder. The researchers working with Prof. Dr. Marcella Rietschel from the Central Institute of Mental Health of Mannheim, Prof. Dr. Markus M. Nöthen from the University of Bonn Hospital and Prof. Dr. Sven Cichon from the University of Basel Hospital are now using unprecedented numbers of patients in an international research collaboration: New genetic data from 2266 patients with manic-depressive disorder and 5028 control persons were obtained, merged with existing data sets and analyzed together. In total, data on the genetic material of 9747 patients were compared with data from 14,278 healthy persons. \"The investigation of the genetic foundations of bipolar disorder on this scale is unique worldwide to date,\" says Prof. Rietschel from the Central Institute of Mental Health of Mannheim. The search for genes involved in manic-depressive disorder is like looking for a needle in a haystack. \"The contributions of individual genes are so minor that they normally cannot be identified in the 'background noise' of genetic differences,\" explains Prof. Cichon from the University of Basel Hospital. Only when the DNA from very large numbers of patients with bipolar disorder are compared to the genetic material from an equally large number of healthy persons can differences be confirmed statistically. Such suspect regions which indicate a disease are known by scientists as candidate genes. Two new gene regions discovered and three known gene regions confirmed Using automated analysis methods, the researchers recorded about 2.3 million different regions in the genetic material of patients and comparators, respectively. The subsequent evaluation using biostatistical methods revealed a total of five risk regions on the DNA associated with bipolar disorder. Two of these regions were newly discovered: The gene \"ADCY2\" on chromosome five and the so-called \"MIR2113-POU3F2\" region on chromosome six. The risk regions \"ANK3\", \"ODZ4\" and \"TRANK1\" have already been described in prior studies. \"These gene regions were, however, statistically better confirmed in our current investigation - the connection with bipolar disorder has now become even clearer,\" says Prof. Nöthen. The researchers are particularly interested in the newly discovered gene region \"ADCY2\". It codes an enzyme which is involved in the conduction of signals into nerve cells. \"This fits very well with observations that the signal transfer in certain regions of the brain is impaired in patients with bipolar disorder,\" explains the human geneticist of the University of Bonn Hospital. With their search for genetic regions, the scientists are gradually clarifying the causes of manic-depressive disorder. \"Only when we know the biological foundations of this disease can be also identify starting points for new therapies,\" says Prof. Nöthen. ", "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 Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large samples are necessary to detect these risk loci. Here we present results from the largest BD GWAS to date by investigating 2.3 million single-nucleotide polymorphisms (SNPs) in a sample of 24,025 patients and controls. We detect 56 genome-wide significant SNPs in five chromosomal regions including previously reported risk loci ANK3 , ODZ4 and TRANK1, as well as the risk locus ADCY2 (5p15.31) and a region between MIR2113 and POU3F2 (6q16.1). ADCY2 is a key enzyme in cAMP signalling and our finding provides new insights into the biological mechanisms involved in the development of BD. Introduction Bipolar disorder (BD) is a severe disorder of mood, characterized by recurrent episodes of mania and depression, which affect thought, perception, emotion and social behaviour. With a lifetime prevalence of 1% in the general population, BD is a common condition. The World Health Organisation classifies BD as one of the top 10 leading causes of the global burden of disease for the age group of 15–44-year-old people. Formal and molecular genetic data strongly suggest that BD is a multifactorial disease 1 . This means that many genetic and environmental factors influence the risk of disease. The heritability estimates for BD range between 60 and 80% 2 . This suggests a substantial involvement of genetic factors in the development of the disease, but the particular factors underlying the pathophysiology and aetiology of BD are still largely unknown. Since the first genome-wide association study (GWAS) of BD 3 in 2007, a handful of risk loci have been identified through some larger GWAS, which replicated in adequately sized follow-up studies 4 , 5 , notably ANK3 , NCAN , CACNA1C and ODZ4. These first genes provide valuable insights into the molecular mechanisms involved in BD and form a basis for future exploration of the molecular pathomechanisms and possibly drug targets. The genetic risk variants at these loci show unprecedented statistical support, but explain only a smaller fraction of BD’s heritability. However, this is in line with results of recent studies that provide evidence for a strong polygenic component in BD, suggesting the presence of a large number of additional risk loci, each mediating small disease susceptibility 6 , 7 . Motivated by this and the successes of GWAS for non-psychiatric phenotypes, a big step forward was taken through a recent large BD GWAS by the multi-national Psychiatric Genomics Consortium Bipolar Disorder Working Group (PGC-BD) 7 . We have previously published a GWAS of BD using a German sample (named Germany I) 8 that was thereafter included in the GWAS of the PGC-BD 7 and another subsequent BD GWAS 9 . Here we generate new and so far unpublished genome-wide SNP data from 2,266 clinically well-characterized patients with BD ( ∼ 76% BD type I) and 5,028 ethnically matched controls, derived from the MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia) consortium. The samples originate from four European countries, Canada and Australia. To increase power for detection of risk variants with small genetic effect, we combine and jointly analyse our MooDS samples with the 7,481 patients and 9,250 controls from the aforementioned PGC-BD study (MooDS-PGC). We find strong evidence for common risk variants at three known loci ( ANK3 , ODZ4 and TRANK1 ) and identify two risk loci ( ADCY2 and the region between MIR2113 and POU3F2 ), which have not been implicated in BD before. Results Association analyses A total of 2,267,487 imputed SNPs from 9,747 patients and 14,278 controls ( Table 1 ) passed our stringent quality control (QC) and association analysis of autosomal SNPs was performed using a fixed-effects meta-analysis (Methods). Sex chromosomes were not analysed because the published PGC data do not contain the respective information. To adequately correct for inflation of P values due to varying sizes of the MooDS and PGC samples, we adjusted the P values of the MooDS-PGC analysis ( P GC ) using a standardized λ factor for genomic control (GC), which was 1.018 (Methods, Fig. 1 ). A P value plot showing an overview of the genome-wide association results is provided in Fig. 2a . Table 1 Phenotypic data for patients with bipolar disorder and controls following QC. Full size table Figure 1: Quantile–quantile plot of the MooDS-PGC GWAS of BD. A quantile–quantile (QQ) plot displays the relationship between the experimentally observed P values (vertical axis) to the expected P values of a null distribution (horizontal axis). The grey area represents the 95% concentration band. QQ plots are commonly used for graphical illustration of the effect of a QC on GWAS data. The dashed line (bold) indicates the threshold for genome-wide significance ( P GC =5 × 10 −8 ). Here we show the effect of a standardised λ factor for GC on the 2,267,487 autosomal P values from the fixed-effects meta-analysis (blue curve) in the last step of our QC procedure (Methods). After the application, a systematic adjustment of P values ( P GC , black curve) can be seen, suggesting that this QC step counteracts an inflation of P values by varying sample sizes in the MooDS and PGC data. Full size image Figure 2: Association results for the MooDS-PGC GWAS and the two new risk loci for BD. ( a ) Manhattan plot for all analysed SNPs, ( b , c ) regional association plots for the SNPs analysed at ADCY2 (5p15.31) and MIR2113 - POU3F2 (6q16.1). Regional association plots were drawn using SNAP 54 and data for LD (red) and recombination frequency (blue line) from the 1000 Genomes Project. Full size image The MooDS-PGC GWAS revealed 56 SNPs reaching genome-wide significance at five genomic loci, three of which had been described before ( ANK3 , ODZ4<|im_end|> <|im_start|>assistant First on top of the world and then in the depths of despair – this is what the extreme mood changes for people with bipolar disorder are like. Under the direction of scientists from the University of Bonn Hospital, the Central Institute of Mental Health of Mannheim and the University of Basel Hospital, an international collaboration of researchers discovered two new gene regions which are connected with the prevalent disease. In addition, they were able to confirm three additional suspect genes. In this unparalleled worldwide study, the scientists are utilizing unprecedented numbers of patients. The results are now being published in the renowned journal Nature Communications. Throughout the course of their lives, about one percent of the population suffers from bipolar disorder, also known as manic-depressive disorder. The patients undergo a veritable rollercoaster of emotions: During extreme shifts, they experience manic phases with delusions of grandeur, increased drive and a decreased need for sleep as well as depressive episodes with a severely depressed mood to the point of suicidal thoughts. The causes of the disease are not yet fully understood, however in addition to psychosocial triggers, genetic factors play a large role. "There is no one gene that has a significant effect on the development of bipolar disorder," says Prof. Dr. Markus M. Nöthen, Director of the Institute of Human Genetics of the University of Bonn Hospital. "Many different genes are evidently involved and these genes work together with environmental factors in a complex way." Scale of the investigation is unparalleled worldwide In recent years, scientists at the Institute of Human Genetics were already involved in decoding several genes associated with bipolar disorder. The researchers working with Prof. Dr. Marcella Rietschel from the Central Institute of Mental Health of Mannheim, Prof. Dr. Markus M. Nöthen from the University of Bonn Hospital and Prof. Dr. Sven Cichon from the University of Basel Hospital are now using unprecedented numbers of patients in an international research collaboration: New genetic data from 2266 patients with manic-depressive disorder and 5028 control persons were obtained, merged with existing data sets and analyzed together. In total, data on the genetic material of 9747 patients were compared with data from 14,278 healthy persons. "The investigation of the genetic foundations of bipolar disorder on this scale is unique worldwide to date," says Prof. Rietschel from the Central Institute of Mental Health of Mannheim. The search for genes involved in manic-depressive disorder is like looking for a needle in a haystack. "The contributions of individual genes are so minor that they normally cannot be identified in the 'background noise' of genetic differences," explains Prof. Cichon from the University of Basel Hospital. Only when the DNA from very large numbers of patients with bipolar disorder are compared to the genetic material from an equally large number of healthy persons can differences be confirmed statistically. Such suspect regions which indicate a disease are known by scientists as candidate genes. Two new gene regions discovered and three known gene regions confirmed Using automated analysis methods, the researchers recorded about 2.3 million different regions in the genetic material of patients and comparators, respectively. The subsequent evaluation using biostatistical methods revealed a total of five risk regions on the DNA associated with bipolar disorder. Two of these regions were newly discovered: The gene "ADCY2" on chromosome five and the so-called "MIR2113-POU3F2" region on chromosome six. The risk regions "ANK3", "ODZ4" and "TRANK1" have already been described in prior studies. "These gene regions were, however, statistically better confirmed in our current investigation - the connection with bipolar disorder has now become even clearer," says Prof. Nöthen. The researchers are particularly interested in the newly discovered gene region "ADCY2". It codes an enzyme which is involved in the conduction of signals into nerve cells. "This fits very well with observations that the signal transfer in certain regions of the brain is impaired in patients with bipolar disorder," explains the human geneticist of the University of Bonn Hospital. With their search for genetic regions, the scientists are gradually clarifying the causes of manic-depressive disorder. "Only when we know the biological foundations of this disease can be also identify starting points for new therapies," says Prof. Nöthen. <|im_end|>

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1603, 13, 18591, 10229, 29060, 362, 2860, 315, 220, 17, 11, 16567, 11, 22184, 737, 19849, 18407, 21051, 505, 220, 24, 11, 23619, 6978, 323, 220, 975, 11, 16949, 11835, 320, 6771, 220, 16, 883, 5946, 1057, 70099, 4367, 2585, 320, 62142, 8, 323, 15360, 6492, 315, 47972, 53911, 18407, 21051, 574, 10887, 1701, 264, 8521, 75888, 8999, 56536, 320, 18337, 570, 6834, 83181, 1051, 539, 67458, 1606, 279, 4756, 393, 23710, 828, 656, 539, 6782, 279, 20081, 2038, 13, 2057, 49672, 4495, 369, 25544, 315, 393, 2819, 4245, 311, 29865, 12562, 315, 279, 83096, 6061, 323, 393, 23710, 10688, 11, 584, 24257, 279, 393, 2819, 315, 279, 83096, 6061, 9483, 23710, 6492, 320, 393, 23186, 883, 1701, 264, 51114, 49438, 8331, 369, 81064, 2585, 320, 23710, 705, 902, 574, 220, 16, 13, 16745, 320, 18337, 11, 23966, 13, 220, 16, 7609, 362, 393, 907, 7234, 9204, 459, 24131, 315, 279, 33869, 25480, 15360, 3135, 374, 3984, 304, 23966, 13, 220, 17, 64, 662, 6771, 220, 16, 69883, 37941, 292, 828, 369, 6978, 449, 65919, 19823, 323, 11835, 2768, 43707, 13, 8797, 1404, 2007, 19575, 220, 16, 25, 32541, 458, 4235, 31548, 458, 7234, 315, 279, 83096, 6061, 9483, 23710, 42353, 1950, 315, 40410, 13, 362, 10484, 458, 4235, 31548, 458, 320, 49126, 8, 7234, 19207, 279, 5133, 1990, 279, 9526, 750, 13468, 393, 2819, 320, 15651, 8183, 8, 311, 279, 3685, 393, 2819, 315, 264, 854, 8141, 320, 31729, 8183, 570, 578, 20366, 3158, 11105, 279, 220, 2721, 4, 20545, 7200, 13, 74215, 31794, 527, 17037, 1511, 369, 54243, 40134, 315, 279, 2515, 315, 264, 43707, 389, 42353, 1950, 828, 13, 578, 67822, 1584, 320, 15168, 8, 15151, 279, 12447, 369, 33869, 25480, 26431, 320, 393, 23186, 284, 20, 25800, 220, 605, 25173, 23, 7609, 5810, 584, 1501, 279, 2515, 315, 264, 5410, 4147, 49438, 8331, 369, 23186, 389, 279, 220, 17, 11, 16567, 11, 22184, 47972, 53911, 393, 2819, 505, 279, 8521, 75888, 8999, 56536, 320, 12481, 16029, 8, 304, 279, 1566, 3094, 315, 1057, 43707, 10537, 320, 18337, 570, 4740, 279, 3851, 11, 264, 37538, 28174, 315, 393, 2819, 320, 393, 23186, 1174, 3776, 16029, 8, 649, 387, 3970, 11, 23377, 430, 420, 43707, 3094, 5663, 11613, 459, 25544, 315, 393, 2819, 555, 29865, 6205, 12562, 304, 279, 83096, 6061, 323, 393, 23710, 828, 13, 8797, 1404, 2217, 19575, 220, 17, 25, 10229, 3135, 369, 279, 83096, 6061, 9483, 23710, 42353, 1950, 323, 279, 1403, 502, 5326, 1353, 72, 369, 40410, 13, 320, 264, 883, 29890, 7234, 369, 682, 67458, 18407, 21051, 11, 320, 293, 1174, 272, 883, 15481, 15360, 31794, 369, 279, 18407, 21051, 67458, 520, 22858, 56, 17, 320, 20, 79, 868, 13, 2148, 8, 323, 386, 2871, 11483, 18, 482, 393, 12188, 18, 37, 17, 320, 21, 80, 845, 13, 16, 570, 26361, 15360, 31794, 1051, 15107, 1701, 93633, 220, 4370, 323, 828, 369, 29977, 320, 1171, 8, 323, 312, 76128, 11900, 320, 12481, 1584, 8, 505, 279, 220, 1041, 15, 9500, 20969, 5907, 13, 8797, 1404, 2217, 578, 83096, 6061, 9483, 23710, 42353, 1950, 10675, 220, 3487, 18407, 21051, 19261, 33869, 25480, 26431, 520, 4330, 81064, 1353, 72, 11, 2380, 315, 902, 1047, 1027, 7633, 1603, 320, 2147, 42, 18, 1174, 53832, 57, 19, 128257, 198, 128256, 78191, 198, 5451, 389, 1948, 315, 279, 1917, 323, 1243, 304, 279, 43957, 315, 46996, 1389, 420, 374, 1148, 279, 14560, 20247, 4442, 369, 1274, 449, 65919, 19823, 527, 1093, 13, 9636, 279, 5216, 315, 14248, 505, 279, 3907, 315, 13789, 77, 15429, 11, 279, 10913, 10181, 315, 38895, 6401, 315, 30960, 21215, 323, 279, 3907, 315, 90558, 15429, 11, 459, 6625, 20632, 315, 12074, 11352, 1403, 502, 15207, 13918, 902, 527, 8599, 449, 279, 46941, 8624, 13, 763, 5369, 11, 814, 1051, 3025, 311, 7838, 2380, 5217, 15562, 21389, 13, 763, 420, 71257, 15603, 4007, 11, 279, 14248, 527, 35988, 31069, 5219, 315, 6978, 13, 578, 3135, 527, 1457, 1694, 4756, 304, 279, 37048, 8486, 22037, 26545, 13, 46982, 279, 3388, 315, 872, 6439, 11, 922, 832, 3346, 315, 279, 7187, 47521, 505, 65919, 19823, 11, 1101, 3967, 439, 70222, 6953, 69563, 19823, 13, 578, 6978, 37771, 264, 2807, 15729, 29551, 1030, 2352, 315, 21958, 25, 12220, 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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 Prior to European settlement, swamps, marshes, lakes, and streams were the major landscape features of the Chicago region. Much of this has been altered or lost in the past one-hundred-and-fifty years. We examined the changes in aquatic environments and fauna in Cook County, Illinois, using 1890–1910 and 1997–2017 as our focus intervals. The extents of aquatic features from historical topographic maps were imported into a GIS database and compared with the modern USGS National Hydrography Dataset. Historical and modern spatial data on aquatic animals were collected from museum collection and survey reports. Overall, the total area of wetlands and water bodies has decreased by about a third, while swamps and marshes have been drained or converted into lakes and ponds. Fifty-four of 80 historic molluscan species are not recently recorded, and 26 current species are not recorded in the historical data, including 6 considered to be invasive. Of 54 fish species in the historic data, 23 are no longer present and about 50% of the remaining species have undergone range reductions. Three out of 10 species of reptiles have disappeared. All 25 aquatic birds reported from the 1890–1910 period are still extant and an additional 13 have been reported in recent times, possibly due to increased collection effort. The Chicago region provides a case study of the impact of anthropogenic landscape change on biota. Large scale extirpations of native species have corresponded to a shift to a highly fragmented landscape of small ponds and reduced swamps and marshes. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction A major cause of landscape change in the Midwestern United States over the last 150 years has been the loss of wetlands due primarily to draining and filling, as well as river channelization. Wetlands are areas with water at or near the soil surface for varying periods of the year, with habitats including marshes, bogs and fens, and the boundary regions of streams, rivers, and lakes. These habitats are critical to the environment because they can regulate processes such as pollutant removal, groundwater recharge and discharge, basin connectivity, and nutrient cycling (Jackson and Pringle 2010 ; Montgomery and Eames 2008 ; Wright et al. 2006 ), as well as host diverse ecologies (Lehikoinen et al. 2016 ; Quesnelle et al. 2015 ). Between 1780 and 1980, 53% of wetlands were lost in the United States and 85% of wetlands were lost in Illinois (Adelmann 1998 ; Dahl 1990 ; Roadcap et al. 2005 ) coincident with a global reduction in freshwater ecosystem biodiversity (Dudgeon et al. 2006 ). Concerns with the decrease led to the 1989 adoption by the United States of a “no net loss” policy concerning wetlands, meaning that an equal amount of wetland ecospace must be established in a different location for every amount that is destroyed. This policy resulted in wetlands being shifted 10’s to 100’s of kilometers to underdeveloped areas leading to declines in biodiversity (Robertson 2004 ; Robertson 2006 ; BenDor et al. 2007 ; BenDor 2009 ; BenDor et al. 2009 ; Ward et al. 2010 ; BenDor and Riggsbee 2011 ). In the Chicago Wilderness Region, which includes the city of Chicago, IL, and roughly 7 million surrounding acres including portions of Illinois, Wisconsin, Indiana, and Michigan (Brant et al. 2017 ), massive losses of wetlands have occurred as a result of urbanization (Sullivan 1997 ; Robertson 2004 ; Robertson 2006 ; BenDor et al. 2007 ; BenDor 2009 ; Ward et al. 2010 ). These include the total loss of the marshes surrounding the Kankakee River (Clark and Slusher 2000 ) and the extensive loss of the wetlands of the Calumet region (Greenberg 2002 ). These losses have been accompanied by major shifts in the hydrology of the river systems, most notably the 1900 opening of the Chicago Sanitary and Ship Canal. The Sanitary and Ship canal, along with locks built at the mouth of the Chicago River at Lake Michigan, had the effect of reversing the flow of the Chicago River so that wastewater no longer flowed into the lake (Hill 2000 ). At the same time, the development of the Calumet Sag Channel also led to the reversal of the Little Calumet River toward the Mississippi (Schoon 2003 ). Since the reversal of the Chicago and Little Calumet Rivers, many of the rivers and lakes in the region have been further altered through development. Much of the Grand Calumet, Little Calumet, and Kankakee Rivers have been engineered to flow through straightened channels (Schoon, 2003 ). The Chicago River has also been engineered, with areas such as parts of Bubbly Creek (South Fork of the South Branch of the Chicago River) filled in due to severe pollution caused by the Union Stockyards in the 20th Century (Hill, 2000 ). Furthermore, Lake Calumet (connected to the Grand Calumet River) has been significantly reduced in size and degraded from industrial pollution, landfill, river flow reversal, and use as the Port of Chicago (Schoon, 2003 ). The urbanization of the Chicago region has led to reductions in the amount of total wetland area and quality over time. These reductions have had a major impact on the biodiversity of wetland ecosystems within the Chicago region (Sullivan 1997 ; Greenberg 2002 ). Although there have been many broad analyses on wetlands in Chicago and Cook County, IL, including analysis of modern changes in wetland faunal biodiversity (Ward et al. 2010 ), effects of urbanization on wetland plant biodiversity (Matthews et al. 2009 ; Skultety and Matthews 2017 ), modern changes in land use (Wang and Moskovits 2001 ), and modern policy effects on wetlands (Robertson 2004 ; Roberston 2006; BenDor et al. 2007 ; Robertson and Hayden 2008 ; BenDor 2009 ), no analysis has characterized long-term wetland faunal biodiversity and coincident long-term changes in wetland area for Cook County, IL. Here, we use historical topographic maps and Geographic Information Systems (GIS) to quantitatively assess changes", "role": "user" }, { "content": "Prior to European settlement, wetlands, lakes and streams were the major landscape features of the Chicago region. Much of this has been altered or lost in the past 150 years, most notably by the reversal of the Chicago River in 1900 with the construction of the Sanitary and Ship Canal. Many animal species that lived in these habitats also disappeared. Now, a group of graduate students at the University of Illinois at Chicago have quantified over a century of these changes in detail. In a paper published in the journal Urban Ecosystems, students from the departments of earth and environmental sciences and biological sciences have measured both the extent of wetland loss in Cook County since the time of the river reversal and the alterations in the animal populations. The paper, which is the result of a class project for the course \"Extinctions: Modern and Ancient,\" compares the changes in aquatic environments and fauna in Cook County during two intervals: 1890-1910 and 1997-2017. \"The areas of aquatic features from historical topographic maps were imported into a GIS database and compared with the modern United States Geological Survey's National Hydrography Dataset,\" said Joey Pasterski, UIC Ph.D. student in earth and environmental sciences and first author of the paper. \"It demonstrates the utility of digitized museum collections for long term studies, and it provides further evidence of the uneven impact of urban development on native faunal communities, here specifically in Cook County.\" Digitized maps of the region circa 1900 were used to estimate the area and distribution of wetlands and lakes for comparison with current patterns. According to the researchers, the area of wetlands has decreased by more than 80%, with many of these being drained or converted into small and relatively isolated lakes and ponds. The remaining wetlands are also small and fragmented. Museum records and natural history surveys from sources such as the Field Museum and the Chicago Academy of Sciences allowed them to reconstruct the historic existence of species in the wetlands and lakes for comparison with modern data. The researchers found that 23 species of fish, 54 species of clams and snails, and three species of reptiles have disappeared locally. There also are many new invasive species. All 25 aquatic birds reported from the 1890-1910 period still exist and an additional 13 have been reported in recent times. Increased observations by birders are cited as the potential factor for the number of new bird species recorded. The students hope the study can help inform the direction of future research aimed at restoring the health of aquatic ecosystems within Cook County and elsewhere. \"This could spawn a series of similar studies to help improve the accuracy of our understanding of the long-term effects of urbanization on native communities across the world in varying climates, environments, and urban systems, with the expressed goal of improving the health of urban ecosystems,\" Pasterski said. The Chicago region provides a case study of the impact of human landscape change on regional animal and plant life, notes Roy Plotnick, UIC professor of earth and environmental sciences. \"We err in thinking global change is just global warming. On all scales, humans have profoundly changed their environment,\" said Plotnick, who supervised the study and is senior author of the paper. ", "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 Prior to European settlement, swamps, marshes, lakes, and streams were the major landscape features of the Chicago region. Much of this has been altered or lost in the past one-hundred-and-fifty years. We examined the changes in aquatic environments and fauna in Cook County, Illinois, using 1890–1910 and 1997–2017 as our focus intervals. The extents of aquatic features from historical topographic maps were imported into a GIS database and compared with the modern USGS National Hydrography Dataset. Historical and modern spatial data on aquatic animals were collected from museum collection and survey reports. Overall, the total area of wetlands and water bodies has decreased by about a third, while swamps and marshes have been drained or converted into lakes and ponds. Fifty-four of 80 historic molluscan species are not recently recorded, and 26 current species are not recorded in the historical data, including 6 considered to be invasive. Of 54 fish species in the historic data, 23 are no longer present and about 50% of the remaining species have undergone range reductions. Three out of 10 species of reptiles have disappeared. All 25 aquatic birds reported from the 1890–1910 period are still extant and an additional 13 have been reported in recent times, possibly due to increased collection effort. The Chicago region provides a case study of the impact of anthropogenic landscape change on biota. Large scale extirpations of native species have corresponded to a shift to a highly fragmented landscape of small ponds and reduced swamps and marshes. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction A major cause of landscape change in the Midwestern United States over the last 150 years has been the loss of wetlands due primarily to draining and filling, as well as river channelization. Wetlands are areas with water at or near the soil surface for varying periods of the year, with habitats including marshes, bogs and fens, and the boundary regions of streams, rivers, and lakes. These habitats are critical to the environment because they can regulate processes such as pollutant removal, groundwater recharge and discharge, basin connectivity, and nutrient cycling (Jackson and Pringle 2010 ; Montgomery and Eames 2008 ; Wright et al. 2006 ), as well as host diverse ecologies (Lehikoinen et al. 2016 ; Quesnelle et al. 2015 ). Between 1780 and 1980, 53% of wetlands were lost in the United States and 85% of wetlands were lost in Illinois (Adelmann 1998 ; Dahl 1990 ; Roadcap et al. 2005 ) coincident with a global reduction in freshwater ecosystem biodiversity (Dudgeon et al. 2006 ). Concerns with the decrease led to the 1989 adoption by the United States of a “no net loss” policy concerning wetlands, meaning that an equal amount of wetland ecospace must be established in a different location for every amount that is destroyed. This policy resulted in wetlands being shifted 10’s to 100’s of kilometers to underdeveloped areas leading to declines in biodiversity (Robertson 2004 ; Robertson 2006 ; BenDor et al. 2007 ; BenDor 2009 ; BenDor et al. 2009 ; Ward et al. 2010 ; BenDor and Riggsbee 2011 ). In the Chicago Wilderness Region, which includes the city of Chicago, IL, and roughly 7 million surrounding acres including portions of Illinois, Wisconsin, Indiana, and Michigan (Brant et al. 2017 ), massive losses of wetlands have occurred as a result of urbanization (Sullivan 1997 ; Robertson 2004 ; Robertson 2006 ; BenDor et al. 2007 ; BenDor 2009 ; Ward et al. 2010 ). These include the total loss of the marshes surrounding the Kankakee River (Clark and Slusher 2000 ) and the extensive loss of the wetlands of the Calumet region (Greenberg 2002 ). These losses have been accompanied by major shifts in the hydrology of the river systems, most notably the 1900 opening of the Chicago Sanitary and Ship Canal. The Sanitary and Ship canal, along with locks built at the mouth of the Chicago River at Lake Michigan, had the effect of reversing the flow of the Chicago River so that wastewater no longer flowed into the lake (Hill 2000 ). At the same time, the development of the Calumet Sag Channel also led to the reversal of the Little Calumet River toward the Mississippi (Schoon 2003 ). Since the reversal of the Chicago and Little Calumet Rivers, many of the rivers and lakes in the region have been further altered through development. Much of the Grand Calumet, Little Calumet, and Kankakee Rivers have been engineered to flow through straightened channels (Schoon, 2003 ). The Chicago River has also been engineered, with areas such as parts of Bubbly Creek (South Fork of the South Branch of the Chicago River) filled in due to severe pollution caused by the Union Stockyards in the 20th Century (Hill, 2000 ). Furthermore, Lake Calumet (connected to the Grand Calumet River) has been significantly reduced in size and degraded from industrial pollution, landfill, river flow reversal, and use as the Port of Chicago (Schoon, 2003 ). The urbanization of the Chicago region has led to reductions in the amount of total wetland area and quality over time. These reductions have had a major impact on the biodiversity of wetland ecosystems within the Chicago region (Sullivan 1997 ; Greenberg 2002 ). Although there have been many broad analyses on wetlands in Chicago and Cook County, IL, including analysis of modern changes in wetland faunal biodiversity (Ward et al. 2010 ), effects of urbanization on wetland plant biodiversity (Matthews et al. 2009 ; Skultety and Matthews 2017 ), modern changes in land use (Wang and Moskovits 2001 ), and modern policy effects on wetlands (Robertson 2004 ; Roberston 2006; BenDor et al. 2007 ; Robertson and Hayden 2008 ; BenDor 2009 ), no analysis has characterized long-term wetland faunal biodiversity and coincident long-term changes in wetland area for Cook County, IL. Here, we use historical topographic maps and Geographic Information Systems (GIS) to quantitatively assess changes<|im_end|> <|im_start|>assistant Prior to European settlement, wetlands, lakes and streams were the major landscape features of the Chicago region. Much of this has been altered or lost in the past 150 years, most notably by the reversal of the Chicago River in 1900 with the construction of the Sanitary and Ship Canal. Many animal species that lived in these habitats also disappeared. Now, a group of graduate students at the University of Illinois at Chicago have quantified over a century of these changes in detail. In a paper published in the journal Urban Ecosystems, students from the departments of earth and environmental sciences and biological sciences have measured both the extent of wetland loss in Cook County since the time of the river reversal and the alterations in the animal populations. The paper, which is the result of a class project for the course "Extinctions: Modern and Ancient," compares the changes in aquatic environments and fauna in Cook County during two intervals: 1890-1910 and 1997-2017. "The areas of aquatic features from historical topographic maps were imported into a GIS database and compared with the modern United States Geological Survey's National Hydrography Dataset," said Joey Pasterski, UIC Ph.D. student in earth and environmental sciences and first author of the paper. "It demonstrates the utility of digitized museum collections for long term studies, and it provides further evidence of the uneven impact of urban development on native faunal communities, here specifically in Cook County." Digitized maps of the region circa 1900 were used to estimate the area and distribution of wetlands and lakes for comparison with current patterns. According to the researchers, the area of wetlands has decreased by more than 80%, with many of these being drained or converted into small and relatively isolated lakes and ponds. The remaining wetlands are also small and fragmented. Museum records and natural history surveys from sources such as the Field Museum and the Chicago Academy of Sciences allowed them to reconstruct the historic existence of species in the wetlands and lakes for comparison with modern data. The researchers found that 23 species of fish, 54 species of clams and snails, and three species of reptiles have disappeared locally. There also are many new invasive species. All 25 aquatic birds reported from the 1890-1910 period still exist and an additional 13 have been reported in recent times. Increased observations by birders are cited as the potential factor for the number of new bird species recorded. The students hope the study can help inform the direction of future research aimed at restoring the health of aquatic ecosystems within Cook County and elsewhere. "This could spawn a series of similar studies to help improve the accuracy of our understanding of the long-term effects of urbanization on native communities across the world in varying climates, environments, and urban systems, with the expressed goal of improving the health of urban ecosystems," Pasterski said. The Chicago region provides a case study of the impact of human landscape change on regional animal and plant life, notes Roy Plotnick, UIC professor of earth and environmental sciences. "We err in thinking global change is just global warming. On all scales, humans have profoundly changed their environment," said Plotnick, who supervised the study and is senior author of the paper. <|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 Explosive percolation is an experimentally-elusive phenomenon where network connectivity coincides with onset of an additional modification of the system; materials with correlated localisation of percolating particles and emergent conductive paths can realise sharp transitions and high conductivities characteristic of the explosively-grown network. Nanocomposites present a structurally- and chemically-varied playground to realise explosive percolation in practically-applicable systems but this is yet to be exploited by design. Herein, we demonstrate composites of graphene oxide and synthetic polymer latex which form segregated networks, leading to low percolation threshold and localisation of conductive pathways. In situ reduction of the graphene oxide at temperatures of <150 °C drives chemical modification of the polymer matrix to produce species with phenolic groups, which are known crosslinking agents. This leads to conductivities exceeding those of dense-packed networks of reduced graphene oxide, illustrating the potential of explosive percolation by design to realise low-loading composites with dramatically-enhanced electrical transport properties. Introduction The segregated network approach is a technically-simple way of using hierarchical assembly to produce functional micro- and nano-structures with low filler loadings, by comparison to isotropic random mixtures. Segregated networks may be formed using colloidal dispersions of filler and matrix particles 1 , such as polymer latex and nanosheets of graphene or other nanomaterials (with applications in coatings), or other colloidal particles such as those of silicon, with carbon nanotubes forming the filler in state-of-the-art battery electrodes 2 . The excluded volume created by the matrix particles during drying confines the filler particles to the interstitial space, where the excluded volume can be modified by tailoring the particle size distribution 3 . This method is an increasingly common way to produce nanocomposites 4 as it gives control of the structure at the nanoscale. The networks of conductive particles formed during the preparation of segregated networks often display properties consistent with percolation theory. Percolation theory describes the non-linear scaling of transport properties with loading level in statistically-filled systems due to the random nature of particle-particle connections. A universal scaling relation for electrical conductivity σ according to percolation theory relates a parameter describing the conductivity of the filler network σ 0 , the loading level ϕ , the percolation threshold loading ϕ c and scaling exponent μ by 5 : $$\\sigma={\\sigma }_{0}{\\left(\\phi -{\\phi }_{c}\\right)}^{\\mu }$$ It is well understood that systems wherein the filler is distributed randomly have a scaling exponent which is dictated only by the dimensionality of the domain upon which the particles are distributed— μ ≈ 1.33 in 2D systems, such as thin coatings, and μ = 2 in 3D systems, such as bulk composites. Many experimental reports of nanocomposites fall within these two limits 6 . Deviations from the universal values are associated with changes to the distribution of conductances within the system 5 , as well as changes to the spatial distribution of the particles. In the former case, broadening of the inter-particle contact resistance distribution (for example) leads to a monotonic increase in μ above the universal value; 5 exponents more than double the expected value 7 , and even as high as 11.9 8 , have been reported for experimental systems. In the latter case, where the spatial distribution of particles in the system displays strong local correlations, a reduction in μ below the universal value may be obtained. In this case, the addition of new particles leads to aggregation with existing particles, leading to the growth of dense conductive clusters. Once the percolation threshold is reached, a dense system-spanning conductive network is formed with high conductivity, that increases only marginally with the presence of additional particles (corresponding to a low value of 0 < μ < 1). This has been described as explosive percolation in theoretical studies 9 , and is characterised by a relatively high percolation threshold (delayed conductivity onset) and a low critical exponent, when compared to isotropic percolative systems 9 . Latices have been increasingly well studied for the formation of composites that are variously transparent, flexible, and conductive using metal powder 10 , 11 or carbon black 12 as fillers. In addition to manipulation of the nanostructure, latex-based systems have the added benefit that no volatile organic components (VOCs) are released during film formation. Indeed, such nanocomposite systems have been used as platforms for investigating the predictions of percolation theory in an experimental space. The influence of latex size distribution, and aspect ratio and size distributions of the nanomaterial fillers 5 on properties such as the percolation threshold have been examined by previous work, including that of Grunlan and co-workers 13 in 2001 with carbon black, and more recently by Jurewicz et al. using carbon nanotubes 14 and graphene nanosheets 15 , 16 . Graphene oxide (GO), a chemically-modified graphene derivative, can be readily exfoliated to produce laterally-large monolayer sheets with a high aspect ratio. GO has the additional benefits of commercial availability at a large scale, low cost, and may be processed entirely in water, making it highly compatible with a latex-based composite approach. However, GO requires thermal and/or chemical reduction to realise appreciable electrical conductivity 17 . It is well-documented in the literature for individual flakes, as well as films and membranes, that temperatures greater than 300 °C, and often in excess of 700 °C, are usually required to achieve a sufficiently high degree of reduction for conductive percolating networks of rGO to form 18 , 19 , 20 , 21 . The studies cited, as well as many others, demonstrate that reduction at lower temperatures causes only partial removal of oxygen functionalities, accompanied by the formation of topological defects which require annealing for a high-quality sp 2 structure to be obtained. We note, however, that the reduction of GO is a partially-exothermic process. This is since the decomposition of epoxy basal plane functionalities, which are metastable, releases significant heat. As such, there is potential for the reduction of GO to be used as a platform for in situ chemistry, even at the relatively low temperature of ~200 °C which causes decomposition of epoxy functionalities 22", "role": "user" }, { "content": "In new research published in Nature Communications, University of Sussex scientists demonstrate how a highly conductive paint coating that they have developed mimics the network spread of a virus through a process called 'explosive percolation'—a mathematical process which can also be applied to population growth, financial systems and computer networks, but which has not been seen before in materials systems. The finding was a serendipitous development as well as a scientific first for the researchers. The process of percolation—the statistical connectivity in a system, such as when water flows through soil or through coffee grounds—is an important component in the development of liquid technology. And it was that process which researchers in the University of Sussex Material Physics group were expecting to see when they added graphene oxide to polymer latex spheres, such as those used in emulsion paint, to make a polymer composite. But when they gently heated the graphene oxide to make it electrically conductive, the scientists kick-started a process that saw this conductive system grow exponentially, to the extent that the new material created consumed the network, similar to the way a new strain of a virus can become dominant. This emergent material behavior led to a new highly-conductive paint solution that, because graphene oxide is a cheap and easy to mass produce nanomaterial, is both one of the most affordable and most conductive low-loading composites reported. Before, now, it was accepted that such paints or coatings were necessarily one or the other. Electrically conductive paints and inks have a range of useful applications in new printed technologies, for example by imparting coatings with properties such as anti-static or making coatings that block electromagnetic interference (EMI), as well as being vital in the development of wearable health monitors. Alan Dalton, Professor of Experimental Physics, who heads up the Materials Physics Group at the University of Sussex explains the potential of this serendipitous finding: \"My research team and I have been working on developing conductive paints and inks for the last ten years and it was to both my surprise and delight that we have discovered the key to revolutionizing this work is a mathematical process that we normally associate with population growth and virus transmission.\" \"By enabling us to create highly-conductive polymer composites that are also affordable, thanks to the cheap and scalable nature of graphene oxide, this development opens up the doors to a range of applications that we've not even been able to fully consider yet, but which could greatly enhance the sustainability of Electric Vehicle materials—including batteries—as well as having the potential to add conductive coatings to materials, such as ceramics, that aren't inherently so. We can't wait to get going on exploring the possibilities.\" Dr. Sean Ogilvie, a research fellow in Professor Dalton's Materials Physics Group at the University of Sussex, who worked on this development adds, \"The most exciting aspect of these nanocomposites is that we are using a very simple process, similar to applying emulsion paint and drying with a heat gun, which then kickstarts a process creating chemical bridges between the graphene sheets, producing electrical paths which are more conductive than if they were made entirely from graphene.\" \"The growth of this network is analogous to the emergence of high-transmission viral variants and could allow us to use epidemic modeling to develop exciting new materials or even materials to understand epidemic transmission.\" About the experiment The scientists took polymer latex spheres and added graphene oxide. Through drying this solution, as you would dry paint, the graphene oxide becomes trapped between the spheres and as more graphene is added, the sheets eventually form a 'percolating' network within the latex film. However, because graphene oxide isn't electrically conductive, the scientists performed some mild heating to eliminate chemical defects (150 C, similar to the temperature of a heat gun used to dry paint). When they did this, they found that the films not only become conductive—as expected—but became more conductive than if they were made entirely from the graphene. The reason for this is that the sheets are trapped together between the latex spheres (rather than randomly arranged), the mild heating kick-starts chemical modification of the graphene which in turn chemically modifies the polymer to produce small molecules which crosslink (form chemical bridges between) the sheets which dramatically increases their conductivity. This phenomenon where, only at the point of percolation, the materials go through a 'phase transition' to form a completely different network than if they weren't connected is known as 'explosive percolation.' It can be thought of reaching a critical level of connectivity where the new material grows explosively through the network. The full paper 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 Explosive percolation is an experimentally-elusive phenomenon where network connectivity coincides with onset of an additional modification of the system; materials with correlated localisation of percolating particles and emergent conductive paths can realise sharp transitions and high conductivities characteristic of the explosively-grown network. Nanocomposites present a structurally- and chemically-varied playground to realise explosive percolation in practically-applicable systems but this is yet to be exploited by design. Herein, we demonstrate composites of graphene oxide and synthetic polymer latex which form segregated networks, leading to low percolation threshold and localisation of conductive pathways. In situ reduction of the graphene oxide at temperatures of <150 °C drives chemical modification of the polymer matrix to produce species with phenolic groups, which are known crosslinking agents. This leads to conductivities exceeding those of dense-packed networks of reduced graphene oxide, illustrating the potential of explosive percolation by design to realise low-loading composites with dramatically-enhanced electrical transport properties. Introduction The segregated network approach is a technically-simple way of using hierarchical assembly to produce functional micro- and nano-structures with low filler loadings, by comparison to isotropic random mixtures. Segregated networks may be formed using colloidal dispersions of filler and matrix particles 1 , such as polymer latex and nanosheets of graphene or other nanomaterials (with applications in coatings), or other colloidal particles such as those of silicon, with carbon nanotubes forming the filler in state-of-the-art battery electrodes 2 . The excluded volume created by the matrix particles during drying confines the filler particles to the interstitial space, where the excluded volume can be modified by tailoring the particle size distribution 3 . This method is an increasingly common way to produce nanocomposites 4 as it gives control of the structure at the nanoscale. The networks of conductive particles formed during the preparation of segregated networks often display properties consistent with percolation theory. Percolation theory describes the non-linear scaling of transport properties with loading level in statistically-filled systems due to the random nature of particle-particle connections. A universal scaling relation for electrical conductivity σ according to percolation theory relates a parameter describing the conductivity of the filler network σ 0 , the loading level ϕ , the percolation threshold loading ϕ c and scaling exponent μ by 5 : $$\sigma={\sigma }_{0}{\left(\phi -{\phi }_{c}\right)}^{\mu }$$ It is well understood that systems wherein the filler is distributed randomly have a scaling exponent which is dictated only by the dimensionality of the domain upon which the particles are distributed— μ ≈ 1.33 in 2D systems, such as thin coatings, and μ = 2 in 3D systems, such as bulk composites. Many experimental reports of nanocomposites fall within these two limits 6 . Deviations from the universal values are associated with changes to the distribution of conductances within the system 5 , as well as changes to the spatial distribution of the particles. In the former case, broadening of the inter-particle contact resistance distribution (for example) leads to a monotonic increase in μ above the universal value; 5 exponents more than double the expected value 7 , and even as high as 11.9 8 , have been reported for experimental systems. In the latter case, where the spatial distribution of particles in the system displays strong local correlations, a reduction in μ below the universal value may be obtained. In this case, the addition of new particles leads to aggregation with existing particles, leading to the growth of dense conductive clusters. Once the percolation threshold is reached, a dense system-spanning conductive network is formed with high conductivity, that increases only marginally with the presence of additional particles (corresponding to a low value of 0 < μ < 1). This has been described as explosive percolation in theoretical studies 9 , and is characterised by a relatively high percolation threshold (delayed conductivity onset) and a low critical exponent, when compared to isotropic percolative systems 9 . Latices have been increasingly well studied for the formation of composites that are variously transparent, flexible, and conductive using metal powder 10 , 11 or carbon black 12 as fillers. In addition to manipulation of the nanostructure, latex-based systems have the added benefit that no volatile organic components (VOCs) are released during film formation. Indeed, such nanocomposite systems have been used as platforms for investigating the predictions of percolation theory in an experimental space. The influence of latex size distribution, and aspect ratio and size distributions of the nanomaterial fillers 5 on properties such as the percolation threshold have been examined by previous work, including that of Grunlan and co-workers 13 in 2001 with carbon black, and more recently by Jurewicz et al. using carbon nanotubes 14 and graphene nanosheets 15 , 16 . Graphene oxide (GO), a chemically-modified graphene derivative, can be readily exfoliated to produce laterally-large monolayer sheets with a high aspect ratio. GO has the additional benefits of commercial availability at a large scale, low cost, and may be processed entirely in water, making it highly compatible with a latex-based composite approach. However, GO requires thermal and/or chemical reduction to realise appreciable electrical conductivity 17 . It is well-documented in the literature for individual flakes, as well as films and membranes, that temperatures greater than 300 °C, and often in excess of 700 °C, are usually required to achieve a sufficiently high degree of reduction for conductive percolating networks of rGO to form 18 , 19 , 20 , 21 . The studies cited, as well as many others, demonstrate that reduction at lower temperatures causes only partial removal of oxygen functionalities, accompanied by the formation of topological defects which require annealing for a high-quality sp 2 structure to be obtained. We note, however, that the reduction of GO is a partially-exothermic process. This is since the decomposition of epoxy basal plane functionalities, which are metastable, releases significant heat. As such, there is potential for the reduction of GO to be used as a platform for in situ chemistry, even at the relatively low temperature of ~200 °C which causes decomposition of epoxy functionalities 22<|im_end|> <|im_start|>assistant In new research published in Nature Communications, University of Sussex scientists demonstrate how a highly conductive paint coating that they have developed mimics the network spread of a virus through a process called 'explosive percolation'—a mathematical process which can also be applied to population growth, financial systems and computer networks, but which has not been seen before in materials systems. The finding was a serendipitous development as well as a scientific first for the researchers. The process of percolation—the statistical connectivity in a system, such as when water flows through soil or through coffee grounds—is an important component in the development of liquid technology. And it was that process which researchers in the University of Sussex Material Physics group were expecting to see when they added graphene oxide to polymer latex spheres, such as those used in emulsion paint, to make a polymer composite. But when they gently heated the graphene oxide to make it electrically conductive, the scientists kick-started a process that saw this conductive system grow exponentially, to the extent that the new material created consumed the network, similar to the way a new strain of a virus can become dominant. This emergent material behavior led to a new highly-conductive paint solution that, because graphene oxide is a cheap and easy to mass produce nanomaterial, is both one of the most affordable and most conductive low-loading composites reported. Before, now, it was accepted that such paints or coatings were necessarily one or the other. Electrically conductive paints and inks have a range of useful applications in new printed technologies, for example by imparting coatings with properties such as anti-static or making coatings that block electromagnetic interference (EMI), as well as being vital in the development of wearable health monitors. Alan Dalton, Professor of Experimental Physics, who heads up the Materials Physics Group at the University of Sussex explains the potential of this serendipitous finding: "My research team and I have been working on developing conductive paints and inks for the last ten years and it was to both my surprise and delight that we have discovered the key to revolutionizing this work is a mathematical process that we normally associate with population growth and virus transmission." "By enabling us to create highly-conductive polymer composites that are also affordable, thanks to the cheap and scalable nature of graphene oxide, this development opens up the doors to a range of applications that we've not even been able to fully consider yet, but which could greatly enhance the sustainability of Electric Vehicle materials—including batteries—as well as having the potential to add conductive coatings to materials, such as ceramics, that aren't inherently so. We can't wait to get going on exploring the possibilities." Dr. Sean Ogilvie, a research fellow in Professor Dalton's Materials Physics Group at the University of Sussex, who worked on this development adds, "The most exciting aspect of these nanocomposites is that we are using a very simple process, similar to applying emulsion paint and drying with a heat gun, which then kickstarts a process creating chemical bridges between the graphene sheets, producing electrical paths which are more conductive than if they were made entirely from graphene." "The growth of this network is analogous to the emergence of high-transmission viral variants and could allow us to use epidemic modeling to develop exciting new materials or even materials to understand epidemic transmission." About the experiment The scientists took polymer latex spheres and added graphene oxide. Through drying this solution, as you would dry paint, the graphene oxide becomes trapped between the spheres and as more graphene is added, the sheets eventually form a 'percolating' network within the latex film. However, because graphene oxide isn't electrically conductive, the scientists performed some mild heating to eliminate chemical defects (150 C, similar to the temperature of a heat gun used to dry paint). When they did this, they found that the films not only become conductive—as expected—but became more conductive than if they were made entirely from the graphene. The reason for this is that the sheets are trapped together between the latex spheres (rather than randomly arranged), the mild heating kick-starts chemical modification of the graphene which in turn chemically modifies the polymer to produce small molecules which crosslink (form chemical bridges between) the sheets which dramatically increases their conductivity. This phenomenon where, only at the point of percolation, the materials go through a 'phase transition' to form a completely different network than if they weren't connected is known as 'explosive percolation.' It can be thought of reaching a critical level of connectivity where the new material grows explosively through the network. The full paper is published in 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 Cilial pumping is a powerful strategy used by biological organisms to control and manipulate fluids at the microscale. However, despite numerous recent advances in optically, magnetically and electrically driven actuation, development of an engineered cilial platform with the potential for applications has remained difficult to realize 1 , 2 , 3 , 4 , 5 , 6 . Here we report on active metasurfaces of electronically actuated artificial cilia that can create arbitrary flow patterns in liquids near a surface. We first create voltage-actuated cilia that generate non-reciprocal motions to drive surface flows at tens of microns per second at actuation voltages of 1 volt. We then show that a cilia unit cell can locally create a range of elemental flow geometries. By combining these unit cells, we create an active cilia metasurface that can generate and switch between any desired surface flow pattern. Finally, we integrate the cilia with a light-powered complementary metal–oxide–semiconductor (CMOS) clock circuit to demonstrate wireless operation. As a proof of concept, we use this circuit to output voltage pulses with various phase delays to demonstrate improved pumping efficiency using metachronal waves. These powerful results, demonstrated experimentally and confirmed using theoretical computations, illustrate a pathway towards fine-scale microfluidic manipulation, with applications from microfluidic pumping to microrobotic locomotion. Main Ciliary pumping is one of the most important and ubiquitous fluidic transport methods in the microscopic world 7 , 8 , 9 , 10 , 11 , 12 , 13 ; however, it is challenging to engineer artificial cilia platforms that can be widely adopted 2 , 14 . Several pioneering studies have demonstrated methods for fabricating artificial cilia with actuation based on pressure 15 , light 16 , 17 , electrostatic 18 and magnetic 19 , 20 interactions; however, these systems have severe limitations. For example, cilia that are pressure-driven or optically driven can be locally actuated. These systems have, however, been challenging to implement at the microscale 6 , 15 . Moreover, there is no clear pathway for integrating them with mobile micromachines while retaining local actuation 21 . Electrostatically actuated cilia has been shown as a powerful method for rapid pumping and mixing 18 . The actuators demonstrated thus far are, however, driven by large voltages. This large voltage makes them incompatible with complementary metal–oxide–semiconductor (CMOS) electronics for untethered control. In addition, they cannot be operated in aqueous solutions, owing to hydrolysis at voltages above approximately 1.2 V. Finally, there has been much excitement about making artificial cilia out of magnetically responsive materials. Various groups have demonstrated pumping 5 , metachronal waves 4 , 22 , 23 and mixing 24 . In such magnetic systems, however, it is difficult to localize the actuation or change the magnetization of the cilia in situ to reconfigure the flows. Thus, to obtain wide adoption for this transport method in engineered systems, there remains a critical need for development of novel artificial cilia platforms. Here we show that recently developed surface electrochemical actuators 25 , 26 can be used to overcome many of these challenges. Each artificial cilium consists of a lithographically fabricated strip that is approximately 50 μm long, 5 μm wide and only about 10 nm thin, attached to the substrate at one end, as shown in Fig. 1a . The strip comprises a 7-nm-thick platinum (Pt) thin film capped on one side by a passive layer of titanium (Ti) (Fig. 1a , left; see Methods and Extended Data Fig. 1 for the fabrication process). Actuation of the artificial cilium in phosphate-buffered saline (PBS; 1×, pH 7.45) is induced by raising its potential to about 1 V relative to the Ag/AgCl reference electrode, triggering electrochemical oxidation of the exposed Pt surface while avoiding bubble formation. The oxidation expands the Pt surface 26 and causes the actuator to bend (Fig. 1a , red reaction pathway, left → right). Applying a voltage of approximately −0.2 V reduces the Pt film, which returns the actuator to its initial state (Fig. 1a , blue reaction pathway, right → left). The current density is approximately 1 mA cm −2 (Extended Data Fig. 2 ), which means that a 1 cm × 1 cm device fully covered by artificial cilia would only consume about 1 mW of power at a sweep rate of 1 V s −1 . To prevent twisting of the actuator we pattern three horizontal polymer pads spaced at 15-μm intervals along each cilium. Because surface electrochemical actuators can be lithographically fabricated, millions could be fabricated on one 4-inch wafer; the actuation of cilia arrays with 80 cilia is shown in Supplementary Video 1 . We show a scanning electron microscope (SEM) image of a small region of the released cilia in Fig. 1b . Each cilia array is connected through a busbar that enables independent actuation. In the bottom-right inset of Fig. 1b , we show an annular dark-field scanning transmission electron microscope (STEM) image of a fabricated cilium cross-section. This ciliary platform enables an advantageous combination of features including local electrical actuation, operation in aqueous solutions, and compatibility with CMOS electronics to generate complex switchable microfluidic manipulations. Fig. 1: Artificial cilia based on surface electrochemical actuators. a , Each cilium consists of a thin surface electrochemical actuator made of a platinum strip capped on one side by a titanium film 25 , 26 . b , SEM image of released artificial cilia arrays with each row connected by a single busbar. A STEM image of a cilium cross-section showing the platinum (white) and titanium (black) is presented in the bottom-right inset. c , Experimental results for pumping velocity versus frequency for a single cilia array such as the one shown in the top-left inset. The velocities are obtained for tracer particles in a 20 μm by 20 μm by 5 μm region surrounding the cilia tips. The data points show the mean pumping velocity over five different measurements at different actuation frequencies and the shaded regions indicate the standard deviation. The highest pumping velocity of 60 μm", "role": "user" }, { "content": "Cilia are the body's diligent ushers. These microscopic hairs, which move fluid by rhythmic beating, are responsible for pushing cerebrospinal fluid in your brain, clearing the phlegm and dirt from your lungs, and keeping other organs and tissues clean. A technical marvel, cilia have proved difficult to reproduce in engineering applications, especially at the microscale. Cornell researchers have now designed a micro-sized artificial cilial system using platinum-based components that can control the movement of fluids at such a scale. The technology could someday enable low-cost, portable diagnostic devices for testing blood samples, manipulating cells or assisting in microfabrication processes. The group's paper, \"Cilia Metasurfaces for Electronically Programmable Microfluidic Manipulation,\" published May 25 in Nature. The lead author is doctoral student Wei Wang. \"There are lots of ways to make artificial cilia that respond to light, magnetic or electrostatic forces,\" Wang said. \"But we are the first to use our new nano actuator to demonstrate artificial cilia that are individually controlled.\" The project, led by the paper's senior author, Itai Cohen, professor of physics in the College of Arts and Sciences, builds off a platinum-based, electrically-powered actuator—the part of the device that moves—his group previously created to enable microscopic robots to walk. The mechanics of those bending bot legs is similar, but the cilia system's function and applications are different, and quite flexible. \"What we're showing here,\" Cohen said, \"is that once you can individually address these cilia, you can manipulate the flows in any way you want. You can create multiple separate trajectories, you can create circular flow, you can create transport, or flows that split up into two paths and then recombine. You can get flow lines in three dimensions. Anything is possible.\" \"It's been very hard to use existing platforms to create cilia that are small, work in water, are electrically addressable and can be integrated with interesting electronics,\" Cohen said. \"This system solves these problems. And with this kind of platform, we're hoping to develop the next wave of microfluid manipulation devices.\" A typical device consists of a chip that contains 16 square units with 8 cilia arrays per unit, and 8 cilia per array, with each cilium about 50 micrometers long, resulting in a \"carpet\" of about a thousand artificial cilia. As the voltage on each cilium oscillates, its surface oxidizes and reduces periodically, which makes the cilium bend back and forth, allowing it to pump fluid at tens of microns per second. Different arrays can be activated independently, therefore creating an endless combination of flow patterns mimicking the flexibility observed in their biological counterparts. As a bonus, the team created a cilia device that is equipped with a complementary metal-oxide-semiconductor (CMOS) clock circuit—essentially an electronic \"brain\" that allows the cilia to operate without being tethered to a conventional computer system. That opens the door to developing a host of low-cost diagnostic tests that could be performed in the field. \"You can imagine in the future, people taking this tiny centimeter-by-centimeter device, putting a drop of blood on it and conducting all the assays,\" Cohen said. \"You wouldn't have to have a fancy pump, you wouldn't have to have any equipment, you would just literally put it under sunlight and it would work. It could cost on the order of $1 to $10.\" The research was published in 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 Cilial pumping is a powerful strategy used by biological organisms to control and manipulate fluids at the microscale. However, despite numerous recent advances in optically, magnetically and electrically driven actuation, development of an engineered cilial platform with the potential for applications has remained difficult to realize 1 , 2 , 3 , 4 , 5 , 6 . Here we report on active metasurfaces of electronically actuated artificial cilia that can create arbitrary flow patterns in liquids near a surface. We first create voltage-actuated cilia that generate non-reciprocal motions to drive surface flows at tens of microns per second at actuation voltages of 1 volt. We then show that a cilia unit cell can locally create a range of elemental flow geometries. By combining these unit cells, we create an active cilia metasurface that can generate and switch between any desired surface flow pattern. Finally, we integrate the cilia with a light-powered complementary metal–oxide–semiconductor (CMOS) clock circuit to demonstrate wireless operation. As a proof of concept, we use this circuit to output voltage pulses with various phase delays to demonstrate improved pumping efficiency using metachronal waves. These powerful results, demonstrated experimentally and confirmed using theoretical computations, illustrate a pathway towards fine-scale microfluidic manipulation, with applications from microfluidic pumping to microrobotic locomotion. Main Ciliary pumping is one of the most important and ubiquitous fluidic transport methods in the microscopic world 7 , 8 , 9 , 10 , 11 , 12 , 13 ; however, it is challenging to engineer artificial cilia platforms that can be widely adopted 2 , 14 . Several pioneering studies have demonstrated methods for fabricating artificial cilia with actuation based on pressure 15 , light 16 , 17 , electrostatic 18 and magnetic 19 , 20 interactions; however, these systems have severe limitations. For example, cilia that are pressure-driven or optically driven can be locally actuated. These systems have, however, been challenging to implement at the microscale 6 , 15 . Moreover, there is no clear pathway for integrating them with mobile micromachines while retaining local actuation 21 . Electrostatically actuated cilia has been shown as a powerful method for rapid pumping and mixing 18 . The actuators demonstrated thus far are, however, driven by large voltages. This large voltage makes them incompatible with complementary metal–oxide–semiconductor (CMOS) electronics for untethered control. In addition, they cannot be operated in aqueous solutions, owing to hydrolysis at voltages above approximately 1.2 V. Finally, there has been much excitement about making artificial cilia out of magnetically responsive materials. Various groups have demonstrated pumping 5 , metachronal waves 4 , 22 , 23 and mixing 24 . In such magnetic systems, however, it is difficult to localize the actuation or change the magnetization of the cilia in situ to reconfigure the flows. Thus, to obtain wide adoption for this transport method in engineered systems, there remains a critical need for development of novel artificial cilia platforms. Here we show that recently developed surface electrochemical actuators 25 , 26 can be used to overcome many of these challenges. Each artificial cilium consists of a lithographically fabricated strip that is approximately 50 μm long, 5 μm wide and only about 10 nm thin, attached to the substrate at one end, as shown in Fig. 1a . The strip comprises a 7-nm-thick platinum (Pt) thin film capped on one side by a passive layer of titanium (Ti) (Fig. 1a , left; see Methods and Extended Data Fig. 1 for the fabrication process). Actuation of the artificial cilium in phosphate-buffered saline (PBS; 1×, pH 7.45) is induced by raising its potential to about 1 V relative to the Ag/AgCl reference electrode, triggering electrochemical oxidation of the exposed Pt surface while avoiding bubble formation. The oxidation expands the Pt surface 26 and causes the actuator to bend (Fig. 1a , red reaction pathway, left → right). Applying a voltage of approximately −0.2 V reduces the Pt film, which returns the actuator to its initial state (Fig. 1a , blue reaction pathway, right → left). The current density is approximately 1 mA cm −2 (Extended Data Fig. 2 ), which means that a 1 cm × 1 cm device fully covered by artificial cilia would only consume about 1 mW of power at a sweep rate of 1 V s −1 . To prevent twisting of the actuator we pattern three horizontal polymer pads spaced at 15-μm intervals along each cilium. Because surface electrochemical actuators can be lithographically fabricated, millions could be fabricated on one 4-inch wafer; the actuation of cilia arrays with 80 cilia is shown in Supplementary Video 1 . We show a scanning electron microscope (SEM) image of a small region of the released cilia in Fig. 1b . Each cilia array is connected through a busbar that enables independent actuation. In the bottom-right inset of Fig. 1b , we show an annular dark-field scanning transmission electron microscope (STEM) image of a fabricated cilium cross-section. This ciliary platform enables an advantageous combination of features including local electrical actuation, operation in aqueous solutions, and compatibility with CMOS electronics to generate complex switchable microfluidic manipulations. Fig. 1: Artificial cilia based on surface electrochemical actuators. a , Each cilium consists of a thin surface electrochemical actuator made of a platinum strip capped on one side by a titanium film 25 , 26 . b , SEM image of released artificial cilia arrays with each row connected by a single busbar. A STEM image of a cilium cross-section showing the platinum (white) and titanium (black) is presented in the bottom-right inset. c , Experimental results for pumping velocity versus frequency for a single cilia array such as the one shown in the top-left inset. The velocities are obtained for tracer particles in a 20 μm by 20 μm by 5 μm region surrounding the cilia tips. The data points show the mean pumping velocity over five different measurements at different actuation frequencies and the shaded regions indicate the standard deviation. The highest pumping velocity of 60 μm<|im_end|> <|im_start|>assistant Cilia are the body's diligent ushers. These microscopic hairs, which move fluid by rhythmic beating, are responsible for pushing cerebrospinal fluid in your brain, clearing the phlegm and dirt from your lungs, and keeping other organs and tissues clean. A technical marvel, cilia have proved difficult to reproduce in engineering applications, especially at the microscale. Cornell researchers have now designed a micro-sized artificial cilial system using platinum-based components that can control the movement of fluids at such a scale. The technology could someday enable low-cost, portable diagnostic devices for testing blood samples, manipulating cells or assisting in microfabrication processes. The group's paper, "Cilia Metasurfaces for Electronically Programmable Microfluidic Manipulation," published May 25 in Nature. The lead author is doctoral student Wei Wang. "There are lots of ways to make artificial cilia that respond to light, magnetic or electrostatic forces," Wang said. "But we are the first to use our new nano actuator to demonstrate artificial cilia that are individually controlled." The project, led by the paper's senior author, Itai Cohen, professor of physics in the College of Arts and Sciences, builds off a platinum-based, electrically-powered actuator—the part of the device that moves—his group previously created to enable microscopic robots to walk. The mechanics of those bending bot legs is similar, but the cilia system's function and applications are different, and quite flexible. "What we're showing here," Cohen said, "is that once you can individually address these cilia, you can manipulate the flows in any way you want. You can create multiple separate trajectories, you can create circular flow, you can create transport, or flows that split up into two paths and then recombine. You can get flow lines in three dimensions. Anything is possible." "It's been very hard to use existing platforms to create cilia that are small, work in water, are electrically addressable and can be integrated with interesting electronics," Cohen said. "This system solves these problems. And with this kind of platform, we're hoping to develop the next wave of microfluid manipulation devices." A typical device consists of a chip that contains 16 square units with 8 cilia arrays per unit, and 8 cilia per array, with each cilium about 50 micrometers long, resulting in a "carpet" of about a thousand artificial cilia. As the voltage on each cilium oscillates, its surface oxidizes and reduces periodically, which makes the cilium bend back and forth, allowing it to pump fluid at tens of microns per second. Different arrays can be activated independently, therefore creating an endless combination of flow patterns mimicking the flexibility observed in their biological counterparts. As a bonus, the team created a cilia device that is equipped with a complementary metal-oxide-semiconductor (CMOS) clock circuit—essentially an electronic "brain" that allows the cilia to operate without being tethered to a conventional computer system. That opens the door to developing a host of low-cost diagnostic tests that could be performed in the field. "You can imagine in the future, people taking this tiny centimeter-by-centimeter device, putting a drop of blood on it and conducting all the assays," Cohen said. "You wouldn't have to have a fancy pump, you wouldn't have to have any equipment, you would just literally put it under sunlight and it would work. It could cost on the order of $1 to $10." The research was published in Nature. <|im_end|>

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24529, 18488, 13, 578, 71162, 52956, 279, 52170, 7479, 220, 1627, 323, 11384, 279, 1180, 46262, 311, 37920, 320, 30035, 13, 220, 16, 64, 1174, 2579, 13010, 38970, 11, 2163, 11651, 1314, 570, 90701, 264, 22465, 315, 13489, 25173, 15, 13, 17, 650, 26338, 279, 52170, 4632, 11, 902, 4780, 279, 1180, 46262, 311, 1202, 2926, 1614, 320, 30035, 13, 220, 16, 64, 1174, 6437, 13010, 38970, 11, 1314, 11651, 2163, 570, 578, 1510, 17915, 374, 13489, 220, 16, 99877, 10166, 25173, 17, 320, 54290, 2956, 23966, 13, 220, 17, 7026, 902, 3445, 430, 264, 220, 16, 10166, 25800, 220, 16, 10166, 3756, 7373, 9960, 555, 21075, 272, 25045, 1053, 1193, 25024, 922, 220, 16, 296, 54, 315, 2410, 520, 264, 24021, 4478, 315, 220, 16, 650, 274, 25173, 16, 662, 2057, 5471, 80654, 315, 279, 1180, 46262, 584, 5497, 2380, 16600, 47393, 37095, 64928, 520, 220, 868, 12, 44223, 76, 28090, 3235, 1855, 62444, 2411, 13, 9393, 7479, 25396, 32056, 81553, 3046, 649, 387, 46282, 65031, 70554, 11, 11990, 1436, 387, 70554, 389, 832, 220, 19, 25224, 10667, 809, 26, 279, 1180, 4090, 315, 272, 25045, 18893, 449, 220, 1490, 272, 25045, 374, 6982, 304, 99371, 8519, 220, 16, 662, 1226, 1501, 264, 36201, 17130, 73757, 320, 84839, 8, 2217, 315, 264, 2678, 5654, 315, 279, 6004, 272, 25045, 304, 23966, 13, 220, 16, 65, 662, 9062, 272, 25045, 1358, 374, 8599, 1555, 264, 5951, 2308, 430, 20682, 9678, 1180, 4090, 13, 763, 279, 5740, 6840, 55959, 315, 23966, 13, 220, 16, 65, 1174, 584, 1501, 459, 3008, 1299, 6453, 19677, 36201, 18874, 17130, 73757, 320, 15642, 8, 2217, 315, 264, 70554, 62444, 2411, 5425, 22327, 13, 1115, 272, 35546, 5452, 20682, 459, 76824, 10824, 315, 4519, 2737, 2254, 20314, 1180, 4090, 11, 5784, 304, 66300, 788, 10105, 11, 323, 25780, 449, 18582, 3204, 31591, 311, 7068, 6485, 3480, 481, 8162, 67125, 292, 14951, 7607, 13, 23966, 13, 220, 16, 25, 59294, 272, 25045, 3196, 389, 7479, 25396, 32056, 81553, 3046, 13, 264, 1174, 9062, 62444, 2411, 17610, 315, 264, 15792, 7479, 25396, 32056, 1180, 46262, 1903, 315, 264, 63327, 13619, 61246, 389, 832, 3185, 555, 264, 71404, 4632, 220, 914, 1174, 220, 1627, 662, 293, 1174, 46544, 2217, 315, 6004, 21075, 272, 25045, 18893, 449, 1855, 2872, 8599, 555, 264, 3254, 5951, 2308, 13, 362, 64182, 2217, 315, 264, 62444, 2411, 5425, 22327, 9204, 279, 63327, 320, 5902, 8, 323, 71404, 320, 11708, 8, 374, 10666, 304, 279, 5740, 6840, 55959, 13, 272, 1174, 57708, 3135, 369, 53226, 15798, 19579, 11900, 369, 264, 3254, 272, 25045, 1358, 1778, 439, 279, 832, 6982, 304, 279, 1948, 8109, 55959, 13, 578, 75157, 527, 12457, 369, 65406, 19252, 304, 264, 220, 508, 33983, 76, 555, 220, 508, 33983, 76, 555, 220, 20, 33983, 76, 5654, 14932, 279, 272, 25045, 10631, 13, 578, 828, 3585, 1501, 279, 3152, 53226, 15798, 927, 4330, 2204, 22323, 520, 2204, 1180, 4090, 34873, 323, 279, 92866, 13918, 13519, 279, 5410, 38664, 13, 578, 8592, 53226, 15798, 315, 220, 1399, 33983, 76, 128257, 198, 128256, 78191, 198, 34, 25045, 527, 279, 2547, 596, 97653, 603, 71, 388, 13, 4314, 90090, 66060, 11, 902, 3351, 15962, 555, 29171, 21914, 27242, 11, 527, 8647, 369, 17919, 28091, 15222, 2203, 992, 15962, 304, 701, 8271, 11, 33850, 279, 1343, 1978, 76, 323, 26351, 505, 701, 45274, 11, 323, 10494, 1023, 36853, 323, 39881, 4335, 13, 362, 11156, 45882, 11, 272, 25045, 617, 19168, 5107, 311, 23645, 304, 15009, 8522, 11, 5423, 520, 279, 8162, 12727, 13, 56819, 12074, 617, 1457, 6319, 264, 8162, 28935, 21075, 62444, 532, 1887, 1701, 63327, 6108, 6956, 430, 649, 2585, 279, 7351, 315, 56406, 520, 1778, 264, 5569, 13, 578, 5557, 1436, 54108, 7431, 3428, 41238, 11, 23665, 15439, 7766, 369, 7649, 6680, 10688, 11, 63614, 7917, 477, 46927, 304, 8162, 86254, 367, 11618, 13, 578, 1912, 596, 5684, 11, 330, 34, 25045, 6344, 300, 324, 7760, 369, 77976, 2740, 75010, 481, 18654, 67125, 292, 62011, 2987, 1359, 4756, 3297, 220, 914, 304, 22037, 13, 578, 3063, 3229, 374, 74657, 5575, 53548, 29346, 13, 330, 3947, 527, 10283, 315, 5627, 311, 1304, 21075, 272, 25045, 430, 6013, 311, 3177, 11, 24924, 477, 25396, 2020, 8603, 1359, 29346, 1071, 13, 330, 4071, 584, 527, 279, 1176, 311, 1005, 1057, 502, 51593, 1180, 46262, 311, 20461, 21075, 272, 25045, 430, 527, 32399, 14400, 1210, 578, 2447, 11, 6197, 555, 279, 5684, 596, 10195, 3229, 11, 1102, 2192, 32196, 11, 14561, 315, 22027, 304, 279, 9304, 315, 17979, 323, 23199, 11, 22890, 1022, 264, 63327, 6108, 11, 9249, 750, 41503, 1180, 46262, 22416, 961, 315, 279, 3756, 430, 11031, 2345, 26301, 1912, 8767, 3549, 311, 7431, 90090, 29807, 311, 4321, 13, 578, 30126, 315, 1884, 58218, 11164, 14535, 374, 4528, 11, 719, 279, 272, 25045, 1887, 596, 734, 323, 8522, 527, 2204, 11, 323, 5115, 19303, 13, 330, 3923, 584, 2351, 9204, 1618, 1359, 32196, 1071, 11, 330, 285, 430, 3131, 499, 649, 32399, 2686, 1521, 272, 25045, 11, 499, 649, 37735, 279, 28555, 304, 904, 1648, 499, 1390, 13, 1472, 649, 1893, 5361, 8821, 86648, 11, 499, 649, 1893, 28029, 6530, 11, 499, 649, 1893, 7710, 11, 477, 28555, 430, 6859, 709, 1139, 1403, 13006, 323, 1243, 312, 64236, 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13, 34496, 18893, 649, 387, 22756, 29235, 11, 9093, 6968, 459, 26762, 10824, 315, 6530, 12912, 28003, 16671, 279, 25152, 13468, 304, 872, 24156, 38495, 13, 1666, 264, 12306, 11, 279, 2128, 3549, 264, 272, 25045, 3756, 430, 374, 19167, 449, 264, 58535, 9501, 12, 55189, 70789, 52592, 320, 10190, 3204, 8, 9042, 16622, 2345, 434, 31668, 459, 14683, 330, 54160, 1, 430, 6276, 279, 272, 25045, 311, 14816, 2085, 1694, 80665, 291, 311, 264, 21349, 6500, 1887, 13, 3011, 16264, 279, 6134, 311, 11469, 264, 3552, 315, 3428, 41238, 15439, 7177, 430, 1436, 387, 10887, 304, 279, 2115, 13, 330, 2675, 649, 13085, 304, 279, 3938, 11, 1274, 4737, 420, 13987, 2960, 26402, 14656, 21911, 26402, 3756, 11, 10917, 264, 6068, 315, 6680, 389, 433, 323, 31474, 682, 279, 99592, 1359, 32196, 1071, 13, 330, 2675, 8434, 956, 617, 311, 617, 264, 27555, 14155, 11, 499, 8434, 956, 617, 311, 617, 904, 7241, 11, 499, 1053, 1120, 16280, 2231, 433, 1234, 40120, 323, 433, 1053, 990, 13, 1102, 1436, 2853, 389, 279, 2015, 315, 400, 16, 311, 400, 605, 1210, 578, 3495, 574, 4756, 304, 22037, 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 best available data indicate that the world is heading towards a pandemic of extensively drug-resistant Neisseria gonorrhoeae . At the same time, clinical microbiology laboratories have moved away from using culture-based methods to diagnose gonorrhoea, thus undermining our ability to detect antimicrobial resistance (AMR) using current technologies. In this Opinion article, we discuss the problem of N. gonorrhoeae AMR, particularly emerging resistance to the cephalosporin ceftriaxone, outline current concerns about the surveillance of N. gonorrhoeae AMR and propose the use of molecular methods on a large scale to systematically enhance surveillance. Main Neisseria gonorrhoeae is the aetiological agent of the sexually transmitted infection gonorrhoea. In men, gonorrhoea is a common cause of urethritis and can lead to epididymo-orchitis (which is swelling of the testes associated with acute scrotal pain). In women, gonorrhoea causes cervicitis, which is usually asymptomatic and can lead to pelvic inflammatory disease and infertility. Extragenital infection of the pharynx and rectum is also often asymptomatic and is an important reservoir for further transmission. Gonorrhoea also enhances the transmission of HIV. Additionally, although uncommon, gonococcal infection can also become disseminated 1 . Over time, a wide range of antibiotics have been used to treat gonorrhoea; however, the easy availability and injudicious use of antibiotics has resulted in the emergence of resistance to many of these compounds ( Fig. 1 ). The situation has been further exacerbated by the extraordinary ability of N. gonorrhoeae to acquire and retain antimicrobial resistance (AMR) genes and/or mutations, even in the absence of ongoing treatment pressure 2 , 3 , 4 , 5 , 6 . A large proportion of gonococci that are in circulation worldwide are only a few resistance markers away from developing into extensively drug resistant (XDR) strains, which are defined as strains that are resistant to two or more of the antibiotic classes that are generally recommended for the treatment of gonorrhoea or three or more of the classes that are less frequently used for treatment 7 . The first two XDR gonococcal strains, N. gonorrhoeae H041 and N. gonorrhoeae F89, were recently reported from Japan and Europe respectively; both are resistant to the extended-spectrum cephalosporin ceftriaxone, which is the last fully effective antimicrobial for gonorrhoea 8 , 9 . The recent detection of a gonococcal strain with a TEM-135 β-lactamase — which confers resistance to the β-lactam antibiotic penicillin and is considered to be an intermediate between the TEM-1 β-lactamase and an extended-spectrum β-lactamase (ESBL), which confers resistance to multiple β-lactams — is also alarming 10 , 11 . Beyond ceftriaxone, there are no known new antibiotics for the treatment of gonorrhoea in development, and only limited data are available to inform the use of newer drugs such as solithromycin, which is a novel macrolide 12 , and ertapenem 13 , or to assess whether bringing old drugs, such as gentamicin and spectinomycin, back into clinical use is viable 14 , 15 . However, it is interesting to note that recent clinical trial data indicate that dual therapies comprising either gentamicin or gemifloxacin plus azithromycin are suitable treatment options 16 . Figure 1: The history of Neisseria gonorrhoeae antimicrobial resistance. Since 1935, a wide range of antibiotics have been used to treat gonorrhoea; the figure shows the date of introduction of each antibiotic into clinical use and the year in which resistance was first observed; the numbers on the bars reflect the number of years the antibiotic was in use before resistance was reported. PowerPoint slide Full size image Both the World Health Organization (WHO) and the United States Centers for Disease Control and Prevention (CDC) have called for research into the development not only of alternative gonorrhoea treatment options but also of enhanced N. gonorrhoeae AMR surveillance systems in response to the increasing incidence of cephalosporin resistance 17 , 18 . A dual therapy comprising ceftriaxone plus azithromycin has recently been implemented in the USA, UK and elsewhere as a strategy to stem the development of N. gonorrhoeae AMR 19 , 20 , 21 . However, new antimicrobials are still desperately needed. There is therefore an urgent need to strengthen N. gonorrhoeae AMR surveillance in order to better guide the use of current gonorrhoea treatments and to maintain global control of this disease. In this Opinion article, we briefly explore the genetics of N. gonorrhoeae AMR and the emergence of ceftriaxone resistance and highlight the current limitations of bacterial culture-based N. gonorrhoeae AMR surveillance. Moreover, in an era in which gonorrhoea is increasingly being diagnosed by nucleic acid amplification tests (NAATs) and the numbers of isolates that are available for classical AMR testing are diminishing, we consider the use of molecular methods as a means of enhancing N. gonorrhoeae AMR surveillance. The genetics of N. gonorrhoeae AMR N. gonorrhoeae AMR can be plasmid- or chromosome-mediated 22 , and the main mechanisms are briefly summarized here and illustrated in Fig. 2 . Figure 2: Neisseria gonorrhoeae -targeting antibiotics and the corresponding resistance genes. There are various targets for antibiotics in N. gonorrohoeae . a | Spectinomycin and azithromycin bind to ribosomes to inhibit protein synthesis. Mutations in the 16S and 23S rRNA-encoding genes confer resistance to spectinomycin and azithromycin, respectively. b | Fluoroquinolones inhibit the activity of topoisomerases that are involved in DNA replication. Resistance to fluoroquinolones is conferred by mutations in the topoisomerase-encoding genes gyrA and parC . c | β-lactam antibiotics target penicillin-binding protein 1 (PBP1) and PBP2, which are required for peptidoglycan synthesis. Mutations in ponA and penA , which encode PBP1 and PBP2, respectively, confer resistance to β-lactams. d | Various classes of antibiotics enter N. gonorrhoeae cells through PorB, which is a major outer membrane porin. Structural alterations in PorB reduce this permeability, conferring resistance. e | The MtrCDE efflux pump expels antibiotics of various classes from N. gonorrhoeae cells. Mutations in efflux pump genes, particularly in the promoter of mtrR , which encodes the MtrR repressor protein, lead to overexpression and hence increased activity of this efflux pump complex, conferring", "role": "user" }, { "content": "(Medical Xpress)—A pandemic of super-resistant gonorrhoea could be kept in check using new methods to track outbreaks of the disease, according to a University of Queensland infectious diseases expert. Associate Professor David Whiley and his team have developed molecular tools to detect outbreaks of resistant strains of gonorrhoea, a sexually transmitted disease causing serious health complications. He said molecular methods for detecting resistance worked by detecting specific mutations in an organism's DNA that made it resistant to antibiotics. \"This is quite different to traditional methods of detecting resistance that rely on growing live bacteria,\" he said. While antibiotics can cure gonorrhoea, drug-resistant strains are increasing in many parts of the world and successful treatment is becoming more difficult. Notification rates of gonorrhoea have increased over the past 10 years and there are about 13,000 gonorrhoea notifications in Australia each year. Associate Professor Whiley, from UQ's Queensland Children's Medical Research Institute, said there was an urgent need to strengthen gonorrhoea surveillance to guide the use of treatments and maintain global control of the disease. \"The World Health Organisation (WHO) and the United States Centres for Disease Control and Prevention have called for research into the development of alternative treatment options and enhanced gonorrhoea surveillance systems,\" he said. \"We propose that molecular methods will complement existing testing regimes and offer improved ability to detect whether any strains are resistant to antibiotic treatments.\" Currently, resistant gonorrhoea is detected through culture-based diagnosis, which involves growing live bacteria and testing it to determine susceptibility to antibiotics. Associate Professor Whiley said the method was effective, but required highly technical skills and resources. \"It may also be unsuccessful if samples have been transported over long distances as this may kill the bug and prevent resistance testing.\" He said such issues had prompted laboratories to move away from culture-based testing, but this could compromise the detection of resistant strains. \"This is quite scary as it leaves health authorities without early warning signs if super-resistant strains arrive,\" he said. \"Our team has had initial success in using a new molecular method to screen for resistant gonorrhoea in clinical samples collected in remote Australian communities, where penicillin-based treatments are typically used for the disease. \"The molecular method can confirm if a strain is sensitive to penicillin and the method is now being used to help inform guidelines for the clinical management of locally acquired gonorrhoea in remote Australian communities. \"We know that molecular methods are successful and, if used in conjunction with traditional culture-based methods, will increase our ability to track and hopefully limit the spread of super-resistant strains. \"This knowledge will enable us to quickly identify patients with resistant strains and if needed to administer more appropriate treatment and to prevent further disease transmission.\" The research has been published in this month's Nature Reviews Microbiology (March 2014). Gonorrhoea: Gonorrhoea is a bacterial infection with similar characteristics to chlamydia. Like chlamydia, gonorrhoea infects reproductive organs, can be asymptomatic and increases the chances of contracting other infections. If left untreated, gonorrhoea can also cause infertility in men and women. While antibiotics can cure gonorrhoea, drug-resistant strains are increasing in many parts of the world and successful treatment is becoming more difficult. In contrast with chlamydia, more men than women were diagnosed with gonorrhoea in 2011: 8056 men, compared with 3789 women. Men aged 20-24 years had the highest diagnosis rate, with 213 diagnoses per 100,000, followed by 185 per 100,000 for those aged 25-29 years. For women, the highest rates of diagnosis were in the youngest age groups, with 178 and 128 diagnosed per 100,000 for those aged 15-19 years and 20-24 years respectively. Men and women aged between 15 and 34 years accounted for nearly three quarters (74 per cent) of total gonorrhoea diagnoses. For both men and women, the rate of diagnosis has increased over the past 10 years, particularly among people aged 45 years and over. For men aged 45-49 years, the rate more than doubled between 2001 and 2011, from 25 per 100,000 to 66 per 100,000. Women of the same age range experienced a similar increase, from 3.4 per 100,000 to 8.6 per 100,000. ", "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 best available data indicate that the world is heading towards a pandemic of extensively drug-resistant Neisseria gonorrhoeae . At the same time, clinical microbiology laboratories have moved away from using culture-based methods to diagnose gonorrhoea, thus undermining our ability to detect antimicrobial resistance (AMR) using current technologies. In this Opinion article, we discuss the problem of N. gonorrhoeae AMR, particularly emerging resistance to the cephalosporin ceftriaxone, outline current concerns about the surveillance of N. gonorrhoeae AMR and propose the use of molecular methods on a large scale to systematically enhance surveillance. Main Neisseria gonorrhoeae is the aetiological agent of the sexually transmitted infection gonorrhoea. In men, gonorrhoea is a common cause of urethritis and can lead to epididymo-orchitis (which is swelling of the testes associated with acute scrotal pain). In women, gonorrhoea causes cervicitis, which is usually asymptomatic and can lead to pelvic inflammatory disease and infertility. Extragenital infection of the pharynx and rectum is also often asymptomatic and is an important reservoir for further transmission. Gonorrhoea also enhances the transmission of HIV. Additionally, although uncommon, gonococcal infection can also become disseminated 1 . Over time, a wide range of antibiotics have been used to treat gonorrhoea; however, the easy availability and injudicious use of antibiotics has resulted in the emergence of resistance to many of these compounds ( Fig. 1 ). The situation has been further exacerbated by the extraordinary ability of N. gonorrhoeae to acquire and retain antimicrobial resistance (AMR) genes and/or mutations, even in the absence of ongoing treatment pressure 2 , 3 , 4 , 5 , 6 . A large proportion of gonococci that are in circulation worldwide are only a few resistance markers away from developing into extensively drug resistant (XDR) strains, which are defined as strains that are resistant to two or more of the antibiotic classes that are generally recommended for the treatment of gonorrhoea or three or more of the classes that are less frequently used for treatment 7 . The first two XDR gonococcal strains, N. gonorrhoeae H041 and N. gonorrhoeae F89, were recently reported from Japan and Europe respectively; both are resistant to the extended-spectrum cephalosporin ceftriaxone, which is the last fully effective antimicrobial for gonorrhoea 8 , 9 . The recent detection of a gonococcal strain with a TEM-135 β-lactamase — which confers resistance to the β-lactam antibiotic penicillin and is considered to be an intermediate between the TEM-1 β-lactamase and an extended-spectrum β-lactamase (ESBL), which confers resistance to multiple β-lactams — is also alarming 10 , 11 . Beyond ceftriaxone, there are no known new antibiotics for the treatment of gonorrhoea in development, and only limited data are available to inform the use of newer drugs such as solithromycin, which is a novel macrolide 12 , and ertapenem 13 , or to assess whether bringing old drugs, such as gentamicin and spectinomycin, back into clinical use is viable 14 , 15 . However, it is interesting to note that recent clinical trial data indicate that dual therapies comprising either gentamicin or gemifloxacin plus azithromycin are suitable treatment options 16 . Figure 1: The history of Neisseria gonorrhoeae antimicrobial resistance. Since 1935, a wide range of antibiotics have been used to treat gonorrhoea; the figure shows the date of introduction of each antibiotic into clinical use and the year in which resistance was first observed; the numbers on the bars reflect the number of years the antibiotic was in use before resistance was reported. PowerPoint slide Full size image Both the World Health Organization (WHO) and the United States Centers for Disease Control and Prevention (CDC) have called for research into the development not only of alternative gonorrhoea treatment options but also of enhanced N. gonorrhoeae AMR surveillance systems in response to the increasing incidence of cephalosporin resistance 17 , 18 . A dual therapy comprising ceftriaxone plus azithromycin has recently been implemented in the USA, UK and elsewhere as a strategy to stem the development of N. gonorrhoeae AMR 19 , 20 , 21 . However, new antimicrobials are still desperately needed. There is therefore an urgent need to strengthen N. gonorrhoeae AMR surveillance in order to better guide the use of current gonorrhoea treatments and to maintain global control of this disease. In this Opinion article, we briefly explore the genetics of N. gonorrhoeae AMR and the emergence of ceftriaxone resistance and highlight the current limitations of bacterial culture-based N. gonorrhoeae AMR surveillance. Moreover, in an era in which gonorrhoea is increasingly being diagnosed by nucleic acid amplification tests (NAATs) and the numbers of isolates that are available for classical AMR testing are diminishing, we consider the use of molecular methods as a means of enhancing N. gonorrhoeae AMR surveillance. The genetics of N. gonorrhoeae AMR N. gonorrhoeae AMR can be plasmid- or chromosome-mediated 22 , and the main mechanisms are briefly summarized here and illustrated in Fig. 2 . Figure 2: Neisseria gonorrhoeae -targeting antibiotics and the corresponding resistance genes. There are various targets for antibiotics in N. gonorrohoeae . a | Spectinomycin and azithromycin bind to ribosomes to inhibit protein synthesis. Mutations in the 16S and 23S rRNA-encoding genes confer resistance to spectinomycin and azithromycin, respectively. b | Fluoroquinolones inhibit the activity of topoisomerases that are involved in DNA replication. Resistance to fluoroquinolones is conferred by mutations in the topoisomerase-encoding genes gyrA and parC . c | β-lactam antibiotics target penicillin-binding protein 1 (PBP1) and PBP2, which are required for peptidoglycan synthesis. Mutations in ponA and penA , which encode PBP1 and PBP2, respectively, confer resistance to β-lactams. d | Various classes of antibiotics enter N. gonorrhoeae cells through PorB, which is a major outer membrane porin. Structural alterations in PorB reduce this permeability, conferring resistance. e | The MtrCDE efflux pump expels antibiotics of various classes from N. gonorrhoeae cells. Mutations in efflux pump genes, particularly in the promoter of mtrR , which encodes the MtrR repressor protein, lead to overexpression and hence increased activity of this efflux pump complex, conferring<|im_end|> <|im_start|>assistant (Medical Xpress)—A pandemic of super-resistant gonorrhoea could be kept in check using new methods to track outbreaks of the disease, according to a University of Queensland infectious diseases expert. Associate Professor David Whiley and his team have developed molecular tools to detect outbreaks of resistant strains of gonorrhoea, a sexually transmitted disease causing serious health complications. He said molecular methods for detecting resistance worked by detecting specific mutations in an organism's DNA that made it resistant to antibiotics. "This is quite different to traditional methods of detecting resistance that rely on growing live bacteria," he said. While antibiotics can cure gonorrhoea, drug-resistant strains are increasing in many parts of the world and successful treatment is becoming more difficult. Notification rates of gonorrhoea have increased over the past 10 years and there are about 13,000 gonorrhoea notifications in Australia each year. Associate Professor Whiley, from UQ's Queensland Children's Medical Research Institute, said there was an urgent need to strengthen gonorrhoea surveillance to guide the use of treatments and maintain global control of the disease. "The World Health Organisation (WHO) and the United States Centres for Disease Control and Prevention have called for research into the development of alternative treatment options and enhanced gonorrhoea surveillance systems," he said. "We propose that molecular methods will complement existing testing regimes and offer improved ability to detect whether any strains are resistant to antibiotic treatments." Currently, resistant gonorrhoea is detected through culture-based diagnosis, which involves growing live bacteria and testing it to determine susceptibility to antibiotics. Associate Professor Whiley said the method was effective, but required highly technical skills and resources. "It may also be unsuccessful if samples have been transported over long distances as this may kill the bug and prevent resistance testing." He said such issues had prompted laboratories to move away from culture-based testing, but this could compromise the detection of resistant strains. "This is quite scary as it leaves health authorities without early warning signs if super-resistant strains arrive," he said. "Our team has had initial success in using a new molecular method to screen for resistant gonorrhoea in clinical samples collected in remote Australian communities, where penicillin-based treatments are typically used for the disease. "The molecular method can confirm if a strain is sensitive to penicillin and the method is now being used to help inform guidelines for the clinical management of locally acquired gonorrhoea in remote Australian communities. "We know that molecular methods are successful and, if used in conjunction with traditional culture-based methods, will increase our ability to track and hopefully limit the spread of super-resistant strains. "This knowledge will enable us to quickly identify patients with resistant strains and if needed to administer more appropriate treatment and to prevent further disease transmission." The research has been published in this month's Nature Reviews Microbiology (March 2014). Gonorrhoea: Gonorrhoea is a bacterial infection with similar characteristics to chlamydia. Like chlamydia, gonorrhoea infects reproductive organs, can be asymptomatic and increases the chances of contracting other infections. If left untreated, gonorrhoea can also cause infertility in men and women. While antibiotics can cure gonorrhoea, drug-resistant strains are increasing in many parts of the world and successful treatment is becoming more difficult. In contrast with chlamydia, more men than women were diagnosed with gonorrhoea in 2011: 8056 men, compared with 3789 women. Men aged 20-24 years had the highest diagnosis rate, with 213 diagnoses per 100,000, followed by 185 per 100,000 for those aged 25-29 years. For women, the highest rates of diagnosis were in the youngest age groups, with 178 and 128 diagnosed per 100,000 for those aged 15-19 years and 20-24 years respectively. Men and women aged between 15 and 34 years accounted for nearly three quarters (74 per cent) of total gonorrhoea diagnoses. For both men and women, the rate of diagnosis has increased over the past 10 years, particularly among people aged 45 years and over. For men aged 45-49 years, the rate more than doubled between 2001 and 2011, from 25 per 100,000 to 66 per 100,000. Women of the same age range experienced a similar increase, from 3.4 per 100,000 to 8.6 per 100,000. <|im_end|>

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2,455

[ { "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 At the historic Shelter Island Conference on the Foundations of Quantum Mechanics in 1947, Willis Lamb reported an unexpected feature in the fine structure of atomic hydrogen: a separation of the 2S 1/2 and 2P 1/2 states 1 . The observation of this separation, now known as the Lamb shift, marked an important event in the evolution of modern physics, inspiring others to develop the theory of quantum electrodynamics 2 , 3 , 4 , 5 . Quantum electrodynamics also describes antimatter, but it has only recently become possible to synthesize and trap atomic antimatter to probe its structure. Mirroring the historical development of quantum atomic physics in the twentieth century, modern measurements on anti-atoms represent a unique approach for testing quantum electrodynamics and the foundational symmetries of the standard model. Here we report measurements of the fine structure in the n = 2 states of antihydrogen, the antimatter counterpart of the hydrogen atom. Using optical excitation of the 1S–2P Lyman-α transitions in antihydrogen 6 , we determine their frequencies in a magnetic field of 1 tesla to a precision of 16 parts per billion. Assuming the standard Zeeman and hyperfine interactions, we infer the zero-field fine-structure splitting (2P 1/2 –2P 3/2 ) in antihydrogen. The resulting value is consistent with the predictions of quantum electrodynamics to a precision of 2 per cent. Using our previously measured value of the 1S–2S transition frequency 6 , 7 , we find that the classic Lamb shift in antihydrogen (2S 1/2 –2P 1/2 splitting at zero field) is consistent with theory at a level of 11 per cent. Our observations represent an important step towards precision measurements of the fine structure and the Lamb shift in the antihydrogen spectrum as tests of the charge–parity–time symmetry 8 and towards the determination of other fundamental quantities, such as the antiproton charge radius 9 , 10 , in this antimatter system. Main The fine-structure splitting of the n = 2 states of hydrogen is the separation of the 2P 3/2 and 2P 1/2 levels at zero magnetic field. This splitting, predicted by the Dirac theory of relativistic quantum mechanics 11 , originates from the spin–orbit interaction between the non-zero orbital angular momentum ( L = 1) and the electron spin. The ‘classic’ Lamb shift is defined as the splitting between the 2S 1/2 and 2P 1/2 states at zero field 12 , and is a manifestation of the interaction of the electron with the quantum fluctuations of the vacuum electromagnetic field, an effect explained by quantum electrodynamics (QED) 12 , 13 , 14 . Today, it is understood that the classic Lamb shift in hydrogen is dominated by the QED effects on the 2S energy level, and that the 1S level receives even stronger QED corrections than the 2S level 12 , 13 . Although QED corrections in levels n ≠ 2 are now also sometimes referred to as Lamb shifts, in this Article we restrict our definition of the Lamb shift to be the classic n = 2 shift. In a magnetic field, the Zeeman effect causes the 2P 3/2 state to also split into four sublevels (labelled 2P a , 2P b , 2P c and 2P d ), whereas the 2S 1/2 and 2P 1/2 states each split into two (2S ab and 2S cd ; 2P e and 2P f ). These fine-structure levels further split into two hyperfine states owing to the proton spin (see Fig. 1 for the expected energy levels for the case of antihydrogen, where the spin orientations are reversed with respect to those of hydrogen.) Fig. 1: Expected antihydrogen energy levels. Calculated energies of the fine structure and the hyperfine sublevels of the 1S 1/2 , 2S 1/2 , 2P 3/2 and 2P 1/2 states are shown as functions of magnetic-field strength. The spin orientations for antihydrogen are shown; they are reversed for hydrogen. The centroid energy difference, E 1S–2S = 2.4661 × 10 15 Hz, has been suppressed on the vertical axis. Details of the energy levels relevant to this work at a magnetic field of B = 1.0329 T are shown on the right. Each state is labelled using conventional notation. For the 1S and 2S states, the hyperfine states are labelled with subscripts a–d in order of increasing energy (see, for example, ref. 7 ); namely, \${{\\rm{S}}}_{{\\rm{a}}}=|\\uparrow \\Downarrow \\rangle \$ , \${{\\rm{S}}}_{{\\rm{b}}}=|\\uparrow \\Uparrow \\rangle \$ , \${{\\rm{S}}}_{{\\rm{c}}}=|\\downarrow \\Uparrow \\rangle \$ and \${{\\rm{S}}}_{{\\rm{d}}}=|\\downarrow \\Downarrow \\rangle \$ , where the ket notation represents the positron spin (left; ↓ or ↑) and antiproton spin (right; ⇓ or ⇑ ) states in the high-field limit. The labels S ab and S cd are used when the antiproton spins are unpolarized. For the 2P states, the fine-structure splittings are labelled with subscripts a–f in order of decreasing energy at low magnetic fields, whereas the hyperfine splitting due to the antiproton spin is specified by subscripts + and − for spin parallel ( ⇑ ) and anti-parallel ( ⇓ ) to the magnetic field in the high-field limit, respectively. The symbol (0, ↑) or (1,↓) for the 2P states in the figure indicates that the positron spin states are mixed for the 2P c and 2P f states, where the first value (0 or 1) in the label corresponds to the magnetic quantum number m L of the orbital angular momentum L = 1 in the 2P state, while the second label ↑ or ↓ indicates the positron spin. The vertical solid arrows indicate the one-photon laser transitions probed here: 1S d → 2P f− (bold red), 1S c → 2P f+ (thin red), 1S d → 2P c− (bold blue) and 1S c → 2P c+ (thin blue). The dashed red and blue arrows indicate relaxation to the same trappable level, which is not detectable in the present experiment, and the dashed black arrows indicate relaxation to untrappable levels, which is detectable via annihilation signals (see text). The bold black arrow shows the microwave transition used to eliminate", "role": "user" }, { "content": "The ALPHA collaboration at CERN has reported the first measurements of certain quantum effects in the energy structure of antihydrogen, the antimatter counterpart of hydrogen. These quantum effects are known to exist in matter, and studying them could reveal as yet unobserved differences between the behavior of matter and antimatter. The results, described in a paper published today in the journal Nature, show that these first measurements are consistent with theoretical predictions of the effects in \"normal\" hydrogen, and pave the way for more precise measurements of these and other fundamental quantities. \"Finding any difference between these two forms of matter would shake the foundations of the Standard Model of particle physics, and these new measurements probe aspects of antimatter interaction—such as the Lamb shift—that we have long looked forward to addressing,\" says Jeffrey Hangst, spokesperson for the ALPHA experiment. \"Next on our list is chilling large samples of antihydrogen using state-of-the-art laser cooling techniques. These techniques will transform antimatter studies and will allow unprecedentedly high-precision comparisons between matter and antimatter.\" The ALPHA team creates antihydrogen atoms by binding antiprotons delivered by CERN's Antiproton Decelerator with antielectrons, more commonly called \"positrons.\" It then confines them in a magnetic trap in an ultra-high vacuum, which prevents them from coming into contact with matter and annihilating. Laser light is then shone onto the trapped atoms to measure their spectral response. This technique helps measure known quantum effects like the so-called fine structure and the Lamb shift, which correspond to tiny splittings in certain energy levels of the atom, and were measured in this study in the antihydrogen atom for the first time. The team previously used this approach to measure other quantum effects in antihydrogen, the latest being a measurement of the Lyman-alpha transition. The fine structure was measured in atomic hydrogen more than a century ago, and laid the foundation for the introduction of a fundamental constant of nature that describes the strength of the electromagnetic interaction between elementary charged particles. The Lamb shift was discovered in the same system about 70 years ago and was a key element in the development of quantum electrodynamics, the theory of how matter and light interact. The Lamb-shift measurement, which won Willis Lamb the Nobel Prize in Physics in 1955, was reported in 1947 at the famous Shelter Island conference—the first important opportunity for leaders of the American physics community to gather after the war. Technical Note Both the fine structure and the Lamb shift are small splittings in certain energy levels (or spectral lines) of an atom, which can be studied with spectroscopy. The fine-structure splitting of the second energy level of hydrogen is a separation between the so-called 2P3/2 and 2P1/2 levels in the absence of a magnetic field. The splitting is caused by the interaction between the velocity of the atom's electron and its intrinsic (quantum) rotation. The \"classic\" Lamb shift is the splitting between the 2S1/2 and 2P1/2 levels, also in the absence of a magnetic field. It is the result of the effect on the electron of quantum fluctuations associated with virtual photons popping in and out of existence in a vacuum. In their new study, the ALPHA team determined the fine-structure splitting and the Lamb shift by inducing and studying transitions between the lowest energy level of antihydrogen and the 2P3/2 and 2P1/2 levels in the presence of a magnetic field of 1 Tesla. Using the value of the frequency of a transition that they had previously measured, the 1S–2S transition, and assuming that certain quantum interactions were valid for antihydrogen, the researchers inferred from their results the values of the fine-structure splitting and the Lamb shift. They found that the inferred values are consistent with theoretical predictions of the splittings in \"normal\" hydrogen, within the experimental uncertainty of 2% for the fine-structure splitting and of 11% for the Lamb shift. ", "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 At the historic Shelter Island Conference on the Foundations of Quantum Mechanics in 1947, Willis Lamb reported an unexpected feature in the fine structure of atomic hydrogen: a separation of the 2S 1/2 and 2P 1/2 states 1 . The observation of this separation, now known as the Lamb shift, marked an important event in the evolution of modern physics, inspiring others to develop the theory of quantum electrodynamics 2 , 3 , 4 , 5 . Quantum electrodynamics also describes antimatter, but it has only recently become possible to synthesize and trap atomic antimatter to probe its structure. Mirroring the historical development of quantum atomic physics in the twentieth century, modern measurements on anti-atoms represent a unique approach for testing quantum electrodynamics and the foundational symmetries of the standard model. Here we report measurements of the fine structure in the n = 2 states of antihydrogen, the antimatter counterpart of the hydrogen atom. Using optical excitation of the 1S–2P Lyman-α transitions in antihydrogen 6 , we determine their frequencies in a magnetic field of 1 tesla to a precision of 16 parts per billion. Assuming the standard Zeeman and hyperfine interactions, we infer the zero-field fine-structure splitting (2P 1/2 –2P 3/2 ) in antihydrogen. The resulting value is consistent with the predictions of quantum electrodynamics to a precision of 2 per cent. Using our previously measured value of the 1S–2S transition frequency 6 , 7 , we find that the classic Lamb shift in antihydrogen (2S 1/2 –2P 1/2 splitting at zero field) is consistent with theory at a level of 11 per cent. Our observations represent an important step towards precision measurements of the fine structure and the Lamb shift in the antihydrogen spectrum as tests of the charge–parity–time symmetry 8 and towards the determination of other fundamental quantities, such as the antiproton charge radius 9 , 10 , in this antimatter system. Main The fine-structure splitting of the n = 2 states of hydrogen is the separation of the 2P 3/2 and 2P 1/2 levels at zero magnetic field. This splitting, predicted by the Dirac theory of relativistic quantum mechanics 11 , originates from the spin–orbit interaction between the non-zero orbital angular momentum ( L = 1) and the electron spin. The ‘classic’ Lamb shift is defined as the splitting between the 2S 1/2 and 2P 1/2 states at zero field 12 , and is a manifestation of the interaction of the electron with the quantum fluctuations of the vacuum electromagnetic field, an effect explained by quantum electrodynamics (QED) 12 , 13 , 14 . Today, it is understood that the classic Lamb shift in hydrogen is dominated by the QED effects on the 2S energy level, and that the 1S level receives even stronger QED corrections than the 2S level 12 , 13 . Although QED corrections in levels n ≠ 2 are now also sometimes referred to as Lamb shifts, in this Article we restrict our definition of the Lamb shift to be the classic n = 2 shift. In a magnetic field, the Zeeman effect causes the 2P 3/2 state to also split into four sublevels (labelled 2P a , 2P b , 2P c and 2P d ), whereas the 2S 1/2 and 2P 1/2 states each split into two (2S ab and 2S cd ; 2P e and 2P f ). These fine-structure levels further split into two hyperfine states owing to the proton spin (see Fig. 1 for the expected energy levels for the case of antihydrogen, where the spin orientations are reversed with respect to those of hydrogen.) Fig. 1: Expected antihydrogen energy levels. Calculated energies of the fine structure and the hyperfine sublevels of the 1S 1/2 , 2S 1/2 , 2P 3/2 and 2P 1/2 states are shown as functions of magnetic-field strength. The spin orientations for antihydrogen are shown; they are reversed for hydrogen. The centroid energy difference, E 1S–2S = 2.4661 × 10 15 Hz, has been suppressed on the vertical axis. Details of the energy levels relevant to this work at a magnetic field of B = 1.0329 T are shown on the right. Each state is labelled using conventional notation. For the 1S and 2S states, the hyperfine states are labelled with subscripts a–d in order of increasing energy (see, for example, ref. 7 ); namely, ${{\rm{S}}}_{{\rm{a}}}=|\uparrow \Downarrow \rangle $ , ${{\rm{S}}}_{{\rm{b}}}=|\uparrow \Uparrow \rangle $ , ${{\rm{S}}}_{{\rm{c}}}=|\downarrow \Uparrow \rangle $ and ${{\rm{S}}}_{{\rm{d}}}=|\downarrow \Downarrow \rangle $ , where the ket notation represents the positron spin (left; ↓ or ↑) and antiproton spin (right; ⇓ or ⇑ ) states in the high-field limit. The labels S ab and S cd are used when the antiproton spins are unpolarized. For the 2P states, the fine-structure splittings are labelled with subscripts a–f in order of decreasing energy at low magnetic fields, whereas the hyperfine splitting due to the antiproton spin is specified by subscripts + and − for spin parallel ( ⇑ ) and anti-parallel ( ⇓ ) to the magnetic field in the high-field limit, respectively. The symbol (0, ↑) or (1,↓) for the 2P states in the figure indicates that the positron spin states are mixed for the 2P c and 2P f states, where the first value (0 or 1) in the label corresponds to the magnetic quantum number m L of the orbital angular momentum L = 1 in the 2P state, while the second label ↑ or ↓ indicates the positron spin. The vertical solid arrows indicate the one-photon laser transitions probed here: 1S d → 2P f− (bold red), 1S c → 2P f+ (thin red), 1S d → 2P c− (bold blue) and 1S c → 2P c+ (thin blue). The dashed red and blue arrows indicate relaxation to the same trappable level, which is not detectable in the present experiment, and the dashed black arrows indicate relaxation to untrappable levels, which is detectable via annihilation signals (see text). The bold black arrow shows the microwave transition used to eliminate<|im_end|> <|im_start|>assistant The ALPHA collaboration at CERN has reported the first measurements of certain quantum effects in the energy structure of antihydrogen, the antimatter counterpart of hydrogen. These quantum effects are known to exist in matter, and studying them could reveal as yet unobserved differences between the behavior of matter and antimatter. The results, described in a paper published today in the journal Nature, show that these first measurements are consistent with theoretical predictions of the effects in "normal" hydrogen, and pave the way for more precise measurements of these and other fundamental quantities. "Finding any difference between these two forms of matter would shake the foundations of the Standard Model of particle physics, and these new measurements probe aspects of antimatter interaction—such as the Lamb shift—that we have long looked forward to addressing," says Jeffrey Hangst, spokesperson for the ALPHA experiment. "Next on our list is chilling large samples of antihydrogen using state-of-the-art laser cooling techniques. These techniques will transform antimatter studies and will allow unprecedentedly high-precision comparisons between matter and antimatter." The ALPHA team creates antihydrogen atoms by binding antiprotons delivered by CERN's Antiproton Decelerator with antielectrons, more commonly called "positrons." It then confines them in a magnetic trap in an ultra-high vacuum, which prevents them from coming into contact with matter and annihilating. Laser light is then shone onto the trapped atoms to measure their spectral response. This technique helps measure known quantum effects like the so-called fine structure and the Lamb shift, which correspond to tiny splittings in certain energy levels of the atom, and were measured in this study in the antihydrogen atom for the first time. The team previously used this approach to measure other quantum effects in antihydrogen, the latest being a measurement of the Lyman-alpha transition. The fine structure was measured in atomic hydrogen more than a century ago, and laid the foundation for the introduction of a fundamental constant of nature that describes the strength of the electromagnetic interaction between elementary charged particles. The Lamb shift was discovered in the same system about 70 years ago and was a key element in the development of quantum electrodynamics, the theory of how matter and light interact. The Lamb-shift measurement, which won Willis Lamb the Nobel Prize in Physics in 1955, was reported in 1947 at the famous Shelter Island conference—the first important opportunity for leaders of the American physics community to gather after the war. Technical Note Both the fine structure and the Lamb shift are small splittings in certain energy levels (or spectral lines) of an atom, which can be studied with spectroscopy. The fine-structure splitting of the second energy level of hydrogen is a separation between the so-called 2P3/2 and 2P1/2 levels in the absence of a magnetic field. The splitting is caused by the interaction between the velocity of the atom's electron and its intrinsic (quantum) rotation. The "classic" Lamb shift is the splitting between the 2S1/2 and 2P1/2 levels, also in the absence of a magnetic field. It is the result of the effect on the electron of quantum fluctuations associated with virtual photons popping in and out of existence in a vacuum. In their new study, the ALPHA team determined the fine-structure splitting and the Lamb shift by inducing and studying transitions between the lowest energy level of antihydrogen and the 2P3/2 and 2P1/2 levels in the presence of a magnetic field of 1 Tesla. Using the value of the frequency of a transition that they had previously measured, the 1S–2S transition, and assuming that certain quantum interactions were valid for antihydrogen, the researchers inferred from their results the values of the fine-structure splitting and the Lamb shift. They found that the inferred values are consistent with theoretical predictions of the splittings in "normal" hydrogen, within the experimental uncertainty of 2% for the fine-structure splitting and of 11% for the Lamb shift. <|im_end|>

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11651, 220, 17, 47, 272, 10, 320, 64771, 6437, 570, 578, 67822, 2579, 323, 6437, 38057, 13519, 43685, 311, 279, 1890, 490, 87484, 2237, 11, 902, 374, 539, 11388, 481, 304, 279, 3118, 9526, 11, 323, 279, 67822, 3776, 38057, 13519, 43685, 311, 653, 376, 87484, 5990, 11, 902, 374, 11388, 481, 4669, 3008, 92341, 17738, 320, 4151, 1495, 570, 578, 14265, 3776, 18404, 5039, 279, 42374, 9320, 1511, 311, 22472, 128257, 198, 128256, 78191, 198, 791, 83897, 20632, 520, 356, 13974, 706, 5068, 279, 1176, 22323, 315, 3738, 31228, 6372, 304, 279, 4907, 6070, 315, 3276, 7141, 68107, 4469, 11, 279, 79312, 1683, 45116, 315, 35784, 13, 4314, 31228, 6372, 527, 3967, 311, 3073, 304, 5030, 11, 323, 21630, 1124, 1436, 16805, 439, 3686, 653, 5598, 2841, 12062, 1990, 279, 7865, 315, 5030, 323, 79312, 1683, 13, 578, 3135, 11, 7633, 304, 264, 5684, 4756, 3432, 304, 279, 8486, 22037, 11, 1501, 430, 1521, 1176, 22323, 527, 13263, 449, 32887, 20492, 315, 279, 6372, 304, 330, 8416, 1, 35784, 11, 323, 94123, 279, 1648, 369, 810, 24473, 22323, 315, 1521, 323, 1023, 16188, 33776, 13, 330, 52522, 904, 6811, 1990, 1521, 1403, 7739, 315, 5030, 1053, 27116, 279, 41582, 315, 279, 12028, 5008, 315, 19320, 22027, 11, 323, 1521, 502, 22323, 22477, 13878, 315, 79312, 1683, 16628, 2345, 21470, 439, 279, 32402, 6541, 41128, 584, 617, 1317, 7111, 4741, 311, 28118, 1359, 2795, 42107, 41875, 267, 11, 29003, 369, 279, 83897, 9526, 13, 330, 5971, 389, 1057, 1160, 374, 62724, 3544, 10688, 315, 3276, 7141, 68107, 4469, 1701, 1614, 8838, 10826, 38921, 21120, 28015, 12823, 13, 4314, 12823, 690, 5276, 79312, 1683, 7978, 323, 690, 2187, 31069, 398, 1579, 12, 28281, 36595, 1990, 5030, 323, 79312, 1683, 1210, 578, 83897, 2128, 11705, 3276, 7141, 68107, 4469, 33299, 555, 11212, 3276, 49889, 35511, 12886, 555, 356, 13974, 596, 6898, 49889, 783, 3799, 8023, 859, 449, 3276, 648, 772, 26692, 11, 810, 17037, 2663, 330, 2792, 26692, 1210, 1102, 1243, 91120, 1124, 304, 264, 24924, 23709, 304, 459, 24955, 28661, 29302, 11, 902, 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51248, 11, 279, 10334, 315, 1268, 5030, 323, 3177, 16681, 13, 578, 32402, 91043, 19179, 11, 902, 2834, 67742, 32402, 279, 48078, 32293, 304, 28415, 304, 220, 6280, 20, 11, 574, 5068, 304, 220, 6393, 22, 520, 279, 11495, 75921, 10951, 10017, 22416, 1176, 3062, 6776, 369, 6164, 315, 279, 3778, 22027, 4029, 311, 9762, 1306, 279, 4208, 13, 27766, 7181, 11995, 279, 7060, 6070, 323, 279, 32402, 6541, 527, 2678, 12786, 53359, 304, 3738, 4907, 5990, 320, 269, 57077, 5238, 8, 315, 459, 19670, 11, 902, 649, 387, 20041, 449, 66425, 51856, 13, 578, 7060, 12, 7993, 45473, 315, 279, 2132, 4907, 2237, 315, 35784, 374, 264, 25768, 1990, 279, 779, 19434, 220, 17, 47, 18, 14, 17, 323, 220, 17, 47, 16, 14, 17, 5990, 304, 279, 19821, 315, 264, 24924, 2115, 13, 578, 45473, 374, 9057, 555, 279, 16628, 1990, 279, 15798, 315, 279, 19670, 596, 17130, 323, 1202, 47701, 320, 31548, 372, 8, 12984, 13, 578, 330, 80809, 1, 32402, 6541, 374, 279, 45473, 1990, 279, 220, 17, 50, 16, 14, 17, 323, 220, 17, 47, 16, 14, 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27924, 315, 220, 17, 4, 369, 279, 7060, 12, 7993, 45473, 323, 315, 220, 806, 4, 369, 279, 32402, 6541, 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 Soliton microcombs—phase-locked microcavity frequency combs—have become the foundation of several classical technologies in integrated photonics, including spectroscopy, LiDAR and optical computing. Despite the predicted multimode entanglement across the comb, experimental study of the quantum optics of the soliton microcomb has been elusive. In this work we use second-order photon correlations to study the underlying quantum processes of soliton microcombs in an integrated silicon carbide microresonator. We show that a stable temporal lattice of solitons can isolate a multimode below-threshold Gaussian state from any admixture of coherent light, and predict that all-to-all entanglement can be realized for the state. Our work opens a pathway toward a soliton-based multimode quantum resource. Main Kerr optical frequency combs 1 , 2 , 3 are multimode states of light generated via a third-order optical nonlinearity in an optical resonator. When a Kerr resonator is pumped weakly, spontaneous parametric processes populate resonator modes in pairs. In this regime, Kerr combs can be a quantum resource for the generation of heralded single photons and energy-time entangled pairs 4 , 5 , 6 , multiphoton entangled states 7 , 8 , 9 and squeezed vacuum 10 , 11 , 12 . When pumped more strongly, the parametric gain can exceed the resonator loss and give rise to optical parametric oscillation (OPO) and bright comb formation. The modes of a Kerr comb can become phase-locked to form a stable, low-noise dissipative Kerr soliton (DKS). This regime of Kerr comb operation has become the foundation of multiple technologies, including comb-based spectroscopy 13 , LIDAR 14 , optical frequency synthesizers 15 and optical processors 16 . Although the soliton microcomb has been mostly studied classically, it is nonetheless fundamentally governed by the dynamics of quantized parametric processes: each resonator mode is coupled to every other mode through a four-photon interaction. The multimode coupled processes of the DKS resemble those of the well-studied synchronously pumped OPO 17 , 18 . If the quantum processes can be harnessed, soliton microcombs may open a pathway toward the experimental realization of a multimode quantum resource 18 , 19 , 20 in a scalable, chip-integrated platform 21 , 22 . Recent demonstrations of a fully integrated squeezing measurement 23 and a squeezed below-threshold microcomb 24 provide a technological road map for developing the DKS state as a resource for continuous-variable quantum computing 25 , 26 , 27 , 28 ; however, the quantum-optical properties of soliton microcombs have not yet been directly observed: the first glimpse into non-classicality was the recent measurement of the quantum-limited timing jitter of the DKS state 29 , 30 . Linearization 31 —the formal separation of the optical state into the mean field solution and the quantum fluctuations—is one approach to simplify the otherwise intractable many-body quartic Hamiltonian of the DKS. The result of this approximation is a quadratic Hamiltonian, where the classical amplitudes A m , obtained, for example, through the spatiotemporal Lugiato–Lefever equation (LLE) 32 , drive the spontaneous parametric processes between quantum modes \${\\hat{a}}_{j}\$ : $${\\hat{H}}_{{{{\\rm{int}}}}}=-\\frac{{g}_{0}}{2}\\mathop{\\sum}\\limits_{m,n,j,k}{\\delta }_{{{{\\rm{FWM}}}}}({A}_{m}{A}_{n}{\\hat{a}}_{j}^{{\\dagger} }{\\hat{a}}_{k}^{{\\dagger} }+{A}_{k}^{* }{A}_{n}{\\hat{a}}_{j}^{{\\dagger} }{\\hat{a}}_{m}+{{{\\rm{h}}}}.{{{\\rm{c}}}}.)$$ (1) where δ FWM = δ ( j + k − m − n ) is the four-wave mixing (FWM) mode number matching condition, g 0 is the nonlinear coupling coefficient, and h.c. is the Hermitian conjugate. This approximation has been used to model 33 the quantum correlations developed by a coherent soliton pulse after propagating through a fibre 34 . Unlike the fibre soliton, however, the microcavity soliton features an interplay of dissipation and strong Kerr interactions in the regime where linearization can break down and yield unphysical predictions 35 , 36 . Experimentally verifying the validity of this model for the DKS is a prerequisite for exploring its application in quantum technologies. In this work we use second-order photon correlation measurements to experimentally validate the linearized model (equation ( 1 )) for describing the spontaneous parametric processes in DKS states. We first study the quantum formation dynamics of Kerr frequency combs, including coherence broadening of spontaneous FWM photon pairs near the OPO threshold. We then identify a class of DKS states—perfect soliton crystals 37 , 38 —which naturally isolate a subset of quantum optical fields from the coherent mean-field (Fig. 1 ); we measure the correlation matrix of the below-threshold modes to numerically infer the multimode entanglement structure of the state. We find that the DKS state may be engineered as an on-chip source of all-to-all entanglement. Fig. 1: Linearized model for quantum optical fields in a DKS state. A schematic depiction of a Kerr microresonator with a circulating perfect soliton crystal state. The full optical state is modelled as a coherent classical comb (blue) that drives the quantum comb (red) via spontaneous parametric processes. Full size image The observation of the full optical spectrum of a Kerr frequency comb—including the above- and below-threshold processes—requires single-photon sensitivity and a high dynamic range. For this purpose, we designed a single-photon optical spectrum analyser (SPOSA) using multipass grating monochromators and superconducting nanowire single-photon detectors (SNSPDs; PhotonSpot). The SPOSA has a broadband (>200 nm) quantum efficiency of around 20%, and close-in dynamic range of >140 dB at ±0.8 nm. We generate Kerr frequency combs using microring resonators with a 350 GHz free spectral range (FSR) fabricated in 4H-silicon carbide-on-insulator, a platform with favourable nonlinear 39 and quantum 40 optical properties. With intrinsic quality factors (Q) as high as 5.6 × 10 6 , low-threshold OPO (0.5 mW) and low-power soliton operation (2.3 mW) are achieved (Supplementary Fig. 4 ). We use the SPOSA to characterize the Kerr microcomb spectra through all stages of DKS formation (Fig. 2a,b ). The sech 2 soliton envelope is seen to persist at the tails of the DKS, in modes with very low photon number \$\\left\\langle {a}_{j}^{{\\dagger} }{a}_{j}\\right\\rangle < 1{0}^{-3}\$ (corresponding to a photon count rate of <1 kHz). The quantum fluctuations generated in the DKS state and responsible for its quantum-limited timing jitter 29 , 30 are obscured in the single-soliton spectrum. A perfect soliton crystal 37 , 38 (henceforth referred", "role": "user" }, { "content": "Unlike the jumble of frequencies produced by the light that surrounds us in daily life, each frequency of light in a specialized light source known as a \"soliton\" frequency comb oscillates in unison, generating solitary pulses with consistent timing. Each \"tooth\" of the comb is a different color of light, spaced so precisely that this system is used to measure all manner of phenomena and characteristics. Miniaturized versions of these combs—called microcombs—that are currently in development have the potential to enhance countless technologies, including GPS systems, telecommunications, autonomous vehicles, greenhouse gas tracking, spacecraft autonomy and ultra-precise timekeeping. The lab of Stanford University electrical engineer Jelena Vučković only recently joined the microcomb community. \"Many groups have demonstrated on-chip frequency combs in a variety of materials, including recently in silicon carbide by our team. However, until now, the quantum optical properties of frequency combs have been elusive,\" said Vučković, the Jensen Huang Professor of Global Leadership in the School of Engineering and professor of electrical engineering at Stanford. \"We wanted to leverage the quantum optics background of our group to study the quantum properties of the soliton microcomb.\" While soliton microcombs have been made in other labs, the Stanford researchers are among the first to investigate the system's quantum optical properties, using a process that they outline in a paper published Dec. 16 in Nature Photonics. When created in pairs, microcomb solitons are thought to exhibit entanglement—a relationship between particles that allows them to influence each other even at incredible distances, which underpins our understanding of quantum physics and is the basis of all proposed quantum technologies. Most of the \"classical\" light we encounter on a daily basis does not exhibit entanglement. \"This is one of the first demonstrations that this miniaturized frequency comb can generate interesting quantum light—non-classical light—on a chip,\" said Kiyoul Yang, a research scientist in Vučković's Nanoscale and Quantum Photonics Lab and co-author of the paper. \"That can open a new pathway toward broader explorations of quantum light using the frequency comb and photonic integrated circuits for large-scale experiments.\" Proving the utility of their tool, the researchers also provided convincing evidence of quantum entanglement within the soliton microcomb, which has been theorized and assumed but has yet to be proven by any existing studies. \"I would really like to see solitons become useful for quantum computing because it's a highly studied system,\" said Melissa Guidry, a graduate student in the Nanoscale and Quantum Photonics Lab and co-author of the paper. \"We have a lot of technology at this point for generating solitons on chips at low power, so it would be exciting to be able to take that and show that you have entanglement.\" Conceptual diagram of the frequency comb and the microring, with solitons, that produces it. The frequency comb diagram shows both the coherent light teeth and the quantum light between those teeth. Credit: Vučković Lab Between the teeth Former Stanford physics professor Theodor W. Hänsch won the Nobel Prize in 2005 for his work on developing the first frequency comb. To create what Hänsch studied requires complicated, tabletop-sized equipment. Instead, these researchers chose to focus on the newer, \"micro\" version, where all of the parts of the system are integrated into a single device and designed to fit on a microchip. This design saves on cost, size and energy. To create their miniature comb, the researchers pump laser light through a microscopic ring of silicon carbide (which was painstakingly designed and fabricated using the resources of the Stanford Nano Shared Facilities and Stanford Nanofabrication Facilities). Traveling around the ring, the laser builds up intensity and, if all goes well, a soliton is born. \"It's fascinating that, instead of having this fancy, complicated machine, you can just take a laser pump and a really tiny circle and produce the same sort of specialized light,\" said Daniil Lukin, a graduate student in the Nanoscale and Quantum Photonics Lab and co-author of the paper. He added that generating the microcomb on a chip enabled a wide spacing between the teeth, which was one step toward being able to look at the comb's finer details. The next steps involved equipment capable of detecting single particles of the light and packing the micro-ring with several solitons, creating a soliton crystal. \"With the soliton crystal, you can see there are actually smaller pulses of light in between the teeth, which is what we measure to infer the entanglement structure,\" explained Guidry. \"If you park your detectors there, you can get a good look at the interesting quantum behavior without drowning it out with the coherent light that makes up the teeth.\" Seeing as they were performing some of the first experimental studies of the quantum aspects of this system, the researchers decided to try to confirm a theoretical model, called the linearized model, which is commonly used as a shortcut to describe complex quantum systems. When they ran the comparison, they were astonished to find that the experiment matched the theory very well. So, while they have not yet directly measured that their microcomb has quantum entanglement, they have shown that its performance matches a theory that implies entanglement. \"The take-home message is that this opens the door for theorists to do more theory because now, with this system, it's possible to experimentally verify that work,\" said Lukin. Proving and using quantum entanglement Microcombs in data centers could boost the speed of data transfer; in satellites, they could provide more precise GPS or analyze the chemical composition of far-away objects. The Vučković team is particularly interested in the potential for solitons in certain types of quantum computing because solitons are predicted to be highly entangled as soon as they are generated. With their platform, and the ability to study it from a quantum perspective, the Nanoscale and Quantum Photonics Lab researchers are keeping an open mind about what they could do next. Near the top of their list of ideas is the possibility of performing measurements on their system that definitively prove quantum entanglement. ", "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 Soliton microcombs—phase-locked microcavity frequency combs—have become the foundation of several classical technologies in integrated photonics, including spectroscopy, LiDAR and optical computing. Despite the predicted multimode entanglement across the comb, experimental study of the quantum optics of the soliton microcomb has been elusive. In this work we use second-order photon correlations to study the underlying quantum processes of soliton microcombs in an integrated silicon carbide microresonator. We show that a stable temporal lattice of solitons can isolate a multimode below-threshold Gaussian state from any admixture of coherent light, and predict that all-to-all entanglement can be realized for the state. Our work opens a pathway toward a soliton-based multimode quantum resource. Main Kerr optical frequency combs 1 , 2 , 3 are multimode states of light generated via a third-order optical nonlinearity in an optical resonator. When a Kerr resonator is pumped weakly, spontaneous parametric processes populate resonator modes in pairs. In this regime, Kerr combs can be a quantum resource for the generation of heralded single photons and energy-time entangled pairs 4 , 5 , 6 , multiphoton entangled states 7 , 8 , 9 and squeezed vacuum 10 , 11 , 12 . When pumped more strongly, the parametric gain can exceed the resonator loss and give rise to optical parametric oscillation (OPO) and bright comb formation. The modes of a Kerr comb can become phase-locked to form a stable, low-noise dissipative Kerr soliton (DKS). This regime of Kerr comb operation has become the foundation of multiple technologies, including comb-based spectroscopy 13 , LIDAR 14 , optical frequency synthesizers 15 and optical processors 16 . Although the soliton microcomb has been mostly studied classically, it is nonetheless fundamentally governed by the dynamics of quantized parametric processes: each resonator mode is coupled to every other mode through a four-photon interaction. The multimode coupled processes of the DKS resemble those of the well-studied synchronously pumped OPO 17 , 18 . If the quantum processes can be harnessed, soliton microcombs may open a pathway toward the experimental realization of a multimode quantum resource 18 , 19 , 20 in a scalable, chip-integrated platform 21 , 22 . Recent demonstrations of a fully integrated squeezing measurement 23 and a squeezed below-threshold microcomb 24 provide a technological road map for developing the DKS state as a resource for continuous-variable quantum computing 25 , 26 , 27 , 28 ; however, the quantum-optical properties of soliton microcombs have not yet been directly observed: the first glimpse into non-classicality was the recent measurement of the quantum-limited timing jitter of the DKS state 29 , 30 . Linearization 31 —the formal separation of the optical state into the mean field solution and the quantum fluctuations—is one approach to simplify the otherwise intractable many-body quartic Hamiltonian of the DKS. The result of this approximation is a quadratic Hamiltonian, where the classical amplitudes A m , obtained, for example, through the spatiotemporal Lugiato–Lefever equation (LLE) 32 , drive the spontaneous parametric processes between quantum modes ${\hat{a}}_{j}$ : $${\hat{H}}_{{{{\rm{int}}}}}=-\frac{{g}_{0}}{2}\mathop{\sum}\limits_{m,n,j,k}{\delta }_{{{{\rm{FWM}}}}}({A}_{m}{A}_{n}{\hat{a}}_{j}^{{\dagger} }{\hat{a}}_{k}^{{\dagger} }+{A}_{k}^{* }{A}_{n}{\hat{a}}_{j}^{{\dagger} }{\hat{a}}_{m}+{{{\rm{h}}}}.{{{\rm{c}}}}.)$$ (1) where δ FWM = δ ( j + k − m − n ) is the four-wave mixing (FWM) mode number matching condition, g 0 is the nonlinear coupling coefficient, and h.c. is the Hermitian conjugate. This approximation has been used to model 33 the quantum correlations developed by a coherent soliton pulse after propagating through a fibre 34 . Unlike the fibre soliton, however, the microcavity soliton features an interplay of dissipation and strong Kerr interactions in the regime where linearization can break down and yield unphysical predictions 35 , 36 . Experimentally verifying the validity of this model for the DKS is a prerequisite for exploring its application in quantum technologies. In this work we use second-order photon correlation measurements to experimentally validate the linearized model (equation ( 1 )) for describing the spontaneous parametric processes in DKS states. We first study the quantum formation dynamics of Kerr frequency combs, including coherence broadening of spontaneous FWM photon pairs near the OPO threshold. We then identify a class of DKS states—perfect soliton crystals 37 , 38 —which naturally isolate a subset of quantum optical fields from the coherent mean-field (Fig. 1 ); we measure the correlation matrix of the below-threshold modes to numerically infer the multimode entanglement structure of the state. We find that the DKS state may be engineered as an on-chip source of all-to-all entanglement. Fig. 1: Linearized model for quantum optical fields in a DKS state. A schematic depiction of a Kerr microresonator with a circulating perfect soliton crystal state. The full optical state is modelled as a coherent classical comb (blue) that drives the quantum comb (red) via spontaneous parametric processes. Full size image The observation of the full optical spectrum of a Kerr frequency comb—including the above- and below-threshold processes—requires single-photon sensitivity and a high dynamic range. For this purpose, we designed a single-photon optical spectrum analyser (SPOSA) using multipass grating monochromators and superconducting nanowire single-photon detectors (SNSPDs; PhotonSpot). The SPOSA has a broadband (>200 nm) quantum efficiency of around 20%, and close-in dynamic range of >140 dB at ±0.8 nm. We generate Kerr frequency combs using microring resonators with a 350 GHz free spectral range (FSR) fabricated in 4H-silicon carbide-on-insulator, a platform with favourable nonlinear 39 and quantum 40 optical properties. With intrinsic quality factors (Q) as high as 5.6 × 10 6 , low-threshold OPO (0.5 mW) and low-power soliton operation (2.3 mW) are achieved (Supplementary Fig. 4 ). We use the SPOSA to characterize the Kerr microcomb spectra through all stages of DKS formation (Fig. 2a,b ). The sech 2 soliton envelope is seen to persist at the tails of the DKS, in modes with very low photon number $\left\langle {a}_{j}^{{\dagger} }{a}_{j}\right\rangle < 1{0}^{-3}$ (corresponding to a photon count rate of <1 kHz). The quantum fluctuations generated in the DKS state and responsible for its quantum-limited timing jitter 29 , 30 are obscured in the single-soliton spectrum. A perfect soliton crystal 37 , 38 (henceforth referred<|im_end|> <|im_start|>assistant Unlike the jumble of frequencies produced by the light that surrounds us in daily life, each frequency of light in a specialized light source known as a "soliton" frequency comb oscillates in unison, generating solitary pulses with consistent timing. Each "tooth" of the comb is a different color of light, spaced so precisely that this system is used to measure all manner of phenomena and characteristics. Miniaturized versions of these combs—called microcombs—that are currently in development have the potential to enhance countless technologies, including GPS systems, telecommunications, autonomous vehicles, greenhouse gas tracking, spacecraft autonomy and ultra-precise timekeeping. The lab of Stanford University electrical engineer Jelena Vučković only recently joined the microcomb community. "Many groups have demonstrated on-chip frequency combs in a variety of materials, including recently in silicon carbide by our team. However, until now, the quantum optical properties of frequency combs have been elusive," said Vučković, the Jensen Huang Professor of Global Leadership in the School of Engineering and professor of electrical engineering at Stanford. "We wanted to leverage the quantum optics background of our group to study the quantum properties of the soliton microcomb." While soliton microcombs have been made in other labs, the Stanford researchers are among the first to investigate the system's quantum optical properties, using a process that they outline in a paper published Dec. 16 in Nature Photonics. When created in pairs, microcomb solitons are thought to exhibit entanglement—a relationship between particles that allows them to influence each other even at incredible distances, which underpins our understanding of quantum physics and is the basis of all proposed quantum technologies. Most of the "classical" light we encounter on a daily basis does not exhibit entanglement. "This is one of the first demonstrations that this miniaturized frequency comb can generate interesting quantum light—non-classical light—on a chip," said Kiyoul Yang, a research scientist in Vučković's Nanoscale and Quantum Photonics Lab and co-author of the paper. "That can open a new pathway toward broader explorations of quantum light using the frequency comb and photonic integrated circuits for large-scale experiments." Proving the utility of their tool, the researchers also provided convincing evidence of quantum entanglement within the soliton microcomb, which has been theorized and assumed but has yet to be proven by any existing studies. "I would really like to see solitons become useful for quantum computing because it's a highly studied system," said Melissa Guidry, a graduate student in the Nanoscale and Quantum Photonics Lab and co-author of the paper. "We have a lot of technology at this point for generating solitons on chips at low power, so it would be exciting to be able to take that and show that you have entanglement." Conceptual diagram of the frequency comb and the microring, with solitons, that produces it. The frequency comb diagram shows both the coherent light teeth and the quantum light between those teeth. Credit: Vučković Lab Between the teeth Former Stanford physics professor Theodor W. Hänsch won the Nobel Prize in 2005 for his work on developing the first frequency comb. To create what Hänsch studied requires complicated, tabletop-sized equipment. Instead, these researchers chose to focus on the newer, "micro" version, where all of the parts of the system are integrated into a single device and designed to fit on a microchip. This design saves on cost, size and energy. To create their miniature comb, the researchers pump laser light through a microscopic ring of silicon carbide (which was painstakingly designed and fabricated using the resources of the Stanford Nano Shared Facilities and Stanford Nanofabrication Facilities). Traveling around the ring, the laser builds up intensity and, if all goes well, a soliton is born. "It's fascinating that, instead of having this fancy, complicated machine, you can just take a laser pump and a really tiny circle and produce the same sort of specialized light," said Daniil Lukin, a graduate student in the Nanoscale and Quantum Photonics Lab and co-author of the paper. He added that generating the microcomb on a chip enabled a wide spacing between the teeth, which was one step toward being able to look at the comb's finer details. The next steps involved equipment capable of detecting single particles of the light and packing the micro-ring with several solitons, creating a soliton crystal. "With the soliton crystal, you can see there are actually smaller pulses of light in between the teeth, which is what we measure to infer the entanglement structure," explained Guidry. "If you park your detectors there, you can get a good look at the interesting quantum behavior without drowning it out with the coherent light that makes up the teeth." Seeing as they were performing some of the first experimental studies of the quantum aspects of this system, the researchers decided to try to confirm a theoretical model, called the linearized model, which is commonly used as a shortcut to describe complex quantum systems. When they ran the comparison, they were astonished to find that the experiment matched the theory very well. So, while they have not yet directly measured that their microcomb has quantum entanglement, they have shown that its performance matches a theory that implies entanglement. "The take-home message is that this opens the door for theorists to do more theory because now, with this system, it's possible to experimentally verify that work," said Lukin. Proving and using quantum entanglement Microcombs in data centers could boost the speed of data transfer; in satellites, they could provide more precise GPS or analyze the chemical composition of far-away objects. The Vučković team is particularly interested in the potential for solitons in certain types of quantum computing because solitons are predicted to be highly entangled as soon as they are generated. With their platform, and the ability to study it from a quantum perspective, the Nanoscale and Quantum Photonics Lab researchers are keeping an open mind about what they could do next. Near the top of their list of ideas is the possibility of performing measurements on their system that definitively prove quantum entanglement. <|im_end|>

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24229, 6067, 11, 62866, 11, 39293, 11731, 11, 37647, 6962, 15194, 11, 42640, 51360, 323, 24955, 12, 10872, 1082, 892, 33494, 13, 578, 10278, 315, 31788, 3907, 20314, 24490, 622, 301, 7304, 57702, 13453, 119066, 7886, 1193, 6051, 11096, 279, 8162, 22631, 4029, 13, 330, 8607, 5315, 617, 21091, 389, 11843, 575, 11900, 470, 1302, 304, 264, 8205, 315, 7384, 11, 2737, 6051, 304, 51692, 35872, 579, 555, 1057, 2128, 13, 4452, 11, 3156, 1457, 11, 279, 31228, 29393, 6012, 315, 11900, 470, 1302, 617, 1027, 66684, 1359, 1071, 57702, 13453, 119066, 7886, 11, 279, 65109, 59509, 17054, 315, 8121, 37263, 304, 279, 6150, 315, 17005, 323, 14561, 315, 20314, 15009, 520, 31788, 13, 330, 1687, 4934, 311, 33164, 279, 31228, 70985, 4092, 315, 1057, 1912, 311, 4007, 279, 31228, 6012, 315, 279, 2092, 63537, 8162, 22631, 1210, 6104, 2092, 63537, 8162, 884, 1302, 617, 1027, 1903, 304, 1023, 51048, 11, 279, 31788, 12074, 527, 4315, 279, 1176, 311, 19874, 279, 1887, 596, 31228, 29393, 6012, 11, 1701, 264, 1920, 430, 814, 21782, 304, 264, 5684, 4756, 3799, 13, 220, 845, 304, 22037, 63238, 1233, 13, 3277, 3549, 304, 13840, 11, 8162, 22631, 2092, 275, 2439, 527, 3463, 311, 31324, 1218, 526, 1001, 29096, 5133, 1990, 19252, 430, 6276, 1124, 311, 10383, 1855, 1023, 1524, 520, 15400, 27650, 11, 902, 1234, 75658, 1057, 8830, 315, 31228, 22027, 323, 374, 279, 8197, 315, 682, 11223, 31228, 14645, 13, 7648, 315, 279, 330, 1058, 950, 1, 3177, 584, 13123, 389, 264, 7446, 8197, 1587, 539, 31324, 1218, 526, 1001, 13, 330, 2028, 374, 832, 315, 279, 1176, 44895, 430, 420, 13726, 2693, 1534, 11900, 3698, 649, 7068, 7185, 31228, 3177, 2345, 6414, 15144, 950, 3177, 2345, 263, 264, 16797, 1359, 1071, 30558, 9514, 75, 25482, 11, 264, 3495, 28568, 304, 57702, 13453, 119066, 7886, 596, 33242, 437, 2296, 323, 56413, 63238, 1233, 11868, 323, 1080, 43802, 315, 279, 5684, 13, 330, 4897, 649, 1825, 264, 502, 38970, 9017, 27927, 48539, 811, 315, 31228, 3177, 1701, 279, 11900, 3698, 323, 4604, 14338, 18751, 46121, 369, 3544, 13230, 21896, 1210, 1322, 4504, 279, 15919, 315, 872, 5507, 11, 279, 12074, 1101, 3984, 40661, 6029, 315, 31228, 1218, 526, 1001, 2949, 279, 2092, 63537, 8162, 22631, 11, 902, 706, 1027, 46820, 1534, 323, 19655, 719, 706, 3686, 311, 387, 17033, 555, 904, 6484, 7978, 13, 330, 40, 1053, 2216, 1093, 311, 1518, 2092, 275, 2439, 3719, 5505, 369, 31228, 25213, 1606, 433, 596, 264, 7701, 20041, 1887, 1359, 1071, 48148, 12433, 894, 11, 264, 19560, 5575, 304, 279, 33242, 437, 2296, 323, 56413, 63238, 1233, 11868, 323, 1080, 43802, 315, 279, 5684, 13, 330, 1687, 617, 264, 2763, 315, 5557, 520, 420, 1486, 369, 24038, 2092, 275, 2439, 389, 24512, 520, 3428, 2410, 11, 779, 433, 1053, 387, 13548, 311, 387, 3025, 311, 1935, 430, 323, 1501, 430, 499, 617, 1218, 526, 1001, 1210, 35455, 940, 13861, 315, 279, 11900, 3698, 323, 279, 19748, 90679, 11, 449, 2092, 275, 2439, 11, 430, 19159, 433, 13, 578, 11900, 3698, 13861, 5039, 2225, 279, 56887, 3177, 18311, 323, 279, 31228, 3177, 1990, 1884, 18311, 13, 16666, 25, 57702, 13453, 119066, 7886, 11868, 28232, 279, 18311, 33600, 31788, 22027, 14561, 578, 50017, 468, 13, 91693, 4511, 331, 2834, 279, 48078, 32293, 304, 220, 1049, 20, 369, 813, 990, 389, 11469, 279, 1176, 11900, 3698, 13, 2057, 1893, 1148, 91693, 4511, 331, 20041, 7612, 17395, 11, 89571, 28935, 7241, 13, 12361, 11, 1521, 12074, 14896, 311, 5357, 389, 279, 26627, 11, 330, 41543, 1, 2373, 11, 1405, 682, 315, 279, 5596, 315, 279, 1887, 527, 18751, 1139, 264, 3254, 3756, 323, 6319, 311, 5052, 389, 264, 8162, 30762, 13, 1115, 2955, 27024, 389, 2853, 11, 1404, 323, 4907, 13, 2057, 1893, 872, 57863, 3698, 11, 279, 12074, 14155, 21120, 3177, 1555, 264, 90090, 10264, 315, 51692, 35872, 579, 320, 8370, 574, 98713, 398, 6319, 323, 70554, 1701, 279, 5070, 315, 279, 31788, 64051, 17423, 66389, 323, 31788, 33242, 1073, 29997, 367, 66389, 570, 18589, 287, 2212, 279, 10264, 11, 279, 21120, 22890, 709, 21261, 323, 11, 422, 682, 5900, 1664, 11, 264, 2092, 63537, 374, 9405, 13, 330, 2181, 596, 27387, 430, 11, 4619, 315, 3515, 420, 27555, 11, 17395, 5780, 11, 499, 649, 1120, 1935, 264, 21120, 14155, 323, 264, 2216, 13987, 12960, 323, 8356, 279, 1890, 3460, 315, 28175, 3177, 1359, 1071, 30639, 321, 55757, 258, 11, 264, 19560, 5575, 304, 279, 33242, 437, 2296, 323, 56413, 63238, 1233, 11868, 323, 1080, 43802, 315, 279, 5684, 13, 1283, 3779, 430, 24038, 279, 8162, 22631, 389, 264, 16797, 9147, 264, 7029, 27032, 1990, 279, 18311, 11, 902, 574, 832, 3094, 9017, 1694, 3025, 311, 1427, 520, 279, 3698, 596, 73886, 3649, 13, 578, 1828, 7504, 6532, 7241, 13171, 315, 54626, 3254, 19252, 315, 279, 3177, 323, 36813, 279, 8162, 77029, 449, 3892, 2092, 275, 2439, 11, 6968, 264, 2092, 63537, 26110, 13, 330, 2409, 279, 2092, 63537, 26110, 11, 499, 649, 1518, 1070, 527, 3604, 9333, 66557, 315, 3177, 304, 1990, 279, 18311, 11, 902, 374, 1148, 584, 6767, 311, 24499, 279, 1218, 526, 1001, 6070, 1359, 11497, 12433, 894, 13, 330, 2746, 499, 6246, 701, 69087, 1070, 11, 499, 649, 636, 264, 1695, 1427, 520, 279, 7185, 31228, 7865, 2085, 74537, 433, 704, 449, 279, 56887, 3177, 430, 3727, 709, 279, 18311, 1210, 56124, 439, 814, 1051, 16785, 1063, 315, 279, 1176, 22772, 7978, 315, 279, 31228, 13878, 315, 420, 1887, 11, 279, 12074, 6773, 311, 1456, 311, 7838, 264, 32887, 1646, 11, 2663, 279, 13790, 1534, 1646, 11, 902, 374, 17037, 1511, 439, 264, 38215, 311, 7664, 6485, 31228, 6067, 13, 3277, 814, 10837, 279, 12593, 11, 814, 1051, 100174, 311, 1505, 430, 279, 9526, 18545, 279, 10334, 1633, 1664, 13, 2100, 11, 1418, 814, 617, 539, 3686, 6089, 17303, 430, 872, 8162, 22631, 706, 31228, 1218, 526, 1001, 11, 814, 617, 6982, 430, 1202, 5178, 9248, 264, 10334, 430, 24897, 1218, 526, 1001, 13, 330, 791, 1935, 25389, 1984, 374, 430, 420, 16264, 279, 6134, 369, 84062, 311, 656, 810, 10334, 1606, 1457, 11, 449, 420, 1887, 11, 433, 596, 3284, 311, 9526, 750, 10356, 430, 990, 1359, 1071, 55757, 258, 13, 1322, 4504, 323, 1701, 31228, 1218, 526, 1001, 18654, 884, 1302, 304, 828, 19169, 1436, 7916, 279, 4732, 315, 828, 8481, 26, 304, 47710, 11, 814, 1436, 3493, 810, 24473, 24229, 477, 24564, 279, 11742, 18528, 315, 3117, 90724, 6302, 13, 578, 57702, 13453, 119066, 7886, 2128, 374, 8104, 8173, 304, 279, 4754, 369, 2092, 275, 2439, 304, 3738, 4595, 315, 31228, 25213, 1606, 2092, 275, 2439, 527, 19698, 311, 387, 7701, 1218, 40040, 439, 5246, 439, 814, 527, 8066, 13, 3161, 872, 5452, 11, 323, 279, 5845, 311, 4007, 433, 505, 264, 31228, 13356, 11, 279, 33242, 437, 2296, 323, 56413, 63238, 1233, 11868, 12074, 527, 10494, 459, 1825, 4059, 922, 1148, 814, 1436, 656, 1828, 13, 31494, 279, 1948, 315, 872, 1160, 315, 6848, 374, 279, 13336, 315, 16785, 22323, 389, 872, 1887, 430, 31388, 3210, 12391, 31228, 1218, 526, 1001, 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 world is on the cusp of a post-antibiotic era, but researchers and medical doctors have found a way forward—by looking back at how infections were treated before the advent of antibiotics, namely using phage therapy. Although bacteriophages (phages) continue to lack drug approval in Western medicine, an increasing number of patients are being treated on an expanded-access emergency investigational new drug basis. To streamline the production of high-quality and clinically safe phage preparations, we developed a systematic procedure for medicinal phage isolation, liter-scale cultivation, concentration and purification. The 16- to 21-day procedure described in this protocol uses a combination of modified classic techniques, modern membrane filtration processes and no organic solvents to yield on average 23 mL of 10 11 plaque-forming units (PFUs) per milliliter for Pseudomonas , Klebsiella , and Serratia phages tested. Thus, a single production run can produce up to 64,000 treatment doses at 10 9 PFUs, which would be sufficient for most expanded-access phage therapy cases and potentially for clinical phase I/II applications. The protocol focuses on removing endotoxins early by conducting multiple low-speed centrifugations, microfiltration, and cross-flow ultrafiltration, which reduced endotoxins by up to 10 6 -fold in phage preparations. Implementation of a standardized phage cultivation and purification across research laboratories participating in phage production for expanded-access phage therapy might be pivotal to reintroduce phage therapy to Western medicine. Introduction Academic and military research institutions are being called to immediate action to produce bacteriophages—viruses that kill bacteria—for the treatment of antibiotic-resistant infections before drug approval 1 , 2 , 3 , 4 . Sometimes called compassionate use, expanded access provides a patient with an immediately life-threatening condition or serious disease rapid access to an investigational new drug (IND) when no satisfactory alternative therapy options are available 5 . Although demand for bacteriophages (‘phages’ for short) is increasing in several fields, including human and veterinary drugs, biological products, food supply and cosmetics 4 , 6 , 7 , only a limited number of phage products are produced under the regulations covering Good Manufacturing Practices (GMP) 8 , 9 . However, an argument can be made that an effective, consistent and controllable process for phage production, which also meets safety and efficacy demands for human and animal clinical use, has yet to be achieved 10 , 11 . That is, medicinal phage products have generally been of low purity and titer 1 , 4 , 12 , 13 , 14 . According to the Centers for Disease Control and Prevention (CDC) and the World Health Organization, deaths from antibiotic drug-resistant bacteria are at historic highs 15 , 16 . In the United States, more than 2.8 million multidrug-resistant (MDR) infections occur each year, and more than 35,000 people die as a result 15 . As the usefulness of antibiotics is waning, there is an urgent need to develop new ways to treat infections, or MDR infections will be the leading cause of human death worldwide by 2050 (ref. 16 ). Now, researchers and medical doctors have found a way forward—by looking back at how infections were treated before the advent of antibiotics 1 , 2 . Phage therapy started with its first clinical application in 1919 (ref. 17 ) and has seen continuous improvement to this day. Although phages continue to lack drug approval in Western medicine, an increasing number of patients have been treated on an emergency IND (eIND) basis under US Food and Drug Administration (FDA) or European Medicines Agency approval 1 , 2 , 3 , 4 , 14 . With IND clinical approvals taking an average of 8 years from entry into clinical trials, patients experiencing antibiotic failure and their family members are themselves advocating for expanded-access phage therapy. Thus, as the antibiotic resistance crisis continues to rise globally, expanded-access phage therapy is bridging the gap between current antibiotic failures and future clinical trials. As a type of virus, phages can reproduce only within a bacterial cell 18 , 19 . Therefore, a major hurdle to creating medicinal phages is the separation of phages from bacterial cell debris such as endotoxins (i.e., lipopolysaccharides (LPS)), peptidoglycan, exotoxins, flagella, nucleic acids, and other compounds. If not adequately removed, these gross impurities could trigger potentially life-threatening inflammation, sepsis, and septic shock in humans 20 , 21 , 22 . To date, the major safety concern with phage products for human use has been endotoxin content 1 , 10 , 14 . Adequately removing endotoxins from phage products for human eIND phage therapy has been problematic, often requiring significant product dilution, which concurrently reduces the active agent of phages 1 , 3 , 4 . In addition, GMP pharmaceutical phage products have reported endotoxin quantity that would not be actionable for low-dose or topical applications and could be indicative of adverse effects if administered in certain routes of administration, such as intravenously (i.v.), which is a common route of phage administration recommended by the Center for Innovative Phage Applications and Therapeutics 1 , 2 , 4 . Moreover, phage production methods have largely disregarded other unknown gross impurities that might risk human health. Indeed, phage preparations can be safe in animal models 23 , 24 , 25 , 26 . However, experimental phage therapy studies generally cultivate phages with laboratory-adapted reference bacterial strains. For expanded-access eIND use, large quantities of a pathogen—often a clinical MDR bacterial isolate—are required to produce a high number of phages. Several ad hoc laboratory approaches are currently employed for phage cultivation and purification for human use, which have been largely developed for small experimental studies 1 , 2 , 3 , 4 , 14 , 18 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 . However, several pitfalls have materialized, including low phage recovery, high gross impurities, inadequate endotoxin removal and addition of toxic chemicals (see the ‘Comparison with other practiced protocols’ section). Large-scale GMP pharmaceutical production of large phage libraries will likely be needed to meet the demands for personalized phage", "role": "user" }, { "content": "When clinicians resort to phage therapy for patients who don't respond to antibiotics, the patients are usually very ill and time is of the essence. But the average time for labs to produce therapeutic phages is more than a month. The main reason for this is the lack of a standardized phage purification process for research labs, despite the fact that phage therapy—which uses viruses to destroy disease causing bacteria—has been around for over a century. Now, a San Diego State University lab that produces phage therapeutics for clinicians across the country for compassionate use has developed standardized guidelines intended to not only streamline the process using existing lab equipment, but also shorten it to two to three weeks, cutting the typical processing time by half. \"Many of our patients have so little time, so speed is of the essence and this protocol would really make a difference, since one run can produce enough doses to treat a patient for months,\" said Dwayne Roach, the Conrad Prebys chair of virology and assistant professor at SDSU. The protocol, he said, combines traditional techniques with modern filtration technology to produce higher phage yields and reduce endotoxin levels compared to previously developed methods. The open source guidelines were published in a paper in Nature Protocols in July. Bacteriophages and phage therapy Typical candidates for phage therapy are patients who have multi-drug resistant bacteria, a more and more common fallout of overusing antibiotics. Phage is short for bacteriophage, which literally means \"bacteria eater.\" They are viruses that only attack bacteria, not people, and are found in soil, water and sewage, requiring them to be purified before use. Phage therapy is not approved yet in the United States and Europe, except on a case-by-case basis under compassionate use. The military is also interested in phage therapy for the battlefield, where it could be used as a sterilizing wash to remove bacteria from wounds. Since this is still an emerging field, labs take varying approaches to phage purification. The protocols developed by the SDSU researchers are straightforward, and use simple, standard microbiology lab equipment to remain affordable. They are suitable even for labs in countries with limited resources that wish to ramp up phage production. Lack of protocols a key bottleneck Since Roach's lab has a library of phages on hand, much of the back-end work of collecting and cultivating them has already been completed. The protocols allow his team to supply clinicians with the best-fit phages in as little as a week. San Diego State University microbiologist Dwayne Roach's phage lab has developed new guidelines to prepare phage that will accelerate the time to therapy while streamlining the process. Credit: SDSU \"Our protocol provides a standard of production for medicinal phages that consistently provides potentially thousands of phage treatment doses,\" said Tiffany Luong, first author and a doctoral student in Roach's lab. \"We provide instruction and rationale for each step in our process which allows the user to tailor the procedure to their specific equipment and bacterial species.\" Identifying groups of phages that are effective against multi-drug resistant bacteria has become easier over the years. But Dr. Robert 'Chip' Schooley, director of the Center for Innovative Phage Applications and Therapeutics at the University of California San Diego, said however that the absence of rigorous, scalable approaches for producing therapeutic phages in academic laboratories and delivering them to the patient's bedside is a major bottleneck. \"Dr. Roach's protocol guidelines are an outstanding example of the rigor required to safely take phages into the clinic,\" Schooley said. \"These guidelines will be of great interest to other academic laboratories and to regulatory agencies as we move into the next phases of phage therapeutics.\" Reducing endotoxins When Roach's team began working with physicians in spring 2019, they had to figure out how to streamline the process. By scrutinizing each step and comparing different methods, the team identified cross-flow filtration—when the flow travels across the surface of the filter instead of into it—as the most efficient and effective purification method, and Roach presented the results and accelerated timeline at a conference later in the year. While Roach and Luong looked at process optimization, Ann-Charlott Salabarria, a postdoctoral researcher, worked on setting parameters for ensuring safety of the end product with multiple tests, including confirming that endotoxin levels met U.S. Food and Drug Administration (FDA) guidelines. One of the FDA's major concerns with phage products is its endotoxin levels, which can harm patients and need to be removed as part of the purification process. The published protocol will help ensure the phage products are safe above and beyond the FDA minimum requirements, Roach explained. \"Our tests do validate that this process removes almost all endotoxins and exotoxins,\" Roach said. \"We wanted to publish our protocol as a resource for other labs because purification has been very time consuming, taking away time from research.\" Phage strain selection is another important aspect to developing phage therapeutics. To screen out unwanted genes in phage genomes, Roach enlisted the help of SDSU microbial geneticist and bioinformatics expert Robert Edwards. \"Phage genomes contain so many different components and may mobilize other toxins or antibiotic resistance genes,\" Edwards said. \"It is absolutely imperative that we understand these viruses at the molecular level to ensure that we are not introducing anything potentially harmful into already ill patients.\" The researchers will continue to focus on improving safety in phage therapy, by testing it on tissue and mice cell cultures. \"We hope this protocol will allow more research labs to participate in re-introducing phages to Western medicine,\" Luong 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 world is on the cusp of a post-antibiotic era, but researchers and medical doctors have found a way forward—by looking back at how infections were treated before the advent of antibiotics, namely using phage therapy. Although bacteriophages (phages) continue to lack drug approval in Western medicine, an increasing number of patients are being treated on an expanded-access emergency investigational new drug basis. To streamline the production of high-quality and clinically safe phage preparations, we developed a systematic procedure for medicinal phage isolation, liter-scale cultivation, concentration and purification. The 16- to 21-day procedure described in this protocol uses a combination of modified classic techniques, modern membrane filtration processes and no organic solvents to yield on average 23 mL of 10 11 plaque-forming units (PFUs) per milliliter for Pseudomonas , Klebsiella , and Serratia phages tested. Thus, a single production run can produce up to 64,000 treatment doses at 10 9 PFUs, which would be sufficient for most expanded-access phage therapy cases and potentially for clinical phase I/II applications. The protocol focuses on removing endotoxins early by conducting multiple low-speed centrifugations, microfiltration, and cross-flow ultrafiltration, which reduced endotoxins by up to 10 6 -fold in phage preparations. Implementation of a standardized phage cultivation and purification across research laboratories participating in phage production for expanded-access phage therapy might be pivotal to reintroduce phage therapy to Western medicine. Introduction Academic and military research institutions are being called to immediate action to produce bacteriophages—viruses that kill bacteria—for the treatment of antibiotic-resistant infections before drug approval 1 , 2 , 3 , 4 . Sometimes called compassionate use, expanded access provides a patient with an immediately life-threatening condition or serious disease rapid access to an investigational new drug (IND) when no satisfactory alternative therapy options are available 5 . Although demand for bacteriophages (‘phages’ for short) is increasing in several fields, including human and veterinary drugs, biological products, food supply and cosmetics 4 , 6 , 7 , only a limited number of phage products are produced under the regulations covering Good Manufacturing Practices (GMP) 8 , 9 . However, an argument can be made that an effective, consistent and controllable process for phage production, which also meets safety and efficacy demands for human and animal clinical use, has yet to be achieved 10 , 11 . That is, medicinal phage products have generally been of low purity and titer 1 , 4 , 12 , 13 , 14 . According to the Centers for Disease Control and Prevention (CDC) and the World Health Organization, deaths from antibiotic drug-resistant bacteria are at historic highs 15 , 16 . In the United States, more than 2.8 million multidrug-resistant (MDR) infections occur each year, and more than 35,000 people die as a result 15 . As the usefulness of antibiotics is waning, there is an urgent need to develop new ways to treat infections, or MDR infections will be the leading cause of human death worldwide by 2050 (ref. 16 ). Now, researchers and medical doctors have found a way forward—by looking back at how infections were treated before the advent of antibiotics 1 , 2 . Phage therapy started with its first clinical application in 1919 (ref. 17 ) and has seen continuous improvement to this day. Although phages continue to lack drug approval in Western medicine, an increasing number of patients have been treated on an emergency IND (eIND) basis under US Food and Drug Administration (FDA) or European Medicines Agency approval 1 , 2 , 3 , 4 , 14 . With IND clinical approvals taking an average of 8 years from entry into clinical trials, patients experiencing antibiotic failure and their family members are themselves advocating for expanded-access phage therapy. Thus, as the antibiotic resistance crisis continues to rise globally, expanded-access phage therapy is bridging the gap between current antibiotic failures and future clinical trials. As a type of virus, phages can reproduce only within a bacterial cell 18 , 19 . Therefore, a major hurdle to creating medicinal phages is the separation of phages from bacterial cell debris such as endotoxins (i.e., lipopolysaccharides (LPS)), peptidoglycan, exotoxins, flagella, nucleic acids, and other compounds. If not adequately removed, these gross impurities could trigger potentially life-threatening inflammation, sepsis, and septic shock in humans 20 , 21 , 22 . To date, the major safety concern with phage products for human use has been endotoxin content 1 , 10 , 14 . Adequately removing endotoxins from phage products for human eIND phage therapy has been problematic, often requiring significant product dilution, which concurrently reduces the active agent of phages 1 , 3 , 4 . In addition, GMP pharmaceutical phage products have reported endotoxin quantity that would not be actionable for low-dose or topical applications and could be indicative of adverse effects if administered in certain routes of administration, such as intravenously (i.v.), which is a common route of phage administration recommended by the Center for Innovative Phage Applications and Therapeutics 1 , 2 , 4 . Moreover, phage production methods have largely disregarded other unknown gross impurities that might risk human health. Indeed, phage preparations can be safe in animal models 23 , 24 , 25 , 26 . However, experimental phage therapy studies generally cultivate phages with laboratory-adapted reference bacterial strains. For expanded-access eIND use, large quantities of a pathogen—often a clinical MDR bacterial isolate—are required to produce a high number of phages. Several ad hoc laboratory approaches are currently employed for phage cultivation and purification for human use, which have been largely developed for small experimental studies 1 , 2 , 3 , 4 , 14 , 18 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 . However, several pitfalls have materialized, including low phage recovery, high gross impurities, inadequate endotoxin removal and addition of toxic chemicals (see the ‘Comparison with other practiced protocols’ section). Large-scale GMP pharmaceutical production of large phage libraries will likely be needed to meet the demands for personalized phage<|im_end|> <|im_start|>assistant When clinicians resort to phage therapy for patients who don't respond to antibiotics, the patients are usually very ill and time is of the essence. But the average time for labs to produce therapeutic phages is more than a month. The main reason for this is the lack of a standardized phage purification process for research labs, despite the fact that phage therapy—which uses viruses to destroy disease causing bacteria—has been around for over a century. Now, a San Diego State University lab that produces phage therapeutics for clinicians across the country for compassionate use has developed standardized guidelines intended to not only streamline the process using existing lab equipment, but also shorten it to two to three weeks, cutting the typical processing time by half. "Many of our patients have so little time, so speed is of the essence and this protocol would really make a difference, since one run can produce enough doses to treat a patient for months," said Dwayne Roach, the Conrad Prebys chair of virology and assistant professor at SDSU. The protocol, he said, combines traditional techniques with modern filtration technology to produce higher phage yields and reduce endotoxin levels compared to previously developed methods. The open source guidelines were published in a paper in Nature Protocols in July. Bacteriophages and phage therapy Typical candidates for phage therapy are patients who have multi-drug resistant bacteria, a more and more common fallout of overusing antibiotics. Phage is short for bacteriophage, which literally means "bacteria eater." They are viruses that only attack bacteria, not people, and are found in soil, water and sewage, requiring them to be purified before use. Phage therapy is not approved yet in the United States and Europe, except on a case-by-case basis under compassionate use. The military is also interested in phage therapy for the battlefield, where it could be used as a sterilizing wash to remove bacteria from wounds. Since this is still an emerging field, labs take varying approaches to phage purification. The protocols developed by the SDSU researchers are straightforward, and use simple, standard microbiology lab equipment to remain affordable. They are suitable even for labs in countries with limited resources that wish to ramp up phage production. Lack of protocols a key bottleneck Since Roach's lab has a library of phages on hand, much of the back-end work of collecting and cultivating them has already been completed. The protocols allow his team to supply clinicians with the best-fit phages in as little as a week. San Diego State University microbiologist Dwayne Roach's phage lab has developed new guidelines to prepare phage that will accelerate the time to therapy while streamlining the process. Credit: SDSU "Our protocol provides a standard of production for medicinal phages that consistently provides potentially thousands of phage treatment doses," said Tiffany Luong, first author and a doctoral student in Roach's lab. "We provide instruction and rationale for each step in our process which allows the user to tailor the procedure to their specific equipment and bacterial species." Identifying groups of phages that are effective against multi-drug resistant bacteria has become easier over the years. But Dr. Robert 'Chip' Schooley, director of the Center for Innovative Phage Applications and Therapeutics at the University of California San Diego, said however that the absence of rigorous, scalable approaches for producing therapeutic phages in academic laboratories and delivering them to the patient's bedside is a major bottleneck. "Dr. Roach's protocol guidelines are an outstanding example of the rigor required to safely take phages into the clinic," Schooley said. "These guidelines will be of great interest to other academic laboratories and to regulatory agencies as we move into the next phases of phage therapeutics." Reducing endotoxins When Roach's team began working with physicians in spring 2019, they had to figure out how to streamline the process. By scrutinizing each step and comparing different methods, the team identified cross-flow filtration—when the flow travels across the surface of the filter instead of into it—as the most efficient and effective purification method, and Roach presented the results and accelerated timeline at a conference later in the year. While Roach and Luong looked at process optimization, Ann-Charlott Salabarria, a postdoctoral researcher, worked on setting parameters for ensuring safety of the end product with multiple tests, including confirming that endotoxin levels met U.S. Food and Drug Administration (FDA) guidelines. One of the FDA's major concerns with phage products is its endotoxin levels, which can harm patients and need to be removed as part of the purification process. The published protocol will help ensure the phage products are safe above and beyond the FDA minimum requirements, Roach explained. "Our tests do validate that this process removes almost all endotoxins and exotoxins," Roach said. "We wanted to publish our protocol as a resource for other labs because purification has been very time consuming, taking away time from research." Phage strain selection is another important aspect to developing phage therapeutics. To screen out unwanted genes in phage genomes, Roach enlisted the help of SDSU microbial geneticist and bioinformatics expert Robert Edwards. "Phage genomes contain so many different components and may mobilize other toxins or antibiotic resistance genes," Edwards said. "It is absolutely imperative that we understand these viruses at the molecular level to ensure that we are not introducing anything potentially harmful into already ill patients." The researchers will continue to focus on improving safety in phage therapy, by testing it on tissue and mice cell cultures. "We hope this protocol will allow more research labs to participate in re-introducing phages to Western medicine," Luong 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 Constructing agents with planning capabilities has long been one of the main challenges in the pursuit of artificial intelligence. Tree-based planning methods have enjoyed huge success in challenging domains, such as chess 1 and Go 2 , where a perfect simulator is available. However, in real-world problems, the dynamics governing the environment are often complex and unknown. Here we present the MuZero algorithm, which, by combining a tree-based search with a learned model, achieves superhuman performance in a range of challenging and visually complex domains, without any knowledge of their underlying dynamics. The MuZero algorithm learns an iterable model that produces predictions relevant to planning: the action-selection policy, the value function and the reward. When evaluated on 57 different Atari games 3 —the canonical video game environment for testing artificial intelligence techniques, in which model-based planning approaches have historically struggled 4 —the MuZero algorithm achieved state-of-the-art performance. When evaluated on Go, chess and shogi—canonical environments for high-performance planning—the MuZero algorithm matched, without any knowledge of the game dynamics, the superhuman performance of the AlphaZero algorithm 5 that was supplied with the rules of the game. Main Planning algorithms based on lookahead search have achieved remarkable successes in artificial intelligence. Human world champions have been defeated in classic games such as checkers 6 , chess 1 , Go 2 and poker 7 , 8 , and planning algorithms have had real-world impact in applications from logistics 9 to chemical synthesis 10 . However, these planning algorithms all rely on knowledge of the environment’s dynamics, such as the rules of the game or an accurate simulator, preventing their direct application to real-world domains such as robotics, industrial control or intelligent assistants, where the dynamics are normally unknown. Model-based reinforcement learning (RL) 11 aims to address this issue by first learning a model of the environment’s dynamics and then planning with respect to the learned model. Typically, these models have either focused on reconstructing the true environmental state 12 , 13 , 14 or the sequence of full observations 15 , 16 . However, previous work 15 , 16 , 17 remains far from the state of the art in visually rich domains, such as Atari 2600 games 3 . Instead, the most successful methods are based on model-free RL 18 , 19 , 20 —that is, they estimate the optimal policy and/or value function directly from interactions with the environment. However, model-free algorithms are in turn far from the state of the art in domains that require precise and sophisticated lookahead, such as chess and Go. Here we introduce MuZero, a new approach to model-based RL that achieves both state-of-the-art performance in Atari 2600 games—a visually complex set of domains—and superhuman performance in precision planning tasks such as chess, shogi and Go, without prior knowledge of the game dynamics. MuZero builds on AlphaZero’s 5 powerful search and policy iteration algorithms, but incorporates a learned model into the training procedure. MuZero also extends AlphaZero to a broader set of environments, including single agent domains and non-zero rewards at intermediate time steps. The main idea of the algorithm (summarized in Fig. 1 ) is to predict those aspects of the future that are directly relevant for planning. The model receives the observation (for example, an image of the Go board or the Atari screen) as an input and transforms it into a hidden state. The hidden state is then updated iteratively by a recurrent process that receives the previous hidden state and a hypothetical next action. At every one of these steps, the model produces a policy (predicting the move to play), value function (predicting the cumulative reward, for example, the eventual winner) and immediate reward prediction (for example, the points scored by playing a move). The model is trained end to end, with the sole objective of accurately estimating these three important quantities, to match the improved policy and value function generated by search, as well as the observed reward. There is no direct requirement or constraint on the hidden state to capture all information necessary to reconstruct the original observation, drastically reducing the amount of information the model has to maintain and predict. Neither is there any requirement for the hidden state to match the unknown, true state of the environment; nor any other constraints on the semantics of state. Instead, the hidden states are free to represent any state that correctly estimates the policy, value function and reward. Intuitively, the agent can invent, internally, any dynamics that lead to accurate planning. Fig. 1: Planning, acting and training with a learned model. a , How MuZero uses its model to plan. The model consists of three connected components for representation, dynamics and prediction. Given a previous hidden state s k −1 and a candidate action a k , the dynamics function g produces an immediate reward r k and a new hidden state s k . The policy p k and value function v k are computed from the hidden state s k by a prediction function f . The initial hidden state s 0 is obtained by passing the past observations (for example, the Go board or Atari screen) into a representation function h . b , How MuZero acts in the environment. An MCTS is performed at each timestep t , as described in a . An action a t +1 is sampled from the search policy π t , which is proportional to the visit count for each action from the root node. The environment receives the action and generates a new observation o t +1 and reward u t +1 . At the end of the episode, the trajectory data are stored into a replay buffer. c , How MuZero trains its model. A trajectory is sampled from the replay buffer. For the initial step, the representation function h receives as input the past observations o 1 , ..., o t from the selected trajectory. The model is subsequently unrolled recurrently for K steps. At each step", "role": "user" }, { "content": "Albert Einstein once said, \"You have to learn the rules of the game, and then you have to play better than anyone else.\" That could well be the motto at DeepMind, as a new report reveals it has developed a program that can master complex games without even knowing the rules. DeepMind, a subsidiary of Alphabet, has previously made groundbreaking strides using reinforcement learning to teach programs to master the Chinese board game Go and the Japanese strategy game Shogi, as well as chess and challenging Atari video games. In all those instances, computers were given the rules of the game. But Nature reported today that DeepMind's MuZero has accomplished the same feats—and in some instances, beat the earlier programs—without first learning the rules. Programmers at DeepMind relied on a principle called \"look-ahead search.\" With that approach, MuZero assesses a number of potential moves based on how an opponent would respond. While there would likely be a staggering number of potential moves in complex games such as chess, MuZero prioritizes the most relevant and most likely maneuvers, learning from successful gambits and avoiding ones that failed. When performing against Atari's Ms. Pac-Man, MuZero was restricted to considering only six or seven potential future moves, yet still performed admirably, according to researchers. \"For the first time, we actually have a system that is able to build its own understanding of how the world works and use that understanding to do this kind of sophisticated look-ahead planning that you've previously seen for games like chess,\" said DeepMind's principal research scientist David Silver. MuZero can \"start from nothing, and just through trial and error, both discover the rules of the world and use those rules to achieve kind of superhuman performance.\" Silver envisions greater applications for MuZero than mere games. Progress has already been made on video compression, a challenging task considering the huge number of varying video formats and numerous modes of compression. So far, they have achieved a 5% improvement in compression, no small feat for the company owned by Google, which also handles the gigantic cache of videos on the world's second-most popular web site, YouTube, where a billion hours of content are viewed daily. (The No. 1 web site? Google.) Silver says the laboratory is also looking into robotics programming and protein architecture design, which holds promise for personalized production of drugs. It is a \"significant step forward,\" according to Wendy Hall, professor of computer science at the University of Southampton and a member of England's AI council. \"The results of DeepMind's work are quite astounding and I marvel at what they are going to be able to achieve in the future given the resources they have available to them,\" she said. But she also raised a concern about the potential of abuse. \"My worry is that whilst constantly striving to improve the performance of their algorithms and apply the results for the benefit of society, the teams at DeepMind are not putting as much effort into thinking through potential unintended consequences of their work,\" she said. In fact, the U.S. Air Force had tapped early research papers covering MuZero that were made public last year and used the information to design an AI system that could launch missiles from a U-2 spy plane against specified targets. When asked by Wired what he thought of such military applications, Silver left no doubt about his concerns. \"I oppose the use of AI in any deadly weapon, and I wish we had made more progress toward a ban on lethal autonomous weapons,\" he said. He added that DeepMind and its co-founders have all signed the Lethal Autonomous Weapons Pledge, which asserts the belief that deadly technology should always remain under human control, and not AI-based algorithms. Silver says the challenges ahead are to understand and implement algorithms as effective and powerful as the human brain. \"We should be aiming to achieve that. The first step in taking that journey is to try to understand what it even means to achieve intelligence,\" he said. \"We think this really matters for enriching what AI can actually do because the world is a messy place. It's unknown—no one gives us this amazing rulebook that says, \"Oh, this is exactly how the world works,'\" Silver said. \"If we want our AI to go out there into the world and be able to plan and look ahead in problems where no one gives us the rulebook, we really, really need this.\" ", "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 Constructing agents with planning capabilities has long been one of the main challenges in the pursuit of artificial intelligence. Tree-based planning methods have enjoyed huge success in challenging domains, such as chess 1 and Go 2 , where a perfect simulator is available. However, in real-world problems, the dynamics governing the environment are often complex and unknown. Here we present the MuZero algorithm, which, by combining a tree-based search with a learned model, achieves superhuman performance in a range of challenging and visually complex domains, without any knowledge of their underlying dynamics. The MuZero algorithm learns an iterable model that produces predictions relevant to planning: the action-selection policy, the value function and the reward. When evaluated on 57 different Atari games 3 —the canonical video game environment for testing artificial intelligence techniques, in which model-based planning approaches have historically struggled 4 —the MuZero algorithm achieved state-of-the-art performance. When evaluated on Go, chess and shogi—canonical environments for high-performance planning—the MuZero algorithm matched, without any knowledge of the game dynamics, the superhuman performance of the AlphaZero algorithm 5 that was supplied with the rules of the game. Main Planning algorithms based on lookahead search have achieved remarkable successes in artificial intelligence. Human world champions have been defeated in classic games such as checkers 6 , chess 1 , Go 2 and poker 7 , 8 , and planning algorithms have had real-world impact in applications from logistics 9 to chemical synthesis 10 . However, these planning algorithms all rely on knowledge of the environment’s dynamics, such as the rules of the game or an accurate simulator, preventing their direct application to real-world domains such as robotics, industrial control or intelligent assistants, where the dynamics are normally unknown. Model-based reinforcement learning (RL) 11 aims to address this issue by first learning a model of the environment’s dynamics and then planning with respect to the learned model. Typically, these models have either focused on reconstructing the true environmental state 12 , 13 , 14 or the sequence of full observations 15 , 16 . However, previous work 15 , 16 , 17 remains far from the state of the art in visually rich domains, such as Atari 2600 games 3 . Instead, the most successful methods are based on model-free RL 18 , 19 , 20 —that is, they estimate the optimal policy and/or value function directly from interactions with the environment. However, model-free algorithms are in turn far from the state of the art in domains that require precise and sophisticated lookahead, such as chess and Go. Here we introduce MuZero, a new approach to model-based RL that achieves both state-of-the-art performance in Atari 2600 games—a visually complex set of domains—and superhuman performance in precision planning tasks such as chess, shogi and Go, without prior knowledge of the game dynamics. MuZero builds on AlphaZero’s 5 powerful search and policy iteration algorithms, but incorporates a learned model into the training procedure. MuZero also extends AlphaZero to a broader set of environments, including single agent domains and non-zero rewards at intermediate time steps. The main idea of the algorithm (summarized in Fig. 1 ) is to predict those aspects of the future that are directly relevant for planning. The model receives the observation (for example, an image of the Go board or the Atari screen) as an input and transforms it into a hidden state. The hidden state is then updated iteratively by a recurrent process that receives the previous hidden state and a hypothetical next action. At every one of these steps, the model produces a policy (predicting the move to play), value function (predicting the cumulative reward, for example, the eventual winner) and immediate reward prediction (for example, the points scored by playing a move). The model is trained end to end, with the sole objective of accurately estimating these three important quantities, to match the improved policy and value function generated by search, as well as the observed reward. There is no direct requirement or constraint on the hidden state to capture all information necessary to reconstruct the original observation, drastically reducing the amount of information the model has to maintain and predict. Neither is there any requirement for the hidden state to match the unknown, true state of the environment; nor any other constraints on the semantics of state. Instead, the hidden states are free to represent any state that correctly estimates the policy, value function and reward. Intuitively, the agent can invent, internally, any dynamics that lead to accurate planning. Fig. 1: Planning, acting and training with a learned model. a , How MuZero uses its model to plan. The model consists of three connected components for representation, dynamics and prediction. Given a previous hidden state s k −1 and a candidate action a k , the dynamics function g produces an immediate reward r k and a new hidden state s k . The policy p k and value function v k are computed from the hidden state s k by a prediction function f . The initial hidden state s 0 is obtained by passing the past observations (for example, the Go board or Atari screen) into a representation function h . b , How MuZero acts in the environment. An MCTS is performed at each timestep t , as described in a . An action a t +1 is sampled from the search policy π t , which is proportional to the visit count for each action from the root node. The environment receives the action and generates a new observation o t +1 and reward u t +1 . At the end of the episode, the trajectory data are stored into a replay buffer. c , How MuZero trains its model. A trajectory is sampled from the replay buffer. For the initial step, the representation function h receives as input the past observations o 1 , ..., o t from the selected trajectory. The model is subsequently unrolled recurrently for K steps. At each step<|im_end|> <|im_start|>assistant Albert Einstein once said, "You have to learn the rules of the game, and then you have to play better than anyone else." That could well be the motto at DeepMind, as a new report reveals it has developed a program that can master complex games without even knowing the rules. DeepMind, a subsidiary of Alphabet, has previously made groundbreaking strides using reinforcement learning to teach programs to master the Chinese board game Go and the Japanese strategy game Shogi, as well as chess and challenging Atari video games. In all those instances, computers were given the rules of the game. But Nature reported today that DeepMind's MuZero has accomplished the same feats—and in some instances, beat the earlier programs—without first learning the rules. Programmers at DeepMind relied on a principle called "look-ahead search." With that approach, MuZero assesses a number of potential moves based on how an opponent would respond. While there would likely be a staggering number of potential moves in complex games such as chess, MuZero prioritizes the most relevant and most likely maneuvers, learning from successful gambits and avoiding ones that failed. When performing against Atari's Ms. Pac-Man, MuZero was restricted to considering only six or seven potential future moves, yet still performed admirably, according to researchers. "For the first time, we actually have a system that is able to build its own understanding of how the world works and use that understanding to do this kind of sophisticated look-ahead planning that you've previously seen for games like chess," said DeepMind's principal research scientist David Silver. MuZero can "start from nothing, and just through trial and error, both discover the rules of the world and use those rules to achieve kind of superhuman performance." Silver envisions greater applications for MuZero than mere games. Progress has already been made on video compression, a challenging task considering the huge number of varying video formats and numerous modes of compression. So far, they have achieved a 5% improvement in compression, no small feat for the company owned by Google, which also handles the gigantic cache of videos on the world's second-most popular web site, YouTube, where a billion hours of content are viewed daily. (The No. 1 web site? Google.) Silver says the laboratory is also looking into robotics programming and protein architecture design, which holds promise for personalized production of drugs. It is a "significant step forward," according to Wendy Hall, professor of computer science at the University of Southampton and a member of England's AI council. "The results of DeepMind's work are quite astounding and I marvel at what they are going to be able to achieve in the future given the resources they have available to them," she said. But she also raised a concern about the potential of abuse. "My worry is that whilst constantly striving to improve the performance of their algorithms and apply the results for the benefit of society, the teams at DeepMind are not putting as much effort into thinking through potential unintended consequences of their work," she said. In fact, the U.S. Air Force had tapped early research papers covering MuZero that were made public last year and used the information to design an AI system that could launch missiles from a U-2 spy plane against specified targets. When asked by Wired what he thought of such military applications, Silver left no doubt about his concerns. "I oppose the use of AI in any deadly weapon, and I wish we had made more progress toward a ban on lethal autonomous weapons," he said. He added that DeepMind and its co-founders have all signed the Lethal Autonomous Weapons Pledge, which asserts the belief that deadly technology should always remain under human control, and not AI-based algorithms. Silver says the challenges ahead are to understand and implement algorithms as effective and powerful as the human brain. "We should be aiming to achieve that. The first step in taking that journey is to try to understand what it even means to achieve intelligence," he said. "We think this really matters for enriching what AI can actually do because the world is a messy place. It's unknown—no one gives us this amazing rulebook that says, "Oh, this is exactly how the world works,'" Silver said. "If we want our AI to go out there into the world and be able to plan and look ahead in problems where no one gives us the rulebook, we really, really need this." <|im_end|>

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2,131

[ { "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 Materials made from active, living, or robotic components can display emergent properties arising from local sensing and computation. Here, we realize a freestanding active metabeam with piezoelectric elements and electronic feed-forward control that gives rise to an odd micropolar elasticity absent in energy-conserving media. The non-reciprocal odd modulus enables bending and shearing cycles that convert electrical energy into mechanical work, and vice versa. The sign of this elastic modulus is linked to a non-Hermitian topological index that determines the localization of vibrational modes to sample boundaries. At finite frequency, we can also tune the phase angle of the active modulus to produce a direction-dependent bending modulus and control non-Hermitian vibrational properties. Our continuum approach, built on symmetries and conservation laws, could be exploited to design others systems such as synthetic biofilaments and membranes with feed-forward control loops. Introduction Responsive materials in both biology and engineering distinguish themselves by their ability to respond to external stimuli in tailored ways 1 , 2 , 3 , 4 , 5 , 6 , 7 . For example, muscles contract in response to electrical signals 8 and mechanocaloric solids undergo dramatic deformations in response to temperature changes 9 . Unlike computers or multicellular organisms with specialized functional components, the undifferentiated physical machinery available in a distributed material presents unique challenges for sensing, information processing, and response. Yet, the range of available functionalities is fundamentally extended when the materials possess distributed, local reservoirs of energy 4 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . Such active materials exhibit responses not allowed by their passive, or energy conserving, counterparts. Activity is intimately connected, but not equivalent, to a family of material symmetries collectively known as reciprocity 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 . Here we distinguish between two notions of reciprocity relevant for the design of mechanical metamaterials. The first notion is a generalization of Newton’s third law, which states that the forces between any two components of a mechanically isolated system must be equal and opposite. This notion of reciprocity can be formulated for other generalized momenta, such as angular momentum. Mechanical systems that violate this version of reciprocity must fundamentally be in contact with an external medium, such as a substrate or a background fluid, to act as a momentum sink. For systems described by a Lagrangian or Hamiltonian, translational (or rotational) symmetry gives rise to conservation of linear (or angular) momentum. Hence, systems with translational symmetry that violate this first notion of reciprocity must either be dissipative, driven, or active. A second conceptually distinct notion of reciprocity is known as Maxwell-Betti reciprocity, which can be roughly defined as the symmetry between perturbation and response. When a mechanical system is deformed, the work done can schematically be written as \${{{\\rm{d}}}}W=\\mathop{\\sum}\\limits_{a}{\\sigma }_{a}{{{{{\\rm{d}}}}}}{u}_{a}\$ . Here, \${u}_{a}\$ is a short hand notation for mechanical degrees of freedom such as displacements, rotations or strains, and \${\\sigma }_{a}\$ labels the conjugate forces, moments or stresses. For small perturbations about an undeformed state, we may write \${\\sigma }_{a}={M}_{{ab}}{u}_{b}\$ . A generic medium is said to obey Maxwell-Betti reciprocity if and only if \${M}_{{ab}}\$ is symmetric, i.e. \${M}_{{ab}}={M}_{{ba}}\$ . As long as the system’s linear response obeys Maxwell-Betti reciprocity, the forces can be derived from gradients of an energetic potential \${V=\\frac{1}{2}M}_{{ab}}{u}_{a}{u}_{b}\$ . However, if the linear response of the medium violates Maxwell-Betti reciprocity, the internal energy is no longer a function of the coordinates \${u}_{a}\$ . In other words, the medium can perform nonzero work along a closed cycle of deformations 27 . Such a medium necessarily contains non-conservative forces that require an internal or external source of energy to be present. While Maxwell-Betti reciprocity and momentum conservation are distinct, one can certainly design and build mechanical systems that harness linear or angular momentum sources to achieve violations of Maxwell-Betti reciprocity 7 , 20 , 29 . Such approaches, however, inherently involve mechanical coupling to an external medium. Here we take an alternative route. We explore the case where \${\\sigma }_{a}\$ represents shear and moment stresses, which conserve currents of linear and angular momentum. In this case \${u}_{a}\$ represents geometric deformations and \${M}_{{ab}}\$ represents the stiffness matrix containing all of the material’s elastic moduli. We refer to the antisymmetric components \$\\left({M}_{{ab}}-{M}_{{ba}}\\right)/2\$ as odd elasticity 27 , 30 , 31 , 32 . A material displaying odd elasticity must violate Maxwell-Betti reciprocity, though it needs not rely on external sources of linear or angular momentum. Recent advances in metamaterial design and prototyping have utilized active components to achieve functionalities such as sensing, lasing, and cloaking 10 , 11 , 12 , 15 , frequency dependent reflectivity 33 , unidirectional wave amplification 7 , 34 , 35 , energy harvesting 16 , and analog computation 17 . Nonetheless, all the active non-reciprocal metamaterials so-far realized exhibit either of the following fundamental limitations: the active non-reciprocal effects either vanish from the linear response in the quasistatic limit 33 or they require the presence of background sources of linear or angular momentum 7 , 29 , 36 . As a result, their functionalities are largely restricted to finite-frequency control or fundamentally require the sample to be in contact with an additional medium that acts as a momentum sink or source. Here, we report the design, construction, and experimental demonstration of a freestanding metamaterial whose elasticity is unattainable in passive media (Fig. 1a–d ). The metamaterial is constructed with piezoelectric elements 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 mounted on a beam and controlled by electrical circuits. Our approach enables an asymmetric coupling between bending and shearing in micropolar solids 47 , 48 . This results in an odd micropolar material that simultaneously breaks parity and Maxwell-Betti reciprocity. The spectrum of the metabeam exhibits a non-Hermitian topological index which results in the localization of vibrational modes at sample boundaries.", "role": "user" }, { "content": "Move over, Hollywood—science fiction is getting ready to leap off the big screen and enter the real world. While recent science fiction movies have demonstrated the power of artificially intelligent computer programs, such as the fictional character J.A.R.V.I.S. in the Avenger film series, to make independent decisions to carry out a set of actions, these imagined movie scenarios could now be closer to becoming a reality. In a recent study published in Nature Communications, a journal of Nature, researchers at the University of Missouri and University of Chicago have developed an artificial material, called a metamaterial, which can respond to its environment, independently make a decision, and perform an action not directed by a human being. For example, a drone making a delivery might evaluate its environment including wind direction, speed or wildlife, and automatically change course in order to complete the delivery safely. Guoliang Huang, Huber and Helen Croft Chair in Engineering, and co-author on the study, said the mechanical design of their new artificial material incorporates three main functions also displayed by materials found in nature—sensing; information processing; and actuation, or movement. Some examples of these natural materials include the quick reaction of a Venus fly trap's leafy jaws to capture an insect, chameleons changing the color of their skin to blend into their surroundings, and pine cones adjusting their shapes in response to changes in air humidity, Huang said. \"Basically, we are controlling how this material responds to changes in external stimuli found in its surroundings,\" Huang said. \"For example, we can apply this material to stealth technology in the aerospace industry by attaching the material to aerospace structures. It can help control and decrease noises coming from the aircraft, such as engine vibrations, which can increase its multifunctional capabilities.\" The material uses a computer chip to control or manipulate the processing of information that's needed to perform the requested actions, then uses the electrical power to convert that energy into mechanical energy. The researchers' next step is to implement their idea in a real-world environment. \"Realization of active metamaterials with odd micropolar elasticity,\" was 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 Materials made from active, living, or robotic components can display emergent properties arising from local sensing and computation. Here, we realize a freestanding active metabeam with piezoelectric elements and electronic feed-forward control that gives rise to an odd micropolar elasticity absent in energy-conserving media. The non-reciprocal odd modulus enables bending and shearing cycles that convert electrical energy into mechanical work, and vice versa. The sign of this elastic modulus is linked to a non-Hermitian topological index that determines the localization of vibrational modes to sample boundaries. At finite frequency, we can also tune the phase angle of the active modulus to produce a direction-dependent bending modulus and control non-Hermitian vibrational properties. Our continuum approach, built on symmetries and conservation laws, could be exploited to design others systems such as synthetic biofilaments and membranes with feed-forward control loops. Introduction Responsive materials in both biology and engineering distinguish themselves by their ability to respond to external stimuli in tailored ways 1 , 2 , 3 , 4 , 5 , 6 , 7 . For example, muscles contract in response to electrical signals 8 and mechanocaloric solids undergo dramatic deformations in response to temperature changes 9 . Unlike computers or multicellular organisms with specialized functional components, the undifferentiated physical machinery available in a distributed material presents unique challenges for sensing, information processing, and response. Yet, the range of available functionalities is fundamentally extended when the materials possess distributed, local reservoirs of energy 4 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . Such active materials exhibit responses not allowed by their passive, or energy conserving, counterparts. Activity is intimately connected, but not equivalent, to a family of material symmetries collectively known as reciprocity 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 . Here we distinguish between two notions of reciprocity relevant for the design of mechanical metamaterials. The first notion is a generalization of Newton’s third law, which states that the forces between any two components of a mechanically isolated system must be equal and opposite. This notion of reciprocity can be formulated for other generalized momenta, such as angular momentum. Mechanical systems that violate this version of reciprocity must fundamentally be in contact with an external medium, such as a substrate or a background fluid, to act as a momentum sink. For systems described by a Lagrangian or Hamiltonian, translational (or rotational) symmetry gives rise to conservation of linear (or angular) momentum. Hence, systems with translational symmetry that violate this first notion of reciprocity must either be dissipative, driven, or active. A second conceptually distinct notion of reciprocity is known as Maxwell-Betti reciprocity, which can be roughly defined as the symmetry between perturbation and response. When a mechanical system is deformed, the work done can schematically be written as ${{{\rm{d}}}}W=\mathop{\sum}\limits_{a}{\sigma }_{a}{{{{{\rm{d}}}}}}{u}_{a}$ . Here, ${u}_{a}$ is a short hand notation for mechanical degrees of freedom such as displacements, rotations or strains, and ${\sigma }_{a}$ labels the conjugate forces, moments or stresses. For small perturbations about an undeformed state, we may write ${\sigma }_{a}={M}_{{ab}}{u}_{b}$ . A generic medium is said to obey Maxwell-Betti reciprocity if and only if ${M}_{{ab}}$ is symmetric, i.e. ${M}_{{ab}}={M}_{{ba}}$ . As long as the system’s linear response obeys Maxwell-Betti reciprocity, the forces can be derived from gradients of an energetic potential ${V=\frac{1}{2}M}_{{ab}}{u}_{a}{u}_{b}$ . However, if the linear response of the medium violates Maxwell-Betti reciprocity, the internal energy is no longer a function of the coordinates ${u}_{a}$ . In other words, the medium can perform nonzero work along a closed cycle of deformations 27 . Such a medium necessarily contains non-conservative forces that require an internal or external source of energy to be present. While Maxwell-Betti reciprocity and momentum conservation are distinct, one can certainly design and build mechanical systems that harness linear or angular momentum sources to achieve violations of Maxwell-Betti reciprocity 7 , 20 , 29 . Such approaches, however, inherently involve mechanical coupling to an external medium. Here we take an alternative route. We explore the case where ${\sigma }_{a}$ represents shear and moment stresses, which conserve currents of linear and angular momentum. In this case ${u}_{a}$ represents geometric deformations and ${M}_{{ab}}$ represents the stiffness matrix containing all of the material’s elastic moduli. We refer to the antisymmetric components $\left({M}_{{ab}}-{M}_{{ba}}\right)/2$ as odd elasticity 27 , 30 , 31 , 32 . A material displaying odd elasticity must violate Maxwell-Betti reciprocity, though it needs not rely on external sources of linear or angular momentum. Recent advances in metamaterial design and prototyping have utilized active components to achieve functionalities such as sensing, lasing, and cloaking 10 , 11 , 12 , 15 , frequency dependent reflectivity 33 , unidirectional wave amplification 7 , 34 , 35 , energy harvesting 16 , and analog computation 17 . Nonetheless, all the active non-reciprocal metamaterials so-far realized exhibit either of the following fundamental limitations: the active non-reciprocal effects either vanish from the linear response in the quasistatic limit 33 or they require the presence of background sources of linear or angular momentum 7 , 29 , 36 . As a result, their functionalities are largely restricted to finite-frequency control or fundamentally require the sample to be in contact with an additional medium that acts as a momentum sink or source. Here, we report the design, construction, and experimental demonstration of a freestanding metamaterial whose elasticity is unattainable in passive media (Fig. 1a–d ). The metamaterial is constructed with piezoelectric elements 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 mounted on a beam and controlled by electrical circuits. Our approach enables an asymmetric coupling between bending and shearing in micropolar solids 47 , 48 . This results in an odd micropolar material that simultaneously breaks parity and Maxwell-Betti reciprocity. The spectrum of the metabeam exhibits a non-Hermitian topological index which results in the localization of vibrational modes at sample boundaries.<|im_end|> <|im_start|>assistant Move over, Hollywood—science fiction is getting ready to leap off the big screen and enter the real world. While recent science fiction movies have demonstrated the power of artificially intelligent computer programs, such as the fictional character J.A.R.V.I.S. in the Avenger film series, to make independent decisions to carry out a set of actions, these imagined movie scenarios could now be closer to becoming a reality. In a recent study published in Nature Communications, a journal of Nature, researchers at the University of Missouri and University of Chicago have developed an artificial material, called a metamaterial, which can respond to its environment, independently make a decision, and perform an action not directed by a human being. For example, a drone making a delivery might evaluate its environment including wind direction, speed or wildlife, and automatically change course in order to complete the delivery safely. Guoliang Huang, Huber and Helen Croft Chair in Engineering, and co-author on the study, said the mechanical design of their new artificial material incorporates three main functions also displayed by materials found in nature—sensing; information processing; and actuation, or movement. Some examples of these natural materials include the quick reaction of a Venus fly trap's leafy jaws to capture an insect, chameleons changing the color of their skin to blend into their surroundings, and pine cones adjusting their shapes in response to changes in air humidity, Huang said. "Basically, we are controlling how this material responds to changes in external stimuli found in its surroundings," Huang said. "For example, we can apply this material to stealth technology in the aerospace industry by attaching the material to aerospace structures. It can help control and decrease noises coming from the aircraft, such as engine vibrations, which can increase its multifunctional capabilities." The material uses a computer chip to control or manipulate the processing of information that's needed to perform the requested actions, then uses the electrical power to convert that energy into mechanical energy. The researchers' next step is to implement their idea in a real-world environment. "Realization of active metamaterials with odd micropolar elasticity," was published in 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 Enzymes of the TET family are methylcytosine dioxygenases that undergo frequent mutational or functional inactivation in human cancers. Recurrent loss-of-function mutations in TET proteins are frequent in human diffuse large B cell lymphoma (DLBCL). Here, we investigate the role of TET proteins in B cell homeostasis and development of B cell lymphomas with features of DLBCL. We show that deletion of Tet2 and Tet3 genes in mature B cells in mice perturbs B cell homeostasis and results in spontaneous development of germinal center (GC)-derived B cell lymphomas with increased G-quadruplexes and R-loops. At a genome-wide level, G-quadruplexes and R-loops were associated with increased DNA double-strand breaks (DSBs) at immunoglobulin switch regions. Deletion of the DNA methyltransferase DNMT1 in TET-deficient B cells prevented expansion of GC B cells, diminished the accumulation of G-quadruplexes and R-loops and delayed B lymphoma development, consistent with the opposing functions of DNMT and TET enzymes in DNA methylation and demethylation. Clustered regularly interspaced short palindromic repeats (CRISPR)-mediated depletion of nucleases and helicases that regulate G-quadruplexes and R-loops decreased the viability of TET-deficient B cells. Our studies suggest a molecular mechanism by which TET loss of function might predispose to the development of B cell malignancies. Main The three mammalian TET enzymes (TET1, TET2 and TET3) are Fe(II)-, oxygen- and α-ketoglutarate-dependent dioxygenases that sequentially oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) 1 , 2 , 3 . TET enzymes regulate enhancer activity and DNA methylation dynamics during development (including B cell development) 4 , 5 , 6 , 7 , 8 , cell differentiation and cell lineage specification (reviewed in refs. 9 , 10 , 11 , 12 ). TET2 gene mutations and/or decreased TET activity have been observed in many hematological malignancies and solid cancers, often through impaired regulation of metabolic enzymes that affect TET activity (reviewed in refs. 9 , 13 , 14 , 15 , 16 ). For instance, TET2 is recurrently mutated in ~10% of DLBCL 17 , 18 , 19 , a heterogeneous malignancy originating in mature B cells undergoing activation and differentiation in GCs. TET2 mutations represent an early driver event in DLBCL 6 ; in mouse models, deletion of Tet2 in hematopoietic lineages disrupted GC B cell homeostasis and promoted development of more aggressive lymphomas when the transcription factor BCL6 was constitutively overexpressed 6 . 5hmC deposition has been observed at sites of DNA DSBs in HeLa cells 20 , and TET2 is associated with degradation of stalled replication forks in BRCA2-deficient mouse cells 21 , suggesting that TET proteins regulate genomic integrity. Two non-canonical DNA structures, R-loops and G-quadruplexes, can act as physical impediments to DNA and RNA polymerases during transcription and DNA replication and have been linked to replication fork stalling and genome instability (reviewed in refs. 22 , 23 , 24 , 25 , 26 ). R-loops form, mostly at genomic regions with high GC content, when RNA binds to the transcribed strand of DNA, displacing the non-transcribed DNA strand 22 , 23 . G-quadruplexes often form on the displaced G-rich strand when four guanines, one from each of four tracts of two or more guanine bases interspersed with variable numbers of random nucleotides (G >2 N 1–n G >2 N 1–n G >2 N 1–n G >2 ), form square planar structures known as G-quartets that are stabilized by Hoogsteen hydrogen bonding 23 , 25 , 27 , 28 , 29 . G-quartets stack above each other, and the resulting G-quadruplex structure is further stabilized by monovalent cations 24 , 25 , 26 . G-quadruplexes and R-loops are commonly associated with gene promoters, 5′-untranslated regions (5′-UTRs), DNA replication origins, telomeres and other regulatory elements in the mammalian genome 22 , 24 , 25 , 26 , 30 , 31 , 32 . The pathological effects of these structures can be mitigated by the concerted actions of diverse nucleases and helicases, among them RNases H1 and H2, which destroy RNA in RNA–DNA hybrids 22 , 23 , and several helicases (for example, ATRX, FANCD2 and Werner’s (WRN) and Bloom (BLM) syndrome Recq-like DNA helicases) that can bind and resolve G-quadruplexes 24 , 25 , 26 . Here, we show that profound TET loss of function, induced by deletion of the Tet2 and Tet3 genes in mature B cells in mice, is associated with the rapid development of DLBCL-like tumors from GC B cells. Like other malignancies associated with TET loss of function in primary mouse cells 33 , 34 , 35 , Tet2 / Tet3 -deficient B cells exhibit increased DNA damage based on increased staining with phosphorylated histone H2AX (γH2AX). 5hmC deposition has been observed at sites of DNA DSBs in HeLa cells 20 , and while exploring possible mechanisms for increased γH2AX staining, we noticed a marked accumulation of G-quadruplex structures and R-loops in expanded TET-deficient B, T and myeloid cells. CRISPR-mediated depletion of RNase H1 or ATRX, FANCD2 and BLM helicases led to a slight increase in DNA damage and apoptosis in TET-deficient compared to control B cells. Genome-wide mapping and high-throughput genome-wide translocation sequencing (HTGTS) showed a strong correlation of increased G-quadruplex and R-loop structures with increased DNA DSBs in switch regions of immunoglobulin genes in TET-deficient B cells. TET-deficient B cells also showed upregulation of the maintenance DNA methyltransferase DNMT1 as well as a slight but significant increase in DNA methylation at regions associated with G-quadruplexes and R-loops. DNMT1 was recently shown to bind G-quadruplex structures 36 , and deletion of Dnmt1 in TET-deficient B cells was associated with a striking reduction in GC B cells, decreased levels of G-quadruplex and R-loop structures in the surviving B cells and a marked delay in B lymphoma development. Together, our findings suggest molecular mechanisms through which TET loss of function could promote oncogenesis and genome instability in multiple TET-deficient cell types. Results TET deficiency in mature B cells causes B cell lymphoma Tet2 and Tet3 are the major TET paralogs expressed in mature B cells 4 , 5 ,", "role": "user" }, { "content": "A new cancer study reports that DNA manifested as knot-like folds and third rungs between DNA's two strands may drive cancer development, and an important regulatory enzyme could be associated with the formation of these unusual structures. Scientists from Northwestern Medicine and the La Jolla Institute for Immunology (LJI) have discovered that the loss of TET enzymes—a family of enzymes crucial for removing DNA methylation marks—is associated with B-cell lymphoma. Reduced activity of TET enzymes is common in many different cancers. Understanding the mechanisms behind cancer development upon loss of TET function may open the door for new drug treatment strategies to target multiple cancers. The research was recently published in the journal Nature Immunology. Previous research demonstrated specific mutations in cancer cells can result in loss of TET function in patients with blood cancers and solid cancers, causing delays in cell communication. Past studies have also identified genomic instabilities such as double-stranded breaks in the DNA code in cancer cells. Before now, the two dangerous cell features had not been linked. Strange, unusual structures appear in the DNA Vipul Shukla, an assistant professor of cell and developmental biology at Northwestern University Feinberg School of Medicine, along with Anjana Rao, a professor in LJI Center for Cancer Immunotherapy, and Daniela Samaniego-Castruita, a University of California San Diego graduate student, hoped to explore one potential way TET deficiency and genomic instability may be connected. \"Loss of TET function happens in cancer; genomic instability happens in cancer,\" Shukla said. \"Genomic instability also happens in TET-deficient cells. What we found was that altered regulation of secondary DNA structures might be the reason for how these two events are related to one another.\" The scientist first deleted two types of TET enzymes (TET2 and TET3) in mature B cells of mice. A type of white blood cell, B cells make antibodies for the immune system to protect our bodies from infection. According to Shukla, deleting TET enzymes had huge implications on the homeostasis of B cells, and genomic instabilities began to appear. \"The TET-deficient mice developed lymphoma, and we observed an increase in marks associated with genomic instability, such as double-stranded breaks,\" Samaniego-Castruita said. The team then looked for clues to what was happening at the molecular level by performing a genomic analysis and found that without TET2 and TET3, unusual structures called G-quadruplexes and R-loops started littering the DNA of B cells. Typically, DNA looks like two parallel train rails. As proteins move along the track and read through and communicate code, they pull the tracks slightly apart. But both DNA structures appeared to make it difficult for the cell to read DNA code. R-loops, made of RNA, slipped in as a third rail in DNA, and G-quadruplexes appeared as knots on the outer rails, making it difficult for the original strands to \"unzip.\" According to Shukla, the structures make DNA sites very fragile and breakable. \"They function as impediments in the DNA and if they don't resolve properly, they cause genomic instability,\" Shukla said. \"This study enlightened us that at least one of the reasons TET-deficient cells have more genomic instability might be due to the accumulation of these structures.\" Understanding how dangerous genomic instabilities and telltale TET mutations interact brings the team a step closer to understanding B cell malignancies. Delaying the development of B-cell lymphoma Shukla said he wanted to know why the structures appeared in the first place because then his team could learn more about stopping them from forming. They looked to one regulatory enzyme called DNMT1 that appeared to change in response to TET levels. In TET-deficient B cells, levels of DNMT1, proteins that helps maintain DNA methylation, were higher. DNA methylation is an important regulatory mark in the genome that is typically removed by TET enzymes. The team wanted to see if deleting the DNMT1 protein in TET-deficient B cells would restore the balance of G-quadruplex and R-loop structures. Remarkably, deleting DNMT1 was linked to a stark delay in the development of aggressive B-cell lymphomas. As hoped, it also was associated with decreased levels of G-quadruplexes and R-loops. The researchers plan to further explore the effects of TET enzymes and believe that regulating G-quadruplexes and R-loops may be one of many ways TET enzymes control genomic stability. In the future, the findings of the paper could be used to help patients across cancer types. Shukla's lab ultimately hopes to see how drugs can stabilize the abnormal structures and work as an effective treatment for malignant cells in many cancers. Shukla said there is lots of potential, and lots more to learn. \"The structures are like black boxes,\" Shukla said. \"Because normally when you think about DNA, you think of a linear code with four letters. But this is asking you to think about not just the sequence itself, it's also the way DNA can fold into alternative conformations besides the double helix. This study sheds light on a new aspect of genome biology.\" Recently joining Northwestern from LJI, Shukla and his lab focus on studying alternative structural conformations in the DNA. Additional study authors include Zhen Dong, Edahi Gonzalez-Avalos, Qingqing Yan and Kavitha Sarma. ", "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 Enzymes of the TET family are methylcytosine dioxygenases that undergo frequent mutational or functional inactivation in human cancers. Recurrent loss-of-function mutations in TET proteins are frequent in human diffuse large B cell lymphoma (DLBCL). Here, we investigate the role of TET proteins in B cell homeostasis and development of B cell lymphomas with features of DLBCL. We show that deletion of Tet2 and Tet3 genes in mature B cells in mice perturbs B cell homeostasis and results in spontaneous development of germinal center (GC)-derived B cell lymphomas with increased G-quadruplexes and R-loops. At a genome-wide level, G-quadruplexes and R-loops were associated with increased DNA double-strand breaks (DSBs) at immunoglobulin switch regions. Deletion of the DNA methyltransferase DNMT1 in TET-deficient B cells prevented expansion of GC B cells, diminished the accumulation of G-quadruplexes and R-loops and delayed B lymphoma development, consistent with the opposing functions of DNMT and TET enzymes in DNA methylation and demethylation. Clustered regularly interspaced short palindromic repeats (CRISPR)-mediated depletion of nucleases and helicases that regulate G-quadruplexes and R-loops decreased the viability of TET-deficient B cells. Our studies suggest a molecular mechanism by which TET loss of function might predispose to the development of B cell malignancies. Main The three mammalian TET enzymes (TET1, TET2 and TET3) are Fe(II)-, oxygen- and α-ketoglutarate-dependent dioxygenases that sequentially oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) 1 , 2 , 3 . TET enzymes regulate enhancer activity and DNA methylation dynamics during development (including B cell development) 4 , 5 , 6 , 7 , 8 , cell differentiation and cell lineage specification (reviewed in refs. 9 , 10 , 11 , 12 ). TET2 gene mutations and/or decreased TET activity have been observed in many hematological malignancies and solid cancers, often through impaired regulation of metabolic enzymes that affect TET activity (reviewed in refs. 9 , 13 , 14 , 15 , 16 ). For instance, TET2 is recurrently mutated in ~10% of DLBCL 17 , 18 , 19 , a heterogeneous malignancy originating in mature B cells undergoing activation and differentiation in GCs. TET2 mutations represent an early driver event in DLBCL 6 ; in mouse models, deletion of Tet2 in hematopoietic lineages disrupted GC B cell homeostasis and promoted development of more aggressive lymphomas when the transcription factor BCL6 was constitutively overexpressed 6 . 5hmC deposition has been observed at sites of DNA DSBs in HeLa cells 20 , and TET2 is associated with degradation of stalled replication forks in BRCA2-deficient mouse cells 21 , suggesting that TET proteins regulate genomic integrity. Two non-canonical DNA structures, R-loops and G-quadruplexes, can act as physical impediments to DNA and RNA polymerases during transcription and DNA replication and have been linked to replication fork stalling and genome instability (reviewed in refs. 22 , 23 , 24 , 25 , 26 ). R-loops form, mostly at genomic regions with high GC content, when RNA binds to the transcribed strand of DNA, displacing the non-transcribed DNA strand 22 , 23 . G-quadruplexes often form on the displaced G-rich strand when four guanines, one from each of four tracts of two or more guanine bases interspersed with variable numbers of random nucleotides (G >2 N 1–n G >2 N 1–n G >2 N 1–n G >2 ), form square planar structures known as G-quartets that are stabilized by Hoogsteen hydrogen bonding 23 , 25 , 27 , 28 , 29 . G-quartets stack above each other, and the resulting G-quadruplex structure is further stabilized by monovalent cations 24 , 25 , 26 . G-quadruplexes and R-loops are commonly associated with gene promoters, 5′-untranslated regions (5′-UTRs), DNA replication origins, telomeres and other regulatory elements in the mammalian genome 22 , 24 , 25 , 26 , 30 , 31 , 32 . The pathological effects of these structures can be mitigated by the concerted actions of diverse nucleases and helicases, among them RNases H1 and H2, which destroy RNA in RNA–DNA hybrids 22 , 23 , and several helicases (for example, ATRX, FANCD2 and Werner’s (WRN) and Bloom (BLM) syndrome Recq-like DNA helicases) that can bind and resolve G-quadruplexes 24 , 25 , 26 . Here, we show that profound TET loss of function, induced by deletion of the Tet2 and Tet3 genes in mature B cells in mice, is associated with the rapid development of DLBCL-like tumors from GC B cells. Like other malignancies associated with TET loss of function in primary mouse cells 33 , 34 , 35 , Tet2 / Tet3 -deficient B cells exhibit increased DNA damage based on increased staining with phosphorylated histone H2AX (γH2AX). 5hmC deposition has been observed at sites of DNA DSBs in HeLa cells 20 , and while exploring possible mechanisms for increased γH2AX staining, we noticed a marked accumulation of G-quadruplex structures and R-loops in expanded TET-deficient B, T and myeloid cells. CRISPR-mediated depletion of RNase H1 or ATRX, FANCD2 and BLM helicases led to a slight increase in DNA damage and apoptosis in TET-deficient compared to control B cells. Genome-wide mapping and high-throughput genome-wide translocation sequencing (HTGTS) showed a strong correlation of increased G-quadruplex and R-loop structures with increased DNA DSBs in switch regions of immunoglobulin genes in TET-deficient B cells. TET-deficient B cells also showed upregulation of the maintenance DNA methyltransferase DNMT1 as well as a slight but significant increase in DNA methylation at regions associated with G-quadruplexes and R-loops. DNMT1 was recently shown to bind G-quadruplex structures 36 , and deletion of Dnmt1 in TET-deficient B cells was associated with a striking reduction in GC B cells, decreased levels of G-quadruplex and R-loop structures in the surviving B cells and a marked delay in B lymphoma development. Together, our findings suggest molecular mechanisms through which TET loss of function could promote oncogenesis and genome instability in multiple TET-deficient cell types. Results TET deficiency in mature B cells causes B cell lymphoma Tet2 and Tet3 are the major TET paralogs expressed in mature B cells 4 , 5 ,<|im_end|> <|im_start|>assistant A new cancer study reports that DNA manifested as knot-like folds and third rungs between DNA's two strands may drive cancer development, and an important regulatory enzyme could be associated with the formation of these unusual structures. Scientists from Northwestern Medicine and the La Jolla Institute for Immunology (LJI) have discovered that the loss of TET enzymes—a family of enzymes crucial for removing DNA methylation marks—is associated with B-cell lymphoma. Reduced activity of TET enzymes is common in many different cancers. Understanding the mechanisms behind cancer development upon loss of TET function may open the door for new drug treatment strategies to target multiple cancers. The research was recently published in the journal Nature Immunology. Previous research demonstrated specific mutations in cancer cells can result in loss of TET function in patients with blood cancers and solid cancers, causing delays in cell communication. Past studies have also identified genomic instabilities such as double-stranded breaks in the DNA code in cancer cells. Before now, the two dangerous cell features had not been linked. Strange, unusual structures appear in the DNA Vipul Shukla, an assistant professor of cell and developmental biology at Northwestern University Feinberg School of Medicine, along with Anjana Rao, a professor in LJI Center for Cancer Immunotherapy, and Daniela Samaniego-Castruita, a University of California San Diego graduate student, hoped to explore one potential way TET deficiency and genomic instability may be connected. "Loss of TET function happens in cancer; genomic instability happens in cancer," Shukla said. "Genomic instability also happens in TET-deficient cells. What we found was that altered regulation of secondary DNA structures might be the reason for how these two events are related to one another." The scientist first deleted two types of TET enzymes (TET2 and TET3) in mature B cells of mice. A type of white blood cell, B cells make antibodies for the immune system to protect our bodies from infection. According to Shukla, deleting TET enzymes had huge implications on the homeostasis of B cells, and genomic instabilities began to appear. "The TET-deficient mice developed lymphoma, and we observed an increase in marks associated with genomic instability, such as double-stranded breaks," Samaniego-Castruita said. The team then looked for clues to what was happening at the molecular level by performing a genomic analysis and found that without TET2 and TET3, unusual structures called G-quadruplexes and R-loops started littering the DNA of B cells. Typically, DNA looks like two parallel train rails. As proteins move along the track and read through and communicate code, they pull the tracks slightly apart. But both DNA structures appeared to make it difficult for the cell to read DNA code. R-loops, made of RNA, slipped in as a third rail in DNA, and G-quadruplexes appeared as knots on the outer rails, making it difficult for the original strands to "unzip." According to Shukla, the structures make DNA sites very fragile and breakable. "They function as impediments in the DNA and if they don't resolve properly, they cause genomic instability," Shukla said. "This study enlightened us that at least one of the reasons TET-deficient cells have more genomic instability might be due to the accumulation of these structures." Understanding how dangerous genomic instabilities and telltale TET mutations interact brings the team a step closer to understanding B cell malignancies. Delaying the development of B-cell lymphoma Shukla said he wanted to know why the structures appeared in the first place because then his team could learn more about stopping them from forming. They looked to one regulatory enzyme called DNMT1 that appeared to change in response to TET levels. In TET-deficient B cells, levels of DNMT1, proteins that helps maintain DNA methylation, were higher. DNA methylation is an important regulatory mark in the genome that is typically removed by TET enzymes. The team wanted to see if deleting the DNMT1 protein in TET-deficient B cells would restore the balance of G-quadruplex and R-loop structures. Remarkably, deleting DNMT1 was linked to a stark delay in the development of aggressive B-cell lymphomas. As hoped, it also was associated with decreased levels of G-quadruplexes and R-loops. The researchers plan to further explore the effects of TET enzymes and believe that regulating G-quadruplexes and R-loops may be one of many ways TET enzymes control genomic stability. In the future, the findings of the paper could be used to help patients across cancer types. Shukla's lab ultimately hopes to see how drugs can stabilize the abnormal structures and work as an effective treatment for malignant cells in many cancers. Shukla said there is lots of potential, and lots more to learn. "The structures are like black boxes," Shukla said. "Because normally when you think about DNA, you think of a linear code with four letters. But this is asking you to think about not just the sequence itself, it's also the way DNA can fold into alternative conformations besides the double helix. This study sheds light on a new aspect of genome biology." Recently joining Northwestern from LJI, Shukla and his lab focus on studying alternative structural conformations in the DNA. Additional study authors include Zhen Dong, Edahi Gonzalez-Avalos, Qingqing Yan and Kavitha Sarma. <|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 Rad51 (also known as RecA) family of recombinases executes the critical step in homologous recombination: the search for homologous DNA to serve as a template during the repair of DNA double-strand breaks (DSBs) 1 , 2 , 3 , 4 , 5 , 6 , 7 . Although budding yeast Rad51 has been extensively characterized in vitro 3 , 4 , 6 , 7 , 8 , 9 , the stringency of its search and sensitivity to mismatched sequences in vivo remain poorly defined. Here, in Saccharomyces cerevisiae , we analysed Rad51-dependent break-induced replication in which the invading DSB end and its donor template share a 108-base-pair homology region and the donor carries different densities of single-base-pair mismatches. With every eighth base pair mismatched, repair was about 14% of that of completely homologous sequences. With every sixth base pair mismatched, repair was still more than 5%. Thus, completing break-induced replication in vivo overcomes the apparent requirement for at least 6–8 consecutive paired bases that has been inferred from in vitro studies 6 , 8 . When recombination occurs without a protruding nonhomologous 3′ tail, the mismatch repair protein Msh2 does not discourage homeologous recombination. However, when the DSB end contains a 3′ protruding nonhomologous tail, Msh2 promotes the rejection of mismatched substrates. Mismatch correction of strand invasion heteroduplex DNA is strongly polar, favouring correction close to the DSB end. Nearly all mismatch correction depends on the proofreading activity of DNA polymerase-δ, although the repair proteins Msh2, Mlh1 and Exo1 influence the extent of correction. Main Each monomer of Rad51 (homologue of bacterial RecA) binds three nucleotides of single-strand DNA (ssDNA). The resulting nucleoprotein filament engages in a search for homologous double-stranded DNA (dsDNA) to carry out strand exchange, the first step in DSB repair by homologous recombination 3 . A recent in vitro study concluded that an initial, stable encounter between Rad51- or RecA-bound ssDNA and mismatched dsDNA requires eight perfectly matched bases, and that extension of the heteroduplex proceeds in steps of three nucleotides bound to each Rad51 or RecA monomer 6 . Another study concluded that RecA-promoted strand exchange required segments of eight nucleotides that could tolerate a single mismatch 7 . To examine the stringency of Rad51-mediated recombination in vivo , we designed substrates that placed mismatches along a 108-bp donor template and monitored DSB repair by break-induced replication (BIR). In BIR, only one DSB end shares homology with a donor ( Fig. 1a ). Strand invasion between the resected, Rad51-coated single-stranded DSB end and the donor results in recruitment of DNA polymerases and copying of sequences to the end of the chromosome arm 10 . Our design sidesteps the need to excise a 3′-ended nonhomologous tail from the invading end before initiating new DNA synthesis 11 , 12 , 13 , 14 , 15 . Tail removal proves to be a confounding variable when measuring the success of homologous recombination (see below). Figure 1: Stringency and sensitivity of Rad51-mediated recombination. a , A DSB is repaired for BIR using a homologous or homeologous donor (108 bp). UR, first 400 bp of the URA3 open reading frame (ORF); SD, splice donor; SA, splice acceptor; A3, the remaining 404 bp of the URA3 ORF. b–e , Viability of Ura3 + cells completing BIR with donors with 108-, 54- or 27-bp homology ( b ); donors differing by a single base pair ( c ); donors containing 0, 1, 2, 3 or 4 mismatches ( d ); or donors containing mismatches every 12th position, 11th position and so on ( e ). Error bars represent s.e.m. ** P < 0.01, Student’s t -test. PowerPoint slide Full size image A DSB was created using the galactose-inducible, site-specific homothallic switching (HO) endonuclease in strains lacking natural HO recognition sites 16 . The 108-bp region of shared homology includes the 5′ end of an artificial intron, so that when BIR is completed, a functional intron is formed and yeast become Ura3 + ( Fig. 1a ). In the absence of mismatches, the viability of Ura3 + cells completing BIR was 14% ( Fig. 1b ). When shared homology was reduced from 108 bp to 54 or 27 bp, the frequency of Ura3 + cells fell to 1% and 0.002%, respectively. Nonhomologous end-joining events, which do not cause cells to become Ura3 + , occurred at a frequency of about 0.8% and were not considered. BIR was not sensitive to donors with a single mismatch at different positions relative to the 3′ end of the invading strand ( Fig. 1c and Extended Data Fig. 1a ). The use of a donor containing a single-base-pair insertion or deletion also did not reduce BIR ( Fig. 1c ). When donors contained two, three or four evenly spaced mismatches, BIR frequencies decreased progressively to 45% of the no-mismatch control ( Fig. 1d and Extended Data Fig. 1b ). BIR was successful when donor sequences contained mismatches at every twelfth position, eleventh position and so on, down to every sixth base pair (around 6% success) ( Fig. 1e ). Donors carrying mismatches every fifth base pair were as defective as a rad51 Δ strain without mismatches ( Fig. 1e ); however, even these recombinants were Rad51-dependent ( Extended Data Fig. 2 ). Thus recombination in vivo can occur when there is no possibility of eight consecutive base pairs; indeed, five consecutive base pairs appears to be sufficient to assure a modest level of recombination when the strand exchange machinery can ‘step over’ a mismatch and extend the heteroduplex. For successful recombination, heteroduplex DNA apparently must extend over most of the 108-bp length, because even 54 bp of perfect homology had a lower rate of recombination than the 108-bp segment with every ninth base pair mismatched (compare Fig. 1b and e ). If we adopt the assumptions of the in vitro -modelled initial step 7 , 17 , involving three Rad51 monomers (nine possible base pairs), our data imply that recombination can be successful in cases", "role": "user" }, { "content": "A new paper in the prestigious journal Nature from Brandeis researchers in the laboratory of James Haber provides a detailed description of the processes of DNA repair. Chromosomes undergo DNA repair to correct insults to our genetic code, caused either by errors in copying the DNA or by external factors such as exposure to radiation or toxins. Most damage gets accurately repaired, so the cell is unaffected, but some result in permanent errors (mutations or chromosome rearrangements) that may lead to diseases, including cancer. Especially dangerous are double-strand DNA breaks (DSB's) that sever the chromosome. The work was principally carried out by postdoctoral fellow Ranjith Anand with contributions by technician Annette Beach and physics Phd student Kevin Li. They examined repair of a double-strand break in yeast cells. When a DSB occurs, the cell needs to patch up the break by matching up the ends of the broken chromosome with similar DNA sequences located on an intact chromosome; the intact sequences can be used as a template to repair the break by DNA copying. To accomplish repair, the cell must be able to locate another chromosome with similar sequences to use as a template. Finding such a template is no easy task. Chromosomes are made up of base pairs—pairings of the molecules guanine and cytosine or adenine and thymine. (As you may remember from biology class, G goes with C and A with T). The end of the broken chromosome must be compared with millions of possible short DNA regions in order to find a chromosome with the same arrangement of base pairs. This search is mediated by the RAD51 protein, which promotes the matching up of the broken end with potential donor sequences. But how perfect does the match have to be? Ranjith Anand, the first author on the Nature paper, said this was one of the central questions that the Haber lab wanted to answer. They found that repair was still possible when every sixth base in a stretch of about 100 bases was different. Previous studies of RAD51 in the test tube had suggested that the protein had a much more stringent requirement for matching. That one of the six base pairs could be a mismatch surprised the scientists. The process \"is permissive of mismatches during the repairing,\" says Anand, now an organism engineer at Ginkgo Bioworks in Boston. There was another big surprise in the lab's results. Researchers had thought that mismatches such as an adenine paired with a cytosine were corrected by what are called mismatch repair proteins such as MSH2 or MSH6 whereby the cytosine was removed and replaced by the properly-paired thymine. Instead, Haber and his fellow researchers found an enzyme called DNA polymerase delta serves this proofreading 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 The Rad51 (also known as RecA) family of recombinases executes the critical step in homologous recombination: the search for homologous DNA to serve as a template during the repair of DNA double-strand breaks (DSBs) 1 , 2 , 3 , 4 , 5 , 6 , 7 . Although budding yeast Rad51 has been extensively characterized in vitro 3 , 4 , 6 , 7 , 8 , 9 , the stringency of its search and sensitivity to mismatched sequences in vivo remain poorly defined. Here, in Saccharomyces cerevisiae , we analysed Rad51-dependent break-induced replication in which the invading DSB end and its donor template share a 108-base-pair homology region and the donor carries different densities of single-base-pair mismatches. With every eighth base pair mismatched, repair was about 14% of that of completely homologous sequences. With every sixth base pair mismatched, repair was still more than 5%. Thus, completing break-induced replication in vivo overcomes the apparent requirement for at least 6–8 consecutive paired bases that has been inferred from in vitro studies 6 , 8 . When recombination occurs without a protruding nonhomologous 3′ tail, the mismatch repair protein Msh2 does not discourage homeologous recombination. However, when the DSB end contains a 3′ protruding nonhomologous tail, Msh2 promotes the rejection of mismatched substrates. Mismatch correction of strand invasion heteroduplex DNA is strongly polar, favouring correction close to the DSB end. Nearly all mismatch correction depends on the proofreading activity of DNA polymerase-δ, although the repair proteins Msh2, Mlh1 and Exo1 influence the extent of correction. Main Each monomer of Rad51 (homologue of bacterial RecA) binds three nucleotides of single-strand DNA (ssDNA). The resulting nucleoprotein filament engages in a search for homologous double-stranded DNA (dsDNA) to carry out strand exchange, the first step in DSB repair by homologous recombination 3 . A recent in vitro study concluded that an initial, stable encounter between Rad51- or RecA-bound ssDNA and mismatched dsDNA requires eight perfectly matched bases, and that extension of the heteroduplex proceeds in steps of three nucleotides bound to each Rad51 or RecA monomer 6 . Another study concluded that RecA-promoted strand exchange required segments of eight nucleotides that could tolerate a single mismatch 7 . To examine the stringency of Rad51-mediated recombination in vivo , we designed substrates that placed mismatches along a 108-bp donor template and monitored DSB repair by break-induced replication (BIR). In BIR, only one DSB end shares homology with a donor ( Fig. 1a ). Strand invasion between the resected, Rad51-coated single-stranded DSB end and the donor results in recruitment of DNA polymerases and copying of sequences to the end of the chromosome arm 10 . Our design sidesteps the need to excise a 3′-ended nonhomologous tail from the invading end before initiating new DNA synthesis 11 , 12 , 13 , 14 , 15 . Tail removal proves to be a confounding variable when measuring the success of homologous recombination (see below). Figure 1: Stringency and sensitivity of Rad51-mediated recombination. a , A DSB is repaired for BIR using a homologous or homeologous donor (108 bp). UR, first 400 bp of the URA3 open reading frame (ORF); SD, splice donor; SA, splice acceptor; A3, the remaining 404 bp of the URA3 ORF. b–e , Viability of Ura3 + cells completing BIR with donors with 108-, 54- or 27-bp homology ( b ); donors differing by a single base pair ( c ); donors containing 0, 1, 2, 3 or 4 mismatches ( d ); or donors containing mismatches every 12th position, 11th position and so on ( e ). Error bars represent s.e.m. ** P < 0.01, Student’s t -test. PowerPoint slide Full size image A DSB was created using the galactose-inducible, site-specific homothallic switching (HO) endonuclease in strains lacking natural HO recognition sites 16 . The 108-bp region of shared homology includes the 5′ end of an artificial intron, so that when BIR is completed, a functional intron is formed and yeast become Ura3 + ( Fig. 1a ). In the absence of mismatches, the viability of Ura3 + cells completing BIR was 14% ( Fig. 1b ). When shared homology was reduced from 108 bp to 54 or 27 bp, the frequency of Ura3 + cells fell to 1% and 0.002%, respectively. Nonhomologous end-joining events, which do not cause cells to become Ura3 + , occurred at a frequency of about 0.8% and were not considered. BIR was not sensitive to donors with a single mismatch at different positions relative to the 3′ end of the invading strand ( Fig. 1c and Extended Data Fig. 1a ). The use of a donor containing a single-base-pair insertion or deletion also did not reduce BIR ( Fig. 1c ). When donors contained two, three or four evenly spaced mismatches, BIR frequencies decreased progressively to 45% of the no-mismatch control ( Fig. 1d and Extended Data Fig. 1b ). BIR was successful when donor sequences contained mismatches at every twelfth position, eleventh position and so on, down to every sixth base pair (around 6% success) ( Fig. 1e ). Donors carrying mismatches every fifth base pair were as defective as a rad51 Δ strain without mismatches ( Fig. 1e ); however, even these recombinants were Rad51-dependent ( Extended Data Fig. 2 ). Thus recombination in vivo can occur when there is no possibility of eight consecutive base pairs; indeed, five consecutive base pairs appears to be sufficient to assure a modest level of recombination when the strand exchange machinery can ‘step over’ a mismatch and extend the heteroduplex. For successful recombination, heteroduplex DNA apparently must extend over most of the 108-bp length, because even 54 bp of perfect homology had a lower rate of recombination than the 108-bp segment with every ninth base pair mismatched (compare Fig. 1b and e ). If we adopt the assumptions of the in vitro -modelled initial step 7 , 17 , involving three Rad51 monomers (nine possible base pairs), our data imply that recombination can be successful in cases<|im_end|> <|im_start|>assistant A new paper in the prestigious journal Nature from Brandeis researchers in the laboratory of James Haber provides a detailed description of the processes of DNA repair. Chromosomes undergo DNA repair to correct insults to our genetic code, caused either by errors in copying the DNA or by external factors such as exposure to radiation or toxins. Most damage gets accurately repaired, so the cell is unaffected, but some result in permanent errors (mutations or chromosome rearrangements) that may lead to diseases, including cancer. Especially dangerous are double-strand DNA breaks (DSB's) that sever the chromosome. The work was principally carried out by postdoctoral fellow Ranjith Anand with contributions by technician Annette Beach and physics Phd student Kevin Li. They examined repair of a double-strand break in yeast cells. When a DSB occurs, the cell needs to patch up the break by matching up the ends of the broken chromosome with similar DNA sequences located on an intact chromosome; the intact sequences can be used as a template to repair the break by DNA copying. To accomplish repair, the cell must be able to locate another chromosome with similar sequences to use as a template. Finding such a template is no easy task. Chromosomes are made up of base pairs—pairings of the molecules guanine and cytosine or adenine and thymine. (As you may remember from biology class, G goes with C and A with T). The end of the broken chromosome must be compared with millions of possible short DNA regions in order to find a chromosome with the same arrangement of base pairs. This search is mediated by the RAD51 protein, which promotes the matching up of the broken end with potential donor sequences. But how perfect does the match have to be? Ranjith Anand, the first author on the Nature paper, said this was one of the central questions that the Haber lab wanted to answer. They found that repair was still possible when every sixth base in a stretch of about 100 bases was different. Previous studies of RAD51 in the test tube had suggested that the protein had a much more stringent requirement for matching. That one of the six base pairs could be a mismatch surprised the scientists. The process "is permissive of mismatches during the repairing," says Anand, now an organism engineer at Ginkgo Bioworks in Boston. There was another big surprise in the lab's results. Researchers had thought that mismatches such as an adenine paired with a cytosine were corrected by what are called mismatch repair proteins such as MSH2 or MSH6 whereby the cytosine was removed and replaced by the properly-paired thymine. Instead, Haber and his fellow researchers found an enzyme called DNA polymerase delta serves this proofreading function. <|im_end|>

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2,067

[ { "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 Employing a methodology reported in a recent theoretical study on male astronauts, this study estimated the effects of body size and aerobic countermeasure (CM) exercise in a four-person, all-female crew composed of individuals drawn from a stature range (1.50- to 1.90-m) representative of current space agency requirements (which exist for stature, but not for body mass) upon total energy expenditure (TEE), oxygen (O 2 ) consumption, carbon dioxide (CO 2 ) and metabolic heat (H prod ) production, and water requirements for hydration, during space exploration missions. Assuming geometric similarity across the stature range, estimates were derived using available female astronaut data (mean age: 40-years; BMI: 22.7-kg·m −2 ; resting VO 2 and VO 2max : 3.3- and 40.5-mL·kg −1 ·min −1 ) on 30- and 1080-day missions, without and with, ISS-like countermeasure exercise (modelled as 2 × 30-min aerobic exercise at 75% VO 2max , 6-day·week −1 ). Where spaceflight-specific data/equations were not available, terrestrial equivalents were used. Body size alone increased 24-h TEE (+ 30%), O 2 consumption (+ 60%), CO 2 (+ 60%) and H prod (+ 60%) production, and water requirements (+ 17%). With CM exercise, the increases were + 25–31%, + 29%, + 32%, + 38% and + 17–25% across the stature range. Compared to the previous study of theoretical male astronauts, the effect of body size on TEE was markedly less in females, and, at equivalent statures, all parameter estimates were lower for females, with relative differences ranging from -5% to -29%. When compared at the 50th percentile for stature for US females and males, these differences increased to − 11% to − 41% and translated to larger reductions in TEE, O 2 and water requirements, and less CO 2 and H prod during 1080-day missions using CM exercise. Differences between female and male theoretical astronauts result from lower resting and exercising O 2 requirements (based on available astronaut data) of female astronauts, who are lighter than male astronauts at equivalent statures and have lower relative VO 2max values. These data, combined with the current move towards smaller diameter space habitat modules, point to a number of potential advantages of all-female crews during future human space exploration missions. Introduction Human basal metabolism is, in absolute terms, proportional with body size, with larger individuals possessing higher resting oxygen consumption (VO 2 ), carbon dioxide production (VCO 2 ) and metabolic heat production 1 . These differences persist when metabolism is elevated during physical activity (e.g., 75% maximal oxygen uptake [VO 2max ]), assuming equal aerobic fitness (VO 2max relative to body mass) 2 . In most occupational settings, these differences do not have significant implications. Even in closed terrestrial (i.e., artificially sustained) environments, such differences have minimal impact, as long exposure times occur in relatively large and well-resourced environments (e.g., submarines), or in highly confined environments exposures are short and crew activity levels are relatively low (e.g., operating submersibles). Current missions to the International Space Station (ISS) in Low Earth Orbit (LEO) combine an artificially sustained closed environment with relatively high levels of physical activity due to daily countermeasure (CM) exercise 3 , performed in an attempt to ameliorate multi-system adaptation associated with prolonged spaceflight 4 . Regular (7–8 per year) re-supply of food and life support resources to LEO is currently provided for NASA by SpaceX and Northrup Grumman, in addition to Rocosmos’s ‘Progress’ and JAXA’s ‘HTV’ spacecraft. Beyond LEO, however, such as Artemis missions to Gateway and the Lunar surface 5 , re-supply will be significantly more difficult, with even greater challenges as exploration missions go beyond the Moon to destinations such as Mars. Total energy intake by ISS astronauts is reportedly as much as ~ 20–25% below recommended levels 6 , 7 , with overall in-flight physical activity associated with spaceflight-induced total energy expenditure (TEE) and body composition changes and thus energy requirements 6 . As a result, during future exploration missions, where CM exercise programmes with high levels of physical activity (and thus energy expenditure) will be combined with more restrictive life-support constraints 8 , crewmember total metabolic activity may become a critical mission planning consideration 9 . Given this, we 9 estimated the implications of body size (across a stature range of 1.50- to 1.90-m) and the use of CM exercise in an all-male crew upon mission resources. This study estimated that increasing stature from 1.50-m to 1.90-m increased (+ 44%) 24-h TEE, O 2 consumption, and CO 2 and metabolic heat production (+60%), and water required for hydration (+ 19%), with ISS-like CM exercise further increasing TEE (+ 29–32%), O 2 consumption (+ 31%), CO 2 (+ 35%) and metabolic heat (+ 42%) production, and water requirements (+ 23–33%) across the stature range. The previous study did not evaluate the effect of body size and the use of CM exercise in females, yet, the first orbital spaceflight by a female (Valentina Tereshkova) in Vostok 6 on June 16th, 1963 was just two years after the first male Soviet cosmonaut, Yuri Gagarin (April 12th, 1961). In the United States (US), Brigadier General Donald Flickinger and Dr. W. Randolph Lovelace II, the NASA medical staff that tested male candidate pilots for the Mercury 7 space programme, considered the inclusion of women as early as 1959. As described in Ryan et al. 10 , Flickinger and Lovelace II identified a number of potential benefits of flying females. These included (compared to males) lower body mass (and thus reducing the fuel required to reach orbit), lower oxygen consumption 11 , as well as a lower risk of heart attack, a belief that the female reproductive organs were less susceptible to ionizing radiation, and the suggestion that females had better tolerance to cramped spaces and prolonged isolation 12 , 13 . Although the ‘Woman in Space Earliest’ (WISE) Programme, established by Flickinger with the aim of extending the testing that had been undertaken by male candidates for the Mercury programme, was cancelled, Flickinger’s continued efforts resulted in the private ‘Woman in Space Programme’.", "role": "user" }, { "content": "As humans contemplate life on other planets, we are immediately confronted with two choices. One is a journey to another solar system that would take tens of thousands of years (with current technology), requiring around 2,000 generations to live out their existence in the cramped confines of a spacecraft while adhering to a strict population control scheme. The other choice is Mars. Mars has several advantages, not the least of which is proximity, eliminating the need to push people out of airlocks when the spacecraft is at capacity. It would also allow an advance team to set up basic infrastructure and to be the most efficient—the team should all be female. Researchers from the Space Medicine Team, European Space Agency in Germany have conducted a study published in Scientific Reports that found female astronauts have lower water requirements for hydration, total energy expenditure, oxygen (O2) consumption, carbon dioxide (CO2) and metabolic heat production during space exploration missions compared to their male counterparts. In the study, \"Effects of body size and countermeasure exercise on estimates of life support resources during all-female crewed exploration missions,\" the team utilized an approach developed to estimate the effects of body \"size\" on life support requirements in male astronauts. For all parameters at all statures, estimates for females were lower than for comparable male astronauts. When considering the limited space, energy, weight, and life support systems packed into a spacecraft on a long mission, the study finds that the female form is the most efficient body type for space exploration. According to NASA, the cost of getting payloads to the International Space Station (ISS) is $93,400 per kg. The study found that on a 1080-day mission, a four-member all-female crew would require 1695 kg less food weight. With some simple arithmetic, the mission could save over $158 million and free up 2.3 m3 of space (food packaging), the equivalent of approximately 4% of the habitable volume (60 m3) of a \"Gateway\" HALO module in NASA's proposed lunar orbit space station. Both factors would be highly significant operationally, but there is more. Compared to a previous study of theoretical male astronauts, the effect of body size on total energy expenditure was markedly less in females, with relative differences ranging from 5% to 29% lower. Compared at the 50th percentile stature for US females (1.6m), the reductions were even more significant at 11% to 41%. This translates into reduced use of oxygen, production of CO2, metabolic heat, and water use. When exposed to the prolonged microgravity of space, bad things happen to astronaut bodies. Physiological changes induce muscle atrophy, bone loss, and reduced aerobic and sensorimotor capacity, potentially affecting crewmember health and ability to perform mission tasks. Exercise in space is called \"countermeasure exercise\" as it is designed to counter the physiological effects of being weightless. During these exercises (two 30-min aerobic exercises, six days a week), astronauts have higher rates of O2 consumption, production of CO2, metabolic heat production, and require more water to rehydrate. While body size alone correlates to energy metrics (smaller stature, less energy used), missions requiring countermeasure exercise increase this disparity as larger bodies use more energy, need more oxygen, produce more CO2 and create more heat. Additionally, the study found that females had 29% less water loss through sweating during a single bout of aerobic countermeasure exercise and so required less water to rehydrate. The theoretical differences between female and male astronauts result from lower resting and exercising O2 requirements of female astronauts, who are lighter than male astronauts at equivalent statures and have lower relative VO2max (the rate at which the heart, lungs, and muscles can effectively use oxygen during exercise) values. Aside from resource usage, there are also advantages in functional workspaces, especially when multiple astronauts are working in the same confined area, as often happens on the ISS. Aboard the ISS, the astronauts have just enough room to stand and work shoulder-to-shoulder or back-to-back when necessary. The spaces in the proposed NASA Gateway craft are tighter, creating a less ergonomic environment for multiple crew members to work together. Tighter spaces could operate just as efficiently with a smaller crew. The study data, combined with the move towards smaller diameter habitat space for currently proposed mission modules, suggest that there may be several operational advantages to all-female crews during future human space exploration missions, with the most significant improvement coming from shorter females. ", "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 Employing a methodology reported in a recent theoretical study on male astronauts, this study estimated the effects of body size and aerobic countermeasure (CM) exercise in a four-person, all-female crew composed of individuals drawn from a stature range (1.50- to 1.90-m) representative of current space agency requirements (which exist for stature, but not for body mass) upon total energy expenditure (TEE), oxygen (O 2 ) consumption, carbon dioxide (CO 2 ) and metabolic heat (H prod ) production, and water requirements for hydration, during space exploration missions. Assuming geometric similarity across the stature range, estimates were derived using available female astronaut data (mean age: 40-years; BMI: 22.7-kg·m −2 ; resting VO 2 and VO 2max : 3.3- and 40.5-mL·kg −1 ·min −1 ) on 30- and 1080-day missions, without and with, ISS-like countermeasure exercise (modelled as 2 × 30-min aerobic exercise at 75% VO 2max , 6-day·week −1 ). Where spaceflight-specific data/equations were not available, terrestrial equivalents were used. Body size alone increased 24-h TEE (+ 30%), O 2 consumption (+ 60%), CO 2 (+ 60%) and H prod (+ 60%) production, and water requirements (+ 17%). With CM exercise, the increases were + 25–31%, + 29%, + 32%, + 38% and + 17–25% across the stature range. Compared to the previous study of theoretical male astronauts, the effect of body size on TEE was markedly less in females, and, at equivalent statures, all parameter estimates were lower for females, with relative differences ranging from -5% to -29%. When compared at the 50th percentile for stature for US females and males, these differences increased to − 11% to − 41% and translated to larger reductions in TEE, O 2 and water requirements, and less CO 2 and H prod during 1080-day missions using CM exercise. Differences between female and male theoretical astronauts result from lower resting and exercising O 2 requirements (based on available astronaut data) of female astronauts, who are lighter than male astronauts at equivalent statures and have lower relative VO 2max values. These data, combined with the current move towards smaller diameter space habitat modules, point to a number of potential advantages of all-female crews during future human space exploration missions. Introduction Human basal metabolism is, in absolute terms, proportional with body size, with larger individuals possessing higher resting oxygen consumption (VO 2 ), carbon dioxide production (VCO 2 ) and metabolic heat production 1 . These differences persist when metabolism is elevated during physical activity (e.g., 75% maximal oxygen uptake [VO 2max ]), assuming equal aerobic fitness (VO 2max relative to body mass) 2 . In most occupational settings, these differences do not have significant implications. Even in closed terrestrial (i.e., artificially sustained) environments, such differences have minimal impact, as long exposure times occur in relatively large and well-resourced environments (e.g., submarines), or in highly confined environments exposures are short and crew activity levels are relatively low (e.g., operating submersibles). Current missions to the International Space Station (ISS) in Low Earth Orbit (LEO) combine an artificially sustained closed environment with relatively high levels of physical activity due to daily countermeasure (CM) exercise 3 , performed in an attempt to ameliorate multi-system adaptation associated with prolonged spaceflight 4 . Regular (7–8 per year) re-supply of food and life support resources to LEO is currently provided for NASA by SpaceX and Northrup Grumman, in addition to Rocosmos’s ‘Progress’ and JAXA’s ‘HTV’ spacecraft. Beyond LEO, however, such as Artemis missions to Gateway and the Lunar surface 5 , re-supply will be significantly more difficult, with even greater challenges as exploration missions go beyond the Moon to destinations such as Mars. Total energy intake by ISS astronauts is reportedly as much as ~ 20–25% below recommended levels 6 , 7 , with overall in-flight physical activity associated with spaceflight-induced total energy expenditure (TEE) and body composition changes and thus energy requirements 6 . As a result, during future exploration missions, where CM exercise programmes with high levels of physical activity (and thus energy expenditure) will be combined with more restrictive life-support constraints 8 , crewmember total metabolic activity may become a critical mission planning consideration 9 . Given this, we 9 estimated the implications of body size (across a stature range of 1.50- to 1.90-m) and the use of CM exercise in an all-male crew upon mission resources. This study estimated that increasing stature from 1.50-m to 1.90-m increased (+ 44%) 24-h TEE, O 2 consumption, and CO 2 and metabolic heat production (+60%), and water required for hydration (+ 19%), with ISS-like CM exercise further increasing TEE (+ 29–32%), O 2 consumption (+ 31%), CO 2 (+ 35%) and metabolic heat (+ 42%) production, and water requirements (+ 23–33%) across the stature range. The previous study did not evaluate the effect of body size and the use of CM exercise in females, yet, the first orbital spaceflight by a female (Valentina Tereshkova) in Vostok 6 on June 16th, 1963 was just two years after the first male Soviet cosmonaut, Yuri Gagarin (April 12th, 1961). In the United States (US), Brigadier General Donald Flickinger and Dr. W. Randolph Lovelace II, the NASA medical staff that tested male candidate pilots for the Mercury 7 space programme, considered the inclusion of women as early as 1959. As described in Ryan et al. 10 , Flickinger and Lovelace II identified a number of potential benefits of flying females. These included (compared to males) lower body mass (and thus reducing the fuel required to reach orbit), lower oxygen consumption 11 , as well as a lower risk of heart attack, a belief that the female reproductive organs were less susceptible to ionizing radiation, and the suggestion that females had better tolerance to cramped spaces and prolonged isolation 12 , 13 . Although the ‘Woman in Space Earliest’ (WISE) Programme, established by Flickinger with the aim of extending the testing that had been undertaken by male candidates for the Mercury programme, was cancelled, Flickinger’s continued efforts resulted in the private ‘Woman in Space Programme’.<|im_end|> <|im_start|>assistant As humans contemplate life on other planets, we are immediately confronted with two choices. One is a journey to another solar system that would take tens of thousands of years (with current technology), requiring around 2,000 generations to live out their existence in the cramped confines of a spacecraft while adhering to a strict population control scheme. The other choice is Mars. Mars has several advantages, not the least of which is proximity, eliminating the need to push people out of airlocks when the spacecraft is at capacity. It would also allow an advance team to set up basic infrastructure and to be the most efficient—the team should all be female. Researchers from the Space Medicine Team, European Space Agency in Germany have conducted a study published in Scientific Reports that found female astronauts have lower water requirements for hydration, total energy expenditure, oxygen (O2) consumption, carbon dioxide (CO2) and metabolic heat production during space exploration missions compared to their male counterparts. In the study, "Effects of body size and countermeasure exercise on estimates of life support resources during all-female crewed exploration missions," the team utilized an approach developed to estimate the effects of body "size" on life support requirements in male astronauts. For all parameters at all statures, estimates for females were lower than for comparable male astronauts. When considering the limited space, energy, weight, and life support systems packed into a spacecraft on a long mission, the study finds that the female form is the most efficient body type for space exploration. According to NASA, the cost of getting payloads to the International Space Station (ISS) is $93,400 per kg. The study found that on a 1080-day mission, a four-member all-female crew would require 1695 kg less food weight. With some simple arithmetic, the mission could save over $158 million and free up 2.3 m3 of space (food packaging), the equivalent of approximately 4% of the habitable volume (60 m3) of a "Gateway" HALO module in NASA's proposed lunar orbit space station. Both factors would be highly significant operationally, but there is more. Compared to a previous study of theoretical male astronauts, the effect of body size on total energy expenditure was markedly less in females, with relative differences ranging from 5% to 29% lower. Compared at the 50th percentile stature for US females (1.6m), the reductions were even more significant at 11% to 41%. This translates into reduced use of oxygen, production of CO2, metabolic heat, and water use. When exposed to the prolonged microgravity of space, bad things happen to astronaut bodies. Physiological changes induce muscle atrophy, bone loss, and reduced aerobic and sensorimotor capacity, potentially affecting crewmember health and ability to perform mission tasks. Exercise in space is called "countermeasure exercise" as it is designed to counter the physiological effects of being weightless. During these exercises (two 30-min aerobic exercises, six days a week), astronauts have higher rates of O2 consumption, production of CO2, metabolic heat production, and require more water to rehydrate. While body size alone correlates to energy metrics (smaller stature, less energy used), missions requiring countermeasure exercise increase this disparity as larger bodies use more energy, need more oxygen, produce more CO2 and create more heat. Additionally, the study found that females had 29% less water loss through sweating during a single bout of aerobic countermeasure exercise and so required less water to rehydrate. The theoretical differences between female and male astronauts result from lower resting and exercising O2 requirements of female astronauts, who are lighter than male astronauts at equivalent statures and have lower relative VO2max (the rate at which the heart, lungs, and muscles can effectively use oxygen during exercise) values. Aside from resource usage, there are also advantages in functional workspaces, especially when multiple astronauts are working in the same confined area, as often happens on the ISS. Aboard the ISS, the astronauts have just enough room to stand and work shoulder-to-shoulder or back-to-back when necessary. The spaces in the proposed NASA Gateway craft are tighter, creating a less ergonomic environment for multiple crew members to work together. Tighter spaces could operate just as efficiently with a smaller crew. The study data, combined with the move towards smaller diameter habitat space for currently proposed mission modules, suggest that there may be several operational advantages to all-female crews during future human space exploration missions, with the most significant improvement coming from shorter females. <|im_end|>

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2,367

[ { "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 Fusion energy research has in the past 40 years focused primarily on the tokamak concept, but recent advances in plasma theory and computational power have led to renewed interest in stellarators. The largest and most sophisticated stellarator in the world, Wendelstein 7-X (W7-X), has just started operation, with the aim to show that the earlier weaknesses of this concept have been addressed successfully, and that the intrinsic advantages of the concept persist, also at plasma parameters approaching those of a future fusion power plant. Here we show the first physics results, obtained before plasma operation: that the carefully tailored topology of nested magnetic surfaces needed for good confinement is realized, and that the measured deviations are smaller than one part in 100,000. This is a significant step forward in stellarator research, since it shows that the complicated and delicate magnetic topology can be created and verified with the required accuracy. Introduction Fusion has the potential to cover the energy needs of the world’s population into the distant future. Lawson showed in 1957 that magnetic confinement fusion based on deuterium–tritium fusion can work as a net energy source if one achieves a sufficiently high triple product, keV m −3 s for the plasma, approximately valid for ion temperatures T i in the range 10–40 keV (ref. 1 ). Here n i is the ion density, and is the energy confinement time, which for a typical operating point in magnetic fusion reactor studies is a few seconds. A promising approach to meeting this challenge is the use of a magnetic field that creates toroidal magnetic surfaces. Of these concepts, the tokamak has so far shown the best confinement properties, but the stellarator is not far behind, and there is reason to believe that it can catch up. In a stellarator, nested toroidal magnetic surfaces are created from external magnetic coils, see Fig. 1 . Each magnetic field line meanders around on its magnetic surface; it never leaves it. In general, if one follows a field line from one point on a magnetic surface, one never comes back to the same exact location. Instead, one covers the surface, coming infinitely close to any point of the surface. Figure 1: Layout of W7-X. Some representative nested magnetic surfaces are shown in different colours in this computer-aided design (CAD) rendering, together with a magnetic field line that lies on the green surface. The coil sets that create the magnetic surfaces are also shown, planar coils in brown, non-planar coils in grey. Some coils are left out of the rendering, allowing for a view of the nested surfaces (left) and a Poincaré section of the shown surfaces (right). Four out of the five external trim coils are shown in yellow. The fifth coil, which is not shown, would appear at the front of the rendering. Full size image The stellarator is different from the other toroidal magnetic surface concepts in that both the toroidal and the poloidal field components—which together create the magnetic surface topology—are created from currents in external coils. In the tokamak and the reversed-field pinch 2 , a strong toroidal current driven within the plasma is needed to generate the poloidal magnetic-field component. The stellarator’s lack of a strong current parallel to the magnetic field greatly reduces macroscopic plasma instabilities, and it eliminates the need for steady-state current drive. This makes it a more stable configuration, capable of steady-state operation. These are important advantages for a power plant. The stellarator was invented by Lyman Spitzer in the 1950s (ref. 3 ). So why did it fall behind? And why do some believe that it is about to have a comeback? Plasma confinement in early stellarators was disappointing. This was due to poorly confined particle orbits—many of the particle trajectories were not fully confined, even though the magnetic field lines were. If each guiding centre (the point around which the particle performs its rapid gyration) were to stay exactly on the magnetic field line it starts out on, the magnetic surfaces would guarantee good confinement. But for all toroidal magnetic systems, the orbits deviate from the field lines, since the guiding centres drift perpendicular to the magnetic field. This is due to the field-line curvature and magnetic field strength inhomogeneities inherent to the toroidal magnetic topology. In a magnetically confined fusion plasma, the drift is on the order of 10,000 times slower than the particle velocity, but, at 100 ms −1 , it will lead to particle losses in less than 1/10 of a second, if the drifts do not average out or stay within the magnetic surface, but instead carry the particle from the inner to the outer magnetic surfaces. This was the case in early stellarator experiments. The tokamak and the reversed-field pinch do not suffer from this problem since their toroidal symmetry makes the particle drifts average out for all the particles and therefore only cause minor excursions from the magnetic surface. Advances in plasma theory, in particular in the 1980s and 1990s, allowed the development of stellarator magnetic field configurations that display greatly improved confinement (see refs 4 , 5 ), reducing the drift orbit losses to a level sufficiently small so that it is predicted to be compatible with an economically feasible fusion power plant. The optimization itself, as well as the associated design of coils that realize the optimized magnetic fields, requires computer power that only became available in the 1980s. The first generation of optimized stellarators started operation in the 1990s, and confirmed many of the expected improvements 6 , 7 . These devices were, however, too small to reach the high ion temperatures where the optimization really comes to its test. Moreover, they were built with copper coils, which are adequate for proof-of-principle studies but incompatible with steady-state operation at high magnetic field strengths. The Wendelstein 7-X (W7-X) stellarator experiment is the first representative of the new generation of optimized stellarators, and aims to show with its superconducting coil system and relatively large size (major", "role": "user" }, { "content": "Physicist Sam Lazerson of the U.S. Department of Energy's (DOE) Princeton Plasma Physics Laboratory (PPPL) has teamed with German scientists to confirm that the Wendelstein 7-X (W7-X) fusion energy device called a stellarator in Greifswald, Germany, produces high-quality magnetic fields that are consistent with their complex design. The findings, published in the November 30 issue of Nature Communications , revealed an error field—or deviation from the designed configuration—of less than one part in 100,000. Such results could become a key step toward verifying the feasibility of stellarators as models for future fusion reactors. W7-X, for which PPPL is the leading U.S. collaborator, is the largest and most sophisticated stellarator in the world. Built by the Max Planck Institute for Plasma Physics in Greifswald, it was completed in 2015 as the vanguard of the stellarator design. Other collaborators on the U.S. team include DOE's Oak Ridge and Los Alamos National Laboratories, along with Auburn University, the Massachusetts Institute of Technology, the University of Wisconsin-Madison and Xanthos Technologies. Twisty magnetic fields Stellarators confine the hot, charged gas, otherwise known as plasma, that fuels fusion reactions in twisty—or 3-D—magnetic fields, compared with the symmetrical—or 2D —fields that the more widely used tokamaks create. The twisty configuration enables stellarators to control the plasma with no need for the current that tokamaks must induce in the gas to complete the magnetic field. Stellarator plasmas thus run little risk of disrupting, as can happen in tokamaks, causing the internal current to abruptly halt and fusion reactions to shut down. PPPL has played key roles in the W7-X project. The Laboratory designed and delivered five barn door-sized trim coils that fine-tune the stellarator's magnetic fields and made their measurement possible. \"We've confirmed that the magnetic cage that we've built works as designed,\" said Lazerson, who led roughly half the experiments that validated the configuration of the field. \"This reflects U.S. contributions to W7-X,\" he added, \"and highlights PPPL's ability to conduct international collaborations.\" Support for this work comes from Euratom and the DOE Office of Science. To measure the magnetic field, the scientists launched an electron beam along the field lines. They next obtained a cross-section of the entire magnetic surface by using a fluorescent rod to intersect and sweep through the lines, thereby inducing fluorescent light in the shape of the surface. Remarkable fidelity Results showed a remarkable fidelity to the design of the highly complex magnetic field. \"To our knowledge,\" the authors write of the discrepancy of less than one part in 100,000, \"this is an unprecedented accuracy, both in terms of the as-built engineering of a fusion device, as well as in the measurement of magnetic topology.\" The W7-X is the most recent version of the stellarator concept, which Lyman Spitzer, a Princeton University astrophysicist and founder of PPPL, originated during the 1950s. Stellarators mostly gave way to tokamaks a decade later, since the doughnut-shaped facilities are simpler to design and build and generally confine plasma better. But recent advances in plasma theory and computational power have led to renewed interest in stellarators. Such advances caused the authors to wonder if devices like the W7-X can provide an answer to the question of whether stellarators are the right concept for fusion energy. Years of plasma physics research will be needed to find out, they conclude, and \"that task has just started.\" ", "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 Fusion energy research has in the past 40 years focused primarily on the tokamak concept, but recent advances in plasma theory and computational power have led to renewed interest in stellarators. The largest and most sophisticated stellarator in the world, Wendelstein 7-X (W7-X), has just started operation, with the aim to show that the earlier weaknesses of this concept have been addressed successfully, and that the intrinsic advantages of the concept persist, also at plasma parameters approaching those of a future fusion power plant. Here we show the first physics results, obtained before plasma operation: that the carefully tailored topology of nested magnetic surfaces needed for good confinement is realized, and that the measured deviations are smaller than one part in 100,000. This is a significant step forward in stellarator research, since it shows that the complicated and delicate magnetic topology can be created and verified with the required accuracy. Introduction Fusion has the potential to cover the energy needs of the world’s population into the distant future. Lawson showed in 1957 that magnetic confinement fusion based on deuterium–tritium fusion can work as a net energy source if one achieves a sufficiently high triple product, keV m −3 s for the plasma, approximately valid for ion temperatures T i in the range 10–40 keV (ref. 1 ). Here n i is the ion density, and is the energy confinement time, which for a typical operating point in magnetic fusion reactor studies is a few seconds. A promising approach to meeting this challenge is the use of a magnetic field that creates toroidal magnetic surfaces. Of these concepts, the tokamak has so far shown the best confinement properties, but the stellarator is not far behind, and there is reason to believe that it can catch up. In a stellarator, nested toroidal magnetic surfaces are created from external magnetic coils, see Fig. 1 . Each magnetic field line meanders around on its magnetic surface; it never leaves it. In general, if one follows a field line from one point on a magnetic surface, one never comes back to the same exact location. Instead, one covers the surface, coming infinitely close to any point of the surface. Figure 1: Layout of W7-X. Some representative nested magnetic surfaces are shown in different colours in this computer-aided design (CAD) rendering, together with a magnetic field line that lies on the green surface. The coil sets that create the magnetic surfaces are also shown, planar coils in brown, non-planar coils in grey. Some coils are left out of the rendering, allowing for a view of the nested surfaces (left) and a Poincaré section of the shown surfaces (right). Four out of the five external trim coils are shown in yellow. The fifth coil, which is not shown, would appear at the front of the rendering. Full size image The stellarator is different from the other toroidal magnetic surface concepts in that both the toroidal and the poloidal field components—which together create the magnetic surface topology—are created from currents in external coils. In the tokamak and the reversed-field pinch 2 , a strong toroidal current driven within the plasma is needed to generate the poloidal magnetic-field component. The stellarator’s lack of a strong current parallel to the magnetic field greatly reduces macroscopic plasma instabilities, and it eliminates the need for steady-state current drive. This makes it a more stable configuration, capable of steady-state operation. These are important advantages for a power plant. The stellarator was invented by Lyman Spitzer in the 1950s (ref. 3 ). So why did it fall behind? And why do some believe that it is about to have a comeback? Plasma confinement in early stellarators was disappointing. This was due to poorly confined particle orbits—many of the particle trajectories were not fully confined, even though the magnetic field lines were. If each guiding centre (the point around which the particle performs its rapid gyration) were to stay exactly on the magnetic field line it starts out on, the magnetic surfaces would guarantee good confinement. But for all toroidal magnetic systems, the orbits deviate from the field lines, since the guiding centres drift perpendicular to the magnetic field. This is due to the field-line curvature and magnetic field strength inhomogeneities inherent to the toroidal magnetic topology. In a magnetically confined fusion plasma, the drift is on the order of 10,000 times slower than the particle velocity, but, at 100 ms −1 , it will lead to particle losses in less than 1/10 of a second, if the drifts do not average out or stay within the magnetic surface, but instead carry the particle from the inner to the outer magnetic surfaces. This was the case in early stellarator experiments. The tokamak and the reversed-field pinch do not suffer from this problem since their toroidal symmetry makes the particle drifts average out for all the particles and therefore only cause minor excursions from the magnetic surface. Advances in plasma theory, in particular in the 1980s and 1990s, allowed the development of stellarator magnetic field configurations that display greatly improved confinement (see refs 4 , 5 ), reducing the drift orbit losses to a level sufficiently small so that it is predicted to be compatible with an economically feasible fusion power plant. The optimization itself, as well as the associated design of coils that realize the optimized magnetic fields, requires computer power that only became available in the 1980s. The first generation of optimized stellarators started operation in the 1990s, and confirmed many of the expected improvements 6 , 7 . These devices were, however, too small to reach the high ion temperatures where the optimization really comes to its test. Moreover, they were built with copper coils, which are adequate for proof-of-principle studies but incompatible with steady-state operation at high magnetic field strengths. The Wendelstein 7-X (W7-X) stellarator experiment is the first representative of the new generation of optimized stellarators, and aims to show with its superconducting coil system and relatively large size (major<|im_end|> <|im_start|>assistant Physicist Sam Lazerson of the U.S. Department of Energy's (DOE) Princeton Plasma Physics Laboratory (PPPL) has teamed with German scientists to confirm that the Wendelstein 7-X (W7-X) fusion energy device called a stellarator in Greifswald, Germany, produces high-quality magnetic fields that are consistent with their complex design. The findings, published in the November 30 issue of Nature Communications , revealed an error field—or deviation from the designed configuration—of less than one part in 100,000. Such results could become a key step toward verifying the feasibility of stellarators as models for future fusion reactors. W7-X, for which PPPL is the leading U.S. collaborator, is the largest and most sophisticated stellarator in the world. Built by the Max Planck Institute for Plasma Physics in Greifswald, it was completed in 2015 as the vanguard of the stellarator design. Other collaborators on the U.S. team include DOE's Oak Ridge and Los Alamos National Laboratories, along with Auburn University, the Massachusetts Institute of Technology, the University of Wisconsin-Madison and Xanthos Technologies. Twisty magnetic fields Stellarators confine the hot, charged gas, otherwise known as plasma, that fuels fusion reactions in twisty—or 3-D—magnetic fields, compared with the symmetrical—or 2D —fields that the more widely used tokamaks create. The twisty configuration enables stellarators to control the plasma with no need for the current that tokamaks must induce in the gas to complete the magnetic field. Stellarator plasmas thus run little risk of disrupting, as can happen in tokamaks, causing the internal current to abruptly halt and fusion reactions to shut down. PPPL has played key roles in the W7-X project. The Laboratory designed and delivered five barn door-sized trim coils that fine-tune the stellarator's magnetic fields and made their measurement possible. "We've confirmed that the magnetic cage that we've built works as designed," said Lazerson, who led roughly half the experiments that validated the configuration of the field. "This reflects U.S. contributions to W7-X," he added, "and highlights PPPL's ability to conduct international collaborations." Support for this work comes from Euratom and the DOE Office of Science. To measure the magnetic field, the scientists launched an electron beam along the field lines. They next obtained a cross-section of the entire magnetic surface by using a fluorescent rod to intersect and sweep through the lines, thereby inducing fluorescent light in the shape of the surface. Remarkable fidelity Results showed a remarkable fidelity to the design of the highly complex magnetic field. "To our knowledge," the authors write of the discrepancy of less than one part in 100,000, "this is an unprecedented accuracy, both in terms of the as-built engineering of a fusion device, as well as in the measurement of magnetic topology." The W7-X is the most recent version of the stellarator concept, which Lyman Spitzer, a Princeton University astrophysicist and founder of PPPL, originated during the 1950s. Stellarators mostly gave way to tokamaks a decade later, since the doughnut-shaped facilities are simpler to design and build and generally confine plasma better. But recent advances in plasma theory and computational power have led to renewed interest in stellarators. Such advances caused the authors to wonder if devices like the W7-X can provide an answer to the question of whether stellarators are the right concept for fusion energy. Years of plasma physics research will be needed to find out, they conclude, and "that task has just started." <|im_end|>

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36282, 34738, 77933, 311, 279, 24924, 2115, 13, 1115, 374, 4245, 311, 279, 2115, 8614, 83233, 323, 24924, 2115, 8333, 304, 35940, 34224, 1385, 38088, 311, 279, 5801, 71916, 24924, 45982, 13, 763, 264, 33297, 2740, 45408, 37608, 32426, 11, 279, 34738, 374, 389, 279, 2015, 315, 220, 605, 11, 931, 3115, 29493, 1109, 279, 19320, 15798, 11, 719, 11, 520, 220, 1041, 10030, 25173, 16, 1174, 433, 690, 3063, 311, 19320, 18151, 304, 2753, 1109, 220, 16, 14, 605, 315, 264, 2132, 11, 422, 279, 34738, 82, 656, 539, 5578, 704, 477, 4822, 2949, 279, 24924, 7479, 11, 719, 4619, 6920, 279, 19320, 505, 279, 9358, 311, 279, 16335, 24924, 27529, 13, 1115, 574, 279, 1162, 304, 4216, 48317, 859, 21896, 13, 578, 9825, 109605, 323, 279, 28537, 19677, 50346, 656, 539, 7831, 505, 420, 3575, 2533, 872, 5801, 71916, 46220, 3727, 279, 19320, 34738, 82, 5578, 704, 369, 682, 279, 19252, 323, 9093, 1193, 5353, 9099, 3521, 76339, 505, 279, 24924, 7479, 13, 91958, 304, 32426, 10334, 11, 304, 4040, 304, 279, 220, 3753, 15, 82, 323, 220, 2550, 15, 82, 11, 5535, 279, 4500, 315, 48317, 859, 24924, 2115, 33483, 430, 3113, 19407, 13241, 66678, 320, 4151, 44243, 220, 19, 1174, 220, 20, 7026, 18189, 279, 34738, 27605, 18151, 311, 264, 2237, 40044, 2678, 779, 430, 433, 374, 19698, 311, 387, 18641, 449, 459, 47379, 43303, 37608, 2410, 6136, 13, 578, 26329, 5196, 11, 439, 1664, 439, 279, 5938, 2955, 315, 71860, 430, 13383, 279, 34440, 24924, 5151, 11, 7612, 6500, 2410, 430, 1193, 6244, 2561, 304, 279, 220, 3753, 15, 82, 13, 578, 1176, 9659, 315, 34440, 48317, 3046, 3940, 5784, 304, 279, 220, 2550, 15, 82, 11, 323, 11007, 1690, 315, 279, 3685, 18637, 220, 21, 1174, 220, 22, 662, 4314, 7766, 1051, 11, 4869, 11, 2288, 2678, 311, 5662, 279, 1579, 28772, 20472, 1405, 279, 26329, 2216, 4131, 311, 1202, 1296, 13, 23674, 11, 814, 1051, 5918, 449, 24166, 71860, 11, 902, 527, 26613, 369, 11311, 8838, 27748, 16379, 7978, 719, 53924, 449, 24981, 21395, 5784, 520, 1579, 24924, 2115, 36486, 13, 578, 42368, 301, 12711, 220, 22, 31650, 320, 54, 22, 31650, 8, 48317, 859, 9526, 374, 279, 1176, 18740, 315, 279, 502, 9659, 315, 34440, 48317, 3046, 11, 323, 22262, 311, 1501, 449, 1202, 2307, 77752, 287, 40760, 1887, 323, 12309, 3544, 1404, 320, 37605, 128257, 198, 128256, 78191, 198, 67171, 292, 380, 8388, 98903, 1293, 315, 279, 549, 815, 13, 6011, 315, 12634, 596, 320, 5989, 36, 8, 50421, 65632, 28415, 32184, 320, 4505, 2989, 8, 706, 61310, 449, 6063, 14248, 311, 7838, 430, 279, 42368, 301, 12711, 220, 22, 31650, 320, 54, 22, 31650, 8, 37608, 4907, 3756, 2663, 264, 48317, 859, 304, 13842, 333, 2332, 4852, 11, 10057, 11, 19159, 1579, 22867, 24924, 5151, 430, 527, 13263, 449, 872, 6485, 2955, 13, 578, 14955, 11, 4756, 304, 279, 6841, 220, 966, 4360, 315, 22037, 26545, 1174, 10675, 459, 1493, 2115, 51749, 38664, 505, 279, 6319, 6683, 2345, 1073, 2753, 1109, 832, 961, 304, 220, 1041, 11, 931, 13, 15483, 3135, 1436, 3719, 264, 1401, 3094, 9017, 69963, 279, 69543, 315, 48317, 3046, 439, 4211, 369, 3938, 37608, 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369, 279, 1510, 430, 9825, 309, 10011, 2011, 49853, 304, 279, 6962, 311, 4686, 279, 24924, 2115, 13, 95642, 859, 628, 300, 7044, 8617, 1629, 2697, 5326, 315, 87843, 11, 439, 649, 3621, 304, 9825, 309, 10011, 11, 14718, 279, 5419, 1510, 311, 60845, 27365, 323, 37608, 25481, 311, 9495, 1523, 13, 30950, 2989, 706, 6476, 1401, 13073, 304, 279, 468, 22, 31650, 2447, 13, 578, 32184, 6319, 323, 12886, 4330, 33419, 6134, 28935, 11259, 71860, 430, 7060, 2442, 2957, 279, 48317, 859, 596, 24924, 5151, 323, 1903, 872, 19179, 3284, 13, 330, 1687, 3077, 11007, 430, 279, 24924, 36460, 430, 584, 3077, 5918, 4375, 439, 6319, 1359, 1071, 98903, 1293, 11, 889, 6197, 17715, 4376, 279, 21896, 430, 33432, 279, 6683, 315, 279, 2115, 13, 330, 2028, 27053, 549, 815, 13, 19564, 311, 468, 22, 31650, 1359, 568, 3779, 11, 330, 438, 22020, 30950, 2989, 596, 5845, 311, 6929, 6625, 83663, 1210, 9365, 369, 420, 990, 4131, 505, 85477, 22612, 323, 279, 93157, 8410, 315, 10170, 13, 2057, 6767, 279, 24924, 2115, 11, 279, 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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 antisense transcription is a widespread event in the mammalian genome, double-stranded RNA (dsRNA) formation between sense and antisense transcripts is very rare and mechanisms that control dsRNA remain unknown. By characterizing the FGF-2 regulated transcriptome in normal and cancer cells, we identified sense and antisense transcripts IER3 and IER3-AS1 that play a critical role in FGF-2 controlled oncogenic pathways. We show that IER3 and IER3-AS1 regulate each other’s transcription through HnRNPK-mediated post-transcriptional regulation. HnRNPK controls the mRNA stability and colocalization of IER3 and IER3-AS1. HnRNPK interaction with IER3 and IER3-AS1 determines their oncogenic functions by maintaining them in a single-stranded form. hnRNPK depletion neutralizes their oncogenic functions through promoting dsRNA formation and cytoplasmic accumulation. Intriguingly, hnRNPK loss-of-function and gain-of-function experiments reveal its role in maintaining global single- and double-stranded RNA. Thus, our data unveil the critical role of HnRNPK in maintaining single-stranded RNAs and their physiological functions by blocking RNA-RNA interactions. Introduction Antisense long noncoding RNAs (lncRNAs), which often overlap with the transcripts encoded from the sense strand, constitute the largest sub-class of lncRNAs 1 , 2 . They have been shown to regulate the expression of overlapping sense transcripts positively or negatively. Diverse antisense lncRNA-regulated transcriptional and post-transcriptional-based mechanisms have been proposed in the regulation of overlapping protein coding genes, some of which include mRNA stability, alternative splicing, and chromatin level regulation 3 . In a few instances, protein coding RNAs have also been implicated in the regulation of antisense lncRNAs 4 . In these contexts, however, the molecular mechanisms that control expression interdependence between an antisense lncRNA and its sense protein-coding partner remain unknown. Another interesting aspect is that many antisense transcripts show significant overlap with their sense counterparts 2 , but there has not been much data showing RNA–RNA interaction between the overlapping transcripts. This raises the interesting question whether there are any unique mechanisms that maintain single stranded forms of the sense and antisense transcripts to prevent RNA–RNA interactions or double-stranded RNA (dsRNA) formation between them to maintain transcript-specific functions? Thus, there are several outstanding questions that remain unanswered regarding the genome-wide regulation of the expression and functions of overlapping transcripts. The FGF/FGFR signalling cascade comprises fibroblast growth factors (FGF −1 to −23) and their highly conserved transmembrane tyrosine kinase receptors (FGFR −1 to −4), which control a wide range of developmental signalling pathways with implications in cell specification during early embryonic development to organogenesis in adult organisms 5 . Over the last few years, substantial evidence has accumulated that supports aberrant FGF signalling as an underlying factor in the pathogenesis of multiple cancer types by promoting cell survival and cell proliferation via supporting angiogenesis 6 , 7 . FGF-2 is a prototypical example of the FGF family and its elevated levels in blood plasma have been reported in multiple cancer types 8 , 9 . Several studies have shown that FGF-2 is a key tumour-promoting factor, and it promotes tumour progression through downstream pro-survival signalling pathways such as, RAS-MAPK, PI3K-AKT, PLCγ, and signal transducer and activator of transcription (STAT) 10 . Consistent with its pro-survival functions, as well as its ability to induce stem cell proliferation, aberrant activation of FGF-2 signalling is associated with enhanced chemotherapy resistance 11 . Currently multiple FGFR inhibitors are being used as monotherapy or as part of combination therapies to treat therapy-resistant cancers 12 . As these inhibitors affect multiple tyrosine receptor kinases, including all FGFR receptors (1–4), it is very important to specifically target the FGF-2/FGFR pathway by understanding its downstream regulated gene circuits to minimize the side-effects of FGFR inhibitors. The functional link between FGF-2 signalling and its downstream target genes, including lncRNAs, is largely unexplored in normal and cancer cells. Thus, identifying the FGF-2 regulated gene networks in these contexts will help in devising FGF-2-based therapeutic approaches for cancer. In this investigation, we characterize the FGF-2 regulated transcriptome in immortalized human embryonic kidney cells HEK293 and cancer cell lines such as HeLa and BT-549 and identify common and uniquely enriched FGF-2 regulated biological pathways in normal and cancer cells. By using FGF-2 induced sense and antisense transcripts IER3 and IER3-AS1 as a model system we investigate how their spatial localization, as well as RNA duplex formation between them, contribute to IER3 and IER3-AS1 oncogenic functions. Of note, we investigate the role of hnRNPK in these unique biological mechanisms. Results Characterization of FGF-2 controlled pathways in normal and cancer cell lines To identify the FGF-2 regulated transcriptome in normal and cancer cells, we treated HEK293 and cancer cell lines like the human cervical cancer cell line HeLa, and the breast cancer cell line BT-549, with FGF-2 for 6 h and performed RNA-seq analysis. We identified several differentially expressed genes (DEGs) that were induced by FGF-2 in all the three cell lines (Fig. 1a, b ). Gene Ontology (GO) analysis of the common DEGs from the three cell lines revealed several cancer-associated biological processes, such as cellular response to fibroblast growth factor stimulus, protein kinase signalling, NFKB pathway, chemokine signalling and angiogenesis (Supplementary Fig. 1a ). The complete list of significant DEGs between FGF-2 treated and untreated samples and biological pathways for all the three cell lines are listed in Supplementary Data File 1 . We chose to concentrate on HeLa and HEK293 cell lines for further detailed functional investigations on FGF-2 regulated gene networks and biological pathways. FGF-2 treated HEK293 and HeLa cell lines revealed several common and unique (Supplementary Fig. 1b, c, d ) differentially expressed protein-coding and non-coding genes. GO analysis of cell line-specific uniquely expressed genes revealed enrichment of cell differentiation and development-associated pathways in the FGF-2 treated HEK293 cells (Supplementary Fig. 2a ). On the other hand, in the FGF-2 treated HeLa cells, overrepresentation of cancer-associated pathways such as chemotaxis, angiogenesis, cell proliferation, inflammation and apoptotic pathways was observed (Supplementary Fig. 2b ), indicating different roles of FGF-2 in cancer and normal cells. GO analysis of the common FGF-2 regulated genes revealed biological pathways linked to cancer and cell differentiation (Supplementary Fig.", "role": "user" }, { "content": "Researchers at the University of Gothenburg have identified a previously unknown mechanism controlling tumor growth in cultured cells and mice. This discovery may potentially enable future development of new drugs against a range of cancer diseases. In a research article published in the journal Nature Communications, the Gothenburg scientists have described their discovery. It concerns a protein that binds genetic material and, as the researchers now show, also controls properties that regulate tumor development. The protein—known as HnRNPK—binds to messenger-RNA (mRNA), which the two genes IER3 and IER3-AS1 code for. These genes are highly active in several forms of cancer. By binding to the mRNA of these genes, the HnRNPK prevents double-strand RNA forming between them and keeps them separate. Impact on tumor growth \"Keeping these two genes' RNA separate promotes growth of tumors that depend on growth factors. Without the HnRNPK protein, the properties that promote tumor growth are neutralized, paving the way for development of drugs that block the HnRNPK,\" says Chandrasekhar Kanduri, Professor of Medical Genetics, Sahlgrenska Academy at the University of Gothenburg, who is one of the research leaders behind the study. The study also shows that, similarly, the HnRNPK protein binds to the mRNA of several other genes, preventing the formation of double-strand RNA. The discovery affords scope for indirectly influencing the FGF-2 growth factor, which is well known to be key both to the process whereby stem cells mature into various cell types and to early embryonic development. Fewer side effects Meena Kanduri, associate professor of molecular medicine at Sahlgrenska Academy, is the corresponding author of the article. \"Given the crucial role of FGF-2 in normal human development, using drugs that target the growth factor directly would have too many side effects. The mechanism we've now identified is part of the same signaling chain, but further downstream. So, the mechanism has the potential to become a more attractive cancer treatment option, with fewer side effects,\" she says. More research is needed to verify the transferability of the finding from cell culture and mouse studies to humans. In the next stage, the group plans to conduct extended studies to examine in more detail how the pair of genes regulated by FGF-2 govern the growth environment of 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 Although antisense transcription is a widespread event in the mammalian genome, double-stranded RNA (dsRNA) formation between sense and antisense transcripts is very rare and mechanisms that control dsRNA remain unknown. By characterizing the FGF-2 regulated transcriptome in normal and cancer cells, we identified sense and antisense transcripts IER3 and IER3-AS1 that play a critical role in FGF-2 controlled oncogenic pathways. We show that IER3 and IER3-AS1 regulate each other’s transcription through HnRNPK-mediated post-transcriptional regulation. HnRNPK controls the mRNA stability and colocalization of IER3 and IER3-AS1. HnRNPK interaction with IER3 and IER3-AS1 determines their oncogenic functions by maintaining them in a single-stranded form. hnRNPK depletion neutralizes their oncogenic functions through promoting dsRNA formation and cytoplasmic accumulation. Intriguingly, hnRNPK loss-of-function and gain-of-function experiments reveal its role in maintaining global single- and double-stranded RNA. Thus, our data unveil the critical role of HnRNPK in maintaining single-stranded RNAs and their physiological functions by blocking RNA-RNA interactions. Introduction Antisense long noncoding RNAs (lncRNAs), which often overlap with the transcripts encoded from the sense strand, constitute the largest sub-class of lncRNAs 1 , 2 . They have been shown to regulate the expression of overlapping sense transcripts positively or negatively. Diverse antisense lncRNA-regulated transcriptional and post-transcriptional-based mechanisms have been proposed in the regulation of overlapping protein coding genes, some of which include mRNA stability, alternative splicing, and chromatin level regulation 3 . In a few instances, protein coding RNAs have also been implicated in the regulation of antisense lncRNAs 4 . In these contexts, however, the molecular mechanisms that control expression interdependence between an antisense lncRNA and its sense protein-coding partner remain unknown. Another interesting aspect is that many antisense transcripts show significant overlap with their sense counterparts 2 , but there has not been much data showing RNA–RNA interaction between the overlapping transcripts. This raises the interesting question whether there are any unique mechanisms that maintain single stranded forms of the sense and antisense transcripts to prevent RNA–RNA interactions or double-stranded RNA (dsRNA) formation between them to maintain transcript-specific functions? Thus, there are several outstanding questions that remain unanswered regarding the genome-wide regulation of the expression and functions of overlapping transcripts. The FGF/FGFR signalling cascade comprises fibroblast growth factors (FGF −1 to −23) and their highly conserved transmembrane tyrosine kinase receptors (FGFR −1 to −4), which control a wide range of developmental signalling pathways with implications in cell specification during early embryonic development to organogenesis in adult organisms 5 . Over the last few years, substantial evidence has accumulated that supports aberrant FGF signalling as an underlying factor in the pathogenesis of multiple cancer types by promoting cell survival and cell proliferation via supporting angiogenesis 6 , 7 . FGF-2 is a prototypical example of the FGF family and its elevated levels in blood plasma have been reported in multiple cancer types 8 , 9 . Several studies have shown that FGF-2 is a key tumour-promoting factor, and it promotes tumour progression through downstream pro-survival signalling pathways such as, RAS-MAPK, PI3K-AKT, PLCγ, and signal transducer and activator of transcription (STAT) 10 . Consistent with its pro-survival functions, as well as its ability to induce stem cell proliferation, aberrant activation of FGF-2 signalling is associated with enhanced chemotherapy resistance 11 . Currently multiple FGFR inhibitors are being used as monotherapy or as part of combination therapies to treat therapy-resistant cancers 12 . As these inhibitors affect multiple tyrosine receptor kinases, including all FGFR receptors (1–4), it is very important to specifically target the FGF-2/FGFR pathway by understanding its downstream regulated gene circuits to minimize the side-effects of FGFR inhibitors. The functional link between FGF-2 signalling and its downstream target genes, including lncRNAs, is largely unexplored in normal and cancer cells. Thus, identifying the FGF-2 regulated gene networks in these contexts will help in devising FGF-2-based therapeutic approaches for cancer. In this investigation, we characterize the FGF-2 regulated transcriptome in immortalized human embryonic kidney cells HEK293 and cancer cell lines such as HeLa and BT-549 and identify common and uniquely enriched FGF-2 regulated biological pathways in normal and cancer cells. By using FGF-2 induced sense and antisense transcripts IER3 and IER3-AS1 as a model system we investigate how their spatial localization, as well as RNA duplex formation between them, contribute to IER3 and IER3-AS1 oncogenic functions. Of note, we investigate the role of hnRNPK in these unique biological mechanisms. Results Characterization of FGF-2 controlled pathways in normal and cancer cell lines To identify the FGF-2 regulated transcriptome in normal and cancer cells, we treated HEK293 and cancer cell lines like the human cervical cancer cell line HeLa, and the breast cancer cell line BT-549, with FGF-2 for 6 h and performed RNA-seq analysis. We identified several differentially expressed genes (DEGs) that were induced by FGF-2 in all the three cell lines (Fig. 1a, b ). Gene Ontology (GO) analysis of the common DEGs from the three cell lines revealed several cancer-associated biological processes, such as cellular response to fibroblast growth factor stimulus, protein kinase signalling, NFKB pathway, chemokine signalling and angiogenesis (Supplementary Fig. 1a ). The complete list of significant DEGs between FGF-2 treated and untreated samples and biological pathways for all the three cell lines are listed in Supplementary Data File 1 . We chose to concentrate on HeLa and HEK293 cell lines for further detailed functional investigations on FGF-2 regulated gene networks and biological pathways. FGF-2 treated HEK293 and HeLa cell lines revealed several common and unique (Supplementary Fig. 1b, c, d ) differentially expressed protein-coding and non-coding genes. GO analysis of cell line-specific uniquely expressed genes revealed enrichment of cell differentiation and development-associated pathways in the FGF-2 treated HEK293 cells (Supplementary Fig. 2a ). On the other hand, in the FGF-2 treated HeLa cells, overrepresentation of cancer-associated pathways such as chemotaxis, angiogenesis, cell proliferation, inflammation and apoptotic pathways was observed (Supplementary Fig. 2b ), indicating different roles of FGF-2 in cancer and normal cells. GO analysis of the common FGF-2 regulated genes revealed biological pathways linked to cancer and cell differentiation (Supplementary Fig.<|im_end|> <|im_start|>assistant Researchers at the University of Gothenburg have identified a previously unknown mechanism controlling tumor growth in cultured cells and mice. This discovery may potentially enable future development of new drugs against a range of cancer diseases. In a research article published in the journal Nature Communications, the Gothenburg scientists have described their discovery. It concerns a protein that binds genetic material and, as the researchers now show, also controls properties that regulate tumor development. The protein—known as HnRNPK—binds to messenger-RNA (mRNA), which the two genes IER3 and IER3-AS1 code for. These genes are highly active in several forms of cancer. By binding to the mRNA of these genes, the HnRNPK prevents double-strand RNA forming between them and keeps them separate. Impact on tumor growth "Keeping these two genes' RNA separate promotes growth of tumors that depend on growth factors. Without the HnRNPK protein, the properties that promote tumor growth are neutralized, paving the way for development of drugs that block the HnRNPK," says Chandrasekhar Kanduri, Professor of Medical Genetics, Sahlgrenska Academy at the University of Gothenburg, who is one of the research leaders behind the study. The study also shows that, similarly, the HnRNPK protein binds to the mRNA of several other genes, preventing the formation of double-strand RNA. The discovery affords scope for indirectly influencing the FGF-2 growth factor, which is well known to be key both to the process whereby stem cells mature into various cell types and to early embryonic development. Fewer side effects Meena Kanduri, associate professor of molecular medicine at Sahlgrenska Academy, is the corresponding author of the article. "Given the crucial role of FGF-2 in normal human development, using drugs that target the growth factor directly would have too many side effects. The mechanism we've now identified is part of the same signaling chain, but further downstream. So, the mechanism has the potential to become a more attractive cancer treatment option, with fewer side effects," she says. More research is needed to verify the transferability of the finding from cell culture and mouse studies to humans. In the next stage, the group plans to conduct extended studies to examine in more detail how the pair of genes regulated by FGF-2 govern the growth environment of 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 Defining mechanisms by which Plasmodium virulence is regulated is central to understanding the pathogenesis of human malaria. Serial blood passage of Plasmodium through rodents 1 , 2 , 3 , primates 4 or humans 5 increases parasite virulence, suggesting that vector transmission regulates Plasmodium virulence within the mammalian host. In agreement, disease severity can be modified by vector transmission 6 , 7 , 8 , which is assumed to ‘reset’ Plasmodium to its original character 3 . However, direct evidence that vector transmission regulates Plasmodium virulence is lacking. Here we use mosquito transmission of serially blood passaged (SBP) Plasmodium chabaudi chabaudi 9 to interrogate regulation of parasite virulence. Analysis of SBP P. c. chabaudi before and after mosquito transmission demonstrates that vector transmission intrinsically modifies the asexual blood-stage parasite, which in turn modifies the elicited mammalian immune response, which in turn attenuates parasite growth and associated pathology. Attenuated parasite virulence associates with modified expression of the pir multi-gene family. Vector transmission of Plasmodium therefore regulates gene expression of probable variant antigens in the erythrocytic cycle, modifies the elicited mammalian immune response, and thus regulates parasite virulence. These results place the mosquito at the centre of our efforts to dissect mechanisms of protective immunity to malaria for the development of an effective vaccine. Main The definitive host for mammalian Plasmodium is the anopheline mosquito. Within this vector, a complex series of developmental events, including fertilization and meiosis, culminates in invasion of the salivary glands by infective sporozoites, which are transmitted to the mammalian host through mosquito bite. Sporozoites deposited in the dermis migrate to the liver, invade hepatocytes and undergo further developmental processes before the release of merozoites that invade erythrocytes. The subsequent erythrocytic cycle is entirely responsible for the morbidity and mortality associated with malaria. The complexity of the Plasmodium life cycle has led to much of the basic biology of the blood-stage infection being studied in isolation, with in vivo experiments largely initiated through direct injection of infected erythrocytes. However, serial blood passage of Plasmodium increases parasite virulence 1 , 2 , 3 , 4 , 5 , suggesting that regulation of Plasmodium virulence is an inherent consequence of vector transmission 3 . This could result indirectly from vector control of inoculum size or the passage of large parasite populations through extreme bottlenecks, although these consequences of mosquito transmission are not thought to be major determinants of disease severity 8 , 10 . Alternatively, vector transmission may regulate Plasmodium virulence by intrinsically modifying the parasite and its interaction with the mammalian host. In this context, the immune response elicited by Plasmodium influences disease severity 11 , and can therefore dictate parasite virulence. The interrelationship between the vector, parasite and mammalian immune system could thus underpin the pathogenesis of malaria. To study regulation of Plasmodium virulence we developed routine mosquito transmission of SBP P. c. chabaudi 9 , a rodent malaria parasite that has many characteristics associated with the pathogenesis of human infection 12 . This allowed us to directly compare SBP parasites before and after vector transmission. Accordingly, mice were infected with SBP P. c. chabaudi AS either by injection of parasitized erythrocytes (pE) or mosquito bite (see Methods). Following mosquito transmission, asexual blood-stage parasite growth was attenuated ( Fig. 1a ), and a low-grade, recrudescing infection with extended chronicity was established ( Supplementary Fig. 1 ). Attenuated parasite growth in the erythrocytic cycle was not influenced by dose (ref. 9 and Supplementary Fig. 2 ) or, importantly, by the pre-erythrocytic stages of infection, as attenuated parasite growth was similarly observed when mice were injected with pE derived from recently mosquito-transmitted (MT) parasite lines ( Fig. 1b ). Similar results were observed with cloned parasites derived from SBP P. c. chabaudi AS ( Supplementary Fig. 3 ), and with the hypervirulent P. c. chabaudi CB ( Supplementary Fig. 4 ). Mosquito transmission therefore attenuated the asexual blood-stage parasite. As expected, serial blood passage of MT P. c. chabaudi AS rapidly increased parasite growth ( Supplementary Fig. 5 ). Mice infected with P. c. chabaudi AS through mosquito bite did not show the severe hypothermia, cachexia or hepatic cellular damage that was observed during the acute phase of infection in mice injected with SBP parasites, although they still showed severe anaemia despite attenuated parasite growth ( Fig. 1c–f ). Mosquito transmission therefore reduced disease severity in the mammalian host. Despite attenuated parasite growth and reduced pathogenicity, MT P. c. chabaudi AS elicited robust, long-term protection to reinfection with homologous or heterologous blood-stage parasites ( Fig. 1g and Supplementary Fig. 6 ). Thus, vector transmission regulates the virulence of Plasmodium by intrinsically modifying the asexual blood-stage parasite, without influencing the capacity of the mammalian host to acquire robust immunity to reinfection. Figure 1: Mosquito transmission of P. c. chabaudi AS attenuates virulence. a , Parasitaemia of C57BL/6 mice injected with 10 5 SBP P. c. chabaudi AS (Pcc AS) or infected with Pcc AS through mosquito bite. b , Parasitaemia of C57BL/6 mice injected with 10 5 SBP Pcc AS or injected with 10 4 or 10 5 pE derived from one of four recently MT lines of Pcc AS. c – e , Temperature ( c ), weight ( d ) and erythrocyte count ( e ) of C57BL/6 mice injected with 10 5 SBP Pcc AS or infected with Pcc AS through mosquito bite. f , Liver enzyme concentration on day 10 post-infection in plasma of C57BL/6 mice injected with 10 5 SBP Pcc AS or infected with Pcc AS through mosquito bite. Data presented as fold-change relative to uninfected control mice. ALB, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; BA, bile acids; BUN, blood urea nitrogen; CHO, cholesterol; TBI, total bilirubin. g , Parasitaemia of C57BL/6 mice injected with 10 6 SBP P. c. chabaudi CB (Pcc CB) as a first infection (open symbols), or as a rechallenge (closed symbols) 90 days after injection with 10 5 SBP Pcc AS or infection with Pcc AS or CB", "role": "user" }, { "content": "(Medical Xpress)—For the first time, researchers have proven that the way in which malaria is transmitted to the host affects how severe the resulting infection will be. The route of infection modifies the malaria parasite's gene activity levels and regulates the parasite's spread in the blood by controlling the mouse's immune response. This study begins to understand how protective immunity to malaria occurs, an important step for the development of effective vaccines. Researchers have known that the severity of symptoms of malaria increases when the malaria parasite is transferred repeatedly through blood samples in mice rather than by a mosquito, but up until now they have not known why. \"Understanding how malaria becomes more or less virulent is central to understanding how to manage and treat the disease,\" says Dr Matt Berriman, a senior author from the Wellcome Trust Sanger Institute. \"We studied a rodent malaria species, that exhibits many of the same responses as seen in a human malaria infection. Our understanding of how the parasite interacts with the immune system is fundamentally changed by this study.\" To explore the effect that the route of transmission had, the team examined the levels of gene activity in the malaria parasite during its life cycle in mice. They found that P.c. chabaudi 'resets' its genetic activity when it is transmitted between the mosquito and mouse, making it less virulent. However, transferring the parasite through multiple blood transfers between mice in the laboratory loses this resetting. Because there is no reset the malaria parasite multiples much more quickly in mice after blood transfers, and causes an increase in disease severity. The team uncovered a direct association between a specific gene family in the malaria parasite, known as cir genes, and the control of severity of the disease symptoms in mice. It appears that malaria parasite genes control the immune response of mice to the disease. \"Our research is helping to better understand vaccine targets,\" says Dr Adam Reid, author from the Wellcome Trust Sanger Institute. \"RNA sequencing allowed us to identify a set of Plasmodium genes that control the immune response and the degree of severity of the disease in mice. We anticipate that we will be able to transfer the findings from our study in mice to human malaria studies, the next phase of our research.\" The team expect that the cir gene family plays a role in activating the immune system and controls the level of parasite in the blood to keep malaria from harming the host. This is the largest gene family in malaria parasites, including the deadly human parasite, P. falciparum. The study was led by Dr Jean Langhorne based at the Medical Research Council National Institute for Medical Research: \"These results place the mosquito at the centre of our efforts to pick apart the processes behind protective immunity to malaria. Malaria is both preventable and curable but still has a huge burden on those who are vulnerable to severe forms of the infection, mostly young children. Understanding protective immunity in the body would be an important first step towards developing an effective vaccine.\" ", "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 Defining mechanisms by which Plasmodium virulence is regulated is central to understanding the pathogenesis of human malaria. Serial blood passage of Plasmodium through rodents 1 , 2 , 3 , primates 4 or humans 5 increases parasite virulence, suggesting that vector transmission regulates Plasmodium virulence within the mammalian host. In agreement, disease severity can be modified by vector transmission 6 , 7 , 8 , which is assumed to ‘reset’ Plasmodium to its original character 3 . However, direct evidence that vector transmission regulates Plasmodium virulence is lacking. Here we use mosquito transmission of serially blood passaged (SBP) Plasmodium chabaudi chabaudi 9 to interrogate regulation of parasite virulence. Analysis of SBP P. c. chabaudi before and after mosquito transmission demonstrates that vector transmission intrinsically modifies the asexual blood-stage parasite, which in turn modifies the elicited mammalian immune response, which in turn attenuates parasite growth and associated pathology. Attenuated parasite virulence associates with modified expression of the pir multi-gene family. Vector transmission of Plasmodium therefore regulates gene expression of probable variant antigens in the erythrocytic cycle, modifies the elicited mammalian immune response, and thus regulates parasite virulence. These results place the mosquito at the centre of our efforts to dissect mechanisms of protective immunity to malaria for the development of an effective vaccine. Main The definitive host for mammalian Plasmodium is the anopheline mosquito. Within this vector, a complex series of developmental events, including fertilization and meiosis, culminates in invasion of the salivary glands by infective sporozoites, which are transmitted to the mammalian host through mosquito bite. Sporozoites deposited in the dermis migrate to the liver, invade hepatocytes and undergo further developmental processes before the release of merozoites that invade erythrocytes. The subsequent erythrocytic cycle is entirely responsible for the morbidity and mortality associated with malaria. The complexity of the Plasmodium life cycle has led to much of the basic biology of the blood-stage infection being studied in isolation, with in vivo experiments largely initiated through direct injection of infected erythrocytes. However, serial blood passage of Plasmodium increases parasite virulence 1 , 2 , 3 , 4 , 5 , suggesting that regulation of Plasmodium virulence is an inherent consequence of vector transmission 3 . This could result indirectly from vector control of inoculum size or the passage of large parasite populations through extreme bottlenecks, although these consequences of mosquito transmission are not thought to be major determinants of disease severity 8 , 10 . Alternatively, vector transmission may regulate Plasmodium virulence by intrinsically modifying the parasite and its interaction with the mammalian host. In this context, the immune response elicited by Plasmodium influences disease severity 11 , and can therefore dictate parasite virulence. The interrelationship between the vector, parasite and mammalian immune system could thus underpin the pathogenesis of malaria. To study regulation of Plasmodium virulence we developed routine mosquito transmission of SBP P. c. chabaudi 9 , a rodent malaria parasite that has many characteristics associated with the pathogenesis of human infection 12 . This allowed us to directly compare SBP parasites before and after vector transmission. Accordingly, mice were infected with SBP P. c. chabaudi AS either by injection of parasitized erythrocytes (pE) or mosquito bite (see Methods). Following mosquito transmission, asexual blood-stage parasite growth was attenuated ( Fig. 1a ), and a low-grade, recrudescing infection with extended chronicity was established ( Supplementary Fig. 1 ). Attenuated parasite growth in the erythrocytic cycle was not influenced by dose (ref. 9 and Supplementary Fig. 2 ) or, importantly, by the pre-erythrocytic stages of infection, as attenuated parasite growth was similarly observed when mice were injected with pE derived from recently mosquito-transmitted (MT) parasite lines ( Fig. 1b ). Similar results were observed with cloned parasites derived from SBP P. c. chabaudi AS ( Supplementary Fig. 3 ), and with the hypervirulent P. c. chabaudi CB ( Supplementary Fig. 4 ). Mosquito transmission therefore attenuated the asexual blood-stage parasite. As expected, serial blood passage of MT P. c. chabaudi AS rapidly increased parasite growth ( Supplementary Fig. 5 ). Mice infected with P. c. chabaudi AS through mosquito bite did not show the severe hypothermia, cachexia or hepatic cellular damage that was observed during the acute phase of infection in mice injected with SBP parasites, although they still showed severe anaemia despite attenuated parasite growth ( Fig. 1c–f ). Mosquito transmission therefore reduced disease severity in the mammalian host. Despite attenuated parasite growth and reduced pathogenicity, MT P. c. chabaudi AS elicited robust, long-term protection to reinfection with homologous or heterologous blood-stage parasites ( Fig. 1g and Supplementary Fig. 6 ). Thus, vector transmission regulates the virulence of Plasmodium by intrinsically modifying the asexual blood-stage parasite, without influencing the capacity of the mammalian host to acquire robust immunity to reinfection. Figure 1: Mosquito transmission of P. c. chabaudi AS attenuates virulence. a , Parasitaemia of C57BL/6 mice injected with 10 5 SBP P. c. chabaudi AS (Pcc AS) or infected with Pcc AS through mosquito bite. b , Parasitaemia of C57BL/6 mice injected with 10 5 SBP Pcc AS or injected with 10 4 or 10 5 pE derived from one of four recently MT lines of Pcc AS. c – e , Temperature ( c ), weight ( d ) and erythrocyte count ( e ) of C57BL/6 mice injected with 10 5 SBP Pcc AS or infected with Pcc AS through mosquito bite. f , Liver enzyme concentration on day 10 post-infection in plasma of C57BL/6 mice injected with 10 5 SBP Pcc AS or infected with Pcc AS through mosquito bite. Data presented as fold-change relative to uninfected control mice. ALB, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; BA, bile acids; BUN, blood urea nitrogen; CHO, cholesterol; TBI, total bilirubin. g , Parasitaemia of C57BL/6 mice injected with 10 6 SBP P. c. chabaudi CB (Pcc CB) as a first infection (open symbols), or as a rechallenge (closed symbols) 90 days after injection with 10 5 SBP Pcc AS or infection with Pcc AS or CB<|im_end|> <|im_start|>assistant (Medical Xpress)—For the first time, researchers have proven that the way in which malaria is transmitted to the host affects how severe the resulting infection will be. The route of infection modifies the malaria parasite's gene activity levels and regulates the parasite's spread in the blood by controlling the mouse's immune response. This study begins to understand how protective immunity to malaria occurs, an important step for the development of effective vaccines. Researchers have known that the severity of symptoms of malaria increases when the malaria parasite is transferred repeatedly through blood samples in mice rather than by a mosquito, but up until now they have not known why. "Understanding how malaria becomes more or less virulent is central to understanding how to manage and treat the disease," says Dr Matt Berriman, a senior author from the Wellcome Trust Sanger Institute. "We studied a rodent malaria species, that exhibits many of the same responses as seen in a human malaria infection. Our understanding of how the parasite interacts with the immune system is fundamentally changed by this study." To explore the effect that the route of transmission had, the team examined the levels of gene activity in the malaria parasite during its life cycle in mice. They found that P.c. chabaudi 'resets' its genetic activity when it is transmitted between the mosquito and mouse, making it less virulent. However, transferring the parasite through multiple blood transfers between mice in the laboratory loses this resetting. Because there is no reset the malaria parasite multiples much more quickly in mice after blood transfers, and causes an increase in disease severity. The team uncovered a direct association between a specific gene family in the malaria parasite, known as cir genes, and the control of severity of the disease symptoms in mice. It appears that malaria parasite genes control the immune response of mice to the disease. "Our research is helping to better understand vaccine targets," says Dr Adam Reid, author from the Wellcome Trust Sanger Institute. "RNA sequencing allowed us to identify a set of Plasmodium genes that control the immune response and the degree of severity of the disease in mice. We anticipate that we will be able to transfer the findings from our study in mice to human malaria studies, the next phase of our research." The team expect that the cir gene family plays a role in activating the immune system and controls the level of parasite in the blood to keep malaria from harming the host. This is the largest gene family in malaria parasites, including the deadly human parasite, P. falciparum. The study was led by Dr Jean Langhorne based at the Medical Research Council National Institute for Medical Research: "These results place the mosquito at the centre of our efforts to pick apart the processes behind protective immunity to malaria. Malaria is both preventable and curable but still has a huge burden on those who are vulnerable to severe forms of the infection, mostly young children. Understanding protective immunity in the body would be an important first step towards developing an effective vaccine." <|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 During organismal development, cells undergo complex changes in shape whose causal relationship to individual morphogenetic processes remains unclear. The modular nature of such processes suggests that it should be possible to isolate individual modules, determine the minimum set of requirements sufficient to drive tissue remodeling, and re-construct morphogenesis. Here we use optogenetics to reconstitute epithelial folding in embryonic Drosophila tissues that otherwise would not undergo invagination. We show that precise spatial and temporal activation of Rho signaling is sufficient to trigger apical constriction and tissue folding. Induced furrows can occur at any position along the dorsal–ventral or anterior–posterior embryo axis in response to the spatial pattern and level of optogenetic activation. Thus, epithelial folding is a direct function of the spatio-temporal organization and strength of Rho signaling that on its own is sufficient to drive tissue internalization independently of any pre-determined condition or differentiation program associated with endogenous invagination processes. Introduction Traditional genetic approaches have played a pivotal role in establishing the requirement of individual gene activities and cell behaviors in complex morphogenetic processes 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 . More recent advances in synthetic biology are opening the possibility to engineer gene circuits 10 , signaling systems 11 , 12 , and biomaterials 13 , 14 not only to probe morphogenesis, but also to re-construct it and direct it 15 , 16 . These approaches, which are converging into the nascent field of synthetic morphogenesis 17 , will be instrumental to define the minimum set of requirements sufficient to drive morphogenesis, and will therefore, also facilitate the building of artificial tissues for potential applications in regenerative medicine. Here, we used optogenetics to synthetically reconstitute morphogenesis in the early Drosophila embryo. We focused on epithelial folding, a conserved morphogenetic process driving internalization of tissues during animal development 18 . A large body of experimental evidence indicates that apical constriction driven by phosphorylation and activation of the molecular motor myosin II is required for tissue invagination 6 . However, the extent to which apical constriction is on its own sufficient to drive tissue internalization is unknown. During this process, cells undergo a series of complex changes in shape and intracellular organization, whose causal relationship to apical constriction and inward folding remain poorly understood 19 , 20 , 21 , 22 . Furthermore, the organismal scale cells occupy defined positions and are organized in specific geometrical patterns, which might facilitate or constrain invagination. Finally, apical constriction is not always coupled with invagination and several invagination processes are independent of apical constrictions 23 . For example, during salivary gland invagination, apical constriction and tissue invagination are uncoupled. When apical constriction is inhibited, compressing forces exerted by a supracellular myosin cable surrounding the salivary gland pit are sufficient to push cells inward 24 . Similar actomyosin-cable-mediated forces drive neural tube closure during chick embryogenesis 25 . Other examples of invaginations independent of apical constriction include the folding of Drosophila leg epithelium, which is driven by whole-cell shrinkage coupled with apoptosis 22 , and ascidian gastrulation, which is driven by a basolateral accumulation of myosin II and apicobasal cell shortening 26 . In addition, basal wedging rather than apical constriction seems to be the major force driving tissue internalization during mouse neuronal tube development 27 . Even in the case of Drosophila ventral furrow invagination, arguably the best characterized example of epithelial folding, the extent to which apical constriction drive invagination is unknown. Computer simulations suggest the requirement of additional pushing forces exerted by lateral ectodermal cells 28 , 29 , and relaxation of the basal surface of invaginating cells 30 . At the tissue-scale, the emergence of collective contractile behavior and its relationship to tissue geometry and invagination also remains the focus of active investigations 31 , 32 , 33 . In this study, we employ an optogenetic method to synthetically reconstruct epithelial folding during early Drosophila embryogenesis. In this context, “synthetic” refers to guided spatio-temporal control over the signaling pathway driving apical constriction, which is otherwise dependent upon the differentiation program of the embryo. Using this approach, we test the extent to which apical constriction on its own can drive invagination, and how different contractile behaviors arise in response to different temporal and spatial patterns of optogenetic activation. Collectively, our results indicate that apical constriction is sufficient to drive tissue invagination, but it is not sufficient to fold an invagination into a tube-like shape. Furthermore, our results provide insights into the emergence of pulsatile contractions and impact of tissue geometry on coordinated contractile behavior. Results RhoGEF2 plasma membrane recruitment and tissue responses To study the impact of apical constriction on tissue folding, independently of any pre-defined conditions, associated with normal invagination processes, we used an optogenetic system to activate Rho signaling 34 , 35 at the apical surface of developing Drosophila embryos prior to any sign of morphological differentiation (Fig. 1a, b ). At the end of cellularization, the Drosophila embryo is composed of a monolayer of epithelial cells without any morphological difference along the antero-posterior (AP) or dorso-ventral (DV) axes. To avoid any contribution from endogenous invagination processes, experiments were performed on the dorsal side of the embryo. In this region, the twist and snail transcription factors, that control ventral furrow invagination 36 , are not expressed and there is no morphological movement at this stage 37 . Fig. 1 Light-mediated recruitment of RhoGEF2 at the plasma membrane causes tissue-level responses. a Schematic illustration of the CRY2/CIBN optogenetic system used for controlling plasma membrane recruitment of the Rho1 activator RhoGEF2 during early Drosophila embryogenesis. The DHPH catalytic domain of the GTP Exchange factor RhoGEF2 was fused to the light-sensitive PHR domain of CRY2 and either tagged with mCherry or left without a fluorescent tag. In the absence of light, RhoGEF2-CRY2::mCherry localizes to the cytoplasm (left). Upon two-photon illumination, CRY2 undergoes a specific conformational change and binds to the plasma membrane anchor CIBN::pmGFP (right). At the plasma membrane, RhoGEF2-CRY2::mCherry triggers", "role": "user" }, { "content": "Constructing biological tissues, such as skin, muscle, or bone, in customized shapes is now one step closer. Researchers at EMBL have succeeded in guiding the folding and thus shape of tissues with optogenetics: a technique to control protein activity with light. Nature Communications publishes their results, with implications for regenerative medicine, on 18 June. The changing of tissue shapes in an embryo is essential for healthy development. Stefano De Renzis and his group members at EMBL are interested in the mechanisms behind these shape transitions, also called morphogenesis. They use optogenetics—a technique providing precise light-mediated control of protein activity—to study changes in tissue shapes. Uncoupling the link between shape and function In the current paper, Emiliano Izquierdo, Theresa Quinkler, and Stefano De Renzis used optogenetics to reconstruct epithelial folding: a fundamental process during development, where cells move inwards and fold into the embryo, eventually giving rise to internal tissues like muscles, for example. Remarkably, they achieved this in cells that normally do not undergo this process. De Renzis, who led the study: \"We've uncoupled the link between the shape and function of a cell. This allows us to, for the first time, built tissues in certain shape without affecting the cell's expertise.\" Example of optogenetics-guided tissue folding. The top image shows an embryo 10 minutes after illumination, and the bottom one 13 minutes afterwards: light-activated cells have folded inwards and thus moved downwards, creating a furrow. Credit: Stefano De Renzis, EMBL Precise control \"The great thing about using optogenetics to guide morphogenesis is that it is a very precise technique\", says Emiliano Izquierdo, first author of the study. \"We were able to define various shapes, and by alternating the timing and strength of illumination, we could control how far the cells folded inwards.\" From fruit fly to the clinic? The research was done in developing fruit flies, but since epithelial folding is a conserved process across evolution, De Renzis expects these methods to also be applicable in other organisms and ex vivo stem cell culture systems. In that case, optogenetics could be an ideal technique for reconstructing and directing tissue development, which could be used to (re)build artificial tissues in regenerative 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 During organismal development, cells undergo complex changes in shape whose causal relationship to individual morphogenetic processes remains unclear. The modular nature of such processes suggests that it should be possible to isolate individual modules, determine the minimum set of requirements sufficient to drive tissue remodeling, and re-construct morphogenesis. Here we use optogenetics to reconstitute epithelial folding in embryonic Drosophila tissues that otherwise would not undergo invagination. We show that precise spatial and temporal activation of Rho signaling is sufficient to trigger apical constriction and tissue folding. Induced furrows can occur at any position along the dorsal–ventral or anterior–posterior embryo axis in response to the spatial pattern and level of optogenetic activation. Thus, epithelial folding is a direct function of the spatio-temporal organization and strength of Rho signaling that on its own is sufficient to drive tissue internalization independently of any pre-determined condition or differentiation program associated with endogenous invagination processes. Introduction Traditional genetic approaches have played a pivotal role in establishing the requirement of individual gene activities and cell behaviors in complex morphogenetic processes 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 . More recent advances in synthetic biology are opening the possibility to engineer gene circuits 10 , signaling systems 11 , 12 , and biomaterials 13 , 14 not only to probe morphogenesis, but also to re-construct it and direct it 15 , 16 . These approaches, which are converging into the nascent field of synthetic morphogenesis 17 , will be instrumental to define the minimum set of requirements sufficient to drive morphogenesis, and will therefore, also facilitate the building of artificial tissues for potential applications in regenerative medicine. Here, we used optogenetics to synthetically reconstitute morphogenesis in the early Drosophila embryo. We focused on epithelial folding, a conserved morphogenetic process driving internalization of tissues during animal development 18 . A large body of experimental evidence indicates that apical constriction driven by phosphorylation and activation of the molecular motor myosin II is required for tissue invagination 6 . However, the extent to which apical constriction is on its own sufficient to drive tissue internalization is unknown. During this process, cells undergo a series of complex changes in shape and intracellular organization, whose causal relationship to apical constriction and inward folding remain poorly understood 19 , 20 , 21 , 22 . Furthermore, the organismal scale cells occupy defined positions and are organized in specific geometrical patterns, which might facilitate or constrain invagination. Finally, apical constriction is not always coupled with invagination and several invagination processes are independent of apical constrictions 23 . For example, during salivary gland invagination, apical constriction and tissue invagination are uncoupled. When apical constriction is inhibited, compressing forces exerted by a supracellular myosin cable surrounding the salivary gland pit are sufficient to push cells inward 24 . Similar actomyosin-cable-mediated forces drive neural tube closure during chick embryogenesis 25 . Other examples of invaginations independent of apical constriction include the folding of Drosophila leg epithelium, which is driven by whole-cell shrinkage coupled with apoptosis 22 , and ascidian gastrulation, which is driven by a basolateral accumulation of myosin II and apicobasal cell shortening 26 . In addition, basal wedging rather than apical constriction seems to be the major force driving tissue internalization during mouse neuronal tube development 27 . Even in the case of Drosophila ventral furrow invagination, arguably the best characterized example of epithelial folding, the extent to which apical constriction drive invagination is unknown. Computer simulations suggest the requirement of additional pushing forces exerted by lateral ectodermal cells 28 , 29 , and relaxation of the basal surface of invaginating cells 30 . At the tissue-scale, the emergence of collective contractile behavior and its relationship to tissue geometry and invagination also remains the focus of active investigations 31 , 32 , 33 . In this study, we employ an optogenetic method to synthetically reconstruct epithelial folding during early Drosophila embryogenesis. In this context, “synthetic” refers to guided spatio-temporal control over the signaling pathway driving apical constriction, which is otherwise dependent upon the differentiation program of the embryo. Using this approach, we test the extent to which apical constriction on its own can drive invagination, and how different contractile behaviors arise in response to different temporal and spatial patterns of optogenetic activation. Collectively, our results indicate that apical constriction is sufficient to drive tissue invagination, but it is not sufficient to fold an invagination into a tube-like shape. Furthermore, our results provide insights into the emergence of pulsatile contractions and impact of tissue geometry on coordinated contractile behavior. Results RhoGEF2 plasma membrane recruitment and tissue responses To study the impact of apical constriction on tissue folding, independently of any pre-defined conditions, associated with normal invagination processes, we used an optogenetic system to activate Rho signaling 34 , 35 at the apical surface of developing Drosophila embryos prior to any sign of morphological differentiation (Fig. 1a, b ). At the end of cellularization, the Drosophila embryo is composed of a monolayer of epithelial cells without any morphological difference along the antero-posterior (AP) or dorso-ventral (DV) axes. To avoid any contribution from endogenous invagination processes, experiments were performed on the dorsal side of the embryo. In this region, the twist and snail transcription factors, that control ventral furrow invagination 36 , are not expressed and there is no morphological movement at this stage 37 . Fig. 1 Light-mediated recruitment of RhoGEF2 at the plasma membrane causes tissue-level responses. a Schematic illustration of the CRY2/CIBN optogenetic system used for controlling plasma membrane recruitment of the Rho1 activator RhoGEF2 during early Drosophila embryogenesis. The DHPH catalytic domain of the GTP Exchange factor RhoGEF2 was fused to the light-sensitive PHR domain of CRY2 and either tagged with mCherry or left without a fluorescent tag. In the absence of light, RhoGEF2-CRY2::mCherry localizes to the cytoplasm (left). Upon two-photon illumination, CRY2 undergoes a specific conformational change and binds to the plasma membrane anchor CIBN::pmGFP (right). At the plasma membrane, RhoGEF2-CRY2::mCherry triggers<|im_end|> <|im_start|>assistant Constructing biological tissues, such as skin, muscle, or bone, in customized shapes is now one step closer. Researchers at EMBL have succeeded in guiding the folding and thus shape of tissues with optogenetics: a technique to control protein activity with light. Nature Communications publishes their results, with implications for regenerative medicine, on 18 June. The changing of tissue shapes in an embryo is essential for healthy development. Stefano De Renzis and his group members at EMBL are interested in the mechanisms behind these shape transitions, also called morphogenesis. They use optogenetics—a technique providing precise light-mediated control of protein activity—to study changes in tissue shapes. Uncoupling the link between shape and function In the current paper, Emiliano Izquierdo, Theresa Quinkler, and Stefano De Renzis used optogenetics to reconstruct epithelial folding: a fundamental process during development, where cells move inwards and fold into the embryo, eventually giving rise to internal tissues like muscles, for example. Remarkably, they achieved this in cells that normally do not undergo this process. De Renzis, who led the study: "We've uncoupled the link between the shape and function of a cell. This allows us to, for the first time, built tissues in certain shape without affecting the cell's expertise." Example of optogenetics-guided tissue folding. The top image shows an embryo 10 minutes after illumination, and the bottom one 13 minutes afterwards: light-activated cells have folded inwards and thus moved downwards, creating a furrow. Credit: Stefano De Renzis, EMBL Precise control "The great thing about using optogenetics to guide morphogenesis is that it is a very precise technique", says Emiliano Izquierdo, first author of the study. "We were able to define various shapes, and by alternating the timing and strength of illumination, we could control how far the cells folded inwards." From fruit fly to the clinic? The research was done in developing fruit flies, but since epithelial folding is a conserved process across evolution, De Renzis expects these methods to also be applicable in other organisms and ex vivo stem cell culture systems. In that case, optogenetics could be an ideal technique for reconstructing and directing tissue development, which could be used to (re)build artificial tissues in regenerative medicine. <|im_end|>

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1,951

[ { "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 Tyrolean Iceman is an extraordinarily well-preserved natural mummy that lived south of the Alpine ridge ~5,200 years before present (ybp), during the Copper Age. Despite studies that have investigated his genetic profile, the relation of the Iceman´s maternal lineage with present-day mitochondrial variation remains elusive. Studies of the Iceman have shown that his mitochondrial DNA (mtDNA) belongs to a novel lineage of haplogroup K1 (K1f) not found in extant populations. We analyzed the complete mtDNA sequences of 42 haplogroup K bearing individuals from populations of the Eastern Italian Alps – putatively in genetic continuity with the Tyrolean Iceman—and compared his mitogenome with a large dataset of worldwide K1 sequences. Our results allow a re-definition of the K1 phylogeny and indicate that the K1f haplogroup is absent or rare in present-day populations. We suggest that mtDNA Iceman´s lineage could have disappeared during demographic events starting in Europe from ~5,000 ybp. Based on the comparison of our results with published data, we propose a scenario that could explain the apparent contrast between the phylogeographic features of maternal and paternal lineages of the Tyrolean Iceman within the context of the demographic dynamics happening in Europe from 8,000 ybp. Introduction The Tyrolean Iceman (also known as Ötzi or Similaun Man) was discovered in 1991 on the Tisenjoch Pass in the Italian part of the Ötztal Alps, close to the Austrian border (3210 m s.l.m.). The Iceman is one of the oldest natural European mummies (dated to 5350–5100 ybp) and an extraordinarily well-preserved individual due to a spontaneous freeze-drying process. Scientific interest is further increased by the preservation of parts of his clothes and equipment (e.g. loincloth, shoes, leggings, axe, bow). This important finding provided unprecedented insights into aspects of the daily life during the Copper Age in central Europe 1 , 2 , 3 . Both stable isotopes analyses of Iceman’ s teeth and bones and the identification of pollen and moss fragments in his intestines have pinpointed his origin to south of the Alpine ridge to a few valleys within ~60 kilometers South-East of the discovery site ( Vinschgau and Schnals valleys in actual South-Tyrol, Eastern Italian Alps) 4 , 5 . The Tyrolean Iceman has also been extensively characterized genetically. Whole genome sequencing data indicate that the Iceman was blood group 0, lactose intolerant and genetically predisposed to cardiovascular diseases 6 . Moreover, Keller and colleagues 6 showed that the Iceman belongs to the Y-chromosome haplogroup G2a-L91. Comparing the Iceman’s genomic data to the human reference genome (UCSC hg19) specified the Iceman´s lineage into one of the four sub-branches of G2a L-91 (G2a2a1a2a1a-FGC5672) following the latest version of the Y-DNA Haplogroup Tree 7 . Comparative analysis based on informative autosomal SNPs and Y-chromosome data showed a clear link with genetic diversity of extant populations further supported by recent whole genome-data analysis 8 . However, an important question regarding the Iceman genetic heritage remains unanswered. In fact, despite the mitochondrial DNA (mtDNA) of the Iceman being well characterised 9 , 10 , 11 , 12 , the relation of his lineage with present-day mitochondrial diversity remains elusive. The first study on the complete mtDNA of the Iceman 11 showed that the ancient mitogenome was a novel lineage of mtDNA haplogroup K1 (named K1f), not yet detected in extant populations. Ermini et al. 11 proposed that the Iceman’s haplogroup may remain undetected simply due to inadequate sampling. This hypothesis should be considered due to the paucity of data regarding K1 haplogroups available at the time of the study, especially from alpine populations, which are putatively in genetic continuity with the Iceman. Alternatively, the K1f haplogroup and its closest neighbors may have been lost during repeated demographic and population events occurring in the Alps since the Neolithic. To shed new light on these issues, we analyzed the mitogenomes of 42 K–haplogroup samples from Eastern Italian Alps and compared the Iceman´s sequence with a large dataset of worldwide K1 mitogenomes. The results are discussed with currently available ancient mtDNA data from European Neolithic specimens. Finally, we combine mtDNA and Y-chromosomal data to propose a scenario that could explain the complex genetic history of the Tyrolean Iceman. Results and Discussion The Iceman mitochondrial genetic heritage The mitogenomes of 42 haplogroup K individuals from Eastern Italian Alps were analyzed ( Table S1 ). The most frequently observed K1 Alpine haplogroups were K1a4 and K1a1, similar to the worldwide K1 distribution ( Fig. 1 ) and K1a + 195 ( Table S2 ). Rare haplogroups were also observed in this study such as K1a19 and K1a24 and K1e1, which was represented in our dataset by a novel haplotype defined by a specific transition in the coding region (transition A15244G; sample #111Gm in the Fig. S2 ). Neither the Iceman’s lineage nor any other intermediate haplotypes of K1f were detected. Figure 1 Main skeleton of haplogroup K1 and its branches based on all of the mitogenomes. The area of the triangles is proportional to the occurrence of K1 haplogroups in the total dataset (see also Table S2 ). The haplogroup assignment of K1 Alpine mitogenomes (thirty-six from the present study and six from 37 ) are listed on the right-hand side of the tree. Age estimates of haplogroups are reported close to each branch (see also Table S3 ). Full size image Next, we analyzed all K1 mitogenomes available in the literature, scanning databases, in combination with our dataset ( n = 1077; Table S2 ). The whole K1 tree was updated and the Iceman’s sequence was added to the phylogeny ( Fig. 1 ). This tree was compared with the one presented by Ermini and collaborators 11 that used in total 115 K sequences (85 of which were K1 mitogenomes). The Iceman’s mitogenome falls within a cluster defined by transition T16362C (K1 + 16362) that includes K1d (5.6 thousand years [kya]; standard error: 0.6–10.7) and K1e (13.8 kya; standard error: 6.5–21.4) haplogroups. The collected data created a clearer and more robust representation of K1 + 16362 cluster", "role": "user" }, { "content": "A study was published last week on the DNA of Helicobacter pylori, the pathogen extracted from the stomach of Ötzi, the ice mummy who has provided valuable information on the life of Homo Sapiens. New research at the European Academy of Bolzano/Bozen (EURAC) further clarifies the genetic history of man who lived in the Eastern Alps over 5,300 years ago. In 2012 a complete analysis of the Y chromosome (transmitted from fathers to their sons) showed that Ötzi's paternal genetic line is still present in modern-day populations. In contrast, studies of mitochondrial DNA (transmitted solely via the mother to her offspring) left many questions still open. To clarify whether the genetic maternal line of the Iceman, who lived in the eastern Alps over 5,300 years ago, has left its mark in current populations, researchers at the European Academy of Bolzano/Bozen (EURAC) have now compared his mitochondrial DNA with 1,077 modern samples. The study concluded that the Iceman's maternal line—named K1f—is now extinct. A second part of the study, a comparison of genetic data of the mummy with data from other European Neolithic samples, provided information regarding the origin of K1f: researchers postulate that the mitochondrial lineage of the Iceman originated locally in the Alps, in a population that did not grow demographically. The study, which also clarifies Ötzi's genetic history in the context of European demographic changes from Neolithic times onwards, was published in Scientific Reports, an open access journal of the Nature group. \"The mummy's mitochondrial DNA was the first to be analysed, in 1994.\" says Valentina Coia, a biologist at EURAC and first author of the study. \"It was relatively easy to analyse and—along with the Y chromosome—allows us to go back in time, telling us about the genetic history of an individual. Despite this, the genetic relationship between the Iceman's maternal lineage and lineages found in modern populations was not yet clear.\" The most recent study regarding the analysis of Ötzi's complete mitochondrial DNA, conducted in 2008 by other research teams showed that the Iceman's maternal lineage—named K1f—was no longer traceable in modern populations. The study did not make clear, however, whether this was due to an insufficient number of comparison samples or whether K1f was indeed extinct. Valentina Coia explains further: \"The first hypothesis could not be ruled out given that the study considered only 85 modern comparison samples from the K1 lineage—the genetic lineage that also includes that of Ötzi—which comprised few samples from Europe and especially none from the eastern Alps, which are home to populations that presumably have a genetic continuity with the Iceman. To test the two hypotheses, we needed to compare Ötzi's mitochondrial DNA with a larger number of modern samples.\" The EURAC research team, in collaboration with the Sapienza University of Rome and the University of Santiago de Compostela, thus compared the mitochondrial DNA of the Iceman with that from 1,077 individuals belonging to the K1 lineage, of which 42 samples originated from the eastern Alps and were for the first time analysed in this study. The new comparison showed that neither the Iceman's lineage nor any other evolutionarily close lineages are present in modern populations: the researchers therefore lean towards the hypothesis that Ötzi's maternal genetic branch has died out. It remains to be explained why Ötzi's maternal lineage has disappeared, while his paternal lineage— named G2a—still exists in Europe. To clarify this point, researchers at EURAC compared Ötzi's mitochondrial DNA and Y chromosome with available data from numerous ancient samples found at 14 different archaeological sites throughout Europe. The results showed that the paternal lineage of Ötzi was very common in different regions in Europe during the Neolithic age, while his maternal lineage probably existed only in the Alps. Putting together the genetic data on the ancient and modern samples, namely those already present in the literature and those analysed in this study, researchers have now proposed the following scenario to explain the Iceman's genetic history: Ötzi's paternal lineage, G2a, is part of an ancient genetic substrate that arrived in Europe from the Near East with the migrations of the first Neolithic peoples some 8,000 years ago. Additional migrations and other demographic events occurring after the Neolithic Age in Europe then partially replaced G2a with other lineages, except in geographically isolated areas such as Sardinia. In contrast, the Iceman's maternal branch originated locally in the eastern Alps at least 5,300 years ago. The same migrations that have replaced only in part his paternal lineage caused the extinction of his maternal lineage that was inherited in a small and demographic stationary population. The groups from the eastern Alps in fact significantly increased in size only from the Bronze Age onwards, as evidenced by archaeological studies conducted in the territory inhabited by the Iceman. ", "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 Tyrolean Iceman is an extraordinarily well-preserved natural mummy that lived south of the Alpine ridge ~5,200 years before present (ybp), during the Copper Age. Despite studies that have investigated his genetic profile, the relation of the Iceman´s maternal lineage with present-day mitochondrial variation remains elusive. Studies of the Iceman have shown that his mitochondrial DNA (mtDNA) belongs to a novel lineage of haplogroup K1 (K1f) not found in extant populations. We analyzed the complete mtDNA sequences of 42 haplogroup K bearing individuals from populations of the Eastern Italian Alps – putatively in genetic continuity with the Tyrolean Iceman—and compared his mitogenome with a large dataset of worldwide K1 sequences. Our results allow a re-definition of the K1 phylogeny and indicate that the K1f haplogroup is absent or rare in present-day populations. We suggest that mtDNA Iceman´s lineage could have disappeared during demographic events starting in Europe from ~5,000 ybp. Based on the comparison of our results with published data, we propose a scenario that could explain the apparent contrast between the phylogeographic features of maternal and paternal lineages of the Tyrolean Iceman within the context of the demographic dynamics happening in Europe from 8,000 ybp. Introduction The Tyrolean Iceman (also known as Ötzi or Similaun Man) was discovered in 1991 on the Tisenjoch Pass in the Italian part of the Ötztal Alps, close to the Austrian border (3210 m s.l.m.). The Iceman is one of the oldest natural European mummies (dated to 5350–5100 ybp) and an extraordinarily well-preserved individual due to a spontaneous freeze-drying process. Scientific interest is further increased by the preservation of parts of his clothes and equipment (e.g. loincloth, shoes, leggings, axe, bow). This important finding provided unprecedented insights into aspects of the daily life during the Copper Age in central Europe 1 , 2 , 3 . Both stable isotopes analyses of Iceman’ s teeth and bones and the identification of pollen and moss fragments in his intestines have pinpointed his origin to south of the Alpine ridge to a few valleys within ~60 kilometers South-East of the discovery site ( Vinschgau and Schnals valleys in actual South-Tyrol, Eastern Italian Alps) 4 , 5 . The Tyrolean Iceman has also been extensively characterized genetically. Whole genome sequencing data indicate that the Iceman was blood group 0, lactose intolerant and genetically predisposed to cardiovascular diseases 6 . Moreover, Keller and colleagues 6 showed that the Iceman belongs to the Y-chromosome haplogroup G2a-L91. Comparing the Iceman’s genomic data to the human reference genome (UCSC hg19) specified the Iceman´s lineage into one of the four sub-branches of G2a L-91 (G2a2a1a2a1a-FGC5672) following the latest version of the Y-DNA Haplogroup Tree 7 . Comparative analysis based on informative autosomal SNPs and Y-chromosome data showed a clear link with genetic diversity of extant populations further supported by recent whole genome-data analysis 8 . However, an important question regarding the Iceman genetic heritage remains unanswered. In fact, despite the mitochondrial DNA (mtDNA) of the Iceman being well characterised 9 , 10 , 11 , 12 , the relation of his lineage with present-day mitochondrial diversity remains elusive. The first study on the complete mtDNA of the Iceman 11 showed that the ancient mitogenome was a novel lineage of mtDNA haplogroup K1 (named K1f), not yet detected in extant populations. Ermini et al. 11 proposed that the Iceman’s haplogroup may remain undetected simply due to inadequate sampling. This hypothesis should be considered due to the paucity of data regarding K1 haplogroups available at the time of the study, especially from alpine populations, which are putatively in genetic continuity with the Iceman. Alternatively, the K1f haplogroup and its closest neighbors may have been lost during repeated demographic and population events occurring in the Alps since the Neolithic. To shed new light on these issues, we analyzed the mitogenomes of 42 K–haplogroup samples from Eastern Italian Alps and compared the Iceman´s sequence with a large dataset of worldwide K1 mitogenomes. The results are discussed with currently available ancient mtDNA data from European Neolithic specimens. Finally, we combine mtDNA and Y-chromosomal data to propose a scenario that could explain the complex genetic history of the Tyrolean Iceman. Results and Discussion The Iceman mitochondrial genetic heritage The mitogenomes of 42 haplogroup K individuals from Eastern Italian Alps were analyzed ( Table S1 ). The most frequently observed K1 Alpine haplogroups were K1a4 and K1a1, similar to the worldwide K1 distribution ( Fig. 1 ) and K1a + 195 ( Table S2 ). Rare haplogroups were also observed in this study such as K1a19 and K1a24 and K1e1, which was represented in our dataset by a novel haplotype defined by a specific transition in the coding region (transition A15244G; sample #111Gm in the Fig. S2 ). Neither the Iceman’s lineage nor any other intermediate haplotypes of K1f were detected. Figure 1 Main skeleton of haplogroup K1 and its branches based on all of the mitogenomes. The area of the triangles is proportional to the occurrence of K1 haplogroups in the total dataset (see also Table S2 ). The haplogroup assignment of K1 Alpine mitogenomes (thirty-six from the present study and six from 37 ) are listed on the right-hand side of the tree. Age estimates of haplogroups are reported close to each branch (see also Table S3 ). Full size image Next, we analyzed all K1 mitogenomes available in the literature, scanning databases, in combination with our dataset ( n = 1077; Table S2 ). The whole K1 tree was updated and the Iceman’s sequence was added to the phylogeny ( Fig. 1 ). This tree was compared with the one presented by Ermini and collaborators 11 that used in total 115 K sequences (85 of which were K1 mitogenomes). The Iceman’s mitogenome falls within a cluster defined by transition T16362C (K1 + 16362) that includes K1d (5.6 thousand years [kya]; standard error: 0.6–10.7) and K1e (13.8 kya; standard error: 6.5–21.4) haplogroups. The collected data created a clearer and more robust representation of K1 + 16362 cluster<|im_end|> <|im_start|>assistant A study was published last week on the DNA of Helicobacter pylori, the pathogen extracted from the stomach of Ötzi, the ice mummy who has provided valuable information on the life of Homo Sapiens. New research at the European Academy of Bolzano/Bozen (EURAC) further clarifies the genetic history of man who lived in the Eastern Alps over 5,300 years ago. In 2012 a complete analysis of the Y chromosome (transmitted from fathers to their sons) showed that Ötzi's paternal genetic line is still present in modern-day populations. In contrast, studies of mitochondrial DNA (transmitted solely via the mother to her offspring) left many questions still open. To clarify whether the genetic maternal line of the Iceman, who lived in the eastern Alps over 5,300 years ago, has left its mark in current populations, researchers at the European Academy of Bolzano/Bozen (EURAC) have now compared his mitochondrial DNA with 1,077 modern samples. The study concluded that the Iceman's maternal line—named K1f—is now extinct. A second part of the study, a comparison of genetic data of the mummy with data from other European Neolithic samples, provided information regarding the origin of K1f: researchers postulate that the mitochondrial lineage of the Iceman originated locally in the Alps, in a population that did not grow demographically. The study, which also clarifies Ötzi's genetic history in the context of European demographic changes from Neolithic times onwards, was published in Scientific Reports, an open access journal of the Nature group. "The mummy's mitochondrial DNA was the first to be analysed, in 1994." says Valentina Coia, a biologist at EURAC and first author of the study. "It was relatively easy to analyse and—along with the Y chromosome—allows us to go back in time, telling us about the genetic history of an individual. Despite this, the genetic relationship between the Iceman's maternal lineage and lineages found in modern populations was not yet clear." The most recent study regarding the analysis of Ötzi's complete mitochondrial DNA, conducted in 2008 by other research teams showed that the Iceman's maternal lineage—named K1f—was no longer traceable in modern populations. The study did not make clear, however, whether this was due to an insufficient number of comparison samples or whether K1f was indeed extinct. Valentina Coia explains further: "The first hypothesis could not be ruled out given that the study considered only 85 modern comparison samples from the K1 lineage—the genetic lineage that also includes that of Ötzi—which comprised few samples from Europe and especially none from the eastern Alps, which are home to populations that presumably have a genetic continuity with the Iceman. To test the two hypotheses, we needed to compare Ötzi's mitochondrial DNA with a larger number of modern samples." The EURAC research team, in collaboration with the Sapienza University of Rome and the University of Santiago de Compostela, thus compared the mitochondrial DNA of the Iceman with that from 1,077 individuals belonging to the K1 lineage, of which 42 samples originated from the eastern Alps and were for the first time analysed in this study. The new comparison showed that neither the Iceman's lineage nor any other evolutionarily close lineages are present in modern populations: the researchers therefore lean towards the hypothesis that Ötzi's maternal genetic branch has died out. It remains to be explained why Ötzi's maternal lineage has disappeared, while his paternal lineage— named G2a—still exists in Europe. To clarify this point, researchers at EURAC compared Ötzi's mitochondrial DNA and Y chromosome with available data from numerous ancient samples found at 14 different archaeological sites throughout Europe. The results showed that the paternal lineage of Ötzi was very common in different regions in Europe during the Neolithic age, while his maternal lineage probably existed only in the Alps. Putting together the genetic data on the ancient and modern samples, namely those already present in the literature and those analysed in this study, researchers have now proposed the following scenario to explain the Iceman's genetic history: Ötzi's paternal lineage, G2a, is part of an ancient genetic substrate that arrived in Europe from the Near East with the migrations of the first Neolithic peoples some 8,000 years ago. Additional migrations and other demographic events occurring after the Neolithic Age in Europe then partially replaced G2a with other lineages, except in geographically isolated areas such as Sardinia. In contrast, the Iceman's maternal branch originated locally in the eastern Alps at least 5,300 years ago. The same migrations that have replaced only in part his paternal lineage caused the extinction of his maternal lineage that was inherited in a small and demographic stationary population. The groups from the eastern Alps in fact significantly increased in size only from the Bronze Age onwards, as evidenced by archaeological studies conducted in the territory inhabited by the Iceman. <|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 Flowers of the hop plant provide both bitterness and “hoppy” flavor to beer. Hops are, however, both a water and energy intensive crop and vary considerably in essential oil content, making it challenging to achieve a consistent hoppy taste in beer. Here, we report that brewer’s yeast can be engineered to biosynthesize aromatic monoterpene molecules that impart hoppy flavor to beer by incorporating recombinant DNA derived from yeast, mint, and basil. Whereas metabolic engineering of biosynthetic pathways is commonly enlisted to maximize product titers, tuning expression of pathway enzymes to affect target production levels of multiple commercially important metabolites without major collateral metabolic changes represents a unique challenge. By applying state-of-the-art engineering techniques and a framework to guide iterative improvement, strains are generated with target performance characteristics. Beers produced using these strains are perceived as hoppier than traditionally hopped beers by a sensory panel in a double-blind tasting. Introduction During the brewing process, Saccharomyces cerevisiae converts the fermentable sugars from grains into ethanol and a host of other flavor-determining by-products. Flowers of the hop plant, Humulus lupulus L., are typically added during the wort boil to impart bitter flavor and immediately before or during the fermentation to impart “hoppy” flavor and fragrance (Fig. 1 a). Over the past two decades, consumers have displayed an increasing preference for beers that contain hoppy flavor. Hops are an expensive ingredient for breweries to source (total domestic sales have tripled over the past 10 years due to heightened demand) and a crop that requires a large amount of natural resources: ~100 billion L of water is required for annual irrigation of domestic hops and considerable infrastructure is required to deliver water from its source to the farm 1 , 2 . Further, hops vary considerable in essential oil content, making it challenging to achieve a consistent hoppy taste in beer. Fig. 1 Engineering brewer’s yeast to express monoterpene biosynthetic pathways thereby replacing flavor hop addition. a During the brewing process, S . cerevisiae converts wort—a barley extract solution rich in fermentable sugars—into ethanol and other by-products. Hops are added immediately before, during, or after fermentation to impart “hoppy” flavor. Engineered strains produce linalool and geraniol, primary flavor components of hoppy beer, thereby replacing hop additions. b Six full-length plant-derived linalool synthase genes, as well as PTS-truncated variants, were expressed on high-copy plasmids. Full-length genes and PTS-truncated genes predicted by either ChloroP (C) or the RR-heuristic method (RR) are indicated by colored lines. c Error bars correspond to mean ± standard deviation of three biological replicates. Asterisks indicate statistically significant increases in monoterpene production compared with the control strain (Y) as determined by a t -test using p -value <0.025. The LIS from the California wildflower Clarkia breweri has been shown to increase production of linalool when heterologously expressed in plants 47 and in yeast 48 . However, when C . breweri LIS was expressed, either with native codons (n Cb ) or “yeast-optimized” codons ( Cb ), linalool was not detected. The Mentha citrata LIS ( Mc ) truncated at the RR motif was identified as sufficiently active to allow for monoterpene production at levels characteristic of commercial beer and was chosen for integration into brewer’s yeast strains Full size image Hop flowers are densely covered by glandular trichomes, specialized structures that secrete secondary metabolites into epidermal outgrowths 3 . These secretions accumulate as essential oil, which is rich in various terpenes, the class of metabolites that impart hoppy flavor to beer. Considerable research has investigated which of these molecules are primarily responsible for this flavor 4 ; these studies are complicated by genetic, environmental, and process-level variation 5 and have suggested that the bouquet of flavor molecules contributed to beer by hops is complex. Nonetheless, the two monoterpene molecules linalool and geraniol have been identified as primary flavor determinants by several sensory analyses of hop extract aroma 6 , 7 , 8 and finished beer taste and aroma 7 , 9 , 10 , 11 , and together, they are major drivers of the floral aroma of Cascade hops 9 , the most widely used hop in American craft brewing 12 . Previous metabolic engineering efforts have achieved microbial monoterpene biosynthesis in various microbial hosts. Work in a domesticated wine yeast has demonstrated the feasibility of producing monoterpene compounds by biosynthesis in yeast by overexpression of a geraniol synthase from a high-copy plasmid propagated in selective media 13 . However, engineering genetically stable, controlled, precise production of a combination of specific flavorants in any industrial food-processing agent has remained a formidable challenge. In this work, we create drop-in brewer’s yeast strains capable of biosynthesizing monoterpenes that give rise to hoppy flavor in finished beer, without the addition of flavor hops. To achieve this end, we identify genes suitable for monoterpene biosynthesis in yeast; we develop methods to overcome the difficulties associated with stable integration of large constructs in industrial strains; we adapt genetic tools to generate a collection of engineered industrial yeast strains on an unprecedented scale; we develop computational methods to affect precise biosynthetic control and leverage them to create a iterative framework towards target production levels. Ultimately, sensory analysis performed with beer brewed in pilot industrial fermentations demonstrates that engineered strains confer hoppy flavor to finished beer. Results Identification of yeast-active linalool and geraniol synthases The monoterpene synthases that catalyze the reaction of geranyl pyrophosphate (GPP) to linalool and geraniol in hops have not yet been identified 14 . However, genes from other plant species have been shown to encode these activities. To identify a linalool synthase (LIS) gene for functional heterologous expression in yeast, we expressed six different plant-derived LIS genes in a lab yeast strain engineered for high GPP precursor supply (Fig. 1b ). However, none of the full-length proteins exhibited sufficient activity to achieve target monoterpene concentrations in finished beer (Fig. 1c ). In plants, monoterpenes are biosynthesized in chloroplasts; plant monoterpene synthases, therefore, typically contain an N-terminal plastid targeting sequence (PTS) composed of 20–80 polar amino", "role": "user" }, { "content": "Hoppy beer is all the rage among craft brewers and beer lovers, and now UC Berkeley biologists have come up with a way to create these unique flavors and aromas without using hops. The researchers created strains of brewer's yeast that not only ferment the beer but also provide two of the prominent flavor notes provided by hops. In double-blind taste tests, employees of Lagunitas Brewing Company in Petaluma, California, characterized beer made from the engineered strains as more hoppy than a control beer made with regular yeast and Cascade hops. Bryan Donaldson, innovations manager at Lagunitas, detected notes of \"fruit-loops\" and \"orange blossom\" with no off flavors. Why would brewers want to use yeast instead of hops to impart flavor and aroma? According to Charles Denby, one of two first authors of a paper appearing this week in the journal Nature Communications, growing hops uses lots of water, not to mention fertilizer and energy to transport the crop, all of which could be avoided by using yeast to make a hop-forward brew. A pint of craft beer can require 50 pints of water merely to grow the hops, which are the dried flowers of a climbing plant. \"My hope is that if we can use the technology to make great beer that is produced with a more sustainable process, people will embrace that,\" Denby said. Hops' flavorful components, or essential oils, are also highly variable from year to year and plot to plot, so using a standardized yeast would allow uniformity of flavor. And hops are expensive. A former UC Berkeley postdoctoral fellow, Denby has launched a startup called Berkeley Brewing Science with Rachel Li, the second first author and a UC Berkeley doctoral candidate. They hope to market hoppy yeasts to brewers, including strains that contain more of the natural hop flavor components, and create other strains that incorporate novel plant flavors not typical of beer brewed from the canonical ingredients: water, barley, hops and yeast. Using DNA scissors The engineered yeast strains were altered using CRISPR-Cas9, a simple and inexpensive gene-editing tool invented at UC Berkeley. Denby and Li inserted four new genes plus the promoters that regulate the genes into industrial brewer's yeast. Two of the genes - linalool synthase and geraniol synthase - code for enzymes that produce flavor components common to many plants. In this instance, the genes came from mint and basil, respectively. Genes from other plants that were reported to have linalool synthase activity, such as olive and strawberry, were not as easy to work with. The two other genes were from yeast and boosted the production of precursor molecules needed to make linalool and geraniol, the hoppy flavor components. All of the genetic components - the Cas9 gene, four yeast, mint and basil genes and promoters - were inserted into yeast on a tiny circular DNA plasmid. The yeast cells then translated the Cas9 gene into the Cas9 proteins, which cut the yeast DNA at specific points. Yeast repair enzymes then spliced in the four genes plus promoters. The researchers used a specially designed software program to get just the right mix of promoters to produce linalool and geraniol in proportions similar to the proportions in commercial beers produced by Sierra Nevada Brewing Company, which operates a tap room not far from the startup. The classic ingredients of beer, hops and barley, are combined with water and yeast to produce a refreshing brew. UC Berkeley scientists have found a way to avoid expensive, variable and water-intensive hops by endowing yeast with the ability to create a hoppy flavor without using hops. Credit: Roxanne Makasdjian and Stephen McNally, UC Berkeley They then asked Charles Bamforth, a malting and brewing authority at UC Davis, to brew a beer from three of the most promising strains, using hops only in the initial stage of brewing - the wort - to get the bitterness without the hoppy flavor. Hop flavor was supplied only by the new yeast strains. Bamforth also brewed a beer with standard yeast and hops, and asked a former student, Lagunitas's Donaldson, to conduct a blind comparison taste test with 27 brewery employees. \"This was one of our very first sensory tests, so being rated as hoppier than the two beers that were actually dry-hopped at conventional hopping rates was very encouraging,\" Li said. From sustainable fuels to sustainable beer Denby came to UC Berkeley to work on sustainable transportation fuels with Jay Keasling, a pioneer in the field of synthetic biology and a professor of chemical and biomolecular engineering. The strategy developed by Keasling is to make microbes, primarily bacteria and yeast, ramp up their production of complex molecules called terpenes, and then insert genes that turn these terpenes into commercial products. These microbes can make such chemicals as the antimalarial drug, artemisinin, fuels such as butanol, and aromas and flavors used in the cosmetic industry. But the brewing project \"found me,\" Denby said \"I started home brewing out of curiosity with a group of friends while I was starting out in Jay's lab, in part because I enjoy beer and in part because I was interested in fermentation processes,\" he said. \"I found out that the molecules that give hops their hoppy flavor are terpene molecules, and it wouldn't be too big of a stretch to think we could develop strains that make terpenes at the same concentrations that you get when you make beer and add hops to them.\" The final hook was that a hoppy strain of yeast would make the brewing process more sustainable than using agriculturally produced hops, which is a very natural resource-intensive product, he said. \"We started our work on engineering microbes to produce isoprenoids - like flavors, fragrances and artemisinin - about 20 years ago,\" said Keasling. \"At the same time, we were building tools to accurately control metabolism. With this project, we are able to use some of the tools others and we developed to accurately control metabolism to produce just the right amount of hops flavors for beer.\" Denby and Li first had to overcome some hurdles, such as learning how to genetically engineer commercial brewer's yeast. Unlike the yeast used in research labs, which have one set of chromosomes, brewer's yeast has four sets of chromosomes. They found out that they needed to add the same four genes plus promoters to each set of chromosomes to obtain a stable strain of yeast; if not, as the yeast propagated they lost the added genes. They also had to find out, through computational analytics performed by Zak Costello, which promoters would produce the amounts of linalool and geraniol at the right times to approximate the concentrations in a hoppy beer, and then scale up fermentation by a factor of about 100 from test tube quantities to 40-liter kettles. In the end, they were able to drink their research project, and continue to do so at their startup as they ferment batches of beer to test new strains of yeast. \"Charles and Rachel have shown that using the appropriate tools to control production of these flavors can result in a beer with a more consistent hoppy flavor, even better than what nature can do itself,\" Keasling 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 Flowers of the hop plant provide both bitterness and “hoppy” flavor to beer. Hops are, however, both a water and energy intensive crop and vary considerably in essential oil content, making it challenging to achieve a consistent hoppy taste in beer. Here, we report that brewer’s yeast can be engineered to biosynthesize aromatic monoterpene molecules that impart hoppy flavor to beer by incorporating recombinant DNA derived from yeast, mint, and basil. Whereas metabolic engineering of biosynthetic pathways is commonly enlisted to maximize product titers, tuning expression of pathway enzymes to affect target production levels of multiple commercially important metabolites without major collateral metabolic changes represents a unique challenge. By applying state-of-the-art engineering techniques and a framework to guide iterative improvement, strains are generated with target performance characteristics. Beers produced using these strains are perceived as hoppier than traditionally hopped beers by a sensory panel in a double-blind tasting. Introduction During the brewing process, Saccharomyces cerevisiae converts the fermentable sugars from grains into ethanol and a host of other flavor-determining by-products. Flowers of the hop plant, Humulus lupulus L., are typically added during the wort boil to impart bitter flavor and immediately before or during the fermentation to impart “hoppy” flavor and fragrance (Fig. 1 a). Over the past two decades, consumers have displayed an increasing preference for beers that contain hoppy flavor. Hops are an expensive ingredient for breweries to source (total domestic sales have tripled over the past 10 years due to heightened demand) and a crop that requires a large amount of natural resources: ~100 billion L of water is required for annual irrigation of domestic hops and considerable infrastructure is required to deliver water from its source to the farm 1 , 2 . Further, hops vary considerable in essential oil content, making it challenging to achieve a consistent hoppy taste in beer. Fig. 1 Engineering brewer’s yeast to express monoterpene biosynthetic pathways thereby replacing flavor hop addition. a During the brewing process, S . cerevisiae converts wort—a barley extract solution rich in fermentable sugars—into ethanol and other by-products. Hops are added immediately before, during, or after fermentation to impart “hoppy” flavor. Engineered strains produce linalool and geraniol, primary flavor components of hoppy beer, thereby replacing hop additions. b Six full-length plant-derived linalool synthase genes, as well as PTS-truncated variants, were expressed on high-copy plasmids. Full-length genes and PTS-truncated genes predicted by either ChloroP (C) or the RR-heuristic method (RR) are indicated by colored lines. c Error bars correspond to mean ± standard deviation of three biological replicates. Asterisks indicate statistically significant increases in monoterpene production compared with the control strain (Y) as determined by a t -test using p -value <0.025. The LIS from the California wildflower Clarkia breweri has been shown to increase production of linalool when heterologously expressed in plants 47 and in yeast 48 . However, when C . breweri LIS was expressed, either with native codons (n Cb ) or “yeast-optimized” codons ( Cb ), linalool was not detected. The Mentha citrata LIS ( Mc ) truncated at the RR motif was identified as sufficiently active to allow for monoterpene production at levels characteristic of commercial beer and was chosen for integration into brewer’s yeast strains Full size image Hop flowers are densely covered by glandular trichomes, specialized structures that secrete secondary metabolites into epidermal outgrowths 3 . These secretions accumulate as essential oil, which is rich in various terpenes, the class of metabolites that impart hoppy flavor to beer. Considerable research has investigated which of these molecules are primarily responsible for this flavor 4 ; these studies are complicated by genetic, environmental, and process-level variation 5 and have suggested that the bouquet of flavor molecules contributed to beer by hops is complex. Nonetheless, the two monoterpene molecules linalool and geraniol have been identified as primary flavor determinants by several sensory analyses of hop extract aroma 6 , 7 , 8 and finished beer taste and aroma 7 , 9 , 10 , 11 , and together, they are major drivers of the floral aroma of Cascade hops 9 , the most widely used hop in American craft brewing 12 . Previous metabolic engineering efforts have achieved microbial monoterpene biosynthesis in various microbial hosts. Work in a domesticated wine yeast has demonstrated the feasibility of producing monoterpene compounds by biosynthesis in yeast by overexpression of a geraniol synthase from a high-copy plasmid propagated in selective media 13 . However, engineering genetically stable, controlled, precise production of a combination of specific flavorants in any industrial food-processing agent has remained a formidable challenge. In this work, we create drop-in brewer’s yeast strains capable of biosynthesizing monoterpenes that give rise to hoppy flavor in finished beer, without the addition of flavor hops. To achieve this end, we identify genes suitable for monoterpene biosynthesis in yeast; we develop methods to overcome the difficulties associated with stable integration of large constructs in industrial strains; we adapt genetic tools to generate a collection of engineered industrial yeast strains on an unprecedented scale; we develop computational methods to affect precise biosynthetic control and leverage them to create a iterative framework towards target production levels. Ultimately, sensory analysis performed with beer brewed in pilot industrial fermentations demonstrates that engineered strains confer hoppy flavor to finished beer. Results Identification of yeast-active linalool and geraniol synthases The monoterpene synthases that catalyze the reaction of geranyl pyrophosphate (GPP) to linalool and geraniol in hops have not yet been identified 14 . However, genes from other plant species have been shown to encode these activities. To identify a linalool synthase (LIS) gene for functional heterologous expression in yeast, we expressed six different plant-derived LIS genes in a lab yeast strain engineered for high GPP precursor supply (Fig. 1b ). However, none of the full-length proteins exhibited sufficient activity to achieve target monoterpene concentrations in finished beer (Fig. 1c ). In plants, monoterpenes are biosynthesized in chloroplasts; plant monoterpene synthases, therefore, typically contain an N-terminal plastid targeting sequence (PTS) composed of 20–80 polar amino<|im_end|> <|im_start|>assistant Hoppy beer is all the rage among craft brewers and beer lovers, and now UC Berkeley biologists have come up with a way to create these unique flavors and aromas without using hops. The researchers created strains of brewer's yeast that not only ferment the beer but also provide two of the prominent flavor notes provided by hops. In double-blind taste tests, employees of Lagunitas Brewing Company in Petaluma, California, characterized beer made from the engineered strains as more hoppy than a control beer made with regular yeast and Cascade hops. Bryan Donaldson, innovations manager at Lagunitas, detected notes of "fruit-loops" and "orange blossom" with no off flavors. Why would brewers want to use yeast instead of hops to impart flavor and aroma? According to Charles Denby, one of two first authors of a paper appearing this week in the journal Nature Communications, growing hops uses lots of water, not to mention fertilizer and energy to transport the crop, all of which could be avoided by using yeast to make a hop-forward brew. A pint of craft beer can require 50 pints of water merely to grow the hops, which are the dried flowers of a climbing plant. "My hope is that if we can use the technology to make great beer that is produced with a more sustainable process, people will embrace that," Denby said. Hops' flavorful components, or essential oils, are also highly variable from year to year and plot to plot, so using a standardized yeast would allow uniformity of flavor. And hops are expensive. A former UC Berkeley postdoctoral fellow, Denby has launched a startup called Berkeley Brewing Science with Rachel Li, the second first author and a UC Berkeley doctoral candidate. They hope to market hoppy yeasts to brewers, including strains that contain more of the natural hop flavor components, and create other strains that incorporate novel plant flavors not typical of beer brewed from the canonical ingredients: water, barley, hops and yeast. Using DNA scissors The engineered yeast strains were altered using CRISPR-Cas9, a simple and inexpensive gene-editing tool invented at UC Berkeley. Denby and Li inserted four new genes plus the promoters that regulate the genes into industrial brewer's yeast. Two of the genes - linalool synthase and geraniol synthase - code for enzymes that produce flavor components common to many plants. In this instance, the genes came from mint and basil, respectively. Genes from other plants that were reported to have linalool synthase activity, such as olive and strawberry, were not as easy to work with. The two other genes were from yeast and boosted the production of precursor molecules needed to make linalool and geraniol, the hoppy flavor components. All of the genetic components - the Cas9 gene, four yeast, mint and basil genes and promoters - were inserted into yeast on a tiny circular DNA plasmid. The yeast cells then translated the Cas9 gene into the Cas9 proteins, which cut the yeast DNA at specific points. Yeast repair enzymes then spliced in the four genes plus promoters. The researchers used a specially designed software program to get just the right mix of promoters to produce linalool and geraniol in proportions similar to the proportions in commercial beers produced by Sierra Nevada Brewing Company, which operates a tap room not far from the startup. The classic ingredients of beer, hops and barley, are combined with water and yeast to produce a refreshing brew. UC Berkeley scientists have found a way to avoid expensive, variable and water-intensive hops by endowing yeast with the ability to create a hoppy flavor without using hops. Credit: Roxanne Makasdjian and Stephen McNally, UC Berkeley They then asked Charles Bamforth, a malting and brewing authority at UC Davis, to brew a beer from three of the most promising strains, using hops only in the initial stage of brewing - the wort - to get the bitterness without the hoppy flavor. Hop flavor was supplied only by the new yeast strains. Bamforth also brewed a beer with standard yeast and hops, and asked a former student, Lagunitas's Donaldson, to conduct a blind comparison taste test with 27 brewery employees. "This was one of our very first sensory tests, so being rated as hoppier than the two beers that were actually dry-hopped at conventional hopping rates was very encouraging," Li said. From sustainable fuels to sustainable beer Denby came to UC Berkeley to work on sustainable transportation fuels with Jay Keasling, a pioneer in the field of synthetic biology and a professor of chemical and biomolecular engineering. The strategy developed by Keasling is to make microbes, primarily bacteria and yeast, ramp up their production of complex molecules called terpenes, and then insert genes that turn these terpenes into commercial products. These microbes can make such chemicals as the antimalarial drug, artemisinin, fuels such as butanol, and aromas and flavors used in the cosmetic industry. But the brewing project "found me," Denby said "I started home brewing out of curiosity with a group of friends while I was starting out in Jay's lab, in part because I enjoy beer and in part because I was interested in fermentation processes," he said. "I found out that the molecules that give hops their hoppy flavor are terpene molecules, and it wouldn't be too big of a stretch to think we could develop strains that make terpenes at the same concentrations that you get when you make beer and add hops to them." The final hook was that a hoppy strain of yeast would make the brewing process more sustainable than using agriculturally produced hops, which is a very natural resource-intensive product, he said. "We started our work on engineering microbes to produce isoprenoids - like flavors, fragrances and artemisinin - about 20 years ago," said Keasling. "At the same time, we were building tools to accurately control metabolism. With this project, we are able to use some of the tools others and we developed to accurately control metabolism to produce just the right amount of hops flavors for beer." Denby and Li first had to overcome some hurdles, such as learning how to genetically engineer commercial brewer's yeast. Unlike the yeast used in research labs, which have one set of chromosomes, brewer's yeast has four sets of chromosomes. They found out that they needed to add the same four genes plus promoters to each set of chromosomes to obtain a stable strain of yeast; if not, as the yeast propagated they lost the added genes. They also had to find out, through computational analytics performed by Zak Costello, which promoters would produce the amounts of linalool and geraniol at the right times to approximate the concentrations in a hoppy beer, and then scale up fermentation by a factor of about 100 from test tube quantities to 40-liter kettles. In the end, they were able to drink their research project, and continue to do so at their startup as they ferment batches of beer to test new strains of yeast. "Charles and Rachel have shown that using the appropriate tools to control production of these flavors can result in a beer with a more consistent hoppy flavor, even better than what nature can do itself," Keasling said. <|im_end|>

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2,863

[ { "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 Estimates of atmospheric moisture are critical for understanding the links and feedbacks between atmospheric CO 2 and global climate. At present, there are few quantitative moisture proxies that are applicable to deep time. We present a new proxy for atmospheric moisture derived from modern climate and leaf biomarker data from North and Central America. Plants have a direct genetic pathway to regulate the production of lipids in response to osmotic stress, which is manifested in a change in the distribution of simple aliphatic lipids such as n- alkanes. The Average Chain Length (ACL) of these lipids is therefore statistically related to mean annual vapor pressure deficit (VPD av ), enabling quantitative reconstruction of VPD from sedimentary n- alkanes. We apply this transfer function to the Armantes section of the Calatayud-Daroca Basin in Central Spain, that spans the Middle Miocene Climatic Optimum (MMCO) and the Middle Miocene Climate Transition (MMCT). Reconstructed VPD av rises from 0.13 to 0.92 kPa between 16.5 and 12.4 Ma, indicating a substantial drying through the MMCT. These data are consistent with fossil assemblages and mammalian stable isotope data, highlighting the utility of this new organic molecular tool for quantifying hydrologic variability over geologic timescales. Introduction The distribution of ecosystems across the globe is strongly regulated by the availability of water 1 . In the face of predicted future climate shifts, reconstructions of past climate and hydrology provide critical opportunities to evaluate the relationship between atmospheric CO 2 and hydrological regimes during periods when Earth was significantly warmer than today 2 . At present, however, reconstructions of past water availability suffer from large uncertainties, especially in regions that are prone to large fluctuations in climate and hydrology in response to variations in p CO 2 (e.g. Western North America). A number of semi-quantitative geochemical methods have been used to infer paleoaridity. These include: (i) stable isotopes of fossil bones/teeth 3 , 4 , speleothems 5 , and soil carbonates 6 , 7 ; (ii) the presence and/or provenance of dust in ice cores 8 ; (iii) the carbon isotope composition of plants 9 , 10 ; and (iv) the geochemical composition of paleosols 11 , 12 . While these methods have advanced our understanding of paleohydrological processes, they possess a number of significant mechanistic, temporal or spatial limitations. For example, dust in ice cores is strongly influenced by changes in wind strength and direction, in addition to aridity 13 . Ice cores also only record the last few million years of glacial conditions, placing important temporal constraints on paleoclimatic reconstructions. Conflict between paleosol and fossil bone carbonate δ 18 O records 4 , 12 is likely due to the fact that the isotopic composition of ungulate tooth enamel can record the influence of a complex mixture of factors such as temperature, water availability and atmospheric circulation patterns 14 , as well as the ability of animals to migrate significant distances to continue residing in their ideal habitat 15 . Furthermore, soil carbonates only form in a discrete range of hydrologic conditions. A shift from a dry environment (characterized by soil carbonate formation) to wetter conditions is often marked by a reduction or complete absence of soil carbonate nodules. In recent decades, there has been a dramatic upsurge in the use of molecules present in the epicuticular waxes coating leaves of terrestrial and aquatic higher plants (Fig. 1 ) as proxies for paleoclimatic and paleoenvironmental reconstructions 16 . The are many advantages to this biomarker-based approach. n- Alkyl lipids from higher plants are found in both terrestrial and marine sedimentary systems 10 , 17 , 18 , 19 , 20 , and are relatively resistant to shallow burial diagenesis 21 , 22 , 23 , enabling paleoenvironmental reconstruction over hundreds of millions of years of Earth history 24 , 25 . A number of methods have been used to infer paleoclimatic information from leaf wax biomarkers. The δ 13 C compositions of n- alkanes in sedimentary archives are commonly used to identify the proportion of C 3 and C 4 plants, and hence extrapolate changes in temperature and aridity 26 , 27 . Relative humidity and the availability of moisture are also thought to be important determinants of the relationship between the hydrogen isotope composition of precipitation and the δD signal recorded by leaf waxes 28 . The extent that leaf wax n- alkane δD values record this aridity/transpiration signal, however, remains controversial. Some studies of modern vegetation suggest that transpiration influences n- alkane δD values 29 , yet grasses grown under controlled greenhouse conditions show no n- alkane δD shifts in response to changes in relative humidity 30 . In addition, biochemical processes are shown to drive interspecies variation in n -alkane δD among modern plants 31 , 32 , suggesting that mechanisms controlling leaf wax lipid hydrogen isotope compositions are not yet fully constrained. Figure 1 Schematic showing the morphology and chemistry of leaf epicuticular waxes: ( a ) transverse view of the epidermal cells showing intracellular and epicuticular wax, alongside the cell wall and other photosynthetic and non-photosynthetic cell arrangements (figure adapted from 68 with the permission of Elsevier); ( b ) long chain n- alkanes and fatty acids, ubiquitous compounds in leaf waxes from terrestrial higher plants; and ( c ) typical chromatogram of leaf wax n- alkanes from terrestrial higher plants showing the distribution of long-chain homologues. Leaf photograph shown is reproduced under CC0 1.0. Full size image The molecular distribution of leaf wax n -alkanes, commonly described by indices such as the Average Chain Length (ACL), is shown to vary along a latitudinal gradient, a phenomenon previously interpreted to be driven by changes in temperature 33 , 34 , 35 . However, correlation does not necessarily imply causation. ACL is also known to be related to changes in the availability of moisture, with longer chain lengths prevalent in more arid environments 34 , 36 , 37 , 38 . The trend for plants to synthesize longer alkane homologues under conditions with", "role": "user" }, { "content": "New research, published in Scientific Reports, has outlined a new methodology for estimating ancient atmospheric water content based on fossil plant leaf waxes. As the Earth's surface and atmosphere warm, the amount of moisture - water vapour - in the atmosphere will increase. Understanding the size of this increase is important for predicting future climates as water vapour is a significant greenhouse gas. Atmospheric moisture content also influences the patterns and intensity of rainfall events. The relationship between temperature and moisture content can be explored by the study of intervals in Earth's history when climates where significantly warmer than those seen in modern times, which necessitates a method for estimating ancient atmospheric moisture content. Dr Yvette Eley, from the University of Birmingham, explained, \"If we want to understand how the Earth would work with a climate substantially warmer than today, we have to study intervals millions of years in the past - made difficult because these warm climates are much older than our oldest climate records from Antarctic ice cores (less than one million years old).\" To try and understand climate properties related to the atmosphere - like rainfall and atmospheric moisture content - in such ancient times is very challenging. Existing methods, using calcium carbonate concretions that form in soils, or the chemistry of fossilised mammal teeth, are both hampered by their relative rarity in ancient sediments. Dr Eley added, \"Our new approach to quantifying ancient atmospheric moisture content relies on the fundamental properties of plant leaves, and how they alter their protective waxy coverings in response to water stress. These leaf waxes are tough and resistant, and are regularly found as what we call biomarker compounds in ancient river, lake and even marine sediments.\" A method of estimating ancient moisture content based on these plant wax compounds overcomes the limitations of other methods because plant waxes are commonly found in soils and sediments stretching back tens or even hundreds of millions of years and across many environments. The validity of this new tool was proven in studies of modern soils across the US and Central America, carried out by the research team of Associate Professor Michael Hren in the Center for Integrative Geosciences at the University of Connecticut. These studies showed a clear relationship between the chemistry of these waxy compounds and the amount of moisture in the atmosphere. \"What we see is that the distribution of organic compounds preserved in soils seems to be strongly related to the difference between how much water is in an air mass, and how much the air mass can hold, or what is known as the vapour pressure deficit,\" says Dr Hren. Eley and Hren then applied their new proxy to reconstruct atmospheric moisture content in Central Spain during an interval 15 to 17 million years ago. Although consistently much warmer than pre-industrial conditions, this interval marks one of the cooling steps that led to the development of the modern world. The new data confirms the expectations of climate models, that atmospheric cooling is coupled to less atmospheric moisture. The reconstructed changes in atmospheric moisture also align with results from other independent proxies used to investigate changes in temperature and rainfall in the region. Dr Eley said, \"This gives us the confidence that our proxy works, and we have every reason to believe that it will do so for future exploration into the even deeper past. We hope the results of this exploration will provide direct data to test our understanding of the relationship between global warming, atmospheric moisture content and rainfall systems.\" ", "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 Estimates of atmospheric moisture are critical for understanding the links and feedbacks between atmospheric CO 2 and global climate. At present, there are few quantitative moisture proxies that are applicable to deep time. We present a new proxy for atmospheric moisture derived from modern climate and leaf biomarker data from North and Central America. Plants have a direct genetic pathway to regulate the production of lipids in response to osmotic stress, which is manifested in a change in the distribution of simple aliphatic lipids such as n- alkanes. The Average Chain Length (ACL) of these lipids is therefore statistically related to mean annual vapor pressure deficit (VPD av ), enabling quantitative reconstruction of VPD from sedimentary n- alkanes. We apply this transfer function to the Armantes section of the Calatayud-Daroca Basin in Central Spain, that spans the Middle Miocene Climatic Optimum (MMCO) and the Middle Miocene Climate Transition (MMCT). Reconstructed VPD av rises from 0.13 to 0.92 kPa between 16.5 and 12.4 Ma, indicating a substantial drying through the MMCT. These data are consistent with fossil assemblages and mammalian stable isotope data, highlighting the utility of this new organic molecular tool for quantifying hydrologic variability over geologic timescales. Introduction The distribution of ecosystems across the globe is strongly regulated by the availability of water 1 . In the face of predicted future climate shifts, reconstructions of past climate and hydrology provide critical opportunities to evaluate the relationship between atmospheric CO 2 and hydrological regimes during periods when Earth was significantly warmer than today 2 . At present, however, reconstructions of past water availability suffer from large uncertainties, especially in regions that are prone to large fluctuations in climate and hydrology in response to variations in p CO 2 (e.g. Western North America). A number of semi-quantitative geochemical methods have been used to infer paleoaridity. These include: (i) stable isotopes of fossil bones/teeth 3 , 4 , speleothems 5 , and soil carbonates 6 , 7 ; (ii) the presence and/or provenance of dust in ice cores 8 ; (iii) the carbon isotope composition of plants 9 , 10 ; and (iv) the geochemical composition of paleosols 11 , 12 . While these methods have advanced our understanding of paleohydrological processes, they possess a number of significant mechanistic, temporal or spatial limitations. For example, dust in ice cores is strongly influenced by changes in wind strength and direction, in addition to aridity 13 . Ice cores also only record the last few million years of glacial conditions, placing important temporal constraints on paleoclimatic reconstructions. Conflict between paleosol and fossil bone carbonate δ 18 O records 4 , 12 is likely due to the fact that the isotopic composition of ungulate tooth enamel can record the influence of a complex mixture of factors such as temperature, water availability and atmospheric circulation patterns 14 , as well as the ability of animals to migrate significant distances to continue residing in their ideal habitat 15 . Furthermore, soil carbonates only form in a discrete range of hydrologic conditions. A shift from a dry environment (characterized by soil carbonate formation) to wetter conditions is often marked by a reduction or complete absence of soil carbonate nodules. In recent decades, there has been a dramatic upsurge in the use of molecules present in the epicuticular waxes coating leaves of terrestrial and aquatic higher plants (Fig. 1 ) as proxies for paleoclimatic and paleoenvironmental reconstructions 16 . The are many advantages to this biomarker-based approach. n- Alkyl lipids from higher plants are found in both terrestrial and marine sedimentary systems 10 , 17 , 18 , 19 , 20 , and are relatively resistant to shallow burial diagenesis 21 , 22 , 23 , enabling paleoenvironmental reconstruction over hundreds of millions of years of Earth history 24 , 25 . A number of methods have been used to infer paleoclimatic information from leaf wax biomarkers. The δ 13 C compositions of n- alkanes in sedimentary archives are commonly used to identify the proportion of C 3 and C 4 plants, and hence extrapolate changes in temperature and aridity 26 , 27 . Relative humidity and the availability of moisture are also thought to be important determinants of the relationship between the hydrogen isotope composition of precipitation and the δD signal recorded by leaf waxes 28 . The extent that leaf wax n- alkane δD values record this aridity/transpiration signal, however, remains controversial. Some studies of modern vegetation suggest that transpiration influences n- alkane δD values 29 , yet grasses grown under controlled greenhouse conditions show no n- alkane δD shifts in response to changes in relative humidity 30 . In addition, biochemical processes are shown to drive interspecies variation in n -alkane δD among modern plants 31 , 32 , suggesting that mechanisms controlling leaf wax lipid hydrogen isotope compositions are not yet fully constrained. Figure 1 Schematic showing the morphology and chemistry of leaf epicuticular waxes: ( a ) transverse view of the epidermal cells showing intracellular and epicuticular wax, alongside the cell wall and other photosynthetic and non-photosynthetic cell arrangements (figure adapted from 68 with the permission of Elsevier); ( b ) long chain n- alkanes and fatty acids, ubiquitous compounds in leaf waxes from terrestrial higher plants; and ( c ) typical chromatogram of leaf wax n- alkanes from terrestrial higher plants showing the distribution of long-chain homologues. Leaf photograph shown is reproduced under CC0 1.0. Full size image The molecular distribution of leaf wax n -alkanes, commonly described by indices such as the Average Chain Length (ACL), is shown to vary along a latitudinal gradient, a phenomenon previously interpreted to be driven by changes in temperature 33 , 34 , 35 . However, correlation does not necessarily imply causation. ACL is also known to be related to changes in the availability of moisture, with longer chain lengths prevalent in more arid environments 34 , 36 , 37 , 38 . The trend for plants to synthesize longer alkane homologues under conditions with<|im_end|> <|im_start|>assistant New research, published in Scientific Reports, has outlined a new methodology for estimating ancient atmospheric water content based on fossil plant leaf waxes. As the Earth's surface and atmosphere warm, the amount of moisture - water vapour - in the atmosphere will increase. Understanding the size of this increase is important for predicting future climates as water vapour is a significant greenhouse gas. Atmospheric moisture content also influences the patterns and intensity of rainfall events. The relationship between temperature and moisture content can be explored by the study of intervals in Earth's history when climates where significantly warmer than those seen in modern times, which necessitates a method for estimating ancient atmospheric moisture content. Dr Yvette Eley, from the University of Birmingham, explained, "If we want to understand how the Earth would work with a climate substantially warmer than today, we have to study intervals millions of years in the past - made difficult because these warm climates are much older than our oldest climate records from Antarctic ice cores (less than one million years old)." To try and understand climate properties related to the atmosphere - like rainfall and atmospheric moisture content - in such ancient times is very challenging. Existing methods, using calcium carbonate concretions that form in soils, or the chemistry of fossilised mammal teeth, are both hampered by their relative rarity in ancient sediments. Dr Eley added, "Our new approach to quantifying ancient atmospheric moisture content relies on the fundamental properties of plant leaves, and how they alter their protective waxy coverings in response to water stress. These leaf waxes are tough and resistant, and are regularly found as what we call biomarker compounds in ancient river, lake and even marine sediments." A method of estimating ancient moisture content based on these plant wax compounds overcomes the limitations of other methods because plant waxes are commonly found in soils and sediments stretching back tens or even hundreds of millions of years and across many environments. The validity of this new tool was proven in studies of modern soils across the US and Central America, carried out by the research team of Associate Professor Michael Hren in the Center for Integrative Geosciences at the University of Connecticut. These studies showed a clear relationship between the chemistry of these waxy compounds and the amount of moisture in the atmosphere. "What we see is that the distribution of organic compounds preserved in soils seems to be strongly related to the difference between how much water is in an air mass, and how much the air mass can hold, or what is known as the vapour pressure deficit," says Dr Hren. Eley and Hren then applied their new proxy to reconstruct atmospheric moisture content in Central Spain during an interval 15 to 17 million years ago. Although consistently much warmer than pre-industrial conditions, this interval marks one of the cooling steps that led to the development of the modern world. The new data confirms the expectations of climate models, that atmospheric cooling is coupled to less atmospheric moisture. The reconstructed changes in atmospheric moisture also align with results from other independent proxies used to investigate changes in temperature and rainfall in the region. Dr Eley said, "This gives us the confidence that our proxy works, and we have every reason to believe that it will do so for future exploration into the even deeper past. We hope the results of this exploration will provide direct data to test our understanding of the relationship between global warming, atmospheric moisture content and rainfall systems." <|im_end|>

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2,046

[ { "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 Main article text Supplementary Material CONFLICTS OF INTEREST REFERENCES Author and article information Comments /*<![CDATA[*/ so_init('toc2', { containerId: 'affc9d0a-6871-bbb6-4922-561f8e5bd832' }); /*]]>*/ Zoonoses Volume 3, Issue 1 RNA-seq Analysis of the BCG Vaccine in a Humanized Mouse Model Novel Clinical and Genomic Signatures of the 2022 Monkeypox Virus A Marked Decline in Taenia solium Taeniasis and Cysticercosis Infections in China: Possible Reasons from the Ecological Determinants Perspective PRNP Sequences of Tibetan Antelope, Blue Sheep, and Plateau Pika from the Qinghai-Tibet Plateau and Reactivity of PrP Proteins to Rodent-Adapted Scrapie Strains in RT-QuIC and PMCA Yersinia pestis and Plague: Some Knowns and Unknowns Global Infectious Diseases in December 2022: Monthly Analysis Identification of Novel Mutations Associated with Bedaquiline Resistance in Mycobacterium Marinum Trypanosoma brucei Lipophosphoglycan Activates Host Immune Responses via the TLR-mediated p38 MAP Kinase and NF-κB Pathways Preparation of Equine Immunoglobulin F(ab′) 2 against Smallpox and Evaluation of its Immunoprotective Effect Global Infectious Diseases in January 2023: Monthly Analysis Effectiveness of Oral Fluid in Pathogenic Surveillance of Acute Respiratory Infection Syncytial and Congregative Effects of Dengue and Zika Viruses on the Aedes Albopictus Cell Line Differ among Viral Strains Global Infectious Diseases in February 2023: Monthly Analysis Corrigendum to: Pattern Recognition Receptors in Innate Immunity to Obligate Intracellular Bacteria The Epidemiology of Circulating Rotavirus Associated with Diarrhea in Egyptian Kids and Calves: A Review The Coordinating Research on Emerging Arboviral Threats Encompassing the Neotropics (CREATE-NEO) Global Infectious Diseases in March 2023: Monthly Analysis Next-Generation Vaccines against COVID-19 Variants: Beyond the Spike Protein Purified Immunoglobulin F(ab′) 2 Protects Mice and Rhesus Monkeys against Lethal Ricin Intoxication Co-circulation, Co-infection of SARS-CoV-2 and Influenza Virus, Where Will it Go? Mild Infections with Multiple Spotted Fever Grouped Rickettsia Species among Forest Rangers with Tick Bites CRISPR-Cas- and Aptamer-based Systems for Diagnosing Pathogens: A Review Roles of Host Phospholipase D during Aspergillus fumigatus Infection in Mice Molecular Epidemiology and the Control and Prevention of Cystic Echinococcosis in China: What is Known from Current Research Global Infectious Diseases in April 2023: Monthly Analysis Successful Treatment of Pasteurella multocida -Related Invasive Infections with a Beta-Lactamase Inhibitor-Sparing Combination Antibiotic Regimen: A Case Series Antimicrobial Resistance in Non-typhoidal Salmonella from Retail Foods Collected in 2020 in China Global Infectious Diseases in May 2023: Monthly Analysis /*<![CDATA[*/ so_init('paginator', { id: 'paginator', itemSelector: '.so-tab-l', selectedSelector: '.so--selected', pageSize: 5 }); /*]]>*/ /*<![CDATA[*/ so_init('floatingPanel', { id: 'ec9a27bd-5d62-3ca3-4c5b-2190ab308591', endId: 'c97ddaf1-ed6a-8e82-4f05-811c7b1b0db0' }) /*]]>*/ Record : found Abstract : found Article : found Is Open Access PRNP Sequences of Tibetan Antelope, Blue Sheep, and Plateau Pika from the Qinghai-Tibet Plateau and Reactivity of PrP Proteins to Rodent-Adapted Scrapie Strains in RT-QuIC and PMCA research-article Author(s): named anchor Yue-Zhang Wu 1 , # , named anchor Jing-Xing Wu 1 , # , named anchor Xue-Hua Yang 1 , named anchor Shan Lu 2 , named anchor Kang Xiao 1 , named anchor Dong-Dong Chen 1 , named anchor Li-Ping Gao 1 , named anchor Qi Shi 1 , 3 , * , , named anchor Jian-Guo Xu 2 , * , , named anchor Xiao-Ping Dong 1 , 3 , 4 , 5 , * , Publication date (Electronic): 18 January 2023 Journal: Zoonoses Publisher: Compuscript Keywords: Tibetan antelope , blue sheep , plateau pika , PRNP , RT-QuIC , PMCA Print Download XML /*<![CDATA[*/ so_init('dropdown', { 'buttonID': \"id16\", 'dropdownID': \"id17\" }); /*]]>*/ Review Review article Invite someone to review /*<![CDATA[*/ so_init('dropdown', { 'buttonID': \"id18\", 'dropdownID': \"id19\", 'alignment': 'DROPDOWN_END' }); /*]]>*/ Bookmark /*<![CDATA[*/ so_init('dropdown', { 'buttonID': \"id1b\", 'dropdownID': \"id1a\" }); /*]]>*/ /*<![CDATA[*/ so_init('dropdown', { 'buttonID': \"id1d\", 'dropdownID': \"id1c\" }); /*]]>*/ Share Twitter Sina Weibo Facebook Email /*<![CDATA[*/ so_init('dropdown', { 'buttonID': \"id1e\", 'dropdownID': \"id1f\" }); /*]]>*/ Cite as... /*<![CDATA[*/ so_init('cite', {\"buttonIds\":[\"id24\",\"stats-cite-qzxl7t\"],\"exports\":[{\"name\":\"BibTex\",\"ext\":\"bib\",\"url\":\"./document_citation/4bc81952-d4c5-4de5-8ca4-67b88a10c0eb/BIBTEX\"},{\"name\":\"EndNote\",\"ext\":\"enw\",\"url\":\"./document_citation/4bc81952-d4c5-4de5-8ca4-67b88a10c0eb/ENDNOTE\"},{\"name\":\"Reference Manager (RIS)\",\"ext\":\"ris\",\"url\":\"./document_citation/4bc81952-d4c5-4de5-8ca4-67b88a10c0eb/RIS\"},{\"name\":\"HTML\",\"ext\":\"html\",\"url\":\"./document_citation/4bc81952-d4c5-4de5-8ca4-67b88a10c0eb/HTML\"}]}); /*]]>*/ /*<![CDATA[*/ so_init('contentErrorReportButton', { 'id': \"78a25ffd-9a6c-8db2-4335-5d209d557970\", 'contentId': \"4bc81952-d4c5-4de5-8ca4-67b88a10c0eb\", 'isWithoutCssClassSoProp': \"true\" }); /*]]>*/ ?xml version=\"1.0\" encoding=\"UTF-8\"? Abstract named anchor Background: Tibetan antelope ( Rhinopithecus ), blue sheep ( Pseudois nayauris ), and plateau pika ( Ochotona curzoniae ) are wild animals living on the Qinghai-Tibet Plateau. There have been no reports of naturally-occurring transmissible spongioform encephalopathies (TSEs) involving these animals. Furthermore, the PRNP genes have not been described in the literature. named anchor Methods: The PRNP genes from 21 Tibetan antelopes, 4 blue sheep, and 3 plateau pikas were obtained and sequenced. The recombinant proteins were then prepared. Using scrapie strains (263K, 139A, ME7, and S15) as the seeds, the reactivity of the PrP proteins from sheep (rSheepPrP25-234) and pika (rPikaPrP23-230) were tested using real-time quaking-induced conversion (RT-QuIC). Protein misfolding cyclic amplification (PMCA) tests of the brain homogenates from domestic sheep and rabbits were performed with the seeds of strains 263K and ME7. named anchor Results: The PRNP genes of bovids were 771 bp long and encoded 256 amino acids (aa), showing 100% homology with the wild-type sheep prion protein (PrP) aa sequence. The PRNP gene of pika was 759 bp long and encoded 252 amino acids, showing 92.1% homology with the aa sequence of domestic rabbits. The sheep and pika proteins revealed positive reactions in 10 -5 diluted seeds. Only rPikaPrP23-230 produced positive curves in 10 -7 diluted seeds. The PMCA tests failed to produce proteinase K (PK)-resistant PrP (PrP res ). named anchor Conclusion: This is the first description of PRNP genes and PrP aa sequences of Tibetan antelope, blue sheep, and plateau pike from the Qinghai-Tibet Plateau. In the presence of rodent prions, the PrPs of sheep and pika efficiently induce fibrillation in RT-QuIC, but do not generate PrP res in PMCA. Our results indicate that pika, as one of the important links in the Qinghai-Tibet Plateau biological chain, may play an important role in the prion circulation. Pika PrP deserves further analysis for its potential application value in assays for human prion disease. Main article text named anchor INTRODUCTION Prion disease is a type of transmissible spongiform encephalopathy (TSE) that affects a species of mammals, such as, Creutzfeldt-Jacob disease (CJD) in humans, scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, and chronic wasting disease (CWD) in deer [ 1", "role": "user" }, { "content": "Tibetan antelope (Rhinopithecus), blue sheep (Pseudois nayauris), and plateau pika (Ochotona curzoniae) are wild animals living on the Qinghai-Tibet Plateau. There have been no reports of naturally occurring transmissible spongioform encephalopathies (TSEs) involving these animals. Furthermore, the PRNP genes have not been described in the literature. For a study published in Zoonoses, the PRNP genes from 21 Tibetan antelopes, four blue sheep, and three plateau pikas were obtained and sequenced. The recombinant proteins were then prepared. Using scrapie strains (263K, 139A, ME7, and S15) as the seeds, the reactivity of the PrP proteins from sheep (rSheepPrP25-234) and pika (rPikaPrP23-230) were tested using real-time quaking-induced conversion (RT-QuIC). Protein misfolding cyclic amplification (PMCA) tests of the brain homogenates from domestic sheep and rabbits were performed with the seeds of strains 263K and ME7. The PRNP genes of bovids were 771 bp long and encoded 256 amino acids (aa), showing 100% homology with the wild-type sheep prion protein (PrP) aa sequence. The PRNP gene of pika was 759 bp long and encoded 252 amino acids, showing 92.1% homology with the aa sequence of domestic rabbits. The sheep and pika proteins revealed positive reactions in 10-5 diluted seeds. Only rPikaPrP23-230 produced positive curves in 10-7 diluted seeds. The PMCA tests failed to produce proteinase K (PK)-resistant PrP (PrPres). This is the first description of PRNP genes and PrP aa sequences of Tibetan antelope, blue sheep, and plateau pike from the Qinghai-Tibet Plateau. In the presence of rodent prions, the PrPs of sheep and pika efficiently induce fibrillation in RT-QuIC, but do not generate PrPres in PMCA. Our results indicate that pika, as one of the important links in the Qinghai-Tibet Plateau biological chain, may play an important role in the prion circulation. Pika PrP deserves further analysis for its potential application value in assays for human prion 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 Main article text Supplementary Material CONFLICTS OF INTEREST REFERENCES Author and article information Comments /*<![CDATA[*/ so_init('toc2', { containerId: 'affc9d0a-6871-bbb6-4922-561f8e5bd832' }); /*]]>*/ Zoonoses Volume 3, Issue 1 RNA-seq Analysis of the BCG Vaccine in a Humanized Mouse Model Novel Clinical and Genomic Signatures of the 2022 Monkeypox Virus A Marked Decline in Taenia solium Taeniasis and Cysticercosis Infections in China: Possible Reasons from the Ecological Determinants Perspective PRNP Sequences of Tibetan Antelope, Blue Sheep, and Plateau Pika from the Qinghai-Tibet Plateau and Reactivity of PrP Proteins to Rodent-Adapted Scrapie Strains in RT-QuIC and PMCA Yersinia pestis and Plague: Some Knowns and Unknowns Global Infectious Diseases in December 2022: Monthly Analysis Identification of Novel Mutations Associated with Bedaquiline Resistance in Mycobacterium Marinum Trypanosoma brucei Lipophosphoglycan Activates Host Immune Responses via the TLR-mediated p38 MAP Kinase and NF-κB Pathways Preparation of Equine Immunoglobulin F(ab′) 2 against Smallpox and Evaluation of its Immunoprotective Effect Global Infectious Diseases in January 2023: Monthly Analysis Effectiveness of Oral Fluid in Pathogenic Surveillance of Acute Respiratory Infection Syncytial and Congregative Effects of Dengue and Zika Viruses on the Aedes Albopictus Cell Line Differ among Viral Strains Global Infectious Diseases in February 2023: Monthly Analysis Corrigendum to: Pattern Recognition Receptors in Innate Immunity to Obligate Intracellular Bacteria The Epidemiology of Circulating Rotavirus Associated with Diarrhea in Egyptian Kids and Calves: A Review The Coordinating Research on Emerging Arboviral Threats Encompassing the Neotropics (CREATE-NEO) Global Infectious Diseases in March 2023: Monthly Analysis Next-Generation Vaccines against COVID-19 Variants: Beyond the Spike Protein Purified Immunoglobulin F(ab′) 2 Protects Mice and Rhesus Monkeys against Lethal Ricin Intoxication Co-circulation, Co-infection of SARS-CoV-2 and Influenza Virus, Where Will it Go? Mild Infections with Multiple Spotted Fever Grouped Rickettsia Species among Forest Rangers with Tick Bites CRISPR-Cas- and Aptamer-based Systems for Diagnosing Pathogens: A Review Roles of Host Phospholipase D during Aspergillus fumigatus Infection in Mice Molecular Epidemiology and the Control and Prevention of Cystic Echinococcosis in China: What is Known from Current Research Global Infectious Diseases in April 2023: Monthly Analysis Successful Treatment of Pasteurella multocida -Related Invasive Infections with a Beta-Lactamase Inhibitor-Sparing Combination Antibiotic Regimen: A Case Series Antimicrobial Resistance in Non-typhoidal Salmonella from Retail Foods Collected in 2020 in China Global Infectious Diseases in May 2023: Monthly Analysis /*<![CDATA[*/ so_init('paginator', { id: 'paginator', itemSelector: '.so-tab-l', selectedSelector: '.so--selected', pageSize: 5 }); /*]]>*/ /*<![CDATA[*/ so_init('floatingPanel', { id: 'ec9a27bd-5d62-3ca3-4c5b-2190ab308591', endId: 'c97ddaf1-ed6a-8e82-4f05-811c7b1b0db0' }) /*]]>*/ Record : found Abstract : found Article : found Is Open Access PRNP Sequences of Tibetan Antelope, Blue Sheep, and Plateau Pika from the Qinghai-Tibet Plateau and Reactivity of PrP Proteins to Rodent-Adapted Scrapie Strains in RT-QuIC and PMCA research-article Author(s): named anchor Yue-Zhang Wu 1 , # , named anchor Jing-Xing Wu 1 , # , named anchor Xue-Hua Yang 1 , named anchor Shan Lu 2 , named anchor Kang Xiao 1 , named anchor Dong-Dong Chen 1 , named anchor Li-Ping Gao 1 , named anchor Qi Shi 1 , 3 , * , , named anchor Jian-Guo Xu 2 , * , , named anchor Xiao-Ping Dong 1 , 3 , 4 , 5 , * , Publication date (Electronic): 18 January 2023 Journal: Zoonoses Publisher: Compuscript Keywords: Tibetan antelope , blue sheep , plateau pika , PRNP , RT-QuIC , PMCA Print Download XML /*<![CDATA[*/ so_init('dropdown', { 'buttonID': "id16", 'dropdownID': "id17" }); /*]]>*/ Review Review article Invite someone to review /*<![CDATA[*/ so_init('dropdown', { 'buttonID': "id18", 'dropdownID': "id19", 'alignment': 'DROPDOWN_END' }); /*]]>*/ Bookmark /*<![CDATA[*/ so_init('dropdown', { 'buttonID': "id1b", 'dropdownID': "id1a" }); /*]]>*/ /*<![CDATA[*/ so_init('dropdown', { 'buttonID': "id1d", 'dropdownID': "id1c" }); /*]]>*/ Share Twitter Sina Weibo Facebook Email /*<![CDATA[*/ so_init('dropdown', { 'buttonID': "id1e", 'dropdownID': "id1f" }); /*]]>*/ Cite as... /*<![CDATA[*/ so_init('cite', {"buttonIds":["id24","stats-cite-qzxl7t"],"exports":[{"name":"BibTex","ext":"bib","url":"./document_citation/4bc81952-d4c5-4de5-8ca4-67b88a10c0eb/BIBTEX"},{"name":"EndNote","ext":"enw","url":"./document_citation/4bc81952-d4c5-4de5-8ca4-67b88a10c0eb/ENDNOTE"},{"name":"Reference Manager (RIS)","ext":"ris","url":"./document_citation/4bc81952-d4c5-4de5-8ca4-67b88a10c0eb/RIS"},{"name":"HTML","ext":"html","url":"./document_citation/4bc81952-d4c5-4de5-8ca4-67b88a10c0eb/HTML"}]}); /*]]>*/ /*<![CDATA[*/ so_init('contentErrorReportButton', { 'id': "78a25ffd-9a6c-8db2-4335-5d209d557970", 'contentId': "4bc81952-d4c5-4de5-8ca4-67b88a10c0eb", 'isWithoutCssClassSoProp': "true" }); /*]]>*/ ?xml version="1.0" encoding="UTF-8"? Abstract named anchor Background: Tibetan antelope ( Rhinopithecus ), blue sheep ( Pseudois nayauris ), and plateau pika ( Ochotona curzoniae ) are wild animals living on the Qinghai-Tibet Plateau. There have been no reports of naturally-occurring transmissible spongioform encephalopathies (TSEs) involving these animals. Furthermore, the PRNP genes have not been described in the literature. named anchor Methods: The PRNP genes from 21 Tibetan antelopes, 4 blue sheep, and 3 plateau pikas were obtained and sequenced. The recombinant proteins were then prepared. Using scrapie strains (263K, 139A, ME7, and S15) as the seeds, the reactivity of the PrP proteins from sheep (rSheepPrP25-234) and pika (rPikaPrP23-230) were tested using real-time quaking-induced conversion (RT-QuIC). Protein misfolding cyclic amplification (PMCA) tests of the brain homogenates from domestic sheep and rabbits were performed with the seeds of strains 263K and ME7. named anchor Results: The PRNP genes of bovids were 771 bp long and encoded 256 amino acids (aa), showing 100% homology with the wild-type sheep prion protein (PrP) aa sequence. The PRNP gene of pika was 759 bp long and encoded 252 amino acids, showing 92.1% homology with the aa sequence of domestic rabbits. The sheep and pika proteins revealed positive reactions in 10 -5 diluted seeds. Only rPikaPrP23-230 produced positive curves in 10 -7 diluted seeds. The PMCA tests failed to produce proteinase K (PK)-resistant PrP (PrP res ). named anchor Conclusion: This is the first description of PRNP genes and PrP aa sequences of Tibetan antelope, blue sheep, and plateau pike from the Qinghai-Tibet Plateau. In the presence of rodent prions, the PrPs of sheep and pika efficiently induce fibrillation in RT-QuIC, but do not generate PrP res in PMCA. Our results indicate that pika, as one of the important links in the Qinghai-Tibet Plateau biological chain, may play an important role in the prion circulation. Pika PrP deserves further analysis for its potential application value in assays for human prion disease. Main article text named anchor INTRODUCTION Prion disease is a type of transmissible spongiform encephalopathy (TSE) that affects a species of mammals, such as, Creutzfeldt-Jacob disease (CJD) in humans, scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, and chronic wasting disease (CWD) in deer [ 1<|im_end|> <|im_start|>assistant Tibetan antelope (Rhinopithecus), blue sheep (Pseudois nayauris), and plateau pika (Ochotona curzoniae) are wild animals living on the Qinghai-Tibet Plateau. There have been no reports of naturally occurring transmissible spongioform encephalopathies (TSEs) involving these animals. Furthermore, the PRNP genes have not been described in the literature. For a study published in Zoonoses, the PRNP genes from 21 Tibetan antelopes, four blue sheep, and three plateau pikas were obtained and sequenced. The recombinant proteins were then prepared. Using scrapie strains (263K, 139A, ME7, and S15) as the seeds, the reactivity of the PrP proteins from sheep (rSheepPrP25-234) and pika (rPikaPrP23-230) were tested using real-time quaking-induced conversion (RT-QuIC). Protein misfolding cyclic amplification (PMCA) tests of the brain homogenates from domestic sheep and rabbits were performed with the seeds of strains 263K and ME7. The PRNP genes of bovids were 771 bp long and encoded 256 amino acids (aa), showing 100% homology with the wild-type sheep prion protein (PrP) aa sequence. The PRNP gene of pika was 759 bp long and encoded 252 amino acids, showing 92.1% homology with the aa sequence of domestic rabbits. The sheep and pika proteins revealed positive reactions in 10-5 diluted seeds. Only rPikaPrP23-230 produced positive curves in 10-7 diluted seeds. The PMCA tests failed to produce proteinase K (PK)-resistant PrP (PrPres). This is the first description of PRNP genes and PrP aa sequences of Tibetan antelope, blue sheep, and plateau pike from the Qinghai-Tibet Plateau. In the presence of rodent prions, the PrPs of sheep and pika efficiently induce fibrillation in RT-QuIC, but do not generate PrPres in PMCA. Our results indicate that pika, as one of the important links in the Qinghai-Tibet Plateau biological chain, may play an important role in the prion circulation. Pika PrP deserves further analysis for its potential application value in assays for human prion disease. <|im_end|>

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84008, 11, 323, 31403, 2933, 393, 11755, 505, 279, 63012, 26279, 9469, 581, 295, 31403, 2933, 323, 3676, 1968, 315, 2394, 47, 15542, 1354, 311, 13611, 306, 12, 2654, 2756, 291, 80185, 648, 4610, 1771, 304, 10860, 12, 2232, 1341, 323, 5975, 5158, 3495, 78505, 7030, 1161, 1680, 7086, 17543, 82131, 11419, 21313, 37230, 220, 16, 1174, 674, 1174, 7086, 17543, 86539, 31650, 287, 37230, 220, 16, 1174, 674, 1174, 7086, 17543, 1630, 361, 11529, 4381, 25482, 220, 16, 1174, 7086, 17543, 60867, 18866, 220, 17, 1174, 7086, 17543, 55376, 66690, 220, 16, 1174, 7086, 17543, 53483, 9607, 647, 25507, 220, 16, 1174, 7086, 17543, 14851, 9483, 287, 480, 3524, 220, 16, 1174, 7086, 17543, 58094, 41804, 220, 16, 1174, 220, 18, 1174, 353, 1174, 1174, 7086, 17543, 88404, 12279, 24012, 57514, 220, 17, 1174, 353, 1174, 1174, 7086, 17543, 66690, 9483, 287, 53483, 220, 16, 1174, 220, 18, 1174, 220, 19, 1174, 220, 20, 1174, 353, 1174, 57994, 2457, 320, 90743, 1680, 220, 972, 6186, 220, 2366, 18, 10139, 25, 1901, 9186, 20274, 40233, 25, 13620, 355, 1250, 56795, 25, 73074, 3276, 82665, 1174, 6437, 33012, 1174, 65388, 281, 11755, 1174, 8743, 27321, 1174, 10860, 12, 2232, 1341, 1174, 5975, 5158, 8377, 8745, 12138, 1416, 77163, 55102, 58, 1850, 779, 6265, 493, 11385, 518, 314, 364, 2208, 926, 1232, 330, 307, 845, 498, 364, 11385, 926, 1232, 330, 307, 1114, 1, 18605, 1416, 120485, 1850, 10506, 10506, 4652, 86023, 4423, 311, 3477, 1416, 77163, 55102, 58, 1850, 779, 6265, 493, 11385, 518, 314, 364, 2208, 926, 1232, 330, 307, 972, 498, 364, 11385, 926, 1232, 330, 307, 777, 498, 364, 45698, 1232, 364, 47727, 23370, 11137, 6, 18605, 1416, 120485, 1850, 56518, 1416, 77163, 55102, 58, 1850, 779, 6265, 493, 11385, 518, 314, 364, 2208, 926, 1232, 330, 307, 16, 65, 498, 364, 11385, 926, 1232, 330, 307, 16, 64, 1, 18605, 1416, 120485, 1850, 1416, 77163, 55102, 58, 1850, 779, 6265, 493, 11385, 518, 314, 364, 2208, 926, 1232, 330, 307, 16, 67, 498, 364, 11385, 926, 1232, 330, 307, 16, 66, 1, 18605, 1416, 120485, 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14, 19, 9081, 18831, 4103, 1773, 19, 66, 20, 12, 19, 451, 20, 12, 23, 936, 19, 12, 3080, 65, 2421, 64, 605, 66, 15, 3141, 19945, 1669, 37609, 609, 3332, 5959, 2247, 428, 3332, 1580, 2247, 1103, 3332, 1761, 6190, 669, 7709, 14, 19, 9081, 18831, 4103, 1773, 19, 66, 20, 12, 19, 451, 20, 12, 23, 936, 19, 12, 3080, 65, 2421, 64, 605, 66, 15, 3141, 14, 5959, 9388, 14316, 1237, 1416, 120485, 1850, 1416, 77163, 55102, 58, 1850, 779, 6265, 493, 1834, 1480, 10577, 1597, 518, 314, 364, 307, 1232, 330, 2495, 64, 914, 73654, 12, 24, 64, 21, 66, 12, 23, 2042, 17, 12, 20153, 20, 12, 20, 67, 12652, 67, 23906, 21133, 498, 364, 1834, 769, 1232, 330, 19, 9081, 18831, 4103, 1773, 19, 66, 20, 12, 19, 451, 20, 12, 23, 936, 19, 12, 3080, 65, 2421, 64, 605, 66, 15, 3141, 498, 364, 285, 27131, 41375, 1999, 4516, 2051, 1232, 330, 1904, 1, 18605, 1416, 120485, 1850, 949, 6591, 2373, 429, 16, 13, 15, 1, 11418, 429, 8729, 12, 23, 44969, 13822, 7086, 17543, 25837, 25, 73074, 3276, 82665, 320, 18452, 258, 454, 275, 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279, 3062, 7902, 304, 279, 63012, 26279, 9469, 581, 295, 31403, 2933, 24156, 8957, 11, 1253, 1514, 459, 3062, 3560, 304, 279, 550, 290, 35855, 13, 393, 11755, 2394, 47, 30675, 4726, 6492, 369, 1202, 4754, 3851, 907, 304, 99592, 369, 3823, 550, 290, 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 Quantized sound waves—phonons—govern the elastic response of crystalline materials, and also play an integral part in determining their thermodynamic properties and electrical response (for example, by binding electrons into superconducting Cooper pairs) 1 , 2 , 3 . The physics of lattice phonons and elasticity is absent in simulators of quantum solids constructed of neutral atoms in periodic light potentials: unlike real solids, traditional optical lattices are silent because they are infinitely stiff 4 . Optical-lattice realizations of crystals therefore lack some of the central dynamical degrees of freedom that determine the low-temperature properties of real materials. Here, we create an optical lattice with phonon modes using a Bose–Einstein condensate (BEC) coupled to a confocal optical resonator. Playing the role of an active quantum gas microscope, the multimode cavity QED system both images the phonons and induces the crystallization that supports phonons via short-range, photon-mediated atom–atom interactions. Dynamical susceptibility measurements reveal the phonon dispersion relation, showing that these collective excitations exhibit a sound speed dependent on the BEC–photon coupling strength. Our results pave the way for exploring the rich physics of elasticity in quantum solids, ranging from quantum melting transitions 5 to exotic ‘fractonic’ topological defects 6 in the quantum regime. Main Ultracold neutral atoms confined in optical lattices have been a fruitful platform for ‘emulating’ the itinerant motion of electrons in crystals 7 . Optical lattices, however, lack a crucial feature of real crystal lattices, which is elasticity. Real crystal lattices vibrate, deform in response to electrons, and transmit stresses; in contrast, optical lattices are non-dynamical. Elasticity has recently seen a revival of interest, motivated by developments such as ‘fracton-elasticity duality’ 6 . While the motion of ions in real crystals is classical, a natural question is how elasticity would change in the presence of strong quantum zero-point motion of the atoms in the crystal; few controlled experimental studies of this regime exist. We realize a system that combines crystalline elasticity with quantum-degenerate motion, in the form of a compliant optical lattice arising from the crystallization of Bose-condensed Rb atoms. While mimicking the effect of phonons in static optical lattices has been proposed 8 , our method yields a continuum of phonon modes akin to those in solid-state materials. Crystallization is the spontaneous breaking of the continuous translational symmetry of space. Due to this symmetry-breaking, a crystal has a manifold of physically distinct equilibrium states, which are related to one another by global translations (that is, by sliding the entire crystal). Global, zero-momentum ( k = 0) translations connect these equilibrium states and cost no free energy. Additionally, crystals with local interactions have a continuum of finite- k modes with arbitrarily low energies: these modes, called phonons, involve locally sliding the crystal by an amount that varies slowly in space with a period 2π/ k . Because global translations cost no energy, while local translations do, a crystal is rigid, and responds globally to local stresses. The phonon excitation branch, which is the Goldstone mode of the broken translational symmetry, governs the elastic properties of crystals. The properties of the phonon branch are intimately tied to those of topological defects, such as dislocations, which have recently been identified as fractonic excitations. In contrast, for symmetry-breaking arising from all-to-all interactions (or other sufficiently long-range interactions), while the k = 0 zero mode may remain in place, there is a gap to all k ≠ 0 excitations. This gives topological defects an extensive energy cost, and thus, in these long-range crystals, any nontrivial elastic response is frozen out. (When the atoms forming a crystal are already Bose-condensed, so that the crystal is a ‘supersolid’, there are additional superfluid Goldstone modes. These superfluid modes are associated with the U (1) phase of the condensate itself and also exist in the absence of a lattice 9 , 10 . Sound propagation and diffusion have been studied with strongly interacting fermions 11 , 12 .) The primarily contact interactions among Rb atoms do not support crystallization. Optical cavity photons, however, can mediate interactions that do support crystallization, as follows. We begin by considering a pump field that is oriented transverse to a Fabry–Pérot cavity axis that is far detuned from all but a single resonance. Above a critical threshold pump strength, a density wave (DW) polariton condensate 13 forms via a superradiant (Hepp–Lieb–Dicke) phase transition: the N intracavity atoms cooperatively scatter pump photons into the cavity, forming a coherent optical state, while concomitantly the atoms adopt one of two chequerboard configurations of the λ /2-period lattice 14 , 15 . This \$\\cos \\,{k}_{r}x\\,\\cos \\,{k}_{r}z\$ lattice is formed by the interference of the pump field with the emergent cavity field. The two-photon scattering process excites the k = 0 BEC into a superposition of \$|{k}_{x},{k}_{z}\\rangle =|\\pm {k}_{r},\\,\\pm {k}_{r}\\rangle \$ momentum modes, where \$\\hat{x}\$ ( \$\\hat{z}\$ ) is the pump (cavity) axis, the pump and cavity fields are of wavelength λ ≈ 780 nm, and k r = 2π/ λ ≈ 8 rad µm −1 is the recoil momentum; \$\\hbar {\\omega }_{r}={\\hbar }^{2}{k}_{r}^{2}/2m\\approx 2{\\rm{\\pi }}\\hbar \\times 3.8\$ kHz is the recoil energy, where \$2{\\rm{\\pi }}\\hbar \$ is Planck’s constant. The state is stable if the pump frequency ω P is red-detuned by ∆ C = ω P − ω C < 0 from the cavity resonance ω C . Such single-mode experiments have enabled the exploration of a variety of quantum collective phenomena 16 , 17 , 18 , 19 , but do not have a continuous translational symmetry and are thus neither rigid nor elastic. A continuous translational symmetry can be restored if one adds a second cavity mode. For example, one emerges from the phase difference of forward- and backward-travelling waves in a ring-cavity geometry 20 , 21 , 22 , 23 , or from the amplitude ratio when crossing two cavities 24 , 25 . In both these cases, this gives rise to a continuous U (1) family of steady states, which can be related by continuous global displacement of the atoms.", "role": "user" }, { "content": "When sound was first incorporated into movies in the 1920s, it opened up new possibilities for filmmakers such as music and spoken dialogue. Physicists may be on the verge of a similar revolution, thanks to a new device developed at Stanford University that promises to bring an audio dimension to previously silent quantum science experiments. In particular, it could bring sound to a common quantum science setup known as an optical lattice, which uses a crisscrossing mesh of laser beams to arrange atoms in an orderly manner resembling a crystal. This tool is commonly used to study the fundamental characteristics of solids and other phases of matter that have repeating geometries. A shortcoming of these lattices, however, is that they are silent. \"Without sound or vibration, we miss a crucial degree of freedom that exists in real materials,\" said Benjamin Lev, associate professor of applied physics and of physics, who set his sights on this issue when he first came to Stanford in 2011. \"It's like making soup and forgetting the salt; it really takes the flavor out of the quantum 'soup.'\" After a decade of engineering and benchmarking, Lev and collaborators from Pennsylvania State University and the University of St. Andrews have produced the first optical lattice of atoms that incorporates sound. The research was published Nov. 11 in Nature. By designing a very precise cavity that held the lattice between two highly reflective mirrors, the researchers made it so the atoms could \"see\" themselves repeated thousands of times via particles of light, or photons, that bounce back and forth between the mirrors. This feedback causes the photons to behave like phonons—the building blocks of sound. \"If it were possible to put your ear to the optical lattice of atoms, you would hear their vibration at around 1 kHz,\" said Lev. A supersolid with sound Previous optical lattice experiments were silent affairs because they lacked the special elasticity of this new system. Lev, young graduate student Sarang Gopalakrishnan—now an assistant professor of physics at Penn State and co-author of the paper—and Paul Goldbart (now provost of Stony Brook University) came up with the foundational theory for this system. But it took collaboration with Jonathan Keeling—a reader at the University of St. Andrews and co-author of the paper—and years of work to build the corresponding device. To create this setup, the researchers filled an empty mirror cavity with an ultracold quantum gas of rubidium. By itself, this is a superfluid, which is a phase of matter in which atoms can flow in swirls without resistance. When exposed to light, the rubidium superfluid spontaneously rearranges into a supersolid—a rare phase of matter that simultaneously displays the order seen in crystals and the extraordinary fluidity of superfluids. A view of the cavity inside a vacuum chamber, where the two ultra-reflective mirrors are visible at the top and bottom. Credit: Lev Lab What brought sound to the cavity were two carefully spaced concave mirrors that are so reflective that there is a fraction of 1 percent chance that a single photon would pass through them. That reflectivity and the specific geometry of the setup—the radius of the curved mirrors is equal to the distance between them—causes the photons pumped into the cavity to pass by the atoms more than 10,000 times. In doing so, the photons form a special tight bond with the atoms, forcing them to arrange as a lattice. \"The cavity we use provides a lot more flexibility in terms of the shape of the light that bounces back and forth between the mirrors,\" said Lev. \"It's as if, instead of just being allowed to make a single wave in a trough of water, you can now splash about to make any sort of wave pattern.\" This special cavity allowed the lattice of superfluid atoms (the supersolid) to move about so that, unlike other optical lattices, it is free to distort when poked—and that creates sound waves. To initiate this launch of phonons through the flexible lattice, the researchers poked it using an instrument called a spatial light modulator, which enables them to program different patterns in the light they inject into the cavity. The researchers assessed how this affected the contents of the cavity by capturing a hologram of the light that made its way out. The hologram records both the light wave's amplitude and phase, allowing phonons to be imaged. In addition to mediating interesting physics, the high curvature of the mirrors inside the device produces a high-resolution image, like a microscope, which led the researchers to name their creation an \"active quantum gas microscope.\" Graduate student and lead author Yudan Guo, who received a Q-FARM fellowship to support this work, led the effort to confirm the presence of phonons in the device, which was done by sending in different patterns of light, measuring what came out and comparing that to a Goldstone dispersion curve. This curve shows how energy, including sound, is expected to move through crystals; the fact that their findings matched it confirmed both the existence of phonons and the vibrating supersolid state. Two-of-a-kind There are many directions that Lev hopes his lab—and perhaps others—will take this invention, including studying the physics of exotic superconductors and the creation of quantum neural networks—which is why the team is already working to create a second version of their device. \"Open up a canonical textbook of solid-state physics, and you see a large portion has to do with phonons,\" said Lev. \"And, up until now, we couldn't study anything built upon that with quantum simulators employing atoms and photons because we couldn't emulate this basic form of sound.\" Stanford graduate students Ronen Kroeze and Brendan Marsh are also co-authors of this 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 Quantized sound waves—phonons—govern the elastic response of crystalline materials, and also play an integral part in determining their thermodynamic properties and electrical response (for example, by binding electrons into superconducting Cooper pairs) 1 , 2 , 3 . The physics of lattice phonons and elasticity is absent in simulators of quantum solids constructed of neutral atoms in periodic light potentials: unlike real solids, traditional optical lattices are silent because they are infinitely stiff 4 . Optical-lattice realizations of crystals therefore lack some of the central dynamical degrees of freedom that determine the low-temperature properties of real materials. Here, we create an optical lattice with phonon modes using a Bose–Einstein condensate (BEC) coupled to a confocal optical resonator. Playing the role of an active quantum gas microscope, the multimode cavity QED system both images the phonons and induces the crystallization that supports phonons via short-range, photon-mediated atom–atom interactions. Dynamical susceptibility measurements reveal the phonon dispersion relation, showing that these collective excitations exhibit a sound speed dependent on the BEC–photon coupling strength. Our results pave the way for exploring the rich physics of elasticity in quantum solids, ranging from quantum melting transitions 5 to exotic ‘fractonic’ topological defects 6 in the quantum regime. Main Ultracold neutral atoms confined in optical lattices have been a fruitful platform for ‘emulating’ the itinerant motion of electrons in crystals 7 . Optical lattices, however, lack a crucial feature of real crystal lattices, which is elasticity. Real crystal lattices vibrate, deform in response to electrons, and transmit stresses; in contrast, optical lattices are non-dynamical. Elasticity has recently seen a revival of interest, motivated by developments such as ‘fracton-elasticity duality’ 6 . While the motion of ions in real crystals is classical, a natural question is how elasticity would change in the presence of strong quantum zero-point motion of the atoms in the crystal; few controlled experimental studies of this regime exist. We realize a system that combines crystalline elasticity with quantum-degenerate motion, in the form of a compliant optical lattice arising from the crystallization of Bose-condensed Rb atoms. While mimicking the effect of phonons in static optical lattices has been proposed 8 , our method yields a continuum of phonon modes akin to those in solid-state materials. Crystallization is the spontaneous breaking of the continuous translational symmetry of space. Due to this symmetry-breaking, a crystal has a manifold of physically distinct equilibrium states, which are related to one another by global translations (that is, by sliding the entire crystal). Global, zero-momentum ( k = 0) translations connect these equilibrium states and cost no free energy. Additionally, crystals with local interactions have a continuum of finite- k modes with arbitrarily low energies: these modes, called phonons, involve locally sliding the crystal by an amount that varies slowly in space with a period 2π/ k . Because global translations cost no energy, while local translations do, a crystal is rigid, and responds globally to local stresses. The phonon excitation branch, which is the Goldstone mode of the broken translational symmetry, governs the elastic properties of crystals. The properties of the phonon branch are intimately tied to those of topological defects, such as dislocations, which have recently been identified as fractonic excitations. In contrast, for symmetry-breaking arising from all-to-all interactions (or other sufficiently long-range interactions), while the k = 0 zero mode may remain in place, there is a gap to all k ≠ 0 excitations. This gives topological defects an extensive energy cost, and thus, in these long-range crystals, any nontrivial elastic response is frozen out. (When the atoms forming a crystal are already Bose-condensed, so that the crystal is a ‘supersolid’, there are additional superfluid Goldstone modes. These superfluid modes are associated with the U (1) phase of the condensate itself and also exist in the absence of a lattice 9 , 10 . Sound propagation and diffusion have been studied with strongly interacting fermions 11 , 12 .) The primarily contact interactions among Rb atoms do not support crystallization. Optical cavity photons, however, can mediate interactions that do support crystallization, as follows. We begin by considering a pump field that is oriented transverse to a Fabry–Pérot cavity axis that is far detuned from all but a single resonance. Above a critical threshold pump strength, a density wave (DW) polariton condensate 13 forms via a superradiant (Hepp–Lieb–Dicke) phase transition: the N intracavity atoms cooperatively scatter pump photons into the cavity, forming a coherent optical state, while concomitantly the atoms adopt one of two chequerboard configurations of the λ /2-period lattice 14 , 15 . This $\cos \,{k}_{r}x\,\cos \,{k}_{r}z$ lattice is formed by the interference of the pump field with the emergent cavity field. The two-photon scattering process excites the k = 0 BEC into a superposition of $|{k}_{x},{k}_{z}\rangle =|\pm {k}_{r},\,\pm {k}_{r}\rangle $ momentum modes, where $\hat{x}$ ( $\hat{z}$ ) is the pump (cavity) axis, the pump and cavity fields are of wavelength λ ≈ 780 nm, and k r = 2π/ λ ≈ 8 rad µm −1 is the recoil momentum; $\hbar {\omega }_{r}={\hbar }^{2}{k}_{r}^{2}/2m\approx 2{\rm{\pi }}\hbar \times 3.8$ kHz is the recoil energy, where $2{\rm{\pi }}\hbar $ is Planck’s constant. The state is stable if the pump frequency ω P is red-detuned by ∆ C = ω P − ω C < 0 from the cavity resonance ω C . Such single-mode experiments have enabled the exploration of a variety of quantum collective phenomena 16 , 17 , 18 , 19 , but do not have a continuous translational symmetry and are thus neither rigid nor elastic. A continuous translational symmetry can be restored if one adds a second cavity mode. For example, one emerges from the phase difference of forward- and backward-travelling waves in a ring-cavity geometry 20 , 21 , 22 , 23 , or from the amplitude ratio when crossing two cavities 24 , 25 . In both these cases, this gives rise to a continuous U (1) family of steady states, which can be related by continuous global displacement of the atoms.<|im_end|> <|im_start|>assistant When sound was first incorporated into movies in the 1920s, it opened up new possibilities for filmmakers such as music and spoken dialogue. Physicists may be on the verge of a similar revolution, thanks to a new device developed at Stanford University that promises to bring an audio dimension to previously silent quantum science experiments. In particular, it could bring sound to a common quantum science setup known as an optical lattice, which uses a crisscrossing mesh of laser beams to arrange atoms in an orderly manner resembling a crystal. This tool is commonly used to study the fundamental characteristics of solids and other phases of matter that have repeating geometries. A shortcoming of these lattices, however, is that they are silent. "Without sound or vibration, we miss a crucial degree of freedom that exists in real materials," said Benjamin Lev, associate professor of applied physics and of physics, who set his sights on this issue when he first came to Stanford in 2011. "It's like making soup and forgetting the salt; it really takes the flavor out of the quantum 'soup.'" After a decade of engineering and benchmarking, Lev and collaborators from Pennsylvania State University and the University of St. Andrews have produced the first optical lattice of atoms that incorporates sound. The research was published Nov. 11 in Nature. By designing a very precise cavity that held the lattice between two highly reflective mirrors, the researchers made it so the atoms could "see" themselves repeated thousands of times via particles of light, or photons, that bounce back and forth between the mirrors. This feedback causes the photons to behave like phonons—the building blocks of sound. "If it were possible to put your ear to the optical lattice of atoms, you would hear their vibration at around 1 kHz," said Lev. A supersolid with sound Previous optical lattice experiments were silent affairs because they lacked the special elasticity of this new system. Lev, young graduate student Sarang Gopalakrishnan—now an assistant professor of physics at Penn State and co-author of the paper—and Paul Goldbart (now provost of Stony Brook University) came up with the foundational theory for this system. But it took collaboration with Jonathan Keeling—a reader at the University of St. Andrews and co-author of the paper—and years of work to build the corresponding device. To create this setup, the researchers filled an empty mirror cavity with an ultracold quantum gas of rubidium. By itself, this is a superfluid, which is a phase of matter in which atoms can flow in swirls without resistance. When exposed to light, the rubidium superfluid spontaneously rearranges into a supersolid—a rare phase of matter that simultaneously displays the order seen in crystals and the extraordinary fluidity of superfluids. A view of the cavity inside a vacuum chamber, where the two ultra-reflective mirrors are visible at the top and bottom. Credit: Lev Lab What brought sound to the cavity were two carefully spaced concave mirrors that are so reflective that there is a fraction of 1 percent chance that a single photon would pass through them. That reflectivity and the specific geometry of the setup—the radius of the curved mirrors is equal to the distance between them—causes the photons pumped into the cavity to pass by the atoms more than 10,000 times. In doing so, the photons form a special tight bond with the atoms, forcing them to arrange as a lattice. "The cavity we use provides a lot more flexibility in terms of the shape of the light that bounces back and forth between the mirrors," said Lev. "It's as if, instead of just being allowed to make a single wave in a trough of water, you can now splash about to make any sort of wave pattern." This special cavity allowed the lattice of superfluid atoms (the supersolid) to move about so that, unlike other optical lattices, it is free to distort when poked—and that creates sound waves. To initiate this launch of phonons through the flexible lattice, the researchers poked it using an instrument called a spatial light modulator, which enables them to program different patterns in the light they inject into the cavity. The researchers assessed how this affected the contents of the cavity by capturing a hologram of the light that made its way out. The hologram records both the light wave's amplitude and phase, allowing phonons to be imaged. In addition to mediating interesting physics, the high curvature of the mirrors inside the device produces a high-resolution image, like a microscope, which led the researchers to name their creation an "active quantum gas microscope." Graduate student and lead author Yudan Guo, who received a Q-FARM fellowship to support this work, led the effort to confirm the presence of phonons in the device, which was done by sending in different patterns of light, measuring what came out and comparing that to a Goldstone dispersion curve. This curve shows how energy, including sound, is expected to move through crystals; the fact that their findings matched it confirmed both the existence of phonons and the vibrating supersolid state. Two-of-a-kind There are many directions that Lev hopes his lab—and perhaps others—will take this invention, including studying the physics of exotic superconductors and the creation of quantum neural networks—which is why the team is already working to create a second version of their device. "Open up a canonical textbook of solid-state physics, and you see a large portion has to do with phonons," said Lev. "And, up until now, we couldn't study anything built upon that with quantum simulators employing atoms and photons because we couldn't emulate this basic form of sound." Stanford graduate students Ronen Kroeze and Brendan Marsh are also co-authors of this research. <|im_end|>

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2,644

[ { "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 Electromagnetic momentum carried by light is observable through the mechanical effects radiation pressure exerts on illuminated objects. Momentum conversion from electromagnetic fields to elastic waves within a solid object proceeds through a string of electrodynamic and elastodynamic phenomena, collectively bound by momentum and energy continuity. The details of this conversion predicted by theory have yet to be validated by experiments, as it is difficult to distinguish displacements driven by momentum from those driven by heating due to light absorption. Here, we have measured temporal variations of the surface displacements induced by laser pulses reflected from a solid dielectric mirror. Ab initio modelling of momentum flow describes the transfer of momentum from the electromagnetic field to the dielectric mirror, with subsequent creation/propagation of multicomponent elastic waves. Complete consistency between predictions and absolute measurements of surface displacements offers compelling evidence of elastic transients driven predominantly by the momentum of light. Introduction Over a century ago, it was predicted by Maxwell in 1873 1 and Bartoli in 1876 2 that radiation pressure exists due to momentum residing in electromagnetic fields. The simplest illustration of radiation pressure is the classic case of a short plane-wave light pulse normally incident onto a flat, perfectly reflective, motionless slab. The pulse carries finite momentum in its electromagnetic fields and, upon reflection from the slab, must impart a normal mechanical momentum that is twice the incident pulse momentum to conserve total momentum. In the ideal case of a rigid slab, the normal mechanical momentum is instantaneously distributed throughout the slab and the slab moves uniformly at constant velocity along the incident pulse trajectory. In the realistic case of a deformable slab, the normal mechanical momentum is transported throughout the slab by elastic waves travelling at finite velocities. If the pulse has a finite cross-section, the pulse edges also induce elastic waves that transport a shear mechanical momentum component perpendicular to the incident pulse trajectory. Momentum-carrying elastic waves are the fundamental mechanism by which radiation pressure manifests in deformable media and play an important role in applications such as optical tweezers in soft matter 3 , 4 , 5 , 6 , 7 , 8 , 9 . Radiation-pressure-driven elastic waves have been recently detected in solids 10 . The physical origin of these waves was validated by agreement of measured amplitudes with a simple one-dimensional model and consistency of propagation velocity with time-of-flight predictions. In addition to amplitude and velocity, the shape of radiation-pressure-driven elastic waves gives rich insights into light–matter interaction, which could potentially be used to differentiate various theoretical formulations describing light-matter coupling. To fully understand elastic waveform features, the physics underlying their creation and propagation must be modelled and then compared to a measurable quantity, such as the material displacement induced by these transient waves. Displacements associated with these elastic waves propagate at acoustic velocities and have peak amplitudes of the order of picometers. Experimental measurement of elastic wave propagation on absolute scales requires fast (>1 MHz bandwidth), sensitive (~10 fm resolution), and well-calibrated surface displacement detection. Even with adequate temporal and spatial resolution, isolation of momentum-driven elastic waves is difficult due to the presence of absorption-driven thermoelastic waves 11 , which are typically the dominant elastic wave component created during light–matter interaction. Therefore, definitive measurement of momentum-driven elastic waves requires absorption mitigation to reduce thermoelastic wave contributions and a means of tracing different elastic wave components to either absorption or momentum transfer. Thermoelastic wave components and momentum-driven elastic wave components can be modelled from first principles. The latter is complicated by the existence of multiple electrodynamic theories that describe the spatial distribution of normal and shear force densities in differing ways 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , an ongoing debate related to the Abraham–Minkowski controversy 27 , 28 . The most-used electrodynamic theories are the Abraham, Minkowski, Einstein-Laub, Chu, and Amperian formulations 21 , 22 . Using these theories in conjunction with elastodynamic theory, it is possible to simulate the shape, amplitude, and speed of momentum-driven elastic waves using the elastic properties of the medium and the properties of the incident light (i.e., without fitting parameters). Comparison between absolute surface displacement measurements and simulated displacements based on first principles provides a highly rigorous, yet unexplored, method to correlate the elastic waves in an illuminated object to the electromagnetic momentum delivered by incident light. In this paper, we have measured elastic waves driven predominantly by the momentum of light. We use an experimental configuration in which a solid-state dielectric mirror is illuminated by short laser pulses from air, generating transient elastic waves detected as ripples on the surface of the mirror. The use of a solid-state medium enables the design of a near-perfect mirror with minimal absorption at the frequency of the incident pulse. The elastic wave amplitudes generated on solids are smaller than those previously measured in liquids 29 , 30 , 31 , but are easier to interpret due to negligible redistribution of matter and insignificant effects of the gravitational and surface tension forces 32 . Elastic waves are captured using a piezoelectric detection method that measures surface displacement at various positions adjacent to the site of pulse reflection. Displacements have been measured with sufficient spatial (1 mm lateral and 40 fm vertical) and temporal (0.2 μs) resolution to visualize elastic wave propagation. To determine the origin of the measured waveforms, we use ab initio modelling of momentum deposition 20 , 21 and material deformation 11 , 33 . Predicted waveforms match the shape and amplitude of those measured in the experiments. The amplitude of the measured waveforms can be primarily attributed to radiation pressure, since the thermoelastic contribution to the displacements is within the uncertainty of the whole measurement chain. This work provides a method to quantitatively measure momentum coupling between electromagnetic fields and matter, which can be applied to characterize materials and to further advance optical", "role": "user" }, { "content": "The idea that light has momentum is not new, but the exact nature of how light interacts with matter has remained a mystery for close to 150 years. New research from UBC's Okanagan campus, recently published in Nature Communications, may have uncovered the key to one of the darkest secrets of light. Johannes Kepler, famed German astronomer and mathematician, first suggested in 1619 that pressure from sunlight could be responsible for a comet's tail always pointing away from the Sun, says study co-author and UBC Okanagan engineering professor Kenneth Chau. It wasn't until 1873 that James Clerk Maxwell predicted that this radiation pressure was due to the momentum residing within the electromagnetic fields of light itself. \"Until now, we hadn't determined how this momentum is converted into force or movement,\" says Chau. \"Because the amount of momentum carried by light is very small, we haven't had equipment sensitive enough to solve this.\" Now, technology has caught up and Chau, with his international research team from Slovenia and Brazil, are shedding light on this mystery. To measure these extremely weak interactions between light photons, the team constructed a special mirror fitted with acoustic sensors and heat shielding to keep interference and background noise to a minimum. They then shot laser pulses at the mirror and used the sound sensors to detect elastic waves as they moved across the surface of the mirror, like watching ripples on a pond. \"We can't directly measure photon momentum, so our approach was to detect its effect on a mirror by 'listening' to the elastic waves that traveled through it,\" says Chau. \"We were able to trace the features of those waves back to the momentum residing in the light pulse itself, which opens the door to finally defining and modelling how light momentum exists inside materials.\" The discovery is important in advancing our fundamental understanding of light, but Chau also points to practical applications of radiation pressure. \"Imagine travelling to distant stars on interstellar yachts powered by solar sails,\" says Chau. \"Or perhaps, here on Earth, developing optical tweezers that could assemble microscopic machines.\" \"We're not there yet, but the discovery in this work is an important step and I'm excited to see where it takes us next.\" ", "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 Electromagnetic momentum carried by light is observable through the mechanical effects radiation pressure exerts on illuminated objects. Momentum conversion from electromagnetic fields to elastic waves within a solid object proceeds through a string of electrodynamic and elastodynamic phenomena, collectively bound by momentum and energy continuity. The details of this conversion predicted by theory have yet to be validated by experiments, as it is difficult to distinguish displacements driven by momentum from those driven by heating due to light absorption. Here, we have measured temporal variations of the surface displacements induced by laser pulses reflected from a solid dielectric mirror. Ab initio modelling of momentum flow describes the transfer of momentum from the electromagnetic field to the dielectric mirror, with subsequent creation/propagation of multicomponent elastic waves. Complete consistency between predictions and absolute measurements of surface displacements offers compelling evidence of elastic transients driven predominantly by the momentum of light. Introduction Over a century ago, it was predicted by Maxwell in 1873 1 and Bartoli in 1876 2 that radiation pressure exists due to momentum residing in electromagnetic fields. The simplest illustration of radiation pressure is the classic case of a short plane-wave light pulse normally incident onto a flat, perfectly reflective, motionless slab. The pulse carries finite momentum in its electromagnetic fields and, upon reflection from the slab, must impart a normal mechanical momentum that is twice the incident pulse momentum to conserve total momentum. In the ideal case of a rigid slab, the normal mechanical momentum is instantaneously distributed throughout the slab and the slab moves uniformly at constant velocity along the incident pulse trajectory. In the realistic case of a deformable slab, the normal mechanical momentum is transported throughout the slab by elastic waves travelling at finite velocities. If the pulse has a finite cross-section, the pulse edges also induce elastic waves that transport a shear mechanical momentum component perpendicular to the incident pulse trajectory. Momentum-carrying elastic waves are the fundamental mechanism by which radiation pressure manifests in deformable media and play an important role in applications such as optical tweezers in soft matter 3 , 4 , 5 , 6 , 7 , 8 , 9 . Radiation-pressure-driven elastic waves have been recently detected in solids 10 . The physical origin of these waves was validated by agreement of measured amplitudes with a simple one-dimensional model and consistency of propagation velocity with time-of-flight predictions. In addition to amplitude and velocity, the shape of radiation-pressure-driven elastic waves gives rich insights into light–matter interaction, which could potentially be used to differentiate various theoretical formulations describing light-matter coupling. To fully understand elastic waveform features, the physics underlying their creation and propagation must be modelled and then compared to a measurable quantity, such as the material displacement induced by these transient waves. Displacements associated with these elastic waves propagate at acoustic velocities and have peak amplitudes of the order of picometers. Experimental measurement of elastic wave propagation on absolute scales requires fast (>1 MHz bandwidth), sensitive (~10 fm resolution), and well-calibrated surface displacement detection. Even with adequate temporal and spatial resolution, isolation of momentum-driven elastic waves is difficult due to the presence of absorption-driven thermoelastic waves 11 , which are typically the dominant elastic wave component created during light–matter interaction. Therefore, definitive measurement of momentum-driven elastic waves requires absorption mitigation to reduce thermoelastic wave contributions and a means of tracing different elastic wave components to either absorption or momentum transfer. Thermoelastic wave components and momentum-driven elastic wave components can be modelled from first principles. The latter is complicated by the existence of multiple electrodynamic theories that describe the spatial distribution of normal and shear force densities in differing ways 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , an ongoing debate related to the Abraham–Minkowski controversy 27 , 28 . The most-used electrodynamic theories are the Abraham, Minkowski, Einstein-Laub, Chu, and Amperian formulations 21 , 22 . Using these theories in conjunction with elastodynamic theory, it is possible to simulate the shape, amplitude, and speed of momentum-driven elastic waves using the elastic properties of the medium and the properties of the incident light (i.e., without fitting parameters). Comparison between absolute surface displacement measurements and simulated displacements based on first principles provides a highly rigorous, yet unexplored, method to correlate the elastic waves in an illuminated object to the electromagnetic momentum delivered by incident light. In this paper, we have measured elastic waves driven predominantly by the momentum of light. We use an experimental configuration in which a solid-state dielectric mirror is illuminated by short laser pulses from air, generating transient elastic waves detected as ripples on the surface of the mirror. The use of a solid-state medium enables the design of a near-perfect mirror with minimal absorption at the frequency of the incident pulse. The elastic wave amplitudes generated on solids are smaller than those previously measured in liquids 29 , 30 , 31 , but are easier to interpret due to negligible redistribution of matter and insignificant effects of the gravitational and surface tension forces 32 . Elastic waves are captured using a piezoelectric detection method that measures surface displacement at various positions adjacent to the site of pulse reflection. Displacements have been measured with sufficient spatial (1 mm lateral and 40 fm vertical) and temporal (0.2 μs) resolution to visualize elastic wave propagation. To determine the origin of the measured waveforms, we use ab initio modelling of momentum deposition 20 , 21 and material deformation 11 , 33 . Predicted waveforms match the shape and amplitude of those measured in the experiments. The amplitude of the measured waveforms can be primarily attributed to radiation pressure, since the thermoelastic contribution to the displacements is within the uncertainty of the whole measurement chain. This work provides a method to quantitatively measure momentum coupling between electromagnetic fields and matter, which can be applied to characterize materials and to further advance optical<|im_end|> <|im_start|>assistant The idea that light has momentum is not new, but the exact nature of how light interacts with matter has remained a mystery for close to 150 years. New research from UBC's Okanagan campus, recently published in Nature Communications, may have uncovered the key to one of the darkest secrets of light. Johannes Kepler, famed German astronomer and mathematician, first suggested in 1619 that pressure from sunlight could be responsible for a comet's tail always pointing away from the Sun, says study co-author and UBC Okanagan engineering professor Kenneth Chau. It wasn't until 1873 that James Clerk Maxwell predicted that this radiation pressure was due to the momentum residing within the electromagnetic fields of light itself. "Until now, we hadn't determined how this momentum is converted into force or movement," says Chau. "Because the amount of momentum carried by light is very small, we haven't had equipment sensitive enough to solve this." Now, technology has caught up and Chau, with his international research team from Slovenia and Brazil, are shedding light on this mystery. To measure these extremely weak interactions between light photons, the team constructed a special mirror fitted with acoustic sensors and heat shielding to keep interference and background noise to a minimum. They then shot laser pulses at the mirror and used the sound sensors to detect elastic waves as they moved across the surface of the mirror, like watching ripples on a pond. "We can't directly measure photon momentum, so our approach was to detect its effect on a mirror by 'listening' to the elastic waves that traveled through it," says Chau. "We were able to trace the features of those waves back to the momentum residing in the light pulse itself, which opens the door to finally defining and modelling how light momentum exists inside materials." The discovery is important in advancing our fundamental understanding of light, but Chau also points to practical applications of radiation pressure. "Imagine travelling to distant stars on interstellar yachts powered by solar sails," says Chau. "Or perhaps, here on Earth, developing optical tweezers that could assemble microscopic machines." "We're not there yet, but the discovery in this work is an important step and I'm excited to see where it takes us next." <|im_end|>

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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 social difficulties of autism spectrum disorder (ASD) are typically explained as a disruption in the Shared Attention Mechanism (SAM) sub-component of the theory of mind (ToM) system. In the current paper, we explore the hypothesis that SAM’s capacity to construct the self-other-object relations necessary for shared-attention arises from a self-categorization process, which is weaker among those with more autistic-like traits. We present participants with self-categorization and shared-attention tasks, and measure their autism-spectrum quotient (AQ). Results reveal a negative relationship between AQ and shared-attention, via self-categorization, suggesting a role for self-categorization in the disruption in SAM seen in ASD. Implications for intervention, and for a ToM model in which weak central coherence plays a role are discussed. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction The social difficulties of autism spectrum disorder (ASD) are typically explained as outcomes of disruption in the ‘theory of mind’ (ToM) system, particularly of the Shared Attention Mechanism (SAM; Baron-Cohen 2005 ). Disruption in SAM inhibits individuals from sharing attention with others, which further impairs downstream abilities in other ToM domains, resulting in the social difficulties on which diagnosis is based. Although it is descriptively well-elaborated in Baron-Cohen’s ( 2005 ) Empathizing System Model, the cognitive underpinnings of SAM’s representational capacities are not well understood. In the current paper, we hypothesize that SAM relies fundamentally on the cognitive process of self-categorization (Turner et al. 1987 ) for its proper functioning, and that disruption of this process explains the difficulties in shared attention seen on the autism spectrum. We further suggest that understanding self-categorization as the cognitive mechanism underlying SAM could lead to a more unified model of ASD, in which weak central coherence (WCC) has a role to play in the ToM difficulties. The social impairments of ASD have traditionally been understood as a deficit in the ToM system (Baron-Cohen et al. 1985 ). Baron-Cohen ( 2005 ) suggests that the ToM system is composed of six modules, which develop at different developmental periods. The Intentionality Detector (ID), The Emotion Detector (TED), and the Eye Direction Detector (EDD) develop in early infancy. Maturation of these modules supports the development, in later infancy, of the Shared Attention Mechanism (SAM). The development of SAM further enables the emergence, in early childhood, of The Empathizing SyStem (TESS), and the Theory of Mind Mechanism (ToMM). In a typically developing individual, these modules function as an interconnected system, enabling him or her to represent, feel, infer, and interpret the mental, emotional and behavioral states of others, and thus to function in a socially adaptive manner. However, in people with ASD the functioning of SAM is thought to be disrupted. This prevents shared attention behaviors from arising, and constrains development of the person’s ability to represent the mental states of others and to function adaptively in social interactions. According to Baron-Cohen ( 2005 ), SAM’s primary contribution to the ToM system is to build triadic representations of self, other, and object. These triadic representations allow a perceiver to determine if his or her attention and that of another perceiver are directed towards the same event or physical object. As a function of this sharing of attention, typically developing children will gradually come to share their experiences with, and learn from, others, through joint attention behaviors such as gaze monitoring (Loveland and Landry 1986 ) and proto-declarative pointing (Baron-Cohen 1989 ). In children with ASD, on the other hand, these joint attention behaviours appear to be impaired (Mastrogiuseppe et al. 2015 ; Mundy 2016 ), and this impairment is known to be predictive of later dysfunction in other ToM domains (Mundy et al. 1994 ; Sodian and Kristen-Antonow 2015 ), and in social functioning (Brooks and Meltzoff 2015 ; Mundy 1995 ). This body of work provides a well-elaborated account of the functions of SAM and the consequences of its functions being diminished. Nevertheless, the precise cognitive mechanism responsible for the emergence and construction of self-other-object representations is not well understood. Typically, models of shared attention focus on understanding the cognitive mechanisms that underpin joint attention behaviors , rather than elaborating on the processes involved in producing triadic representations. Edwards, Stephenson, Dalmaso and Bayliss ( 2015 ), for example, propose the existence of a cognitive mechanism that allows a perceiver to respond to the gaze-following behavior of others. Similarly, Mundy and Newell ( 2007 ) suggest that the joint attention behaviors of responding to joint attention and initiating joint attention rely on the domain-general posterior perceptual and the anterior volitional attention systems, respectively. These are important findings that chart the developmental trajectory of the antecedents of joint attention behaviors, particularly gaze monitoring, gestural communication, and general attention. However, they do not resolve the specific issue of how the cognitive system combines self, other and object into the useable and context-specific triadic representations necessary for shared attention. Importantly, though, this gap has recently been addressed by theorizing in social psychology. Shteynberg ( 2015 ) suggests that shared attention arises from a psychological ‘shared-attention state’, which he defines as “the perception of in-the-moment attention to an object from a first-person-plural perspective” (581pp.). Footnote 1 The shared-attention state is therefore a triadic representation of self, other, and object, where self and other have become merged into a psychological “we-mode” (e.g., Searle 1995 ). The “we-mode”—also commonly referred to as a social identity (Tajfel and Turner 1979 )—itself emerges when a perceiver becomes aware that relationally close or socially equivalent others are synchronously co-attending to a stimulus. Importantly, the extent to which others are perceived to be socially equivalent is a function of the well-elaborated cognitive process of self-categorization (Turner et al. 1987 ). In short, by recognizing the importance of (1) social identity to shared attention, and (2) self-categorization to social identity, Shteynberg’s ( 2015 ) shared-attention state model provides a plausible cognitive process to explain how SAM constructs triadic representations. At the broadest level, self-categorization is the process of using social categories (e.g., age, gender", "role": "user" }, { "content": "Research by The University of Queensland may provide a better understanding of the social functioning difficulties of people with autism. A study led by UQ School of Psychology researcher Dr Daniel Skorich has shown a relationship between features of autism spectrum disorder (ASD) that were previously thought to be unrelated. \"Autism is a multi-faceted disorder characterised by distinct clusters of features,\" Dr Skorich said. \"One of these clusters relates to the ability to share attention with others, and to focus attention on the objects or events on which someone else is focused. People with ASD show a decreased tendency to do this. \"A second cluster is related to information processing, where people with ASD process information in a less integrated manner, referred to as 'weak central coherence'. \"Our research suggests that weak central coherence actually causes the shared attention difficulties. \"We found that the information processing needed for self-categorisation—the process of coming to see oneself as interchangeable with other members of groups to which we belong—is weaker the more autistic-like traits a person possesses, which in turn predicts the decreased tendency to share attention. \"So it seems that the decreased tendency to see oneself as part of a group is at the heart of the differences people with ASD show in their social interactions with others.\" Dr Skorich said the research had implications for intervention. \"By linking ASD with self-categorisation, our research suggests that a social cure perspective on health and well-being, such as UQ's Groups 4 Health program, could be adapted to treat the much higher rates of anxiety and depression seen in people with ASD,\" he said. Groups 4 Health, designed to help people develop, enhance and maintain their group-based social identification, has been shown to be effective in treating several mental health conditions. Dr Skorich said UQ's Secret Agent Society social skills program for children aged eight to 12 also could be useful. The research is published in the Journal of Autism and Developmental Disorders. ", "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 social difficulties of autism spectrum disorder (ASD) are typically explained as a disruption in the Shared Attention Mechanism (SAM) sub-component of the theory of mind (ToM) system. In the current paper, we explore the hypothesis that SAM’s capacity to construct the self-other-object relations necessary for shared-attention arises from a self-categorization process, which is weaker among those with more autistic-like traits. We present participants with self-categorization and shared-attention tasks, and measure their autism-spectrum quotient (AQ). Results reveal a negative relationship between AQ and shared-attention, via self-categorization, suggesting a role for self-categorization in the disruption in SAM seen in ASD. Implications for intervention, and for a ToM model in which weak central coherence plays a role are discussed. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction The social difficulties of autism spectrum disorder (ASD) are typically explained as outcomes of disruption in the ‘theory of mind’ (ToM) system, particularly of the Shared Attention Mechanism (SAM; Baron-Cohen 2005 ). Disruption in SAM inhibits individuals from sharing attention with others, which further impairs downstream abilities in other ToM domains, resulting in the social difficulties on which diagnosis is based. Although it is descriptively well-elaborated in Baron-Cohen’s ( 2005 ) Empathizing System Model, the cognitive underpinnings of SAM’s representational capacities are not well understood. In the current paper, we hypothesize that SAM relies fundamentally on the cognitive process of self-categorization (Turner et al. 1987 ) for its proper functioning, and that disruption of this process explains the difficulties in shared attention seen on the autism spectrum. We further suggest that understanding self-categorization as the cognitive mechanism underlying SAM could lead to a more unified model of ASD, in which weak central coherence (WCC) has a role to play in the ToM difficulties. The social impairments of ASD have traditionally been understood as a deficit in the ToM system (Baron-Cohen et al. 1985 ). Baron-Cohen ( 2005 ) suggests that the ToM system is composed of six modules, which develop at different developmental periods. The Intentionality Detector (ID), The Emotion Detector (TED), and the Eye Direction Detector (EDD) develop in early infancy. Maturation of these modules supports the development, in later infancy, of the Shared Attention Mechanism (SAM). The development of SAM further enables the emergence, in early childhood, of The Empathizing SyStem (TESS), and the Theory of Mind Mechanism (ToMM). In a typically developing individual, these modules function as an interconnected system, enabling him or her to represent, feel, infer, and interpret the mental, emotional and behavioral states of others, and thus to function in a socially adaptive manner. However, in people with ASD the functioning of SAM is thought to be disrupted. This prevents shared attention behaviors from arising, and constrains development of the person’s ability to represent the mental states of others and to function adaptively in social interactions. According to Baron-Cohen ( 2005 ), SAM’s primary contribution to the ToM system is to build triadic representations of self, other, and object. These triadic representations allow a perceiver to determine if his or her attention and that of another perceiver are directed towards the same event or physical object. As a function of this sharing of attention, typically developing children will gradually come to share their experiences with, and learn from, others, through joint attention behaviors such as gaze monitoring (Loveland and Landry 1986 ) and proto-declarative pointing (Baron-Cohen 1989 ). In children with ASD, on the other hand, these joint attention behaviours appear to be impaired (Mastrogiuseppe et al. 2015 ; Mundy 2016 ), and this impairment is known to be predictive of later dysfunction in other ToM domains (Mundy et al. 1994 ; Sodian and Kristen-Antonow 2015 ), and in social functioning (Brooks and Meltzoff 2015 ; Mundy 1995 ). This body of work provides a well-elaborated account of the functions of SAM and the consequences of its functions being diminished. Nevertheless, the precise cognitive mechanism responsible for the emergence and construction of self-other-object representations is not well understood. Typically, models of shared attention focus on understanding the cognitive mechanisms that underpin joint attention behaviors , rather than elaborating on the processes involved in producing triadic representations. Edwards, Stephenson, Dalmaso and Bayliss ( 2015 ), for example, propose the existence of a cognitive mechanism that allows a perceiver to respond to the gaze-following behavior of others. Similarly, Mundy and Newell ( 2007 ) suggest that the joint attention behaviors of responding to joint attention and initiating joint attention rely on the domain-general posterior perceptual and the anterior volitional attention systems, respectively. These are important findings that chart the developmental trajectory of the antecedents of joint attention behaviors, particularly gaze monitoring, gestural communication, and general attention. However, they do not resolve the specific issue of how the cognitive system combines self, other and object into the useable and context-specific triadic representations necessary for shared attention. Importantly, though, this gap has recently been addressed by theorizing in social psychology. Shteynberg ( 2015 ) suggests that shared attention arises from a psychological ‘shared-attention state’, which he defines as “the perception of in-the-moment attention to an object from a first-person-plural perspective” (581pp.). Footnote 1 The shared-attention state is therefore a triadic representation of self, other, and object, where self and other have become merged into a psychological “we-mode” (e.g., Searle 1995 ). The “we-mode”—also commonly referred to as a social identity (Tajfel and Turner 1979 )—itself emerges when a perceiver becomes aware that relationally close or socially equivalent others are synchronously co-attending to a stimulus. Importantly, the extent to which others are perceived to be socially equivalent is a function of the well-elaborated cognitive process of self-categorization (Turner et al. 1987 ). In short, by recognizing the importance of (1) social identity to shared attention, and (2) self-categorization to social identity, Shteynberg’s ( 2015 ) shared-attention state model provides a plausible cognitive process to explain how SAM constructs triadic representations. At the broadest level, self-categorization is the process of using social categories (e.g., age, gender<|im_end|> <|im_start|>assistant Research by The University of Queensland may provide a better understanding of the social functioning difficulties of people with autism. A study led by UQ School of Psychology researcher Dr Daniel Skorich has shown a relationship between features of autism spectrum disorder (ASD) that were previously thought to be unrelated. "Autism is a multi-faceted disorder characterised by distinct clusters of features," Dr Skorich said. "One of these clusters relates to the ability to share attention with others, and to focus attention on the objects or events on which someone else is focused. People with ASD show a decreased tendency to do this. "A second cluster is related to information processing, where people with ASD process information in a less integrated manner, referred to as 'weak central coherence'. "Our research suggests that weak central coherence actually causes the shared attention difficulties. "We found that the information processing needed for self-categorisation—the process of coming to see oneself as interchangeable with other members of groups to which we belong—is weaker the more autistic-like traits a person possesses, which in turn predicts the decreased tendency to share attention. "So it seems that the decreased tendency to see oneself as part of a group is at the heart of the differences people with ASD show in their social interactions with others." Dr Skorich said the research had implications for intervention. "By linking ASD with self-categorisation, our research suggests that a social cure perspective on health and well-being, such as UQ's Groups 4 Health program, could be adapted to treat the much higher rates of anxiety and depression seen in people with ASD," he said. Groups 4 Health, designed to help people develop, enhance and maintain their group-based social identification, has been shown to be effective in treating several mental health conditions. Dr Skorich said UQ's Secret Agent Society social skills program for children aged eight to 12 also could be useful. The research is published in the Journal of Autism and Developmental Disorders. <|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 Bias in clinical practice, in particular in relation to race and gender, is a persistent cause of healthcare disparities. We investigated the potential of a peer-network approach to reduce bias in medical treatment decisions within an experimental setting. We created “egalitarian” information exchange networks among practicing clinicians who provided recommendations for the clinical management of patient scenarios, presented via standardized patient videos of actors portraying patients with cardiac chest pain. The videos, which were standardized for relevant clinical factors, presented either a white male actor or Black female actor of similar age, wearing the same attire and in the same clinical setting, portraying a patient with clinically significant chest pain symptoms. We found significant disparities in the treatment recommendations given to the white male patient-actor and Black female patient-actor, which when translated into real clinical scenarios would result in the Black female patient being significantly more likely to receive unsafe undertreatment, rather than the guideline-recommended treatment. In the experimental control group, clinicians who were asked to independently reflect on the standardized patient videos did not show any significant reduction in bias. However, clinicians who exchanged real-time information in structured peer networks significantly improved their clinical accuracy and showed no bias in their final recommendations. The findings indicate that clinician network interventions might be used in healthcare settings to reduce significant disparities in patient treatment. Introduction Bias is an enduring cause of healthcare disparities by race and gender 1 , 2 , 3 , 4 , 5 , 6 , 7 . Previous experimental work demonstrated that clinicians reviewing video-based vignettes of high-risk patients with chest pain disproportionately referred men compared to women, and white patients compared to Black patients for the guideline-recommended treatment, cardiac catheterization 1 , 7 . Proposed solutions for addressing bias have focused on cognitive strategies that increase clinicians’ awareness of their own biases 6 , 8 , 9 , 10 , 11 . However, no approaches have yet been found that successfully reduce race and gender bias in clinical treatment recommendations 6 , 10 . Recent research in non-clinical settings has shown that information exchange in large social networks with uniform—i.e. egalitarian 12 —connectivity can be effective for improving collective intelligence in both health-related and non-health-related risk assessments 13 , 14 , 15 , 16 . Studies of bias reduction in partisan networks 15 , 16 have found that this process of collective learning in egalitarian networks can effectively reduce, and even eliminate longstanding political biases in the evaluation of novel information 16 . Here, we integrate this recent work on bias reduction in egalitarian information-exchange networks with theoretical research on medical reasoning 17 , 18 , 19 , which has argued that improving the accuracy of clinicians’ diagnostic assessments should improve the quality of their treatment recommendations 19 , 20 , 21 . We hypothesize that creating structured information-exchange networks among clinicians will lead to improved clinical assessments that may be effective for reducing observed patterns of race and gender bias in clinical treatment recommendations 13 , 14 . Despite the broad practical 2 , 3 , 4 and scientific 1 , 5 , 6 , 7 importance of understanding and addressing bias in medical settings, it has not been possible to evaluate this hypothesis because such a test requires the ability to experimentally isolate and measure the direct effects of clinical networks on reducing medical bias and treatment disparities. We adopted an experimental approach to evaluate whether large, uniform information-exchange networks among clinicians 13 , 14 , 15 , 16 might significantly reduce observed race and gender bias in clinicians’ treatment recommendations, relative to a control group of independent clinicians who did not participate in information-exchange networks. We recruited 840 practicing clinicians (see Supplementary Information for details) to participate in the online video-based study, which was administered through a proprietary mobile app for clinicians. Each clinician viewed a standardized patient video of either a white male patient-actor or Black female patient-actor, and provided clinical assessments and treatment recommendations for the depicted clinical case (see SI, Supplementary Fig. 5 and Supplementary Fig. 6 ). Both the white male and Black female “patients” in the videos were portrayed by professional actors who appeared 65 years old, were dressed in identical attire, and depicted a patient with clinically significant chest pain symptoms. The actors portraying each patient followed a single script, in which they provided an identical clinical history that included several risk factors for coronary artery disease (age, hyperlipidemia, and discomfort with exertion). Both videos were accompanied by an identical electrocardiogram exhibit showing abnormalities. (Hereafter, we refer to the patient-actors in the standardized patient videos as “patients”.) After viewing the patient video, clinicians were asked to provide their initial clinical assessments and treatment recommendations. Clinical assessments took the form of a probability estimate (from 0 to 100) of the patient’s chance of having a major adverse cardiac event within the next 30 days. The most accurate assessment based on the patient’s HEART score is 16% 22 , 23 . (Additional analyses show the robustness of our findings across a range of assessment values. See SI “Sensitivity Analyses”, Supplementary Fig. 9 and Supplementary Fig. 10 ). Clinicians then selected a single treatment recommendation from four multiple choice options: Option A. daily 81 mg aspirin and return to clinic in one week (i.e. unsafe undertreatment); Option B. daily 81 mg aspirin and stress test within two to three days (i.e. undertreatment); Option C. full-dose aspirin and referral to emergency department for evaluation and monitoring (i.e. highest quality, guideline-recommended treatment); or Option D. full-dose aspirin and referral to cardiology for urgent cardiac catheterization (i.e. overtreatment in the context of unconfirmed diagnosis). Option C is the most appropriate treatment based on currently accepted guidelines from the American College of Cardiology 23 , 24 and represents the highest standard of care 22 , 23 . (In consideration of the fact that some clinicians may choose a less aggressive initial strategy in a patient with atypical symptoms, we conducted sensitivity analyses", "role": "user" }, { "content": "A University of Pennsylvania study published today in Nature Communications offers striking evidence that network science can be used to remove race and gender bias in clinical settings. The study, led by Professor Damon Centola of the Annenberg School for Communication and the School of Engineering and Applied Science, offers an effective new way to ensure safer, more equitable health care for women and minorities through managing clinician peer networks. Using an experimental design, researchers showed that clinicians who initially exhibited significant race and gender bias in their treatment of a clinical case, could be influenced to change their clinical recommendations to exhibit no bias. \"We found that by changing the structure of information-sharing networks among clinicians, we could change doctors' biased perceptions of their patients' clinical information,\" says Centola, who also directs the Network Dynamics Group at the Annenberg School and is a Senior Fellow of Health Economics at the Leonard Davis Institute. \"Put simply, doctors tend to think differently in networks than they do when they are alone.\" In the experiment, the researchers asked 840 clinicians to watch a video of a patient giving a clinical history detailing risk factors for heart disease. Half of the clinicians saw a white male actor portraying the patient, while the other half saw a Black female actor. The videos were otherwise identical. Clinicians then chose one of four treatment recommendations based on the patient's information: an unsafe option, an under-treatment option, the correct guideline-recommended option, or an over-treatment option. Initial results showed the Black female patient was 49% more likely than the white male patient to be sent home. Conversely, the white male patient was 78% more likely than the Black female patient to be referred to the emergency department. The results reinforced a well-documented fact of American health care: extensive race and gender bias in medicine. To mitigate these outcomes, the clinicians were then divided into two conditions: an experimental condition and a control condition. The control groups watched the video alone, with no input from other participants and had the opportunity to revise their recommendations. The control groups showed no change in medical bias. In the experimental condition, the clinicians were connected into large, anonymous peer networks with 40 other clinicians. Each participant was able to see the evaluations made by network peers and had an opportunity to change their recommendations. The peer network effects were remarkable. Not only did the networks lead to improved clinical accuracy, but they eliminated treatment disparities from clinicians' recommendations, resulting in the white male patient and Black female patient receiving the guideline-recommended care at the same rate. \"We tend to think of doctors making rational decisions based on medical evidence,\" says Centola, \"but medical bias is often rooted in professional norms. Altering clinicians' networks can change these norms, leading to higher-quality treatment recommendations for minority patients.\" Strikingly, the findings also revealed that the network approach to bias-reduction improved the quality of care for everyone. Researchers found that the rate of over-treatment—for example, recommending an unnecessary, invasive procedure—increased for both patients in the control groups, while it significantly decreased for both patients in the experimental groups. The rising prevalence of telemedicine and online clinical support networks offers a promising opportunity for new information-sharing technologies to support clinical decision-making. This network approach to eliminating bias may also be implemented in other medical settings that are known to exhibit significant race and gender disparities, from childbirth and acute pain management to mental health and urgent care decisions for COVID-19 related illness. \"Using network technologies to improve health care is the future of medicine,\" Centola says. \"Our next step is working with hospital systems to implement effective peer-networking programs across the country.\" ", "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 Bias in clinical practice, in particular in relation to race and gender, is a persistent cause of healthcare disparities. We investigated the potential of a peer-network approach to reduce bias in medical treatment decisions within an experimental setting. We created “egalitarian” information exchange networks among practicing clinicians who provided recommendations for the clinical management of patient scenarios, presented via standardized patient videos of actors portraying patients with cardiac chest pain. The videos, which were standardized for relevant clinical factors, presented either a white male actor or Black female actor of similar age, wearing the same attire and in the same clinical setting, portraying a patient with clinically significant chest pain symptoms. We found significant disparities in the treatment recommendations given to the white male patient-actor and Black female patient-actor, which when translated into real clinical scenarios would result in the Black female patient being significantly more likely to receive unsafe undertreatment, rather than the guideline-recommended treatment. In the experimental control group, clinicians who were asked to independently reflect on the standardized patient videos did not show any significant reduction in bias. However, clinicians who exchanged real-time information in structured peer networks significantly improved their clinical accuracy and showed no bias in their final recommendations. The findings indicate that clinician network interventions might be used in healthcare settings to reduce significant disparities in patient treatment. Introduction Bias is an enduring cause of healthcare disparities by race and gender 1 , 2 , 3 , 4 , 5 , 6 , 7 . Previous experimental work demonstrated that clinicians reviewing video-based vignettes of high-risk patients with chest pain disproportionately referred men compared to women, and white patients compared to Black patients for the guideline-recommended treatment, cardiac catheterization 1 , 7 . Proposed solutions for addressing bias have focused on cognitive strategies that increase clinicians’ awareness of their own biases 6 , 8 , 9 , 10 , 11 . However, no approaches have yet been found that successfully reduce race and gender bias in clinical treatment recommendations 6 , 10 . Recent research in non-clinical settings has shown that information exchange in large social networks with uniform—i.e. egalitarian 12 —connectivity can be effective for improving collective intelligence in both health-related and non-health-related risk assessments 13 , 14 , 15 , 16 . Studies of bias reduction in partisan networks 15 , 16 have found that this process of collective learning in egalitarian networks can effectively reduce, and even eliminate longstanding political biases in the evaluation of novel information 16 . Here, we integrate this recent work on bias reduction in egalitarian information-exchange networks with theoretical research on medical reasoning 17 , 18 , 19 , which has argued that improving the accuracy of clinicians’ diagnostic assessments should improve the quality of their treatment recommendations 19 , 20 , 21 . We hypothesize that creating structured information-exchange networks among clinicians will lead to improved clinical assessments that may be effective for reducing observed patterns of race and gender bias in clinical treatment recommendations 13 , 14 . Despite the broad practical 2 , 3 , 4 and scientific 1 , 5 , 6 , 7 importance of understanding and addressing bias in medical settings, it has not been possible to evaluate this hypothesis because such a test requires the ability to experimentally isolate and measure the direct effects of clinical networks on reducing medical bias and treatment disparities. We adopted an experimental approach to evaluate whether large, uniform information-exchange networks among clinicians 13 , 14 , 15 , 16 might significantly reduce observed race and gender bias in clinicians’ treatment recommendations, relative to a control group of independent clinicians who did not participate in information-exchange networks. We recruited 840 practicing clinicians (see Supplementary Information for details) to participate in the online video-based study, which was administered through a proprietary mobile app for clinicians. Each clinician viewed a standardized patient video of either a white male patient-actor or Black female patient-actor, and provided clinical assessments and treatment recommendations for the depicted clinical case (see SI, Supplementary Fig. 5 and Supplementary Fig. 6 ). Both the white male and Black female “patients” in the videos were portrayed by professional actors who appeared 65 years old, were dressed in identical attire, and depicted a patient with clinically significant chest pain symptoms. The actors portraying each patient followed a single script, in which they provided an identical clinical history that included several risk factors for coronary artery disease (age, hyperlipidemia, and discomfort with exertion). Both videos were accompanied by an identical electrocardiogram exhibit showing abnormalities. (Hereafter, we refer to the patient-actors in the standardized patient videos as “patients”.) After viewing the patient video, clinicians were asked to provide their initial clinical assessments and treatment recommendations. Clinical assessments took the form of a probability estimate (from 0 to 100) of the patient’s chance of having a major adverse cardiac event within the next 30 days. The most accurate assessment based on the patient’s HEART score is 16% 22 , 23 . (Additional analyses show the robustness of our findings across a range of assessment values. See SI “Sensitivity Analyses”, Supplementary Fig. 9 and Supplementary Fig. 10 ). Clinicians then selected a single treatment recommendation from four multiple choice options: Option A. daily 81 mg aspirin and return to clinic in one week (i.e. unsafe undertreatment); Option B. daily 81 mg aspirin and stress test within two to three days (i.e. undertreatment); Option C. full-dose aspirin and referral to emergency department for evaluation and monitoring (i.e. highest quality, guideline-recommended treatment); or Option D. full-dose aspirin and referral to cardiology for urgent cardiac catheterization (i.e. overtreatment in the context of unconfirmed diagnosis). Option C is the most appropriate treatment based on currently accepted guidelines from the American College of Cardiology 23 , 24 and represents the highest standard of care 22 , 23 . (In consideration of the fact that some clinicians may choose a less aggressive initial strategy in a patient with atypical symptoms, we conducted sensitivity analyses<|im_end|> <|im_start|>assistant A University of Pennsylvania study published today in Nature Communications offers striking evidence that network science can be used to remove race and gender bias in clinical settings. The study, led by Professor Damon Centola of the Annenberg School for Communication and the School of Engineering and Applied Science, offers an effective new way to ensure safer, more equitable health care for women and minorities through managing clinician peer networks. Using an experimental design, researchers showed that clinicians who initially exhibited significant race and gender bias in their treatment of a clinical case, could be influenced to change their clinical recommendations to exhibit no bias. "We found that by changing the structure of information-sharing networks among clinicians, we could change doctors' biased perceptions of their patients' clinical information," says Centola, who also directs the Network Dynamics Group at the Annenberg School and is a Senior Fellow of Health Economics at the Leonard Davis Institute. "Put simply, doctors tend to think differently in networks than they do when they are alone." In the experiment, the researchers asked 840 clinicians to watch a video of a patient giving a clinical history detailing risk factors for heart disease. Half of the clinicians saw a white male actor portraying the patient, while the other half saw a Black female actor. The videos were otherwise identical. Clinicians then chose one of four treatment recommendations based on the patient's information: an unsafe option, an under-treatment option, the correct guideline-recommended option, or an over-treatment option. Initial results showed the Black female patient was 49% more likely than the white male patient to be sent home. Conversely, the white male patient was 78% more likely than the Black female patient to be referred to the emergency department. The results reinforced a well-documented fact of American health care: extensive race and gender bias in medicine. To mitigate these outcomes, the clinicians were then divided into two conditions: an experimental condition and a control condition. The control groups watched the video alone, with no input from other participants and had the opportunity to revise their recommendations. The control groups showed no change in medical bias. In the experimental condition, the clinicians were connected into large, anonymous peer networks with 40 other clinicians. Each participant was able to see the evaluations made by network peers and had an opportunity to change their recommendations. The peer network effects were remarkable. Not only did the networks lead to improved clinical accuracy, but they eliminated treatment disparities from clinicians' recommendations, resulting in the white male patient and Black female patient receiving the guideline-recommended care at the same rate. "We tend to think of doctors making rational decisions based on medical evidence," says Centola, "but medical bias is often rooted in professional norms. Altering clinicians' networks can change these norms, leading to higher-quality treatment recommendations for minority patients." Strikingly, the findings also revealed that the network approach to bias-reduction improved the quality of care for everyone. Researchers found that the rate of over-treatment—for example, recommending an unnecessary, invasive procedure—increased for both patients in the control groups, while it significantly decreased for both patients in the experimental groups. The rising prevalence of telemedicine and online clinical support networks offers a promising opportunity for new information-sharing technologies to support clinical decision-making. This network approach to eliminating bias may also be implemented in other medical settings that are known to exhibit significant race and gender disparities, from childbirth and acute pain management to mental health and urgent care decisions for COVID-19 related illness. "Using network technologies to improve health care is the future of medicine," Centola says. "Our next step is working with hospital systems to implement effective peer-networking programs across the country." <|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 Antibiotics are used to fight pathogens but also target commensal bacteria, disturbing the composition of gut microbiota and causing dysbiosis and disease 1 . Despite this well-known collateral damage, the activity spectrum of different antibiotic classes on gut bacteria remains poorly characterized. Here we characterize further 144 antibiotics from a previous screen of more than 1,000 drugs on 38 representative human gut microbiome species 2 . Antibiotic classes exhibited distinct inhibition spectra, including generation dependence for quinolones and phylogeny independence for β-lactams. Macrolides and tetracyclines, both prototypic bacteriostatic protein synthesis inhibitors, inhibited nearly all commensals tested but also killed several species. Killed bacteria were more readily eliminated from in vitro communities than those inhibited. This species-specific killing activity challenges the long-standing distinction between bactericidal and bacteriostatic antibiotic classes and provides a possible explanation for the strong effect of macrolides on animal 3 , 4 , 5 and human 6 , 7 gut microbiomes. To mitigate this collateral damage of macrolides and tetracyclines, we screened for drugs that specifically antagonized the antibiotic activity against abundant Bacteroides species but not against relevant pathogens. Such antidotes selectively protected Bacteroides species from erythromycin treatment in human-stool-derived communities and gnotobiotic mice. These findings illluminate the activity spectra of antibiotics in commensal bacteria and suggest strategies to circumvent their adverse effects on the gut microbiota. Main Medication is emerging as a major factor influencing the composition of the human gut microbiota 2 , 8 , 9 , 10 . Although the role of non-antibiotic drugs has been, until recently, unappreciated 2 , 10 , 11 , antibiotics developed to have broad-spectum activities are known to also directly affect gut microbiota. As consequence, they cause many gastrointestinal side effects 12 , including Clostridioides difficile infections. This collateral damage of antibiotics on the gut microbiota has recently received more attention. In vivo studies have highlighted links between antibiotic-induced long-term microbiota changes and various allergic, metabolic, immunological and inflammatory malfunctions 3 , 4 , 5 , 6 , 7 , 13 , 14 . However, technical difficulties hamper routine testing of antibiotic susceptibility in anaerobic bacteria 15 , and available data on bacterial susceptibility to antibiotics offer minimal resolution on human gut bacteria 16 . Information is missing even for common or disease-associated 17 , 18 gut species. In addition, animal or cohort studies use few antibiotics or merge data on different antibiotic classes, precluding systematic conclusions on antibiotic collateral damage on gut commensals. We previously assessed the direct effect of 1,197 pharmaceuticals on the growth of 38 prevalent and abundant human-gut-derived bacterial species at a concentration of 20 µM (ref. 2 ). A single wild-type strain was used per species, except for Escherichia coli and Bacteroides fragilis , for which two strains were screened (Supplementary Table 1 ); unless otherwise mentioned, these are also the strains used here when referring to the species. This initial screen (hereafter called ‘screen’) included 144 antibiotics with discernible class-dependent effects on gut bacteria (Fig. 1a , Extended Data Fig. 1 , Supplementary Table 2 ). We validated these results by measuring 815 minimal inhibitory concentrations (MICs) for up to 33 antibiotics and two antifungals across 16 strains from the screen and 11 additional ones to account better for intra- and interspecies variation within the Bacteroides genus (Extended Data Fig. 2 , Supplementary Tables 3 , 4 ). Despite experimental differences, the screen exhibited high specificity and sensitivity when benchmarked against the MIC data (Extended Data Fig. 3a ). The measured MICs also correlated well with the limited available data on antimicrobial susceptibility from EUCAST 16 or ChEMBL 19 ( r s = 0.70 and r s = 0.64; n = 77 and n = 132, respectively), despite differences in strains and media used (Extended Data Fig. 3b ). Importantly, this dataset expands the available MICs, up to 75% for non-pathogenic bacteria (Fig. 1b , Extended Data Fig. 3c ). Altogether, the screen and MIC dataset provide high-resolution information on the target spectrum of antibiotics on commensal bacteria. Fig 1: Activity spectrum of antibiotic classes on human gut commensals. a , Overview of antibiotics tested in initial screen at 20 µM concentration 2 and validated by MIC determination in this study. b , Comparison of measured MICs (dark grey) to available ones from public databases (light grey). Shaded areas represent the overlap. Species are classified as ‘common’ if they are present in the gut microbiome of more than 1% of 727 healthy individuals. c , MICs of drug–species pairs per antibiotic class (colour scheme as in a ) are depicted next to EUCAST clinical (susceptibility) breakpoints for pathogens. Numbers of drug–species pairs (MICs; coloured) and antibiotic per class (EUCAST clinical breakpoints; black) are shown in parentheses. Boxes span the interquartile range (IQR), and whiskers extend to the most extreme data points up to a maximum of 1.5× IQR. The y axis is log 2 scale. Source data Full size image Antibiotic classes exhibited distinct behaviours (Extended Data Fig. 4a ). For example, quinolones acted according to their generation. First-generation variants were effective against few bacterial species; second- and third-generation quinolones had broader activity; and fourth-generation variants (developed to increase activity against anaerobes) inhibited almost all tested species (Extended Data Fig. 4b ). For β-lactams, resistance was phylogenetically patchy, which was corroborated by additional data collected for Bacteroides strains and species (Extended Data Figs. 2 , 4c–e ). β-Lactam sensitivity and phylogenetic relatedness within the Bacteroides genus were uncoupled (Extended Data Fig. 4e ). This implies that β-lactam resistance mechanisms are strain specific and horizontally transferred. Macrolides showed a strong effect on gut commensals and inhibited all tested microorganisms (Extended Data Fig. 4a ), except for C . difficile , which was resistant to macrolides and clindamycin (Extended Data Fig. 2 , red box), consistent with the known risk of C . difficile infection after macrolide or clindamycin treatment 20 . Finally, 8 out of 9 tested tetracyclines inhibited nearly all tested species, which is surprising because the gut microbiota has been considered", "role": "user" }, { "content": "Antibiotics cure bacterial infections and save millions of lives each year. But they can also harm the helpful microbes residing in the gut, weakening one of the body's first lines of defense against pathogens and compromising the multiple beneficial effects our microbiota has for our health. Common side effects of this collateral damage of antibiotics are gastrointestinal problems and recurrent Clostridioides difficile infections. They also include long-term health problems, such as the development of allergic, metabolic, immunological or inflammatory diseases. Researchers from the Typas group at EMBL Heidelberg, the Maier lab at the Cluster of Excellence \"Controlling Microbes to Fight Infections' at the University of Tübingen, and collaborators have analyzed the effects of 144 antibiotics on our most common gut microbes. The study published in the journal Nature substantially improves our understanding of antibiotics' effects on gut microbes. It also suggests a new approach to mitigating the adverse effects of antibiotics therapy on the gut microbiome. The human gut harbors an intricate community of different microbial species as well as many viruses, collectively referred to as the gut microbiome. Together, they enable us to use nutrients more efficiently and hinder pathogenic bacteria from settling in our gut. However, when we treat a bacterial infection with antibiotics, there's a risk of damaging the gut microbiome. \"Many antibiotics inhibit the growth of various pathogenic bacteria. This broad activity spectrum is useful when treating infections, but it increases the risk that the microbes in our gut are targeted as well,\" explained Lisa Maier, DFG Emmy Noether group leader at the University of Tübingen. Maier is an alumna of the Typas lab and one of the two lead authors of the study. If certain gut bacteria are harmed more than others, antibiotics therapy can lead to an imbalance in our microbiota composition, commonly referred to as dysbiosis. Diarrhea is a common short-term effect, while allergic conditions such as asthma or food allergies and obesity are possible long-term consequences. The fact that antibiotics are also active against gut microbes has been known for a long time, but their effects on the large diversity of microbes we carry in our gut had not yet been studied systematically, mostly due to technical challenges. \"So far, our knowledge of the effects of different antibiotics on individual members of our gut microbial communities has been patchy. Our study fills major gaps in our understanding of which type of antibiotic affects which types of bacteria, and in what way,\" said Nassos Typas, Senior Scientist and Group Leader at EMBL Heidelberg. Building on a previous study from EMBL's Typas, Bork, Patil, and Zeller groups, the scientists observed how each of the 144 antibiotics affected the growth and survival of up to 27 bacterial strains commonly inhabiting our guts. The researchers determined the concentrations at which a given antibiotic would affect these bacterial strains for more than 800 antibiotic–strain combinations, expanding existing datasets on antibiotic spectra in gut bacterial species by 75 percent. Importantly, the experiments revealed that tetracyclines and macrolides—two commonly used antibiotics families—not only stopped bacteria from growing, but also lead to their death. About half of the tested gut strains did not survive treatment with these types of antibiotics. \"We didn't expect to see this effect with tetracyclines and macrolides, as these antibiotic classes were considered to have only bacteriostatic effects—which means that they stop bacterial growth, but don't kill bacteria,\" said Camille Goemans, a postdoctoral fellow in the Typas group who shares first authorship with Maier. \"Our experiments show that this assumption is not true for about half of the gut microbes we studied. Doxycycline, erythromycin, and azithromycin, three commonly used antibiotics, killed several abundant gut microbial species, whereas others they just inhibited.\" The selective killing of specific microbes by tetracyclines and macrolides could lead to these microbes being inadvertently lost from the gut microbiota much faster than microbes for which growth is only inhibited, as the authors showed with synthetic microbial communities. This could explain the strong microbiota shifts that some patients being treated with these antibiotics witness. There is a way of reducing the damage, though. \"We have shown before that drugs interact differently across different bacterial species. We therefore explored whether a second drug could mask the harmful effects of antibiotics on abundant gut microbes, but allow antibiotics to retain their activity against pathogens. This would provide something like an antidote, which would reduce the collateral damage of antibiotics on gut bacteria,\" explained Typas. The scientists combined the antibiotics erythromycin or doxycycline with a set of nearly 1,200 pharmaceuticals, to identify drugs that would save two abundant gut bacterial species from the antibiotic. Indeed, the researchers identified several non-antibiotic drugs that could rescue these gut microbes and other related species. Importantly, the combination of an antibiotic with a protective second drug did not compromise the antibiotics' efficacy against pathogenic bacteria. Follow-up experiments indicated that this approach may be working in the context of a natural microbiome as well. With help from collaborators, the scientists showed that the combination of erythromycin with an antidote mitigated the loss of certain abundant gut bacterial species from the mouse gut. Similarly, antidote drugs protected human gut microbes from erythromycin in complex bacterial communities derived from stool samples. \"Our approach that combines antibiotics with a protective antidote could open new opportunities for reducing the harmful side effects of antibiotics on our gut microbiomes,\" concluded Maier. \"No single antidote will be able to protect all the bacteria in our gut—especially since those differ so much across individuals. But this concept opens up the door for developing new personalized strategies to keep our gut microbes healthy.\" Further research will be needed to identify the optimal combinations, dosing, and formulations for antidotes, and to exclude potential long-term effects on the gut microbiome. In the future, the new approach may help to keep our gut microbiome healthy and reduce antibiotics' side effects in patients, without compromising the efficiency of our antibiotics as lifesavers. The study was a collaborative effort, involving researchers from EMBL's Typas, Bork, Zeller, Zimmermann, and Patil groups, as well as colleagues at the University of Tübingen, Ludwig-Maximilians-Universität München, and the Max Delbrück Center for Molecular Medicine in Berlin. ", "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 Antibiotics are used to fight pathogens but also target commensal bacteria, disturbing the composition of gut microbiota and causing dysbiosis and disease 1 . Despite this well-known collateral damage, the activity spectrum of different antibiotic classes on gut bacteria remains poorly characterized. Here we characterize further 144 antibiotics from a previous screen of more than 1,000 drugs on 38 representative human gut microbiome species 2 . Antibiotic classes exhibited distinct inhibition spectra, including generation dependence for quinolones and phylogeny independence for β-lactams. Macrolides and tetracyclines, both prototypic bacteriostatic protein synthesis inhibitors, inhibited nearly all commensals tested but also killed several species. Killed bacteria were more readily eliminated from in vitro communities than those inhibited. This species-specific killing activity challenges the long-standing distinction between bactericidal and bacteriostatic antibiotic classes and provides a possible explanation for the strong effect of macrolides on animal 3 , 4 , 5 and human 6 , 7 gut microbiomes. To mitigate this collateral damage of macrolides and tetracyclines, we screened for drugs that specifically antagonized the antibiotic activity against abundant Bacteroides species but not against relevant pathogens. Such antidotes selectively protected Bacteroides species from erythromycin treatment in human-stool-derived communities and gnotobiotic mice. These findings illluminate the activity spectra of antibiotics in commensal bacteria and suggest strategies to circumvent their adverse effects on the gut microbiota. Main Medication is emerging as a major factor influencing the composition of the human gut microbiota 2 , 8 , 9 , 10 . Although the role of non-antibiotic drugs has been, until recently, unappreciated 2 , 10 , 11 , antibiotics developed to have broad-spectum activities are known to also directly affect gut microbiota. As consequence, they cause many gastrointestinal side effects 12 , including Clostridioides difficile infections. This collateral damage of antibiotics on the gut microbiota has recently received more attention. In vivo studies have highlighted links between antibiotic-induced long-term microbiota changes and various allergic, metabolic, immunological and inflammatory malfunctions 3 , 4 , 5 , 6 , 7 , 13 , 14 . However, technical difficulties hamper routine testing of antibiotic susceptibility in anaerobic bacteria 15 , and available data on bacterial susceptibility to antibiotics offer minimal resolution on human gut bacteria 16 . Information is missing even for common or disease-associated 17 , 18 gut species. In addition, animal or cohort studies use few antibiotics or merge data on different antibiotic classes, precluding systematic conclusions on antibiotic collateral damage on gut commensals. We previously assessed the direct effect of 1,197 pharmaceuticals on the growth of 38 prevalent and abundant human-gut-derived bacterial species at a concentration of 20 µM (ref. 2 ). A single wild-type strain was used per species, except for Escherichia coli and Bacteroides fragilis , for which two strains were screened (Supplementary Table 1 ); unless otherwise mentioned, these are also the strains used here when referring to the species. This initial screen (hereafter called ‘screen’) included 144 antibiotics with discernible class-dependent effects on gut bacteria (Fig. 1a , Extended Data Fig. 1 , Supplementary Table 2 ). We validated these results by measuring 815 minimal inhibitory concentrations (MICs) for up to 33 antibiotics and two antifungals across 16 strains from the screen and 11 additional ones to account better for intra- and interspecies variation within the Bacteroides genus (Extended Data Fig. 2 , Supplementary Tables 3 , 4 ). Despite experimental differences, the screen exhibited high specificity and sensitivity when benchmarked against the MIC data (Extended Data Fig. 3a ). The measured MICs also correlated well with the limited available data on antimicrobial susceptibility from EUCAST 16 or ChEMBL 19 ( r s = 0.70 and r s = 0.64; n = 77 and n = 132, respectively), despite differences in strains and media used (Extended Data Fig. 3b ). Importantly, this dataset expands the available MICs, up to 75% for non-pathogenic bacteria (Fig. 1b , Extended Data Fig. 3c ). Altogether, the screen and MIC dataset provide high-resolution information on the target spectrum of antibiotics on commensal bacteria. Fig 1: Activity spectrum of antibiotic classes on human gut commensals. a , Overview of antibiotics tested in initial screen at 20 µM concentration 2 and validated by MIC determination in this study. b , Comparison of measured MICs (dark grey) to available ones from public databases (light grey). Shaded areas represent the overlap. Species are classified as ‘common’ if they are present in the gut microbiome of more than 1% of 727 healthy individuals. c , MICs of drug–species pairs per antibiotic class (colour scheme as in a ) are depicted next to EUCAST clinical (susceptibility) breakpoints for pathogens. Numbers of drug–species pairs (MICs; coloured) and antibiotic per class (EUCAST clinical breakpoints; black) are shown in parentheses. Boxes span the interquartile range (IQR), and whiskers extend to the most extreme data points up to a maximum of 1.5× IQR. The y axis is log 2 scale. Source data Full size image Antibiotic classes exhibited distinct behaviours (Extended Data Fig. 4a ). For example, quinolones acted according to their generation. First-generation variants were effective against few bacterial species; second- and third-generation quinolones had broader activity; and fourth-generation variants (developed to increase activity against anaerobes) inhibited almost all tested species (Extended Data Fig. 4b ). For β-lactams, resistance was phylogenetically patchy, which was corroborated by additional data collected for Bacteroides strains and species (Extended Data Figs. 2 , 4c–e ). β-Lactam sensitivity and phylogenetic relatedness within the Bacteroides genus were uncoupled (Extended Data Fig. 4e ). This implies that β-lactam resistance mechanisms are strain specific and horizontally transferred. Macrolides showed a strong effect on gut commensals and inhibited all tested microorganisms (Extended Data Fig. 4a ), except for C . difficile , which was resistant to macrolides and clindamycin (Extended Data Fig. 2 , red box), consistent with the known risk of C . difficile infection after macrolide or clindamycin treatment 20 . Finally, 8 out of 9 tested tetracyclines inhibited nearly all tested species, which is surprising because the gut microbiota has been considered<|im_end|> <|im_start|>assistant Antibiotics cure bacterial infections and save millions of lives each year. But they can also harm the helpful microbes residing in the gut, weakening one of the body's first lines of defense against pathogens and compromising the multiple beneficial effects our microbiota has for our health. Common side effects of this collateral damage of antibiotics are gastrointestinal problems and recurrent Clostridioides difficile infections. They also include long-term health problems, such as the development of allergic, metabolic, immunological or inflammatory diseases. Researchers from the Typas group at EMBL Heidelberg, the Maier lab at the Cluster of Excellence "Controlling Microbes to Fight Infections' at the University of Tübingen, and collaborators have analyzed the effects of 144 antibiotics on our most common gut microbes. The study published in the journal Nature substantially improves our understanding of antibiotics' effects on gut microbes. It also suggests a new approach to mitigating the adverse effects of antibiotics therapy on the gut microbiome. The human gut harbors an intricate community of different microbial species as well as many viruses, collectively referred to as the gut microbiome. Together, they enable us to use nutrients more efficiently and hinder pathogenic bacteria from settling in our gut. However, when we treat a bacterial infection with antibiotics, there's a risk of damaging the gut microbiome. "Many antibiotics inhibit the growth of various pathogenic bacteria. This broad activity spectrum is useful when treating infections, but it increases the risk that the microbes in our gut are targeted as well," explained Lisa Maier, DFG Emmy Noether group leader at the University of Tübingen. Maier is an alumna of the Typas lab and one of the two lead authors of the study. If certain gut bacteria are harmed more than others, antibiotics therapy can lead to an imbalance in our microbiota composition, commonly referred to as dysbiosis. Diarrhea is a common short-term effect, while allergic conditions such as asthma or food allergies and obesity are possible long-term consequences. The fact that antibiotics are also active against gut microbes has been known for a long time, but their effects on the large diversity of microbes we carry in our gut had not yet been studied systematically, mostly due to technical challenges. "So far, our knowledge of the effects of different antibiotics on individual members of our gut microbial communities has been patchy. Our study fills major gaps in our understanding of which type of antibiotic affects which types of bacteria, and in what way," said Nassos Typas, Senior Scientist and Group Leader at EMBL Heidelberg. Building on a previous study from EMBL's Typas, Bork, Patil, and Zeller groups, the scientists observed how each of the 144 antibiotics affected the growth and survival of up to 27 bacterial strains commonly inhabiting our guts. The researchers determined the concentrations at which a given antibiotic would affect these bacterial strains for more than 800 antibiotic–strain combinations, expanding existing datasets on antibiotic spectra in gut bacterial species by 75 percent. Importantly, the experiments revealed that tetracyclines and macrolides—two commonly used antibiotics families—not only stopped bacteria from growing, but also lead to their death. About half of the tested gut strains did not survive treatment with these types of antibiotics. "We didn't expect to see this effect with tetracyclines and macrolides, as these antibiotic classes were considered to have only bacteriostatic effects—which means that they stop bacterial growth, but don't kill bacteria," said Camille Goemans, a postdoctoral fellow in the Typas group who shares first authorship with Maier. "Our experiments show that this assumption is not true for about half of the gut microbes we studied. Doxycycline, erythromycin, and azithromycin, three commonly used antibiotics, killed several abundant gut microbial species, whereas others they just inhibited." The selective killing of specific microbes by tetracyclines and macrolides could lead to these microbes being inadvertently lost from the gut microbiota much faster than microbes for which growth is only inhibited, as the authors showed with synthetic microbial communities. This could explain the strong microbiota shifts that some patients being treated with these antibiotics witness. There is a way of reducing the damage, though. "We have shown before that drugs interact differently across different bacterial species. We therefore explored whether a second drug could mask the harmful effects of antibiotics on abundant gut microbes, but allow antibiotics to retain their activity against pathogens. This would provide something like an antidote, which would reduce the collateral damage of antibiotics on gut bacteria," explained Typas. The scientists combined the antibiotics erythromycin or doxycycline with a set of nearly 1,200 pharmaceuticals, to identify drugs that would save two abundant gut bacterial species from the antibiotic. Indeed, the researchers identified several non-antibiotic drugs that could rescue these gut microbes and other related species. Importantly, the combination of an antibiotic with a protective second drug did not compromise the antibiotics' efficacy against pathogenic bacteria. Follow-up experiments indicated that this approach may be working in the context of a natural microbiome as well. With help from collaborators, the scientists showed that the combination of erythromycin with an antidote mitigated the loss of certain abundant gut bacterial species from the mouse gut. Similarly, antidote drugs protected human gut microbes from erythromycin in complex bacterial communities derived from stool samples. "Our approach that combines antibiotics with a protective antidote could open new opportunities for reducing the harmful side effects of antibiotics on our gut microbiomes," concluded Maier. "No single antidote will be able to protect all the bacteria in our gut—especially since those differ so much across individuals. But this concept opens up the door for developing new personalized strategies to keep our gut microbes healthy." Further research will be needed to identify the optimal combinations, dosing, and formulations for antidotes, and to exclude potential long-term effects on the gut microbiome. In the future, the new approach may help to keep our gut microbiome healthy and reduce antibiotics' side effects in patients, without compromising the efficiency of our antibiotics as lifesavers. The study was a collaborative effort, involving researchers from EMBL's Typas, Bork, Zeller, Zimmermann, and Patil groups, as well as colleagues at the University of Tübingen, Ludwig-Maximilians-Universität München, and the Max Delbrück Center for Molecular Medicine in Berlin. <|im_end|>

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2,789

[ { "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 presence of active neurogenic niches in adult humans is controversial. We focused attention to the human olfactory neuroepithelium, an extracranial site supplying input to the olfactory bulbs of the brain. Using single-cell RNA sequencing analyzing 28,726 cells, we identified neural stem cell and neural progenitor cell pools and neurons. Additionally, we detailed the expression of 140 olfactory receptors. These data from the olfactory neuroepithelium niche provide evidence that neuron production may continue for decades in humans. Main Mitotic tracing, fate mapping, and single-cell RNA sequencing (scRNA-seq) analyses have shown that rodent olfactory neuroepithelium supports ongoing neurogenesis through adulthood, that is, up to two years of age 1 , 2 , 3 , 4 , 5 , 6 , but there has been little direct evidence to evaluate how well human olfactory neurogenesis may persist for the longer life span of many decades. Extrapolating from rodent studies, descriptive immunohistochemistry (IHC) using human olfactory neuroepithelium suggested that progenitors may be present, but also identified species-related differences 7 , 8 . In addition, light microscopy examination of adult nonhuman primate olfactory neuroepithelium described basal cell pools, although ages were not specified 9 . To investigate the presence of true neurogenic progenitors and nascent neurons, we obtained fresh tissue samples from adult patients undergoing endoscopic nasal surgery involving resection of the anterior skull base or wide dissection for neurosurgical access ( n = 7 individuals). These cases provided access to normal olfactory cleft or turbinate tissue, which was uninvolved with any pathology but required removal (Supplementary Table 1 ). Samples were processed for scRNA-seq (four cases) and/or IHC. After filtering, analysis of 28,726 single cells was performed (5,538–11,184 cells per case; Fig. 1 , Extended Data Fig. 1 and Supplementary Table 2 ). Data were projected onto two dimensions via uniform manifold approximation and projection (UMAP) to analyze cellular heterogeneity 10 , 11 . Cell type assignments for each cluster were generated using Gene Ontology and pathway analysis, using multiple known murine marker genes for horizontal basal cells (HBCs), globose basal cells (GBCs), immature and mature olfactory neurons, as well as Bowman’s glands, olfactory neuroepithelium sustentacular cells 5 , endothelial/perivascular cells 12 or immune cells (Fig. 1b–d and Extended Data Fig. 1 ). While our samples comprised olfactory and respiratory mucosa, olfactory neuroepithelial cells clustered distinctly from other cell types (Fig. 1a–c ) and aggregated together in batch-corrected samples pooled from separate individuals (Fig. 1b,c ). We hypothesized that, if ongoing neurogenesis is prominent in adult human olfactory neuroepithelium, a small subset of cells should express GBC proneural genes, as in rodents, and that immature neurons should be identifiable. Our results indicated that cell populations present in olfactory mucosa from adult individuals (age 41–52 years) contained several stages of neurogenic pools and immature neurons (Figs. 1d,e and 2 and Extended Data Figs. 2 and 3 ). Fig. 1: Aggregate analysis of 28,726 single cells from human olfactory cleft mucosa. a , Schematic diagram of respiratory versus olfactory epithelia. OEC, olfactory ensheathing cell; VSM, vascular smooth muscle (VSM); WBC, white blood cell. b , UMAP dimensionality reduction plot of 28,726 combined olfactory and respiratory mucosal cells; n = 4 patients. The cell cluster phenotype is noted on the color key legend and labels. c , Plots of individual patient samples; n = 4 patients. Patient 1: 5,683 cells; patient 2: 11,184 cells; patient 3: 5,538 cells; patient 4: 6,321 cells (see also Extended Data Fig. 1c ). d , Heatmap depicting selected gene expression among olfactory cell clusters. e , UMAP depicting GNG8 and GNG13 expression in 694 GBCs and in immature and mature olfactory neurons; n = 4 patients. f , GNG13 immunostaining (red) in adult human and mouse olfactory neuroepithelia; the dashed line marks the basal lamina; nuclei are stained with DAPI (blue). Immunostaining was conducted in triplicate with similar results. Scale bar, 25 µm. Full size image Fig. 2: Gene expression analysis of human olfactory neuroepithelium. a , DotPlot visualization of neuron lineage cell populations from adult human olfactory neuroepithelia; n = 4 patients. b , Cell-type-specific marker validation in human versus mouse olfactory mucosal sections. TUJ1 labels the somata of immature OSNs, which are more abundant in our adult human samples ( n = 3, two-sided Welch’s t -test, P = 0.015). c , SOX2 marks the basal and sustentacular cells; KRT5 labels HBCs, which, in many areas of the human samples, have a reactive rather than flat morphology (inset, enlarged) and are abundant ( n = 3, two-sided Welch’s t -test, P = 0.04). d , KI67 marks proliferative GBCs. e , LHX2 was highly expressed in immature OSNs (DotPlot in a ); IHC confirmed widespread expression in human cell populations and variable expression in mice. Nuclei are stained with DAPI (blue); the dashed line marks the basal lamina. * P < 0.05; the measure of center and error bars are the mean ± s.d. Scale bar, 50 µm; in inset ( c ), 10 µm. f , Focused UMAP plots visualizing gene expression of HES6 and NEUROD1 in GBCs; n = 4 patients. Source data Full size image In the scRNA-seq data, immature neurons represented a surprisingly large proportion (55%) of all human olfactory neurons. In contrast, in adult nonlesioned rodent olfactory neuroepithelium, markers for immature neurons, such as TUJ1 or GAP43, label only about 5–15% of all olfactory neurons, based on widely published staining patterns. 2 Published high-quality murine scRNA-seq datasets analyzed cells from postnatal mice, thus limiting the ability for direct comparison 5 . In this study, we found that in human olfactory neuroepithelium, the G protein subunit guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 (GNG8) is highly enriched in immature neurons, whereas GNG13 marks mature neurons, as described in the mouse 5 (Fig. 1e,f ). A subset analysis of olfactory neural lineage cell clusters, reprojected via UMAP, demonstrated the largely distinct expression patterns of GNG8 and GNG13 (Fig. 1e ). In agreement, using IHC, GNG13 protein expression localizes to the mature olfactory neuron regions in", "role": "user" }, { "content": "Is it possible for an adult brain to make new nerve cells? Scientists have debated this question for decades, with many concluding that neuron-making stops after childhood, or around the age of 13. However, a research team recently rocked the debate again after finding a thriving neuron 'nursery' in a section of adult human nose tissue, the olfactory neuroepithelium. Neurons are the specialized cells in the brain designed to transmit information to other nerve cells and muscles. The olfactory area of the nose houses the neural receptors that give us the ability to smell. Previously, studies had been limited to nasal tissue samples from mice. In the human samples used in the current study, the researchers found that immature neurons or \"baby\" neurons produced by stem cells represented more than half of the neurons in the tissue samples, suggesting that new neurons were produced in the tissue. The findings were published in the journal Nature Neuroscience. The finding has implications for correcting conditions that cause smell damage or loss, and add insights for treating the nervous system as a whole. \"We do not fully understand why people lose their sense of smell, which can occur for many reasons, and our data sets provide a wealth of information about the cell populations present in adult olfactory tissue,\" said Brad Goldstein, M.D., Ph.D., an associate professor and vice chair for research in the Department of Head and Neck Surgery and Communication Sciences, senior author of the study. \"This is an important step in developing treatment strategies for conditions when this tissue may be damaged.\" Approximately one in eight Americans over age 40—up to 13.3 million people—have measurable smell dysfunction, according to the National Institute on Deafness and Other Communication Disorders. \"It will be very useful to use this window to analyze samples from people with conditions in which the nervous system has degeneration, such as Alzheimer's disease,\" said Goldstein. \"Alzheimer's is of particular interest, since these patients lose their sense of smell quite early in the disease process, and we have few treatments for Alzheimer's disease. So, it may make sense to look carefully at regions of the olfactory system in these patients.\" Hiroaki Matsunami, Ph.D., a professor in the Department of Molecular Genetics and Microbiology and co-author on the paper, noted that while the researchers weren't able to observe the neurons being made because of the nature of human samples, the molecular makeup of the immature neurons in the sample provide strong evidence that they were made in the nose during adulthood. \"Because the nose is exposed to the external environment, it might be possible we could one day collect these neuronal stem cells from patients and use them to treat their own brain disorders,\" said Matsunami. \"It is not outside of the realm of possibility.\" ", "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 presence of active neurogenic niches in adult humans is controversial. We focused attention to the human olfactory neuroepithelium, an extracranial site supplying input to the olfactory bulbs of the brain. Using single-cell RNA sequencing analyzing 28,726 cells, we identified neural stem cell and neural progenitor cell pools and neurons. Additionally, we detailed the expression of 140 olfactory receptors. These data from the olfactory neuroepithelium niche provide evidence that neuron production may continue for decades in humans. Main Mitotic tracing, fate mapping, and single-cell RNA sequencing (scRNA-seq) analyses have shown that rodent olfactory neuroepithelium supports ongoing neurogenesis through adulthood, that is, up to two years of age 1 , 2 , 3 , 4 , 5 , 6 , but there has been little direct evidence to evaluate how well human olfactory neurogenesis may persist for the longer life span of many decades. Extrapolating from rodent studies, descriptive immunohistochemistry (IHC) using human olfactory neuroepithelium suggested that progenitors may be present, but also identified species-related differences 7 , 8 . In addition, light microscopy examination of adult nonhuman primate olfactory neuroepithelium described basal cell pools, although ages were not specified 9 . To investigate the presence of true neurogenic progenitors and nascent neurons, we obtained fresh tissue samples from adult patients undergoing endoscopic nasal surgery involving resection of the anterior skull base or wide dissection for neurosurgical access ( n = 7 individuals). These cases provided access to normal olfactory cleft or turbinate tissue, which was uninvolved with any pathology but required removal (Supplementary Table 1 ). Samples were processed for scRNA-seq (four cases) and/or IHC. After filtering, analysis of 28,726 single cells was performed (5,538–11,184 cells per case; Fig. 1 , Extended Data Fig. 1 and Supplementary Table 2 ). Data were projected onto two dimensions via uniform manifold approximation and projection (UMAP) to analyze cellular heterogeneity 10 , 11 . Cell type assignments for each cluster were generated using Gene Ontology and pathway analysis, using multiple known murine marker genes for horizontal basal cells (HBCs), globose basal cells (GBCs), immature and mature olfactory neurons, as well as Bowman’s glands, olfactory neuroepithelium sustentacular cells 5 , endothelial/perivascular cells 12 or immune cells (Fig. 1b–d and Extended Data Fig. 1 ). While our samples comprised olfactory and respiratory mucosa, olfactory neuroepithelial cells clustered distinctly from other cell types (Fig. 1a–c ) and aggregated together in batch-corrected samples pooled from separate individuals (Fig. 1b,c ). We hypothesized that, if ongoing neurogenesis is prominent in adult human olfactory neuroepithelium, a small subset of cells should express GBC proneural genes, as in rodents, and that immature neurons should be identifiable. Our results indicated that cell populations present in olfactory mucosa from adult individuals (age 41–52 years) contained several stages of neurogenic pools and immature neurons (Figs. 1d,e and 2 and Extended Data Figs. 2 and 3 ). Fig. 1: Aggregate analysis of 28,726 single cells from human olfactory cleft mucosa. a , Schematic diagram of respiratory versus olfactory epithelia. OEC, olfactory ensheathing cell; VSM, vascular smooth muscle (VSM); WBC, white blood cell. b , UMAP dimensionality reduction plot of 28,726 combined olfactory and respiratory mucosal cells; n = 4 patients. The cell cluster phenotype is noted on the color key legend and labels. c , Plots of individual patient samples; n = 4 patients. Patient 1: 5,683 cells; patient 2: 11,184 cells; patient 3: 5,538 cells; patient 4: 6,321 cells (see also Extended Data Fig. 1c ). d , Heatmap depicting selected gene expression among olfactory cell clusters. e , UMAP depicting GNG8 and GNG13 expression in 694 GBCs and in immature and mature olfactory neurons; n = 4 patients. f , GNG13 immunostaining (red) in adult human and mouse olfactory neuroepithelia; the dashed line marks the basal lamina; nuclei are stained with DAPI (blue). Immunostaining was conducted in triplicate with similar results. Scale bar, 25 µm. Full size image Fig. 2: Gene expression analysis of human olfactory neuroepithelium. a , DotPlot visualization of neuron lineage cell populations from adult human olfactory neuroepithelia; n = 4 patients. b , Cell-type-specific marker validation in human versus mouse olfactory mucosal sections. TUJ1 labels the somata of immature OSNs, which are more abundant in our adult human samples ( n = 3, two-sided Welch’s t -test, P = 0.015). c , SOX2 marks the basal and sustentacular cells; KRT5 labels HBCs, which, in many areas of the human samples, have a reactive rather than flat morphology (inset, enlarged) and are abundant ( n = 3, two-sided Welch’s t -test, P = 0.04). d , KI67 marks proliferative GBCs. e , LHX2 was highly expressed in immature OSNs (DotPlot in a ); IHC confirmed widespread expression in human cell populations and variable expression in mice. Nuclei are stained with DAPI (blue); the dashed line marks the basal lamina. * P < 0.05; the measure of center and error bars are the mean ± s.d. Scale bar, 50 µm; in inset ( c ), 10 µm. f , Focused UMAP plots visualizing gene expression of HES6 and NEUROD1 in GBCs; n = 4 patients. Source data Full size image In the scRNA-seq data, immature neurons represented a surprisingly large proportion (55%) of all human olfactory neurons. In contrast, in adult nonlesioned rodent olfactory neuroepithelium, markers for immature neurons, such as TUJ1 or GAP43, label only about 5–15% of all olfactory neurons, based on widely published staining patterns. 2 Published high-quality murine scRNA-seq datasets analyzed cells from postnatal mice, thus limiting the ability for direct comparison 5 . In this study, we found that in human olfactory neuroepithelium, the G protein subunit guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 (GNG8) is highly enriched in immature neurons, whereas GNG13 marks mature neurons, as described in the mouse 5 (Fig. 1e,f ). A subset analysis of olfactory neural lineage cell clusters, reprojected via UMAP, demonstrated the largely distinct expression patterns of GNG8 and GNG13 (Fig. 1e ). In agreement, using IHC, GNG13 protein expression localizes to the mature olfactory neuron regions in<|im_end|> <|im_start|>assistant Is it possible for an adult brain to make new nerve cells? Scientists have debated this question for decades, with many concluding that neuron-making stops after childhood, or around the age of 13. However, a research team recently rocked the debate again after finding a thriving neuron 'nursery' in a section of adult human nose tissue, the olfactory neuroepithelium. Neurons are the specialized cells in the brain designed to transmit information to other nerve cells and muscles. The olfactory area of the nose houses the neural receptors that give us the ability to smell. Previously, studies had been limited to nasal tissue samples from mice. In the human samples used in the current study, the researchers found that immature neurons or "baby" neurons produced by stem cells represented more than half of the neurons in the tissue samples, suggesting that new neurons were produced in the tissue. The findings were published in the journal Nature Neuroscience. The finding has implications for correcting conditions that cause smell damage or loss, and add insights for treating the nervous system as a whole. "We do not fully understand why people lose their sense of smell, which can occur for many reasons, and our data sets provide a wealth of information about the cell populations present in adult olfactory tissue," said Brad Goldstein, M.D., Ph.D., an associate professor and vice chair for research in the Department of Head and Neck Surgery and Communication Sciences, senior author of the study. "This is an important step in developing treatment strategies for conditions when this tissue may be damaged." Approximately one in eight Americans over age 40—up to 13.3 million people—have measurable smell dysfunction, according to the National Institute on Deafness and Other Communication Disorders. "It will be very useful to use this window to analyze samples from people with conditions in which the nervous system has degeneration, such as Alzheimer's disease," said Goldstein. "Alzheimer's is of particular interest, since these patients lose their sense of smell quite early in the disease process, and we have few treatments for Alzheimer's disease. So, it may make sense to look carefully at regions of the olfactory system in these patients." Hiroaki Matsunami, Ph.D., a professor in the Department of Molecular Genetics and Microbiology and co-author on the paper, noted that while the researchers weren't able to observe the neurons being made because of the nature of human samples, the molecular makeup of the immature neurons in the sample provide strong evidence that they were made in the nose during adulthood. "Because the nose is exposed to the external environment, it might be possible we could one day collect these neuronal stem cells from patients and use them to treat their own brain disorders," said Matsunami. "It is not outside of the realm of possibility." <|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 Non-alcoholic fatty liver disease (NAFLD) constitutes a metabolic disorder with high worldwide prevalence and increasing incidence. The inflammatory progressive state, non-alcoholic steatohepatitis (NASH), leads to liver fibrosis and carcinogenesis. Here, we evaluated whether tyrosinase mutation underlies NASH pathophysiology. Tyrosinase point-mutated B6 (Cg)- Tyr c-2J /J mice (B6 albino) and C57BL/6J black mice (B6 black) were fed with high cholesterol diet (HCD) for 10 weeks. Normal diet-fed mice served as controls. HCD-fed B6 albino exhibited high NASH susceptibility compared to B6 black, a phenotype not previously reported. Liver injury occurred in approximately 50% of B6 albino from one post HCD feeding, with elevated serum alanine aminotransferase and aspartate aminotransferase levels. NASH was induced following 2 weeks in severe-phenotypic B6 albino (sB6), but B6 black exhibited no symptoms, even after 10 weeks. HCD-fed sB6 albino showed significantly higher mortality rate. Histological analysis of the liver revealed significant inflammatory cell and lipid infiltration and severe fibrosis. Serum lipoprotein analysis revealed significantly higher chylomicron and very low-density lipoprotein levels in sB6 albino. Moreover, significantly higher small intestinal lipid absorption and lower fecal lipid excretion occurred together with elevated intestinal NPC1L1 expression. As the tyrosinase point mutation represents the only genetic difference between B6 albino and B6 black, our work will facilitate the identification of susceptible genetic factors for NASH development and expand the understanding of NASH pathophysiology. Introduction Non-alcoholic fatty liver disease (NAFLD) is a pathological condition characterized by increased lipid accumulation in liver hepatocytes without concomitant alcohol abuse or other liver diseases. NAFLD progression into the inflammatory state, termed non-alcoholic steatohepatitis (NASH), leads to more serious presentation, including hepatic inflammation, hepatocyte damage, and fibrosis 1 . NASH also increases the risk of developing cirrhosis or hepatocellular carcinoma 2 . The estimated worldwide prevalence of NAFLD is approximately 25% 3 , with 10–30% of cases progressing into NASH 4 . NAFLD is frequently associated with obesity, diabetes, dyslipidemia, and hypertension and is considered as the liver manifestation of metabolic syndrome 5 . Current evidence suggests that NAFLD exhibits multifactorial pathophysiology 6 with metabolic syndrome, genetic factors, oxidative stress, inflammatory cytokines, endotoxins, and insulin resistance contributing to disease development. However, the detailed molecular mechanisms involved in disease progression to NASH remain unclear, in part because of the lack of appropriate animal models. Dietary cholesterol contributes to the development of steatohepatitis in both animal models and humans, facilitating NASH development by deregulating inflammation and metabolism-associated gene expression 7 . Extensive deregulation of hepatic cholesterol homeostasis in NAFLD leads to increased hepatic free cholesterol levels 8 ; these are implicated in hepatic lipotoxicity 9 , thereby activating inflammatory recruitment to fatty livers to induce NASH. This can initiate with cholesterol crystal accumulation and hepatic crown-like structure formation 10 , plus cholesterol-induced Kupffer cell and NLRP3 inflammasome activation 11 , 12 . Thus, cholesterol rather than triglyceride and free fatty acid accumulation may constitute an important risk factor of NASH development. The cholesterol level in the body comprises liver-biosynthesized “endogenous cholesterol” and dietary “exogenous cholesterol” 13 , with dietary cholesterol playing a more substantial role in NASH development 14 . These findings highlight the small intestines (SI) as another important regulator of whole-body cholesterol homeostasis. Genetic deletion of Niemann-Pick C1 like 1 protein (NPC1L1), which regulates dietary cholesterol absorption by the SI 15 reduces cholesterol absorption by > 70% in mice 16 . Alternatively, ATP-binding cassette ABCG5/ABCG8 heterodimer is crucial for intestinal cholesterol excretion 17 . Nevertheless, a comprehensive profile of intestinal cholesterol regulation remains to be elucidated. Racial/ethnic disparities in NAFLD prevalence and severity are widely documented. Clarifying the factors underlying these differences may increase understanding of disease pathophysiology. NAFLD prevalence is highest in Hispanics (22.9%), intermediate in whites (14.4%), and lowest in blacks (13%) 18 . NASH risk is also greater among Hispanic patients with NAFLD 19 . Notably, in preliminary in silico analyses we observed that frequencies of single nucleotide polymorphisms (SNPs) in the tyrosinase ( Tyr ) gene also differ among ethnic groups with two main SNPs, G to A at nt 140 20 and G to C at nt 316 21 , exhibiting relatively high allele frequencies in Hispanic populations 22 . Therefore, here we aimed to investigate whether Tyr gene variants enhance NAFLD/NASH susceptibility and severity. Specifically, we evaluated the effects of a high cholesterol diet (HCD) in B6 albino mice, which carry a Tyr SNP, leading to melanin synthesis deficiency and white coat color 23 , along with standard C57BL/6 (B6 black) mice. It has been reported that HCD induces steatohepatitis in mice 14 . Matsuzawa et al. found that an atherogenic diet containing 1.25% cholesterol increased the expression levels of genes related to fatty acid synthesis, oxidative stress, inflammation, and fibrogenesis in the liver 14 . Therefore, we used this HCD to evaluate the characteristics and timing of NASH development including fatty liver and fibrotic phenotype, measuring liver inflammation and lipid deposition along with cholesterol crystal formation and fibrosis. Comparison with human NASH-like disease progression was assessed regarding phenotypical lipid deposition, hepatocyte ballooning, hepatic crown-like structure, inflammation, and rapid fibrosis. We found that SNPs in Tyr may constitute risk factors in NAFLD/NASH susceptibility and severity, representing novel genetic contribution toward NAFLD/NASH pathophysiology and suggest that this rapid model of diet-induced NASH with fibrosis may surpass the limitation of existing NASH models. Results B6 albino mice develop NASH upon HCD feeding To evaluate the high cholesterol effect on a mouse, B6 albino and B6 black male mice (10–12 weeks-old) were fed with 1.25% HCD for 10 weeks. HCD feeding yielded significantly higher mortality in B6 albino than B6 black (Fig. 1 a) with 12/27 vs. 1/17 respective mouse deaths starting from week 2 of HCD feeding. Overall, approximately 50% of B6 albino died throughout the experiments performed. Serum ALT and AST levels were checked biweekly to identify the underlying cause for the severe cachexia and death. Though these levels did not differ between the groups prior to HCD feeding, we observed that the B6 albino could be divided into two", "role": "user" }, { "content": "Non-alcoholic fatty liver disease (NAFLD) is the accumulation of fat in the liver unrelated to alcohol abuse or other liver diseases. It is often associated with obesity and diabetes and is considered a manifestation of metabolic syndrome. It progresses into non-alcoholic steatohepatitis (NASH) with the onset of inflammation, although it is currently unclear how this occurs. NASH can lead to severe complications such as liver failure, cirrhosis, and liver cancer. Now, a team led by the University of Tsukuba has found that albino mice with a point mutation in the tyrosinase gene are more susceptible to NASH than mice carrying the non-mutated gene. The prevalence and severity of NAFLD are known to vary between different human ethnicities, with the highest prevalence in Hispanic populations. The tyrosinase gene encodes an enzyme that is involved in melanin production, affecting skin tone. The team observed in preliminary computational analyses that different point mutations in the tyrosinase gene also vary in frequency between different ethnic groups, with the two main variants observed at high frequencies in Hispanic populations. The researchers therefore hypothesized that tyrosinase gene variants could possibly affect the susceptibility and severity of NAFLD and NASH. The team studied a particular mouse line known as \"C57BL/6,\" or B6, to test this hypothesis. Albino B6 mice have a single change, known as a point mutation, in the gene tyrosinase. This affects the function of the tyrosinase enzyme so that the albino mice cannot produce melanin properly, losing pigmentation and becoming white instead of black. Dietary cholesterol contributes to the development of liver inflammation, and so the team fed both albino and black B6 mice a high cholesterol diet for 10 weeks. They found that black B6 mice exhibited no symptoms over the entire course of the diet, while approximately 50% of the albino B6 mice showed a severe phenotype, developing liver injury after a single day that progressed to NASH after two weeks. The team further showed that the albino B6 mice showed high expression of tyrosinase in the small intestine. \"This could affect the susceptibility of the mice to NASH by affecting the uptake of cholesterol in the small intestine,\" says senior author Assistant Professor Michito Hamada, \"pointing to a potential mechanism for this increased susceptibility.\" \"As the point mutation in the tyrosinase gene is the only genetic difference between B6 albino and B6 black mice,\" explains Assistant Professor Hamada, \"our work will facilitate the identification of genetic susceptibility factors for the development of NASH and expand the understanding of the pathophysiology of NASH.\" ", "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 Non-alcoholic fatty liver disease (NAFLD) constitutes a metabolic disorder with high worldwide prevalence and increasing incidence. The inflammatory progressive state, non-alcoholic steatohepatitis (NASH), leads to liver fibrosis and carcinogenesis. Here, we evaluated whether tyrosinase mutation underlies NASH pathophysiology. Tyrosinase point-mutated B6 (Cg)- Tyr c-2J /J mice (B6 albino) and C57BL/6J black mice (B6 black) were fed with high cholesterol diet (HCD) for 10 weeks. Normal diet-fed mice served as controls. HCD-fed B6 albino exhibited high NASH susceptibility compared to B6 black, a phenotype not previously reported. Liver injury occurred in approximately 50% of B6 albino from one post HCD feeding, with elevated serum alanine aminotransferase and aspartate aminotransferase levels. NASH was induced following 2 weeks in severe-phenotypic B6 albino (sB6), but B6 black exhibited no symptoms, even after 10 weeks. HCD-fed sB6 albino showed significantly higher mortality rate. Histological analysis of the liver revealed significant inflammatory cell and lipid infiltration and severe fibrosis. Serum lipoprotein analysis revealed significantly higher chylomicron and very low-density lipoprotein levels in sB6 albino. Moreover, significantly higher small intestinal lipid absorption and lower fecal lipid excretion occurred together with elevated intestinal NPC1L1 expression. As the tyrosinase point mutation represents the only genetic difference between B6 albino and B6 black, our work will facilitate the identification of susceptible genetic factors for NASH development and expand the understanding of NASH pathophysiology. Introduction Non-alcoholic fatty liver disease (NAFLD) is a pathological condition characterized by increased lipid accumulation in liver hepatocytes without concomitant alcohol abuse or other liver diseases. NAFLD progression into the inflammatory state, termed non-alcoholic steatohepatitis (NASH), leads to more serious presentation, including hepatic inflammation, hepatocyte damage, and fibrosis 1 . NASH also increases the risk of developing cirrhosis or hepatocellular carcinoma 2 . The estimated worldwide prevalence of NAFLD is approximately 25% 3 , with 10–30% of cases progressing into NASH 4 . NAFLD is frequently associated with obesity, diabetes, dyslipidemia, and hypertension and is considered as the liver manifestation of metabolic syndrome 5 . Current evidence suggests that NAFLD exhibits multifactorial pathophysiology 6 with metabolic syndrome, genetic factors, oxidative stress, inflammatory cytokines, endotoxins, and insulin resistance contributing to disease development. However, the detailed molecular mechanisms involved in disease progression to NASH remain unclear, in part because of the lack of appropriate animal models. Dietary cholesterol contributes to the development of steatohepatitis in both animal models and humans, facilitating NASH development by deregulating inflammation and metabolism-associated gene expression 7 . Extensive deregulation of hepatic cholesterol homeostasis in NAFLD leads to increased hepatic free cholesterol levels 8 ; these are implicated in hepatic lipotoxicity 9 , thereby activating inflammatory recruitment to fatty livers to induce NASH. This can initiate with cholesterol crystal accumulation and hepatic crown-like structure formation 10 , plus cholesterol-induced Kupffer cell and NLRP3 inflammasome activation 11 , 12 . Thus, cholesterol rather than triglyceride and free fatty acid accumulation may constitute an important risk factor of NASH development. The cholesterol level in the body comprises liver-biosynthesized “endogenous cholesterol” and dietary “exogenous cholesterol” 13 , with dietary cholesterol playing a more substantial role in NASH development 14 . These findings highlight the small intestines (SI) as another important regulator of whole-body cholesterol homeostasis. Genetic deletion of Niemann-Pick C1 like 1 protein (NPC1L1), which regulates dietary cholesterol absorption by the SI 15 reduces cholesterol absorption by > 70% in mice 16 . Alternatively, ATP-binding cassette ABCG5/ABCG8 heterodimer is crucial for intestinal cholesterol excretion 17 . Nevertheless, a comprehensive profile of intestinal cholesterol regulation remains to be elucidated. Racial/ethnic disparities in NAFLD prevalence and severity are widely documented. Clarifying the factors underlying these differences may increase understanding of disease pathophysiology. NAFLD prevalence is highest in Hispanics (22.9%), intermediate in whites (14.4%), and lowest in blacks (13%) 18 . NASH risk is also greater among Hispanic patients with NAFLD 19 . Notably, in preliminary in silico analyses we observed that frequencies of single nucleotide polymorphisms (SNPs) in the tyrosinase ( Tyr ) gene also differ among ethnic groups with two main SNPs, G to A at nt 140 20 and G to C at nt 316 21 , exhibiting relatively high allele frequencies in Hispanic populations 22 . Therefore, here we aimed to investigate whether Tyr gene variants enhance NAFLD/NASH susceptibility and severity. Specifically, we evaluated the effects of a high cholesterol diet (HCD) in B6 albino mice, which carry a Tyr SNP, leading to melanin synthesis deficiency and white coat color 23 , along with standard C57BL/6 (B6 black) mice. It has been reported that HCD induces steatohepatitis in mice 14 . Matsuzawa et al. found that an atherogenic diet containing 1.25% cholesterol increased the expression levels of genes related to fatty acid synthesis, oxidative stress, inflammation, and fibrogenesis in the liver 14 . Therefore, we used this HCD to evaluate the characteristics and timing of NASH development including fatty liver and fibrotic phenotype, measuring liver inflammation and lipid deposition along with cholesterol crystal formation and fibrosis. Comparison with human NASH-like disease progression was assessed regarding phenotypical lipid deposition, hepatocyte ballooning, hepatic crown-like structure, inflammation, and rapid fibrosis. We found that SNPs in Tyr may constitute risk factors in NAFLD/NASH susceptibility and severity, representing novel genetic contribution toward NAFLD/NASH pathophysiology and suggest that this rapid model of diet-induced NASH with fibrosis may surpass the limitation of existing NASH models. Results B6 albino mice develop NASH upon HCD feeding To evaluate the high cholesterol effect on a mouse, B6 albino and B6 black male mice (10–12 weeks-old) were fed with 1.25% HCD for 10 weeks. HCD feeding yielded significantly higher mortality in B6 albino than B6 black (Fig. 1 a) with 12/27 vs. 1/17 respective mouse deaths starting from week 2 of HCD feeding. Overall, approximately 50% of B6 albino died throughout the experiments performed. Serum ALT and AST levels were checked biweekly to identify the underlying cause for the severe cachexia and death. Though these levels did not differ between the groups prior to HCD feeding, we observed that the B6 albino could be divided into two<|im_end|> <|im_start|>assistant Non-alcoholic fatty liver disease (NAFLD) is the accumulation of fat in the liver unrelated to alcohol abuse or other liver diseases. It is often associated with obesity and diabetes and is considered a manifestation of metabolic syndrome. It progresses into non-alcoholic steatohepatitis (NASH) with the onset of inflammation, although it is currently unclear how this occurs. NASH can lead to severe complications such as liver failure, cirrhosis, and liver cancer. Now, a team led by the University of Tsukuba has found that albino mice with a point mutation in the tyrosinase gene are more susceptible to NASH than mice carrying the non-mutated gene. The prevalence and severity of NAFLD are known to vary between different human ethnicities, with the highest prevalence in Hispanic populations. The tyrosinase gene encodes an enzyme that is involved in melanin production, affecting skin tone. The team observed in preliminary computational analyses that different point mutations in the tyrosinase gene also vary in frequency between different ethnic groups, with the two main variants observed at high frequencies in Hispanic populations. The researchers therefore hypothesized that tyrosinase gene variants could possibly affect the susceptibility and severity of NAFLD and NASH. The team studied a particular mouse line known as "C57BL/6," or B6, to test this hypothesis. Albino B6 mice have a single change, known as a point mutation, in the gene tyrosinase. This affects the function of the tyrosinase enzyme so that the albino mice cannot produce melanin properly, losing pigmentation and becoming white instead of black. Dietary cholesterol contributes to the development of liver inflammation, and so the team fed both albino and black B6 mice a high cholesterol diet for 10 weeks. They found that black B6 mice exhibited no symptoms over the entire course of the diet, while approximately 50% of the albino B6 mice showed a severe phenotype, developing liver injury after a single day that progressed to NASH after two weeks. The team further showed that the albino B6 mice showed high expression of tyrosinase in the small intestine. "This could affect the susceptibility of the mice to NASH by affecting the uptake of cholesterol in the small intestine," says senior author Assistant Professor Michito Hamada, "pointing to a potential mechanism for this increased susceptibility." "As the point mutation in the tyrosinase gene is the only genetic difference between B6 albino and B6 black mice," explains Assistant Professor Hamada, "our work will facilitate the identification of genetic susceptibility factors for the development of NASH and expand the understanding of the pathophysiology of NASH." <|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 Universal quantum information processing requires the execution of single-qubit and two-qubit logic. Across all qubit realizations 1 , spin qubits in quantum dots have great promise to become the central building block for quantum computation 2 . Excellent quantum dot control can be achieved in gallium arsenide 3 , 4 , 5 , and high-fidelity qubit rotations and two-qubit logic have been demonstrated in silicon 6 , 7 , 8 , 9 , but universal quantum logic implemented with local control has yet to be demonstrated. Here we make this step by combining all of these desirable aspects using hole quantum dots in germanium. Good control over tunnel coupling and detuning is obtained by exploiting quantum wells with very low disorder, enabling operation at the charge symmetry point for increased qubit performance. Spin–orbit coupling obviates the need for microscopic elements close to each qubit and enables rapid qubit control with driving frequencies exceeding 100 MHz. We demonstrate a fast universal quantum gate set composed of single-qubit gates with a fidelity of 99.3 per cent and a gate time of 20 nanoseconds, and two-qubit logic operations executed within 75 nanoseconds. Planar germanium has thus matured within a year from a material that can host quantum dots to a platform enabling two-qubit logic, positioning itself as an excellent material for use in quantum information applications. Main Gate-defined quantum dots were recognized early on as a promising platform for quantum information 2 and many materials have been investigated as hosts for the quantum dots. Initial research mainly focused on the low-disorder semiconductor gallium arsenide 10 , 11 . Steady progress in the control and understanding of this system culminated in the initial demonstration and optimization of spin qubit operations 12 and the realization of rudimentary analogue quantum simulations 3 . However, the omnipresent hyperfine interactions in group III–V materials seriously deteriorate the spin coherence. Considerable improvements to the coherence times could be achieved by switching to the group IV semiconductor silicon, in particular when defining spin qubits in an isotopically purified host crystal with vanishing concentrations of non-zero nuclear spins 13 . This enabled single-qubit rotations with fidelities beyond 99.9% 7 and the execution of two-qubit logic gates with fidelities up to 98% 6 , 8 , 9 , underlining the potential of spin qubits for quantum computation. Nevertheless, quantum dots in silicon are often formed at unintended locations, and control over the tunnel coupling determining the strength of two-qubit interactions is limited. Moreover, the absence of a sizable spin–orbit coupling for electrons in silicon requires the inclusion of microscopic components such as on-chip striplines or nanomagnets close to each qubit, which complicates the design of large and dense two-dimensional (2D) structures. Scalability thus remains a challenge for these systems, and a platform that can overcome these limitations would be highly desirable. Hole states in semiconductors 14 typically exhibit strong spin–orbit coupling (SOC), which has enabled the demonstration of fast single-qubit rotations 15 , 16 , 17 . Furthermore, whereas valley degeneracy complicates qubit definition for electrons in silicon, this is absent for holes, and excited states can be well separated in energy. In silicon, unfavourable band alignment prevents strain engineering of low-disorder quantum wells for holes, restricting experiments to metal–oxide–semiconductor structures 18 . Research on germanium has mostly focused on self-assembled nanowires 19 and has demonstrated single-shot spin readout 20 and coherent spin control 17 . However, strained germanium can reach hole mobilities 21 of μ > 10 6 cm 2 V −1 s −1 , and undoped germanium quantum wells were recently shown to support the formation of gate-controlled hole quantum dots 22 . Now, the crucial challenge is the demonstration of coherent control in this platform and the implementation of qubit–qubit gates for scalable quantum information with holes. Here we make this step and demonstrate single- and two-qubit logic with holes in planar germanium. We fabricate devices on silicon substrates, using standard manufacturing materials. We grow undoped strained germanium quantum wells, measured to have high hole mobilities μ > 5 × 10 5 cm 2 V −1 s −1 and a low effective hole mass 22 , 23 m h = 0.09 m e , extrapolated to reach m h = 0.05 m e at zero density 24 , with m e the electron rest mass. This allows us to define quantum dots of comparatively large size, and we find excellent control over the exchange interaction between the two dots. We operate in a multi-hole mode, reducing challenges in tuning and characterization, which is advantageous for scaling. We make use of the spin–orbit interaction for qubit driving and perform single-qubit rotations at frequencies exceeding 100 MHz. This advantage of fast driving becomes further apparent in coherently accessing the Hilbert space of a two-qubit system. For example, in silicon the execution of a controlled NOT (CNOT) gate implemented with an on-chip stripline has been shown using microsecond long pulses 6 , 8 , and this timescale can be reduced to 0.2–0.5 μs by incorporating nanomagnets 9 . Here we demonstrate that the spin–orbit coupling of holes in germanium together with the sizable exchange interaction enables a CNOT within 75 ns. A scanning electron microscope image of the germanium two-qubit device is shown in Fig. 1a . To accumulate holes and define two quantum dots, the circular plunger gates are set to negative potential ( V P1 , V P2 ≈ −2 V). The tunnel coupling between the dots t 12 and the tunnel couplings to the source and drain reservoirs ( t 1S , t 2D ) are controlled by the barrier gates BC, BS and BD, respectively. Working in a virtual gate voltage space ( V V P1 , V V P2 , V t 1S , V t 2D and V t 12 ), we can independently tune these properties (see Supplementary Videos 1 – 3 online for video-mode operation). We measure the transport current through the double dot system (Fig. 1c, d ), and for certain hole", "role": "user" }, { "content": "Transistors based on germanium can perform calculations for future quantum computers. This discovery by the team of Menno Veldhorst is reported in Nature. The development of quantum computing seems to be going very quickly. The building blocks for such a computer are so-called quantum bits. Over the past two decades, researchers around the world have studied new and existing systems to function as quantum bits, including transistors. These tiny switches are present in billions on the chips of our computers, telephones and televisions. \"We have been working with transistors as the building blocks for a quantum computer for some time, now,\" says Nico Hendrickx, first author and Ph.D. student at QuTech. \"Until now, however, it hasn't been possible to perform quantum calculations using only transistors. Other elements were needed, as well, and this provided a limitation for upscaling. We now show that a single transistor can function as a quantum bit by using germanium.\" 1947 \"The very first transistor from 1947 was made of germanium. The whole semiconductor revolution, and thus our mobile phones and all other electronics, could, in theory, have been based on germanium instead of silicon,\" says principal researcher Menno Veldhorst. \"After all, it was known in 1947 that germanium actually has better properties as a semiconductor than silicon. But it turned out that there were difficulties in manufacturing, which made silicon the material of choice for the semiconductor industry.\" The team in the lab (from top to bottom, from left to right): Menno Veldhorst, Amir Sammak, Giordano Scappucci, Nico Hendrickx and David Franke. Credit: Ernst de Groot for QuTech Platform \"We also already knew that germanium could be an excellent material for making quantum bits, but the challenges in manufacturing have long remained a bottleneck,\" says Hendrickx. \"We've now solved these problems, and after that, it went very quickly. In the article in Nature, we show that we can perform reliable and extremely fast quantum calculations with germanium.\" \"This means that germanium has matured in about a year's time from constructing the material to a platform on which quantum calculations can be carried out,\" says Veldhorst. This development is unprecedentedly fast, and that is extremely promising on the road to a functional quantum computer.\" Research groups all over the world are developing germanium as a material for quantum bits. \"QuTech is the leading party in this field. We have been quick to develop germanium quantum technology and are optimistic about the possibilities for further upscaling. In addition, we are already looking at how we can collaborate with partners from industry, with the great advantage that our methods fit in well with the existing technology that provided the basis for our current information age,\" concludes Veldhorst. ", "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 Universal quantum information processing requires the execution of single-qubit and two-qubit logic. Across all qubit realizations 1 , spin qubits in quantum dots have great promise to become the central building block for quantum computation 2 . Excellent quantum dot control can be achieved in gallium arsenide 3 , 4 , 5 , and high-fidelity qubit rotations and two-qubit logic have been demonstrated in silicon 6 , 7 , 8 , 9 , but universal quantum logic implemented with local control has yet to be demonstrated. Here we make this step by combining all of these desirable aspects using hole quantum dots in germanium. Good control over tunnel coupling and detuning is obtained by exploiting quantum wells with very low disorder, enabling operation at the charge symmetry point for increased qubit performance. Spin–orbit coupling obviates the need for microscopic elements close to each qubit and enables rapid qubit control with driving frequencies exceeding 100 MHz. We demonstrate a fast universal quantum gate set composed of single-qubit gates with a fidelity of 99.3 per cent and a gate time of 20 nanoseconds, and two-qubit logic operations executed within 75 nanoseconds. Planar germanium has thus matured within a year from a material that can host quantum dots to a platform enabling two-qubit logic, positioning itself as an excellent material for use in quantum information applications. Main Gate-defined quantum dots were recognized early on as a promising platform for quantum information 2 and many materials have been investigated as hosts for the quantum dots. Initial research mainly focused on the low-disorder semiconductor gallium arsenide 10 , 11 . Steady progress in the control and understanding of this system culminated in the initial demonstration and optimization of spin qubit operations 12 and the realization of rudimentary analogue quantum simulations 3 . However, the omnipresent hyperfine interactions in group III–V materials seriously deteriorate the spin coherence. Considerable improvements to the coherence times could be achieved by switching to the group IV semiconductor silicon, in particular when defining spin qubits in an isotopically purified host crystal with vanishing concentrations of non-zero nuclear spins 13 . This enabled single-qubit rotations with fidelities beyond 99.9% 7 and the execution of two-qubit logic gates with fidelities up to 98% 6 , 8 , 9 , underlining the potential of spin qubits for quantum computation. Nevertheless, quantum dots in silicon are often formed at unintended locations, and control over the tunnel coupling determining the strength of two-qubit interactions is limited. Moreover, the absence of a sizable spin–orbit coupling for electrons in silicon requires the inclusion of microscopic components such as on-chip striplines or nanomagnets close to each qubit, which complicates the design of large and dense two-dimensional (2D) structures. Scalability thus remains a challenge for these systems, and a platform that can overcome these limitations would be highly desirable. Hole states in semiconductors 14 typically exhibit strong spin–orbit coupling (SOC), which has enabled the demonstration of fast single-qubit rotations 15 , 16 , 17 . Furthermore, whereas valley degeneracy complicates qubit definition for electrons in silicon, this is absent for holes, and excited states can be well separated in energy. In silicon, unfavourable band alignment prevents strain engineering of low-disorder quantum wells for holes, restricting experiments to metal–oxide–semiconductor structures 18 . Research on germanium has mostly focused on self-assembled nanowires 19 and has demonstrated single-shot spin readout 20 and coherent spin control 17 . However, strained germanium can reach hole mobilities 21 of μ > 10 6 cm 2 V −1 s −1 , and undoped germanium quantum wells were recently shown to support the formation of gate-controlled hole quantum dots 22 . Now, the crucial challenge is the demonstration of coherent control in this platform and the implementation of qubit–qubit gates for scalable quantum information with holes. Here we make this step and demonstrate single- and two-qubit logic with holes in planar germanium. We fabricate devices on silicon substrates, using standard manufacturing materials. We grow undoped strained germanium quantum wells, measured to have high hole mobilities μ > 5 × 10 5 cm 2 V −1 s −1 and a low effective hole mass 22 , 23 m h = 0.09 m e , extrapolated to reach m h = 0.05 m e at zero density 24 , with m e the electron rest mass. This allows us to define quantum dots of comparatively large size, and we find excellent control over the exchange interaction between the two dots. We operate in a multi-hole mode, reducing challenges in tuning and characterization, which is advantageous for scaling. We make use of the spin–orbit interaction for qubit driving and perform single-qubit rotations at frequencies exceeding 100 MHz. This advantage of fast driving becomes further apparent in coherently accessing the Hilbert space of a two-qubit system. For example, in silicon the execution of a controlled NOT (CNOT) gate implemented with an on-chip stripline has been shown using microsecond long pulses 6 , 8 , and this timescale can be reduced to 0.2–0.5 μs by incorporating nanomagnets 9 . Here we demonstrate that the spin–orbit coupling of holes in germanium together with the sizable exchange interaction enables a CNOT within 75 ns. A scanning electron microscope image of the germanium two-qubit device is shown in Fig. 1a . To accumulate holes and define two quantum dots, the circular plunger gates are set to negative potential ( V P1 , V P2 ≈ −2 V). The tunnel coupling between the dots t 12 and the tunnel couplings to the source and drain reservoirs ( t 1S , t 2D ) are controlled by the barrier gates BC, BS and BD, respectively. Working in a virtual gate voltage space ( V V P1 , V V P2 , V t 1S , V t 2D and V t 12 ), we can independently tune these properties (see Supplementary Videos 1 – 3 online for video-mode operation). We measure the transport current through the double dot system (Fig. 1c, d ), and for certain hole<|im_end|> <|im_start|>assistant Transistors based on germanium can perform calculations for future quantum computers. This discovery by the team of Menno Veldhorst is reported in Nature. The development of quantum computing seems to be going very quickly. The building blocks for such a computer are so-called quantum bits. Over the past two decades, researchers around the world have studied new and existing systems to function as quantum bits, including transistors. These tiny switches are present in billions on the chips of our computers, telephones and televisions. "We have been working with transistors as the building blocks for a quantum computer for some time, now," says Nico Hendrickx, first author and Ph.D. student at QuTech. "Until now, however, it hasn't been possible to perform quantum calculations using only transistors. Other elements were needed, as well, and this provided a limitation for upscaling. We now show that a single transistor can function as a quantum bit by using germanium." 1947 "The very first transistor from 1947 was made of germanium. The whole semiconductor revolution, and thus our mobile phones and all other electronics, could, in theory, have been based on germanium instead of silicon," says principal researcher Menno Veldhorst. "After all, it was known in 1947 that germanium actually has better properties as a semiconductor than silicon. But it turned out that there were difficulties in manufacturing, which made silicon the material of choice for the semiconductor industry." The team in the lab (from top to bottom, from left to right): Menno Veldhorst, Amir Sammak, Giordano Scappucci, Nico Hendrickx and David Franke. Credit: Ernst de Groot for QuTech Platform "We also already knew that germanium could be an excellent material for making quantum bits, but the challenges in manufacturing have long remained a bottleneck," says Hendrickx. "We've now solved these problems, and after that, it went very quickly. In the article in Nature, we show that we can perform reliable and extremely fast quantum calculations with germanium." "This means that germanium has matured in about a year's time from constructing the material to a platform on which quantum calculations can be carried out," says Veldhorst. This development is unprecedentedly fast, and that is extremely promising on the road to a functional quantum computer." Research groups all over the world are developing germanium as a material for quantum bits. "QuTech is the leading party in this field. We have been quick to develop germanium quantum technology and are optimistic about the possibilities for further upscaling. In addition, we are already looking at how we can collaborate with partners from industry, with the great advantage that our methods fit in well with the existing technology that provided the basis for our current information age," concludes Veldhorst. <|im_end|>

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369, 69311, 31228, 2038, 449, 20349, 13, 5810, 584, 1304, 420, 3094, 323, 20461, 3254, 12, 323, 1403, 52708, 60320, 12496, 449, 20349, 304, 3197, 277, 43627, 2411, 13, 1226, 13354, 349, 7766, 389, 51692, 16146, 988, 11, 1701, 5410, 15266, 7384, 13, 1226, 3139, 2073, 16771, 73779, 43627, 2411, 31228, 48396, 11, 17303, 311, 617, 1579, 14512, 12881, 4396, 33983, 871, 220, 20, 25800, 220, 605, 220, 20, 10166, 220, 17, 650, 25173, 16, 274, 25173, 16, 323, 264, 3428, 7524, 14512, 3148, 220, 1313, 1174, 220, 1419, 296, 305, 284, 220, 15, 13, 2545, 296, 384, 1174, 71462, 660, 311, 5662, 296, 305, 284, 220, 15, 13, 2304, 296, 384, 520, 7315, 17915, 220, 1187, 1174, 449, 296, 384, 279, 17130, 2800, 3148, 13, 1115, 6276, 603, 311, 7124, 31228, 32094, 315, 71561, 3544, 1404, 11, 323, 584, 1505, 9250, 2585, 927, 279, 9473, 16628, 1990, 279, 1403, 32094, 13, 1226, 14816, 304, 264, 7447, 87693, 3941, 11, 18189, 11774, 304, 42438, 323, 60993, 11, 902, 374, 76824, 369, 28041, 13, 1226, 1304, 1005, 315, 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1,942

[ { "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 Polyploid species have long been thought to be recalcitrant to whole-genome assembly. By combining high-throughput sequencing, recent developments in parallel computing, and genetic mapping, we derive, de novo , a sequence assembly representing 9.1 Gbp of the highly repetitive 16 Gbp genome of hexaploid wheat, Triticum aestivum , and assign 7.1 Gb of this assembly to chromosomal locations. The genome representation and accuracy of our assembly is comparable or even exceeds that of a chromosome-by-chromosome shotgun assembly. Our assembly and mapping strategy uses only short read sequencing technology and is applicable to any species where it is possible to construct a mapping population. Background The feasibility of whole-genome shotgun (WGS) assembly of large and complex eukaryotic genomes was once a much-debated question [ 1 , 2 ]. The advent of next-generation sequencing and the comparative ease and speed with which WGS assemblies can be constructed for mammalian and many other genomes allowed sequencing projects to move beyond these concerns, accepting high quality draft genomes with nearly complete gene spaces. Some genomes, however, are larger and more complex than the typical mammalian genome, including those of salamanders (>20 gigabases (Gbp)) [ 3 ], hexaploid wheat (16 Gbp) [ 4 , 5 ], and conifers (20 Gbp) [ 6 ]. To mitigate some of the computational challenges of genome assembly from short next-generation sequencing reads for these more complex genomes, various ‘divide and conquer’ strategies have been developed. These strategies include chromosome sorting and capture [ 5 ], large-insert-clone pooling [ 6 , 7 ], and large-clone tiling paths [ 5 , 8 ]. While each approach reduces the sequence assembly problem to a set of smaller, more tractable problems, they require substantial resource development in advance of sequencing. Many of the arguments ‘against a whole-genome shotgun’ [ 2 ] remain valid today. WGS assemblies are often rough drafts consisting of numerous, small contigs with gaps of unknown size between them. Abundant transposable elements that often form nested structures are prone to collapse in WGS assembly, resulting in an underrepresentation and mis-assembly of repetitive sequences in the final assembly [ 9 ]. The experiences derived from sequencing large and highly repetitive plant genomes have made it clear that while WGS assemblies are typically able to deliver a rough draft of the non-repetitive portion of a genome, true reference sequences with high contiguity and near-complete genome representation are only accessible following the paradigm of clone-by-clone-sequencing [ 10 ]. Despite their shortcomings, WGS approaches for large genomes [ 11 ] have important advantages that include (1) simplicity of library preparation and (2) uniformity of coverage. However, for very large (>10 Gbp), complex or polyploid genomes substantial computational resources may be required simply to manage the volume of data, and to address the challenge of resolving near-identical genomic sequences that are longer than the scale set by read length and pairing information. While the human WGS assembly [ 12 ] and other chromosome-scale mammalian assemblies (for example, mouse [ 13 ]) are computational tours de force , they ultimately rely on non-sequence data such as physical maps to assemble the chromosomes. The largest WGS assemblies that have been attempted to date (Norway spruce [ 6 ], white spruce [ 14 ] and loblolly pine [ 15 ], all approximately 20 Gbp) remain highly fragmented and are not yet organized into chromosomes. Importantly, whole genome assemblies of polyploid genomes have not yet been attempted. Instead, artificial diploids in the case of autopolyploids such as potato [ 16 ] or the progenitor species of allopolyploids such as wheat [ 17 , 18 ] and rapeseed [ 19 ] have been sequenced. Hexaploid bread wheat ( Triticum aestivum L., 1C = 16 Gbp, 2n = 6x = 42) is one of the most important agricultural crops, along with rice and maize. It is widely believed, however, that the hexaploid wheat genome is recalcitrant to WGS assembly and genome-wide physical mapping due to a high repeat content and potential difficulties in separating homeologous loci in the different subgenomes, which are not problems with the diploid rice [ 20 ] and maize [ 21 ] genomes. An early attempt at a WGS assembly resulted in a highly fragmented and genetically unanchored assembly [ 4 ]. Therefore, it was considered necessary to isolate individual chromosomes by flow-cytometry prior to sequencing and assembly [ 22 ]. So far, the map-based sequence of a single chromosome has been completed [ 23 ] and shotgun assemblies of the remaining 40 chromosome arms have been published [ 5 ]. Here, we describe an integrated approach to WGS assembly and genome-wide genetic mapping in hexaploid wheat. We shotgun-sequenced two unrelated individuals and a population of their recombinant progeny to varying depths, and constructed an ultra-dense genetic map. By computationally integrating the WGS assemblies and the sequence-based genetic map, we produced linked assemblies that span entire chromosomes, albeit including only the accessible non-repetitive portion of the genome. We achieved short-range contiguity (half the assembly in contigs longer than 7 to 8 kilobases) and physical linkage (half the assembly in scaffolds longer than 20 to 25 kilobases) using large-scale WGS assembly. Longer-range linkage and ordering at the chromosome scale (hundreds of megabases) is achieved through a de novo ultra-dense genetic linkage map based on >10 million single nucleotide polymorphism (SNP) markers. This linkage map also provides internal validation of assembly correctness. We demonstrate that this approach can be used to assemble previously intractable genomes on the scale of the large and repetitive hexaploid bread wheat genome. At the same time, we expand methods similar to those applied in diploid species such as barley [ 24 ], horseshoe crab [ 25 ] or Caenorhabditis elegans [ 26 ] . Results Whole-genome shotgun assembly We generated a total of approximately 175-fold coverage (approximately 3 terabases) Illumina WGS sequence from two (hexaploid) bread wheat lines, ‘Synthetic W7984’ (30-fold coverage) and ‘Opata M85’ (15-fold), and a set of 90 doubled haploid (DH) lines derived from W7984/Opata F 1 hybrids; the ‘SynOpDH’", "role": "user" }, { "content": "Through a combination of high-throughput sequencing, high performance computing, and genetic mapping, DOE JGI researchers have derived a sequence assembly for the highly repetitive plant genome of bread wheat (Triticum aestivum). The researchers pointed out that the strategy they developed and applied to the polyploidy species bread wheat is also applicable to any species, for as long as a mapping population can be constructed. Genome researchers have spoken often of the challenges of sequencing plant genomes with more than two paired sets of chromosomes (polyploidy). For example, in the case of bread wheat (Triticum aestivum), multiple hybridization events have led to a genome that is five times larger than that of humans and more than 80 percent of it made up of repeat sequences. To generate a whole-genome shotgun assembly of such a complex genome, researchers need to be able to assemble short reads coming off next-generation sequencing platforms and also use significant computational resources to manage the data. In the January 31, 2015 issue of Genome Biology, an international team of researchers led by U.S. Department of Energy Joint Genome Institute (DOE JGI), a DOE Office of Science user facility managed by Lawrence Berkeley National Laboratory, described a strategy that employs the above criteria. Using short read sequencing technology, the team assembled over 9-billion basepairs (Gbp) of the 16 Gbp bread wheat genome using Meraculous, a whole genome assembler for next-generation sequencing data geared for large genomes, and access to the Edison supercomputer at the National Energy Research Scientific Computing Center (NERSC), another DOE user facility, saving the team days of compute time. The team's work follows the International Wheat Genome Sequencing Consortium's release of the bread wheat genome in Science. DOE JGI Chief Informatics Officer and former Plant Program head Dan Rokhsar noted that he and his colleagues took part in the IWGSC effort, contributing a dense genetic map. In the current paper, the team highlighted some of the differences between the IWGSC's sequence, and their own whole-genome shotgun draft genome assembly: \"At first glance, the summary statistics of our assembly might look unimpressive…However, the fraction of the genome in assembled contigs is in the same range as the chromosome-by- chromosome shotgun assembly of IWGSC (9.1 Gbp vs. 10.1 Gbp), suggesting that the problems are intrinsic to the wheat genome and short read datasets.\" They added that their whole-genome shotgun approach allowed them to anchor more than 7.1 Gbp of the genome to chromosomal locations, while from the previous reference sequence, only 4 Gbp is anchored. The impact of the team's whole-genome shotgun strategy was highlighted in a separate Genome Biology article, in which the authors compared the DOE JGI's plant genome sequence assembly against the bread wheat sequence released in Science last year. They noted that, \"The combination of whole genome shotgun sequencing and linkage mapping by skim sequencing produced a better genome assembly than both the chromosome arm-based assembly and a previously described whole genome shotgun sequencing assembly approach.\" Additionally, they concluded that \"[this method] … should also be applied to draft genome sequencing of all species, both diploid and polyploid. The team also compared the utility of their whole-genome shotgun assembly of the bread wheat plant genome to the \"highly fragmented assembly\" of barley, which is a DOE JGI Community Science Program project. They noted that the barley assembly has enabled the development of reference-based genetic mapping and cost-efficient resequencing strategies, among other benefits. The longer-term impact of this work is that this improved strategy for dealing with large and complex genomes (frequently characteristic of plants that, as potential biofuel feedstocks, are of major interest to DOE) will accelerate and advance the sequencing of, and exploitation of, plant genomes. ", "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 Polyploid species have long been thought to be recalcitrant to whole-genome assembly. By combining high-throughput sequencing, recent developments in parallel computing, and genetic mapping, we derive, de novo , a sequence assembly representing 9.1 Gbp of the highly repetitive 16 Gbp genome of hexaploid wheat, Triticum aestivum , and assign 7.1 Gb of this assembly to chromosomal locations. The genome representation and accuracy of our assembly is comparable or even exceeds that of a chromosome-by-chromosome shotgun assembly. Our assembly and mapping strategy uses only short read sequencing technology and is applicable to any species where it is possible to construct a mapping population. Background The feasibility of whole-genome shotgun (WGS) assembly of large and complex eukaryotic genomes was once a much-debated question [ 1 , 2 ]. The advent of next-generation sequencing and the comparative ease and speed with which WGS assemblies can be constructed for mammalian and many other genomes allowed sequencing projects to move beyond these concerns, accepting high quality draft genomes with nearly complete gene spaces. Some genomes, however, are larger and more complex than the typical mammalian genome, including those of salamanders (>20 gigabases (Gbp)) [ 3 ], hexaploid wheat (16 Gbp) [ 4 , 5 ], and conifers (20 Gbp) [ 6 ]. To mitigate some of the computational challenges of genome assembly from short next-generation sequencing reads for these more complex genomes, various ‘divide and conquer’ strategies have been developed. These strategies include chromosome sorting and capture [ 5 ], large-insert-clone pooling [ 6 , 7 ], and large-clone tiling paths [ 5 , 8 ]. While each approach reduces the sequence assembly problem to a set of smaller, more tractable problems, they require substantial resource development in advance of sequencing. Many of the arguments ‘against a whole-genome shotgun’ [ 2 ] remain valid today. WGS assemblies are often rough drafts consisting of numerous, small contigs with gaps of unknown size between them. Abundant transposable elements that often form nested structures are prone to collapse in WGS assembly, resulting in an underrepresentation and mis-assembly of repetitive sequences in the final assembly [ 9 ]. The experiences derived from sequencing large and highly repetitive plant genomes have made it clear that while WGS assemblies are typically able to deliver a rough draft of the non-repetitive portion of a genome, true reference sequences with high contiguity and near-complete genome representation are only accessible following the paradigm of clone-by-clone-sequencing [ 10 ]. Despite their shortcomings, WGS approaches for large genomes [ 11 ] have important advantages that include (1) simplicity of library preparation and (2) uniformity of coverage. However, for very large (>10 Gbp), complex or polyploid genomes substantial computational resources may be required simply to manage the volume of data, and to address the challenge of resolving near-identical genomic sequences that are longer than the scale set by read length and pairing information. While the human WGS assembly [ 12 ] and other chromosome-scale mammalian assemblies (for example, mouse [ 13 ]) are computational tours de force , they ultimately rely on non-sequence data such as physical maps to assemble the chromosomes. The largest WGS assemblies that have been attempted to date (Norway spruce [ 6 ], white spruce [ 14 ] and loblolly pine [ 15 ], all approximately 20 Gbp) remain highly fragmented and are not yet organized into chromosomes. Importantly, whole genome assemblies of polyploid genomes have not yet been attempted. Instead, artificial diploids in the case of autopolyploids such as potato [ 16 ] or the progenitor species of allopolyploids such as wheat [ 17 , 18 ] and rapeseed [ 19 ] have been sequenced. Hexaploid bread wheat ( Triticum aestivum L., 1C = 16 Gbp, 2n = 6x = 42) is one of the most important agricultural crops, along with rice and maize. It is widely believed, however, that the hexaploid wheat genome is recalcitrant to WGS assembly and genome-wide physical mapping due to a high repeat content and potential difficulties in separating homeologous loci in the different subgenomes, which are not problems with the diploid rice [ 20 ] and maize [ 21 ] genomes. An early attempt at a WGS assembly resulted in a highly fragmented and genetically unanchored assembly [ 4 ]. Therefore, it was considered necessary to isolate individual chromosomes by flow-cytometry prior to sequencing and assembly [ 22 ]. So far, the map-based sequence of a single chromosome has been completed [ 23 ] and shotgun assemblies of the remaining 40 chromosome arms have been published [ 5 ]. Here, we describe an integrated approach to WGS assembly and genome-wide genetic mapping in hexaploid wheat. We shotgun-sequenced two unrelated individuals and a population of their recombinant progeny to varying depths, and constructed an ultra-dense genetic map. By computationally integrating the WGS assemblies and the sequence-based genetic map, we produced linked assemblies that span entire chromosomes, albeit including only the accessible non-repetitive portion of the genome. We achieved short-range contiguity (half the assembly in contigs longer than 7 to 8 kilobases) and physical linkage (half the assembly in scaffolds longer than 20 to 25 kilobases) using large-scale WGS assembly. Longer-range linkage and ordering at the chromosome scale (hundreds of megabases) is achieved through a de novo ultra-dense genetic linkage map based on >10 million single nucleotide polymorphism (SNP) markers. This linkage map also provides internal validation of assembly correctness. We demonstrate that this approach can be used to assemble previously intractable genomes on the scale of the large and repetitive hexaploid bread wheat genome. At the same time, we expand methods similar to those applied in diploid species such as barley [ 24 ], horseshoe crab [ 25 ] or Caenorhabditis elegans [ 26 ] . Results Whole-genome shotgun assembly We generated a total of approximately 175-fold coverage (approximately 3 terabases) Illumina WGS sequence from two (hexaploid) bread wheat lines, ‘Synthetic W7984’ (30-fold coverage) and ‘Opata M85’ (15-fold), and a set of 90 doubled haploid (DH) lines derived from W7984/Opata F 1 hybrids; the ‘SynOpDH’<|im_end|> <|im_start|>assistant Through a combination of high-throughput sequencing, high performance computing, and genetic mapping, DOE JGI researchers have derived a sequence assembly for the highly repetitive plant genome of bread wheat (Triticum aestivum). The researchers pointed out that the strategy they developed and applied to the polyploidy species bread wheat is also applicable to any species, for as long as a mapping population can be constructed. Genome researchers have spoken often of the challenges of sequencing plant genomes with more than two paired sets of chromosomes (polyploidy). For example, in the case of bread wheat (Triticum aestivum), multiple hybridization events have led to a genome that is five times larger than that of humans and more than 80 percent of it made up of repeat sequences. To generate a whole-genome shotgun assembly of such a complex genome, researchers need to be able to assemble short reads coming off next-generation sequencing platforms and also use significant computational resources to manage the data. In the January 31, 2015 issue of Genome Biology, an international team of researchers led by U.S. Department of Energy Joint Genome Institute (DOE JGI), a DOE Office of Science user facility managed by Lawrence Berkeley National Laboratory, described a strategy that employs the above criteria. Using short read sequencing technology, the team assembled over 9-billion basepairs (Gbp) of the 16 Gbp bread wheat genome using Meraculous, a whole genome assembler for next-generation sequencing data geared for large genomes, and access to the Edison supercomputer at the National Energy Research Scientific Computing Center (NERSC), another DOE user facility, saving the team days of compute time. The team's work follows the International Wheat Genome Sequencing Consortium's release of the bread wheat genome in Science. DOE JGI Chief Informatics Officer and former Plant Program head Dan Rokhsar noted that he and his colleagues took part in the IWGSC effort, contributing a dense genetic map. In the current paper, the team highlighted some of the differences between the IWGSC's sequence, and their own whole-genome shotgun draft genome assembly: "At first glance, the summary statistics of our assembly might look unimpressive…However, the fraction of the genome in assembled contigs is in the same range as the chromosome-by- chromosome shotgun assembly of IWGSC (9.1 Gbp vs. 10.1 Gbp), suggesting that the problems are intrinsic to the wheat genome and short read datasets." They added that their whole-genome shotgun approach allowed them to anchor more than 7.1 Gbp of the genome to chromosomal locations, while from the previous reference sequence, only 4 Gbp is anchored. The impact of the team's whole-genome shotgun strategy was highlighted in a separate Genome Biology article, in which the authors compared the DOE JGI's plant genome sequence assembly against the bread wheat sequence released in Science last year. They noted that, "The combination of whole genome shotgun sequencing and linkage mapping by skim sequencing produced a better genome assembly than both the chromosome arm-based assembly and a previously described whole genome shotgun sequencing assembly approach." Additionally, they concluded that "[this method] … should also be applied to draft genome sequencing of all species, both diploid and polyploid. The team also compared the utility of their whole-genome shotgun assembly of the bread wheat plant genome to the "highly fragmented assembly" of barley, which is a DOE JGI Community Science Program project. They noted that the barley assembly has enabled the development of reference-based genetic mapping and cost-efficient resequencing strategies, among other benefits. The longer-term impact of this work is that this improved strategy for dealing with large and complex genomes (frequently characteristic of plants that, as potential biofuel feedstocks, are of major interest to DOE) will accelerate and advance the sequencing of, and exploitation of, plant genomes. <|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 wing patterns of butterflies and moths (Lepidoptera) are diverse and striking examples of evolutionary diversification by natural selection 1 , 2 . Lepidopteran wing colour patterns are a key innovation, consisting of arrays of coloured scales. We still lack a general understanding of how these patterns are controlled and whether this control shows any commonality across the 160,000 moth and 17,000 butterfly species. Here, we use fine-scale mapping with population genomics and gene expression analyses to identify a gene, cortex , that regulates pattern switches in multiple species across the mimetic radiation in Heliconius butterflies. cortex belongs to a fast-evolving subfamily of the otherwise highly conserved fizzy family of cell-cycle regulators 3 , suggesting that it probably regulates pigmentation patterning by regulating scale cell development. In parallel with findings in the peppered moth ( Biston betularia ) 4 , our results suggest that this mechanism is common within Lepidoptera and that cortex has become a major target for natural selection acting on colour and pattern variation in this group of insects. Main In Heliconius , there is a major effect locus, Yb , that controls a diversity of colour pattern elements across the genus. It is the only locus in Heliconius that regulates all scale types and colours, including the diversity of white and yellow pattern elements in the two co-mimics H. melpomene and H. erato , and whole-wing variation in black, yellow, white, and orange/red elements in H. numata 5 , 6 , 7 . In addition, genetic variation underlying the Bigeye wing pattern mutation in Bicyclus anynana , melanism in the peppered moth, Biston betularia , and melanism and patterning differences in the silkmoth, Bombyx mori , have all been localized to homologous genomic regions 8 , 9 , 10 ( Fig. 1 ). Therefore, this genomic region appears to contain one or more genes that act as major regulators of wing pigmentation and patterning across the Lepidoptera. Figure 1: A homologous genomic region controls a diversity of phenotypes across the Lepidoptera. Left, phylogenetic relationships 29 . Right, chromosome maps with colour pattern intervals in grey; coloured bars represent markers used to assign homology 5 , 8 , 9 , 10 and the first and last genes from Fig. 2 are shown in red. In H. erato the HeCr locus controls the yellow hindwing bar phenotype (grey boxed races). In H. melpomene it controls both the yellow hindwing bar ( HmYb , pink box) and the yellow forewing band ( HmN , blue box). In H. numata it modulates black, yellow and orange elements on both wings ( HnP ), producing phenotypes that mimic butterflies in the genus Melinaea . Morphs/races of Heliconius species included in this study are shown with names. All images are by the authors or are in the public domain. PowerPoint slide Full size image Previous mapping of this locus in H. erato , H. melpomene and H. numata identified a genomic interval of about 1 Mb (refs 11 , 12 , 13 ) ( Extended Data Table 1 ), which also overlaps with the 1.4-Mb region containing the carbonaria locus in B. betularia 9 and a 100-bp non-coding region containing the Ws mutation in B. mori 10 ( Fig. 1 ). We used a population genomics approach to identify the single nucleotide polymorphisms (SNPs) that were most strongly associated with phenotypic variation within the approximately 1-Mb Heliconius interval. The diversity of wing patterning in Heliconius arises from divergence at wing pattern loci 7 , while convergent patterns generally involve the same loci and sometimes even the same alleles 14 , 15 , 16 . We used this pattern of divergence and sharing to identify SNPs associated with colour pattern elements across many individuals from a wide diversity of colour pattern phenotypes ( Fig. 2 ). Figure 2: Association analyses across the genomic region known to contain major colour pattern loci in Heliconius . a , Association in H. erato with the yellow hindwing bar ( n = 45). Coloured SNPs are fixed for a unique state in H. erato demophoon (orange) or H. erato favorinus (purple). b , Genes in H. erato with direct homologues in H. melpomene . Genes are in different colours with exons (coding and UTRs) connected by lines. Grey bars are transposable elements. c , H. melpomene genes and transposable elements. Colours correspond to homologous H. erato genes and microRNAs 30 are black. d , Association in the H. melpomene / timareta /silvaniform group with the yellow hindwing bar (red) and yellow forewing band (blue) ( n = 49). e , Association in H. numata with the bicoloratus morph ( n = 26); inversion positions 13 shown below. In all cases black or dark coloured points are above the strongest associations found outside the colour pattern scaffolds ( H. erato P = 1.63 × 10 −5 ; H. melpomene P = 2.03 × 10 −5 and P = 2.58 × 10 −5 for hindwing bar and forewing band, respectively; H. numata P = 6.81 × 10 −6 ). P values are from score tests for association. PowerPoint slide Source data Full size image In three separate Heliconius species, our analysis consistently implicated the gene cortex as being involved in adaptive differences in wing colour pattern. In H. erato the strongest associations with the presence of a yellow hindwing bar were centred around the genomic region containing cortex ( Fig. 2a ). We identified 108 SNPs that were fixed for one allele in H. erato favorinus , and fixed for the alternative allele in all individuals lacking the yellow bar; the majority of these SNPs were in introns of cortex ( Extended Data Table 2 ). Fifteen SNPs showed a similar fixed pattern for H. erato demophoon , which also has a yellow bar. These SNPs did not overlap with those in H. erato favorinus , consistent with the hypothesis that this phenotype evolved independently in the two disjunct populations 17 . Previous work has suggested that alleles", "role": "user" }, { "content": "The same gene that enables tropical butterflies to mimic each other's bright and colourful patterning also caused British moths to turn black amid the grime of the industrial revolution, researchers have found. Writing in the journal Nature, a team of researchers led by academics at the Universities of Cambridge and Sheffield, report that a fast-evolving gene known as \"cortex\" appears to play a critical role in dictating the colours and patterns on butterfly wings. A parallel paper in the same journal by researchers from the University of Liverpool shows that this same gene also caused the peppered moth to turn black during the mid-19th century, when it evolved to find new ways to camouflage itself; a side-effect of industrial pollution at the time. The finding offers clues about how genetics plays a role in making evolution a predictable process. For reasons the researchers have yet to understand in full, the cortex gene, which helps to regulate cell division in butterflies and moths, has become a major target for natural selection acting on colour and pattern on the wings. Chris Jiggins, Professor of Evolutionary Biology and a Fellow of St John's College, University of Cambridge, said: \"What's exciting is that it turns out to be the same gene in both cases. For the moths, the dark colouration developed because they were trying to hide, but the butterflies use bright colours to advertise their toxicity to predators. It raises the question that given the diversity in butterflies and moths, and the hundreds of genes involved in making a wing, why is it this one every time?\" Dr Nicola Nadeau, a NERC Research Fellow from the University of Sheffield added: \"It's amazing that the same gene controls such a diversity of different colours and patterns in butterflies and a moth. Our study, together with the findings from the University of Liverpool, shows that the cortex gene is important for colour and pattern evolution in this whole group of insects.\" Butterflies and moths comprise the order of insects known as Lepidoptera. Nearly all of the 160,000 types of moth and 17,000 types of butterfly have different wing patterns, which are adapted for purposes like attracting mates, giving off warnings, camouflage (also known as \"crypsis\"), and thermal regulation. These wing patterns are actually made up of tiny coloured scales arranged like tiles on a roof. Although they have been studied by biologists for over a century, the molecular mechanisms which control their development are only now starting to be uncovered. Heliconius melpomene butterfly. The Cambridge-Sheffield study shows that the same gene that influences these butterflies' bright and colorful patterns also turned the peppered moth black during the industrial revolution. Credit: Chris Jiggins, St John's College, University of Cambridge The peppered moth is one of the most famous examples of evolution by natural selection. Until the 19th Century, peppered moths were predominantly pale-coloured, and used this to camouflage themselves against lichen-covered tree trunks, which made them almost invisible to predators. During the industrial revolution, however, the lichen on trees in some parts of the country was killed by pollution, and soot turned the trunks black. A corresponding change was seen in the in peppered moths which turned black as well, helping them to remain camouflaged from birds. The process is known as industrial melanism - melanism meaning the development of dark coloured pigmentation. The Liverpool-led team found that this colour change was produced by a mutation in the cortex gene, which occurred during the mid 1800s, just before the first reported sighting of black peppered moths. Fascinatingly, however, the Cambridge-Sheffield study has now shown that exactly the same gene also influences the extremely bright and colourful patterns of Heliconius - the name given to about 40 different closely-related species of beautiful, tropical butterflies found in South America. Heliconius colour patterns are used to send a signal to potential predators that the butterflies are toxic if eaten, and different types of Heliconius butterfly mimic one another by using their bright colours as warning signals. Unlike the dark colouring of the peppered moth, it is therefore an evolutionary development that is meant to be seen. The researchers carried out fine-scale mapping, looking for parts of the DNA sequence that were specifically different in butterflies with different patterns, in three different Heliconius species, and in each case the cortex gene was found to be responsible for this adaptation in their patterning. Because Heliconius species are extremely diverse, the study of what causes variations in their patterning can provide more general clues about the genetic switches that control diversification in species. In most cases, the genes responsible for these processes are known as \"transcription factors\" - meaning that they are responsible for turning other genes on and off. Intriguingly, what made cortex such an elusive switch to spot was the fact that it does not do this. Instead, it is a cell cycle regulator, which means that it controls when cells divide and thus when different coloured scales develop within a butterfly wing. \"It's a different gene to the one we might have expected and we still need to do more to understand exactly what it's doing, and how it's doing it,\" Jiggins said. Dr Nadeau added \"Our results are even more surprising because the cortex gene was previously thought to only be involved in producing egg cells in female insects, and is very similar to a gene that controls cell division in everything from yeast to humans.\" The study, The gene cortex controls mimicry and crypsis in butterflies and moths, is reported in the June 2 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 The wing patterns of butterflies and moths (Lepidoptera) are diverse and striking examples of evolutionary diversification by natural selection 1 , 2 . Lepidopteran wing colour patterns are a key innovation, consisting of arrays of coloured scales. We still lack a general understanding of how these patterns are controlled and whether this control shows any commonality across the 160,000 moth and 17,000 butterfly species. Here, we use fine-scale mapping with population genomics and gene expression analyses to identify a gene, cortex , that regulates pattern switches in multiple species across the mimetic radiation in Heliconius butterflies. cortex belongs to a fast-evolving subfamily of the otherwise highly conserved fizzy family of cell-cycle regulators 3 , suggesting that it probably regulates pigmentation patterning by regulating scale cell development. In parallel with findings in the peppered moth ( Biston betularia ) 4 , our results suggest that this mechanism is common within Lepidoptera and that cortex has become a major target for natural selection acting on colour and pattern variation in this group of insects. Main In Heliconius , there is a major effect locus, Yb , that controls a diversity of colour pattern elements across the genus. It is the only locus in Heliconius that regulates all scale types and colours, including the diversity of white and yellow pattern elements in the two co-mimics H. melpomene and H. erato , and whole-wing variation in black, yellow, white, and orange/red elements in H. numata 5 , 6 , 7 . In addition, genetic variation underlying the Bigeye wing pattern mutation in Bicyclus anynana , melanism in the peppered moth, Biston betularia , and melanism and patterning differences in the silkmoth, Bombyx mori , have all been localized to homologous genomic regions 8 , 9 , 10 ( Fig. 1 ). Therefore, this genomic region appears to contain one or more genes that act as major regulators of wing pigmentation and patterning across the Lepidoptera. Figure 1: A homologous genomic region controls a diversity of phenotypes across the Lepidoptera. Left, phylogenetic relationships 29 . Right, chromosome maps with colour pattern intervals in grey; coloured bars represent markers used to assign homology 5 , 8 , 9 , 10 and the first and last genes from Fig. 2 are shown in red. In H. erato the HeCr locus controls the yellow hindwing bar phenotype (grey boxed races). In H. melpomene it controls both the yellow hindwing bar ( HmYb , pink box) and the yellow forewing band ( HmN , blue box). In H. numata it modulates black, yellow and orange elements on both wings ( HnP ), producing phenotypes that mimic butterflies in the genus Melinaea . Morphs/races of Heliconius species included in this study are shown with names. All images are by the authors or are in the public domain. PowerPoint slide Full size image Previous mapping of this locus in H. erato , H. melpomene and H. numata identified a genomic interval of about 1 Mb (refs 11 , 12 , 13 ) ( Extended Data Table 1 ), which also overlaps with the 1.4-Mb region containing the carbonaria locus in B. betularia 9 and a 100-bp non-coding region containing the Ws mutation in B. mori 10 ( Fig. 1 ). We used a population genomics approach to identify the single nucleotide polymorphisms (SNPs) that were most strongly associated with phenotypic variation within the approximately 1-Mb Heliconius interval. The diversity of wing patterning in Heliconius arises from divergence at wing pattern loci 7 , while convergent patterns generally involve the same loci and sometimes even the same alleles 14 , 15 , 16 . We used this pattern of divergence and sharing to identify SNPs associated with colour pattern elements across many individuals from a wide diversity of colour pattern phenotypes ( Fig. 2 ). Figure 2: Association analyses across the genomic region known to contain major colour pattern loci in Heliconius . a , Association in H. erato with the yellow hindwing bar ( n = 45). Coloured SNPs are fixed for a unique state in H. erato demophoon (orange) or H. erato favorinus (purple). b , Genes in H. erato with direct homologues in H. melpomene . Genes are in different colours with exons (coding and UTRs) connected by lines. Grey bars are transposable elements. c , H. melpomene genes and transposable elements. Colours correspond to homologous H. erato genes and microRNAs 30 are black. d , Association in the H. melpomene / timareta /silvaniform group with the yellow hindwing bar (red) and yellow forewing band (blue) ( n = 49). e , Association in H. numata with the bicoloratus morph ( n = 26); inversion positions 13 shown below. In all cases black or dark coloured points are above the strongest associations found outside the colour pattern scaffolds ( H. erato P = 1.63 × 10 −5 ; H. melpomene P = 2.03 × 10 −5 and P = 2.58 × 10 −5 for hindwing bar and forewing band, respectively; H. numata P = 6.81 × 10 −6 ). P values are from score tests for association. PowerPoint slide Source data Full size image In three separate Heliconius species, our analysis consistently implicated the gene cortex as being involved in adaptive differences in wing colour pattern. In H. erato the strongest associations with the presence of a yellow hindwing bar were centred around the genomic region containing cortex ( Fig. 2a ). We identified 108 SNPs that were fixed for one allele in H. erato favorinus , and fixed for the alternative allele in all individuals lacking the yellow bar; the majority of these SNPs were in introns of cortex ( Extended Data Table 2 ). Fifteen SNPs showed a similar fixed pattern for H. erato demophoon , which also has a yellow bar. These SNPs did not overlap with those in H. erato favorinus , consistent with the hypothesis that this phenotype evolved independently in the two disjunct populations 17 . Previous work has suggested that alleles<|im_end|> <|im_start|>assistant The same gene that enables tropical butterflies to mimic each other's bright and colourful patterning also caused British moths to turn black amid the grime of the industrial revolution, researchers have found. Writing in the journal Nature, a team of researchers led by academics at the Universities of Cambridge and Sheffield, report that a fast-evolving gene known as "cortex" appears to play a critical role in dictating the colours and patterns on butterfly wings. A parallel paper in the same journal by researchers from the University of Liverpool shows that this same gene also caused the peppered moth to turn black during the mid-19th century, when it evolved to find new ways to camouflage itself; a side-effect of industrial pollution at the time. The finding offers clues about how genetics plays a role in making evolution a predictable process. For reasons the researchers have yet to understand in full, the cortex gene, which helps to regulate cell division in butterflies and moths, has become a major target for natural selection acting on colour and pattern on the wings. Chris Jiggins, Professor of Evolutionary Biology and a Fellow of St John's College, University of Cambridge, said: "What's exciting is that it turns out to be the same gene in both cases. For the moths, the dark colouration developed because they were trying to hide, but the butterflies use bright colours to advertise their toxicity to predators. It raises the question that given the diversity in butterflies and moths, and the hundreds of genes involved in making a wing, why is it this one every time?" Dr Nicola Nadeau, a NERC Research Fellow from the University of Sheffield added: "It's amazing that the same gene controls such a diversity of different colours and patterns in butterflies and a moth. Our study, together with the findings from the University of Liverpool, shows that the cortex gene is important for colour and pattern evolution in this whole group of insects." Butterflies and moths comprise the order of insects known as Lepidoptera. Nearly all of the 160,000 types of moth and 17,000 types of butterfly have different wing patterns, which are adapted for purposes like attracting mates, giving off warnings, camouflage (also known as "crypsis"), and thermal regulation. These wing patterns are actually made up of tiny coloured scales arranged like tiles on a roof. Although they have been studied by biologists for over a century, the molecular mechanisms which control their development are only now starting to be uncovered. Heliconius melpomene butterfly. The Cambridge-Sheffield study shows that the same gene that influences these butterflies' bright and colorful patterns also turned the peppered moth black during the industrial revolution. Credit: Chris Jiggins, St John's College, University of Cambridge The peppered moth is one of the most famous examples of evolution by natural selection. Until the 19th Century, peppered moths were predominantly pale-coloured, and used this to camouflage themselves against lichen-covered tree trunks, which made them almost invisible to predators. During the industrial revolution, however, the lichen on trees in some parts of the country was killed by pollution, and soot turned the trunks black. A corresponding change was seen in the in peppered moths which turned black as well, helping them to remain camouflaged from birds. The process is known as industrial melanism - melanism meaning the development of dark coloured pigmentation. The Liverpool-led team found that this colour change was produced by a mutation in the cortex gene, which occurred during the mid 1800s, just before the first reported sighting of black peppered moths. Fascinatingly, however, the Cambridge-Sheffield study has now shown that exactly the same gene also influences the extremely bright and colourful patterns of Heliconius - the name given to about 40 different closely-related species of beautiful, tropical butterflies found in South America. Heliconius colour patterns are used to send a signal to potential predators that the butterflies are toxic if eaten, and different types of Heliconius butterfly mimic one another by using their bright colours as warning signals. Unlike the dark colouring of the peppered moth, it is therefore an evolutionary development that is meant to be seen. The researchers carried out fine-scale mapping, looking for parts of the DNA sequence that were specifically different in butterflies with different patterns, in three different Heliconius species, and in each case the cortex gene was found to be responsible for this adaptation in their patterning. Because Heliconius species are extremely diverse, the study of what causes variations in their patterning can provide more general clues about the genetic switches that control diversification in species. In most cases, the genes responsible for these processes are known as "transcription factors" - meaning that they are responsible for turning other genes on and off. Intriguingly, what made cortex such an elusive switch to spot was the fact that it does not do this. Instead, it is a cell cycle regulator, which means that it controls when cells divide and thus when different coloured scales develop within a butterfly wing. "It's a different gene to the one we might have expected and we still need to do more to understand exactly what it's doing, and how it's doing it," Jiggins said. Dr Nadeau added "Our results are even more surprising because the cortex gene was previously thought to only be involved in producing egg cells in female insects, and is very similar to a gene that controls cell division in everything from yeast to humans." The study, The gene cortex controls mimicry and crypsis in butterflies and moths, is reported in the June 2 issue of Nature. <|im_end|>

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11, 3411, 369, 5596, 315, 279, 15922, 8668, 430, 1051, 11951, 2204, 304, 81776, 449, 2204, 12912, 11, 304, 2380, 2204, 16183, 1965, 9334, 9606, 11, 323, 304, 1855, 1162, 279, 49370, 15207, 574, 1766, 311, 387, 8647, 369, 420, 34185, 304, 872, 93093, 1251, 13, 9393, 16183, 1965, 9334, 9606, 527, 9193, 17226, 11, 279, 4007, 315, 1148, 11384, 27339, 304, 872, 93093, 1251, 649, 3493, 810, 4689, 43775, 922, 279, 19465, 32267, 430, 2585, 21797, 2461, 304, 9606, 13, 763, 1455, 5157, 11, 279, 21389, 8647, 369, 1521, 11618, 527, 3967, 439, 330, 1485, 1479, 9547, 1, 482, 7438, 430, 814, 527, 8647, 369, 13353, 1023, 21389, 389, 323, 1022, 13, 61894, 343, 7623, 398, 11, 1148, 1903, 49370, 1778, 459, 66684, 3480, 311, 7858, 574, 279, 2144, 430, 433, 1587, 539, 656, 420, 13, 12361, 11, 433, 374, 264, 2849, 11008, 40704, 11, 902, 3445, 430, 433, 11835, 994, 7917, 22497, 323, 8617, 994, 2204, 58919, 29505, 2274, 2949, 264, 56269, 20611, 13, 330, 2181, 596, 264, 2204, 15207, 311, 279, 832, 584, 2643, 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2,560

[ { "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 Resistance to Herceptin represents a significant challenge for successful treatment of HER2-positive breast cancer. Here, we show that in Herceptin-sensitive cells, FOXO3a regulates specific miRNAs to control IGF2 and IRS1 expression, retaining basic IGF2/IGF-1R/IRS1 signaling. The basic activity maintains expression of PPP3CB, a subunit of the serine/threonine-protein phosphatase 2B, to restrict FOXO3a phosphorylation (p-FOXO3a), inducing IGF2 - and IRS1 -targeting miRNAs. However, in Herceptin-resistant cells, p-FOXO3a levels are elevated due to transcriptional suppression of PPP3CB , disrupting the negative feedback inhibition loop formed by FOXO3a and the miRNAs, thereby upregulating IGF2 and IRS1. Moreover, we detect significantly increased IGF2 in blood and IRS1 in the tumors of breast cancer patients with poor response to Herceptin-containing regimens. Collectively, we demonstrate that the IGF2/IGF-1R/IRS1 signaling is aberrantly activated in Herceptin-resistant breast cancer via disruption of the FOXO3a-miRNA negative feedback inhibition. Such insights provide avenues to identify predictive biomarkers and effective strategies overcoming Herceptin resistance. Introduction Breast cancer is the leading cause of cancer-related deaths in women worldwide 1 . As a heterogeneous disease, breast cancer has been classified into several molecular subtypes 2 , including HER2-positive breast cancer which is defined as the subtype with amplified and/or overexpressed HER2 (or erbB2 ) gene 3 . Amplification/overexpression of HER2 is observed in approximately 20–25% of breast cancers and significantly associated with poor prognosis in breast cancer patients 3 , 4 , 5 . Herceptin (or trastuzumab), a humanized anti-HER2 monoclonal antibody (Ab), is an effective HER2-targeted therapy against early and metastatic HER2-positive breast cancers. It has dramatically improved survival of breast cancer patients with HER2-positive tumors 6 , 7 . However, not all HER2-positive breast cancers respond to Herceptin-based regimens. Majority of the patients who achieve an initial response become resistance within one year 8 , 9 , 10 . Resistant tumors likely recur and metastasize to distant organs, which accounts for approximately 90% of cancer deaths 4 , 11 . Many patients with advanced HER2-positive breast cancer ultimately develop brain metastasis 6 . Thus, both primary (de novo) and acquired resistances to Herceptin frequently occur and currently represent a significant clinical obstacle for successful treatment of HER2-positive breast cancer. To date, we lack validated biomarkers predictive for Herceptin response 7 , 12 . It is in urgent need to identify novel therapy overcoming Herceptin resistance with the aim to eliminate mortality of the patients with metastatic HER2-positive breast cancers. Several mechanisms of Herceptin resistance in HER2-positive breast cancer have been proposed 6 , 10 , 13 , 14 , 15 . Among them, compensatory signaling activation by another receptor tyrosine kinase (RTK) attenuates Herceptin binding efficiency due to HER2 dimerization with the RTK. It also provides survival advantage to breast cancer cells, thereby resulting in resistance to Herceptin 6 , 10 . Herceptin resistance can also occur through mechanisms that lead to HER2 reactivation via acquisition of HER2 L755S mutation 16 , activation of the PI-3K/Akt pathway via PIK3CA mutation 17 or PTEN loss 8 , or extracellular matrix triggered integrin β1/Src activation 18 . In addition, a number of studies implicate various components of the insulin-like growth factor (IGF) system in breast cancer progression 19 , 20 . IGF1 and IGF2 are the major ligands in this system, and potent mitogens and anti-apoptotic peptides that affect cancer cell proliferation and survival via activation of the insulin-like growth factor-1 receptor (IGF-1R) signaling. Herceptin-induced growth inhibition was lost in breast cancer cells that overexpressed both HER2 and IGF-1R, and the growth arrest was regained when IGF binding protein-3 (IGFBP-3), which blocked IGF-induced IGF-1R signaling, was added 21 . However, the expression of IGF-1R per se did not predict Herceptin resistance in patients with HER2-positive breast cancer 22 , suggesting that IGF-1R signaling via ligand-stimulation or interaction with another RTK was critical for the development of Herceptin resistance. Indeed, crosstalk occurred between IGF-1R and HER2, and IGF-1R physically interacted with HER2 and induced HER2 activation in Herceptin-resistant, but not -sensitive breast cancer cells 23 . Nonetheless, the precise mechanism through which IGF-1R signaling is highly activated in HER2-positive breast cancer resistant to Herceptin remains elusive. In this study, we seek to investigate the contributions of IGF2 and the insulin receptor substrate-1 (IRS1) to Herceptin resistance and elucidate the underlying mechanism of increased expression of both IGF2 and IRS1 and aberrant activation of IGF-1R signaling in Herceptin-resistant breast cancer. Results IGF2/IGF-1R/IRS1 signaling maintains Herceptin resistance phenotype Our previous studies showed that IGF-1R-initiated signaling played an important role leading to Herceptin resistance in HER2-positive breast cancer cells 24 . To elucidate the underlying mechanism, we explored the regulation of IGF-1R signaling using Herceptin-resistant sublines SKBR3-pool2 (pool2) and BT474-HR20 (HR20), derived from SKBR3 and BT474, respectively, two well-known HER2-positive breast cancer cell lines sensitive to Herceptin 24 . Pool2 and HR20 cells as compared to SKBR3 and BT474, respectively, were resistant to Herceptin-mediated growth inhibition (Supplementary Fig. 1a ). The resistance phenotype was confirmed in in vivo tumor xenografts models. While Herceptin significantly suppressed SKBR3-generated tumor growth in nude mice, it had little effect on the growth of tumors-established from pool2 cells (Supplementary Fig. 1b ). Consistent with our previous findings 24 , the protein levels of IGF-1R were similar in all cell lines (Fig. 1a ). However, the levels of IRS1 and phosphorylated IGF-1R (p-IGF1R), Akt (p-Akt (T308) and p-Akt (S473) ), S6K (p-S6K), and FOXO3a (p-FOXO3a) were much higher in pool2 and HR20 cells than that in SKBR3 and BT474 cells, respectively (Fig. 1a ). S6K is a downstream target of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) 25 , whereas Akt (S473) and FOXO3a are downstream targets of mTOR complex 2 (mTORC2) 26 , 27 . The increase of p-Akt (S473) , p-S6K, and p-FOXO3a suggested activation of both mTORC1 and mTORC2 in the resistant cells. To determine whether the ligands for IGF-1R might trigger activation of the signaling, we examined mRNA expression of IGF1 and IGF2 in the cells by quantitative real-time PCR (qRT-PCR) and measured the protein levels of", "role": "user" }, { "content": "Research conducted by an international team of scientists discovered a mechanism that leads to Herceptin resistance, representing a significant clinical obstacle to successfully treating HER2-positive breast cancer. They also identified a new approach to potentially overcome it. The work is published online in Nature Communications. \"This work attempts to understand why some HER2-positive breast cancer patients do not benefit from treatment with Herceptin, which is a generally effective HER2-targeted therapy,\" explains Bolin Liu, MD, Professor of Genetics at LSU Health New Orleans' School of Medicine and Stanley S. Scott Cancer Center. The researchers found increased signaling by IGF2/IRS1 (genes involved in regulating cell proliferation, growth, migration, differentiation and survival) in the HER2-positive breast cancer cells poorly responding to Herceptin. Further studies showed that disruption of a negative feedback loop formed by an important protein, FOXO3a, and several miRNAs that are controlled by FOXO3a causes abnormal activation of the IGF2/IRS1 signal, thereby leading to Herceptin resistance. \"Resistance to Herceptin frequently occurs and currently represents a major clinical challenge for successful treatment of HER2-positive breast cancer,\" notes Dr. Liu. \"Data presented in the study not only improve our understanding of the molecular mechanism through which IGF-1R signaling activation leads to Herceptin resistance, but also promote identification of precision therapies to reverse the resistance phenotype.\" The researchers write, \"Breast cancer is the leading cause of cancer-related deaths in women worldwide. HER2-positive breast cancer is defined as a breast cancer subtype with amplified and/or overexpressed HER2 (or erbB2) gene. Amplification/overexpression of HER2 is observed in approximately 20-25% of breast cancers and is significantly associated with poor prognosis in breast cancer patients. Herceptin (or trastuzumab), a humanized anti-HER2 monoclonal antibody (Ab), is an effective HER2-targeted therapy against early and metastatic HER2-positive breast cancers. It has dramatically improved the survival of breast cancer patients with HER2-positive tumors, but not all HER2-positive breast cancers respond to Herceptin-based regimens. To date, we lack validated biomarkers predictive for Herceptin response.\" \"Our results may provide new avenues to identify useful biomarkers predictive for Herceptin efficacy and facilitate the development of novel approaches to enhance HER2-targeted therapy, thereby improving the survival of refractory breast cancer patients,\" Dr. Liu 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 Resistance to Herceptin represents a significant challenge for successful treatment of HER2-positive breast cancer. Here, we show that in Herceptin-sensitive cells, FOXO3a regulates specific miRNAs to control IGF2 and IRS1 expression, retaining basic IGF2/IGF-1R/IRS1 signaling. The basic activity maintains expression of PPP3CB, a subunit of the serine/threonine-protein phosphatase 2B, to restrict FOXO3a phosphorylation (p-FOXO3a), inducing IGF2 - and IRS1 -targeting miRNAs. However, in Herceptin-resistant cells, p-FOXO3a levels are elevated due to transcriptional suppression of PPP3CB , disrupting the negative feedback inhibition loop formed by FOXO3a and the miRNAs, thereby upregulating IGF2 and IRS1. Moreover, we detect significantly increased IGF2 in blood and IRS1 in the tumors of breast cancer patients with poor response to Herceptin-containing regimens. Collectively, we demonstrate that the IGF2/IGF-1R/IRS1 signaling is aberrantly activated in Herceptin-resistant breast cancer via disruption of the FOXO3a-miRNA negative feedback inhibition. Such insights provide avenues to identify predictive biomarkers and effective strategies overcoming Herceptin resistance. Introduction Breast cancer is the leading cause of cancer-related deaths in women worldwide 1 . As a heterogeneous disease, breast cancer has been classified into several molecular subtypes 2 , including HER2-positive breast cancer which is defined as the subtype with amplified and/or overexpressed HER2 (or erbB2 ) gene 3 . Amplification/overexpression of HER2 is observed in approximately 20–25% of breast cancers and significantly associated with poor prognosis in breast cancer patients 3 , 4 , 5 . Herceptin (or trastuzumab), a humanized anti-HER2 monoclonal antibody (Ab), is an effective HER2-targeted therapy against early and metastatic HER2-positive breast cancers. It has dramatically improved survival of breast cancer patients with HER2-positive tumors 6 , 7 . However, not all HER2-positive breast cancers respond to Herceptin-based regimens. Majority of the patients who achieve an initial response become resistance within one year 8 , 9 , 10 . Resistant tumors likely recur and metastasize to distant organs, which accounts for approximately 90% of cancer deaths 4 , 11 . Many patients with advanced HER2-positive breast cancer ultimately develop brain metastasis 6 . Thus, both primary (de novo) and acquired resistances to Herceptin frequently occur and currently represent a significant clinical obstacle for successful treatment of HER2-positive breast cancer. To date, we lack validated biomarkers predictive for Herceptin response 7 , 12 . It is in urgent need to identify novel therapy overcoming Herceptin resistance with the aim to eliminate mortality of the patients with metastatic HER2-positive breast cancers. Several mechanisms of Herceptin resistance in HER2-positive breast cancer have been proposed 6 , 10 , 13 , 14 , 15 . Among them, compensatory signaling activation by another receptor tyrosine kinase (RTK) attenuates Herceptin binding efficiency due to HER2 dimerization with the RTK. It also provides survival advantage to breast cancer cells, thereby resulting in resistance to Herceptin 6 , 10 . Herceptin resistance can also occur through mechanisms that lead to HER2 reactivation via acquisition of HER2 L755S mutation 16 , activation of the PI-3K/Akt pathway via PIK3CA mutation 17 or PTEN loss 8 , or extracellular matrix triggered integrin β1/Src activation 18 . In addition, a number of studies implicate various components of the insulin-like growth factor (IGF) system in breast cancer progression 19 , 20 . IGF1 and IGF2 are the major ligands in this system, and potent mitogens and anti-apoptotic peptides that affect cancer cell proliferation and survival via activation of the insulin-like growth factor-1 receptor (IGF-1R) signaling. Herceptin-induced growth inhibition was lost in breast cancer cells that overexpressed both HER2 and IGF-1R, and the growth arrest was regained when IGF binding protein-3 (IGFBP-3), which blocked IGF-induced IGF-1R signaling, was added 21 . However, the expression of IGF-1R per se did not predict Herceptin resistance in patients with HER2-positive breast cancer 22 , suggesting that IGF-1R signaling via ligand-stimulation or interaction with another RTK was critical for the development of Herceptin resistance. Indeed, crosstalk occurred between IGF-1R and HER2, and IGF-1R physically interacted with HER2 and induced HER2 activation in Herceptin-resistant, but not -sensitive breast cancer cells 23 . Nonetheless, the precise mechanism through which IGF-1R signaling is highly activated in HER2-positive breast cancer resistant to Herceptin remains elusive. In this study, we seek to investigate the contributions of IGF2 and the insulin receptor substrate-1 (IRS1) to Herceptin resistance and elucidate the underlying mechanism of increased expression of both IGF2 and IRS1 and aberrant activation of IGF-1R signaling in Herceptin-resistant breast cancer. Results IGF2/IGF-1R/IRS1 signaling maintains Herceptin resistance phenotype Our previous studies showed that IGF-1R-initiated signaling played an important role leading to Herceptin resistance in HER2-positive breast cancer cells 24 . To elucidate the underlying mechanism, we explored the regulation of IGF-1R signaling using Herceptin-resistant sublines SKBR3-pool2 (pool2) and BT474-HR20 (HR20), derived from SKBR3 and BT474, respectively, two well-known HER2-positive breast cancer cell lines sensitive to Herceptin 24 . Pool2 and HR20 cells as compared to SKBR3 and BT474, respectively, were resistant to Herceptin-mediated growth inhibition (Supplementary Fig. 1a ). The resistance phenotype was confirmed in in vivo tumor xenografts models. While Herceptin significantly suppressed SKBR3-generated tumor growth in nude mice, it had little effect on the growth of tumors-established from pool2 cells (Supplementary Fig. 1b ). Consistent with our previous findings 24 , the protein levels of IGF-1R were similar in all cell lines (Fig. 1a ). However, the levels of IRS1 and phosphorylated IGF-1R (p-IGF1R), Akt (p-Akt (T308) and p-Akt (S473) ), S6K (p-S6K), and FOXO3a (p-FOXO3a) were much higher in pool2 and HR20 cells than that in SKBR3 and BT474 cells, respectively (Fig. 1a ). S6K is a downstream target of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) 25 , whereas Akt (S473) and FOXO3a are downstream targets of mTOR complex 2 (mTORC2) 26 , 27 . The increase of p-Akt (S473) , p-S6K, and p-FOXO3a suggested activation of both mTORC1 and mTORC2 in the resistant cells. To determine whether the ligands for IGF-1R might trigger activation of the signaling, we examined mRNA expression of IGF1 and IGF2 in the cells by quantitative real-time PCR (qRT-PCR) and measured the protein levels of<|im_end|> <|im_start|>assistant Research conducted by an international team of scientists discovered a mechanism that leads to Herceptin resistance, representing a significant clinical obstacle to successfully treating HER2-positive breast cancer. They also identified a new approach to potentially overcome it. The work is published online in Nature Communications. "This work attempts to understand why some HER2-positive breast cancer patients do not benefit from treatment with Herceptin, which is a generally effective HER2-targeted therapy," explains Bolin Liu, MD, Professor of Genetics at LSU Health New Orleans' School of Medicine and Stanley S. Scott Cancer Center. The researchers found increased signaling by IGF2/IRS1 (genes involved in regulating cell proliferation, growth, migration, differentiation and survival) in the HER2-positive breast cancer cells poorly responding to Herceptin. Further studies showed that disruption of a negative feedback loop formed by an important protein, FOXO3a, and several miRNAs that are controlled by FOXO3a causes abnormal activation of the IGF2/IRS1 signal, thereby leading to Herceptin resistance. "Resistance to Herceptin frequently occurs and currently represents a major clinical challenge for successful treatment of HER2-positive breast cancer," notes Dr. Liu. "Data presented in the study not only improve our understanding of the molecular mechanism through which IGF-1R signaling activation leads to Herceptin resistance, but also promote identification of precision therapies to reverse the resistance phenotype." The researchers write, "Breast cancer is the leading cause of cancer-related deaths in women worldwide. HER2-positive breast cancer is defined as a breast cancer subtype with amplified and/or overexpressed HER2 (or erbB2) gene. Amplification/overexpression of HER2 is observed in approximately 20-25% of breast cancers and is significantly associated with poor prognosis in breast cancer patients. Herceptin (or trastuzumab), a humanized anti-HER2 monoclonal antibody (Ab), is an effective HER2-targeted therapy against early and metastatic HER2-positive breast cancers. It has dramatically improved the survival of breast cancer patients with HER2-positive tumors, but not all HER2-positive breast cancers respond to Herceptin-based regimens. To date, we lack validated biomarkers predictive for Herceptin response." "Our results may provide new avenues to identify useful biomarkers predictive for Herceptin efficacy and facilitate the development of novel approaches to enhance HER2-targeted therapy, thereby improving the survival of refractory breast cancer patients," Dr. Liu concludes. <|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 whale shark Rhincodon typus was uplisted to ‘Endangered’ in the 2016 IUCN Red List due to >50% population decline, largely caused by continued exploitation in the Indo-Pacific. Though the Philippines protected the whale shark in 1998, concerns remain due to continued take in regional waters. In light of this, understanding the movements of whale sharks in the Philippines, one of the most important hotspots for the species, is vital. We tagged 17 juvenile whale sharks with towed SPOT5 tags from three general areas in the Sulu and Bohol Seas: Panaon Island in Southern Leyte, northern Mindanao, and Tubbataha Reefs Natural Park (TRNP). The sharks all remained in Philippine waters for the duration of tracking (6–126 days, mean 64). Individuals travelled 86–2,580 km (mean 887 km) at a mean horizontal speed of 15.5 ± 13.0 SD km day −1 . Whale sharks tagged in Panaon Island and Mindanao remained close to shore but still spent significant time off the shelf (>200 m). Sharks tagged at TRNP spent most of their time offshore in the Sulu Sea. Three of twelve whale sharks tagged in the Bohol Sea moved through to the Sulu Sea, whilst two others moved east through the Surigao Strait to the eastern coast of Leyte. One individual tagged at TRNP moved to northern Palawan, and subsequently to the eastern coast of Mindanao in the Pacific Ocean. Based on inferred relationships with temperature histograms, whale sharks performed most deep dives (>200 m) during the night, in contrast to results from whale sharks elsewhere. While all sharks stayed in national waters, our results highlight the high mobility of juvenile whale sharks and demonstrate their connectivity across the Sulu and Bohol Seas, highlighting the importance of the area for this endangered species. Cite this as Araujo G, Rohner CA, Labaja J, Conales SJ, Snow SJ, Murray R, Pierce SJ, Ponzo A. 2018 . Satellite tracking of juvenile whale sharks in the Sulu and Bohol Seas, Philippines . PeerJ 6 : e5231 Main article text Introduction The whale shark Rhincodon typus is the world’s largest fish. The species inhabits tropical and sub-temperate waters, with seasonal aggregations across their range, usually associated with high prey availability (e.g., copepods, Motta et al., 2010 ; sergestids, Rohner et al., 2015 ; coral spawn, Holmberg et al., 2008). Most coastal aggregations are dominated by juvenile male sharks ( Norman et al., 2017 ), although Cochran et al. (2016) reported the first known juvenile 1:1 male to female aggregation in the Red Sea. Recent observations from the Galapagos, Qatar, St Helena and Baja California ( Hearn et al., 2016 ; Robinson et al., 2017 ; Clingham et al., 2016 ; Ramírez-Macías et al., 2017 ) have highlighted that adult sharks are likely to have more pelagic habitat preferences than juveniles. Work by Vignaud et al. (2014) suggested that whale sharks are genetically homogenous within the Indo-Pacific. However, photographic-identification (henceforth photo-ID) data from the global online database at Wildbook for Whale Sharks ( ) has revealed little connectivity among Indo-Pacific aggregation sites over short- to medium-term timescales (∼20 years), with few demonstrated movements between non-contiguous feeding areas ( Norman et al., 2017 ). While satellite telemetry studies have found whale sharks regularly cross international boundaries ( Eckert et al., 2002 ; Tyminski et al., 2015 ; Robinson et al., 2017 ; Rohner et al., 2018 ), photo-ID data show that juvenile sharks, in particular, often have a high inter-annual site fidelity to specific feeding areas ( Norman et al., 2017 ). The Philippines is a global hotspot of whale shark abundance, and the associated whale shark tourism industry is important to the local economy. Whale shark tourism in the Philippines started in Donsol, Sorsogon Province, where whale sharks aggregate seasonally (Nov–Jun) to feed ( Pine, Alava & Yaptinchay, 2007 ; Quiros, 2007 ). Donsol now receives up to 27,000 tourists per season and, through dedicated photo-ID, over 500 individual sharks have been identified to date (Wildbook for Whale Sharks, May 2018). Provisioning-based tourism activity arose in late 2011 at Oslob, Cebu Province, which now attracts over 182,000 tourists a year, making it the largest whale shark watching destination in the world ( Thomson et al., 2017 ). Over 350 individuals have been identified at the site, where whale sharks are hand-fed daily through the year, since photo-ID started in March 2012 (Wildbook for Whale Sharks, May 2018). Around 1,000 tourists visit Panaon Island, Southern Leyte Province, per season to swim with the non-fed sharks in this area ( Araujo et al., 2017b ). Over 250 individuals have been identified at this site, typically associated with localised zooplankton blooms that occur between October and June (Wildbook for Whale Sharks, May 2018). Araujo et al. (2014) ; Araujo et al. (2017a) ) elaborate on the connectivity between sites in the Bohol Sea through photo-ID at dedicated study sites and through citizen science contributions, though little connectivity has been observed between these areas and Donsol (<1% of identified sharks) or Tubbataha Reefs Natural Park (TRNP) in the Sulu Sea (also <1%). Through citizen science contributions and opportunistic research effort, over 74 individuals have been identified to date at TRNP (Wildbook for Whale Sharks, May 2018). Whale sharks were targeted by fisheries in the Philippines, before national protection in 1998 ( Alava et al., 2002 ), and in Taiwan into the mid 2000s ( Hsu et al., 2007 ). An estimated 1,000 whale sharks were reportedly landed yearly in Hainan Province, China, alone ( Li, Wang & Norman, 2012 ). Pronounced declines in sightings and catches prompted the inclusion of the species under Appendix II of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) in 2002, an ‘Endangered’ classification on the IUCN Red List of Threatened Species in 2016 ( Pierce & Norman, 2016 ), and a listing on Appendix I of the Convention on Migratory Species (CMS) in 2017. While these conservation tools can be effective for conserving elasmobranchs ( Simpfendorfer & Dulvy, 2017", "role": "user" }, { "content": "A new scientific study published in PeerJ—the Journal of Life and Environmental Sciences has tracked juvenile whale sharks across the Philippines emphasising the importance of the archipelago for the species. The study is the most complete tracking study of whale sharks in the country, with satellite tags deployed on different individuals in multiple sites. The Philippines is an important hotspot for whale sharks and globally hosts the third largest known population of whale sharks (whaleshark.org). While the species has been protected in the Philippines since 1998, globally the species was uplisted in 2016 to 'endangered to extinction' in the IUCN Red List of Threatened Species due to a population decline of more than 50%, largely caused by continued exploitation in the Indo-Pacific. Particularly in South East Asia, concerns remain due to continued fishing in regional waters; understanding the movements of whale sharks in the Philippines is vital if we are to identify conservation priorities for the species. By attaching Wildlife Computers SPOT5 satellite tags to whale sharks, researchers from Large Marine Vertebrates Research Institute Philippines (LAMAVE), Marine Megafauna Foundation (MMF) and Tubbataha Management Office (TMO) were able to follow the movements of juvenile whale sharks in near real-time to gain an insight into their behaviour. The tags work by communicating with passing ARGOS satellites, transmitting a location when the wet/dry sensor is triggered when a tagged whale shark breaks the surface. To aid transmission tags were tethered to a whale shark by a 1.8-meter line to ensure the tags broke the surface more frequently. The team tag a whale shark, surrounded by barracuda in Tubbataha Reefs Natural Park. Credit: Steve De Neef 17 individual whale sharks were tagged in three different locations in the Philippines: Panaon Island (Southern Leyte), northern Mindanao (Misamis Oriental and Surigao del Norte) and Tubbataha Reefs Natural Park (Palawan). Tagging took place between April 2015 and April 2016. All tagged whale sharks were juveniles, ranging in size between 4.5—7 meters and 73% of them were male. In their paper, peer-reviewed and published in PeerJ—the Journal of Life & Environmental Sciences, the researchers discovered that the tracks from the tags showed that all whale sharks stayed within the Philippines over the tracking period, emphasising the importance of the archipelago for the species. The longest track observed was from a whale shark originally tagged in Tubbataha Reefs Natural Park, which appeared to swim through the Sulu and Bohol Seas and into the Pacific, a journey accumulating over 2,500 km in length. While whale sharks are not known for their speed, results revealed that one individual whale shark was averaging 47km a day, further emphasising the species' mobile tendencies. Lead author of the study, Gonzalo Araujo stresses that \"this research highlights the high mobility of whale sharks, even juveniles, and the need for broader scale management and conservation plans for this endangered species.\" Dedicated research by LAMAVE and citizen science has identified over 600 individuals in the Sulu and Bohol Seas, yet the proximity of this population to fisheries in the broader region (South China Sea) means it is vital to monitor this population as a whole to understand if this population is in recovery or continuing to decline. Identifying threats and mitigation strategies is a conservation priority for the species. LAMAVE continues to study whale sharks in five key areas in the Philippines, working with local and national governments as well as collaborating organisations to develop conservation strategies for this iconic species. ", "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 whale shark Rhincodon typus was uplisted to ‘Endangered’ in the 2016 IUCN Red List due to >50% population decline, largely caused by continued exploitation in the Indo-Pacific. Though the Philippines protected the whale shark in 1998, concerns remain due to continued take in regional waters. In light of this, understanding the movements of whale sharks in the Philippines, one of the most important hotspots for the species, is vital. We tagged 17 juvenile whale sharks with towed SPOT5 tags from three general areas in the Sulu and Bohol Seas: Panaon Island in Southern Leyte, northern Mindanao, and Tubbataha Reefs Natural Park (TRNP). The sharks all remained in Philippine waters for the duration of tracking (6–126 days, mean 64). Individuals travelled 86–2,580 km (mean 887 km) at a mean horizontal speed of 15.5 ± 13.0 SD km day −1 . Whale sharks tagged in Panaon Island and Mindanao remained close to shore but still spent significant time off the shelf (>200 m). Sharks tagged at TRNP spent most of their time offshore in the Sulu Sea. Three of twelve whale sharks tagged in the Bohol Sea moved through to the Sulu Sea, whilst two others moved east through the Surigao Strait to the eastern coast of Leyte. One individual tagged at TRNP moved to northern Palawan, and subsequently to the eastern coast of Mindanao in the Pacific Ocean. Based on inferred relationships with temperature histograms, whale sharks performed most deep dives (>200 m) during the night, in contrast to results from whale sharks elsewhere. While all sharks stayed in national waters, our results highlight the high mobility of juvenile whale sharks and demonstrate their connectivity across the Sulu and Bohol Seas, highlighting the importance of the area for this endangered species. Cite this as Araujo G, Rohner CA, Labaja J, Conales SJ, Snow SJ, Murray R, Pierce SJ, Ponzo A. 2018 . Satellite tracking of juvenile whale sharks in the Sulu and Bohol Seas, Philippines . PeerJ 6 : e5231 Main article text Introduction The whale shark Rhincodon typus is the world’s largest fish. The species inhabits tropical and sub-temperate waters, with seasonal aggregations across their range, usually associated with high prey availability (e.g., copepods, Motta et al., 2010 ; sergestids, Rohner et al., 2015 ; coral spawn, Holmberg et al., 2008). Most coastal aggregations are dominated by juvenile male sharks ( Norman et al., 2017 ), although Cochran et al. (2016) reported the first known juvenile 1:1 male to female aggregation in the Red Sea. Recent observations from the Galapagos, Qatar, St Helena and Baja California ( Hearn et al., 2016 ; Robinson et al., 2017 ; Clingham et al., 2016 ; Ramírez-Macías et al., 2017 ) have highlighted that adult sharks are likely to have more pelagic habitat preferences than juveniles. Work by Vignaud et al. (2014) suggested that whale sharks are genetically homogenous within the Indo-Pacific. However, photographic-identification (henceforth photo-ID) data from the global online database at Wildbook for Whale Sharks ( ) has revealed little connectivity among Indo-Pacific aggregation sites over short- to medium-term timescales (∼20 years), with few demonstrated movements between non-contiguous feeding areas ( Norman et al., 2017 ). While satellite telemetry studies have found whale sharks regularly cross international boundaries ( Eckert et al., 2002 ; Tyminski et al., 2015 ; Robinson et al., 2017 ; Rohner et al., 2018 ), photo-ID data show that juvenile sharks, in particular, often have a high inter-annual site fidelity to specific feeding areas ( Norman et al., 2017 ). The Philippines is a global hotspot of whale shark abundance, and the associated whale shark tourism industry is important to the local economy. Whale shark tourism in the Philippines started in Donsol, Sorsogon Province, where whale sharks aggregate seasonally (Nov–Jun) to feed ( Pine, Alava & Yaptinchay, 2007 ; Quiros, 2007 ). Donsol now receives up to 27,000 tourists per season and, through dedicated photo-ID, over 500 individual sharks have been identified to date (Wildbook for Whale Sharks, May 2018). Provisioning-based tourism activity arose in late 2011 at Oslob, Cebu Province, which now attracts over 182,000 tourists a year, making it the largest whale shark watching destination in the world ( Thomson et al., 2017 ). Over 350 individuals have been identified at the site, where whale sharks are hand-fed daily through the year, since photo-ID started in March 2012 (Wildbook for Whale Sharks, May 2018). Around 1,000 tourists visit Panaon Island, Southern Leyte Province, per season to swim with the non-fed sharks in this area ( Araujo et al., 2017b ). Over 250 individuals have been identified at this site, typically associated with localised zooplankton blooms that occur between October and June (Wildbook for Whale Sharks, May 2018). Araujo et al. (2014) ; Araujo et al. (2017a) ) elaborate on the connectivity between sites in the Bohol Sea through photo-ID at dedicated study sites and through citizen science contributions, though little connectivity has been observed between these areas and Donsol (<1% of identified sharks) or Tubbataha Reefs Natural Park (TRNP) in the Sulu Sea (also <1%). Through citizen science contributions and opportunistic research effort, over 74 individuals have been identified to date at TRNP (Wildbook for Whale Sharks, May 2018). Whale sharks were targeted by fisheries in the Philippines, before national protection in 1998 ( Alava et al., 2002 ), and in Taiwan into the mid 2000s ( Hsu et al., 2007 ). An estimated 1,000 whale sharks were reportedly landed yearly in Hainan Province, China, alone ( Li, Wang & Norman, 2012 ). Pronounced declines in sightings and catches prompted the inclusion of the species under Appendix II of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) in 2002, an ‘Endangered’ classification on the IUCN Red List of Threatened Species in 2016 ( Pierce & Norman, 2016 ), and a listing on Appendix I of the Convention on Migratory Species (CMS) in 2017. While these conservation tools can be effective for conserving elasmobranchs ( Simpfendorfer & Dulvy, 2017<|im_end|> <|im_start|>assistant A new scientific study published in PeerJ—the Journal of Life and Environmental Sciences has tracked juvenile whale sharks across the Philippines emphasising the importance of the archipelago for the species. The study is the most complete tracking study of whale sharks in the country, with satellite tags deployed on different individuals in multiple sites. The Philippines is an important hotspot for whale sharks and globally hosts the third largest known population of whale sharks (whaleshark.org). While the species has been protected in the Philippines since 1998, globally the species was uplisted in 2016 to 'endangered to extinction' in the IUCN Red List of Threatened Species due to a population decline of more than 50%, largely caused by continued exploitation in the Indo-Pacific. Particularly in South East Asia, concerns remain due to continued fishing in regional waters; understanding the movements of whale sharks in the Philippines is vital if we are to identify conservation priorities for the species. By attaching Wildlife Computers SPOT5 satellite tags to whale sharks, researchers from Large Marine Vertebrates Research Institute Philippines (LAMAVE), Marine Megafauna Foundation (MMF) and Tubbataha Management Office (TMO) were able to follow the movements of juvenile whale sharks in near real-time to gain an insight into their behaviour. The tags work by communicating with passing ARGOS satellites, transmitting a location when the wet/dry sensor is triggered when a tagged whale shark breaks the surface. To aid transmission tags were tethered to a whale shark by a 1.8-meter line to ensure the tags broke the surface more frequently. The team tag a whale shark, surrounded by barracuda in Tubbataha Reefs Natural Park. Credit: Steve De Neef 17 individual whale sharks were tagged in three different locations in the Philippines: Panaon Island (Southern Leyte), northern Mindanao (Misamis Oriental and Surigao del Norte) and Tubbataha Reefs Natural Park (Palawan). Tagging took place between April 2015 and April 2016. All tagged whale sharks were juveniles, ranging in size between 4.5—7 meters and 73% of them were male. In their paper, peer-reviewed and published in PeerJ—the Journal of Life & Environmental Sciences, the researchers discovered that the tracks from the tags showed that all whale sharks stayed within the Philippines over the tracking period, emphasising the importance of the archipelago for the species. The longest track observed was from a whale shark originally tagged in Tubbataha Reefs Natural Park, which appeared to swim through the Sulu and Bohol Seas and into the Pacific, a journey accumulating over 2,500 km in length. While whale sharks are not known for their speed, results revealed that one individual whale shark was averaging 47km a day, further emphasising the species' mobile tendencies. Lead author of the study, Gonzalo Araujo stresses that "this research highlights the high mobility of whale sharks, even juveniles, and the need for broader scale management and conservation plans for this endangered species." Dedicated research by LAMAVE and citizen science has identified over 600 individuals in the Sulu and Bohol Seas, yet the proximity of this population to fisheries in the broader region (South China Sea) means it is vital to monitor this population as a whole to understand if this population is in recovery or continuing to decline. Identifying threats and mitigation strategies is a conservation priority for the species. LAMAVE continues to study whale sharks in five key areas in the Philippines, working with local and national governments as well as collaborating organisations to develop conservation strategies for this iconic species. <|im_end|>

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2,240

[ { "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 multimodal dusty plasma formed in a positive column of the direct current glow discharge at superfluid helium temperatures has been studied for the first time. Formation of a liquid-like dusty plasma structure occurred after injection of polydisperse cerium oxide particles in the glow discharge. The coupling parameter ~10 determined for the dusty plasma structure corresponds very well to its liquid-like type. The cloud of nanoparticles and non-linear waves within the cloud were observed at T < 2 K. Solid helical filaments with length up to 5 mm, diameter up to 22 μm, total charges ~10 6 е, levitating in the gas discharge at the temperature ~2 K and pressure 4 Pa have been observed for the first time. Analysis of the experimental conditions and the filament composition allows us to conclude that the filaments and nanoclusters were formed due to ion sputtering of dielectric material during the experiments. Introduction Self-organization phenomena in the nature are extremely diverse. They can be found in dissipative systems of varying complexity and scale: from physical systems studied in nanoworld and astronomy up to social and economic processes in the human world. The phenomena of self-organization are inherent for open non-equilibrium systems consisting of non-linearly interacting components. Dusty plasma formed by microscopic charged particles levitating in gas discharge plasma is an example of such systems. Intense scattering of light by microscopic particles allows straightforward observation of particle motions and determination of their coordinates and velocities. This is why a dusty plasma can be used as a convenient tool to study various self-organization phenomena, for example, 3-D 1 , 2 , 3 , 4 , 5 and 2-D 6 phase transitions, formation of non-linear waves 7 , 8 , including rogue waves 9 . Dusty plasma provides unique opportunity to carry out studies within much wider range of neutral gas temperature (temperature changes by at least two orders of magnitude in the case of helium gas) as compared to alternative systems, such as clusters composed of water droplets levitating above hot surfaces 10 , 11 , 12 , 13 . Therefore, the properties of dusty plasma and different processes in this plasma can be investigated at different temperatures of neutral gas. Not many comparative experimental studies of dusty plasmas at 4.2 K and 77 K have been conducted so far 14 , 15 , 16 , 17 , 18 , 19 . The results of these studies have been recently reviewed and analyzed in 20 . Contradictory results on the temperature dependence of the interparticle distance in dusty plasma structures have been discussed in 20 . A formation of superdense ordered dusty plasma structures at the lowest temperatures was expected for many years based on the assumption of the validity of a direct relation between the kinetic energy of microscopic particles and the neutral gas temperature 15 , 19 . Nevertheless, this assumption has not been confirmed experimentally 20 . Another interesting and still unexplained experimental result is a decrease in the dust particle charge with a decrease in the neutral gas temperature 16 , 17 , 18 . No experiments with plasmas at temperatures below 4.2 K have been reported in the literature up to date. Thus the question regarding the lowest possible temperature in dusty plasma systems still remains open. This temperature is of great importance for experimental studies of properties of ultracold dusty plasmas. However, experimental studies of ultracold dusty plasmas can generate very promising results because cryogenic gas discharges are not well studied for temperatures below 5 K. The main problem in developing and studying of such plasma systems is not cooling the discharge tube down to a temperature below 4.2 K (liquid helium can be used as a cryo-coolant), but restriction of the power released in the gas discharge and increased neutral gas temperature 21 . There is no reliable information in the literature on the positive charge carriers in cryogenic glow discharge because even at T≈80 K the densities of molecular ions, He 3 + and He 4 + , reach 10% и 1%, respectively 22 , 23 . It is known that the conductivity mechanism of the helium plasma is changing at T < 5 K 24 and such plasma doesn’t emit light 21 . Consideration has to be given to a possible presence of metastable negative helium ions, He − and He 2 − , with the life times 359 μs 25 and 135 μs 26 , respectively, in the helium plasma at T~1 K. Formation of both helium anions, He − and He 2 − , involves metastable He* atoms 27 . The density of He* atoms may reach values ~10 13 cm −3 at the total density of helium atoms ~10 17 см −3 and T≈10 K 28 , 29 . In this work, we present new experimental results on dusty plasma in direct current (DC) glow discharge inside a tube cooled with superfluid helium 30 . Cooling the neutral and positive ionic components of plasma down to temperatures ≈1 K allows such plasma to be classified as ultracold plasma 31 . Thus, ultracold and strongly coupled dusty plasma with coupling parameter of ~10 has been observed at T < 2 K for the first time. Moreover, a spheroidal plasma dusty structure formed by CeO 2 particles in the stratum of positive column of the glow discharge cooled by superfluid helium was observed together with a cloud of weakly charged nanoclusters with sizes less than 100 nm and with separate levitating solid filaments with the length of a few mm’s. Based on the results obtained in the present study it can be concluded that nanoclusters and solid filaments were formed within the discharge volume due to ion sputtering of dielectric material in the discharge tube at T < 2 К. Methods The experimental setup for investigation of cryogenic helium plasma and dusty plasma structures has been described in more detail elsewhere 32 . The setup to study dusty plasma structures at liquid helium temperatures", "role": "user" }, { "content": "Physicists recently investigated the behavior of particles in a dusty plasma at a temperature below 2 degrees K. The experiment showed that at extremely low temperatures, nanoclusters can form in the plasma, and the synthesis of polymer fibers takes place. The results of the experiment can be used to create new materials with desired and controlled properties. The results of this study are published in Scientific Reports. Scientists from the Joint Institute for High Temperatures, Russian Academy of Sciences together with colleagues from the Branch of Talrose Institute for Energy Problems of Chemical Physics, RAS and Moscow Institute of Physics and Technology studied a multimodal dusty plasma formed in a positive column of the direct current glow discharge at ultralow temperatures (at superfluid helium temperatures). According to Oleg Petrov, director of the Institute for High Temperatures RAS and one of the authors of the article, the scientists managed for the first time to observe dusty plasma in a gas discharge cooled by superfluid helium at a temperature of 1.6 to 2 degrees K. Until now, dusty plasma and even gas discharges have not been studied at temperatures lower than 4.2 degrees K, which is the temperature of liquid helium. In the course of the experiment, ion sputtering of polymers from a special insert resulted in self-organization phenomena, namely, the formation of nanoclusters with sizes less than 100 nm and polymer fibers with a length of up to 5 mm and a diameter of about 10 microns. Obtained at extreme temperatures, the fibers do not collapse when studied later in normal conditions. \"At ultralow temperatures, it becomes possible to precisely control the composition of the sprayed material, since under these conditions any impurities \"freeze\" and precipitate,\" Oleg Petrov says. \"As a result, when spraying a substance in the gaseous helium, it is possible to obtain super-pure materials, which might be the way to obtain fibers with new desired properties—for example, new types of polymers that cannot be obtained by ordinary chemical synthesis. Such materials may be radically different from existing ones.\" Phenomena of self-organization are widespread in nature, and are observed in various systems of complexity and scale, including physical nano-scale events, astronomy, and in biological, social and economic processes. Such phenomena are characteristic of the so-called open (non-equilibrium) systems, which include, among others, dusty plasma formed by charged particles of micron size, retained in the plasma of a gas electric discharge. The intense scattering of laser radiation by particles allows to study the systems formed by charged particles, tracking their coordinates and speeds in real time. Dusty plasma is a convenient tool for studying various phenomena, for example, three-dimensional and two-dimensional phase transitions, as well as the formation of non-linear waves. Compared with alternative systems,dusty plasma provides a unique opportunity to vary the temperature of the plasma-forming gas—gaseous helium—which helps to study the effect of gas temperature changes on properties of plasma and the processes that occur in it. The question of the lower limit of temperatures at which experimental studies of dusty plasma can be carried out remained open until recently. The reason for this lack of knowledge of the gas discharge plasma at temperatures below 4.2 degrees K is related to the fact that the problem is not only to cooling the tube to temperatures below that of liquid helium, but also the power limit in the discharge which leads to heating of gaseous helium. The experiment, the results of which were published in Scientific Reports, was carried out with an optical cryostat on a platform intended to study plasma-dust structures at helium temperatures. At present, scientists of the JIHT RAS plan to continue the experiments and study the phenomena of self-organization in dusty plasmas at ultralow temperatures using various dispersed materials. ", "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 multimodal dusty plasma formed in a positive column of the direct current glow discharge at superfluid helium temperatures has been studied for the first time. Formation of a liquid-like dusty plasma structure occurred after injection of polydisperse cerium oxide particles in the glow discharge. The coupling parameter ~10 determined for the dusty plasma structure corresponds very well to its liquid-like type. The cloud of nanoparticles and non-linear waves within the cloud were observed at T < 2 K. Solid helical filaments with length up to 5 mm, diameter up to 22 μm, total charges ~10 6 е, levitating in the gas discharge at the temperature ~2 K and pressure 4 Pa have been observed for the first time. Analysis of the experimental conditions and the filament composition allows us to conclude that the filaments and nanoclusters were formed due to ion sputtering of dielectric material during the experiments. Introduction Self-organization phenomena in the nature are extremely diverse. They can be found in dissipative systems of varying complexity and scale: from physical systems studied in nanoworld and astronomy up to social and economic processes in the human world. The phenomena of self-organization are inherent for open non-equilibrium systems consisting of non-linearly interacting components. Dusty plasma formed by microscopic charged particles levitating in gas discharge plasma is an example of such systems. Intense scattering of light by microscopic particles allows straightforward observation of particle motions and determination of their coordinates and velocities. This is why a dusty plasma can be used as a convenient tool to study various self-organization phenomena, for example, 3-D 1 , 2 , 3 , 4 , 5 and 2-D 6 phase transitions, formation of non-linear waves 7 , 8 , including rogue waves 9 . Dusty plasma provides unique opportunity to carry out studies within much wider range of neutral gas temperature (temperature changes by at least two orders of magnitude in the case of helium gas) as compared to alternative systems, such as clusters composed of water droplets levitating above hot surfaces 10 , 11 , 12 , 13 . Therefore, the properties of dusty plasma and different processes in this plasma can be investigated at different temperatures of neutral gas. Not many comparative experimental studies of dusty plasmas at 4.2 K and 77 K have been conducted so far 14 , 15 , 16 , 17 , 18 , 19 . The results of these studies have been recently reviewed and analyzed in 20 . Contradictory results on the temperature dependence of the interparticle distance in dusty plasma structures have been discussed in 20 . A formation of superdense ordered dusty plasma structures at the lowest temperatures was expected for many years based on the assumption of the validity of a direct relation between the kinetic energy of microscopic particles and the neutral gas temperature 15 , 19 . Nevertheless, this assumption has not been confirmed experimentally 20 . Another interesting and still unexplained experimental result is a decrease in the dust particle charge with a decrease in the neutral gas temperature 16 , 17 , 18 . No experiments with plasmas at temperatures below 4.2 K have been reported in the literature up to date. Thus the question regarding the lowest possible temperature in dusty plasma systems still remains open. This temperature is of great importance for experimental studies of properties of ultracold dusty plasmas. However, experimental studies of ultracold dusty plasmas can generate very promising results because cryogenic gas discharges are not well studied for temperatures below 5 K. The main problem in developing and studying of such plasma systems is not cooling the discharge tube down to a temperature below 4.2 K (liquid helium can be used as a cryo-coolant), but restriction of the power released in the gas discharge and increased neutral gas temperature 21 . There is no reliable information in the literature on the positive charge carriers in cryogenic glow discharge because even at T≈80 K the densities of molecular ions, He 3 + and He 4 + , reach 10% и 1%, respectively 22 , 23 . It is known that the conductivity mechanism of the helium plasma is changing at T < 5 K 24 and such plasma doesn’t emit light 21 . Consideration has to be given to a possible presence of metastable negative helium ions, He − and He 2 − , with the life times 359 μs 25 and 135 μs 26 , respectively, in the helium plasma at T~1 K. Formation of both helium anions, He − and He 2 − , involves metastable He* atoms 27 . The density of He* atoms may reach values ~10 13 cm −3 at the total density of helium atoms ~10 17 см −3 and T≈10 K 28 , 29 . In this work, we present new experimental results on dusty plasma in direct current (DC) glow discharge inside a tube cooled with superfluid helium 30 . Cooling the neutral and positive ionic components of plasma down to temperatures ≈1 K allows such plasma to be classified as ultracold plasma 31 . Thus, ultracold and strongly coupled dusty plasma with coupling parameter of ~10 has been observed at T < 2 K for the first time. Moreover, a spheroidal plasma dusty structure formed by CeO 2 particles in the stratum of positive column of the glow discharge cooled by superfluid helium was observed together with a cloud of weakly charged nanoclusters with sizes less than 100 nm and with separate levitating solid filaments with the length of a few mm’s. Based on the results obtained in the present study it can be concluded that nanoclusters and solid filaments were formed within the discharge volume due to ion sputtering of dielectric material in the discharge tube at T < 2 К. Methods The experimental setup for investigation of cryogenic helium plasma and dusty plasma structures has been described in more detail elsewhere 32 . The setup to study dusty plasma structures at liquid helium temperatures<|im_end|> <|im_start|>assistant Physicists recently investigated the behavior of particles in a dusty plasma at a temperature below 2 degrees K. The experiment showed that at extremely low temperatures, nanoclusters can form in the plasma, and the synthesis of polymer fibers takes place. The results of the experiment can be used to create new materials with desired and controlled properties. The results of this study are published in Scientific Reports. Scientists from the Joint Institute for High Temperatures, Russian Academy of Sciences together with colleagues from the Branch of Talrose Institute for Energy Problems of Chemical Physics, RAS and Moscow Institute of Physics and Technology studied a multimodal dusty plasma formed in a positive column of the direct current glow discharge at ultralow temperatures (at superfluid helium temperatures). According to Oleg Petrov, director of the Institute for High Temperatures RAS and one of the authors of the article, the scientists managed for the first time to observe dusty plasma in a gas discharge cooled by superfluid helium at a temperature of 1.6 to 2 degrees K. Until now, dusty plasma and even gas discharges have not been studied at temperatures lower than 4.2 degrees K, which is the temperature of liquid helium. In the course of the experiment, ion sputtering of polymers from a special insert resulted in self-organization phenomena, namely, the formation of nanoclusters with sizes less than 100 nm and polymer fibers with a length of up to 5 mm and a diameter of about 10 microns. Obtained at extreme temperatures, the fibers do not collapse when studied later in normal conditions. "At ultralow temperatures, it becomes possible to precisely control the composition of the sprayed material, since under these conditions any impurities "freeze" and precipitate," Oleg Petrov says. "As a result, when spraying a substance in the gaseous helium, it is possible to obtain super-pure materials, which might be the way to obtain fibers with new desired properties—for example, new types of polymers that cannot be obtained by ordinary chemical synthesis. Such materials may be radically different from existing ones." Phenomena of self-organization are widespread in nature, and are observed in various systems of complexity and scale, including physical nano-scale events, astronomy, and in biological, social and economic processes. Such phenomena are characteristic of the so-called open (non-equilibrium) systems, which include, among others, dusty plasma formed by charged particles of micron size, retained in the plasma of a gas electric discharge. The intense scattering of laser radiation by particles allows to study the systems formed by charged particles, tracking their coordinates and speeds in real time. Dusty plasma is a convenient tool for studying various phenomena, for example, three-dimensional and two-dimensional phase transitions, as well as the formation of non-linear waves. Compared with alternative systems,dusty plasma provides a unique opportunity to vary the temperature of the plasma-forming gas—gaseous helium—which helps to study the effect of gas temperature changes on properties of plasma and the processes that occur in it. The question of the lower limit of temperatures at which experimental studies of dusty plasma can be carried out remained open until recently. The reason for this lack of knowledge of the gas discharge plasma at temperatures below 4.2 degrees K is related to the fact that the problem is not only to cooling the tube to temperatures below that of liquid helium, but also the power limit in the discharge which leads to heating of gaseous helium. The experiment, the results of which were published in Scientific Reports, was carried out with an optical cryostat on a platform intended to study plasma-dust structures at helium temperatures. At present, scientists of the JIHT RAS plan to continue the experiments and study the phenomena of self-organization in dusty plasmas at ultralow temperatures using various dispersed materials. <|im_end|>

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2,050

[ { "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 Cognitive decline and mood disorders increase in frequency with age. Many efforts are focused on the identification of molecules and pathways to treat these conditions. Here, we demonstrate that systemic administration of growth differentiation factor 11 (GDF11) in aged mice improves memory and alleviates senescence and depression-like symptoms in a neurogenesis-independent manner. Mechanistically, GDF11 acts directly on hippocampal neurons to enhance neuronal activity via stimulation of autophagy. Transcriptomic and biochemical analyses of these neurons reveal that GDF11 reduces the activity of mammalian target of rapamycin (mTOR), a master regulator of autophagy. Using a murine model of corticosterone-induced depression-like phenotype, we also show that GDF11 attenuates the depressive-like behavior of young mice. Analysis of sera from young adults with major depressive disorder (MDD) reveals reduced GDF11 levels. These findings identify mechanistic pathways related to GDF11 action in the brain and uncover an unknown role for GDF11 as an antidepressant candidate and biomarker. Main Aging is often accompanied by severe cognitive impairments, memory loss and age-related depression 1 . Independently of age, MDD affects around 20% of the population and correlates with short-term and working memory deficits, which exacerbate the effects of aging in some older adults 2 . Depression can resemble a state of accelerated aging as depressed individuals often exhibit a higher incidence of age-associated diseases, including Alzheimer’s and other neurodegenerative diseases 3 . The hippocampus plays a key role in the regulation of memory and depression. Small hippocampal volumes in humans have been associated with MDD, other psychiatric disorders and memory impairments, establishing the hippocampus as a structural link among aging, mood disorders and memory decline 4 . In animal models, depression-like behavior is also associated with structural and functional alterations of the hippocampus and is most often related to impaired neurogenesis 5 . At the cellular level, hippocampal neurogenesis is crucial for memory formation and cognitive function, whereas impaired adult neurogenesis has been linked to memory decline and depression-like phenotypes 6 , 7 . Infusion of youthful blood factors or blocking proaging factors has been shown to attenuate age-related impairments in neurogenesis, memory decline and olfactory perception 8 , 9 , 10 , 11 , 12 , 13 . One of these blood factors is growth differentiation factor 11 (GDF11), a member of the transforming growth factor beta (TGF-β) superfamily, which has a critical role in embryonic development as a key regulator of patterning and formation of several tissues 14 , 15 , 16 , 17 , 18 , 19 . The role of GDF11 in the developing central nervous system regulates the progression of neurogenesis as well as differentiation of neural subtypes 19 , 20 , 21 , 22 . In adults, GDF11 was recently shown to negatively regulate neurogenesis 23 . Because circulating levels of GDF11 decline with age 24 , 25 , supplementation with recombinant GDF11 (rGDF11) in aged mice was previously shown to rejuvenate neurogenesis in both the subventricular zone and hippocampal dentate gyrus (DG) and improve cerebral vasculature 8 , 26 . Despite increasing reports on the various effects of GDF11, it remains unknown whether GDF11 improves cognitive impairments, as well as its precise mechanism of action in the brain. Here, we report that systemic GDF11 treatment in aged mice was sufficient to prevent memory decline and depression-like behavior, enhance hippocampal neurogenesis and autophagy and reduce hippocampal senescence. Mechanistically, GDF11 stimulated neuronal autophagy and inhibited the mTOR pathway in a neurogenesis-independent manner. Using the corticosterone (CORT)-induced murine model of depression-like behavior, we demonstrated that GDF11 inhibited a depression-like phenotype in young mice. Finally, we revealed that GDF11 levels were decreased in young adults with MDD or presenting a current depressive episode, making it a potential biomarker of depression and a possible agent for therapeutic interventions. Results Systemic GDF11 administration restores memory decline and attenuates the depression-like phenotype We treated 22-month-old C57BL/6JRj male mice with rGDF11 via daily intraperitoneal (i.p.) injections at a dose of 1 mg kg −1 , as previously described 24 . Aged-matched controls and young (3-month-old) mice were injected with saline. Mice were injected over the course of 3 weeks, and behavioral tests were performed on the third week (Fig. 1a ). Assessing memory using the novel object recognition test (NORT) showed that aged mice were unable to discriminate the novel object and scored significantly lower than young mice (aged, 48.2% ± 5.5; young, 68.2 ± 1.7; Fig. 1b ). On the contrary, GDF11-treated aged mice presented a significant 44.2% increase in the novel object discrimination index (GDF11 = 69.6 ± 3%; aged, 48.2% ± 5.5; Fig. 1b ). Hippocampus-dependent spatial memory was specifically assessed with the novel object location test, where aged mice spent significantly less time investigating the novel location compared to both young and aged GDF11-treated mice (aged, 42 ± 3.3%; young = 58.2 ± 2.2%; GDF11 = 57.8 ± 5%; Fig. 1c ). In the Y-maze test (used to assess recognition memory), young and GDF11-treated aged mice spent significantly more time investigating the novel arm of the maze than aged mice (aged, 24.4 ± 2.7%; young, 36.1 ± 2.9%; GDF11 = 36.9 ± 3.7%), confirming the effect of GDF11 in improving age-related memory impairments (Fig. 1d ). Fig. 1: Systemic GDF11 administration restores memory decline and depression-like phenotype in aged mice. a , Schematic representation of the experimental procedure. b , Measurement of discrimination index during the NORT (percentage of time spent to observe the novel object divided by the total investigation time for both objects) ( n Young = 10 mice, n Aged = 9 mice, n Aged+GDF11 = 8 mice; F (2, 24) = 10.9). c , Measurement of percent investigation time of the novel location during the novel object location test (NOLT) (percentage of time spent to observe the novel location of the object divided by the total investigation time for both objects) ( n Young = 10 mice, n Aged = 11 mice, n Aged+GDF11 = 12 mice; F (2, 30) = 5.5). d , Measurement of percent investigation time of", "role": "user" }, { "content": "The process of aging is often related to the onset of neurological symptoms such as cognitive decline, memory loss or mood disorders such as depression. Previous studies have shown that the growth factor GDF11, a protein found in blood, has a beneficial effect on olfactory perception and on the generation of new cells in the brains of aged mice. However, the mechanism of action of GDF11 in the brain has remained unknown. Researchers from the Institut Pasteur, CNRS and Inserm have discovered that long-term administration of the GDF11 protein to aged mice improves their memory and significantly reduces behavioral disturbances related to depression, allowing them to return to a behavior similar to that seen in younger mice. The results of this study were published in the journal Nature Aging on February 2, 2023. The scientists conducted further studies in different aged mouse models or mouse models with depression-like behavioral disorders and in vitro neuronal cultures, which enabled them to identify the molecular mechanism of action of GDF11. They discovered that administration of GDF11 activates the natural process of intracellular cleaning, called \"autophagy,\" in the brain and the elimination of senescent cells. The GDF11 protein thus indirectly increases cell turnover in the hippocampus and restores neuronal activity. To better understand the link between depressive disorders and the GDF11 protein in humans, scientists from the Institut Pasteur, CNRS and Inserm, in collaboration with scientists from McMaster University, quantified the protein in the blood serum of an international cohort of young patients with major depressive disorder. They observed that GDF11 levels are significantly lower in these patients. Moreover, by measuring the levels of this protein at different stages, the scientists observed a fluctuation in the level depending on the depressive state. \"This work provides clinical evidence linking low blood levels of GDF11 to mood disorders in patients with depression,\" said Lida Katsimpardi, a researcher in the Institut Pasteur's Perception and Memory Unit, affiliated with Inserm at the Institut Necker-Enfants Malades, and co-last author of the study. \"In the future, this molecule could be used as a biomarker to diagnose depressive episodes. It could also serve as a therapeutic molecule for the treatment of cognitive and affective disorders,\" she 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 Cognitive decline and mood disorders increase in frequency with age. Many efforts are focused on the identification of molecules and pathways to treat these conditions. Here, we demonstrate that systemic administration of growth differentiation factor 11 (GDF11) in aged mice improves memory and alleviates senescence and depression-like symptoms in a neurogenesis-independent manner. Mechanistically, GDF11 acts directly on hippocampal neurons to enhance neuronal activity via stimulation of autophagy. Transcriptomic and biochemical analyses of these neurons reveal that GDF11 reduces the activity of mammalian target of rapamycin (mTOR), a master regulator of autophagy. Using a murine model of corticosterone-induced depression-like phenotype, we also show that GDF11 attenuates the depressive-like behavior of young mice. Analysis of sera from young adults with major depressive disorder (MDD) reveals reduced GDF11 levels. These findings identify mechanistic pathways related to GDF11 action in the brain and uncover an unknown role for GDF11 as an antidepressant candidate and biomarker. Main Aging is often accompanied by severe cognitive impairments, memory loss and age-related depression 1 . Independently of age, MDD affects around 20% of the population and correlates with short-term and working memory deficits, which exacerbate the effects of aging in some older adults 2 . Depression can resemble a state of accelerated aging as depressed individuals often exhibit a higher incidence of age-associated diseases, including Alzheimer’s and other neurodegenerative diseases 3 . The hippocampus plays a key role in the regulation of memory and depression. Small hippocampal volumes in humans have been associated with MDD, other psychiatric disorders and memory impairments, establishing the hippocampus as a structural link among aging, mood disorders and memory decline 4 . In animal models, depression-like behavior is also associated with structural and functional alterations of the hippocampus and is most often related to impaired neurogenesis 5 . At the cellular level, hippocampal neurogenesis is crucial for memory formation and cognitive function, whereas impaired adult neurogenesis has been linked to memory decline and depression-like phenotypes 6 , 7 . Infusion of youthful blood factors or blocking proaging factors has been shown to attenuate age-related impairments in neurogenesis, memory decline and olfactory perception 8 , 9 , 10 , 11 , 12 , 13 . One of these blood factors is growth differentiation factor 11 (GDF11), a member of the transforming growth factor beta (TGF-β) superfamily, which has a critical role in embryonic development as a key regulator of patterning and formation of several tissues 14 , 15 , 16 , 17 , 18 , 19 . The role of GDF11 in the developing central nervous system regulates the progression of neurogenesis as well as differentiation of neural subtypes 19 , 20 , 21 , 22 . In adults, GDF11 was recently shown to negatively regulate neurogenesis 23 . Because circulating levels of GDF11 decline with age 24 , 25 , supplementation with recombinant GDF11 (rGDF11) in aged mice was previously shown to rejuvenate neurogenesis in both the subventricular zone and hippocampal dentate gyrus (DG) and improve cerebral vasculature 8 , 26 . Despite increasing reports on the various effects of GDF11, it remains unknown whether GDF11 improves cognitive impairments, as well as its precise mechanism of action in the brain. Here, we report that systemic GDF11 treatment in aged mice was sufficient to prevent memory decline and depression-like behavior, enhance hippocampal neurogenesis and autophagy and reduce hippocampal senescence. Mechanistically, GDF11 stimulated neuronal autophagy and inhibited the mTOR pathway in a neurogenesis-independent manner. Using the corticosterone (CORT)-induced murine model of depression-like behavior, we demonstrated that GDF11 inhibited a depression-like phenotype in young mice. Finally, we revealed that GDF11 levels were decreased in young adults with MDD or presenting a current depressive episode, making it a potential biomarker of depression and a possible agent for therapeutic interventions. Results Systemic GDF11 administration restores memory decline and attenuates the depression-like phenotype We treated 22-month-old C57BL/6JRj male mice with rGDF11 via daily intraperitoneal (i.p.) injections at a dose of 1 mg kg −1 , as previously described 24 . Aged-matched controls and young (3-month-old) mice were injected with saline. Mice were injected over the course of 3 weeks, and behavioral tests were performed on the third week (Fig. 1a ). Assessing memory using the novel object recognition test (NORT) showed that aged mice were unable to discriminate the novel object and scored significantly lower than young mice (aged, 48.2% ± 5.5; young, 68.2 ± 1.7; Fig. 1b ). On the contrary, GDF11-treated aged mice presented a significant 44.2% increase in the novel object discrimination index (GDF11 = 69.6 ± 3%; aged, 48.2% ± 5.5; Fig. 1b ). Hippocampus-dependent spatial memory was specifically assessed with the novel object location test, where aged mice spent significantly less time investigating the novel location compared to both young and aged GDF11-treated mice (aged, 42 ± 3.3%; young = 58.2 ± 2.2%; GDF11 = 57.8 ± 5%; Fig. 1c ). In the Y-maze test (used to assess recognition memory), young and GDF11-treated aged mice spent significantly more time investigating the novel arm of the maze than aged mice (aged, 24.4 ± 2.7%; young, 36.1 ± 2.9%; GDF11 = 36.9 ± 3.7%), confirming the effect of GDF11 in improving age-related memory impairments (Fig. 1d ). Fig. 1: Systemic GDF11 administration restores memory decline and depression-like phenotype in aged mice. a , Schematic representation of the experimental procedure. b , Measurement of discrimination index during the NORT (percentage of time spent to observe the novel object divided by the total investigation time for both objects) ( n Young = 10 mice, n Aged = 9 mice, n Aged+GDF11 = 8 mice; F (2, 24) = 10.9). c , Measurement of percent investigation time of the novel location during the novel object location test (NOLT) (percentage of time spent to observe the novel location of the object divided by the total investigation time for both objects) ( n Young = 10 mice, n Aged = 11 mice, n Aged+GDF11 = 12 mice; F (2, 30) = 5.5). d , Measurement of percent investigation time of<|im_end|> <|im_start|>assistant The process of aging is often related to the onset of neurological symptoms such as cognitive decline, memory loss or mood disorders such as depression. Previous studies have shown that the growth factor GDF11, a protein found in blood, has a beneficial effect on olfactory perception and on the generation of new cells in the brains of aged mice. However, the mechanism of action of GDF11 in the brain has remained unknown. Researchers from the Institut Pasteur, CNRS and Inserm have discovered that long-term administration of the GDF11 protein to aged mice improves their memory and significantly reduces behavioral disturbances related to depression, allowing them to return to a behavior similar to that seen in younger mice. The results of this study were published in the journal Nature Aging on February 2, 2023. The scientists conducted further studies in different aged mouse models or mouse models with depression-like behavioral disorders and in vitro neuronal cultures, which enabled them to identify the molecular mechanism of action of GDF11. They discovered that administration of GDF11 activates the natural process of intracellular cleaning, called "autophagy," in the brain and the elimination of senescent cells. The GDF11 protein thus indirectly increases cell turnover in the hippocampus and restores neuronal activity. To better understand the link between depressive disorders and the GDF11 protein in humans, scientists from the Institut Pasteur, CNRS and Inserm, in collaboration with scientists from McMaster University, quantified the protein in the blood serum of an international cohort of young patients with major depressive disorder. They observed that GDF11 levels are significantly lower in these patients. Moreover, by measuring the levels of this protein at different stages, the scientists observed a fluctuation in the level depending on the depressive state. "This work provides clinical evidence linking low blood levels of GDF11 to mood disorders in patients with depression," said Lida Katsimpardi, a researcher in the Institut Pasteur's Perception and Memory Unit, affiliated with Inserm at the Institut Necker-Enfants Malades, and co-last author of the study. "In the future, this molecule could be used as a biomarker to diagnose depressive episodes. It could also serve as a therapeutic molecule for the treatment of cognitive and affective disorders," she concludes. <|im_end|>

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1,962

[ { "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 Epigenetic modifications to histone proteins serve an important role in regulating permissive and repressive chromatin states, but despite the identification of many histone PTMs and their perceived role, the epigenetic writers responsible for generating these chromatin signatures are not fully characterized. Here, we report that the canonical histone H3K9 methyltransferases EHMT1/GLP and EHMT2/G9a are capable of catalyzing methylation of histone H3 lysine 23 (H3K23). Our data show that while both enzymes can mono- and di-methylate H3K23, only EHMT1/GLP can tri-methylate H3K23. We also show that pharmacologic inhibition or genetic ablation of EHMT1/GLP and/or EHMT2/G9a leads to decreased H3K23 methylation in mammalian cells. Taken together, this work identifies H3K23 as a new direct methylation target of EHMT1/GLP and EHMT2/G9a, and highlights the differential activity of these enzymes on H3K23 as a substrate. Background Post-translational modifications (PTMs) on lysines of histone proteins have long been implicated in regulating gene expression, DNA replication, DNA damage repair, transposon silencing and other template-dependent processes [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]. Histone lysine methylation is added by histone methyltransferases (HMTs) that catalyze the addition of one (mono-), two (di-) or three (tri-) methyl groups (–CH 3 ) onto a single lysine [ 5 , 7 , 8 , 9 ]. These different modification states can often facilitate differential binding of effector proteins, which ‘read’ the various modification states and help direct additional chromatin modifying complexes to specific genomic regions and help drive locus-specific chromatin remodeling events [ 10 , 11 , 12 , 13 , 14 , 15 ]. The HMTs responsible for the addition of methyl groups to histones are sometimes capable of writing more than one modification state, but often must work in concert with other proteins and HMTs to generate all three modification states genome-wide [ 3 , 4 , 16 , 17 , 18 , 19 , 20 ]. Histone H3, 1 of the 4 core histones, contains several well-characterized lysine targets for modification by methyltransferases within its N-terminal tail, including H3K4, H3K9, H3K27, and H3K36. In eukaryotes where methylation is detected at these positions, some methylation events are linked to gene repression and facilitating a closed chromatin conformation (H3K9me and H3K27me), while methylation at other H3 lysines is connected to active gene transcription and facilitating an open chromatin conformation (H3K4me and H3K36me) [ 3 , 4 , 10 , 16 , 21 , 22 , 23 , 24 ]. Another conserved documented site of histone H3 methylation in organisms ranging from ciliates to mammals is H3K23. Although the biological roles for methylation on this residue are poorly characterized, they have been associated with gene repression and maintaining genome integrity [ 25 , 26 , 27 , 28 ]. While methyltransferases catalyzing H3K23 methylation have been identified in protists, nematodes, and plants, mammalian writers of these methylation marks have not been reported. In this study, we report that H3K23 represents a new target of the enzymes euchromatic histone methyltransferase 1 (EHMT1/GLP) and euchromatic histone methyltransferase 2 (EHMT2/G9a). More specifically, we report that while both EHMT1/GLP and EHMT2/G9a enzymes can catalyze the addition of mono- and di-methylation on H3K23, only EHMT1/GLP can catalyze the addition of tri-methylation on H3K23 in vitro. Additionally, we show that perturbations in EHMT1/GLP and/or EHMT2/G9a at either the protein or gene level leads to decreased methylation on H3K23 in vivo. Interestingly, our in vitro and in vivo studies also revealed H3K18 as a new target for mono-, di- and tri-methylation by both EHMT1/GLP and EHMT2/G9a. Taken together, this work establishes histone H3 lysines 18 and 23 as new methylation targets for EHMT1/GLP and EHMT2/G9a, and identifies their differential activity on H3K23. Results EHMT1/GLP and EHMT/G9a can de novo methylate histone H3K23 in vitro While H3K23 methylation has been observed in mammalian chromatin, mammalian HMTs that catalyze H3K23 methylation have not been reported. However, in other species such as A. thaliana , C. elegans and T. thermophila , histone methyltransferases that modify or are similar to those that modify H3K9 and H3K27 have been shown to also target H3K23 [ 25 , 26 , 27 , 28 ]. To screen which mammalian HMTs act on histone H3K23, we employed an in vitro histone methyltransferase assay. We chose to screen potential H3K23 methyltransferase activity of six known mammalian H3K9 methyltransferases, Suv39h1, Suv39h2, SetDB1, SetDB2, EHMT1/GLP, and EHMT2/G9a. As previously reported, [ 4 , 5 , 7 , 8 ], recombinant Suv39h1, Suv39h2, SetDB1, SetDB2, EHMT1/GLP, and EHMT2/G9a, were all able to de novo methylate H3K9 to different extents (data not shown). Of the HMTs screened, only EHMT1/GLP and EHMT2/G9a showed activity on H3K23. More specifically, our data show that while both EHMT1/GLP and EHMT2/G9a can mono- and di-methylate H3K23, only EHMT1/GLP can tri-methylate H3K23 as evaluated both by western blotting using histone modification specific antibodies for H3K9 and H3K23 (Fig. 1 A) and electron transfer dissociation (EthD) mass spectrometry (Fig. 1 B). To validate that EHMT1/GLP and EHMT2/G9a were not indiscriminately targeting lysines on H3, we tested for two additional well described histone H3 tri-methyl marks by western blotting: H3K4me3 and H3K36me3. Our data show that neither H3K4me3 nor H3K36me3 are generated in our in vitro HMT system by EHMT1/GLP or EHMT2/G9a, suggesting that these enzymes are indeed discriminating between targets and methylation states (Additional file 1 : Fig. S1B). In our western blotting and mass spectrometry analysis, we also observed H3K27 and H3K18 methylation to various extents (Additional file 1 : Fig. S1A–B). While the ability of EHMT1/GLP and EHMT2/G9a to catalyze methylation at H3K27 has been previously reported [ 36 ], we could not find examples in the literature of either of these two enzymes targeting H3K18. A summary of methylation sites targeted by EHMT1/GLP and EHMT2/G9a as detected by our combined western blotting and mass spectrometry data can be found in Table 1 . Taken together, this data identifies H3K18 and H3K23 as new targets of EHMT1/GLP and EHMT2/G9a. Fig. 1 EHMT1/GLP and EHMT2/G9a can de novo", "role": "user" }, { "content": "After an intrepid, decade-long search, Johns Hopkins Medicine scientists say they have found a new role for a pair of enzymes that regulate genome function and, when missing or mutated, are linked to diseases such as brain tumors, blood cancers and Kleefstra syndrome—a rare genetic, neurocognitive disorder. The new findings, published Nov. 21 in Epigenetics & Chromatin, could eventually help scientists understand diseases caused by disruption of these enzymes and develop new treatments for them. \"Developing a better understanding of how enzymes impact the activity of our genomes offers valuable insights into biology and can help researchers design new therapeutic approaches for disease,\" says Sean Taverna, Ph.D., associate professor of pharmacology and molecular sciences at the Johns Hopkins University School of Medicine. The search began more than a decade ago, when Taverna was looking for factors that influence DNA activity in Tetrahymena thermophila—a one-celled, fresh water dwelling organism. During the original study, published in eLife in 2014, the research team found a previously unknown signal that the single-celled creature uses to \"mark\" genes it has turned off. The location of the mark is on histone proteins, which act as spools that tightly wind DNA, often turning off genes and protecting DNA from damage. If Tetrahymena are not able to add the marks—a process called methylation, which adds chemical tags to a part of histones called H3K23—the DNA becomes damaged and the cells grow poorly. In a follow up study published in Nature Communications in 2016, Taverna found that the H3K23 location is conserved between Tetrahymena and mammals, including humans. However, the enzymes that control how the chemical tags are placed on H3K23 differ between the species. Without the identity of these enzymatic H3K23 \"writers\" of methylation, the researchers found it difficult to study H3K23's role in human biology and disease. So, Taverna, recent Ph.D. graduate David Vinson and Srinivasan Yegnasubramanian, M.D., Ph.D., professor of oncology and pathology at the Johns Hopkins Kimmel Cancer Center, led a new study to search for the mammalian enzymes that add the chemical tags to H3K23. After screening many enzymes that write methylation, Vinson found just one pair of enzymes, EHMT1/GLP and EHMT2/G9a, which placed chemical tags on the H3K23 histone location. When the researchers used drug inhibitors and genetic mutations directed against the enzyme pair in human brain cells (neurons) grown in the laboratory, the ability of the enzymes to place methylation tags on the H3K23 histone location reduced significantly. \"With this initial precedent established in human neuronal cells, the door is now wide open to study the role of these enzymes and the H3K23 modification in numerous contexts of health and disease, including human cancer,\" says Yegnasubramanian. Now that the researchers know that EHMT1/GLP and EHMT2/G9a place chemical tags on the H3K23 histone location, they are aiming to understand the precise mechanism of how they do so and develop drugs that target this activity. \"We want to better understand why diseases occur when these enzymes aren't working correctly, and what their connections are to H3K23,\" says Taverna. ", "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 Epigenetic modifications to histone proteins serve an important role in regulating permissive and repressive chromatin states, but despite the identification of many histone PTMs and their perceived role, the epigenetic writers responsible for generating these chromatin signatures are not fully characterized. Here, we report that the canonical histone H3K9 methyltransferases EHMT1/GLP and EHMT2/G9a are capable of catalyzing methylation of histone H3 lysine 23 (H3K23). Our data show that while both enzymes can mono- and di-methylate H3K23, only EHMT1/GLP can tri-methylate H3K23. We also show that pharmacologic inhibition or genetic ablation of EHMT1/GLP and/or EHMT2/G9a leads to decreased H3K23 methylation in mammalian cells. Taken together, this work identifies H3K23 as a new direct methylation target of EHMT1/GLP and EHMT2/G9a, and highlights the differential activity of these enzymes on H3K23 as a substrate. Background Post-translational modifications (PTMs) on lysines of histone proteins have long been implicated in regulating gene expression, DNA replication, DNA damage repair, transposon silencing and other template-dependent processes [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]. Histone lysine methylation is added by histone methyltransferases (HMTs) that catalyze the addition of one (mono-), two (di-) or three (tri-) methyl groups (–CH 3 ) onto a single lysine [ 5 , 7 , 8 , 9 ]. These different modification states can often facilitate differential binding of effector proteins, which ‘read’ the various modification states and help direct additional chromatin modifying complexes to specific genomic regions and help drive locus-specific chromatin remodeling events [ 10 , 11 , 12 , 13 , 14 , 15 ]. The HMTs responsible for the addition of methyl groups to histones are sometimes capable of writing more than one modification state, but often must work in concert with other proteins and HMTs to generate all three modification states genome-wide [ 3 , 4 , 16 , 17 , 18 , 19 , 20 ]. Histone H3, 1 of the 4 core histones, contains several well-characterized lysine targets for modification by methyltransferases within its N-terminal tail, including H3K4, H3K9, H3K27, and H3K36. In eukaryotes where methylation is detected at these positions, some methylation events are linked to gene repression and facilitating a closed chromatin conformation (H3K9me and H3K27me), while methylation at other H3 lysines is connected to active gene transcription and facilitating an open chromatin conformation (H3K4me and H3K36me) [ 3 , 4 , 10 , 16 , 21 , 22 , 23 , 24 ]. Another conserved documented site of histone H3 methylation in organisms ranging from ciliates to mammals is H3K23. Although the biological roles for methylation on this residue are poorly characterized, they have been associated with gene repression and maintaining genome integrity [ 25 , 26 , 27 , 28 ]. While methyltransferases catalyzing H3K23 methylation have been identified in protists, nematodes, and plants, mammalian writers of these methylation marks have not been reported. In this study, we report that H3K23 represents a new target of the enzymes euchromatic histone methyltransferase 1 (EHMT1/GLP) and euchromatic histone methyltransferase 2 (EHMT2/G9a). More specifically, we report that while both EHMT1/GLP and EHMT2/G9a enzymes can catalyze the addition of mono- and di-methylation on H3K23, only EHMT1/GLP can catalyze the addition of tri-methylation on H3K23 in vitro. Additionally, we show that perturbations in EHMT1/GLP and/or EHMT2/G9a at either the protein or gene level leads to decreased methylation on H3K23 in vivo. Interestingly, our in vitro and in vivo studies also revealed H3K18 as a new target for mono-, di- and tri-methylation by both EHMT1/GLP and EHMT2/G9a. Taken together, this work establishes histone H3 lysines 18 and 23 as new methylation targets for EHMT1/GLP and EHMT2/G9a, and identifies their differential activity on H3K23. Results EHMT1/GLP and EHMT/G9a can de novo methylate histone H3K23 in vitro While H3K23 methylation has been observed in mammalian chromatin, mammalian HMTs that catalyze H3K23 methylation have not been reported. However, in other species such as A. thaliana , C. elegans and T. thermophila , histone methyltransferases that modify or are similar to those that modify H3K9 and H3K27 have been shown to also target H3K23 [ 25 , 26 , 27 , 28 ]. To screen which mammalian HMTs act on histone H3K23, we employed an in vitro histone methyltransferase assay. We chose to screen potential H3K23 methyltransferase activity of six known mammalian H3K9 methyltransferases, Suv39h1, Suv39h2, SetDB1, SetDB2, EHMT1/GLP, and EHMT2/G9a. As previously reported, [ 4 , 5 , 7 , 8 ], recombinant Suv39h1, Suv39h2, SetDB1, SetDB2, EHMT1/GLP, and EHMT2/G9a, were all able to de novo methylate H3K9 to different extents (data not shown). Of the HMTs screened, only EHMT1/GLP and EHMT2/G9a showed activity on H3K23. More specifically, our data show that while both EHMT1/GLP and EHMT2/G9a can mono- and di-methylate H3K23, only EHMT1/GLP can tri-methylate H3K23 as evaluated both by western blotting using histone modification specific antibodies for H3K9 and H3K23 (Fig. 1 A) and electron transfer dissociation (EthD) mass spectrometry (Fig. 1 B). To validate that EHMT1/GLP and EHMT2/G9a were not indiscriminately targeting lysines on H3, we tested for two additional well described histone H3 tri-methyl marks by western blotting: H3K4me3 and H3K36me3. Our data show that neither H3K4me3 nor H3K36me3 are generated in our in vitro HMT system by EHMT1/GLP or EHMT2/G9a, suggesting that these enzymes are indeed discriminating between targets and methylation states (Additional file 1 : Fig. S1B). In our western blotting and mass spectrometry analysis, we also observed H3K27 and H3K18 methylation to various extents (Additional file 1 : Fig. S1A–B). While the ability of EHMT1/GLP and EHMT2/G9a to catalyze methylation at H3K27 has been previously reported [ 36 ], we could not find examples in the literature of either of these two enzymes targeting H3K18. A summary of methylation sites targeted by EHMT1/GLP and EHMT2/G9a as detected by our combined western blotting and mass spectrometry data can be found in Table 1 . Taken together, this data identifies H3K18 and H3K23 as new targets of EHMT1/GLP and EHMT2/G9a. Fig. 1 EHMT1/GLP and EHMT2/G9a can de novo<|im_end|> <|im_start|>assistant After an intrepid, decade-long search, Johns Hopkins Medicine scientists say they have found a new role for a pair of enzymes that regulate genome function and, when missing or mutated, are linked to diseases such as brain tumors, blood cancers and Kleefstra syndrome—a rare genetic, neurocognitive disorder. The new findings, published Nov. 21 in Epigenetics & Chromatin, could eventually help scientists understand diseases caused by disruption of these enzymes and develop new treatments for them. "Developing a better understanding of how enzymes impact the activity of our genomes offers valuable insights into biology and can help researchers design new therapeutic approaches for disease," says Sean Taverna, Ph.D., associate professor of pharmacology and molecular sciences at the Johns Hopkins University School of Medicine. The search began more than a decade ago, when Taverna was looking for factors that influence DNA activity in Tetrahymena thermophila—a one-celled, fresh water dwelling organism. During the original study, published in eLife in 2014, the research team found a previously unknown signal that the single-celled creature uses to "mark" genes it has turned off. The location of the mark is on histone proteins, which act as spools that tightly wind DNA, often turning off genes and protecting DNA from damage. If Tetrahymena are not able to add the marks—a process called methylation, which adds chemical tags to a part of histones called H3K23—the DNA becomes damaged and the cells grow poorly. In a follow up study published in Nature Communications in 2016, Taverna found that the H3K23 location is conserved between Tetrahymena and mammals, including humans. However, the enzymes that control how the chemical tags are placed on H3K23 differ between the species. Without the identity of these enzymatic H3K23 "writers" of methylation, the researchers found it difficult to study H3K23's role in human biology and disease. So, Taverna, recent Ph.D. graduate David Vinson and Srinivasan Yegnasubramanian, M.D., Ph.D., professor of oncology and pathology at the Johns Hopkins Kimmel Cancer Center, led a new study to search for the mammalian enzymes that add the chemical tags to H3K23. After screening many enzymes that write methylation, Vinson found just one pair of enzymes, EHMT1/GLP and EHMT2/G9a, which placed chemical tags on the H3K23 histone location. When the researchers used drug inhibitors and genetic mutations directed against the enzyme pair in human brain cells (neurons) grown in the laboratory, the ability of the enzymes to place methylation tags on the H3K23 histone location reduced significantly. "With this initial precedent established in human neuronal cells, the door is now wide open to study the role of these enzymes and the H3K23 modification in numerous contexts of health and disease, including human cancer," says Yegnasubramanian. Now that the researchers know that EHMT1/GLP and EHMT2/G9a place chemical tags on the H3K23 histone location, they are aiming to understand the precise mechanism of how they do so and develop drugs that target this activity. "We want to better understand why diseases occur when these enzymes aren't working correctly, and what their connections are to H3K23," says Taverna. <|im_end|>

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2,488

[ { "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 Snow slab avalanches, characterized by a distinct, broad fracture line, are released following anticrack propagation in highly porous weak snow layers buried below cohesive slabs. The anticrack mechanism is driven by the volumetric collapse of the weak layer, which leads to the closure of crack faces and to the onset of frictional contact. Here, on the basis of snow fracture experiments, full-scale avalanche measurements and numerical simulations, we report the existence of a transition from sub-Rayleigh anticrack to supershear crack propagation. This transition follows the Burridge–Andrews mechanism, in which a supershear daughter crack nucleates ahead of the main fracture front and eventually propagates faster than the shear wave speed. Furthermore, we show that the supershear propagation regime can exist even if the shear-to-normal stress ratio is lower than the static friction coefficient as a result of the loss of frictional resistance during collapse. This finding shows that snow slab avalanches have fundamental similarities with strike-slip earthquakes. Main The release of snow slab avalanches results from a succession of mechanical processes 1 , 2 . A failure is initiated in a highly porous weak snow layer buried beneath a cohesive snow slab, leading to mixed-mode and quasi-brittle crack propagation along the slope 3 . If the slope angle is larger than the weak layer friction angle, the slab eventually slides and releases 4 . Two seemingly conflicting theories have been developed to conceptualize avalanche release mechanisms. The first was introduced by McClung 1 and assumes that the weak layer fails under shear only (mode II). By construction, this approach relies on the slope-parallel component of the load and thus fails to explain field observations of crack propagation on flat terrain and remote avalanche triggering 5 , 6 , 7 . A second theory was thus proposed by Heierli et al. 8 , who extended the concept of anticracks originally introduced to explain deep earthquakes 9 to slab avalanches. In contrast to classical cracks opening under tension (mode I), anticracks refer to a mode of compressive fracture with the closure of crack faces (mode −I). This process thus requires a volume reduction (collapse), which is only possible in porous materials under pressure. In this theory 8 , the volumetric collapse of the weak layer allows the overlaying slab to bend, which induces stress concentrations in the weak layer and drives anticrack propagation, even on low-angle slopes. Despite more recent advances reconciling these two approaches 10 , the dynamic phase of crack propagation prior to frictional sliding remains largely unknown, especially at the slope scale. Very large crack speeds (>150 m s −1 ) were evaluated based on real-scale avalanche observations by Hamre and others 11 . Although these findings only represent indirect measurements and lack validation, the reported values appear larger than the shear wave speed in snow, which contrasts with the substantially lower sub-Rayleigh values measured in small-scale snow fracture experiments 12 . This discrepancy between small-scale experiments and large-scale observations suggests that there could be a transition during fracture propagation. Crack speeds greater than the shear wave speed c s , but less than the longitudinal wave speed c p , have been reported in earthquake dynamics based on seismological observations 13 , 14 , 15 , stick-slip 16 , 17 , 18 and fracture experiments 19 , 20 , and numerical simulations 15 , 21 , 22 . This complex process, at the frontier between fracture and friction, is often referred to as intersonic or supershear crack propagation. It has been conceptualized by Burridge–Andrews 23 , 24 , who showed that a daughter supershear crack can nucleate ahead of the main fracture if the local shear stress exceeds a critical value. Although snow slab avalanches have numerous mechanical features in common with earthquakes, the snow anticrack mechanism, which allows for crack propagation without an external driving shear force, further complicates analyses and prevents direct analogies. In this Article, based on numerical simulations, snow fracture experiments and full-scale avalanche measurements, we show that, under specific conditions, the onset of frictional sliding during slab avalanche release may involve a transition from sub-Rayleigh anticrack to supershear crack propagation. This transition implies the Burridge–Andrews mechanism and can occur even for slope angles smaller than the weak layer friction angle; we attribute this to the loss of frictional resistance during weak layer collapse related to the anticrack. We quantify the so-called super-critical crack length associated with this supershear transition and propose a theoretical shear band model in which the collapse amplitude is accounted for by a reduced effective friction. Experimental mismatch Based on elastic modulus values measured using snow fracture tests 25 , the effective shear wave speed c s in snow is less than 120 m s −1 . Crack propagation speeds obtained based on numerous small-scale (<2 m) snow fracture experiments typically vary between 10 m s −1 and 80 m s −1 (Extended Data Fig. 1 ). However, Hamre et al. 11 reported crack propagation speeds larger than 200 m s −1 , based on slope-scale avalanche observations, suggesting supershear fracture. To explain these contrasting observations, the dynamics of crack propagation in weak snow layers is analysed via numerical simulations, snow fracture experiments and full-scale avalanche measurements. Numerical simulations Numerical simulations of the so-called propagation saw test (PST) 6 were performed based on the material point method (MPM), finite strain elastoplasticity and a constitutive snow model accounting for weak-layer volumetric collapse 3 ( Methods ). The PST consists of creating a crack in a predefined weak layer using a saw, until it reaches a critical crack length a c (corresponding to time t c ), after which the crack propagates in a self-sustained manner. The main differences between snow fracture experiments and real avalanches are the length scale and slope angle ( ψ ), which are generally low in experiments for practical and safety reasons. Accordingly, simulations were performed for very long PSTs, up to 140 m, and for representative slope angles between 0° and 50°. Figure 1a–d shows weak-layer", "role": "user" }, { "content": "Scientists from EPFL and the WSL Institute for Snow and Avalanche Research SLF have gained deeper insight into how snow slab avalanches form, paving the way to more effective risk assessment measures for these catastrophic events that induce more avalanche accidents and fatalities every year than other types of avalanches. The team of EPFL and SLF scientists made a discovery which represents a paradigm shift that could significantly influence their research niche. By expanding the scale for snow slab avalanche simulations from a meter to a hundred meters, they obtained a better understanding of the mechanisms underlying these events. Their discovery also illustrates the benefits that advances in computer processing power can bring to the methods used to observe complex physical phenomena. The team's findings appear in Nature Physics. Their work builds on a 2018 study by EPFL professor Johan Gaume and scientists at the University of California in Los Angeles. That initial study, published in Nature Communications, describes a 3D simulation method that the researchers developed to model snow slab avalanches with unrivaled precision. Today Gaume is the head of EPFL's Snow and Avalanche Simulation Laboratory (SLAB), within EPFL's School of Architecture, Civil and Environmental Engineering (ENAC), and is affiliated with the SLF Institute; he and his Ph.D. student Bertil Trottet took the study further by applying it at a larger scale—and made a surprising discovery. They found that the manner in which cracks propagate changes during the release process of the slab avalanche. For instance, they observed crack propagation speeds exceeding 100 meters per second, which is well beyond the speeds of around 30 meters per second typically measured in experiments. At first the two scientists thought they'd made a mistake. Slab avalanche video analyses. Credit: Titouan Bessire Supershear crack propagation Snow slab avalanches are characterized by a sharp and broad fracture line that occurs at the top of the released snow mass. Such an avalanche forms when a dense layer of snow (the slab) sits on top of a weak snow layer with little cohesion. When an avalanche is triggered, for instance by a skier, the weak layer collapses and the slab loses its underlying support structure. The subsequent slab bending is one of the main drivers of crack propagation. At least that was the mechanism suggested by experiments and numerical models until now, based on tested and simulated slabs measuring less than two meters long. But by modeling slabs measuring around 100 meters, the EPFL and SLF scientists found that once crack propagation extends beyond around three to five meters, slab tension becomes the only driver of the release process, causing the weak layer to fail under shear. This phenomenon is similar to the so-called \"supershear\" rupture mechanism observed in the rare high-magnitude earthquakes that have been reported so far. \"We felt we were on to something important, but we needed experimental data to confirm it,\" says Gaume. Video analyses Then a series of coincidences gave Trottet and Gaume an opportunity to confirm their discovery. First, Gaume attended a conference presentation in which Ron Simenhois from the Colorado Avalanche Information Center described a high-tech video analysis method he's working on. At around the same time, Mathieu Schaer—a former EPFL environmental engineering student who's now a professional snowboarder and an engineer at MétéoSuisse—sent Gaume a video showing how he barely escaped a large snow slab avalanche. \"The avalanche occurred in Col du Cou in the Swiss Alps,\" says Gaume. \"We had snow data on the event, and Schaer's video was of excellent quality because he was filming for a snowboarding movie. By analyzing the video and examining the various parameters, we were able to confirm the results of our model for the first time.\" In total, four real-world avalanches allowed the scientists to confirm a transition from an \"anticrack\" propagation mode to the \"supershear\" mode reported during some large earthquakes. Based on these findings, the SLF Institute is now developing larger-scale experimental facilities in Davos in order to gain further insights into the release process of snow slab avalanches . Toward improved hazard assessment Their work will help snow researchers come up with new assumptions that can simplify computer models of avalanches and shorten the required computing time considerably—from several days to just a few minutes. The enhanced models could be used to determine the size of avalanches, for example, which is crucial information for effective risk prediction and management. ", "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 Snow slab avalanches, characterized by a distinct, broad fracture line, are released following anticrack propagation in highly porous weak snow layers buried below cohesive slabs. The anticrack mechanism is driven by the volumetric collapse of the weak layer, which leads to the closure of crack faces and to the onset of frictional contact. Here, on the basis of snow fracture experiments, full-scale avalanche measurements and numerical simulations, we report the existence of a transition from sub-Rayleigh anticrack to supershear crack propagation. This transition follows the Burridge–Andrews mechanism, in which a supershear daughter crack nucleates ahead of the main fracture front and eventually propagates faster than the shear wave speed. Furthermore, we show that the supershear propagation regime can exist even if the shear-to-normal stress ratio is lower than the static friction coefficient as a result of the loss of frictional resistance during collapse. This finding shows that snow slab avalanches have fundamental similarities with strike-slip earthquakes. Main The release of snow slab avalanches results from a succession of mechanical processes 1 , 2 . A failure is initiated in a highly porous weak snow layer buried beneath a cohesive snow slab, leading to mixed-mode and quasi-brittle crack propagation along the slope 3 . If the slope angle is larger than the weak layer friction angle, the slab eventually slides and releases 4 . Two seemingly conflicting theories have been developed to conceptualize avalanche release mechanisms. The first was introduced by McClung 1 and assumes that the weak layer fails under shear only (mode II). By construction, this approach relies on the slope-parallel component of the load and thus fails to explain field observations of crack propagation on flat terrain and remote avalanche triggering 5 , 6 , 7 . A second theory was thus proposed by Heierli et al. 8 , who extended the concept of anticracks originally introduced to explain deep earthquakes 9 to slab avalanches. In contrast to classical cracks opening under tension (mode I), anticracks refer to a mode of compressive fracture with the closure of crack faces (mode −I). This process thus requires a volume reduction (collapse), which is only possible in porous materials under pressure. In this theory 8 , the volumetric collapse of the weak layer allows the overlaying slab to bend, which induces stress concentrations in the weak layer and drives anticrack propagation, even on low-angle slopes. Despite more recent advances reconciling these two approaches 10 , the dynamic phase of crack propagation prior to frictional sliding remains largely unknown, especially at the slope scale. Very large crack speeds (>150 m s −1 ) were evaluated based on real-scale avalanche observations by Hamre and others 11 . Although these findings only represent indirect measurements and lack validation, the reported values appear larger than the shear wave speed in snow, which contrasts with the substantially lower sub-Rayleigh values measured in small-scale snow fracture experiments 12 . This discrepancy between small-scale experiments and large-scale observations suggests that there could be a transition during fracture propagation. Crack speeds greater than the shear wave speed c s , but less than the longitudinal wave speed c p , have been reported in earthquake dynamics based on seismological observations 13 , 14 , 15 , stick-slip 16 , 17 , 18 and fracture experiments 19 , 20 , and numerical simulations 15 , 21 , 22 . This complex process, at the frontier between fracture and friction, is often referred to as intersonic or supershear crack propagation. It has been conceptualized by Burridge–Andrews 23 , 24 , who showed that a daughter supershear crack can nucleate ahead of the main fracture if the local shear stress exceeds a critical value. Although snow slab avalanches have numerous mechanical features in common with earthquakes, the snow anticrack mechanism, which allows for crack propagation without an external driving shear force, further complicates analyses and prevents direct analogies. In this Article, based on numerical simulations, snow fracture experiments and full-scale avalanche measurements, we show that, under specific conditions, the onset of frictional sliding during slab avalanche release may involve a transition from sub-Rayleigh anticrack to supershear crack propagation. This transition implies the Burridge–Andrews mechanism and can occur even for slope angles smaller than the weak layer friction angle; we attribute this to the loss of frictional resistance during weak layer collapse related to the anticrack. We quantify the so-called super-critical crack length associated with this supershear transition and propose a theoretical shear band model in which the collapse amplitude is accounted for by a reduced effective friction. Experimental mismatch Based on elastic modulus values measured using snow fracture tests 25 , the effective shear wave speed c s in snow is less than 120 m s −1 . Crack propagation speeds obtained based on numerous small-scale (<2 m) snow fracture experiments typically vary between 10 m s −1 and 80 m s −1 (Extended Data Fig. 1 ). However, Hamre et al. 11 reported crack propagation speeds larger than 200 m s −1 , based on slope-scale avalanche observations, suggesting supershear fracture. To explain these contrasting observations, the dynamics of crack propagation in weak snow layers is analysed via numerical simulations, snow fracture experiments and full-scale avalanche measurements. Numerical simulations Numerical simulations of the so-called propagation saw test (PST) 6 were performed based on the material point method (MPM), finite strain elastoplasticity and a constitutive snow model accounting for weak-layer volumetric collapse 3 ( Methods ). The PST consists of creating a crack in a predefined weak layer using a saw, until it reaches a critical crack length a c (corresponding to time t c ), after which the crack propagates in a self-sustained manner. The main differences between snow fracture experiments and real avalanches are the length scale and slope angle ( ψ ), which are generally low in experiments for practical and safety reasons. Accordingly, simulations were performed for very long PSTs, up to 140 m, and for representative slope angles between 0° and 50°. Figure 1a–d shows weak-layer<|im_end|> <|im_start|>assistant Scientists from EPFL and the WSL Institute for Snow and Avalanche Research SLF have gained deeper insight into how snow slab avalanches form, paving the way to more effective risk assessment measures for these catastrophic events that induce more avalanche accidents and fatalities every year than other types of avalanches. The team of EPFL and SLF scientists made a discovery which represents a paradigm shift that could significantly influence their research niche. By expanding the scale for snow slab avalanche simulations from a meter to a hundred meters, they obtained a better understanding of the mechanisms underlying these events. Their discovery also illustrates the benefits that advances in computer processing power can bring to the methods used to observe complex physical phenomena. The team's findings appear in Nature Physics. Their work builds on a 2018 study by EPFL professor Johan Gaume and scientists at the University of California in Los Angeles. That initial study, published in Nature Communications, describes a 3D simulation method that the researchers developed to model snow slab avalanches with unrivaled precision. Today Gaume is the head of EPFL's Snow and Avalanche Simulation Laboratory (SLAB), within EPFL's School of Architecture, Civil and Environmental Engineering (ENAC), and is affiliated with the SLF Institute; he and his Ph.D. student Bertil Trottet took the study further by applying it at a larger scale—and made a surprising discovery. They found that the manner in which cracks propagate changes during the release process of the slab avalanche. For instance, they observed crack propagation speeds exceeding 100 meters per second, which is well beyond the speeds of around 30 meters per second typically measured in experiments. At first the two scientists thought they'd made a mistake. Slab avalanche video analyses. Credit: Titouan Bessire Supershear crack propagation Snow slab avalanches are characterized by a sharp and broad fracture line that occurs at the top of the released snow mass. Such an avalanche forms when a dense layer of snow (the slab) sits on top of a weak snow layer with little cohesion. When an avalanche is triggered, for instance by a skier, the weak layer collapses and the slab loses its underlying support structure. The subsequent slab bending is one of the main drivers of crack propagation. At least that was the mechanism suggested by experiments and numerical models until now, based on tested and simulated slabs measuring less than two meters long. But by modeling slabs measuring around 100 meters, the EPFL and SLF scientists found that once crack propagation extends beyond around three to five meters, slab tension becomes the only driver of the release process, causing the weak layer to fail under shear. This phenomenon is similar to the so-called "supershear" rupture mechanism observed in the rare high-magnitude earthquakes that have been reported so far. "We felt we were on to something important, but we needed experimental data to confirm it," says Gaume. Video analyses Then a series of coincidences gave Trottet and Gaume an opportunity to confirm their discovery. First, Gaume attended a conference presentation in which Ron Simenhois from the Colorado Avalanche Information Center described a high-tech video analysis method he's working on. At around the same time, Mathieu Schaer—a former EPFL environmental engineering student who's now a professional snowboarder and an engineer at MétéoSuisse—sent Gaume a video showing how he barely escaped a large snow slab avalanche. "The avalanche occurred in Col du Cou in the Swiss Alps," says Gaume. "We had snow data on the event, and Schaer's video was of excellent quality because he was filming for a snowboarding movie. By analyzing the video and examining the various parameters, we were able to confirm the results of our model for the first time." In total, four real-world avalanches allowed the scientists to confirm a transition from an "anticrack" propagation mode to the "supershear" mode reported during some large earthquakes. Based on these findings, the SLF Institute is now developing larger-scale experimental facilities in Davos in order to gain further insights into the release process of snow slab avalanches . Toward improved hazard assessment Their work will help snow researchers come up with new assumptions that can simplify computer models of avalanches and shorten the required computing time considerably—from several days to just a few minutes. The enhanced models could be used to determine the size of avalanches, for example, which is crucial information for effective risk prediction and management. <|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 Phonons and their interactions with other phonons, electrons or photons drive energy gain, loss and transport in materials. Although the phonon density of states has been measured and calculated in bulk crystalline semiconductors 1 , phonons remain poorly understood in nanomaterials 2 , 3 , 4 , 5 , despite the increasing prevalence of bottom-up fabrication of semiconductors from nanomaterials and the integration of nanometre-sized components into devices 6 , 7 , 8 . Here we quantify the phononic properties of bottom-up fabricated semiconductors as a function of crystallite size using inelastic neutron scattering measurements and ab initio molecular dynamics simulations. We show that, unlike in microcrystalline semiconductors, the phonon modes of semiconductors with nanocrystalline domains exhibit both reduced symmetry and low energy owing to mechanical softness at the surface of those domains. These properties become important when phonons couple to electrons in semiconductor devices. Although it was initially believed that the coupling between electrons and phonons is suppressed in nanocrystalline materials owing to the scarcity of electronic states and their large energy separation 9 , it has since been shown that the electron–phonon coupling is large and allows high energy-dissipation rates exceeding one electronvolt per picosecond (refs 10 , 11 , 12 , 13 ). Despite detailed investigations into the role of phonons in exciton dynamics, leading to a variety of suggestions as to the origins of these fast transition rates 14 , 15 and including attempts to numerically calculate them 12 , 13 , 16 , fundamental questions surrounding electron–phonon interactions in nanomaterials remain unresolved. By combining the microscopic and thermodynamic theories of phonons 1 , 17 , 18 , 19 and our findings on the phononic properties of nanomaterials, we are able to explain and then experimentally confirm the strong electron–phonon coupling and fast multi-phonon transition rates of charge carriers to trap states. This improved understanding of phonon processes permits the rational selection of nanomaterials, their surface treatments, and the design of devices incorporating them. Main To study phonons as a function of crystalline domain size, we select nanocrystal (NC)-based solids as a model system. Colloidal NCs offer excellent size tunability and monodispersity and are usually assembled into thin films such that their nanosized dimensions and quantum-confined properties are retained 8 . We work with lead sulfide (PbS) because the phonon properties of bulk PbS have been well studied, microcrystalline PbS is readily available, and PbS NC-solids (that is, compact solids formed from closely attached NCs) have been used for LEDs 20 , photodetectors 21 , solar cells 7 , 22 and thermoelectrics 23 . We quantify the phononic properties using inelastic neutron scattering (INS). For each sample ( Table 1 ), we reconstruct the dynamic structure factor ( S ( q , ω )) as a function of the momentum ( q ) and energy ( ω ) gained by the scattered neutron, from which we can approximate the mean square displacement (〈 u 2 〉) of atoms in the material and calculate the phonon density of states ( g ( ω )). Supplementary Methods 1–6 detail sample preparation, measurement, characterization and analysis. Table 1 Samples studied by INS Full size table First, we compare measurements on microcrystalline PbS (sample S1) with those on two NC-solids having increasingly smaller crystallite sizes (radius r = 8.2 nm (S2) and r = 1.33 nm (S3)) ( Fig. 1a ). For microcrystalline PbS, we observe Bragg reflections around ω = 0 cm −1 that are characteristic of the PbS crystal lattice, and a distinct structure along the q axis at finite energy transfers ( ω ≠ 0 cm −1 ) due to the Bloch-wave symmetry of the phonons that results from the discrete translational symmetry of the crystal lattice. With decreasing crystallite size, these features progressively disappear, indicating a breakdown of the Bloch-wave symmetry of the phonon modes. We calculate 〈 u 2 〉 = 0.042 ± 0.007 Å 2 for S1, in agreement with previous measurements 24 ( Supplementary Methods 5 ). For nanocrystalline samples, 〈 u 2 〉 increases twofold ( Table 1 ), signalling increased atomic motion. The measured g ( ω ) of the microcrystalline sample shows excellent agreement with density-functional-theory (DFT) calculations for bulk PbS ( Supplementary Methods 8 ), with transverse acoustic (TA) modes at 48.8 cm −1 and longitudinal acoustic (LA) modes at 84.4 cm −1 ( Fig. 1b ). With decreasing crystallite size, the TA and LA bulk modes reduce in relative weight and new modes appear at 25 cm −1 ( Fig. 1b inset). Figure 1: Inelastic neutron scattering (INS) measurements. a , The intensity ( I ) of the elastic line ( ω = 0) and the dynamic structure factor ( S ( q , ω )) reconstructed from INS data for bulk PbS (S1) and two NC-solids with crystallite radii r = 8.2 nm (S2) and r = 1.33 nm (S3). a.u., arbitrary units. b , Phonon density of states ( g ( ω )) for samples S1 (black), S2 (dark blue) and S3 (light blue). Below, the partial g ( ω ) for Pb atoms (grey) and S atoms (yellow) calculated by density-functional theory (DFT). All g ( ω ) are normalized to an area of 1 between 0 and 300 cm −1 . Peaks are the Van Hove singularities of transverse acoustic (TA) and longitudinal acoustic (LA) modes. NC-solids (S2, S3) show a mode at 25 cm −1 (Gaussian fit in inset). c , g ( ω ) for samples S4–S7 with radii between 1.5 nm and 3.3 nm. Peaks at 90, 150 and 250 cm −1 are attributed to vibrations of the linker molecule 1,2-ethanedithiol (EDT), which do not appear in sample S3 (blue) using deuterated EDT (EDT-d4) (for better visibility g ( ω ) of S3 (blue) is scaled by 0.68). Ab initio molecular dynamics calculations of EDT bound to a Pb atom are shown below (grey) ( Supplementary Methods 11 ). PowerPoint slide Full size image Next, we investigate the impact of", "role": "user" }, { "content": "All materials are made up of atoms, which vibrate. These vibrations, or 'phonons', are responsible, for example, for how electric charge and heat is transported in materials. Vibrations of metals, semiconductors, and insulators in are well studied; however, now materials are being nanosized to bring better performance to applications such as displays, sensors, batteries, and catalytic membranes. What happens to vibrations when a material is nanosized has until now not been understood. Soft Surfaces Vibrate Strongly In a recent publication in Nature, ETH Professor Vanessa Wood and her colleagues explain what happens to atomic vibrations when materials are nanosized and how this knowledge can be used to systematically engineer nanomaterials for different applications. The paper shows that when materials are made smaller than about 10 to 20 nanometers—that is, 5,000 times thinner than a human air—the vibrations of the outermost atomic layers on surface of the nanoparticle are large and play an important role in how this material behaves. \"For some applications, like catalysis, thermoelectrics, or superconductivity, these large vibrations may be good, but for other applications like LEDs or solar cells, these vibrations are undesirable,\" explains Wood. Indeed, the paper explains why nanoparticle-based solar cells have until now not met their full promise. The researchers showed using both experiment and theory that surface vibrations interact with electrons to reduce the photocurrent in solar cells. \"Now that we have proven that surface vibrations are important, we can systematically design materials to suppress or enhance these vibrations,\" say Wood. Improving Solar Cells Wood's research group has worked for a long time on a particular type of nanomaterial—colloidal nanocrystals—semiconductors with a diameter of 2 to 10 nanometers. These materials are interesting because their optical and electrical properties are dependent on their size, which can be easily changed during their synthesis. These materials are now used commercially as red- and green-light emitters in LED-based TVs and are being explored as possible materials for low cost, solution-processed solar cells. Researchers have noticed that placing certain atoms around the surface of the nanocrystal can improve the performance of solar cells. The reason why this worked had not been understood. The work published in the Nature paper now gives the answer: a hard shell of atoms can suppress the vibrations and their interaction with electrons. This means a higher photocurrent and a higher efficiency solar cell. Big Science to Study the Nanoscale Experiments were conducted in Professor Wood's labs at ETH Zurich and at the Swiss Spallation Neutron Source at the Paul Scherrer Institute. By observing how neutrons scatter off atoms in a material, it is possible to quantify how atoms in a material vibrate. To understand the neutron measurements, simulations of the atomic vibrations were run at the Swiss National Supercomputing Center (CSCS) in Lugano. Wood says, \"without access to these large facilities, this work would not have been possible. We are incredibly fortunate here in Switzerland to have these world class facilities.\" ", "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 Phonons and their interactions with other phonons, electrons or photons drive energy gain, loss and transport in materials. Although the phonon density of states has been measured and calculated in bulk crystalline semiconductors 1 , phonons remain poorly understood in nanomaterials 2 , 3 , 4 , 5 , despite the increasing prevalence of bottom-up fabrication of semiconductors from nanomaterials and the integration of nanometre-sized components into devices 6 , 7 , 8 . Here we quantify the phononic properties of bottom-up fabricated semiconductors as a function of crystallite size using inelastic neutron scattering measurements and ab initio molecular dynamics simulations. We show that, unlike in microcrystalline semiconductors, the phonon modes of semiconductors with nanocrystalline domains exhibit both reduced symmetry and low energy owing to mechanical softness at the surface of those domains. These properties become important when phonons couple to electrons in semiconductor devices. Although it was initially believed that the coupling between electrons and phonons is suppressed in nanocrystalline materials owing to the scarcity of electronic states and their large energy separation 9 , it has since been shown that the electron–phonon coupling is large and allows high energy-dissipation rates exceeding one electronvolt per picosecond (refs 10 , 11 , 12 , 13 ). Despite detailed investigations into the role of phonons in exciton dynamics, leading to a variety of suggestions as to the origins of these fast transition rates 14 , 15 and including attempts to numerically calculate them 12 , 13 , 16 , fundamental questions surrounding electron–phonon interactions in nanomaterials remain unresolved. By combining the microscopic and thermodynamic theories of phonons 1 , 17 , 18 , 19 and our findings on the phononic properties of nanomaterials, we are able to explain and then experimentally confirm the strong electron–phonon coupling and fast multi-phonon transition rates of charge carriers to trap states. This improved understanding of phonon processes permits the rational selection of nanomaterials, their surface treatments, and the design of devices incorporating them. Main To study phonons as a function of crystalline domain size, we select nanocrystal (NC)-based solids as a model system. Colloidal NCs offer excellent size tunability and monodispersity and are usually assembled into thin films such that their nanosized dimensions and quantum-confined properties are retained 8 . We work with lead sulfide (PbS) because the phonon properties of bulk PbS have been well studied, microcrystalline PbS is readily available, and PbS NC-solids (that is, compact solids formed from closely attached NCs) have been used for LEDs 20 , photodetectors 21 , solar cells 7 , 22 and thermoelectrics 23 . We quantify the phononic properties using inelastic neutron scattering (INS). For each sample ( Table 1 ), we reconstruct the dynamic structure factor ( S ( q , ω )) as a function of the momentum ( q ) and energy ( ω ) gained by the scattered neutron, from which we can approximate the mean square displacement (〈 u 2 〉) of atoms in the material and calculate the phonon density of states ( g ( ω )). Supplementary Methods 1–6 detail sample preparation, measurement, characterization and analysis. Table 1 Samples studied by INS Full size table First, we compare measurements on microcrystalline PbS (sample S1) with those on two NC-solids having increasingly smaller crystallite sizes (radius r = 8.2 nm (S2) and r = 1.33 nm (S3)) ( Fig. 1a ). For microcrystalline PbS, we observe Bragg reflections around ω = 0 cm −1 that are characteristic of the PbS crystal lattice, and a distinct structure along the q axis at finite energy transfers ( ω ≠ 0 cm −1 ) due to the Bloch-wave symmetry of the phonons that results from the discrete translational symmetry of the crystal lattice. With decreasing crystallite size, these features progressively disappear, indicating a breakdown of the Bloch-wave symmetry of the phonon modes. We calculate 〈 u 2 〉 = 0.042 ± 0.007 Å 2 for S1, in agreement with previous measurements 24 ( Supplementary Methods 5 ). For nanocrystalline samples, 〈 u 2 〉 increases twofold ( Table 1 ), signalling increased atomic motion. The measured g ( ω ) of the microcrystalline sample shows excellent agreement with density-functional-theory (DFT) calculations for bulk PbS ( Supplementary Methods 8 ), with transverse acoustic (TA) modes at 48.8 cm −1 and longitudinal acoustic (LA) modes at 84.4 cm −1 ( Fig. 1b ). With decreasing crystallite size, the TA and LA bulk modes reduce in relative weight and new modes appear at 25 cm −1 ( Fig. 1b inset). Figure 1: Inelastic neutron scattering (INS) measurements. a , The intensity ( I ) of the elastic line ( ω = 0) and the dynamic structure factor ( S ( q , ω )) reconstructed from INS data for bulk PbS (S1) and two NC-solids with crystallite radii r = 8.2 nm (S2) and r = 1.33 nm (S3). a.u., arbitrary units. b , Phonon density of states ( g ( ω )) for samples S1 (black), S2 (dark blue) and S3 (light blue). Below, the partial g ( ω ) for Pb atoms (grey) and S atoms (yellow) calculated by density-functional theory (DFT). All g ( ω ) are normalized to an area of 1 between 0 and 300 cm −1 . Peaks are the Van Hove singularities of transverse acoustic (TA) and longitudinal acoustic (LA) modes. NC-solids (S2, S3) show a mode at 25 cm −1 (Gaussian fit in inset). c , g ( ω ) for samples S4–S7 with radii between 1.5 nm and 3.3 nm. Peaks at 90, 150 and 250 cm −1 are attributed to vibrations of the linker molecule 1,2-ethanedithiol (EDT), which do not appear in sample S3 (blue) using deuterated EDT (EDT-d4) (for better visibility g ( ω ) of S3 (blue) is scaled by 0.68). Ab initio molecular dynamics calculations of EDT bound to a Pb atom are shown below (grey) ( Supplementary Methods 11 ). PowerPoint slide Full size image Next, we investigate the impact of<|im_end|> <|im_start|>assistant All materials are made up of atoms, which vibrate. These vibrations, or 'phonons', are responsible, for example, for how electric charge and heat is transported in materials. Vibrations of metals, semiconductors, and insulators in are well studied; however, now materials are being nanosized to bring better performance to applications such as displays, sensors, batteries, and catalytic membranes. What happens to vibrations when a material is nanosized has until now not been understood. Soft Surfaces Vibrate Strongly In a recent publication in Nature, ETH Professor Vanessa Wood and her colleagues explain what happens to atomic vibrations when materials are nanosized and how this knowledge can be used to systematically engineer nanomaterials for different applications. The paper shows that when materials are made smaller than about 10 to 20 nanometers—that is, 5,000 times thinner than a human air—the vibrations of the outermost atomic layers on surface of the nanoparticle are large and play an important role in how this material behaves. "For some applications, like catalysis, thermoelectrics, or superconductivity, these large vibrations may be good, but for other applications like LEDs or solar cells, these vibrations are undesirable," explains Wood. Indeed, the paper explains why nanoparticle-based solar cells have until now not met their full promise. The researchers showed using both experiment and theory that surface vibrations interact with electrons to reduce the photocurrent in solar cells. "Now that we have proven that surface vibrations are important, we can systematically design materials to suppress or enhance these vibrations," say Wood. Improving Solar Cells Wood's research group has worked for a long time on a particular type of nanomaterial—colloidal nanocrystals—semiconductors with a diameter of 2 to 10 nanometers. These materials are interesting because their optical and electrical properties are dependent on their size, which can be easily changed during their synthesis. These materials are now used commercially as red- and green-light emitters in LED-based TVs and are being explored as possible materials for low cost, solution-processed solar cells. Researchers have noticed that placing certain atoms around the surface of the nanocrystal can improve the performance of solar cells. The reason why this worked had not been understood. The work published in the Nature paper now gives the answer: a hard shell of atoms can suppress the vibrations and their interaction with electrons. This means a higher photocurrent and a higher efficiency solar cell. Big Science to Study the Nanoscale Experiments were conducted in Professor Wood's labs at ETH Zurich and at the Swiss Spallation Neutron Source at the Paul Scherrer Institute. By observing how neutrons scatter off atoms in a material, it is possible to quantify how atoms in a material vibrate. To understand the neutron measurements, simulations of the atomic vibrations were run at the Swiss National Supercomputing Center (CSCS) in Lugano. Wood says, "without access to these large facilities, this work would not have been possible. We are incredibly fortunate here in Switzerland to have these world class facilities." <|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 Medullary bone (MB), an estrogen-dependent reproductive tissue present in extant gravid birds, is texturally, histologically and compositionally distinct from other bone types. Phylogenetic proximity led to the proposal that MB would be present in non-avian dinosaurs and recent studies have used microscopic, morphological and regional homologies to identify this reproductive tissue in both theropod and ornithischian dinosaurs. Here, we capitalize on the unique chemical and histological fingerprint of MB in birds to characterize, at the molecular level, MB in the non-avian theropod Tyrannosaurus rex (MOR 1125) and show that the retention of original molecular components in fossils allows deeper physiological and evolutionary questions to be addressed. Introduction Medullary bone (MB) is a reproductive tissue present only in birds among living organisms 1 . It is a short-lived, rapidly deposited bony tissue arising from the endosteum (connective tissue lining the marrow space) and extending into the medullary cavity and inter-trabecular spaces of long bones of gravid female birds. MB was first identified in neognaths ( 2 , 3 , 4 and references therein) and later in ratites 5 . To date, it has been identified in virtually all birds, with the possible exception of some songbirds 6 . MB is classified as a reproductive tissue because its formation and depletion are tightly regulated by serum levels of estrogens 4 , 7 that accompany ovulation. These hormones stimulate osteoblasts within the endosteum to produce new bone that extends into and in some cases fills the medullary cavity of laying birds 8 . MB provides little structural support (but see 7 , 9 ), rather its primary function is to serve as an easily mobilized source of calcium for eggshell mineralization 7 , 10 , 11 , 12 . MB is gender-specific and does not occur naturally in males or juveniles, only in mature females; however, it can be induced in male birds with the administration of excess estrogen 13 , 14 . Members of Crocodylia, which along with Aves represent the extant taxa most closely related to non-avian dinosaurs, do not produce MB and it cannot be induced in these animals 1 , 15 , 16 . MB is easily diagnosed in living birds, by its location (primarily long bones 4 , 7 , 9 , 10 , 17 , 18 , 19 ); microstructure (highly vascular, non-lamellar collagen fibrils and isotropy, lack of secondary osteons due to extensive resorption cycles); greater mineral to collagen ratios than other bone types 10 , 18 , 19 , 20 , 21 ; and stimulus (estrogen dependent 3 , 7 , 10 , 12 , 17 , 18 , 20 , 22 ). Additionally, it is visible in hand sample and easily separated from overlying cortical bone (CB, Fig. 1 ). Figure 1 Morphological differentiation between MB and CB. ( A ) Mid shaft section from reproductively active laying hen femur shows textural differences between CB and MB. ( B ) more proximal region of hen femur shows that trabecular bone (T) can be differentiated from MB in hand sample and that MB is deposited between trabeculae, infilling trabecular spaces. ( C ) MB in hand sample of ostrich femur appears to grade from CB, but can be differentiated by color and spiculation, as well as the presence of large erosion rooms (ER, arrows) at the boundary between layers. Infilling of erosion rooms with crystalline MB is also seen (*). ( D ) Ground section of ostrich at higher magnification shows clear separation of MB and CB. Bone fragment of MOR 1125 femur in ( E ) cross section and ( F ) medial, or medullary face orientation shows both textural and color differences between CB and MB, as well as the distinct separation between bone types. ( G ) Transverse section of MOR 1125 whole femur, showing almost complete infilling of the medullary cavity with MB. No gross deformation (corresponding to fracture callus) or bony expansion (corresponding to osteopetrosis) can be seen. Red line marks boundary between dense cortical bone and endosteal lamellar bone penetrated by multiple erosion rooms. Erosion rooms can be seen extending deep into the cortex in one region of the bone (*). ( H ) Petrographic ground section of deep CB layer and adjacent, internal MB of MOR 1125, showing change in texture and vascularity. Black arrows show distinct separation between innermost endosteal bone with erosion rooms and region of MB deposition. Trabeculae (T) of laminar bone can be seen surrounded by MB. Scale bars as indicated. Full size image It was hypothesized that MB would be present in non-avian theropod dinosaurs 23 , 24 and thus would provide a means for unambiguous gender determination and reproductive status in extinct theropods. Because of its extensive mineralization, MB has high preservation potential and has been identified in fossil birds 21 , 25 , 26 , including non-crown group taxa 27 . Location, texture and microstructure were recently used to diagnose MB in fossil non-avian dinosaur remains, including the theropods Tyrannosaurus rex 5 and Allosaurus fragilis 28 and surprisingly, two ornithischian dinosaurs not on the direct lineage to birds 28 , 29 . This distribution suggests that MB may be a basal trait for dinosaurs and, because it is not produced by crocodiles (or any living non-archosaur) 1 , may have arisen in this lineage after the divergence of Avemetatarsalia and Pseudosuchia ( 30 and references therein). However, because some pathologies 31 or in some cases, metaphyseal resorption and redeposition during normal growth (e.g., compacted coarse cancellous bone 32 ) may approximate microstructural aspects of MB, morphological and histological traits alone cannot provide conclusive evidence that a tissue is homologous with avian MB. To diagnose MB in non-avian dinosaurs requires a thorough understanding of its structure, distribution and chemical composition across modern avian taxa. Although MB contains osteoblasts (bone forming cells) like other bone, MB osteoblasts have receptors on their nuclei for estrogen 33 , 34 making this bone type more responsive to changes in serum estrogen levels. Thus, when estrogen", "role": "user" }, { "content": "A pregnant Tyrannosaurus rex that roamed Montana 68 million years ago may be the key to discerning gender differences between theropod, or meat-eating dinosaur, species. Researchers from North Carolina State University and the North Carolina Museum of Natural Sciences have confirmed the presence of medullary bone - a gender-specific reproductive tissue - in a fossilized T. rex femur. Beyond giving paleontologists a definitively female fossil to study, their findings could shed light on the evolution of egg laying in modern birds. Medullary bone is only found in female birds, and then only during the period before or during egg laying. It is chemically distinct from other bone types, like the dense cortical bone that makes up the outer portion of our bones, or the spongy cancellous bone found inside them. This is because medullary bone has to be laid down and mobilized quickly in order for birds to shell their eggs. Theropod dinosaurs, the broader dinosaurian group that includes modern birds and other toothy relatives such as T. rex, also laid eggs in order to reproduce, and paleontologists have hypothesized that they may have had medullary bone as well. In 2005, Mary Schweitzer, an NC State paleontologist with a joint appointment at the NC Museum of Natural Sciences and lead author of a paper describing the research, found what she believed to be medullary bone in the femur of a 68 million year old T. rex fossil (MOR 1125). \"All the evidence we had at the time pointed to this tissue being medullary bone,\" Schweitzer says, \"but there are some bone diseases that occur in birds, like osteopetrosis, that can mimic the appearance of medullary bone under the microscope. So to be sure we needed to do chemical analysis of the tissue.\" Medullary bone contains keratan sulfate, a substance not present in other bone types, but it was previously thought that none of the original chemistry of dinosaur bone would survive millions of years. However, Schweitzer and her colleagues conducted a number of different tests on the T. rex sample, including testing for keratan sulfate using monoclonal antibodies, and compared their results to the same tests performed on known medullary tissue from ostrich and chicken bone. Their findings confirmed that the tissue from the T. rex was medullary bone. \"This analysis allows us to determine the gender of this fossil, and gives us a window into the evolution of egg laying in modern birds,\" Schweitzer says, although she adds that the fleeting nature of medullary bone means that finding more of it in the fossil record may be difficult. The femur of MOR1125 was already broken when Schweitzer got it, and she acknowledges that most paleontologists wouldn't want to cut open or demineralize their fossils in order to search for rare medullary bone. However, co-author Lindsay Zanno, an NC State paleontologist with a joint appointment at the NC Museum of Natural Sciences, showed that CT scans of fossils may help narrow down the search. \"It's a dirty secret, but we know next to nothing about sex-linked traits in extinct dinosaurs. Dinosaurs weren't shy about sexual signaling, all those bells and whistles, horns, crests, and frills, and yet we just haven't had a reliable way to tell males from females,\" Zanno says. \"Just being able to identify a dinosaur definitively as a female opens up a whole new world of possibilities. Now that we can show pregnant dinosaurs have a chemical fingerprint, we need a concerted effort to find more.\" The research appears in Scientific Reports. ", "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 Medullary bone (MB), an estrogen-dependent reproductive tissue present in extant gravid birds, is texturally, histologically and compositionally distinct from other bone types. Phylogenetic proximity led to the proposal that MB would be present in non-avian dinosaurs and recent studies have used microscopic, morphological and regional homologies to identify this reproductive tissue in both theropod and ornithischian dinosaurs. Here, we capitalize on the unique chemical and histological fingerprint of MB in birds to characterize, at the molecular level, MB in the non-avian theropod Tyrannosaurus rex (MOR 1125) and show that the retention of original molecular components in fossils allows deeper physiological and evolutionary questions to be addressed. Introduction Medullary bone (MB) is a reproductive tissue present only in birds among living organisms 1 . It is a short-lived, rapidly deposited bony tissue arising from the endosteum (connective tissue lining the marrow space) and extending into the medullary cavity and inter-trabecular spaces of long bones of gravid female birds. MB was first identified in neognaths ( 2 , 3 , 4 and references therein) and later in ratites 5 . To date, it has been identified in virtually all birds, with the possible exception of some songbirds 6 . MB is classified as a reproductive tissue because its formation and depletion are tightly regulated by serum levels of estrogens 4 , 7 that accompany ovulation. These hormones stimulate osteoblasts within the endosteum to produce new bone that extends into and in some cases fills the medullary cavity of laying birds 8 . MB provides little structural support (but see 7 , 9 ), rather its primary function is to serve as an easily mobilized source of calcium for eggshell mineralization 7 , 10 , 11 , 12 . MB is gender-specific and does not occur naturally in males or juveniles, only in mature females; however, it can be induced in male birds with the administration of excess estrogen 13 , 14 . Members of Crocodylia, which along with Aves represent the extant taxa most closely related to non-avian dinosaurs, do not produce MB and it cannot be induced in these animals 1 , 15 , 16 . MB is easily diagnosed in living birds, by its location (primarily long bones 4 , 7 , 9 , 10 , 17 , 18 , 19 ); microstructure (highly vascular, non-lamellar collagen fibrils and isotropy, lack of secondary osteons due to extensive resorption cycles); greater mineral to collagen ratios than other bone types 10 , 18 , 19 , 20 , 21 ; and stimulus (estrogen dependent 3 , 7 , 10 , 12 , 17 , 18 , 20 , 22 ). Additionally, it is visible in hand sample and easily separated from overlying cortical bone (CB, Fig. 1 ). Figure 1 Morphological differentiation between MB and CB. ( A ) Mid shaft section from reproductively active laying hen femur shows textural differences between CB and MB. ( B ) more proximal region of hen femur shows that trabecular bone (T) can be differentiated from MB in hand sample and that MB is deposited between trabeculae, infilling trabecular spaces. ( C ) MB in hand sample of ostrich femur appears to grade from CB, but can be differentiated by color and spiculation, as well as the presence of large erosion rooms (ER, arrows) at the boundary between layers. Infilling of erosion rooms with crystalline MB is also seen (*). ( D ) Ground section of ostrich at higher magnification shows clear separation of MB and CB. Bone fragment of MOR 1125 femur in ( E ) cross section and ( F ) medial, or medullary face orientation shows both textural and color differences between CB and MB, as well as the distinct separation between bone types. ( G ) Transverse section of MOR 1125 whole femur, showing almost complete infilling of the medullary cavity with MB. No gross deformation (corresponding to fracture callus) or bony expansion (corresponding to osteopetrosis) can be seen. Red line marks boundary between dense cortical bone and endosteal lamellar bone penetrated by multiple erosion rooms. Erosion rooms can be seen extending deep into the cortex in one region of the bone (*). ( H ) Petrographic ground section of deep CB layer and adjacent, internal MB of MOR 1125, showing change in texture and vascularity. Black arrows show distinct separation between innermost endosteal bone with erosion rooms and region of MB deposition. Trabeculae (T) of laminar bone can be seen surrounded by MB. Scale bars as indicated. Full size image It was hypothesized that MB would be present in non-avian theropod dinosaurs 23 , 24 and thus would provide a means for unambiguous gender determination and reproductive status in extinct theropods. Because of its extensive mineralization, MB has high preservation potential and has been identified in fossil birds 21 , 25 , 26 , including non-crown group taxa 27 . Location, texture and microstructure were recently used to diagnose MB in fossil non-avian dinosaur remains, including the theropods Tyrannosaurus rex 5 and Allosaurus fragilis 28 and surprisingly, two ornithischian dinosaurs not on the direct lineage to birds 28 , 29 . This distribution suggests that MB may be a basal trait for dinosaurs and, because it is not produced by crocodiles (or any living non-archosaur) 1 , may have arisen in this lineage after the divergence of Avemetatarsalia and Pseudosuchia ( 30 and references therein). However, because some pathologies 31 or in some cases, metaphyseal resorption and redeposition during normal growth (e.g., compacted coarse cancellous bone 32 ) may approximate microstructural aspects of MB, morphological and histological traits alone cannot provide conclusive evidence that a tissue is homologous with avian MB. To diagnose MB in non-avian dinosaurs requires a thorough understanding of its structure, distribution and chemical composition across modern avian taxa. Although MB contains osteoblasts (bone forming cells) like other bone, MB osteoblasts have receptors on their nuclei for estrogen 33 , 34 making this bone type more responsive to changes in serum estrogen levels. Thus, when estrogen<|im_end|> <|im_start|>assistant A pregnant Tyrannosaurus rex that roamed Montana 68 million years ago may be the key to discerning gender differences between theropod, or meat-eating dinosaur, species. Researchers from North Carolina State University and the North Carolina Museum of Natural Sciences have confirmed the presence of medullary bone - a gender-specific reproductive tissue - in a fossilized T. rex femur. Beyond giving paleontologists a definitively female fossil to study, their findings could shed light on the evolution of egg laying in modern birds. Medullary bone is only found in female birds, and then only during the period before or during egg laying. It is chemically distinct from other bone types, like the dense cortical bone that makes up the outer portion of our bones, or the spongy cancellous bone found inside them. This is because medullary bone has to be laid down and mobilized quickly in order for birds to shell their eggs. Theropod dinosaurs, the broader dinosaurian group that includes modern birds and other toothy relatives such as T. rex, also laid eggs in order to reproduce, and paleontologists have hypothesized that they may have had medullary bone as well. In 2005, Mary Schweitzer, an NC State paleontologist with a joint appointment at the NC Museum of Natural Sciences and lead author of a paper describing the research, found what she believed to be medullary bone in the femur of a 68 million year old T. rex fossil (MOR 1125). "All the evidence we had at the time pointed to this tissue being medullary bone," Schweitzer says, "but there are some bone diseases that occur in birds, like osteopetrosis, that can mimic the appearance of medullary bone under the microscope. So to be sure we needed to do chemical analysis of the tissue." Medullary bone contains keratan sulfate, a substance not present in other bone types, but it was previously thought that none of the original chemistry of dinosaur bone would survive millions of years. However, Schweitzer and her colleagues conducted a number of different tests on the T. rex sample, including testing for keratan sulfate using monoclonal antibodies, and compared their results to the same tests performed on known medullary tissue from ostrich and chicken bone. Their findings confirmed that the tissue from the T. rex was medullary bone. "This analysis allows us to determine the gender of this fossil, and gives us a window into the evolution of egg laying in modern birds," Schweitzer says, although she adds that the fleeting nature of medullary bone means that finding more of it in the fossil record may be difficult. The femur of MOR1125 was already broken when Schweitzer got it, and she acknowledges that most paleontologists wouldn't want to cut open or demineralize their fossils in order to search for rare medullary bone. However, co-author Lindsay Zanno, an NC State paleontologist with a joint appointment at the NC Museum of Natural Sciences, showed that CT scans of fossils may help narrow down the search. "It's a dirty secret, but we know next to nothing about sex-linked traits in extinct dinosaurs. Dinosaurs weren't shy about sexual signaling, all those bells and whistles, horns, crests, and frills, and yet we just haven't had a reliable way to tell males from females," Zanno says. "Just being able to identify a dinosaur definitively as a female opens up a whole new world of possibilities. Now that we can show pregnant dinosaurs have a chemical fingerprint, we need a concerted effort to find more." The research appears in Scientific Reports. <|im_end|>

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2,149

[ { "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 Ebola virus disease epidemic in West Africa is the largest on record, responsible for over 28,599 cases and more than 11,299 deaths 1 . Genome sequencing in viral outbreaks is desirable to characterize the infectious agent and determine its evolutionary rate. Genome sequencing also allows the identification of signatures of host adaptation, identification and monitoring of diagnostic targets, and characterization of responses to vaccines and treatments. The Ebola virus (EBOV) genome substitution rate in the Makona strain has been estimated at between 0.87 × 10 −3 and 1.42 × 10 −3 mutations per site per year. This is equivalent to 16–27 mutations in each genome, meaning that sequences diverge rapidly enough to identify distinct sub-lineages during a prolonged epidemic 2 , 3 , 4 , 5 , 6 , 7 . Genome sequencing provides a high-resolution view of pathogen evolution and is increasingly sought after for outbreak surveillance. Sequence data may be used to guide control measures, but only if the results are generated quickly enough to inform interventions 8 . Genomic surveillance during the epidemic has been sporadic owing to a lack of local sequencing capacity coupled with practical difficulties transporting samples to remote sequencing facilities 9 . To address this problem, here we devise a genomic surveillance system that utilizes a novel nanopore DNA sequencing instrument. In April 2015 this system was transported in standard airline luggage to Guinea and used for real-time genomic surveillance of the ongoing epidemic. We present sequence data and analysis of 142 EBOV samples collected during the period March to October 2015. We were able to generate results less than 24 h after receiving an Ebola-positive sample, with the sequencing process taking as little as 15–60 min. We show that real-time genomic surveillance is possible in resource-limited settings and can be established rapidly to monitor outbreaks. Main Conventional sequencing technologies are difficult to deploy in developing countries, where availability of continuous power and cold chains, laboratory space, and trained personnel is restricted. In addition, some genome sequencer instruments, such as those using optical readings, for example the Illumina platform, require precise microscope alignment and repeated calibration by trained engineers 7 , 10 . Recently, a new highly portable genome sequencer has become available. The MinION (Oxford Nanopore Technologies, Oxford, UK) weighs less than 100 g. Data are read off the MinION from a laptop via a Universal Serial Bus (USB) port from which the instrument also draws power. The MinION works by taking frequent electrical current measurements as a single strand of DNA passes through a protein nanopore at 30 bases per second. DNA strands in the pore disrupts ionic flow, resulting in detectable changes in current that is dependent on the nucleotide sequence. Because the MinION detects single molecules it has a much higher error rate (between 10–20% 11 , 12 ) than high-throughput instruments that read clonal copies of DNA molecules. Single-molecule sequencing has the advantage of being able to read extremely long molecules of DNA (50 kb or longer 12 , 13 ). In order to generate accurate sequences, genomic regions must be read many times, with errors eliminated through consensus averaging. This system has previously been used to investigate a bacterial outbreak, but not yet a viral outbreak 14 . We designed a laboratory protocol to permit EBOV genome sequencing on the MinION that employed a targeted reverse transcriptase polymerase chain reaction (RT–PCR) in order to isolate sufficient DNA for sequencing. We considered and rejected an alternative approach, that of total RNA sequencing, as this approach also amplifies human-derived transcripts and dilutes viral signal 15 . We designed a panel of 38 primer pairs that would span the EBOV genome ( Extended Data Fig. 1a , Supplementary Table 1 ). In pilot experiments at the Defence Science and Technology Laboratory (Dstl) Porton Down, UK, we sequenced a historic Zaire Ebolavirus using MinION as well as the Illumina MiSeq. Due to difficulties obtaining equal balancing of each of the 38 amplicon pairs only 65.7% of the EBOV genome was covered by at least 25 reads, compared with 87.4% on Illumina. However, nucleotide variants in those highly covered regions were concordant with those obtained from Illumina sequencing, with the exception of a single variant in a homopolymeric region. MinION sequencing currently cannot easily resolve the length of homopolymers of 5 bases or greater 16 . Next we designed a genome surveillance system that could be transported to West Africa. The system consisted of three MinION instruments (Oxford Nanopore Technologies, UK), four laptops, a thermocycler, a heat block, pipettes and sufficient reagents and consumables to perform sequencing (a full list of equipment is shown in Extended Data Fig. 2 ). We were able to pack this into less than 50 kg of standard airline travel luggage ( Fig. 1a ). We initially installed the genome surveillance system in the European Mobile Laboratory in Donka Hospital in Conakry, Guinea ( Fig. 1b ). Later on, the equipment was moved to a dedicated laboratory, located within the Coyah Ebola Treatment Unit ( Fig. 1c, d ). Figure 1: Deployment of the portable genome surveillance system in Guinea. a , We were able to pack all instruments, reagents and disposable consumables within aircraft baggage. b , We initially established the genomic surveillance laboratory in Donka Hospital, Conakry, Guinea. c , Later we moved the laboratory to a dedicated sequencing laboratory in Coyah prefecture. d , Within this laboratory we separated the sequencing instruments (on the left) from the PCR bench (to the right). An uninterruptable power supply can be seen in the middle that provides power to the thermocycler. (Photographs taken by J.Q. and S.D.) PowerPoint slide Full size image We started sequencing genomes within 2 days of arriving in Guinea. We found early on that we were able to reliably generate long amplicons (around 2 kb in length) using primer pairs ( Supplementary Table 4 ) in different combinations ( Extended Data Fig. 1b, c ). Using as few amplicons as possible", "role": "user" }, { "content": "New research published in Nature has shown how genome sequencing can be rapidly established to monitor outbreaks. Researchers designed a \"genome sequencing laboratory in a suitcase\", employing a novel DNA sequencer, transporting the equipment in less than 50kg of airline luggage. This was initially deployed in Conakry, Guinea in April 2015 where Ebola samples from patients could be sequenced as soon as new cases were diagnosed. This reduced delays shipping to traditional genome laboratories often located on a different continent. The team found that they could generate sequencing information in as little as 24 hours after receiving a sample, with the sequencing process taking less than an hour. Genome sequencing in outbreaks is useful to understand how the virus evolves. However, the information must be available quickly in order for this information to guide control efforts. By sequencing 142 samples from Ebola patients in Guinea they were able to provide very detailed information about how cases were related, providing important clues to World Health Organisation epidemiologists battling to halt transmission of the virus. Co-author of the study Dr Nick Loman, from the Institute of Microbiology and Infection at the University of Birmingham, explained, \"Genome sequencing information is valuable for researchers and epidemiologists during an epidemic. Yet, generating such information is a laborious process typically performed in well-equipped laboratories using large, delicate and expensive hardware. Having a portable DNA sequencing system opens up the possibility to do outbreak genome sequencing in real-time, which can directly impact on the response on the ground, as well as providing a wealth of information about pathogen evolution. Crucially we shared our data as it was generated, increasing its use immensely.\" The lab in Guinea. Credit: European Mobile Lab Dr. Jared Simpson from the Ontario Institute for Cancer Research, also a co-author on the study, said, \"In this paper we've shown that we can find single nucleotide polymorphisms (SNPs) at whole genome resolution using portable technology. While sequencing has until now been confined to a lab, this opens up genomic research to far more applications around the world. We look forward to building upon the work done in this study an applying it to other fields, including cancer research.\" The team employed a lightweight MinION DNA sequencer from Oxford Nanopore Technologies. This device weighs less than 100g, is powered by the USB of a laptop which is currently being used by more than 1,000 researchers worldwide. Dr Loman worked with an interdisciplinary team based on three continents, including the European Mobile Laboratories, Public Health England and Ontario Institute for Cancer Research. The researchers worked with other diagnostic laboratories and WHO epidemiologists based in Guinea. The Ebola outbreak in West Africa was the deadliest occurrence of the disease since its discovery in 1976. Since the first confirmed case was recorded on 23 March 2014, over 11,000 people have died as the result of the virus. The epidemic was officially declared to be over on 14 January 2016. However, just hours later, a new case was confirmed in Sierra Leone. New cases, when sequenced and linked to a database of previous sequences can provide important clues as to their origin. The sequencing laboratory, currently located in Nongo, Guinea, will continue to provide surveillance information until the outbreak is officially declared to be over. ", "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 Ebola virus disease epidemic in West Africa is the largest on record, responsible for over 28,599 cases and more than 11,299 deaths 1 . Genome sequencing in viral outbreaks is desirable to characterize the infectious agent and determine its evolutionary rate. Genome sequencing also allows the identification of signatures of host adaptation, identification and monitoring of diagnostic targets, and characterization of responses to vaccines and treatments. The Ebola virus (EBOV) genome substitution rate in the Makona strain has been estimated at between 0.87 × 10 −3 and 1.42 × 10 −3 mutations per site per year. This is equivalent to 16–27 mutations in each genome, meaning that sequences diverge rapidly enough to identify distinct sub-lineages during a prolonged epidemic 2 , 3 , 4 , 5 , 6 , 7 . Genome sequencing provides a high-resolution view of pathogen evolution and is increasingly sought after for outbreak surveillance. Sequence data may be used to guide control measures, but only if the results are generated quickly enough to inform interventions 8 . Genomic surveillance during the epidemic has been sporadic owing to a lack of local sequencing capacity coupled with practical difficulties transporting samples to remote sequencing facilities 9 . To address this problem, here we devise a genomic surveillance system that utilizes a novel nanopore DNA sequencing instrument. In April 2015 this system was transported in standard airline luggage to Guinea and used for real-time genomic surveillance of the ongoing epidemic. We present sequence data and analysis of 142 EBOV samples collected during the period March to October 2015. We were able to generate results less than 24 h after receiving an Ebola-positive sample, with the sequencing process taking as little as 15–60 min. We show that real-time genomic surveillance is possible in resource-limited settings and can be established rapidly to monitor outbreaks. Main Conventional sequencing technologies are difficult to deploy in developing countries, where availability of continuous power and cold chains, laboratory space, and trained personnel is restricted. In addition, some genome sequencer instruments, such as those using optical readings, for example the Illumina platform, require precise microscope alignment and repeated calibration by trained engineers 7 , 10 . Recently, a new highly portable genome sequencer has become available. The MinION (Oxford Nanopore Technologies, Oxford, UK) weighs less than 100 g. Data are read off the MinION from a laptop via a Universal Serial Bus (USB) port from which the instrument also draws power. The MinION works by taking frequent electrical current measurements as a single strand of DNA passes through a protein nanopore at 30 bases per second. DNA strands in the pore disrupts ionic flow, resulting in detectable changes in current that is dependent on the nucleotide sequence. Because the MinION detects single molecules it has a much higher error rate (between 10–20% 11 , 12 ) than high-throughput instruments that read clonal copies of DNA molecules. Single-molecule sequencing has the advantage of being able to read extremely long molecules of DNA (50 kb or longer 12 , 13 ). In order to generate accurate sequences, genomic regions must be read many times, with errors eliminated through consensus averaging. This system has previously been used to investigate a bacterial outbreak, but not yet a viral outbreak 14 . We designed a laboratory protocol to permit EBOV genome sequencing on the MinION that employed a targeted reverse transcriptase polymerase chain reaction (RT–PCR) in order to isolate sufficient DNA for sequencing. We considered and rejected an alternative approach, that of total RNA sequencing, as this approach also amplifies human-derived transcripts and dilutes viral signal 15 . We designed a panel of 38 primer pairs that would span the EBOV genome ( Extended Data Fig. 1a , Supplementary Table 1 ). In pilot experiments at the Defence Science and Technology Laboratory (Dstl) Porton Down, UK, we sequenced a historic Zaire Ebolavirus using MinION as well as the Illumina MiSeq. Due to difficulties obtaining equal balancing of each of the 38 amplicon pairs only 65.7% of the EBOV genome was covered by at least 25 reads, compared with 87.4% on Illumina. However, nucleotide variants in those highly covered regions were concordant with those obtained from Illumina sequencing, with the exception of a single variant in a homopolymeric region. MinION sequencing currently cannot easily resolve the length of homopolymers of 5 bases or greater 16 . Next we designed a genome surveillance system that could be transported to West Africa. The system consisted of three MinION instruments (Oxford Nanopore Technologies, UK), four laptops, a thermocycler, a heat block, pipettes and sufficient reagents and consumables to perform sequencing (a full list of equipment is shown in Extended Data Fig. 2 ). We were able to pack this into less than 50 kg of standard airline travel luggage ( Fig. 1a ). We initially installed the genome surveillance system in the European Mobile Laboratory in Donka Hospital in Conakry, Guinea ( Fig. 1b ). Later on, the equipment was moved to a dedicated laboratory, located within the Coyah Ebola Treatment Unit ( Fig. 1c, d ). Figure 1: Deployment of the portable genome surveillance system in Guinea. a , We were able to pack all instruments, reagents and disposable consumables within aircraft baggage. b , We initially established the genomic surveillance laboratory in Donka Hospital, Conakry, Guinea. c , Later we moved the laboratory to a dedicated sequencing laboratory in Coyah prefecture. d , Within this laboratory we separated the sequencing instruments (on the left) from the PCR bench (to the right). An uninterruptable power supply can be seen in the middle that provides power to the thermocycler. (Photographs taken by J.Q. and S.D.) PowerPoint slide Full size image We started sequencing genomes within 2 days of arriving in Guinea. We found early on that we were able to reliably generate long amplicons (around 2 kb in length) using primer pairs ( Supplementary Table 4 ) in different combinations ( Extended Data Fig. 1b, c ). Using as few amplicons as possible<|im_end|> <|im_start|>assistant New research published in Nature has shown how genome sequencing can be rapidly established to monitor outbreaks. Researchers designed a "genome sequencing laboratory in a suitcase", employing a novel DNA sequencer, transporting the equipment in less than 50kg of airline luggage. This was initially deployed in Conakry, Guinea in April 2015 where Ebola samples from patients could be sequenced as soon as new cases were diagnosed. This reduced delays shipping to traditional genome laboratories often located on a different continent. The team found that they could generate sequencing information in as little as 24 hours after receiving a sample, with the sequencing process taking less than an hour. Genome sequencing in outbreaks is useful to understand how the virus evolves. However, the information must be available quickly in order for this information to guide control efforts. By sequencing 142 samples from Ebola patients in Guinea they were able to provide very detailed information about how cases were related, providing important clues to World Health Organisation epidemiologists battling to halt transmission of the virus. Co-author of the study Dr Nick Loman, from the Institute of Microbiology and Infection at the University of Birmingham, explained, "Genome sequencing information is valuable for researchers and epidemiologists during an epidemic. Yet, generating such information is a laborious process typically performed in well-equipped laboratories using large, delicate and expensive hardware. Having a portable DNA sequencing system opens up the possibility to do outbreak genome sequencing in real-time, which can directly impact on the response on the ground, as well as providing a wealth of information about pathogen evolution. Crucially we shared our data as it was generated, increasing its use immensely." The lab in Guinea. Credit: European Mobile Lab Dr. Jared Simpson from the Ontario Institute for Cancer Research, also a co-author on the study, said, "In this paper we've shown that we can find single nucleotide polymorphisms (SNPs) at whole genome resolution using portable technology. While sequencing has until now been confined to a lab, this opens up genomic research to far more applications around the world. We look forward to building upon the work done in this study an applying it to other fields, including cancer research." The team employed a lightweight MinION DNA sequencer from Oxford Nanopore Technologies. This device weighs less than 100g, is powered by the USB of a laptop which is currently being used by more than 1,000 researchers worldwide. Dr Loman worked with an interdisciplinary team based on three continents, including the European Mobile Laboratories, Public Health England and Ontario Institute for Cancer Research. The researchers worked with other diagnostic laboratories and WHO epidemiologists based in Guinea. The Ebola outbreak in West Africa was the deadliest occurrence of the disease since its discovery in 1976. Since the first confirmed case was recorded on 23 March 2014, over 11,000 people have died as the result of the virus. The epidemic was officially declared to be over on 14 January 2016. However, just hours later, a new case was confirmed in Sierra Leone. New cases, when sequenced and linked to a database of previous sequences can provide important clues as to their origin. The sequencing laboratory, currently located in Nongo, Guinea, will continue to provide surveillance information until the outbreak is officially declared to be over. <|im_end|>

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1,986

[ { "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 atomic nucleus and its electrons are often thought of as independent systems that are held together in the atom by their mutual attraction. Their interaction, however, leads to other important effects, such as providing an additional decay mode for excited nuclear states, whereby the nucleus releases energy by ejecting an atomic electron instead of by emitting a γ-ray. This ‘internal conversion’ has been known for about a hundred years and can be used to study nuclei and their interaction with their electrons 1 , 2 , 3 . In the inverse process—nuclear excitation by electron capture (NEEC)—a free electron is captured into an atomic vacancy and can excite the nucleus to a higher-energy state, provided that the kinetic energy of the free electron plus the magnitude of its binding energy once captured matches the nuclear energy difference between the two states. NEEC was predicted 4 in 1976 and has not hitherto been observed 5 , 6 . Here we report evidence of NEEC in molybdenum-93 and determine the probability and cross-section for the process in a beam-based experimental scenario. Our results provide a standard for the assessment of theoretical models relevant to NEEC, which predict cross-sections that span many orders of magnitude. The greatest practical effect of the NEEC process may be on the survival of nuclei in stellar environments 7 , in which it could excite isomers (that is, long-lived nuclear states) to shorter-lived states. Such excitations may reduce the abundance of the isotope after its production. This is an example of ‘isomer depletion’, which has been investigated previously through other reactions 8 , 9 , 10 , 11 , 12 , but is used here to obtain evidence for NEEC. Main We searched for evidence of the NEEC process in 93 Mo following an approach adapted from a technique proposed in ref. 13 . Previous theoretical work also considered 93 Mo as a NEEC candidate 6 . This nucleus has a 21/2 + isomer at 2,425 keV with a half-life of 6.85 h and a (17/2) + candidate intermediate state that lies 4.85(9) keV higher at 2,430 keV (ref. 14 ), as illustrated in Fig. 1 . (Uncertainties are quoted at the 1 σ or 68% confidence level, unless otherwise noted.) In our approach, 93 Mo is produced in its metastable state ( 93m Mo) through nuclear reactions. Choosing heavy projectiles and light target nuclei results in recoiling 93m Mo reaction products (‘recoils’) that move at high velocities v (initially more than 10% of the speed of light, c ) in approximately the same direction as the beam. As the fast-moving recoils pass through the target medium, electrons are stripped off, leaving the 93m Mo ions with a high average charge 15 , 16 between about +32 and +36. Subsequent collisions with target atoms reduce the energy of the recoiling ions while simultaneously providing electrons that can be captured back into the vacated atomic orbitals. At the right combination of the charge state of the 93m Mo ion and the effective electron kinetic energy, as seen from the reference frame of the recoiling ion, capture can occur, releasing enough energy to match that needed (Δ E = 4.85 keV) to excite the nucleus from the isomer to the intermediate state—that is, NEEC occurs. As described in detail by recent theoretical calculations 16 , these NEEC conditions could be fulfilled in practice by capture of an electron at the necessary relative kinetic energy, to within the line width of the capturing atomic vacancy (the NEEC resonance width). The intermediate state in 93 Mo that would be populated through NEEC is known to decay (with a half-life of t 1/2 = 3.5 ns) to the ground state through a characteristic sequence of γ-rays at 268 keV, 685 keV and 1,478 keV ( Fig. 1 ). Notably, the 268-keV transition would never be seen in the natural decay of the 21/2 + isomer. Figure 1: Relevant part of the 93 Mo decay scheme. The energy and the spin and parity quantum numbers ( I π , where I denotes the spin and π = +, − the parity) are noted for each level, with tentative assignments in parentheses. The half-lives t 1/2 given for the two isomeric states are from ref. 14 . Level and γ-ray energies are from this study and are given in kiloelectronvolts. The 10-keV transition between the (13/2 − ) and (11/2 − ) states was not observed in this work, but was inferred from the measured coincidence relationships. The NEEC transition from the isomer to the intermediate state is indicated by the dashed red line. The key 268-keV γ-ray is also indicated in red. PowerPoint slide Full size image The 90 Zr + 7 Li fusion–evaporation reaction was selected for our experiment, which was performed at the ATLAS facility at Argonne National Laboratory. An 840-MeV 90 Zr beam was provided with an average beam intensity of about 6 × 10 8 ions s −1 . The multi-layer target was composed of 7 Li supported by a natural carbon ( nat C) foil, followed by a gap of about 3 mm and an additional nat C layer, backed with 208 Pb (see Methods for the choice of reaction and target construction). The target was positioned at the centre of the Gammasphere γ-ray spectrometer 17 , which, at the time of the experiment, comprised 92 Compton-suppressed, high-purity Ge detectors arranged in 16 rings of constant angle relative to the beam direction. A minimum of three γ-rays within a 2-μs coincidence window was required for events to be recorded to disk, although a narrower, sub-microsecond coincidence constraint was imposed in the offline analysis. We operated the array with a digital data acquisition system (Digital Gammasphere 18 ) at average event rates of 40–50 kHz. We collected data for about 62 h in this configuration. After the fusion of the 90 Zr projectiles and the 7 Li target nuclei, and the subsequent evaporation of a proton and three", "role": "user" }, { "content": "For the first time, physicists from the U.S. Department of Energy's (DOE) Argonne National Laboratory and their collaborators, led by a team from the U.S. Army Research Laboratory, demonstrated a long-theorized nuclear effect. This advance tests theoretical models that describe how nuclear and atomic realms interact and may also provide new insights into how star elements are created. Physicists first predicted the effect, called nuclear excitation by electron capture (NEEC), over 40 years ago. But scientists had not seen it until now. Using the Argonne Tandem Linac Accelerator System (ATLAS), and Gammasphere, a powerful gamma ray spectrometer, the researchers created the right conditions to cause and spot the behavior. The NEEC effect occurs when a charged atom captures an electron, giving the atom's nucleus enough energy to jump to a higher excited state. An excited nucleus stays in each energy state for a while before decaying into the state below it, shedding energy in the form of gamma rays. These excited states typically last for much less than a billionth of a second, but in some rare cases, they can live far longer, even for millions of times the age of the universe. The longer-lived energy states are called isomers, and to observe the NEEC effect, the researchers produced an isomer with a half-life of about seven hours. In other words, after seven hours of existing in the isomeric energy level, about half of the nuclei of this type will decay. The scientists chose to produce this nucleus, called 93Mo, an isotope of molybdenum, because of its unique arrangement of energy levels. \"There is an allowed energy level not far above the isomer state,\" said the Army Research Laboratory's Chris Chiara, the study's lead scientist. \"Under normal circumstances, the isomer will decay naturally after about seven hours, but if NEEC occurs, the nucleus is excited out of the isomer to the slightly higher state. That state then quickly decays to a state below the isomer, emitting gamma rays that have distinct energies that we can look for.\" Argonne scientists and collaborators used the Argonne Tandem Linac Accelerator System to help create the right conditions to cause and spot a long-theorized effect called nuclear excitation by electron capture. Credit: Argonne National Laboratory To make 93Mo, the researchers used ATLAS, a DOE Office of Science User Facility, to accelerate a beam of ions towards the atoms in a target foil where the nuclei of the two fused together. These reactions formed 93Mo in a highly excited state at the center of Gammasphere, which waited to detect evidence of the effect in the form of gamma rays. As the 93Mo atoms move through the target material, they bump into atoms that slow them down and strip them of electrons, putting them in a high-charge state. Electrons from the target atoms then fill those vacancies in the 93Mo, and if the electrons have the right energy before the capture, they may excite the nucleus into the next highest state. When this state decays, the nucleus releases a gamma ray that can be traced back to the NEEC reaction. The target, made by ATLAS's in-house target maker, John Greene, played a crucial role in the detection of NEEC. Greene was able to work on the fly, tweaking the target as the scientists learned more about the 93Mo nucleus. With everything in place, the team began to gather data. \"We detected gamma rays from these reactions over the course of the three-day experiment, and we accumulated around eight billion events in total,\" said Mike Carpenter, a group leader at Argonne in charge of Gammasphere. \"From these events, we were able to identify around 500 gamma rays that were emitted during the decay of 93Mo that wouldn't have been released if it weren't for NEEC.\" The power and sensitivity of Gammasphere was vital to the experiment's success. \"We made use of a new digital Gammasphere mode, which allowed us to run at a rate about five times higher than would have been possible with the older analog system,\" said Chiara. But it was not only the hardware at ATLAS that was important. \"As experts in the field of gamma-ray spectroscopy, the Argonne staff provided invaluable scientific and technical support,\" he added. The team's success may lead to advances in astronomy and cosmology as it could improve the accuracy of models scientists use to gauge how stars form. The quantities of elements in a star depend largely on the structure and behavior of nuclei. Over long periods, and with vast numbers of atoms interacting, the survival—or destruction—of specific isomers can have a cumulative influence. Taking the NEEC effect into account could improve our understanding of what stars are made of and how they evolve. Scientists at the Army Research Laboratory are also interested in possible future applications for the controlled release of nuclear energy from isomers via the NEEC effect. If scientists and engineers could harness this energy, it might help develop power sources with 100,000 times greater energy per unit mass than chemical batteries. The results of the experiment were published in a paper titled \"Isomer depletion as experimental evidence of nuclear excitation by electron capture,\" on February 8 in 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 The atomic nucleus and its electrons are often thought of as independent systems that are held together in the atom by their mutual attraction. Their interaction, however, leads to other important effects, such as providing an additional decay mode for excited nuclear states, whereby the nucleus releases energy by ejecting an atomic electron instead of by emitting a γ-ray. This ‘internal conversion’ has been known for about a hundred years and can be used to study nuclei and their interaction with their electrons 1 , 2 , 3 . In the inverse process—nuclear excitation by electron capture (NEEC)—a free electron is captured into an atomic vacancy and can excite the nucleus to a higher-energy state, provided that the kinetic energy of the free electron plus the magnitude of its binding energy once captured matches the nuclear energy difference between the two states. NEEC was predicted 4 in 1976 and has not hitherto been observed 5 , 6 . Here we report evidence of NEEC in molybdenum-93 and determine the probability and cross-section for the process in a beam-based experimental scenario. Our results provide a standard for the assessment of theoretical models relevant to NEEC, which predict cross-sections that span many orders of magnitude. The greatest practical effect of the NEEC process may be on the survival of nuclei in stellar environments 7 , in which it could excite isomers (that is, long-lived nuclear states) to shorter-lived states. Such excitations may reduce the abundance of the isotope after its production. This is an example of ‘isomer depletion’, which has been investigated previously through other reactions 8 , 9 , 10 , 11 , 12 , but is used here to obtain evidence for NEEC. Main We searched for evidence of the NEEC process in 93 Mo following an approach adapted from a technique proposed in ref. 13 . Previous theoretical work also considered 93 Mo as a NEEC candidate 6 . This nucleus has a 21/2 + isomer at 2,425 keV with a half-life of 6.85 h and a (17/2) + candidate intermediate state that lies 4.85(9) keV higher at 2,430 keV (ref. 14 ), as illustrated in Fig. 1 . (Uncertainties are quoted at the 1 σ or 68% confidence level, unless otherwise noted.) In our approach, 93 Mo is produced in its metastable state ( 93m Mo) through nuclear reactions. Choosing heavy projectiles and light target nuclei results in recoiling 93m Mo reaction products (‘recoils’) that move at high velocities v (initially more than 10% of the speed of light, c ) in approximately the same direction as the beam. As the fast-moving recoils pass through the target medium, electrons are stripped off, leaving the 93m Mo ions with a high average charge 15 , 16 between about +32 and +36. Subsequent collisions with target atoms reduce the energy of the recoiling ions while simultaneously providing electrons that can be captured back into the vacated atomic orbitals. At the right combination of the charge state of the 93m Mo ion and the effective electron kinetic energy, as seen from the reference frame of the recoiling ion, capture can occur, releasing enough energy to match that needed (Δ E = 4.85 keV) to excite the nucleus from the isomer to the intermediate state—that is, NEEC occurs. As described in detail by recent theoretical calculations 16 , these NEEC conditions could be fulfilled in practice by capture of an electron at the necessary relative kinetic energy, to within the line width of the capturing atomic vacancy (the NEEC resonance width). The intermediate state in 93 Mo that would be populated through NEEC is known to decay (with a half-life of t 1/2 = 3.5 ns) to the ground state through a characteristic sequence of γ-rays at 268 keV, 685 keV and 1,478 keV ( Fig. 1 ). Notably, the 268-keV transition would never be seen in the natural decay of the 21/2 + isomer. Figure 1: Relevant part of the 93 Mo decay scheme. The energy and the spin and parity quantum numbers ( I π , where I denotes the spin and π = +, − the parity) are noted for each level, with tentative assignments in parentheses. The half-lives t 1/2 given for the two isomeric states are from ref. 14 . Level and γ-ray energies are from this study and are given in kiloelectronvolts. The 10-keV transition between the (13/2 − ) and (11/2 − ) states was not observed in this work, but was inferred from the measured coincidence relationships. The NEEC transition from the isomer to the intermediate state is indicated by the dashed red line. The key 268-keV γ-ray is also indicated in red. PowerPoint slide Full size image The 90 Zr + 7 Li fusion–evaporation reaction was selected for our experiment, which was performed at the ATLAS facility at Argonne National Laboratory. An 840-MeV 90 Zr beam was provided with an average beam intensity of about 6 × 10 8 ions s −1 . The multi-layer target was composed of 7 Li supported by a natural carbon ( nat C) foil, followed by a gap of about 3 mm and an additional nat C layer, backed with 208 Pb (see Methods for the choice of reaction and target construction). The target was positioned at the centre of the Gammasphere γ-ray spectrometer 17 , which, at the time of the experiment, comprised 92 Compton-suppressed, high-purity Ge detectors arranged in 16 rings of constant angle relative to the beam direction. A minimum of three γ-rays within a 2-μs coincidence window was required for events to be recorded to disk, although a narrower, sub-microsecond coincidence constraint was imposed in the offline analysis. We operated the array with a digital data acquisition system (Digital Gammasphere 18 ) at average event rates of 40–50 kHz. We collected data for about 62 h in this configuration. After the fusion of the 90 Zr projectiles and the 7 Li target nuclei, and the subsequent evaporation of a proton and three<|im_end|> <|im_start|>assistant For the first time, physicists from the U.S. Department of Energy's (DOE) Argonne National Laboratory and their collaborators, led by a team from the U.S. Army Research Laboratory, demonstrated a long-theorized nuclear effect. This advance tests theoretical models that describe how nuclear and atomic realms interact and may also provide new insights into how star elements are created. Physicists first predicted the effect, called nuclear excitation by electron capture (NEEC), over 40 years ago. But scientists had not seen it until now. Using the Argonne Tandem Linac Accelerator System (ATLAS), and Gammasphere, a powerful gamma ray spectrometer, the researchers created the right conditions to cause and spot the behavior. The NEEC effect occurs when a charged atom captures an electron, giving the atom's nucleus enough energy to jump to a higher excited state. An excited nucleus stays in each energy state for a while before decaying into the state below it, shedding energy in the form of gamma rays. These excited states typically last for much less than a billionth of a second, but in some rare cases, they can live far longer, even for millions of times the age of the universe. The longer-lived energy states are called isomers, and to observe the NEEC effect, the researchers produced an isomer with a half-life of about seven hours. In other words, after seven hours of existing in the isomeric energy level, about half of the nuclei of this type will decay. The scientists chose to produce this nucleus, called 93Mo, an isotope of molybdenum, because of its unique arrangement of energy levels. "There is an allowed energy level not far above the isomer state," said the Army Research Laboratory's Chris Chiara, the study's lead scientist. "Under normal circumstances, the isomer will decay naturally after about seven hours, but if NEEC occurs, the nucleus is excited out of the isomer to the slightly higher state. That state then quickly decays to a state below the isomer, emitting gamma rays that have distinct energies that we can look for." Argonne scientists and collaborators used the Argonne Tandem Linac Accelerator System to help create the right conditions to cause and spot a long-theorized effect called nuclear excitation by electron capture. Credit: Argonne National Laboratory To make 93Mo, the researchers used ATLAS, a DOE Office of Science User Facility, to accelerate a beam of ions towards the atoms in a target foil where the nuclei of the two fused together. These reactions formed 93Mo in a highly excited state at the center of Gammasphere, which waited to detect evidence of the effect in the form of gamma rays. As the 93Mo atoms move through the target material, they bump into atoms that slow them down and strip them of electrons, putting them in a high-charge state. Electrons from the target atoms then fill those vacancies in the 93Mo, and if the electrons have the right energy before the capture, they may excite the nucleus into the next highest state. When this state decays, the nucleus releases a gamma ray that can be traced back to the NEEC reaction. The target, made by ATLAS's in-house target maker, John Greene, played a crucial role in the detection of NEEC. Greene was able to work on the fly, tweaking the target as the scientists learned more about the 93Mo nucleus. With everything in place, the team began to gather data. "We detected gamma rays from these reactions over the course of the three-day experiment, and we accumulated around eight billion events in total," said Mike Carpenter, a group leader at Argonne in charge of Gammasphere. "From these events, we were able to identify around 500 gamma rays that were emitted during the decay of 93Mo that wouldn't have been released if it weren't for NEEC." The power and sensitivity of Gammasphere was vital to the experiment's success. "We made use of a new digital Gammasphere mode, which allowed us to run at a rate about five times higher than would have been possible with the older analog system," said Chiara. But it was not only the hardware at ATLAS that was important. "As experts in the field of gamma-ray spectroscopy, the Argonne staff provided invaluable scientific and technical support," he added. The team's success may lead to advances in astronomy and cosmology as it could improve the accuracy of models scientists use to gauge how stars form. The quantities of elements in a star depend largely on the structure and behavior of nuclei. Over long periods, and with vast numbers of atoms interacting, the survival—or destruction—of specific isomers can have a cumulative influence. Taking the NEEC effect into account could improve our understanding of what stars are made of and how they evolve. Scientists at the Army Research Laboratory are also interested in possible future applications for the controlled release of nuclear energy from isomers via the NEEC effect. If scientists and engineers could harness this energy, it might help develop power sources with 100,000 times greater energy per unit mass than chemical batteries. The results of the experiment were published in a paper titled "Isomer depletion as experimental evidence of nuclear excitation by electron capture," on February 8 in Nature. <|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 We provide country-level estimates of the cumulative prevalence of mothers bereaved by a child’s death in 170 countries and territories. Methods We generate indicators of the cumulative prevalence of mothers who have had an infant, under-five-year-old or any-age child ever die by using publicly available survey data in 89 countries and an indirect approach that combines formal kinship models and life-table methods in an additional 81 countries. We label these measures the maternal cumulative prevalence of infant mortality (mIM), under-five mortality (mU5M) and offspring mortality (mOM) and generate prevalence estimates for 20–44-year-old and 45–49-year-old mothers. Results In several Asian and European countries, the mIM and mU5M are below 10 per 1000 mothers yet exceed 200 per 1000 mothers in several Middle Eastern and African countries. Global inequality in mothers’ experience of child loss is enormous: mothers in high-mortality-burden African countries are more than 100 times more likely to have had a child die than mothers in low-mortality-burden Asian and European countries. In more than 20 African countries, the mOM exceeds 500 per 1000 mothers, meaning that it is typical for a surviving 45–49-year-old mother to be bereaved. Discussion The study reveals enormous global disparities in mothers’ experience of child loss and identifies a need for more research on the downstream mental and physical health risks associated with parental bereavement. maternal health child health cross-sectional survey Data availability statement All data used in this study are publicly available. DHS data are available at . MICS data are available at . NSFG data are available at . Replication files are posted at Harvard Dataverse, (27). This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: . googletag.cmd.push(function() { googletag.display(\"dfp-ad-mpu\"); }); Statistics from Altmetric.com See more details Picked up by 15 news outlets Blogged by 2 Tweeted by 115 29 readers on Mendeley Supplementary materials 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. maternal health child health cross-sectional survey Key questions What is already known? In sub-Saharan African countries, maternal indicators of the child mortality burden show that—even as infant and child mortality rates decline—having experienced a child’s death remains a common maternal experience. Child death is known to adversely affect mothers’ lives, yet we lack a systematic, global analysis of the maternal prevalence of child loss. What are the new findings? Our results offer estimates of the maternal cumulative prevalence of infant, under-five and all offspring mortality for 20–44-year-old and 45–49-year-old mothers in 170 countries, providing a new view of the burden of premature death across the globe. Global inequality in mothers’ experience of child death is enormous: mothers in select African countries are more than 100 times more likely to have had a child die than mothers in select Asian or European countries; the most dramatic inequalities are between younger mothers (ages 20–34). What do the new findings imply? Quantifying maternal experiences of child loss offers a new perspective of the population burden of child death, reveals how disparate maternal conditions are worldwide and attests to the need for additional individual-level research on the consequences of child loss for families. Background Infant and child mortality rates have declined worldwide over the last 50 years, signifying notable progress for children and their parents. 1 Reductions in annualised rates of infant and child mortality, however, cannot reasonably proxy parents’ cumulative experiences of child loss, a phenomenon we refer to as parental bereavement . A child’s death can have serious and long-lasting consequences for parents, 2–4 but the population prevalence of bereaved parents has only been estimated for a select group of countries in sub-Saharan Africa. 5 From those estimates, as recently as 2015, over one-third of mothers in sub-Saharan Africa had experienced a child death. 5 It remains unclear whether such high levels of maternal bereavement characterise other low-income and middle-income countries and how this burden compares to high-income countries. In this article, we provide the first population-level estimates of the prevalence of bereaved mothers in 170 countries. We generate three indicators of the cumulative prevalence of mothers who have had an infant, under-five-year-old or any-age child die. We label these indicators: the maternal cumulative prevalence of infant mortality (mIM), under-five mortality (mU5M) and offspring mortality (mOM). 5 To achieve global coverage, we generate these indicators through a combination of direct estimation, using publicly available survey data and an indirect-estimation strategy using publicly available age-specific fertility and mortality schedules. 6 Population-level measures of maternal bereavement summarise how infant, child and adolescent mortality conditions accumulate, forming a corresponding shadow population of bereaved parents deserving of public health attention. Global inequalities in the burden of family bereavement reflect disparate health environments and may also compound disadvantage by leaving parents vulnerable to the grief, trauma and other adverse outcomes associated with bereavement. 7–11 A child’s death can have profound and lasting influence on parents’ well-being, including their mental health, physical health and longevity. 2–4 12–20 The health consequences associated with bereavement are especially severe for mothers, and the adverse effects of grief can persist for years—even decades. 16 Child loss can also adversely impact other aspects of parents’ lives, including the health and stability of their marital union. 3 18 The guilt, blame, stigma, stress and relationship strain associated with child loss have been documented across diverse cultural contexts, including in settings where child loss is a tragically common and perhaps, even, an anticipated aspect of motherhood. 21–25 By demonstrating the size and distribution of child loss across the globe, these metrics", "role": "user" }, { "content": "The inequality is enormous: Mothers in select African countries are more than 100 times more likely to have had a child die than mothers in high-income countries. This is what Diego Alburez-Gutierrez (Researcher at the Max Planck Institute for Demographic Research (MPIDR) in Rostock, Germany), Emily Smith-Greenaway (Researcher at the USC Dornsife College of Letters, Arts and Sciences in Los Angeles and Guest Researcher at MPIDR), and co-authors found in their recent paper published in BMJ Global Health. \"We offer the first global estimates of the cumulative number of child deaths experienced by mothers between the ages of 20 and 49, in 170 countries,\" said Smith-Greenaway. Initially, she and her collaborators did so by drawing from the wealth of publicly available survey data, collected between 2010 and 2018, to calculate the proportion of mothers who have ever lost an offspring in 89 countries. A new indirect approach to estimate the prevalence of bereaved mothers \"The innovation of our study lies in the fact that we expanded beyond these 89 countries and provided estimates for those lacking recent, nationally representative survey data by leveraging a novel indirect approach that combines formal kinship models and life-table methods,\" says Alburez-Gutierrez. \"That has allowed us to offer a comprehensive look at bereavement worldwide.\" The estimates generated for these additional 81 countries are interpretable, just as the survey estimates. International inequalities in mothers' experiences of the death of a child will linger beyond the initial improvement in infant and child mortality conditions, given the varied demographic history of populations. In the seven least affected countries, which includes Japan, Finland, and Spain, fewer than 5 per 1,000 mothers who are between 20 and 44 years old have ever lost an offspring younger than one year old. In Germany, only 6 out of 1,000 mothers have ever lost an infant. In 34 countries, mostly in Africa, more than 150 per 1,000 mothers have experienced the death of an infant. That means mothers in these countries are more than 30 times as likely to have had a child die than mothers in the seven countries with the lowest numbers. Moreover, in as many as 16 countries—all located in sub-Saharan Africa and the Middle East—more than 200 per 1,000 mothers have lost an infant. It is concerning that the very parts of the world where the cumulative burden of child death is heaviest for mothers are also the settings where the least is known about the social, economic, relational, and health implications of child death for mothers. \"We hope that this work will emphasize that further efforts to lower child deaths will not only improve the quality and length of life for children across the globe, but will also fundamentally improve the lives of parents,\" said Smith-Greenaway. ", "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 We provide country-level estimates of the cumulative prevalence of mothers bereaved by a child’s death in 170 countries and territories. Methods We generate indicators of the cumulative prevalence of mothers who have had an infant, under-five-year-old or any-age child ever die by using publicly available survey data in 89 countries and an indirect approach that combines formal kinship models and life-table methods in an additional 81 countries. We label these measures the maternal cumulative prevalence of infant mortality (mIM), under-five mortality (mU5M) and offspring mortality (mOM) and generate prevalence estimates for 20–44-year-old and 45–49-year-old mothers. Results In several Asian and European countries, the mIM and mU5M are below 10 per 1000 mothers yet exceed 200 per 1000 mothers in several Middle Eastern and African countries. Global inequality in mothers’ experience of child loss is enormous: mothers in high-mortality-burden African countries are more than 100 times more likely to have had a child die than mothers in low-mortality-burden Asian and European countries. In more than 20 African countries, the mOM exceeds 500 per 1000 mothers, meaning that it is typical for a surviving 45–49-year-old mother to be bereaved. Discussion The study reveals enormous global disparities in mothers’ experience of child loss and identifies a need for more research on the downstream mental and physical health risks associated with parental bereavement. maternal health child health cross-sectional survey Data availability statement All data used in this study are publicly available. DHS data are available at . MICS data are available at . NSFG data are available at . Replication files are posted at Harvard Dataverse, (27). This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: . googletag.cmd.push(function() { googletag.display("dfp-ad-mpu"); }); Statistics from Altmetric.com See more details Picked up by 15 news outlets Blogged by 2 Tweeted by 115 29 readers on Mendeley Supplementary materials 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. maternal health child health cross-sectional survey Key questions What is already known? In sub-Saharan African countries, maternal indicators of the child mortality burden show that—even as infant and child mortality rates decline—having experienced a child’s death remains a common maternal experience. Child death is known to adversely affect mothers’ lives, yet we lack a systematic, global analysis of the maternal prevalence of child loss. What are the new findings? Our results offer estimates of the maternal cumulative prevalence of infant, under-five and all offspring mortality for 20–44-year-old and 45–49-year-old mothers in 170 countries, providing a new view of the burden of premature death across the globe. Global inequality in mothers’ experience of child death is enormous: mothers in select African countries are more than 100 times more likely to have had a child die than mothers in select Asian or European countries; the most dramatic inequalities are between younger mothers (ages 20–34). What do the new findings imply? Quantifying maternal experiences of child loss offers a new perspective of the population burden of child death, reveals how disparate maternal conditions are worldwide and attests to the need for additional individual-level research on the consequences of child loss for families. Background Infant and child mortality rates have declined worldwide over the last 50 years, signifying notable progress for children and their parents. 1 Reductions in annualised rates of infant and child mortality, however, cannot reasonably proxy parents’ cumulative experiences of child loss, a phenomenon we refer to as parental bereavement . A child’s death can have serious and long-lasting consequences for parents, 2–4 but the population prevalence of bereaved parents has only been estimated for a select group of countries in sub-Saharan Africa. 5 From those estimates, as recently as 2015, over one-third of mothers in sub-Saharan Africa had experienced a child death. 5 It remains unclear whether such high levels of maternal bereavement characterise other low-income and middle-income countries and how this burden compares to high-income countries. In this article, we provide the first population-level estimates of the prevalence of bereaved mothers in 170 countries. We generate three indicators of the cumulative prevalence of mothers who have had an infant, under-five-year-old or any-age child die. We label these indicators: the maternal cumulative prevalence of infant mortality (mIM), under-five mortality (mU5M) and offspring mortality (mOM). 5 To achieve global coverage, we generate these indicators through a combination of direct estimation, using publicly available survey data and an indirect-estimation strategy using publicly available age-specific fertility and mortality schedules. 6 Population-level measures of maternal bereavement summarise how infant, child and adolescent mortality conditions accumulate, forming a corresponding shadow population of bereaved parents deserving of public health attention. Global inequalities in the burden of family bereavement reflect disparate health environments and may also compound disadvantage by leaving parents vulnerable to the grief, trauma and other adverse outcomes associated with bereavement. 7–11 A child’s death can have profound and lasting influence on parents’ well-being, including their mental health, physical health and longevity. 2–4 12–20 The health consequences associated with bereavement are especially severe for mothers, and the adverse effects of grief can persist for years—even decades. 16 Child loss can also adversely impact other aspects of parents’ lives, including the health and stability of their marital union. 3 18 The guilt, blame, stigma, stress and relationship strain associated with child loss have been documented across diverse cultural contexts, including in settings where child loss is a tragically common and perhaps, even, an anticipated aspect of motherhood. 21–25 By demonstrating the size and distribution of child loss across the globe, these metrics<|im_end|> <|im_start|>assistant The inequality is enormous: Mothers in select African countries are more than 100 times more likely to have had a child die than mothers in high-income countries. This is what Diego Alburez-Gutierrez (Researcher at the Max Planck Institute for Demographic Research (MPIDR) in Rostock, Germany), Emily Smith-Greenaway (Researcher at the USC Dornsife College of Letters, Arts and Sciences in Los Angeles and Guest Researcher at MPIDR), and co-authors found in their recent paper published in BMJ Global Health. "We offer the first global estimates of the cumulative number of child deaths experienced by mothers between the ages of 20 and 49, in 170 countries," said Smith-Greenaway. Initially, she and her collaborators did so by drawing from the wealth of publicly available survey data, collected between 2010 and 2018, to calculate the proportion of mothers who have ever lost an offspring in 89 countries. A new indirect approach to estimate the prevalence of bereaved mothers "The innovation of our study lies in the fact that we expanded beyond these 89 countries and provided estimates for those lacking recent, nationally representative survey data by leveraging a novel indirect approach that combines formal kinship models and life-table methods," says Alburez-Gutierrez. "That has allowed us to offer a comprehensive look at bereavement worldwide." The estimates generated for these additional 81 countries are interpretable, just as the survey estimates. International inequalities in mothers' experiences of the death of a child will linger beyond the initial improvement in infant and child mortality conditions, given the varied demographic history of populations. In the seven least affected countries, which includes Japan, Finland, and Spain, fewer than 5 per 1,000 mothers who are between 20 and 44 years old have ever lost an offspring younger than one year old. In Germany, only 6 out of 1,000 mothers have ever lost an infant. In 34 countries, mostly in Africa, more than 150 per 1,000 mothers have experienced the death of an infant. That means mothers in these countries are more than 30 times as likely to have had a child die than mothers in the seven countries with the lowest numbers. Moreover, in as many as 16 countries—all located in sub-Saharan Africa and the Middle East—more than 200 per 1,000 mothers have lost an infant. It is concerning that the very parts of the world where the cumulative burden of child death is heaviest for mothers are also the settings where the least is known about the social, economic, relational, and health implications of child death for mothers. "We hope that this work will emphasize that further efforts to lower child deaths will not only improve the quality and length of life for children across the globe, but will also fundamentally improve the lives of parents," said Smith-Greenaway. <|im_end|>

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279, 7639, 9878, 377, 10181, 369, 4829, 12968, 8483, 320, 5901, 926, 49, 8, 304, 432, 537, 1197, 11, 10057, 705, 35266, 9259, 12279, 4542, 14075, 320, 28528, 261, 520, 279, 44379, 423, 44129, 1643, 9304, 315, 45397, 11, 17979, 323, 23199, 304, 9853, 12167, 323, 27307, 8483, 261, 520, 9599, 926, 49, 705, 323, 1080, 34603, 1105, 1766, 304, 872, 3293, 5684, 4756, 304, 20387, 41, 8121, 6401, 13, 330, 1687, 3085, 279, 1176, 3728, 17989, 315, 279, 40944, 1396, 315, 1716, 16779, 10534, 555, 27698, 1990, 279, 17051, 315, 220, 508, 323, 220, 2491, 11, 304, 220, 8258, 5961, 1359, 1071, 9259, 12279, 4542, 14075, 13, 59656, 11, 1364, 323, 1077, 79119, 1550, 779, 555, 13633, 505, 279, 12205, 315, 17880, 2561, 10795, 828, 11, 14890, 1990, 220, 679, 15, 323, 220, 679, 23, 11, 311, 11294, 279, 21801, 315, 27698, 889, 617, 3596, 5675, 459, 46471, 304, 220, 4578, 5961, 13, 362, 502, 25636, 5603, 311, 16430, 279, 38009, 315, 28031, 4234, 27698, 330, 791, 19297, 315, 1057, 4007, 15812, 304, 279, 2144, 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279, 6439, 315, 6699, 1359, 1071, 9259, 12279, 4542, 14075, 13, 220, 128257, 198 ]

1,941

[ { "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 Animal alarm calls can contain detailed information about a predator’s threat, and heterospecific eavesdropping on these signals creates vast communication networks. While eavesdropping is common, this indirect public information is often less reliable than direct predator observations. Red-breasted nuthatches ( Sitta canadensis ) eavesdrop on chickadee mobbing calls and vary their behaviour depending on the threat encoded in those calls. Whether nuthatches propagate this indirect information in their own calls remains unknown. Here we test whether nuthatches propagate direct (high and low threat raptor vocalizations) or indirect (high and low threat chickadee mobbing calls) information about predators differently. When receiving direct information, nuthatches vary their mobbing calls to reflect the predator’s threat. However, when nuthatches obtain indirect information, they produce calls with intermediate acoustic features, suggesting a more generic alarm signal. This suggests nuthatches are sensitive to the source and reliability of information and selectively propagate information in their own mobbing calls. Introduction Predators are a major source of mortality for many species, and animals often use alarm calls to warn each other about danger 1 , 2 , 3 . Mobbing calls are a type of alarm call typically produced in response to predators that do not pose an immediate threat and function to recruit other individuals to drive these predators away from the area, making a future surprise attack less likely 4 , 5 , 6 , 7 . Variations in the acoustic structure of mobbing vocalizations can transmit detailed information about the predator 1 , 4 , 5 , 8 , 9 , including the type, size, distance, behaviour, category, and threat level of the predator 1 , 6 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . These calls are not only used by conspecifics, but are also eavesdropped on by heterospecifics as well 20 , 21 , 22 , 23 , 24 , 25 . Obtaining information about predators from these calls improves receivers’ chances of survival 26 , 27 and their ability to respond appropriately to different types of predatory threats 18 , 28 , and can also allow naïve individuals to learn about new predator species and the threats they pose 29 , 30 , 31 , 32 , 33 . Inappropriate responses to a predator threat can be costly either by overestimating the degree of threat leading to wasted time and energy that could be used for other important behaviours (e.g. foraging or searching for mates), or by underestimating the degree of threat leading to injury or death from the predator 34 , 35 , 36 . Thus, natural selection should favour alarm calling systems in which signals reliably reflect the threat level a potential predator poses and receivers assess the quality of the source of the information and base their responses on this information quality. Although mobbing calls can encode detailed information about the danger posed by a given predator 5 , 16 , 24 , 37 , 38 , the information that receivers extract from these calls may not provide the same degree of information that could be obtained through a direct encounter with the predator. This degree of reliability determines how useful indirect information is to an eavesdropper 20 , 39 , 40 . As individuals can vary their calls in response to the community or group composition 41 , 42 , 43 , information obtained indirectly from alarm calls of others (i.e. public or indirect information) could sometimes provide an inaccurate representation of the threat 44 , 45 , 46 , 47 . A number of factors, for example life history features of a given species 43 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , or predator detection 55 could affect how individuals assess or respond to different threats; because the information included in these calls are thought to be a representation of the caller’s perceived threat, not the threat itself 45 , the reliability or accuracy of these calls to heterospecifics (and sometimes conspecifics) is potentially limited 45 , 53 , 56 . Although studies of alarm calls have provide a rich window on animal perception and behaviour, we still have important and outstanding questions about whether and how animals encode threat levels about predators depending on the source of the information—direct, personal information (e.g. hearing a predator calling) versus indirect, public information (e.g. hearing other species giving alarm calls) 44 , 45 , 46 , 54 , 56 . Here we experimentally test how eavesdroppers in a mixed-species bird community propagate information about predator threat in their alarm calls in response to direct, personal information versus indirect, public information. We study wild red-breasted nuthatches ( Sitta canadensis ), a species that frequently joins nuclear flocks of black-capped chickadees ( Poecile atricapillus ) during the winter. Chickadees are sensitive to the threat levels of different species of avian predators, and are known to vary their alarm calls when they encounter different size raptors 4 or overhear raptor calls 38 . Nuthatches are known to eavesdrop on their mobbing calls and respond appropriately to the information encoded therein 24 , 57 , but little is known about whether or how nuthatches encode information about predator threat level in their own mobbing vocalizations. Here we test the prediction that in response to direct information, nuthatches should produce finely-nuanced alarm calls that accurately reflect the level of threat of the predator; in contrast, in response to less reliable indirect public information, nuthatches should produce alarm calls that reflect the ambiguity in the source of information. In our study, we expose nuthatches to direct information indicating the presence of predators of varying threat levels (playbacks of high and low threat predator calls) and indirect information (chickadee mobbing calls in response to the same predators; Fig. 1 ). Nuthatches change acoustic features of their mobbing calls in response to increased levels of threat depending on the source of the information. They respond", "role": "user" }, { "content": "Every social network has its fake news. And in animal communication networks, even birds discern the trustworthiness of their neighbors, a study from the University of Montana suggests. The study, recently published in the top science journal Nature, is the culmination of decades' worth of research from UM alumni Nora Carlson and Chris Templeton and UM Professor Erick Greene in the College of Humanities and Sciences. It sheds a new light on bird social networks. \"This is the first time people have shown that nuthatches are paying attention to the source of information, and that influences the signal they produce and send along,\" Greene said. Carlson, Templeton and Greene shared an interest in trying to crack the Rosetta Stone of how birds communicate and collected bird calls over the years. Each bird species has a song, usually sung by the males, for \"letting the babes know 'here I am,'\" Greene said, as well as staking out real estate. Their loud and complex calls usually ring out during breeding season. But for warning calls, each sound stands for a specific threat, such as \"snake on the ground,\" \"flying hawk\" and \"perched hawk.\" The calls convey the present danger level and specific information. They also are heard by all species in the woods in a vast communication network that sets them on high alert. \"Everybody is listening to everybody else in the woods,\" Greene said. In the study, Greene and his researchers wanted to determine how black-capped chickadees and red-breasted nuthatches encode information in their calls. In bird communication, a high-pitched \"seet\" from a chickadee indicates a flying hawk and causes a strong reaction—other birds go silent, look up and then dive in the bushes. Alarm calls can travel quickly through the woods. Greene said in previous experiments they clocked the speed of the calls at 100 miles per hour, which he likens to the bow wave on a ship. \"Sometimes birds in the woods know five minutes before a hawk gets there,\" Greene said. A harsh, intensified \"mobbing call\" drives birds from all species to flock together to harass the predator. When the predator hears the mobbing call, it usually has to fly a lot farther to hunt, so the call is very effective. \"The owl is sitting in the tree, going, 'Oh crap!\" Greene said. Greene calls it \"social media networks—the original tweeting.\" For the study with chickadees and nuthatches, the researchers focused on direct information—something a bird sees or hears firsthand—versus indirect information, which is gained through the bird social network and could be a false alarm. The researchers set up multiple microphones throughout the woods to pick up the birds’ calls, analyze their locations and map the “acoustic landscape” of the forest. Credit: University of Montana \"In a way, it kind of has to do with fake news, because if you get information through social media, but you haven't verified it, and you retweet it or pass it along, that's how fake news starts,\" Greene said. Nuthatches and chickadees share the same predators: the great-horned owl and the pygmy owl. To the small birds, the pygmy owl is more dangerous than a great-horned owl due to its smaller turning radius, which allows it to chase prey better. \"If you are eating something that's almost as big as you are, it's worth it to go after it,\" Greene said. Using speakers in the woods, the researchers played the chickadee's warning call for the low-threat great-horned owl and the higher-threat pygmy owl to nuthatches. The calls varied by threat level—great-horned owl versus pygmy owl—and whether they were direct (from the predators themselves) or indirect (from the chickadees). What they discovered about the nuthatches was surprising. Direct information caused the nuthatches to vary their calls according to the high threat and the low threat. But the chickadee's alarm call about both predators elicited only a generic, intermediate call from the nuthatch, regardless of the threat level. Greene said the research points to the nuthatch's ability to make sophisticated decisions about stimuli in their environment and avoid spreading \"fake news\" before they confirm a predator for themselves. \"You gotta take your hat off to them,\" Greene said. \"There's a lot of intelligence there.\" The research, conducted by Carlson, Templeton and Greene around Montana and Washington throughout the years, wasn't without challenges. Most of the set up happened during winter, and nuthatches had to be isolated from chickadees to ensure the warning calls were not a response to witnessing chickadees going crazy. Often a chickadee would appear after everything was set up, and the researchers had to take everything down and try a new location. \"It's quite hard to find nuthatches without chickadees somewhere in the area,\" Greene said. \"That was the most difficult part—to find these conditions out in the wild.\" But the results were worth the work. Greene said the nuthatch study ultimately helps researchers better understand how animal communication networks work and how different species decode information, encode info and pass it along. \"We kind of wish people behaved like nuthatches,\" Greene 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 Animal alarm calls can contain detailed information about a predator’s threat, and heterospecific eavesdropping on these signals creates vast communication networks. While eavesdropping is common, this indirect public information is often less reliable than direct predator observations. Red-breasted nuthatches ( Sitta canadensis ) eavesdrop on chickadee mobbing calls and vary their behaviour depending on the threat encoded in those calls. Whether nuthatches propagate this indirect information in their own calls remains unknown. Here we test whether nuthatches propagate direct (high and low threat raptor vocalizations) or indirect (high and low threat chickadee mobbing calls) information about predators differently. When receiving direct information, nuthatches vary their mobbing calls to reflect the predator’s threat. However, when nuthatches obtain indirect information, they produce calls with intermediate acoustic features, suggesting a more generic alarm signal. This suggests nuthatches are sensitive to the source and reliability of information and selectively propagate information in their own mobbing calls. Introduction Predators are a major source of mortality for many species, and animals often use alarm calls to warn each other about danger 1 , 2 , 3 . Mobbing calls are a type of alarm call typically produced in response to predators that do not pose an immediate threat and function to recruit other individuals to drive these predators away from the area, making a future surprise attack less likely 4 , 5 , 6 , 7 . Variations in the acoustic structure of mobbing vocalizations can transmit detailed information about the predator 1 , 4 , 5 , 8 , 9 , including the type, size, distance, behaviour, category, and threat level of the predator 1 , 6 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . These calls are not only used by conspecifics, but are also eavesdropped on by heterospecifics as well 20 , 21 , 22 , 23 , 24 , 25 . Obtaining information about predators from these calls improves receivers’ chances of survival 26 , 27 and their ability to respond appropriately to different types of predatory threats 18 , 28 , and can also allow naïve individuals to learn about new predator species and the threats they pose 29 , 30 , 31 , 32 , 33 . Inappropriate responses to a predator threat can be costly either by overestimating the degree of threat leading to wasted time and energy that could be used for other important behaviours (e.g. foraging or searching for mates), or by underestimating the degree of threat leading to injury or death from the predator 34 , 35 , 36 . Thus, natural selection should favour alarm calling systems in which signals reliably reflect the threat level a potential predator poses and receivers assess the quality of the source of the information and base their responses on this information quality. Although mobbing calls can encode detailed information about the danger posed by a given predator 5 , 16 , 24 , 37 , 38 , the information that receivers extract from these calls may not provide the same degree of information that could be obtained through a direct encounter with the predator. This degree of reliability determines how useful indirect information is to an eavesdropper 20 , 39 , 40 . As individuals can vary their calls in response to the community or group composition 41 , 42 , 43 , information obtained indirectly from alarm calls of others (i.e. public or indirect information) could sometimes provide an inaccurate representation of the threat 44 , 45 , 46 , 47 . A number of factors, for example life history features of a given species 43 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , or predator detection 55 could affect how individuals assess or respond to different threats; because the information included in these calls are thought to be a representation of the caller’s perceived threat, not the threat itself 45 , the reliability or accuracy of these calls to heterospecifics (and sometimes conspecifics) is potentially limited 45 , 53 , 56 . Although studies of alarm calls have provide a rich window on animal perception and behaviour, we still have important and outstanding questions about whether and how animals encode threat levels about predators depending on the source of the information—direct, personal information (e.g. hearing a predator calling) versus indirect, public information (e.g. hearing other species giving alarm calls) 44 , 45 , 46 , 54 , 56 . Here we experimentally test how eavesdroppers in a mixed-species bird community propagate information about predator threat in their alarm calls in response to direct, personal information versus indirect, public information. We study wild red-breasted nuthatches ( Sitta canadensis ), a species that frequently joins nuclear flocks of black-capped chickadees ( Poecile atricapillus ) during the winter. Chickadees are sensitive to the threat levels of different species of avian predators, and are known to vary their alarm calls when they encounter different size raptors 4 or overhear raptor calls 38 . Nuthatches are known to eavesdrop on their mobbing calls and respond appropriately to the information encoded therein 24 , 57 , but little is known about whether or how nuthatches encode information about predator threat level in their own mobbing vocalizations. Here we test the prediction that in response to direct information, nuthatches should produce finely-nuanced alarm calls that accurately reflect the level of threat of the predator; in contrast, in response to less reliable indirect public information, nuthatches should produce alarm calls that reflect the ambiguity in the source of information. In our study, we expose nuthatches to direct information indicating the presence of predators of varying threat levels (playbacks of high and low threat predator calls) and indirect information (chickadee mobbing calls in response to the same predators; Fig. 1 ). Nuthatches change acoustic features of their mobbing calls in response to increased levels of threat depending on the source of the information. They respond<|im_end|> <|im_start|>assistant Every social network has its fake news. And in animal communication networks, even birds discern the trustworthiness of their neighbors, a study from the University of Montana suggests. The study, recently published in the top science journal Nature, is the culmination of decades' worth of research from UM alumni Nora Carlson and Chris Templeton and UM Professor Erick Greene in the College of Humanities and Sciences. It sheds a new light on bird social networks. "This is the first time people have shown that nuthatches are paying attention to the source of information, and that influences the signal they produce and send along," Greene said. Carlson, Templeton and Greene shared an interest in trying to crack the Rosetta Stone of how birds communicate and collected bird calls over the years. Each bird species has a song, usually sung by the males, for "letting the babes know 'here I am,'" Greene said, as well as staking out real estate. Their loud and complex calls usually ring out during breeding season. But for warning calls, each sound stands for a specific threat, such as "snake on the ground," "flying hawk" and "perched hawk." The calls convey the present danger level and specific information. They also are heard by all species in the woods in a vast communication network that sets them on high alert. "Everybody is listening to everybody else in the woods," Greene said. In the study, Greene and his researchers wanted to determine how black-capped chickadees and red-breasted nuthatches encode information in their calls. In bird communication, a high-pitched "seet" from a chickadee indicates a flying hawk and causes a strong reaction—other birds go silent, look up and then dive in the bushes. Alarm calls can travel quickly through the woods. Greene said in previous experiments they clocked the speed of the calls at 100 miles per hour, which he likens to the bow wave on a ship. "Sometimes birds in the woods know five minutes before a hawk gets there," Greene said. A harsh, intensified "mobbing call" drives birds from all species to flock together to harass the predator. When the predator hears the mobbing call, it usually has to fly a lot farther to hunt, so the call is very effective. "The owl is sitting in the tree, going, 'Oh crap!" Greene said. Greene calls it "social media networks—the original tweeting." For the study with chickadees and nuthatches, the researchers focused on direct information—something a bird sees or hears firsthand—versus indirect information, which is gained through the bird social network and could be a false alarm. The researchers set up multiple microphones throughout the woods to pick up the birds’ calls, analyze their locations and map the “acoustic landscape” of the forest. Credit: University of Montana "In a way, it kind of has to do with fake news, because if you get information through social media, but you haven't verified it, and you retweet it or pass it along, that's how fake news starts," Greene said. Nuthatches and chickadees share the same predators: the great-horned owl and the pygmy owl. To the small birds, the pygmy owl is more dangerous than a great-horned owl due to its smaller turning radius, which allows it to chase prey better. "If you are eating something that's almost as big as you are, it's worth it to go after it," Greene said. Using speakers in the woods, the researchers played the chickadee's warning call for the low-threat great-horned owl and the higher-threat pygmy owl to nuthatches. The calls varied by threat level—great-horned owl versus pygmy owl—and whether they were direct (from the predators themselves) or indirect (from the chickadees). What they discovered about the nuthatches was surprising. Direct information caused the nuthatches to vary their calls according to the high threat and the low threat. But the chickadee's alarm call about both predators elicited only a generic, intermediate call from the nuthatch, regardless of the threat level. Greene said the research points to the nuthatch's ability to make sophisticated decisions about stimuli in their environment and avoid spreading "fake news" before they confirm a predator for themselves. "You gotta take your hat off to them," Greene said. "There's a lot of intelligence there." The research, conducted by Carlson, Templeton and Greene around Montana and Washington throughout the years, wasn't without challenges. Most of the set up happened during winter, and nuthatches had to be isolated from chickadees to ensure the warning calls were not a response to witnessing chickadees going crazy. Often a chickadee would appear after everything was set up, and the researchers had to take everything down and try a new location. "It's quite hard to find nuthatches without chickadees somewhere in the area," Greene said. "That was the most difficult part—to find these conditions out in the wild." But the results were worth the work. Greene said the nuthatch study ultimately helps researchers better understand how animal communication networks work and how different species decode information, encode info and pass it along. "We kind of wish people behaved like nuthatches," Greene 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 Protein fibrillogenesis is a universal tool of nano-to-micro scale construction supporting different forms of biological function. Its exploitable potential in nanoscience and technology is substantial, but the direct observation of homogeneous fibre growth able to underpin a kinetic-based rationale for building customized nanostructures in situ is lacking. Here we introduce a kinetic model of de novo protein fibrillogenesis which we imaged at the nanoscale and in real time, filmed. The model helped to reveal that, in contrast to heterogeneous amyloid assemblies, homogeneous protein recruitment is principally characterized by uniform rates of cooperative growth at both ends of growing fibers, bi-directional growth, with lateral growth arrested at a post-seeding stage. The model provides a foundation for in situ engineering of sequence-prescribed fibrous architectures. Introduction The wealth of information protein fibers support ranges from cell locomotion 1 , 2 , 3 and proliferation 4 , 5 to neurodegeneartion 6 and viral assembly 7 . Despite such functional diversity all protein fibers are near-crystalline assemblies exhibiting hierarchical growth 8 , which is believed to be polar 9 and, in some cases, bidirectional 10 , 11 . Traditional techniques, such as electron and fluorescence microscopy, partly support this conjecture by providing temporal image sequences that link different points of fiber formation 9 , 10 , 11 , 12 . Notable progress has been made in the understanding of type I collagen fibrillogenesis, for which correlative measurements using electron and dark-field light microscopy revealed a unidirectional, the C-to-N terminal direction, mode of assembly 13 . However, direct evidence for protein fibrillogenesis from the monomer up, which would enable a kinetic-based rationale for engineering novel fibrous architectures in situ, is lacking. This can be attributed to two main reasons. Firstly, real-time imaging of a biomolecular process has to be performed under ambient conditions in aqueous media, which excludes the use of electron microscopy. Optical microscopy is well suited for imaging dynamic processes, but is limited in spatial resolution, which has prompted the development of super-resolution techniques 14 , 15 . In particular, structured illumination microscopy (SIM) improves spatial resolution beyond the diffraction limit by illuminating the sample with patterned light to allow detection of normally unobservable high spatial frequency information. In contrast to other super-resolution techniques, SIM is capable of high imaging speeds, up to video rates and does not place additional constraints on fluorophore properties 16 . Secondly, fibrillogenesis is a cooperative process programmed in the folding of monomeric units 17 . These units are not necessarily limited to individual polypeptide chains and may incorporate post-translational modifications that support a specific function without being directly involved in the assembly, or can comprise several populations of low oligomers, with each having different growth kinetics. An auxiliary means, additional to fiber formation, can also be employed to maintain morphological uniformity by arresting thickening 18 or promote polygonal networks by seeding promiscuous interactions 19 . All these introduce structural polymorphism into the assembly. As a consequence, a reductionist approach is required to distinguish folding-assembly pathways from other events implicated in fibrillogenesis. In this regard, a more efficient strategy would be to replicate fiber formation from the monomer up rather than focus on resolving structural differences. De novo sequences encoding simplified folding motifs provide an excellent source of self-assembling monomers 17 . With this in mind, we introduce a fibrillogenesis imaging model (FiM) – an archetypal helical assembly imaged in real time. Results Fibrillogenesis imaging model – design The model is based on a de novo polypeptide sequence, KLAALKQKLAALKKELAALEQELAALEQ, designed to adopt an α-helical coiled-coil conformation – a ubiquitous structural element of α-helical fibers. Coiled coils are rope-like bundles of two or more helices interdigitated with a slight left-handed super-helical twist, which is set up by an amphipathic heptad repeat of hydrophobic (H) and polar (P) residues in their sequences, (HPPHPPP) n – usually designated abcdefg , where a and d cluster into contiguous hydrophobic interfaces 20 . Native α-helical filaments adapt coiled-coil monomers by tuning their sequences into particular oligomerisation states, which alone, however, cannot set up fibrillogenesis 20 . Therefore, different propagation topologies and mechanisms are employed to specify the assembly, with two main principles considered in synergy. The first principle derives from the intrinsic property of complementarity which holds true for all self-oligomerising elements. Co-assembling sequences are sufficient for controlled oligomerisation 21 , but may not be for directed assembly – a shortcoming which in different fibrillogenesis systems is solved by placing complementary sequences axially out of register 22 . For example, α-helical intermediate filaments assemble in abrupt modes 23 , β−structured amyloid fibrils can grow from staggered or out-of-register β−sheets 24 and tropocollagen molecules assemble via side-by-side staggering 11 . The second principle concerns the coiled-coil structure itself. To ensure complementary sequence offsets, engineered coiled coils are arranged to avoid polar residues at a and d sites, while relying exclusively on charge-charge interactions at g and e sites of successive heptads ( g–e ′ interactions) 22 . Thus, a staggered assembly of charged overhangs leads to extended coiled coils and fibers. Based on this recognition, two generic heptads, cationic (KLAALKQ) and anionic (ELAALEQ), were paired sequentially into cationic and anionic halves of the designed sequence to provide oppositely charged two-heptad overhangs ( Fig. 1 ). Figure 1 FiM design. Schematic representations of (a) the linear FiM sequence forming a homo-trimeric parallel coiled coil with two-heptad cationic and anionic overhangs, (b) a staggered assembly of the block, with continuous helical strands highlighted in black and grey (upper), with ribbon diagram of a proposed sticky-ended trimer (lower, PDB 3L4F entry rendered with PyMol) and (c) the sequence configured into coiled-coil helical wheels. Cationic and anionic heptads and residues are shown in blue and red, respectively. Double-headed arrows indicate electrostatic interactions between lysines and glutamates. Only one of the two combinations of interactions, highlighted by bold and dashed arrows, can be formed within one coiled coil (see also Supporting Information ). Full size image End-point assembly and folding Consistent with the design rationale (see Methods), atomic force", "role": "user" }, { "content": "Ebola virus, Alzheimer's amyloid fibrils, tissue collagen scaffolds and cellular cytoskeleton are all filamentous structures that spontaneously assemble from individual proteins. Many protein filaments are well studied and are already finding use in regenerative medicine, molecular electronics and diagnostics. However, the very process of their assembly - protein fibrillogenesis - remains largely unrevealed. A better understanding of this process through direct observation is anticipated to offer new applications in biomedicine and nanotechnology while providing efficient solutions for pathogen detection and molecular therapy. The formation of protein filaments is highly dynamic and occurs over time and length scales that require fast measurements with nano-to-micrometer precision. Although many methods can meet these criteria the caveat is to measure in water and in real time. The challenge is compounded by the need to have a homogeneous assembly characterised by uniform growth rates of uniformly sized filaments. To tackle this challenge, an NPL team devised an archetypal fibrillogenesis model based on an artificial protein whose assembly was recorded in real time using super-resolution microscopy approaches. The findings have been published in Nature Publishing Group's Scientific Reports. Angelo Bella, Higher Research Scientist in NPL's Biotechnology Group explains: \"By being able to continuously image the assembly from the start to maturation we established that protein monomers recruit at both ends of growing filaments at uniform rates in a highly cooperative manner.\" The study provides a measurement foundation for studying different macromolecular assemblies in real time and holds promise for engineering customised nano-to-microscale structures in situ. ", "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 Protein fibrillogenesis is a universal tool of nano-to-micro scale construction supporting different forms of biological function. Its exploitable potential in nanoscience and technology is substantial, but the direct observation of homogeneous fibre growth able to underpin a kinetic-based rationale for building customized nanostructures in situ is lacking. Here we introduce a kinetic model of de novo protein fibrillogenesis which we imaged at the nanoscale and in real time, filmed. The model helped to reveal that, in contrast to heterogeneous amyloid assemblies, homogeneous protein recruitment is principally characterized by uniform rates of cooperative growth at both ends of growing fibers, bi-directional growth, with lateral growth arrested at a post-seeding stage. The model provides a foundation for in situ engineering of sequence-prescribed fibrous architectures. Introduction The wealth of information protein fibers support ranges from cell locomotion 1 , 2 , 3 and proliferation 4 , 5 to neurodegeneartion 6 and viral assembly 7 . Despite such functional diversity all protein fibers are near-crystalline assemblies exhibiting hierarchical growth 8 , which is believed to be polar 9 and, in some cases, bidirectional 10 , 11 . Traditional techniques, such as electron and fluorescence microscopy, partly support this conjecture by providing temporal image sequences that link different points of fiber formation 9 , 10 , 11 , 12 . Notable progress has been made in the understanding of type I collagen fibrillogenesis, for which correlative measurements using electron and dark-field light microscopy revealed a unidirectional, the C-to-N terminal direction, mode of assembly 13 . However, direct evidence for protein fibrillogenesis from the monomer up, which would enable a kinetic-based rationale for engineering novel fibrous architectures in situ, is lacking. This can be attributed to two main reasons. Firstly, real-time imaging of a biomolecular process has to be performed under ambient conditions in aqueous media, which excludes the use of electron microscopy. Optical microscopy is well suited for imaging dynamic processes, but is limited in spatial resolution, which has prompted the development of super-resolution techniques 14 , 15 . In particular, structured illumination microscopy (SIM) improves spatial resolution beyond the diffraction limit by illuminating the sample with patterned light to allow detection of normally unobservable high spatial frequency information. In contrast to other super-resolution techniques, SIM is capable of high imaging speeds, up to video rates and does not place additional constraints on fluorophore properties 16 . Secondly, fibrillogenesis is a cooperative process programmed in the folding of monomeric units 17 . These units are not necessarily limited to individual polypeptide chains and may incorporate post-translational modifications that support a specific function without being directly involved in the assembly, or can comprise several populations of low oligomers, with each having different growth kinetics. An auxiliary means, additional to fiber formation, can also be employed to maintain morphological uniformity by arresting thickening 18 or promote polygonal networks by seeding promiscuous interactions 19 . All these introduce structural polymorphism into the assembly. As a consequence, a reductionist approach is required to distinguish folding-assembly pathways from other events implicated in fibrillogenesis. In this regard, a more efficient strategy would be to replicate fiber formation from the monomer up rather than focus on resolving structural differences. De novo sequences encoding simplified folding motifs provide an excellent source of self-assembling monomers 17 . With this in mind, we introduce a fibrillogenesis imaging model (FiM) – an archetypal helical assembly imaged in real time. Results Fibrillogenesis imaging model – design The model is based on a de novo polypeptide sequence, KLAALKQKLAALKKELAALEQELAALEQ, designed to adopt an α-helical coiled-coil conformation – a ubiquitous structural element of α-helical fibers. Coiled coils are rope-like bundles of two or more helices interdigitated with a slight left-handed super-helical twist, which is set up by an amphipathic heptad repeat of hydrophobic (H) and polar (P) residues in their sequences, (HPPHPPP) n – usually designated abcdefg , where a and d cluster into contiguous hydrophobic interfaces 20 . Native α-helical filaments adapt coiled-coil monomers by tuning their sequences into particular oligomerisation states, which alone, however, cannot set up fibrillogenesis 20 . Therefore, different propagation topologies and mechanisms are employed to specify the assembly, with two main principles considered in synergy. The first principle derives from the intrinsic property of complementarity which holds true for all self-oligomerising elements. Co-assembling sequences are sufficient for controlled oligomerisation 21 , but may not be for directed assembly – a shortcoming which in different fibrillogenesis systems is solved by placing complementary sequences axially out of register 22 . For example, α-helical intermediate filaments assemble in abrupt modes 23 , β−structured amyloid fibrils can grow from staggered or out-of-register β−sheets 24 and tropocollagen molecules assemble via side-by-side staggering 11 . The second principle concerns the coiled-coil structure itself. To ensure complementary sequence offsets, engineered coiled coils are arranged to avoid polar residues at a and d sites, while relying exclusively on charge-charge interactions at g and e sites of successive heptads ( g–e ′ interactions) 22 . Thus, a staggered assembly of charged overhangs leads to extended coiled coils and fibers. Based on this recognition, two generic heptads, cationic (KLAALKQ) and anionic (ELAALEQ), were paired sequentially into cationic and anionic halves of the designed sequence to provide oppositely charged two-heptad overhangs ( Fig. 1 ). Figure 1 FiM design. Schematic representations of (a) the linear FiM sequence forming a homo-trimeric parallel coiled coil with two-heptad cationic and anionic overhangs, (b) a staggered assembly of the block, with continuous helical strands highlighted in black and grey (upper), with ribbon diagram of a proposed sticky-ended trimer (lower, PDB 3L4F entry rendered with PyMol) and (c) the sequence configured into coiled-coil helical wheels. Cationic and anionic heptads and residues are shown in blue and red, respectively. Double-headed arrows indicate electrostatic interactions between lysines and glutamates. Only one of the two combinations of interactions, highlighted by bold and dashed arrows, can be formed within one coiled coil (see also Supporting Information ). Full size image End-point assembly and folding Consistent with the design rationale (see Methods), atomic force<|im_end|> <|im_start|>assistant Ebola virus, Alzheimer's amyloid fibrils, tissue collagen scaffolds and cellular cytoskeleton are all filamentous structures that spontaneously assemble from individual proteins. Many protein filaments are well studied and are already finding use in regenerative medicine, molecular electronics and diagnostics. However, the very process of their assembly - protein fibrillogenesis - remains largely unrevealed. A better understanding of this process through direct observation is anticipated to offer new applications in biomedicine and nanotechnology while providing efficient solutions for pathogen detection and molecular therapy. The formation of protein filaments is highly dynamic and occurs over time and length scales that require fast measurements with nano-to-micrometer precision. Although many methods can meet these criteria the caveat is to measure in water and in real time. The challenge is compounded by the need to have a homogeneous assembly characterised by uniform growth rates of uniformly sized filaments. To tackle this challenge, an NPL team devised an archetypal fibrillogenesis model based on an artificial protein whose assembly was recorded in real time using super-resolution microscopy approaches. The findings have been published in Nature Publishing Group's Scientific Reports. Angelo Bella, Higher Research Scientist in NPL's Biotechnology Group explains: "By being able to continuously image the assembly from the start to maturation we established that protein monomers recruit at both ends of growing filaments at uniform rates in a highly cooperative manner." The study provides a measurement foundation for studying different macromolecular assemblies in real time and holds promise for engineering customised nano-to-microscale structures in situ. <|im_end|>

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1,774

[ { "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 pace of repair declines with age and, while exposure to a young circulation can rejuvenate fracture repair, the cell types and factors responsible for rejuvenation are unknown. Here we report that young macrophage cells produce factors that promote osteoblast differentiation of old bone marrow stromal cells. Heterochronic parabiosis exploiting young mice in which macrophages can be depleted and fractionated bone marrow transplantation experiments show that young macrophages rejuvenate fracture repair, and old macrophage cells slow healing in young mice. Proteomic analysis of the secretomes identify differential proteins secreted between old and young macrophages, such as low-density lipoprotein receptor-related protein 1 (Lrp1). Lrp1 is produced by young cells, and depleting Lrp1 abrogates the ability to rejuvenate fracture repair, while treating old mice with recombinant Lrp1 improves fracture healing. Macrophages and proteins they secrete orchestrate the fracture repair process, and young cells produce proteins that rejuvenate fracture repair in mice. Introduction Tissue repair and regenerative capacity declines with age. The pace of fracture repair slows after skeletal maturity, with 3-month-old-juvenile mice (equivalent of an young adult) healing almost twice as fast as 20-month-old mice (equivalent to a 70 years old) 1 . Four weeks following fracture, a time in which callus from fractures in young animals contain a high proportion of bone, there will still be substantial proportions of undifferentiated mesenchymal or fibrous tissue in older mice. Many factors are proposed to slow the pace of fracture repair in older animals, including intrinsic changes in mesenchymal cells and hormonal changes with aging 2 , 3 , 4 . A smaller proportion of undifferentiated mesenchymal cells differentiate to osteoblasts in older animals, and this block to differentiation is one factor responsible for the delay in fracture healing in aging 5 , 6 , 7 , 8 . Parabiosis and bone marrow transplantation studies show that young hematopoietic cells can rejuvenate of the pace of fracture repair in old mice. Furthermore, conditioned media experiments show that secreted factors can increase the proportion of cells differentiating to osteoblasts in older animals 9 . Whereas this data are consistent with the notion that a secreted factor produced by hematopoietic cells can rejuvenate the pace of fracture repair, neither the hematopoietic cell type, nor the factors are known. One cell type that might be responsible for the rejuvenation effect of young hematopoietic cells is a cell of the monocyte/macrophage lineage. After tissue injury, macrophages are recruited to areas of trauma, where they undergo phenotypic and functional changes coordinating tissue repair 10 . During fracture healing macrophages are found at the fracture site, and when depleted, fractures will not heal effectively 11 , 12 . Macrophage populations and phenotype can change with aging 13 , 14 . Here we investigate the possibility that monocyte/macrophage lineage cells rejuvenate fracture repair. We show that young macrophage cells produce factors that promote osteoblast differentiation in bone marrow stromal cells. Heterochronic parabiosis and bone marrow transplantation studies show that young macrophages rejuvenate fracture repair, and old macrophage cells slow healing in young mice. Comparison of secretomes between old and young cells identifies differential secreted proteins, one of which is low-density lipoprotein receptor-related protein 1 (Lrp1). Depleting Lrp1 abrogates the ability to rejuvenate fracture repair, whereas treating old mice with recombinant Lrp1 improves fracture healing. Results Young macrophages promote osteoblastic differentiation Previous studies found that conditioned media from bone marrow cell populations that adhere to plastic, but not the non-adherent cell population from young animals increased the CFU-O capacity of older animals 9 . One cell type that is in the adherent cell population is the macrophage. Macrophage Fas-induced apoptosis transgenic mice (MaFIA) can be used to deplete macrophage cells. This mouse expresses a mutant human FK506 binding protein 1A, 12 kDa (FKBP12) driven by the mouse Csf1r , (colony stimulating factor 1 receptor) promoter. Expression is limited to macrophages, and when the mice are treated with the dimerizing reagent, AP20187, this induces apoptosis in macrophages 15 . Five days of treatment effectively depletes 90% of macrophage cells. Macrophage cells from these mice also express GFP prior to their depletion. We performed conditioned media experiment using bone marrow cells from young (4 months old) MaFIA mouse to rejuvenate osteogenic differentiation in bone marrow cells from old (20 months old) mice. When the cell cultures were treated with AP20187, to deplete the macrophage population, the rejuvenation effect on osteoblastic differentiation was lost (Fig. 1a ). We then isolated macrophages from bone marrow from young or old mice, and found that conditioned media from young, but not old macrophage cells, would increase the capacity of old bone marrow cells to form CFU-O (Fig. 1b ). Fig. 1 Young macrophage cells rejuvenate osteogenic differentiation and fracture repair. a Numbers of CFU-O (Von Kossa and Alk Phosphate (ALP) staining shown) that form when treated with conditioned media from the young bone marrow cell cultures from MaFIA mice when macrophages are depleted by AP20187 treatment (labeled AP) or when treated with a vehicle (Veh). Representative cell culture plates (left) and each data point is shown as well as means and 95% confidence intervals for data for each experimental group (right). An asterisk over a data point shows a significance p < 0.05 compared to controls with control culture defined as “1,” n = 6, two-tailed t -test. b Conditioned media from isolated macrophages from bone marrow from young, but not old mice increases CFU-O numbers that form from bone marrow cells obtained from old mice. Representative cell culture plates (left) and each data point as well as means and 95% confidence intervals for each experimental group with control culture normalized to “1” (right) are shown, n = 6, ANOVA. c Representative radiographic and Safranin O stained histologic images from the tibia of an old mouse 14 days after the bone was fractured in heterochronic parabiotic pairs in which the young parabiot was a MaFIA mouse (O-Y), or in isochronic parabiotic pairs in which both are old mice (O-O, n = 10). The MaFIA mouse pairs were", "role": "user" }, { "content": "For a child, recovering from a broken bone is typically a short-lived, albeit painful, convalescence. But for older adults, it can be a protracted and potentially life-threatening process. Finding ways to speed bone repair is a public health priority that could save both lives and health care expense. The Centers for Disease Control and Prevention reports that more than 800,000 patients a year are hospitalized because of fall injuries, including broken hips, and these hospitalizations cost an average of $30,000. \"Delayed fracture healing is a major health issue in aging, and strategies to improve the pace of repair and prevent the need for additional surgeries to achieve healing substantially improve patient outcomes,\" said senior author Benjamin Alman, M.D., chair of the Department of Orthopedic Surgery at Duke. Duke Health researchers previously showed that introducing bone marrow stem cells to a bone injury can expedite healing, but the exact process was unclear. Now, the same Duke-led team believes it has pinpointed the \"youth factor\" inside bone marrow stem cells—it's the macrophage, a type of white blood cell, and the proteins it secretes that can have a rejuvenating effect on tissue. Nature Communications will publish the findings online on Dec. 5. After tissue injury, the body dispatches macrophages to areas of trauma, where they undergo functional changes to coordinate tissue repair. During fracture healing, macrophages are found at the fracture site. But when they're depleted, fractures will not heal effectively. Macrophage populations and characteristics can change with aging. \"We show that young macrophage cells produce factors that lead to bone formation, and when introduced in older mice, improves fracture healing,\" said Gurpreet Baht, Ph.D., assistant professor in orthopedic surgery and a lead author of the study. \"While macrophages are known to play a role in repair and regeneration, prior studies do not identify secreted factors responsible for the effect,\" Alman said. \"Here we show that young macrophage cells play a role in the rejuvenation process, and injection of one of the factors produced by the young cells into a fracture in old mice rejuvenates the pace of repair. This suggests a new therapeutic approach to fracture rejuvenation.\" ", "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 pace of repair declines with age and, while exposure to a young circulation can rejuvenate fracture repair, the cell types and factors responsible for rejuvenation are unknown. Here we report that young macrophage cells produce factors that promote osteoblast differentiation of old bone marrow stromal cells. Heterochronic parabiosis exploiting young mice in which macrophages can be depleted and fractionated bone marrow transplantation experiments show that young macrophages rejuvenate fracture repair, and old macrophage cells slow healing in young mice. Proteomic analysis of the secretomes identify differential proteins secreted between old and young macrophages, such as low-density lipoprotein receptor-related protein 1 (Lrp1). Lrp1 is produced by young cells, and depleting Lrp1 abrogates the ability to rejuvenate fracture repair, while treating old mice with recombinant Lrp1 improves fracture healing. Macrophages and proteins they secrete orchestrate the fracture repair process, and young cells produce proteins that rejuvenate fracture repair in mice. Introduction Tissue repair and regenerative capacity declines with age. The pace of fracture repair slows after skeletal maturity, with 3-month-old-juvenile mice (equivalent of an young adult) healing almost twice as fast as 20-month-old mice (equivalent to a 70 years old) 1 . Four weeks following fracture, a time in which callus from fractures in young animals contain a high proportion of bone, there will still be substantial proportions of undifferentiated mesenchymal or fibrous tissue in older mice. Many factors are proposed to slow the pace of fracture repair in older animals, including intrinsic changes in mesenchymal cells and hormonal changes with aging 2 , 3 , 4 . A smaller proportion of undifferentiated mesenchymal cells differentiate to osteoblasts in older animals, and this block to differentiation is one factor responsible for the delay in fracture healing in aging 5 , 6 , 7 , 8 . Parabiosis and bone marrow transplantation studies show that young hematopoietic cells can rejuvenate of the pace of fracture repair in old mice. Furthermore, conditioned media experiments show that secreted factors can increase the proportion of cells differentiating to osteoblasts in older animals 9 . Whereas this data are consistent with the notion that a secreted factor produced by hematopoietic cells can rejuvenate the pace of fracture repair, neither the hematopoietic cell type, nor the factors are known. One cell type that might be responsible for the rejuvenation effect of young hematopoietic cells is a cell of the monocyte/macrophage lineage. After tissue injury, macrophages are recruited to areas of trauma, where they undergo phenotypic and functional changes coordinating tissue repair 10 . During fracture healing macrophages are found at the fracture site, and when depleted, fractures will not heal effectively 11 , 12 . Macrophage populations and phenotype can change with aging 13 , 14 . Here we investigate the possibility that monocyte/macrophage lineage cells rejuvenate fracture repair. We show that young macrophage cells produce factors that promote osteoblast differentiation in bone marrow stromal cells. Heterochronic parabiosis and bone marrow transplantation studies show that young macrophages rejuvenate fracture repair, and old macrophage cells slow healing in young mice. Comparison of secretomes between old and young cells identifies differential secreted proteins, one of which is low-density lipoprotein receptor-related protein 1 (Lrp1). Depleting Lrp1 abrogates the ability to rejuvenate fracture repair, whereas treating old mice with recombinant Lrp1 improves fracture healing. Results Young macrophages promote osteoblastic differentiation Previous studies found that conditioned media from bone marrow cell populations that adhere to plastic, but not the non-adherent cell population from young animals increased the CFU-O capacity of older animals 9 . One cell type that is in the adherent cell population is the macrophage. Macrophage Fas-induced apoptosis transgenic mice (MaFIA) can be used to deplete macrophage cells. This mouse expresses a mutant human FK506 binding protein 1A, 12 kDa (FKBP12) driven by the mouse Csf1r , (colony stimulating factor 1 receptor) promoter. Expression is limited to macrophages, and when the mice are treated with the dimerizing reagent, AP20187, this induces apoptosis in macrophages 15 . Five days of treatment effectively depletes 90% of macrophage cells. Macrophage cells from these mice also express GFP prior to their depletion. We performed conditioned media experiment using bone marrow cells from young (4 months old) MaFIA mouse to rejuvenate osteogenic differentiation in bone marrow cells from old (20 months old) mice. When the cell cultures were treated with AP20187, to deplete the macrophage population, the rejuvenation effect on osteoblastic differentiation was lost (Fig. 1a ). We then isolated macrophages from bone marrow from young or old mice, and found that conditioned media from young, but not old macrophage cells, would increase the capacity of old bone marrow cells to form CFU-O (Fig. 1b ). Fig. 1 Young macrophage cells rejuvenate osteogenic differentiation and fracture repair. a Numbers of CFU-O (Von Kossa and Alk Phosphate (ALP) staining shown) that form when treated with conditioned media from the young bone marrow cell cultures from MaFIA mice when macrophages are depleted by AP20187 treatment (labeled AP) or when treated with a vehicle (Veh). Representative cell culture plates (left) and each data point is shown as well as means and 95% confidence intervals for data for each experimental group (right). An asterisk over a data point shows a significance p < 0.05 compared to controls with control culture defined as “1,” n = 6, two-tailed t -test. b Conditioned media from isolated macrophages from bone marrow from young, but not old mice increases CFU-O numbers that form from bone marrow cells obtained from old mice. Representative cell culture plates (left) and each data point as well as means and 95% confidence intervals for each experimental group with control culture normalized to “1” (right) are shown, n = 6, ANOVA. c Representative radiographic and Safranin O stained histologic images from the tibia of an old mouse 14 days after the bone was fractured in heterochronic parabiotic pairs in which the young parabiot was a MaFIA mouse (O-Y), or in isochronic parabiotic pairs in which both are old mice (O-O, n = 10). The MaFIA mouse pairs were<|im_end|> <|im_start|>assistant For a child, recovering from a broken bone is typically a short-lived, albeit painful, convalescence. But for older adults, it can be a protracted and potentially life-threatening process. Finding ways to speed bone repair is a public health priority that could save both lives and health care expense. The Centers for Disease Control and Prevention reports that more than 800,000 patients a year are hospitalized because of fall injuries, including broken hips, and these hospitalizations cost an average of $30,000. "Delayed fracture healing is a major health issue in aging, and strategies to improve the pace of repair and prevent the need for additional surgeries to achieve healing substantially improve patient outcomes," said senior author Benjamin Alman, M.D., chair of the Department of Orthopedic Surgery at Duke. Duke Health researchers previously showed that introducing bone marrow stem cells to a bone injury can expedite healing, but the exact process was unclear. Now, the same Duke-led team believes it has pinpointed the "youth factor" inside bone marrow stem cells—it's the macrophage, a type of white blood cell, and the proteins it secretes that can have a rejuvenating effect on tissue. Nature Communications will publish the findings online on Dec. 5. After tissue injury, the body dispatches macrophages to areas of trauma, where they undergo functional changes to coordinate tissue repair. During fracture healing, macrophages are found at the fracture site. But when they're depleted, fractures will not heal effectively. Macrophage populations and characteristics can change with aging. "We show that young macrophage cells produce factors that lead to bone formation, and when introduced in older mice, improves fracture healing," said Gurpreet Baht, Ph.D., assistant professor in orthopedic surgery and a lead author of the study. "While macrophages are known to play a role in repair and regeneration, prior studies do not identify secreted factors responsible for the effect," Alman said. "Here we show that young macrophage cells play a role in the rejuvenation process, and injection of one of the factors produced by the young cells into a fracture in old mice rejuvenates the pace of repair. This suggests a new therapeutic approach to fracture rejuvenation." <|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 Collective movement of epithelial cells drives essential multicellular organization during various fundamental physiological processes encompassing embryonic morphogenesis, cancer and wound healing. Yet the molecular mechanism that ensures the coordinated movement of many cells remains elusive. Here we show that a tumour suppressor protein, merlin, coordinates collective migration of tens of cells, by acting as a mechanochemical transducer. In a stationary epithelial monolayer and also in three-dimensional human skin, merlin localizes to cortical cell–cell junctions. During migration initiation, a fraction of cortical merlin relocalizes to the cytoplasm. This relocalization is triggered by the intercellular pulling force of the leading cell and depends on the actomyosin-based cell contractility. Then in migrating cells, taking its cue from the intercellular pulling forces, which show long-distance ordering, merlin coordinates polarized Rac1 activation and lamellipodium formation on the multicellular length scale. Together, these results provide a distinct molecular mechanism linking intercellular forces to collective cell movements in migrating epithelia. Main Collective cell migration refers to the process of many cells migrating as a cohesive group with each individual cell correlating its own movement with that of its neighbours 1 . It is an emergent phenomenon at multicellular level and an inherent part of a developing embryo, a healing wound, a regenerating tissue and a progressing cancer 2 , 3 , 4 , 5 . Of all experimental models of collective cell migration, epithelial sheet migration is presumably the most widely studied one 6 . In an epithelial monolayer, opening of a free surface, either by scratch-wounding or by removing a physical confinement ( Fig. 1a, b ), triggers collective migration of the surrounding cells to fill the gap 7 . Remarkably, cell polarizations and motions within an epithelial monolayer correlate over more than ten cell diameters (>200 μm) in space 8 , 9 . However, the molecular mechanism that governs the length scale of this correlated motion remains unknown 1 , though some fundamental principles have emerged. For example, cells moving as a collective should have the ability to coordinate polarized activation of small Rho GTPases such as Rac1, Cdc42 and RhoA on a multicellular length scale 4 , 10 , 11 , 12 . In addition, cell contractility and rearrangement of cytoskeletal elements must also be synchronized 13 , 14 , 15 . It is evident that the cell–cell junction complexes play a crucial part in this coordination 16 , but the exact molecular factor that critically relates cell–cell junctions to collective cell polarization and migration is not known. Interestingly, beyond this biochemical realm, previous biophysical analyses have shown that such correlation can originate from the cellular tendency to follow the local anisotropic pulling stresses 17 , which are transmitted across cell–cell junctions and show long-distance ordering 18 . Yet the underlying molecular machinery that couples mechanical forces to correlated cellular motions remains elusive. Figure 1: Merlin supports collective migration of epithelial cells. ( a ) Schematic representation of the in vitro wound healing model in an epithelial monolayer. Lifting off the confinement after the cells have grown to confluency triggers epithelial sheet migration. Cell monolayers were 7 mm wide. Two monolayers were separated by a 500 μm wide free space. ( b ) Phase contrast microscopy images of two migrating epithelial monolayers of MDCK cells. ( c ) Velocity map obtained by PIV analysis. Right: a highly correlated velocity domain. ( d ) Both HaCaT and MDCK cells showed long-ranged velocity correlation (for both HaCaT and MDCK, n = 15 samples from three independent experiments). ( e ) Correlation length in control or siRNA-transfected HaCaT cells ( n = 15 samples from three independent experiments in all cases; scramble versus siRNA1, P = 4.03 × 10 −20 ; scramble versus siRNA2, P = 9.25 × 10 −20 ; Wilcoxon rank-sum test). ( f ) Top: western blot (WB) of endogenous canine merlin (cMerlin) and TagGFP2-tagged human merlin (TGFP:hMerlin-FL) in MDCK cells. siRNA3–5 are specific to canine merlin only. Middle: glyceraldehyde-3-phosphate dehydrogenase (GAPDH) loading control. Bottom: depletion of endogenous merlin reduced the collectivity (lanes 3, 4 and 6), which was restored by human merlin (lanes 8 and 9). ( n = 15 samples from three independent experiments in all cases.) ( g ) Localization of merlin in stationary (left) and moving (right) monolayer. ( h , i ) Merlin expression in histological sections of human skin equivalent in unwounded ( h ) and 24 h post wounding ( i ) tissue. ∗ ∗ ∗ P < 0.001 (Wilcoxon rank-sum test). Scale bars, 100 μm. In box plots ( d – f ) the central mark is the median, and the edges of the box are the first and third quartiles. Whiskers extend to the most extreme non-outlier data points. b , c , f (middle) and g – i show representative images of three independent experiments. Uncropped images of blots are shown in Supplementary Fig. 9 . Full size image RESULTS Dynamic localization of merlin to cell–cell junctions during collective migration To study the dynamics of collective cell migration, we cultured a confluent epithelial monolayer within a confined area and then lifted off the confinement, triggering sheet migration ( Fig. 1a, b and Supplementary Fig. 1a ). We used particle image velocimetry (PIV) to measure the velocity field between two time-lapse, phase contrast microscopy images 19 ( Fig. 1b, c and Supplementary Fig. 1b–d ) and determined how far the cells could align or correlate their motion by computing the correlation length of the lateral velocity component ( Supplementary Fig. 1e–g ). Correlation length much greater than average cell diameter indicates collective cell migration 9 . Indeed, monolayers of the human skin epithelial cell line HaCaT and the Madin–Darby canine kidney (MDCK) dog epithelial cell line both showed velocity correlation extending over 10–12 cells in space ( Fig. 1d ). Next, to look for the proteins governing the mechanochemical signalling in collective migration, we targeted the upstream regulators of Hippo 20 , Wnt 21 and planar cell polarity 22 mechanotransduction pathways. We also included", "role": "user" }, { "content": "Cells also follow a herd instinct, and they thereby communicate in a magical collective way. This is because a protein known as merlin, named after the mythical wizard of medieval England, plays an important role in collective movement of cells in the body. This discovery was made by a team headed by scientists from the Max Planck Institute for Intelligent Systems in Stuttgart working in collaboration with University Hospital Heidelberg. In a cell, merlin registers whether and in what direction a neighbouring cell is moving and induces its own cell to creep in the same direction. It is important that cells move as a cohesive group so that wounds heal quickly and effectively, for example. If this group dynamic is disrupted, however, wounds are not only closed more poorly, cancer cells can also spread more easily in the body or embryos may be stunted in their development. The head does not always tell the body what's going on. Skin cells, for instance, find the right way themselves. If there is a tear in the skin, the cells that are closest to the wound migrate to the gap and their neighbours simply go along. At least this is how it happens when merlin performs its role properly. If it doesn't, the individual cells stray in a disoriented fashion through the tissue. Potentially, this could even lead to a particularly noticeable scar or the wound might not heal at all. And if the rogue cells happen to be tumour cells, it is easier for them to spread throughout the body, resulting in the formation of metastases. \"Individual cells that move randomly – in other words in those cells where the tumour-inhibiting protein merlin is at least partially switched off or is not present – can enter the tissue more easily than as an orderly group of several cells\", says Joachim Spatz, Director at the Max Planck Institute for Intelligent Systems and head of the current study. One cell can pull a series of ten other cells with it Researchers in molecular medicine already knew that merlin inhibits the spread of tumour cells. Joachim Spatz and his team have now explained why this is so. The protein actually acts as a brake. In resting cells, merlin sits in the cortex of the cell, a protein-rich layer on the inside of the cell membrane, and more specifically on a protein complex above which neighbouring cells converge. As long as merlin docks there, it also inhibits the protein Rac1, which moves a cell. If a cell moves, it pulls on the neighbouring cell, or more precisely, on the protein complex to which merlin is linked. This results in a mechanical stress, which releases merlin from its parked position in the cortex. The protein then migrates into the cell plasma and no longer blocks Rac1. The cell brake is thereby released: the Rac1 protein now forms so-called lamellipodia towards the precursor cell projections. These projections pull the cell body behind them. In this way, one cell can lead and pull ten to twenty other cells that are in a behind it. Researchers working with Joachim Spatz discovered that this biochemical and mechanical mechanism controls the herd instinct of cells while they were investigating the movement of skin cells. To this end, they tagged the merlin in the test cells with fluorescent proteins so that they could track its route through the respective cell. As the researchers now have a better understanding of how cells move as a group and when they go their own way, this could also result in new approaches in medicine. The findings made by the Stuttgart-based researchers provide clues as to how impairments in wound healing could be eliminated or how the metastasis of tumours could be reduced. They also help developmental biologists in understanding how cells find their intended location in an embryo. After all, such processes are not controlled by magical powers but by the interaction of biochemistry and mechanical forces. ", "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 Collective movement of epithelial cells drives essential multicellular organization during various fundamental physiological processes encompassing embryonic morphogenesis, cancer and wound healing. Yet the molecular mechanism that ensures the coordinated movement of many cells remains elusive. Here we show that a tumour suppressor protein, merlin, coordinates collective migration of tens of cells, by acting as a mechanochemical transducer. In a stationary epithelial monolayer and also in three-dimensional human skin, merlin localizes to cortical cell–cell junctions. During migration initiation, a fraction of cortical merlin relocalizes to the cytoplasm. This relocalization is triggered by the intercellular pulling force of the leading cell and depends on the actomyosin-based cell contractility. Then in migrating cells, taking its cue from the intercellular pulling forces, which show long-distance ordering, merlin coordinates polarized Rac1 activation and lamellipodium formation on the multicellular length scale. Together, these results provide a distinct molecular mechanism linking intercellular forces to collective cell movements in migrating epithelia. Main Collective cell migration refers to the process of many cells migrating as a cohesive group with each individual cell correlating its own movement with that of its neighbours 1 . It is an emergent phenomenon at multicellular level and an inherent part of a developing embryo, a healing wound, a regenerating tissue and a progressing cancer 2 , 3 , 4 , 5 . Of all experimental models of collective cell migration, epithelial sheet migration is presumably the most widely studied one 6 . In an epithelial monolayer, opening of a free surface, either by scratch-wounding or by removing a physical confinement ( Fig. 1a, b ), triggers collective migration of the surrounding cells to fill the gap 7 . Remarkably, cell polarizations and motions within an epithelial monolayer correlate over more than ten cell diameters (>200 μm) in space 8 , 9 . However, the molecular mechanism that governs the length scale of this correlated motion remains unknown 1 , though some fundamental principles have emerged. For example, cells moving as a collective should have the ability to coordinate polarized activation of small Rho GTPases such as Rac1, Cdc42 and RhoA on a multicellular length scale 4 , 10 , 11 , 12 . In addition, cell contractility and rearrangement of cytoskeletal elements must also be synchronized 13 , 14 , 15 . It is evident that the cell–cell junction complexes play a crucial part in this coordination 16 , but the exact molecular factor that critically relates cell–cell junctions to collective cell polarization and migration is not known. Interestingly, beyond this biochemical realm, previous biophysical analyses have shown that such correlation can originate from the cellular tendency to follow the local anisotropic pulling stresses 17 , which are transmitted across cell–cell junctions and show long-distance ordering 18 . Yet the underlying molecular machinery that couples mechanical forces to correlated cellular motions remains elusive. Figure 1: Merlin supports collective migration of epithelial cells. ( a ) Schematic representation of the in vitro wound healing model in an epithelial monolayer. Lifting off the confinement after the cells have grown to confluency triggers epithelial sheet migration. Cell monolayers were 7 mm wide. Two monolayers were separated by a 500 μm wide free space. ( b ) Phase contrast microscopy images of two migrating epithelial monolayers of MDCK cells. ( c ) Velocity map obtained by PIV analysis. Right: a highly correlated velocity domain. ( d ) Both HaCaT and MDCK cells showed long-ranged velocity correlation (for both HaCaT and MDCK, n = 15 samples from three independent experiments). ( e ) Correlation length in control or siRNA-transfected HaCaT cells ( n = 15 samples from three independent experiments in all cases; scramble versus siRNA1, P = 4.03 × 10 −20 ; scramble versus siRNA2, P = 9.25 × 10 −20 ; Wilcoxon rank-sum test). ( f ) Top: western blot (WB) of endogenous canine merlin (cMerlin) and TagGFP2-tagged human merlin (TGFP:hMerlin-FL) in MDCK cells. siRNA3–5 are specific to canine merlin only. Middle: glyceraldehyde-3-phosphate dehydrogenase (GAPDH) loading control. Bottom: depletion of endogenous merlin reduced the collectivity (lanes 3, 4 and 6), which was restored by human merlin (lanes 8 and 9). ( n = 15 samples from three independent experiments in all cases.) ( g ) Localization of merlin in stationary (left) and moving (right) monolayer. ( h , i ) Merlin expression in histological sections of human skin equivalent in unwounded ( h ) and 24 h post wounding ( i ) tissue. ∗ ∗ ∗ P < 0.001 (Wilcoxon rank-sum test). Scale bars, 100 μm. In box plots ( d – f ) the central mark is the median, and the edges of the box are the first and third quartiles. Whiskers extend to the most extreme non-outlier data points. b , c , f (middle) and g – i show representative images of three independent experiments. Uncropped images of blots are shown in Supplementary Fig. 9 . Full size image RESULTS Dynamic localization of merlin to cell–cell junctions during collective migration To study the dynamics of collective cell migration, we cultured a confluent epithelial monolayer within a confined area and then lifted off the confinement, triggering sheet migration ( Fig. 1a, b and Supplementary Fig. 1a ). We used particle image velocimetry (PIV) to measure the velocity field between two time-lapse, phase contrast microscopy images 19 ( Fig. 1b, c and Supplementary Fig. 1b–d ) and determined how far the cells could align or correlate their motion by computing the correlation length of the lateral velocity component ( Supplementary Fig. 1e–g ). Correlation length much greater than average cell diameter indicates collective cell migration 9 . Indeed, monolayers of the human skin epithelial cell line HaCaT and the Madin–Darby canine kidney (MDCK) dog epithelial cell line both showed velocity correlation extending over 10–12 cells in space ( Fig. 1d ). Next, to look for the proteins governing the mechanochemical signalling in collective migration, we targeted the upstream regulators of Hippo 20 , Wnt 21 and planar cell polarity 22 mechanotransduction pathways. We also included<|im_end|> <|im_start|>assistant Cells also follow a herd instinct, and they thereby communicate in a magical collective way. This is because a protein known as merlin, named after the mythical wizard of medieval England, plays an important role in collective movement of cells in the body. This discovery was made by a team headed by scientists from the Max Planck Institute for Intelligent Systems in Stuttgart working in collaboration with University Hospital Heidelberg. In a cell, merlin registers whether and in what direction a neighbouring cell is moving and induces its own cell to creep in the same direction. It is important that cells move as a cohesive group so that wounds heal quickly and effectively, for example. If this group dynamic is disrupted, however, wounds are not only closed more poorly, cancer cells can also spread more easily in the body or embryos may be stunted in their development. The head does not always tell the body what's going on. Skin cells, for instance, find the right way themselves. If there is a tear in the skin, the cells that are closest to the wound migrate to the gap and their neighbours simply go along. At least this is how it happens when merlin performs its role properly. If it doesn't, the individual cells stray in a disoriented fashion through the tissue. Potentially, this could even lead to a particularly noticeable scar or the wound might not heal at all. And if the rogue cells happen to be tumour cells, it is easier for them to spread throughout the body, resulting in the formation of metastases. "Individual cells that move randomly – in other words in those cells where the tumour-inhibiting protein merlin is at least partially switched off or is not present – can enter the tissue more easily than as an orderly group of several cells", says Joachim Spatz, Director at the Max Planck Institute for Intelligent Systems and head of the current study. One cell can pull a series of ten other cells with it Researchers in molecular medicine already knew that merlin inhibits the spread of tumour cells. Joachim Spatz and his team have now explained why this is so. The protein actually acts as a brake. In resting cells, merlin sits in the cortex of the cell, a protein-rich layer on the inside of the cell membrane, and more specifically on a protein complex above which neighbouring cells converge. As long as merlin docks there, it also inhibits the protein Rac1, which moves a cell. If a cell moves, it pulls on the neighbouring cell, or more precisely, on the protein complex to which merlin is linked. This results in a mechanical stress, which releases merlin from its parked position in the cortex. The protein then migrates into the cell plasma and no longer blocks Rac1. The cell brake is thereby released: the Rac1 protein now forms so-called lamellipodia towards the precursor cell projections. These projections pull the cell body behind them. In this way, one cell can lead and pull ten to twenty other cells that are in a behind it. Researchers working with Joachim Spatz discovered that this biochemical and mechanical mechanism controls the herd instinct of cells while they were investigating the movement of skin cells. To this end, they tagged the merlin in the test cells with fluorescent proteins so that they could track its route through the respective cell. As the researchers now have a better understanding of how cells move as a group and when they go their own way, this could also result in new approaches in medicine. The findings made by the Stuttgart-based researchers provide clues as to how impairments in wound healing could be eliminated or how the metastasis of tumours could be reduced. They also help developmental biologists in understanding how cells find their intended location in an embryo. After all, such processes are not controlled by magical powers but by the interaction of biochemistry and mechanical forces. <|im_end|>

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30831, 1022, 279, 66678, 11, 52605, 11071, 12172, 320, 23966, 13, 220, 16, 64, 11, 293, 323, 99371, 23966, 13, 220, 16, 64, 7609, 1226, 1511, 19320, 2217, 41609, 318, 15501, 320, 1932, 53, 8, 311, 6767, 279, 15798, 2115, 1990, 1403, 892, 2922, 7629, 11, 10474, 13168, 92914, 5448, 220, 777, 320, 23966, 13, 220, 16, 65, 11, 272, 323, 99371, 23966, 13, 220, 16, 65, 4235, 67, 883, 323, 11075, 1268, 3117, 279, 7917, 1436, 5398, 477, 81584, 872, 11633, 555, 25213, 279, 26670, 3160, 315, 279, 45569, 15798, 3777, 320, 99371, 23966, 13, 220, 16, 68, 4235, 70, 7609, 4563, 23013, 3160, 1790, 7191, 1109, 5578, 2849, 23899, 15151, 22498, 2849, 12172, 220, 24, 662, 23150, 11, 1647, 337, 5184, 315, 279, 3823, 6930, 64779, 59544, 2849, 1584, 14433, 23389, 51, 323, 279, 9671, 258, 4235, 53773, 1729, 76082, 39042, 320, 6204, 3096, 8, 5679, 64779, 59544, 2849, 1584, 2225, 8710, 15798, 26670, 33459, 927, 220, 605, 4235, 717, 7917, 304, 3634, 320, 23966, 13, 220, 16, 67, 7609, 9479, 11, 311, 1427, 369, 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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 are many challenges to accessing PrEP and thus low uptake in the United States. This review (2007–2017) of PrEP implementation identified barriers to PrEP and interventions to match those barriers. The final set of articles (n = 47) included content on cognitive aspects of HIV service providers and individuals at risk for infection, reviews, and case studies. Cognitive barriers and interventions regarding patients and providers included knowledge, attitudes, and beliefs about PrEP. The “purview paradox” was identified as a key barrier—HIV specialists often do not see HIV-negative patients, while primary care physicians, who often see uninfected patients, are not trained to provide PrEP. Healthcare systems barriers included lack of communication about, funding for, and access to PrEP. The intersection between PrEP-stigma, HIV-stigma, transphobia, homophobia, and disparities across gender, racial, and ethnic groups were identified; but few interventions addressed these barriers. We recommend multilevel interventions targeting barriers at multiple socioecological domains. Resumen Existen muchos desafíos para acceder a PrEP y, por lo tanto, poca aceptación en los Estados Unidos. Esta revisión (2007-17) de la implementación de PrEP identificó las barreras a la PrEP y las intervenciones para hacer coincidir esas barreras. El conjunto final de artículos (n = 47) incluyó contenido sobre los aspectos cognitivos de los proveedores de servicios de VIH y las personas en riesgo de infección, revisiones y estudios de casos. Las barreras cognitivas y las intervenciones con respecto a los pacientes y proveedores incluyeron el conocimiento, las actitudes y las creencias sobre la PrEP. La “purview paradox” se identificó como una barrera clave: los especialistas en VIH a menudo no ven pacientes VIH negativos, mientras que los médicos de atención primaria, que a menudo ven pacientes no infectados, no están capacitados para proporcionar PrEP. Las barreras de los sistemas de salud incluyen la falta de comunicación, financiación y acceso a la PrEP. Se identificó la intersección entre el estigma de la PrEP, el estigma del VIH, la transfobia, la homofobia y las disparidades entre los grupos de género, raciales y étnicos; pero pocas intervenciones abordaron estas barreras. Recomendamos intervenciones multinivel dirigidas a las barreras en múltiples dominios socioecológicos. Working on a manuscript? Avoid the common mistakes Introduction In 2011–2012, the United States Centers for Disease Control and Prevention (CDC) launched the high-impact HIV prevention (HIP) approach to respond to research showing that antiretroviral therapy (ART) reduces HIV transmission by lowering viral load in the bloodstream [ 1 ]. In 2012, the use of ART emerged as the dominant strategy for HIV treatment and prevention [ 2 ]—research predicted reduction of sexual transmission in HIV-serodiscordant couples by more than 96% [ 3 ]. High-impact interventions—HIV testing, linkage to care, and HIV viral suppression with ART—constitute key steps of the HIV Continuum of Care, recommended by the World Health Organization [ 4 , 5 ]. HIP promotes HIV pre-exposure prophylaxis (PrEP). PrEP has been traditionally considered as once daily oral dosing of ART prescribed to individuals at risk for HIV infection. The Food and Drug Administration (FDA) approved Truvada™ [Emtricitabine/Tenofovir Disoproxil Fumarate (TDF/FTC)] in 2012 as a PrEP strategy that reduced the risk of HIV acquisition by 73% among adult men who have sex with men (MSM) and transgender women who took it 90% of the time [ 6 ]; with greater efficacy (up to 99%) for individuals with higher rates of adherence and increased concentrations among serodiscordant heterosexual couples [ 7 , 8 ]. Herein, the steps patients and providers must take to follow policies governing access to PrEP and to navigate healthcare systems will be referred to as “PrEP implementation.” PrEP implementation may appear to be an easy and effective way to stop HIV transmission; however, there are many challenges to accessing and adhering to PrEP, as reflected in low levels of PrEP uptake in the US [ 9 , 10 ]. Concern over rates of adherence and retention have been reported in PrEP care in clinical trials and “real world” PrEP demonstration projects [ 11 , 12 ]. Racial and gender disparities have also been identified, including disproportionately low PrEP uptake among Black MSM [ 13 ]. Research regarding low access, uptake, and adherence to PrEP in the US has focused mostly on breakdowns in the healthcare systems implementing PrEP, lack of provider awareness and willingness to prescribe PrEP [ 9 , 14 ], and unfavorable patient and community attitudes about PrEP [ 15 , 16 ]. Our aim therefore is to comprehensively review this literature, focusing on how barriers to PrEP uptake might affect both individual actors and healthcare systems. Barriers to PrEP implementation occur across gender, racial, and ethnic groups. Various interventions have been proposed to solve this public health problem, including those targeting different domains of prevention and care—patients, providers, and healthcare systems. Nonetheless, proposed interventions to improve PrEP implementation may vary across the fields of medicine, nursing, social work, public health, and the social sciences. Therefore, this review included papers in all these disciplines and sought to identify barriers to PrEP and the interventions available that specifically matched those barriers. We focused specifically on PrEP implementation in the US and on implementation issues faced by at-risk individuals and HIV service providers, the agency settings in which services are offered, and the policies that guide HIV service provision. “HIV service providers” in this context refer to counselors, educators, case managers and others who provide HIV testing, linkage to care, and other services, as well as HIV-care providers. Our review aims to improve HIV-prevention strategies nationwide by demonstrating how to confront identified barriers with interventions that might improve access, uptake, and adherence to PrEP. Methods Literature Review Conceptual Approach The extant literature consistently suggests that to improve PrEP implementation, key barriers need to be overcome and interventions need to be developed at all levels (clients/patients, HIP service providers, healthcare systems, and policy) [ 17 , 18 , 19 ]. Therefore, our review follows a socioecological perspective [ 20 ] suggesting that barriers to PrEP implementation fall within four domains. The Individual and", "role": "user" }, { "content": "Multiple barriers may stop high-risk individuals from accessing an HIV drug that can reduce the subsequent risk of infection, according to a new University of Michigan study. Researchers outlined solutions that would help overcome barriers that make it harder for underserved populations to access pre-exposure prophylaxis (PrEP). The Centers for Disease Control and Prevention reported that nearly 40,000 people—about 43 percent of whom were black or Latino gay and bisexual men—received an HIV diagnosis in 2016. The U-M study, published in the journal AIDS and Behavior, includes 47 peer-reviewed scholarly articles reporting data from HIV prevention and care providers, and from individuals at risk for infection. The researchers listed 31 potential solutions to 30 barriers to accessing PrEP at the patient, provider and health-system levels. One striking barrier to accessing PrEP is created by providers' biases toward those who most need the drug, says lead author Rogério Pinto, associate professor and associate dean for research at the U-M School of Social Work. For example, providers appear to believe that certain patients, such as transgender women and people of color, when given PrEP may be unable to consistently adhere to prescribed regimens or will stop using condoms to prevent HIV transmission. Pinto and colleagues say that perhaps even more concerning than provider-level biased attitudes is a structural barrier referred to as the \"purview paradox.\" On the one hand, infectious disease specialists are often trained to provide PrEP, but that they seldom actually see HIV-negative patients. On the other hand, primary care physicians, who care for mostly uninfected but sometimes at-risk patients, are seldom trained to provide PrEP. Other pervasive structural obstacles—such as homophobia, transphobia and racism across systems of care—may be helped by interventions to disrupt stereotypes about potential PrEP users. \"However, patient assistance in navigating the health care system—including accessing health insurance and co-pay assistance—is a sorely needed intervention,\" Pinto said. Some of the barriers and recommended interventions include: To combat bias against a patient's race or sexual behaviors: Develop and deliver training to increase the provider's \"cultural competency,\" including trans- and gender-affirming care. In response to limited health budgets to sustain PrEP programs: Advocate among those in the medical field for expanded health insurance. In response to legal constraints to providing PrEP for youth: Expand education, screening and referrals to PrEP services, and find improved methods to identify appropriate PrEP candidates. The researchers note, however, that some interventions have had mixed results, in part due to not being aligned to specific barriers. Many barriers, such as interventions to lessen providers' biases and breakdowns in the health system, often target the behavior of individual patients instead of targeting providers and health systems, they say. \"The key message from this review is that barriers to PrEP implementation cut across patient, provider and health-system levels, and that multiple interventions, mapped onto specific barriers, ought to be used,\" Pinto said. In addition, he says that without attention to the ways structural factors affect individuals within health care systems, PrEP implementation \"may actually reinforce existing inequities that place the overwhelming burden of the HIV epidemic on more vulnerable groups.\" ", "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 are many challenges to accessing PrEP and thus low uptake in the United States. This review (2007–2017) of PrEP implementation identified barriers to PrEP and interventions to match those barriers. The final set of articles (n = 47) included content on cognitive aspects of HIV service providers and individuals at risk for infection, reviews, and case studies. Cognitive barriers and interventions regarding patients and providers included knowledge, attitudes, and beliefs about PrEP. The “purview paradox” was identified as a key barrier—HIV specialists often do not see HIV-negative patients, while primary care physicians, who often see uninfected patients, are not trained to provide PrEP. Healthcare systems barriers included lack of communication about, funding for, and access to PrEP. The intersection between PrEP-stigma, HIV-stigma, transphobia, homophobia, and disparities across gender, racial, and ethnic groups were identified; but few interventions addressed these barriers. We recommend multilevel interventions targeting barriers at multiple socioecological domains. Resumen Existen muchos desafíos para acceder a PrEP y, por lo tanto, poca aceptación en los Estados Unidos. Esta revisión (2007-17) de la implementación de PrEP identificó las barreras a la PrEP y las intervenciones para hacer coincidir esas barreras. El conjunto final de artículos (n = 47) incluyó contenido sobre los aspectos cognitivos de los proveedores de servicios de VIH y las personas en riesgo de infección, revisiones y estudios de casos. Las barreras cognitivas y las intervenciones con respecto a los pacientes y proveedores incluyeron el conocimiento, las actitudes y las creencias sobre la PrEP. La “purview paradox” se identificó como una barrera clave: los especialistas en VIH a menudo no ven pacientes VIH negativos, mientras que los médicos de atención primaria, que a menudo ven pacientes no infectados, no están capacitados para proporcionar PrEP. Las barreras de los sistemas de salud incluyen la falta de comunicación, financiación y acceso a la PrEP. Se identificó la intersección entre el estigma de la PrEP, el estigma del VIH, la transfobia, la homofobia y las disparidades entre los grupos de género, raciales y étnicos; pero pocas intervenciones abordaron estas barreras. Recomendamos intervenciones multinivel dirigidas a las barreras en múltiples dominios socioecológicos. Working on a manuscript? Avoid the common mistakes Introduction In 2011–2012, the United States Centers for Disease Control and Prevention (CDC) launched the high-impact HIV prevention (HIP) approach to respond to research showing that antiretroviral therapy (ART) reduces HIV transmission by lowering viral load in the bloodstream [ 1 ]. In 2012, the use of ART emerged as the dominant strategy for HIV treatment and prevention [ 2 ]—research predicted reduction of sexual transmission in HIV-serodiscordant couples by more than 96% [ 3 ]. High-impact interventions—HIV testing, linkage to care, and HIV viral suppression with ART—constitute key steps of the HIV Continuum of Care, recommended by the World Health Organization [ 4 , 5 ]. HIP promotes HIV pre-exposure prophylaxis (PrEP). PrEP has been traditionally considered as once daily oral dosing of ART prescribed to individuals at risk for HIV infection. The Food and Drug Administration (FDA) approved Truvada™ [Emtricitabine/Tenofovir Disoproxil Fumarate (TDF/FTC)] in 2012 as a PrEP strategy that reduced the risk of HIV acquisition by 73% among adult men who have sex with men (MSM) and transgender women who took it 90% of the time [ 6 ]; with greater efficacy (up to 99%) for individuals with higher rates of adherence and increased concentrations among serodiscordant heterosexual couples [ 7 , 8 ]. Herein, the steps patients and providers must take to follow policies governing access to PrEP and to navigate healthcare systems will be referred to as “PrEP implementation.” PrEP implementation may appear to be an easy and effective way to stop HIV transmission; however, there are many challenges to accessing and adhering to PrEP, as reflected in low levels of PrEP uptake in the US [ 9 , 10 ]. Concern over rates of adherence and retention have been reported in PrEP care in clinical trials and “real world” PrEP demonstration projects [ 11 , 12 ]. Racial and gender disparities have also been identified, including disproportionately low PrEP uptake among Black MSM [ 13 ]. Research regarding low access, uptake, and adherence to PrEP in the US has focused mostly on breakdowns in the healthcare systems implementing PrEP, lack of provider awareness and willingness to prescribe PrEP [ 9 , 14 ], and unfavorable patient and community attitudes about PrEP [ 15 , 16 ]. Our aim therefore is to comprehensively review this literature, focusing on how barriers to PrEP uptake might affect both individual actors and healthcare systems. Barriers to PrEP implementation occur across gender, racial, and ethnic groups. Various interventions have been proposed to solve this public health problem, including those targeting different domains of prevention and care—patients, providers, and healthcare systems. Nonetheless, proposed interventions to improve PrEP implementation may vary across the fields of medicine, nursing, social work, public health, and the social sciences. Therefore, this review included papers in all these disciplines and sought to identify barriers to PrEP and the interventions available that specifically matched those barriers. We focused specifically on PrEP implementation in the US and on implementation issues faced by at-risk individuals and HIV service providers, the agency settings in which services are offered, and the policies that guide HIV service provision. “HIV service providers” in this context refer to counselors, educators, case managers and others who provide HIV testing, linkage to care, and other services, as well as HIV-care providers. Our review aims to improve HIV-prevention strategies nationwide by demonstrating how to confront identified barriers with interventions that might improve access, uptake, and adherence to PrEP. Methods Literature Review Conceptual Approach The extant literature consistently suggests that to improve PrEP implementation, key barriers need to be overcome and interventions need to be developed at all levels (clients/patients, HIP service providers, healthcare systems, and policy) [ 17 , 18 , 19 ]. Therefore, our review follows a socioecological perspective [ 20 ] suggesting that barriers to PrEP implementation fall within four domains. The Individual and<|im_end|> <|im_start|>assistant Multiple barriers may stop high-risk individuals from accessing an HIV drug that can reduce the subsequent risk of infection, according to a new University of Michigan study. Researchers outlined solutions that would help overcome barriers that make it harder for underserved populations to access pre-exposure prophylaxis (PrEP). The Centers for Disease Control and Prevention reported that nearly 40,000 people—about 43 percent of whom were black or Latino gay and bisexual men—received an HIV diagnosis in 2016. The U-M study, published in the journal AIDS and Behavior, includes 47 peer-reviewed scholarly articles reporting data from HIV prevention and care providers, and from individuals at risk for infection. The researchers listed 31 potential solutions to 30 barriers to accessing PrEP at the patient, provider and health-system levels. One striking barrier to accessing PrEP is created by providers' biases toward those who most need the drug, says lead author Rogério Pinto, associate professor and associate dean for research at the U-M School of Social Work. For example, providers appear to believe that certain patients, such as transgender women and people of color, when given PrEP may be unable to consistently adhere to prescribed regimens or will stop using condoms to prevent HIV transmission. Pinto and colleagues say that perhaps even more concerning than provider-level biased attitudes is a structural barrier referred to as the "purview paradox." On the one hand, infectious disease specialists are often trained to provide PrEP, but that they seldom actually see HIV-negative patients. On the other hand, primary care physicians, who care for mostly uninfected but sometimes at-risk patients, are seldom trained to provide PrEP. Other pervasive structural obstacles—such as homophobia, transphobia and racism across systems of care—may be helped by interventions to disrupt stereotypes about potential PrEP users. "However, patient assistance in navigating the health care system—including accessing health insurance and co-pay assistance—is a sorely needed intervention," Pinto said. Some of the barriers and recommended interventions include: To combat bias against a patient's race or sexual behaviors: Develop and deliver training to increase the provider's "cultural competency," including trans- and gender-affirming care. In response to limited health budgets to sustain PrEP programs: Advocate among those in the medical field for expanded health insurance. In response to legal constraints to providing PrEP for youth: Expand education, screening and referrals to PrEP services, and find improved methods to identify appropriate PrEP candidates. The researchers note, however, that some interventions have had mixed results, in part due to not being aligned to specific barriers. Many barriers, such as interventions to lessen providers' biases and breakdowns in the health system, often target the behavior of individual patients instead of targeting providers and health systems, they say. "The key message from this review is that barriers to PrEP implementation cut across patient, provider and health-system levels, and that multiple interventions, mapped onto specific barriers, ought to be used," Pinto said. In addition, he says that without attention to the ways structural factors affect individuals within health care systems, PrEP implementation "may actually reinforce existing inequities that place the overwhelming burden of the HIV epidemic on more vulnerable groups." <|im_end|>

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2,095

[ { "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 major goal of biomedicine is to understand the function of every gene in the human genome 1 . Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such ‘human knockouts’ can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high 2 . Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia 3 . We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (<1% minor allele frequency) pLoF mutations. These pLoF mutations are estimated to knock out 1,317 genes, each in at least one participant. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1 , with higher plasma interleukin-8 concentrations; at TREH , with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4 , with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1 , with mediators of calcium and phosphate signalling. Heterozygous deficiency of APOC3 has been shown to protect against coronary heart disease 4 , 5 ; we identified APOC3 homozygous pLoF carriers in our cohort. We recruited these human knockouts and challenged them with an oral fat load. Compared with family members lacking the mutation, individuals with APOC3 knocked out displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a ‘human knockout project’, a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans. Main Across all participants ( Table 1 ), exome sequencing yielded 1,639,223 exonic and splice-site sequence variants in 19,026 autosomal genes that passed initial quality control metrics. Of these, 57,137 mutations across 14,345 autosomal genes were annotated as pLoF mutations (that is, nonsense, frameshift, or canonical splice-site mutations predicted to inactivate a gene). To increase the probability that mutations are correctly annotated as pLoF by automated algorithms, we removed nonsense and frameshift mutations occurring within the last 5% of the transcript and within exons flanked by non-canonical splice sites, splice-site mutations at small (<15 bp) introns, at non-canonical splice sites, and where the purported pLoF allele is observed across primates. Common pLoF alleles are less likely to exert strong functional effects as they are less constrained by purifying selection; thus, we define pLoF mutations in the rest of the manuscript as variants with a minor allele frequency (MAF) of <1% and passing the aforementioned bioinformatic filters. Applying these criteria, we generated a set of 49,138 pLoF mutations across 13,074 autosomal genes. The site-frequency spectrum for these pLoF mutations revealed that the majority was seen only in one or a few individuals ( Extended Data Fig. 1 ). Table 1 Baseline characteristics of exome sequenced study participants Full size table Across all 10,503 PROMIS participants, both copies of 1,317 distinct genes were predicted to be inactivated owing to pLoF mutations. A full listing of all 1,317 genes knocked out, the number of knockout participants for each gene, and the specific pLoF mutation(s) are provided in Supplementary Table 1 . 891 (67.7%) of the genes were knocked out only in one participant ( Fig. 1a ). Nearly 1 in 5 of the participants that were sequenced (1,843 individuals, 17.5%) had at least one gene knocked out by a homozygous pLoF mutation. 1,504 of these 1,843 individuals (81.6%) were homozygous pLoF carriers for just one gene, but the minority of participants had more than one gene knocked out and one participant had six genes with homozygous pLoF genotypes. Figure 1: Homozygous pLoF burden in PROMIS is driven by excess autozygosity. a , Most genes are observed in the homozygous pLoF state in only single individuals. b , The distribution of F inbreeding coefficient of PROMIS participants is compared to those of outbred samples of African (AFR) and European (EUR) ancestry. c , The burden of homozygous pLoF genes per individual is correlated with coefficient of inbreeding. Bars represent 1.5× interquartile range beyond the 25th and 75th percentiles ( b , c ). PowerPoint slide Full size image We compared the coefficient of inbreeding ( F coefficient) in PROMIS participants with that of 15,249 individuals from outbred populations of European or African American ancestry. The F coefficient estimates the excess homozygosity compared with an outbred ancestor. PROMIS participants had a fourfold higher median inbreeding coefficient compared to outbred populations (0.016 versus 0.0041; P < 2 × 10 −16 ) ( Fig. 1b ). Additionally, those in PROMIS who reported that their parents were closely related had even higher median inbreeding coefficients than those who did not (0.023 versus 0.013; P < 2 × 10 −16 ). The F inbreeding coefficient was correlated with the number of homozygous pLoF genes present in each individual (Spearman’s r = 0.31; P = 5 × 10 −231 ) ( Fig. 1c ). When restricted to individuals with high levels of inbreeding ( F inbreeding coefficient >6.25%, the expected degree of autozygosity from a first-cousin union), 721 of 1,585 individuals (45%) were homozygous for at least one pLoF mutation. We compared our results to three recent reports in which homozygous pLoF genes have been catalogued: in Pakistanis living in Britain 6 , in Icelanders 7 , and in the Exome Aggregation Consortium (ExAC) 8 . In the PROMIS study, we identify a total of 734 unique genes with homozygous pLoF mutations that were not observed in the other three studies ( Extended Data Fig. 2 ). Intersection of the four sets of genes from these studies revealed only 25 common to all four studies. To understand the phenotypic consequences of complete disruption of the 1,317 pLoF genes identified in the PROMIS study, we applied three approaches. First, for 426 genes at which two or", "role": "user" }, { "content": "More than 1,800 individuals carrying loss-of-function mutations in both copies of their genes, so-called \"human knockouts,\" are described in the first major study to be published in Nature this week by an international collaboration led by the Perelman School of Medicine at the University of Pennsylvania and colleagues. The program, which has so far sequenced the protein-coding regions of over 10,500 adults living in Pakistan, is illuminating the basic biology and possible therapeutics for several different disorders. The team has identified more than 1,300 genes completely knocked out in at least one individual. They first turned their attention for deeper analysis to genes involved in cardiovascular and metabolic diseases. One gene in particular, APOC3, which regulates the metabolism of triglyceride-rich lipoproteins in the blood, was missing in several dozen individuals in a small fishing village on the coast of Pakistan where first-cousin marriages are culturally prevalent. These APOC3-knockout individuals had very low triglyceride levels. The researchers challenged their system with a high-fat meal. Compared with family members who were not APOC3 knockouts, the APOC3 knockout family members did not have the usual post-meal rise in plasma triglycerides. \"These are the world's first APOC3 human knockouts that have been identified,\" said co-first author and the principal investigator of the study, Danish Saleheen, MD, PhD, an assistant professor of Epidemiology and Biostatistics at Penn. \"Their genetic makeup has provided unique insights about the biology of APOC3, which may further help in validating APOC3 inhibition as a therapeutic target for cardiometabolic diseases - the leading cause of death globally. In addition to Penn, the team includes scientists from the Center for Non-Communicable Diseases (CNCD) in Karachi, Pakistan, the Broad Institute of MIT and Harvard, and the University of Cambridge, UK. Saleheen has been working for over a decade in Pakistan, in collaboration with the CNCD to collect blood samples from all over his country. This Pakistan-based study already includes more than 70,000 participants and the recruitment is rapidly being expanded to include 200,000 people. \"We are continuing protein-coding region sequencing studies in the Pakistani population. If we are able to sequence 200,000 participants, we will be able to identify human knockouts for more than 8,000 unique genes.\" Saleheen said. \"These observations provide us with a roadmap, a systematic way to understand the physiological consequences of complete disruption of genes in humans,\" Saleheen said. \"The Human Genome Project gave us a 'parts' list of 18,000 genes. We are now trying to understand gene function by studying people who naturally lack a 'part,'\" said co-senior author Sekar Kathiresan, Director of the Center for Genomic Medicine at Massachusetts General Hospital. \"We think that over the next ten to twenty years, with a concerted, systematic effort, it's possible to find humans who naturally lack any one of several thousand genes in the genome and understand what the phenotypic consequences are.\" \"The project highlights the value of looking at diverse populations, particularly for genetic analyses—you'll find variants in one ethnicity and not another,\" said co-first author Pradeep Natarajan, an associate scientist at Broad Institute and a postdoctoral research fellow in Kathiresan's lab. Co-senior author Daniel J. Rader, MD, chair of Genetics at Penn, hopes that future dives into this rich dataset will bring even more novel insights into human biology and point toward new therapeutic targets for treating and preventing disease. \"Linking DNA sequencing with deep phenotyping at scale in this population will be an incredible source of new knowledge about how gene alterations influence human health and disease,\" Rader said. In addition to a continued focus on the biology of heart attacks, type 2 diabetes, and stroke, the team will also be looking for clues for early-onset Parkinson's disease, autism, congenital blindness, and mental retardation, among many other conditions. Penn scientists are now collaborating with CNCD researchers to conduct deep phenotyping studies in all human knockouts the project identifies. These studies will include detailed physiological and mechanistic studies to understand the biological and pharmacological consequences of both partial and complete disruption of genes in humans. ", "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 major goal of biomedicine is to understand the function of every gene in the human genome 1 . Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such ‘human knockouts’ can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high 2 . Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia 3 . We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (<1% minor allele frequency) pLoF mutations. These pLoF mutations are estimated to knock out 1,317 genes, each in at least one participant. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1 , with higher plasma interleukin-8 concentrations; at TREH , with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4 , with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1 , with mediators of calcium and phosphate signalling. Heterozygous deficiency of APOC3 has been shown to protect against coronary heart disease 4 , 5 ; we identified APOC3 homozygous pLoF carriers in our cohort. We recruited these human knockouts and challenged them with an oral fat load. Compared with family members lacking the mutation, individuals with APOC3 knocked out displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a ‘human knockout project’, a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans. Main Across all participants ( Table 1 ), exome sequencing yielded 1,639,223 exonic and splice-site sequence variants in 19,026 autosomal genes that passed initial quality control metrics. Of these, 57,137 mutations across 14,345 autosomal genes were annotated as pLoF mutations (that is, nonsense, frameshift, or canonical splice-site mutations predicted to inactivate a gene). To increase the probability that mutations are correctly annotated as pLoF by automated algorithms, we removed nonsense and frameshift mutations occurring within the last 5% of the transcript and within exons flanked by non-canonical splice sites, splice-site mutations at small (<15 bp) introns, at non-canonical splice sites, and where the purported pLoF allele is observed across primates. Common pLoF alleles are less likely to exert strong functional effects as they are less constrained by purifying selection; thus, we define pLoF mutations in the rest of the manuscript as variants with a minor allele frequency (MAF) of <1% and passing the aforementioned bioinformatic filters. Applying these criteria, we generated a set of 49,138 pLoF mutations across 13,074 autosomal genes. The site-frequency spectrum for these pLoF mutations revealed that the majority was seen only in one or a few individuals ( Extended Data Fig. 1 ). Table 1 Baseline characteristics of exome sequenced study participants Full size table Across all 10,503 PROMIS participants, both copies of 1,317 distinct genes were predicted to be inactivated owing to pLoF mutations. A full listing of all 1,317 genes knocked out, the number of knockout participants for each gene, and the specific pLoF mutation(s) are provided in Supplementary Table 1 . 891 (67.7%) of the genes were knocked out only in one participant ( Fig. 1a ). Nearly 1 in 5 of the participants that were sequenced (1,843 individuals, 17.5%) had at least one gene knocked out by a homozygous pLoF mutation. 1,504 of these 1,843 individuals (81.6%) were homozygous pLoF carriers for just one gene, but the minority of participants had more than one gene knocked out and one participant had six genes with homozygous pLoF genotypes. Figure 1: Homozygous pLoF burden in PROMIS is driven by excess autozygosity. a , Most genes are observed in the homozygous pLoF state in only single individuals. b , The distribution of F inbreeding coefficient of PROMIS participants is compared to those of outbred samples of African (AFR) and European (EUR) ancestry. c , The burden of homozygous pLoF genes per individual is correlated with coefficient of inbreeding. Bars represent 1.5× interquartile range beyond the 25th and 75th percentiles ( b , c ). PowerPoint slide Full size image We compared the coefficient of inbreeding ( F coefficient) in PROMIS participants with that of 15,249 individuals from outbred populations of European or African American ancestry. The F coefficient estimates the excess homozygosity compared with an outbred ancestor. PROMIS participants had a fourfold higher median inbreeding coefficient compared to outbred populations (0.016 versus 0.0041; P < 2 × 10 −16 ) ( Fig. 1b ). Additionally, those in PROMIS who reported that their parents were closely related had even higher median inbreeding coefficients than those who did not (0.023 versus 0.013; P < 2 × 10 −16 ). The F inbreeding coefficient was correlated with the number of homozygous pLoF genes present in each individual (Spearman’s r = 0.31; P = 5 × 10 −231 ) ( Fig. 1c ). When restricted to individuals with high levels of inbreeding ( F inbreeding coefficient >6.25%, the expected degree of autozygosity from a first-cousin union), 721 of 1,585 individuals (45%) were homozygous for at least one pLoF mutation. We compared our results to three recent reports in which homozygous pLoF genes have been catalogued: in Pakistanis living in Britain 6 , in Icelanders 7 , and in the Exome Aggregation Consortium (ExAC) 8 . In the PROMIS study, we identify a total of 734 unique genes with homozygous pLoF mutations that were not observed in the other three studies ( Extended Data Fig. 2 ). Intersection of the four sets of genes from these studies revealed only 25 common to all four studies. To understand the phenotypic consequences of complete disruption of the 1,317 pLoF genes identified in the PROMIS study, we applied three approaches. First, for 426 genes at which two or<|im_end|> <|im_start|>assistant More than 1,800 individuals carrying loss-of-function mutations in both copies of their genes, so-called "human knockouts," are described in the first major study to be published in Nature this week by an international collaboration led by the Perelman School of Medicine at the University of Pennsylvania and colleagues. The program, which has so far sequenced the protein-coding regions of over 10,500 adults living in Pakistan, is illuminating the basic biology and possible therapeutics for several different disorders. The team has identified more than 1,300 genes completely knocked out in at least one individual. They first turned their attention for deeper analysis to genes involved in cardiovascular and metabolic diseases. One gene in particular, APOC3, which regulates the metabolism of triglyceride-rich lipoproteins in the blood, was missing in several dozen individuals in a small fishing village on the coast of Pakistan where first-cousin marriages are culturally prevalent. These APOC3-knockout individuals had very low triglyceride levels. The researchers challenged their system with a high-fat meal. Compared with family members who were not APOC3 knockouts, the APOC3 knockout family members did not have the usual post-meal rise in plasma triglycerides. "These are the world's first APOC3 human knockouts that have been identified," said co-first author and the principal investigator of the study, Danish Saleheen, MD, PhD, an assistant professor of Epidemiology and Biostatistics at Penn. "Their genetic makeup has provided unique insights about the biology of APOC3, which may further help in validating APOC3 inhibition as a therapeutic target for cardiometabolic diseases - the leading cause of death globally. In addition to Penn, the team includes scientists from the Center for Non-Communicable Diseases (CNCD) in Karachi, Pakistan, the Broad Institute of MIT and Harvard, and the University of Cambridge, UK. Saleheen has been working for over a decade in Pakistan, in collaboration with the CNCD to collect blood samples from all over his country. This Pakistan-based study already includes more than 70,000 participants and the recruitment is rapidly being expanded to include 200,000 people. "We are continuing protein-coding region sequencing studies in the Pakistani population. If we are able to sequence 200,000 participants, we will be able to identify human knockouts for more than 8,000 unique genes." Saleheen said. "These observations provide us with a roadmap, a systematic way to understand the physiological consequences of complete disruption of genes in humans," Saleheen said. "The Human Genome Project gave us a 'parts' list of 18,000 genes. We are now trying to understand gene function by studying people who naturally lack a 'part,'" said co-senior author Sekar Kathiresan, Director of the Center for Genomic Medicine at Massachusetts General Hospital. "We think that over the next ten to twenty years, with a concerted, systematic effort, it's possible to find humans who naturally lack any one of several thousand genes in the genome and understand what the phenotypic consequences are." "The project highlights the value of looking at diverse populations, particularly for genetic analyses—you'll find variants in one ethnicity and not another," said co-first author Pradeep Natarajan, an associate scientist at Broad Institute and a postdoctoral research fellow in Kathiresan's lab. Co-senior author Daniel J. Rader, MD, chair of Genetics at Penn, hopes that future dives into this rich dataset will bring even more novel insights into human biology and point toward new therapeutic targets for treating and preventing disease. "Linking DNA sequencing with deep phenotyping at scale in this population will be an incredible source of new knowledge about how gene alterations influence human health and disease," Rader said. In addition to a continued focus on the biology of heart attacks, type 2 diabetes, and stroke, the team will also be looking for clues for early-onset Parkinson's disease, autism, congenital blindness, and mental retardation, among many other conditions. Penn scientists are now collaborating with CNCD researchers to conduct deep phenotyping studies in all human knockouts the project identifies. These studies will include detailed physiological and mechanistic studies to understand the biological and pharmacological consequences of both partial and complete disruption of genes in humans. <|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 Opuntia stricta (Haw.) Haw (Cactaceae) is invasive in Laikipia County, Kenya, impacting negatively on biodiversity and livelihoods. To control this invasive plant the biocontrol agent Dactylopius opuntiae (Cockerell) (Hemiptera; Dactylopiidae) ‘stricta’ biotype was released in 2014. A preliminary once-off survey to determine the impact of the cochineal revealed that it had contributed to a significant reduction in the number of cladodes, flowers and fruit of plants with cochineal. Fruits that were produced on plants with the cochineal were also smaller and had fewer seeds. Although still preliminary, an analysis of the costs of implementing this biocontrol programme indicates that it is the most cost-effective management intervention compared to physical and/or chemical control. Although the impact of the cochineal is still fairly localized we are confident that it will establish in much of the invaded range and reduce the impacts of the invasive cactus, consequently improving rangeland condition and livelihoods. Working on a manuscript? Avoid the common mistakes Introduction A large number of cactus species have been introduced to countries around the world as ornamentals (250) or for food and fodder production (45) (Novoa et al. 2015 ). About 20% (57) of those species that have been introduced outside of their native range have become invasive, impacting negatively on biodiversity, livestock production, and rural communities dependent on these resources (Ueckert et al. 1990 ; Beinart 2003 ; Larsson 2004 ; Novoa et al. 2017 , 2019 ; Shackleton et al. 2017 ). South Africa has the highest number of invasive cactus species (35), followed by Australia (26), and Spain (24) (Novoa et al. 2015 ). However, the tropics are not immune to invasions with Opuntia stricta (Haw.) Haw, O. engelmannii Salm-Dyck ex Engelm., O. ficus-indica (L.) Mill., O. monacantha Haw., O. elatior Mill., O. cochenellifera (L.) Mill., Austrocylindropuntia subulata (Muelenpf.) Backeb., Cereus jamacaru DC. and Pereskia aculeata Mill. having been recorded as invasive in Kenya, while other species such as O. microdasys (Lehm.) Pfeiff., Penioecereus serpentinus (Lag. & Rodr.) N.P. Taylor, and Cylindropuntia imbricata (Haw.) F.M. Knuth are present but have not yet escaped cultivation as in other parts of the world (Witt and Luke 2017 ; Witt et al. 2018 ). Of the invasive species present in Kenya O. stricta is considered to be the most widespread and problematic (Witt et al. 2018 ). Introduced to Kenya in 1949 it is most abundant in Laikipia County and Tsavo East National Park, and the adjacent rangelands, where it forms dense stands, preventing access to homes, water resources and pasture (Witt and Luke 2017 ; Witt et al. 2018 ). All of the respondents in a socio-economic survey in Laikipia felt that it contributed to the ill-health and death of livestock (Shackleton et al. 2017 ). Other negative impacts included reductions in native plant populations, rangeland condition, human health, and access to pasture and water resources (Shackleton et al. 2017 ). These negative impacts resulted in economic losses of US$ 500–1000 per household per year for 48% of households (Shackleton et al. 2017 ). Communities in Madagascar reported that O. stricta grew fast, invading land used for crop and pasture production, and encroached on villages and roads (Larsson 2004 ). It was also considered to be useless as a fodder plant and the fruits were regarded as distasteful (Larsson 2004 ). According to villagers, livestock avoided O. stricta , but would eat the cladodes during dry periods, often resulting in animal deaths (Larsson 2004 ). People who consumed the fruit developed diarrhoea, and the glochids on the fruit caused serious infections. The cactus also had a negative impact on native grasses and herbaceous plants, and even impacted trees by inhibiting their growth and regeneration (Larsson 2004 ). Physical and chemical control of cacti is expensive and often ineffective (Novoa et al. 2019 ). The most cost-effective, sustainable and environmentally friendly control option for invasive alien cactus species is biological control (Paterson et al. 2011 ; Zachariades et al. 2017 ; Novoa et al. 2019 ). For example, the cactus biocontrol programme in Australia is estimated to have cost AU$21.1 million resulting in a nett present value of AU$3.1 billion, which is considered to be an underestimate of the total benefits (Page and Lacey 2006 ). In fact, the biological control programme against O. stricta in Australia is considered to be one of the most successful weed control programmes in the world, reducing invasions of O. stricta from an estimated 24 million ha to just a few scattered plants, providing permanent and complete control (Raghu and Walton 2007 ). South Africa can claim similar successes with the benefit: cost ratio of the biocontrol programme against Opuntia aurantiaca Lindl. estimated to be 1154:1 (van Wilgen et al. 2004 ). In South Africa seven cactus species are considered to be under substantial biological control and eight species are considered to be under complete control (Zachariades 2018 ). Most of these successes can be attributed to various cochineal species ( Dactylopius spp.). There are nine known Dactylopius species in the monogeneric, homopteran family, the Dactylopiidae, all of which feed only on cactaceous plants and almost exclusively on the genus Opuntia (Mann 1969 ; De Lotto 1974 ). The co-evolution of Opuntia- feeding insects and their cactus hosts has resulted in the development of specialist insects to the exclusion of nearly all generalist phytophagous insects (see Moran 1980 ). This prolonged evolutionary relationship between the cochineal insects and cactus makes them especially safe insects to use in biological control programmes (Moran and Zimmermann 1984 ). It is widely known that there are a number of different biotypes within the species D. opuntiae , with each biotype being adapted to feed on a particular cactus species (Volchansky et al. 1999 ). In South Africa six cochineal species or biotypes have been released for the control of 11 cactus species, all resulting in substantial or complete control with no recorded or known non-target impacts (Zachariades 2018 ). Six cochineal species or biotypes have been released in Australia (Winston", "role": "user" }, { "content": "The cochineal Dactylopius opuntiae 'stricta' biotype is more effective as a sustainable biocontrol in the fight against the invasive common pest pear Opuntia stricta in Laikipia County, Kenya, compared to physical and/or chemical control—CABI scientists can now reveal. Dr. Arne Witt, based at CABI's center in Nairobi, led on research published in BioControl which shows that the D. opuntiae 'stricta' biotype—that was released in 2014—has contributed to a 'significant reduction' in the number of cladodes, flowers and fruit of plants with cochineal. Following a preliminary once-off survey, Dr. Witt and collaborators Winnie Nunda, Fernadis Makale and Kathryn Reynolds, demonstrated that fruits that were produced on plants with the cochineal were also smaller and had fewer seeds. Dr. Witt said, \"Although still preliminary, an analysis of the costs of implementing the D. opuntiae 'stricta' biotype indicate that it is the most cost-effective management intervention compared to physical and/or chemical control. \"Furthermore, while the impact of the cochineal is still fairly localized, we are confident that it will establish in much of the invaded range and reduce the impacts of the invasive cactus, consequently improving rangeland condition and livelihoods.\" Since its introduction to Kenya in 1949, O. stricta is considered to be the most widespread and problematic cactus species—being most abundant in Laikipia County and Tsavo East National Park and adjacent rangelands where it forms dense stands and prevents access to homes, water resources and pasture. \"It is still too early to confirm if the agent D. opuntiae 'stricta' biotype will contribute to the complete control of O. stricta in Laikipia,\" Dr. Witt added. \"However, early indications do warrant the re-distribution of the agent to Tsavo East NP and the Serengeti-Mara ecosystem, which has some significant invasions.\" Dr. Witt also revealed that a biotype of O. stricta for the control of Opuntia engelmannii has also been sourced in the U.S. and will 'hopefully be released' in Laikipia when approval has been granted from the regulatory authorities. ", "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 Opuntia stricta (Haw.) Haw (Cactaceae) is invasive in Laikipia County, Kenya, impacting negatively on biodiversity and livelihoods. To control this invasive plant the biocontrol agent Dactylopius opuntiae (Cockerell) (Hemiptera; Dactylopiidae) ‘stricta’ biotype was released in 2014. A preliminary once-off survey to determine the impact of the cochineal revealed that it had contributed to a significant reduction in the number of cladodes, flowers and fruit of plants with cochineal. Fruits that were produced on plants with the cochineal were also smaller and had fewer seeds. Although still preliminary, an analysis of the costs of implementing this biocontrol programme indicates that it is the most cost-effective management intervention compared to physical and/or chemical control. Although the impact of the cochineal is still fairly localized we are confident that it will establish in much of the invaded range and reduce the impacts of the invasive cactus, consequently improving rangeland condition and livelihoods. Working on a manuscript? Avoid the common mistakes Introduction A large number of cactus species have been introduced to countries around the world as ornamentals (250) or for food and fodder production (45) (Novoa et al. 2015 ). About 20% (57) of those species that have been introduced outside of their native range have become invasive, impacting negatively on biodiversity, livestock production, and rural communities dependent on these resources (Ueckert et al. 1990 ; Beinart 2003 ; Larsson 2004 ; Novoa et al. 2017 , 2019 ; Shackleton et al. 2017 ). South Africa has the highest number of invasive cactus species (35), followed by Australia (26), and Spain (24) (Novoa et al. 2015 ). However, the tropics are not immune to invasions with Opuntia stricta (Haw.) Haw, O. engelmannii Salm-Dyck ex Engelm., O. ficus-indica (L.) Mill., O. monacantha Haw., O. elatior Mill., O. cochenellifera (L.) Mill., Austrocylindropuntia subulata (Muelenpf.) Backeb., Cereus jamacaru DC. and Pereskia aculeata Mill. having been recorded as invasive in Kenya, while other species such as O. microdasys (Lehm.) Pfeiff., Penioecereus serpentinus (Lag. & Rodr.) N.P. Taylor, and Cylindropuntia imbricata (Haw.) F.M. Knuth are present but have not yet escaped cultivation as in other parts of the world (Witt and Luke 2017 ; Witt et al. 2018 ). Of the invasive species present in Kenya O. stricta is considered to be the most widespread and problematic (Witt et al. 2018 ). Introduced to Kenya in 1949 it is most abundant in Laikipia County and Tsavo East National Park, and the adjacent rangelands, where it forms dense stands, preventing access to homes, water resources and pasture (Witt and Luke 2017 ; Witt et al. 2018 ). All of the respondents in a socio-economic survey in Laikipia felt that it contributed to the ill-health and death of livestock (Shackleton et al. 2017 ). Other negative impacts included reductions in native plant populations, rangeland condition, human health, and access to pasture and water resources (Shackleton et al. 2017 ). These negative impacts resulted in economic losses of US$ 500–1000 per household per year for 48% of households (Shackleton et al. 2017 ). Communities in Madagascar reported that O. stricta grew fast, invading land used for crop and pasture production, and encroached on villages and roads (Larsson 2004 ). It was also considered to be useless as a fodder plant and the fruits were regarded as distasteful (Larsson 2004 ). According to villagers, livestock avoided O. stricta , but would eat the cladodes during dry periods, often resulting in animal deaths (Larsson 2004 ). People who consumed the fruit developed diarrhoea, and the glochids on the fruit caused serious infections. The cactus also had a negative impact on native grasses and herbaceous plants, and even impacted trees by inhibiting their growth and regeneration (Larsson 2004 ). Physical and chemical control of cacti is expensive and often ineffective (Novoa et al. 2019 ). The most cost-effective, sustainable and environmentally friendly control option for invasive alien cactus species is biological control (Paterson et al. 2011 ; Zachariades et al. 2017 ; Novoa et al. 2019 ). For example, the cactus biocontrol programme in Australia is estimated to have cost AU$21.1 million resulting in a nett present value of AU$3.1 billion, which is considered to be an underestimate of the total benefits (Page and Lacey 2006 ). In fact, the biological control programme against O. stricta in Australia is considered to be one of the most successful weed control programmes in the world, reducing invasions of O. stricta from an estimated 24 million ha to just a few scattered plants, providing permanent and complete control (Raghu and Walton 2007 ). South Africa can claim similar successes with the benefit: cost ratio of the biocontrol programme against Opuntia aurantiaca Lindl. estimated to be 1154:1 (van Wilgen et al. 2004 ). In South Africa seven cactus species are considered to be under substantial biological control and eight species are considered to be under complete control (Zachariades 2018 ). Most of these successes can be attributed to various cochineal species ( Dactylopius spp.). There are nine known Dactylopius species in the monogeneric, homopteran family, the Dactylopiidae, all of which feed only on cactaceous plants and almost exclusively on the genus Opuntia (Mann 1969 ; De Lotto 1974 ). The co-evolution of Opuntia- feeding insects and their cactus hosts has resulted in the development of specialist insects to the exclusion of nearly all generalist phytophagous insects (see Moran 1980 ). This prolonged evolutionary relationship between the cochineal insects and cactus makes them especially safe insects to use in biological control programmes (Moran and Zimmermann 1984 ). It is widely known that there are a number of different biotypes within the species D. opuntiae , with each biotype being adapted to feed on a particular cactus species (Volchansky et al. 1999 ). In South Africa six cochineal species or biotypes have been released for the control of 11 cactus species, all resulting in substantial or complete control with no recorded or known non-target impacts (Zachariades 2018 ). Six cochineal species or biotypes have been released in Australia (Winston<|im_end|> <|im_start|>assistant The cochineal Dactylopius opuntiae 'stricta' biotype is more effective as a sustainable biocontrol in the fight against the invasive common pest pear Opuntia stricta in Laikipia County, Kenya, compared to physical and/or chemical control—CABI scientists can now reveal. Dr. Arne Witt, based at CABI's center in Nairobi, led on research published in BioControl which shows that the D. opuntiae 'stricta' biotype—that was released in 2014—has contributed to a 'significant reduction' in the number of cladodes, flowers and fruit of plants with cochineal. Following a preliminary once-off survey, Dr. Witt and collaborators Winnie Nunda, Fernadis Makale and Kathryn Reynolds, demonstrated that fruits that were produced on plants with the cochineal were also smaller and had fewer seeds. Dr. Witt said, "Although still preliminary, an analysis of the costs of implementing the D. opuntiae 'stricta' biotype indicate that it is the most cost-effective management intervention compared to physical and/or chemical control. "Furthermore, while the impact of the cochineal is still fairly localized, we are confident that it will establish in much of the invaded range and reduce the impacts of the invasive cactus, consequently improving rangeland condition and livelihoods." Since its introduction to Kenya in 1949, O. stricta is considered to be the most widespread and problematic cactus species—being most abundant in Laikipia County and Tsavo East National Park and adjacent rangelands where it forms dense stands and prevents access to homes, water resources and pasture. "It is still too early to confirm if the agent D. opuntiae 'stricta' biotype will contribute to the complete control of O. stricta in Laikipia," Dr. Witt added. "However, early indications do warrant the re-distribution of the agent to Tsavo East NP and the Serengeti-Mara ecosystem, which has some significant invasions." Dr. Witt also revealed that a biotype of O. stricta for the control of Opuntia engelmannii has also been sourced in the U.S. and will 'hopefully be released' in Laikipia when approval has been granted from the regulatory authorities. <|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 Heritable microorganisms play critical roles in life cycles of many macro-organisms but their prevalence and functional roles are unknown for most plants. Bioactive ergot alkaloids produced by heritable Periglandula fungi occur in some morning glories (Convolvulaceae), similar to ergot alkaloids in grasses infected with related fungi. Ergot alkaloids have been of longstanding interest given their toxic effects, psychoactive properties, and medical applications. Here we show that ergot alkaloids are concentrated in four morning glory clades exhibiting differences in alkaloid profiles and are more prevalent in species with larger seeds than those with smaller seeds. Further, we found a phylogenetically-independent, positive correlation between seed mass and alkaloid concentrations in symbiotic species. Our findings suggest that heritable symbiosis has diversified among particular clades by vertical transmission through seeds combined with host speciation, and that ergot alkaloids are particularly beneficial to species with larger seeds. Our results are consistent with the defensive symbiosis hypothesis where bioactive ergot alkaloids from Periglandula symbionts protect seeds and seedlings from natural enemies, and provide a framework for exploring microbial chemistry in other plant-microbe interactions. Introduction Microbial biochemistry plays a protective role in many macro-organisms where symbiotic hosts acquire higher fitness than non-hosts in the presence of natural enemies. This stands in contrast to nutritional symbioses where the microbial symbionts provide limiting resources to the host as in symbiotic N-fixation in legumes and provisioning of essential amino acids in aphids 1 . In many protective symbioses, the microbial symbionts are transmitted to offspring through the maternal lineage. For example, beewolf wasps (Hymenoptera) harbor antibiotic-producing symbiotic bacteria that protect larvae from fungal infections 2 , and intracellular bacteria producing kahalalide compounds protect their algal hosts against predation 3 . In many grasses (Poaceae), heritable fungal symbionts produce bioactive ergot alkaloids with anti-herbivory properties 4 . These defensive symbioses represent rich sources of natural products, and tractable systems for investigating the dynamics of interspecific interactions. More generally, understanding the origin, distribution and function of heritable symbioses provide insights into the evolution of major groups of eukaryotes. Some morning glory species (family Convolvulaceae) contain high concentrations of ergot alkaloids (EAs) similar to those found in grasses infected with fungi in the family Clavicipitaceae 4 , 5 . EAs, named for ergot fungi ( Claviceps spp.), are characterized by a common tetracyclic ergoline structure with a variety of complex side chains, and were first isolated from morning glory seeds in 1960 6 based on their use as entheogens by indigenous peoples in Mexico 7 , 8 . EAs have been of longstanding interest given their toxic effects on humans and animals, medical applications and psychoactive properties 9 . For example, the EA lysergic acid provides the precursor for lysergic acid diethylamide (LSD). Much previous research has focused on increased herbivore and stress resistance of symbiotic grasses containing these fungal alkaloids 10 . Morning glories are commonly considered as species of Ipomoea but this large genus is not monophyletic 11 , and a more accurate concept of morning glories is members of the tribe Ipomoeeae (morning glories with spiny pollen) 12 . Species are distributed across the world’s tropical and subtropical regions, are commonly found in disturbed habitats and thrive in open ecotonal areas such as forest and river edges 13 . Morning glories are important for humans as food crops ( I. batatas , sweetpotato; I. aquatica , water spinach), agricultural weeds (I. purpurea, I. triloba ) and ornamental flowers ( I. alba, I. tricolor ), and are an emerging model system for evolutionary studies 14 . While it was known that Claviceps and related species produce EAs in their grass hosts, morning glories were initially thought to produce EAs endogenously until researchers 15 treated I. asarifolia with fungicide and observed that EAs and characteristic epiphytic fungal colonies disappeared, suggesting that EAs in morning glories are also produced by symbiotic fungi. The EA biosynthetic gene, dma W, and nuclear rDNA sequences typical of Clavicipitaceae were identified in the fungus 16 , which infected plants systemically and was vertically transmitted through seeds 17 , 18 . Epiphytic fungal colonies can be observed in many symbiotic morning glory species on the adaxial surface of young leaves and closely associated with oil glands, providing a potential pathway for fungal nutrition and horizontal transmission, which has not been experimentally observed. This new fungal genus associated with Convolvulaceae was named Periglandula and genetic analysis grouped the fungi within the Clavicipitaceae 19 . Prior to the discovery of Periglandula symbiosis, 42 species of morning glories out of 98 tested 5 were reported to contain EAs. All reports were from the tribe Ipomoeeae, which includes the genera Argyreia , Stictocardia , Turbina , and the paraphyletic genus Ipomoea 20 , 21 . Two Periglandula species have been described to date based on their host associations and exhibit considerable genetic differentiation between them 19 . Efforts to cultivate Periglandula have been thus far unsuccessful, suggesting that some host products are necessary for fungal growth. Recent studies 22 , 23 , 24 reported the co-occurrence of Periglandula , ergot alkaloid synthesis genes, and EAs in seeds of 10 additional morning glory species beyond the initial two described. Notably, Periglandula symbiosis with Convolvulaceae is macroscopically asymptomatic with hereditary (vertical) transmission through seeds and EA production at concentrations up to 1000X higher than in grasses infected with symbiotic Epichloë species. Moreover, morning glories are the only dicotyledonous plants known to contain EAs from fungal symbionts that have no known sexual reproduction, spore production or pathogenic relatives, unlike related Clavicipitaceae of grasses. Given the vertical transmission of EAs and Periglandula through host seeds, we hypothesize that both symbiosis and EA chemistry will vary among host lineages through evolutionary diversification and speciation, and reflect the ecological costs and benefits of symbiosis. To address this hypothesis, we (1) quantified EAs in seeds of 210 morning glory species from diverse, worldwide herbarium collections in order to determine the global distribution and diversity of Periglandula symbiosis, (2) obtained phylogenetically-informative ITS sequences from GenBank and determined the distribution", "role": "user" }, { "content": "Thanks to a symbiotic fungus, many species of morning glories contain elements of powerful psychedelic drugs, according to a new Tulane University study published in the journal Communications Biology. The seeds of the common tropical vine, whose namesake trumpet-like blooms only open in the morning, contain compounds that could be useful for treating mental and physical diseases as well as promoting well-being, said plant and fungal biologist Keith Clay, chairman of the Tulane Department of Ecology and Evolutionary Biology. Researchers from Tulane, Indiana University and the West Virginia University obtained samples of morning glory seeds from worldwide herbarium collections and screened them for ergot alkaloids, a compound associated with the hallucinogenic drug LSD, but which have also been used for treating migraine headaches and Parkinson's disease. Many morning glory species contain high concentrations of bioactive ergot alkaloids that are produced by specialized fungal symbionts passed down from mother plant to offspring through their seeds. Researchers found that one-quarter of over 200 species tested contained ergot alkaloids and were therefore symbiotic. \"The symbiosis and ergot alkaloids are specific to particular branches of the morning glory evolutionary tree, and each branch contains different ergot alkaloids and alkaloid mixtures,\" Clay said. Named for the ergot fungus responsible for deadly outbreaks of Saint Anthony's Fire, a disease caused by ingestion of the fungus, in the Middle Ages, ergot alkaloids have had long and convoluted association with humans. The best-known ergot alkaloid is LSD, a synthetic derivative of naturally occurring ergot alkaloids in morning glories produced by their fungal partners. Historically, such alkaloid compounds have been used by indigenous peoples of Central and South America for their effects on the human mind and for regulating human reproduction. More recently they have been used for obstetric issues during labor and delivery and for treatment of migraine, Parkinson's and other maladies. \"We have known a lot about the fungal alkaloid chemistry and its effects on the mind and body for long time,\" Clay said. \"Our study is the first to show how highly coevolved morning glories and their symbiotic fungi are, and that coevolution is manifested by different mixtures and concentrations of ergot alkaloids across the morning glory evolutionary tree.\" ", "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 Heritable microorganisms play critical roles in life cycles of many macro-organisms but their prevalence and functional roles are unknown for most plants. Bioactive ergot alkaloids produced by heritable Periglandula fungi occur in some morning glories (Convolvulaceae), similar to ergot alkaloids in grasses infected with related fungi. Ergot alkaloids have been of longstanding interest given their toxic effects, psychoactive properties, and medical applications. Here we show that ergot alkaloids are concentrated in four morning glory clades exhibiting differences in alkaloid profiles and are more prevalent in species with larger seeds than those with smaller seeds. Further, we found a phylogenetically-independent, positive correlation between seed mass and alkaloid concentrations in symbiotic species. Our findings suggest that heritable symbiosis has diversified among particular clades by vertical transmission through seeds combined with host speciation, and that ergot alkaloids are particularly beneficial to species with larger seeds. Our results are consistent with the defensive symbiosis hypothesis where bioactive ergot alkaloids from Periglandula symbionts protect seeds and seedlings from natural enemies, and provide a framework for exploring microbial chemistry in other plant-microbe interactions. Introduction Microbial biochemistry plays a protective role in many macro-organisms where symbiotic hosts acquire higher fitness than non-hosts in the presence of natural enemies. This stands in contrast to nutritional symbioses where the microbial symbionts provide limiting resources to the host as in symbiotic N-fixation in legumes and provisioning of essential amino acids in aphids 1 . In many protective symbioses, the microbial symbionts are transmitted to offspring through the maternal lineage. For example, beewolf wasps (Hymenoptera) harbor antibiotic-producing symbiotic bacteria that protect larvae from fungal infections 2 , and intracellular bacteria producing kahalalide compounds protect their algal hosts against predation 3 . In many grasses (Poaceae), heritable fungal symbionts produce bioactive ergot alkaloids with anti-herbivory properties 4 . These defensive symbioses represent rich sources of natural products, and tractable systems for investigating the dynamics of interspecific interactions. More generally, understanding the origin, distribution and function of heritable symbioses provide insights into the evolution of major groups of eukaryotes. Some morning glory species (family Convolvulaceae) contain high concentrations of ergot alkaloids (EAs) similar to those found in grasses infected with fungi in the family Clavicipitaceae 4 , 5 . EAs, named for ergot fungi ( Claviceps spp.), are characterized by a common tetracyclic ergoline structure with a variety of complex side chains, and were first isolated from morning glory seeds in 1960 6 based on their use as entheogens by indigenous peoples in Mexico 7 , 8 . EAs have been of longstanding interest given their toxic effects on humans and animals, medical applications and psychoactive properties 9 . For example, the EA lysergic acid provides the precursor for lysergic acid diethylamide (LSD). Much previous research has focused on increased herbivore and stress resistance of symbiotic grasses containing these fungal alkaloids 10 . Morning glories are commonly considered as species of Ipomoea but this large genus is not monophyletic 11 , and a more accurate concept of morning glories is members of the tribe Ipomoeeae (morning glories with spiny pollen) 12 . Species are distributed across the world’s tropical and subtropical regions, are commonly found in disturbed habitats and thrive in open ecotonal areas such as forest and river edges 13 . Morning glories are important for humans as food crops ( I. batatas , sweetpotato; I. aquatica , water spinach), agricultural weeds (I. purpurea, I. triloba ) and ornamental flowers ( I. alba, I. tricolor ), and are an emerging model system for evolutionary studies 14 . While it was known that Claviceps and related species produce EAs in their grass hosts, morning glories were initially thought to produce EAs endogenously until researchers 15 treated I. asarifolia with fungicide and observed that EAs and characteristic epiphytic fungal colonies disappeared, suggesting that EAs in morning glories are also produced by symbiotic fungi. The EA biosynthetic gene, dma W, and nuclear rDNA sequences typical of Clavicipitaceae were identified in the fungus 16 , which infected plants systemically and was vertically transmitted through seeds 17 , 18 . Epiphytic fungal colonies can be observed in many symbiotic morning glory species on the adaxial surface of young leaves and closely associated with oil glands, providing a potential pathway for fungal nutrition and horizontal transmission, which has not been experimentally observed. This new fungal genus associated with Convolvulaceae was named Periglandula and genetic analysis grouped the fungi within the Clavicipitaceae 19 . Prior to the discovery of Periglandula symbiosis, 42 species of morning glories out of 98 tested 5 were reported to contain EAs. All reports were from the tribe Ipomoeeae, which includes the genera Argyreia , Stictocardia , Turbina , and the paraphyletic genus Ipomoea 20 , 21 . Two Periglandula species have been described to date based on their host associations and exhibit considerable genetic differentiation between them 19 . Efforts to cultivate Periglandula have been thus far unsuccessful, suggesting that some host products are necessary for fungal growth. Recent studies 22 , 23 , 24 reported the co-occurrence of Periglandula , ergot alkaloid synthesis genes, and EAs in seeds of 10 additional morning glory species beyond the initial two described. Notably, Periglandula symbiosis with Convolvulaceae is macroscopically asymptomatic with hereditary (vertical) transmission through seeds and EA production at concentrations up to 1000X higher than in grasses infected with symbiotic Epichloë species. Moreover, morning glories are the only dicotyledonous plants known to contain EAs from fungal symbionts that have no known sexual reproduction, spore production or pathogenic relatives, unlike related Clavicipitaceae of grasses. Given the vertical transmission of EAs and Periglandula through host seeds, we hypothesize that both symbiosis and EA chemistry will vary among host lineages through evolutionary diversification and speciation, and reflect the ecological costs and benefits of symbiosis. To address this hypothesis, we (1) quantified EAs in seeds of 210 morning glory species from diverse, worldwide herbarium collections in order to determine the global distribution and diversity of Periglandula symbiosis, (2) obtained phylogenetically-informative ITS sequences from GenBank and determined the distribution<|im_end|> <|im_start|>assistant Thanks to a symbiotic fungus, many species of morning glories contain elements of powerful psychedelic drugs, according to a new Tulane University study published in the journal Communications Biology. The seeds of the common tropical vine, whose namesake trumpet-like blooms only open in the morning, contain compounds that could be useful for treating mental and physical diseases as well as promoting well-being, said plant and fungal biologist Keith Clay, chairman of the Tulane Department of Ecology and Evolutionary Biology. Researchers from Tulane, Indiana University and the West Virginia University obtained samples of morning glory seeds from worldwide herbarium collections and screened them for ergot alkaloids, a compound associated with the hallucinogenic drug LSD, but which have also been used for treating migraine headaches and Parkinson's disease. Many morning glory species contain high concentrations of bioactive ergot alkaloids that are produced by specialized fungal symbionts passed down from mother plant to offspring through their seeds. Researchers found that one-quarter of over 200 species tested contained ergot alkaloids and were therefore symbiotic. "The symbiosis and ergot alkaloids are specific to particular branches of the morning glory evolutionary tree, and each branch contains different ergot alkaloids and alkaloid mixtures," Clay said. Named for the ergot fungus responsible for deadly outbreaks of Saint Anthony's Fire, a disease caused by ingestion of the fungus, in the Middle Ages, ergot alkaloids have had long and convoluted association with humans. The best-known ergot alkaloid is LSD, a synthetic derivative of naturally occurring ergot alkaloids in morning glories produced by their fungal partners. Historically, such alkaloid compounds have been used by indigenous peoples of Central and South America for their effects on the human mind and for regulating human reproduction. More recently they have been used for obstetric issues during labor and delivery and for treatment of migraine, Parkinson's and other maladies. "We have known a lot about the fungal alkaloid chemistry and its effects on the mind and body for long time," Clay said. "Our study is the first to show how highly coevolved morning glories and their symbiotic fungi are, and that coevolution is manifested by different mixtures and concentrations of ergot alkaloids across the morning glory evolutionary tree." <|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 Wolbachia is a genus of obligate intracellular bacteria found in nematodes and arthropods worldwide, including insect vectors that transmit dengue, West Nile, and Zika viruses. Wolbachia ’s unique ability to alter host reproductive behavior through its temperate bacteriophage WO has enabled the development of new vector control strategies. However, our understanding of Wolbachia ’s mobilome beyond its bacteriophages is incomplete. Here, we reconstruct near-complete Wolbachia genomes from individual ovary metagenomes of four wild Culex pipiens mosquitoes captured in France. In addition to viral genes missing from the Wolbachia reference genome, we identify a putative plasmid (pWCP), consisting of a 9.23-kbp circular element with 14 genes. We validate its presence in additional Culex pipiens mosquitoes using PCR, long-read sequencing, and screening of existing metagenomes. The discovery of this previously unrecognized extrachromosomal element opens additional possibilities for genetic manipulation of Wolbachia . Introduction Mosquitoes are major vectors of disease-causing pathogens worldwide including viruses such as dengue, West Nile, Chikungunya, Zika, and yellow fever 1 , 2 , 3 . In the absence of effective vaccines and the off-target effects of insecticides used to control mosquitoes, novel vector biocontrol efforts are the focus of intense study 4 . Over the past decade, the widely distributed endosymbiotic alphaproteobacteria Wolbachia has gained attention as a promising mosquito-control strategy. The basic reasons for its heightened attention is that Wolbachia can cause reproductive parasitism whereby the intracellular bacteria in the reproductive tissues can alter sexual reproduction to enhance its maternal spread through host populations at the expense of host fitness 5 , 6 , 7 . Second and notably, native Wolbachia reduce RNA virus replication in the fruit fly Drosophila 8 , 9 , 10 , and Wolbachia transinfections into mosquito species (i.e., Aedes aegypti , Ae. albopictus , Ae. polynesienses , and Anopheles stephensi ) similarly result in mosquito lines refractory to various types of pathogenic RNA viruses 11 , 12 , 13 , 14 . The combination of a selfish drive system and pathogen blocking by Wolbachia has led to successful pilot trials for suppression of mosquito population size and replacement of infected mosquito populations so they can no longer transmit pathogens 15 , 16 , 17 . Wolbachia are transovarially transmitted from the mother to offspring 6 , 18 , 19 , 20 . In some arthropods, including the naturally infected vector species complex Culex pipiens , Wolbachia ‘modify’ sperm in testes, leading to embryonic lethality if the infected male mates with either an uninfected female or a female harbouring an incompatible Wolbachia strain. When both male and female are infected with the same Wolbachia , the modification is ‘rescued’, and compatibility is restored 21 . This reproductive alteration, termed ‘cytoplasmic incompatibility’ (CI), comprises the most common form of Wolbachia -induced parasitism and, as studied in C. pipiens , can lead to highly diverse unidirectional and bidirectional incompatibility phenotypes 22 . CI is currently used in vector control studies for population replacement by Wolbachia- infected strains that block arbovirus transmission 17 or population suppression that reduces the number of mosquito vectors 23 . Notably, the genes responsible for CI 24 , 25 , 26 occur in the eukaryotic association module of Wolbachia ’s temperate phage WO 25 , 26 , 27 , which laterally transfers between Wolbachia coinfections and evolves rapidly 28 , 29 , 30 , 31 , 32 . Overall, these findings emphasize the importance of further investigating mobile genetic elements in Wolbachia. While recent studies shed light on the role of phage WO in Wolbachia genome evolution and CI, other extrachromosomal elements, such as plasmids, have not been detected in the symbiont. Notably, over half of the species in the closely related Rickettsia genus have plasmids 33 that play roles in DNA replication, partitioning, mobilization, and conjugation 34 , 35 and offer a potential tool for genetic manipulation of diverse members of Rickettsia 36 , 37 . Similar genetic manipulation strategies for Wolbachia are conceivable 27 ; however, previous efforts to search for such extrachromosomal mobile genetic elements have not been successful 38 , 39 . The lack of isolates limit direct insights into Wolbachia genomics, and most metagenomic approaches thus far rely on pooled individuals grown in the laboratory environment due to low infection densities 40 , 41 . Since these limitations can conceal naturally occurring genomic diversity among Wolbachia populations, highly resolved analyses of individual mosquitoes may reveal additional insights into the Wolbachia ‘mobilome’, the pool of all mobile genetic elements associated with Wolbachia populations. Here we sequence ovary samples from four wild-caught C. pipiens individuals captured in Southern France from a single trap. Using genome-resolved metagenomic and pangenomic analysis strategies, we were able to reconstruct and compare near-complete Wolbachia genomes from each individual. Besides a diverse set of virus-associated genes that were missing or absent in the reference Wolbachia genome w Pip Pel, our data reveal the first lines of evidence for an extrachromosomal circular element with genetic and functional hallmarks of a plasmid that we tentatively name pWCP. Results A Wolbachia metagenome-assembled genome (MAG) is recovered in each sample Shotgun sequencing of DNA recovered from ovary samples of four C. pipiens individuals (O03, O07, O11, O12) resulted in 65–78 million paired-end sequences after quality filtering. Metagenomic assembly of each sample individually yielded 147K–183K contiguous DNA segments (contigs) >1 kbp, which recruited 48.1–72.9% of the raw sequencing reads. The relatively high fraction of unmapped reads were likely due to challenges associated with the assembly of environmental metagenomes 42 , 43 , especially in the presence of eukaryotic host genomic DNA. Supplementary Table 1 reports statistics for the raw number of reads and assembly results for each sample. We employed a metagenomic binning strategy that uses sequence composition signatures and differential coverage statistics of contigs across samples. For each ovary sample, we were able to reconstruct a highly complete single bacterial MAG that resolved to Wolbachia (Table 1 ). Table 1 Wolbachia MAG estimates Full size table Wolbachia MAGs include highly covered non-phage contigs The relatively low number", "role": "user" }, { "content": "Controlling mosquito-borne illnesses, such as Dengue or West Nile virus, has historically been difficult due to a lack of effective vaccines and concerns about the environmental impact of insecticides. Thus, scientists have turned to manipulating Wolbachia, a parasitic bacterium within mosquitoes, as a way to control the reproductive fitness of mosquito populations that transmit human disease. In a new study in Nature Communications, an international team including scientists from the Marine Biological Laboratory (MBL) and the University of Chicago identified a new mobile DNA element in Wolbachia, which may contribute to improved control strategies for mosquito vectors of disease. Led by former MBL scientists Julie Reveillaud of INRA, France, and Sarah Bordenstein of Vanderbilt University, the researchers reconstructed near-complete genomes of Wolbachia isolated from individual ovaries of four Culex pipiens mosquitoes. In the process, they identified a novel plasmid—a circular piece of DNA that can replicate independently of the chromosomes. Because a plasmid is a mobile DNA element, it can transfer from one cell to another and can have great implications for the fitness and evolution of a microbial species. Mobile genetic elements that can spread through different Wolbachia cells, and thus across a Wolbachia population, hold promise for controlling mosquito populations that may carry disease. \"Our data show that this novel plasmid is widespread across natural Wolbachia populations that infect C. pipiens mosquitoes throughout the world, which implies it has an essential role. The idea that it may enable transformation of the Wolbachia populations is simply very exciting,\" says the senior author of the study, A. Murat Eren (Meren), an assistant professor of medicine at the University of Chicago and an MBL Fellow. Surface sterilizing a Culex pipiens mosquito sample before dissection. Credit: Julie Reveillaud Wolbachia is transmitted from mother to offspring and can influence the reproductive behavior of its mosquito host. Wolbachia can modify sperm so if an infected male mates with an uninfected female, or with one that carries a different strain of Wolbachia, embryos cannot develop. The mechanism behind this embryonic killing lies within another mobile genetic element in the Wolbachia genome. \"Wolbachia populations do not lend themselves to direct genetic modification. While a natural plasmid sounds very promising to bypass those limitations, we do not yet have any evidence to suggest the possibility or efficacy of any transformation through this plasmid,\" Meren says. \"We just discovered its existence, and the time will tell how useful it is.\" \"Other exciting questions for which we do not have yet clear answers include whether there is an ancestral relationship between the plasmid and other mobile genetic elements of Wolbachia, and whether these interact or not,\" adds Reveillaud. This collaboration began at MBL in 2011, when Meren and Reveillaud brought their computational and molecular evolution backgrounds together to explore questions in microbial ecology in the MBL's Bay Paul Center. (See Reveillaud's blog post about the collaboration.) Years later, they began examining Wolbachia genomic diversity by focusing on individual mosquitoes captured in the wild, rather than using laboratory mosquito strains. With the help of former MBL scientists Sarah Bordenstein and Seth Bordenstein of Vanderbilt University, who have expertise in Wolbachia, they began unraveling the intricacies of the Wolbachia genome. Trap of Culex pipiens mosquitoes from France, provided by EID (Entente Interdépartementale Démoustication) in Montpellier, France. Credit: Julie Reveillaud \"Wolbachia is particularly difficult to study because, unlike free-living bacteria, it cannot be cultured in cell-free media. Through this interdisciplinary collaboration, we were able to tease apart the genomes of the mosquito host, Wolbachia, and its mobile elements,\" says Sarah Bordenstein. While fragments of this novel plasmid had appeared in previous Wolbachia sequencing studies, these fragments had never been assembled into a complete circular piece and its extrachromosomal nature was not recognized, most likely due to computational limitations. The team was able to overcome these limitations by employing a combination of cutting-edge strategies, such as genome-resolved metagenomics and long-read sequencing. \"The key bioinformatics platform that enabled us to study mosquito metagenomes and Wolbachia pangenomes in this study, and the connections between scientists with distinct skills that made this discovery possible, were developed at the MBL,\" Meren says. \"Almost everyone in this paper is somehow linked to the MBL.\" ", "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 Wolbachia is a genus of obligate intracellular bacteria found in nematodes and arthropods worldwide, including insect vectors that transmit dengue, West Nile, and Zika viruses. Wolbachia ’s unique ability to alter host reproductive behavior through its temperate bacteriophage WO has enabled the development of new vector control strategies. However, our understanding of Wolbachia ’s mobilome beyond its bacteriophages is incomplete. Here, we reconstruct near-complete Wolbachia genomes from individual ovary metagenomes of four wild Culex pipiens mosquitoes captured in France. In addition to viral genes missing from the Wolbachia reference genome, we identify a putative plasmid (pWCP), consisting of a 9.23-kbp circular element with 14 genes. We validate its presence in additional Culex pipiens mosquitoes using PCR, long-read sequencing, and screening of existing metagenomes. The discovery of this previously unrecognized extrachromosomal element opens additional possibilities for genetic manipulation of Wolbachia . Introduction Mosquitoes are major vectors of disease-causing pathogens worldwide including viruses such as dengue, West Nile, Chikungunya, Zika, and yellow fever 1 , 2 , 3 . In the absence of effective vaccines and the off-target effects of insecticides used to control mosquitoes, novel vector biocontrol efforts are the focus of intense study 4 . Over the past decade, the widely distributed endosymbiotic alphaproteobacteria Wolbachia has gained attention as a promising mosquito-control strategy. The basic reasons for its heightened attention is that Wolbachia can cause reproductive parasitism whereby the intracellular bacteria in the reproductive tissues can alter sexual reproduction to enhance its maternal spread through host populations at the expense of host fitness 5 , 6 , 7 . Second and notably, native Wolbachia reduce RNA virus replication in the fruit fly Drosophila 8 , 9 , 10 , and Wolbachia transinfections into mosquito species (i.e., Aedes aegypti , Ae. albopictus , Ae. polynesienses , and Anopheles stephensi ) similarly result in mosquito lines refractory to various types of pathogenic RNA viruses 11 , 12 , 13 , 14 . The combination of a selfish drive system and pathogen blocking by Wolbachia has led to successful pilot trials for suppression of mosquito population size and replacement of infected mosquito populations so they can no longer transmit pathogens 15 , 16 , 17 . Wolbachia are transovarially transmitted from the mother to offspring 6 , 18 , 19 , 20 . In some arthropods, including the naturally infected vector species complex Culex pipiens , Wolbachia ‘modify’ sperm in testes, leading to embryonic lethality if the infected male mates with either an uninfected female or a female harbouring an incompatible Wolbachia strain. When both male and female are infected with the same Wolbachia , the modification is ‘rescued’, and compatibility is restored 21 . This reproductive alteration, termed ‘cytoplasmic incompatibility’ (CI), comprises the most common form of Wolbachia -induced parasitism and, as studied in C. pipiens , can lead to highly diverse unidirectional and bidirectional incompatibility phenotypes 22 . CI is currently used in vector control studies for population replacement by Wolbachia- infected strains that block arbovirus transmission 17 or population suppression that reduces the number of mosquito vectors 23 . Notably, the genes responsible for CI 24 , 25 , 26 occur in the eukaryotic association module of Wolbachia ’s temperate phage WO 25 , 26 , 27 , which laterally transfers between Wolbachia coinfections and evolves rapidly 28 , 29 , 30 , 31 , 32 . Overall, these findings emphasize the importance of further investigating mobile genetic elements in Wolbachia. While recent studies shed light on the role of phage WO in Wolbachia genome evolution and CI, other extrachromosomal elements, such as plasmids, have not been detected in the symbiont. Notably, over half of the species in the closely related Rickettsia genus have plasmids 33 that play roles in DNA replication, partitioning, mobilization, and conjugation 34 , 35 and offer a potential tool for genetic manipulation of diverse members of Rickettsia 36 , 37 . Similar genetic manipulation strategies for Wolbachia are conceivable 27 ; however, previous efforts to search for such extrachromosomal mobile genetic elements have not been successful 38 , 39 . The lack of isolates limit direct insights into Wolbachia genomics, and most metagenomic approaches thus far rely on pooled individuals grown in the laboratory environment due to low infection densities 40 , 41 . Since these limitations can conceal naturally occurring genomic diversity among Wolbachia populations, highly resolved analyses of individual mosquitoes may reveal additional insights into the Wolbachia ‘mobilome’, the pool of all mobile genetic elements associated with Wolbachia populations. Here we sequence ovary samples from four wild-caught C. pipiens individuals captured in Southern France from a single trap. Using genome-resolved metagenomic and pangenomic analysis strategies, we were able to reconstruct and compare near-complete Wolbachia genomes from each individual. Besides a diverse set of virus-associated genes that were missing or absent in the reference Wolbachia genome w Pip Pel, our data reveal the first lines of evidence for an extrachromosomal circular element with genetic and functional hallmarks of a plasmid that we tentatively name pWCP. Results A Wolbachia metagenome-assembled genome (MAG) is recovered in each sample Shotgun sequencing of DNA recovered from ovary samples of four C. pipiens individuals (O03, O07, O11, O12) resulted in 65–78 million paired-end sequences after quality filtering. Metagenomic assembly of each sample individually yielded 147K–183K contiguous DNA segments (contigs) >1 kbp, which recruited 48.1–72.9% of the raw sequencing reads. The relatively high fraction of unmapped reads were likely due to challenges associated with the assembly of environmental metagenomes 42 , 43 , especially in the presence of eukaryotic host genomic DNA. Supplementary Table 1 reports statistics for the raw number of reads and assembly results for each sample. We employed a metagenomic binning strategy that uses sequence composition signatures and differential coverage statistics of contigs across samples. For each ovary sample, we were able to reconstruct a highly complete single bacterial MAG that resolved to Wolbachia (Table 1 ). Table 1 Wolbachia MAG estimates Full size table Wolbachia MAGs include highly covered non-phage contigs The relatively low number<|im_end|> <|im_start|>assistant Controlling mosquito-borne illnesses, such as Dengue or West Nile virus, has historically been difficult due to a lack of effective vaccines and concerns about the environmental impact of insecticides. Thus, scientists have turned to manipulating Wolbachia, a parasitic bacterium within mosquitoes, as a way to control the reproductive fitness of mosquito populations that transmit human disease. In a new study in Nature Communications, an international team including scientists from the Marine Biological Laboratory (MBL) and the University of Chicago identified a new mobile DNA element in Wolbachia, which may contribute to improved control strategies for mosquito vectors of disease. Led by former MBL scientists Julie Reveillaud of INRA, France, and Sarah Bordenstein of Vanderbilt University, the researchers reconstructed near-complete genomes of Wolbachia isolated from individual ovaries of four Culex pipiens mosquitoes. In the process, they identified a novel plasmid—a circular piece of DNA that can replicate independently of the chromosomes. Because a plasmid is a mobile DNA element, it can transfer from one cell to another and can have great implications for the fitness and evolution of a microbial species. Mobile genetic elements that can spread through different Wolbachia cells, and thus across a Wolbachia population, hold promise for controlling mosquito populations that may carry disease. "Our data show that this novel plasmid is widespread across natural Wolbachia populations that infect C. pipiens mosquitoes throughout the world, which implies it has an essential role. The idea that it may enable transformation of the Wolbachia populations is simply very exciting," says the senior author of the study, A. Murat Eren (Meren), an assistant professor of medicine at the University of Chicago and an MBL Fellow. Surface sterilizing a Culex pipiens mosquito sample before dissection. Credit: Julie Reveillaud Wolbachia is transmitted from mother to offspring and can influence the reproductive behavior of its mosquito host. Wolbachia can modify sperm so if an infected male mates with an uninfected female, or with one that carries a different strain of Wolbachia, embryos cannot develop. The mechanism behind this embryonic killing lies within another mobile genetic element in the Wolbachia genome. "Wolbachia populations do not lend themselves to direct genetic modification. While a natural plasmid sounds very promising to bypass those limitations, we do not yet have any evidence to suggest the possibility or efficacy of any transformation through this plasmid," Meren says. "We just discovered its existence, and the time will tell how useful it is." "Other exciting questions for which we do not have yet clear answers include whether there is an ancestral relationship between the plasmid and other mobile genetic elements of Wolbachia, and whether these interact or not," adds Reveillaud. This collaboration began at MBL in 2011, when Meren and Reveillaud brought their computational and molecular evolution backgrounds together to explore questions in microbial ecology in the MBL's Bay Paul Center. (See Reveillaud's blog post about the collaboration.) Years later, they began examining Wolbachia genomic diversity by focusing on individual mosquitoes captured in the wild, rather than using laboratory mosquito strains. With the help of former MBL scientists Sarah Bordenstein and Seth Bordenstein of Vanderbilt University, who have expertise in Wolbachia, they began unraveling the intricacies of the Wolbachia genome. Trap of Culex pipiens mosquitoes from France, provided by EID (Entente Interdépartementale Démoustication) in Montpellier, France. Credit: Julie Reveillaud "Wolbachia is particularly difficult to study because, unlike free-living bacteria, it cannot be cultured in cell-free media. Through this interdisciplinary collaboration, we were able to tease apart the genomes of the mosquito host, Wolbachia, and its mobile elements," says Sarah Bordenstein. While fragments of this novel plasmid had appeared in previous Wolbachia sequencing studies, these fragments had never been assembled into a complete circular piece and its extrachromosomal nature was not recognized, most likely due to computational limitations. The team was able to overcome these limitations by employing a combination of cutting-edge strategies, such as genome-resolved metagenomics and long-read sequencing. "The key bioinformatics platform that enabled us to study mosquito metagenomes and Wolbachia pangenomes in this study, and the connections between scientists with distinct skills that made this discovery possible, were developed at the MBL," Meren says. "Almost everyone in this paper is somehow linked to the MBL." <|im_end|>

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2,411

[ { "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 Losses and gains in species diversity affect ecological stability 1 , 2 , 3 , 4 , 5 , 6 , 7 and the sustainability of ecosystem functions and services 8 , 9 , 10 , 11 , 12 , 13 . Experiments and models have revealed positive, negative and no effects of diversity on individual components of stability, such as temporal variability, resistance and resilience 2 , 3 , 6 , 11 , 12 , 14 . How these stability components covary remains poorly understood 15 . Similarly, the effects of diversity on overall ecosystem stability 16 , which is conceptually akin to ecosystem multifunctionality 17 , 18 , remain unknown. Here we studied communities of aquatic ciliates to understand how temporal variability, resistance and overall ecosystem stability responded to diversity (that is, species richness) in a large experiment involving 690 micro-ecosystems sampled 19 times over 40 days, resulting in 12,939 samplings. Species richness increased temporal stability but decreased resistance to warming. Thus, two stability components covaried negatively along the diversity gradient. Previous biodiversity manipulation studies rarely reported such negative covariation despite general predictions of the negative effects of diversity on individual stability components 3 . Integrating our findings with the ecosystem multifunctionality concept revealed hump- and U-shaped effects of diversity on overall ecosystem stability. That is, biodiversity can increase overall ecosystem stability when biodiversity is low, and decrease it when biodiversity is high, or the opposite with a U-shaped relationship. The effects of diversity on ecosystem multifunctionality would also be hump- or U-shaped if diversity had positive effects on some functions and negative effects on others. Linking the ecosystem multifunctionality concept and ecosystem stability can transform the perceived effects of diversity on ecological stability and may help to translate this science into policy-relevant information. Main Ecological stability consists of numerous components, including temporal variability, resistance to environmental change and rate of recovery from disturbance 1 , 2 , 16 . Effects of species losses and gains on these components are of considerable interest, not least because of the potential effects on ecosystem functioning and therefore on the sustainable delivery of ecosystem services 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 . A growing number of experimental studies reveal stabilizing effects of diversity on individual stability components. In particular, higher diversity often—but not always—reduces temporal variability of biomass production 13 . Positive effects of diversity on resistance are common, although neutral and negative effects on resistance and resilience also occur 9 , 13 , 19 , 20 . Although the assessment of individual components of stability is essential, a more integrative approach to ecological stability could lead to clearer conceptual understanding 15 and might help to improve policy guidance concerning ecological stability 16 . Analogous to ecosystem multifunctionality 17 , 18 , a more integrative approach considers variation in multiple stability components and the often-ignored covariation among stability components. The nature of this covariation is of paramount importance, as it defines whether diversity has consistent effects on multiple stability components, or whether some stability components increase with diversity while others decrease. However, the nature, prevalence and implications of negative covariation between stability components along diversity gradients are almost completely overlooked, including the ensuing possibility for non-monotonic effects of diversity on overall ecosystem stability. We first describe our experimental findings of how biodiversity affects the intrinsic stability of ecosystems and their resistance to warming. Temperature is a highly relevant disturbance owing to its importance for biological processes and its great variability across space and time. However, our findings equally apply to and have implications for other environmental changes that could result in opposing effects on stability components, such as flooding 12 or chemical stress 21 . We then review other evidence for negative covariation in effects of diversity on stability and potential mechanisms. Finally, we analyse overall ecosystem stability, a concept that embraces the covariation between stability components and their weighting, and show the plausibility of previously overlooked non-monotonic (hump- and U-shaped) effects of diversity on overall ecosystem stability. We performed a factorial manipulation of the diversity and composition of competing species (1–6 species, 53 unique community compositions) and temperature (six constant levels, modelled as a linear predictor) in microbial communities of bacterial consumers, and recorded community biomass dynamics over time. For each replicate we then calculated two stability components: resistance (that is, the total biomass at T minus the total biomass at 15 °C divided by T minus 15 °C, in which T is the temperature of the replicate) and the temporal stability of biomass (the inverse of the coefficient of variation of community biomass). Although these stability indices are widely used by empiricists, they should not be mistaken for mathematical definitions—such as asymptotic resilience—that are more precise but also more restrictive 22 . Increased species richness caused greater temporal stability of total biomass (Fig. 1a ) (linear mixed-effects model of log inverse coefficient of variation: richness effect size 0.33 ± 0.065 (mean ± s.e.m.)) at all temperatures (Extended Data Fig. 1 ). Total biomass increased during the first week of the experiment and then declined over the next five weeks and total biomass was higher in more species-rich communities (Fig. 1b, c and Extended Data Table 1 ). The effect size for log(richness) was 0.05 ± 0.0096 mg ml −1 per log(species richness) (mean ± s.e.m.). Fig. 1: Biomass and stability in experimental microbial communities. a , Richness increased temporal stability (top, n = 681 independent microcosms), but decreased resistance (bottom, n = 567 independent microcosms). The dashed line indicates zero resistance. b , Average (mean ± s.e.m.) biomass for each diversity level ( n = 12,939 microcosm × day combinations). c , Temporal dynamics of effect sizes (and 95% confidence intervals) of a linear mixed-effects model of total biomass showed, on average, a negative effect of temperature on biomass (top), a positive effect of diversity on biomass (middle) and", "role": "user" }, { "content": "Ecosystems have a variety of benefits to humans, including food, water and other resources, as well as recreational space. It is therefore important that these systems remain functional and stable—especially in view of climate change and environmental pollution. Ecologists at the University of Zurich and the Swiss Federal Institute of Aquatic Science and Technology (Eawag) have now examined the factors that influence this stability in a unique and comprehensive experiment. The scientists specifically researched how biodiversity affects the stability of ecosystems. As model organisms, they used six species of ciliates—tiny protozoans that live in water. The researchers put varying numbers and combinations of these ciliates in sample vials, thereby creating miniature ecosystems that they then let thrive at temperatures between 15 and 25 degrees Celsius. The increased temperatures simulated a climatic change, as the ciliates used in the experiment previously lived at a temperature of 15 degrees Celsius. The researchers then used novel video evaluation techniques to analyze how stable the biomass production in these small ecosystems was. An algorithm developed by the team made it possible to identify the ciliate species in about 20,000 video sequences of the numerous samples recorded under a microscope. Contrary results At first glance, the results of the experiment seem contradictory: High biodiversity simultaneously furthers and hinders the stability of an ecosystem. \"Ecological stability is complex and consists of various components,\" says Frank Pennekamp, first author of the study. \"The experiment shows how biodiversity affects the individual stability components in different ways.\" In other words, the more diverse the species community in the miniature ecosystems was, the less the biomass production fluctuated—regardless of temperature. At higher temperatures, however, the researchers found that protozoans produced less biomass the more species were bustling about the system. \"The fact that various components react differently should be taken into consideration in the management of ecosystems, as non-linear connections may occur between diversity and the overall stability of the ecosystem depending on the weighting of the components,\" says Pennekamp. Literature research showed that other scientists also observe the contrary connection between biodiversity and stability in other ecosystems, such as grassland or algae communities. \"The results make it clear that more species alone is not enough to ensure the overall stability of an ecosystem,\" says Florian Altermatt, professor of aquatic ecology at Eawag. \"In addition to a diversity of species, the species themselves must be able to react to environmental changes in a variety of ways.\" ", "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 Losses and gains in species diversity affect ecological stability 1 , 2 , 3 , 4 , 5 , 6 , 7 and the sustainability of ecosystem functions and services 8 , 9 , 10 , 11 , 12 , 13 . Experiments and models have revealed positive, negative and no effects of diversity on individual components of stability, such as temporal variability, resistance and resilience 2 , 3 , 6 , 11 , 12 , 14 . How these stability components covary remains poorly understood 15 . Similarly, the effects of diversity on overall ecosystem stability 16 , which is conceptually akin to ecosystem multifunctionality 17 , 18 , remain unknown. Here we studied communities of aquatic ciliates to understand how temporal variability, resistance and overall ecosystem stability responded to diversity (that is, species richness) in a large experiment involving 690 micro-ecosystems sampled 19 times over 40 days, resulting in 12,939 samplings. Species richness increased temporal stability but decreased resistance to warming. Thus, two stability components covaried negatively along the diversity gradient. Previous biodiversity manipulation studies rarely reported such negative covariation despite general predictions of the negative effects of diversity on individual stability components 3 . Integrating our findings with the ecosystem multifunctionality concept revealed hump- and U-shaped effects of diversity on overall ecosystem stability. That is, biodiversity can increase overall ecosystem stability when biodiversity is low, and decrease it when biodiversity is high, or the opposite with a U-shaped relationship. The effects of diversity on ecosystem multifunctionality would also be hump- or U-shaped if diversity had positive effects on some functions and negative effects on others. Linking the ecosystem multifunctionality concept and ecosystem stability can transform the perceived effects of diversity on ecological stability and may help to translate this science into policy-relevant information. Main Ecological stability consists of numerous components, including temporal variability, resistance to environmental change and rate of recovery from disturbance 1 , 2 , 16 . Effects of species losses and gains on these components are of considerable interest, not least because of the potential effects on ecosystem functioning and therefore on the sustainable delivery of ecosystem services 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 . A growing number of experimental studies reveal stabilizing effects of diversity on individual stability components. In particular, higher diversity often—but not always—reduces temporal variability of biomass production 13 . Positive effects of diversity on resistance are common, although neutral and negative effects on resistance and resilience also occur 9 , 13 , 19 , 20 . Although the assessment of individual components of stability is essential, a more integrative approach to ecological stability could lead to clearer conceptual understanding 15 and might help to improve policy guidance concerning ecological stability 16 . Analogous to ecosystem multifunctionality 17 , 18 , a more integrative approach considers variation in multiple stability components and the often-ignored covariation among stability components. The nature of this covariation is of paramount importance, as it defines whether diversity has consistent effects on multiple stability components, or whether some stability components increase with diversity while others decrease. However, the nature, prevalence and implications of negative covariation between stability components along diversity gradients are almost completely overlooked, including the ensuing possibility for non-monotonic effects of diversity on overall ecosystem stability. We first describe our experimental findings of how biodiversity affects the intrinsic stability of ecosystems and their resistance to warming. Temperature is a highly relevant disturbance owing to its importance for biological processes and its great variability across space and time. However, our findings equally apply to and have implications for other environmental changes that could result in opposing effects on stability components, such as flooding 12 or chemical stress 21 . We then review other evidence for negative covariation in effects of diversity on stability and potential mechanisms. Finally, we analyse overall ecosystem stability, a concept that embraces the covariation between stability components and their weighting, and show the plausibility of previously overlooked non-monotonic (hump- and U-shaped) effects of diversity on overall ecosystem stability. We performed a factorial manipulation of the diversity and composition of competing species (1–6 species, 53 unique community compositions) and temperature (six constant levels, modelled as a linear predictor) in microbial communities of bacterial consumers, and recorded community biomass dynamics over time. For each replicate we then calculated two stability components: resistance (that is, the total biomass at T minus the total biomass at 15 °C divided by T minus 15 °C, in which T is the temperature of the replicate) and the temporal stability of biomass (the inverse of the coefficient of variation of community biomass). Although these stability indices are widely used by empiricists, they should not be mistaken for mathematical definitions—such as asymptotic resilience—that are more precise but also more restrictive 22 . Increased species richness caused greater temporal stability of total biomass (Fig. 1a ) (linear mixed-effects model of log inverse coefficient of variation: richness effect size 0.33 ± 0.065 (mean ± s.e.m.)) at all temperatures (Extended Data Fig. 1 ). Total biomass increased during the first week of the experiment and then declined over the next five weeks and total biomass was higher in more species-rich communities (Fig. 1b, c and Extended Data Table 1 ). The effect size for log(richness) was 0.05 ± 0.0096 mg ml −1 per log(species richness) (mean ± s.e.m.). Fig. 1: Biomass and stability in experimental microbial communities. a , Richness increased temporal stability (top, n = 681 independent microcosms), but decreased resistance (bottom, n = 567 independent microcosms). The dashed line indicates zero resistance. b , Average (mean ± s.e.m.) biomass for each diversity level ( n = 12,939 microcosm × day combinations). c , Temporal dynamics of effect sizes (and 95% confidence intervals) of a linear mixed-effects model of total biomass showed, on average, a negative effect of temperature on biomass (top), a positive effect of diversity on biomass (middle) and<|im_end|> <|im_start|>assistant Ecosystems have a variety of benefits to humans, including food, water and other resources, as well as recreational space. It is therefore important that these systems remain functional and stable—especially in view of climate change and environmental pollution. Ecologists at the University of Zurich and the Swiss Federal Institute of Aquatic Science and Technology (Eawag) have now examined the factors that influence this stability in a unique and comprehensive experiment. The scientists specifically researched how biodiversity affects the stability of ecosystems. As model organisms, they used six species of ciliates—tiny protozoans that live in water. The researchers put varying numbers and combinations of these ciliates in sample vials, thereby creating miniature ecosystems that they then let thrive at temperatures between 15 and 25 degrees Celsius. The increased temperatures simulated a climatic change, as the ciliates used in the experiment previously lived at a temperature of 15 degrees Celsius. The researchers then used novel video evaluation techniques to analyze how stable the biomass production in these small ecosystems was. An algorithm developed by the team made it possible to identify the ciliate species in about 20,000 video sequences of the numerous samples recorded under a microscope. Contrary results At first glance, the results of the experiment seem contradictory: High biodiversity simultaneously furthers and hinders the stability of an ecosystem. "Ecological stability is complex and consists of various components," says Frank Pennekamp, first author of the study. "The experiment shows how biodiversity affects the individual stability components in different ways." In other words, the more diverse the species community in the miniature ecosystems was, the less the biomass production fluctuated—regardless of temperature. At higher temperatures, however, the researchers found that protozoans produced less biomass the more species were bustling about the system. "The fact that various components react differently should be taken into consideration in the management of ecosystems, as non-linear connections may occur between diversity and the overall stability of the ecosystem depending on the weighting of the components," says Pennekamp. Literature research showed that other scientists also observe the contrary connection between biodiversity and stability in other ecosystems, such as grassland or algae communities. "The results make it clear that more species alone is not enough to ensure the overall stability of an ecosystem," says Florian Altermatt, professor of aquatic ecology at Eawag. "In addition to a diversity of species, the species themselves must be able to react to environmental changes in a variety of ways." <|im_end|>

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1,831

[ { "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 Branched-chain amino acid (BCAA) metabolism fulfills numerous physiological roles and can be harnessed to produce valuable chemicals. However, the lack of eukaryotic biosensors specific for BCAA-derived products has limited the ability to develop high-throughput screens for strain engineering and metabolic studies. Here, we harness the transcriptional regulator Leu3p from Saccharomyces cerevisiae to develop a genetically encoded biosensor for BCAA metabolism. In one configuration, we use the biosensor to monitor yeast production of isobutanol, an alcohol derived from valine degradation. Small modifications allow us to redeploy Leu3p in another biosensor configuration that monitors production of the leucine-derived alcohol, isopentanol. These biosensor configurations are effective at isolating high-producing strains and identifying enzymes with enhanced activity from screens for branched-chain higher alcohol (BCHA) biosynthesis in mitochondria as well as cytosol. Furthermore, this biosensor has the potential to assist in metabolic studies involving BCAA pathways, and offers a blueprint to develop biosensors for other products derived from BCAA metabolism. Introduction The metabolism of branched chain amino acids (BCAAs), including valine, leucine, and isoleucine is central to microbial production of many valuable products 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . Among microbial hosts that produce BCAAs and BCAA-derived compounds, the yeast Saccharomyces cerevisiae is a favored industrial organism due to its genetic tractability, resistance to phage contamination, and ability to grow at low pH and high alcohol concentrations 9 . However, the rate at which genetic diversity can be introduced in strains greatly outpaces the rate at which they can be screened for production; and, unfortunately, there are currently no eukaryotic biosensors specific for individual BCAAs and their derived products, which could be used to develop high-throughput screens and accelerate strain development 10 , 11 , 12 , 13 , 14 , 15 . BCAA and BCAA-derived product biosynthesis originates from mitochondrial pyruvate 16 (Supplementary Fig. 1 ). In the biosynthesis of valine and leucine, an acetolactate synthase (ALS, encoded by ILV2 ) first catalyzes the condensation of two pyruvate molecules to produce acetolactate. The subsequent activities of a ketol-acid reductoisomerase (KARI, encoded by ILV5 ), and a dehydroxyacid dehydratase (DHAD, encoded by ILV3 ) yield α-ketoisovalerate (α-KIV), the precursor to valine. Next, α-KIV is acetylated in either mitochondria or the cytosol by α-isopropylmalate (α-IPM) synthases (encoded by LEU4 and LEU9 ) to produce α-IPM. In the cytosol, α-IPM is converted by isopropylmalate isomerase (encoded by LEU1 ) and β-isopropylmalate dehydrogenase (encoded by LEU2 ) to α-ketoisocaproate (α-KIC), the precursor to leucine. Isoleucine biosynthesis resembles that of valine; however for isoleucine, Ilv2p condenses pyruvate with α-ketobutyrate derived from threonine. Subsequent Ilv5p and Ilv3p activity produces α-keto-3-methylvalerate (α-K3MV), the precursor to isoleucine. Finally, the three α-ketoacid precursors (α-KIV, α-KIC, and α-K3MV) are transaminated by branched-chain amino acid aminotransferases in mitochondria (encoded by BAT1 ) and cytosol (encoded by BAT2 ) to produce valine, leucine, and isoleucine, respectively 16 (Supplementary Fig. 1 ). Many biosensors are based on transcription factors (TFs) that activate expression of a reporter gene, such as green fluorescent protein (GFP), in response to elevated concentrations of a specific molecule, which may be a product of interest, by-product, or precursor 12 , 13 , 17 , 18 , 19 . Leu3p is a yeast TF that regulates several genes in BCAA biosynthesis in response to selectively binding to α-IPM, acting as an activator in the presence of α-IPM and a repressor in its absence 20 , 21 , 22 . Because α-IPM is a by-product of valine biosynthesis and an intermediate of leucine biosynthesis (Supplementary Fig. 1 ), its levels are correlated to the activity of both pathways. This makes Leu3p an ideal TF to use in a biosensor for BCAA metabolic activity, which could enable high-throughput screens for production of BCAA-derived products such as branched-chain higher alcohols (BCHAs). There is great interest in producing BCHAs, as they are among the top ten advanced biofuels identified by the U.S. Department of Energy for their potential to boost gasoline engine efficiency 23 , 24 , and can be upgraded to renewable jet fuel 25 . BCHA production can be enhanced by overexpressing enzymes from the Ehrlich degradation pathway 26 . In this pathway, α-ketoacid decarboxylases (α-KDCs) and alcohol dehydrogenases (ADHs) convert the α-ketoacid precursors α-KIV, α-KIC, and α-K3MV to isobutanol, isopentanol, and 2-methyl-1-butanol, respectively (Supplementary Fig. 1 ). Here, we report the development and application of a genetically encoded biosensor for eukaryotic BCAA metabolism and BCHA biosynthesis. The biosensor is based on the α-IPM-dependent function of Leu3p to control expression of GFP. Two biosensor configurations enable high-throughput screening for improved isobutanol or isopentanol production. These two configurations differ mechanistically, by monitoring α-IPM as either a by-product of isobutanol or a precursor of isopentanol. We apply the biosensor to isolate high-producing strains, identify mutant enzymes with enhanced activity, and construct biosynthetic pathways for production of isobutanol and isopentanol in both mitochondria and cytosol. This biosensor has the potential to accelerate the development of yeast strains to produce BCHAs as well as other products derived from BCAA metabolism. Results Design and construction of a biosensor for branched-chain higher alcohol biosynthesis To construct a biosensor for BCHAs, isobutanol and isopentanol, we introduced a copy of yeast-enhanced green fluorescent protein (yEGFP) under the control of the Leu3p-regulated LEU1 promoter (P LEU1 ) and a constitutively expressed leucine-insensitive Leu4p mutant. We tested 8 different biosensor constructs using 4 different Leu4p variants, and the yEGFP tagged or untagged with a proline-glutamate-serine-threonine-rich (PEST) protein degradation tag 27 to test different stability levels of the reporter. We compared the change in fluorescence caused by overexpressing the BCHA biosynthetic pathway in strains with or without a LEU2 deletion, which respectively favors isobutanol or isopentanol production, in a total of 16 different strains (Supplementary Note 1 ). When LEU2 is deleted, the construct using a Leu4p variant with a truncated leucine regulatory domain (Leu4 1–410 ) and a PEST-tagged yEGFP gives the largest change in fluorescence (Supplementary Fig. 2a ). The better performance of the", "role": "user" }, { "content": "Deploying a technique that promises to supercharge the development of biofuels, researchers at Princeton University have found a way to make yeast cultures glow when producing next generation fuels that could power cars and airplanes. The glowing cultures address a major challenge that has slowed biofuel production: developing yeast strains that produce valuable chemicals and separating them from less productive strains of yeast. Before the development of this new technique, evaluating the performance of yeast was a slow, laborious process. Researchers had to grow separate yeast strains and independently evaluate each strain's ability to produce fuel and other chemicals. This process could take days for each strain. \"The way we'd have to find better strains would be to take a few colonies, grow them overnight in cultures, and then start a fermentation process that would take between 24 and 48 hours,\" said lead researcher José Avalos, assistant professor of chemical and biological engineering. \"Now, we're measuring hundreds of thousands of strains per minute. This is a several-orders-of-magnitude faster way to identify better strains.\" In a paper published Jan. 12 in Nature Communications, Avalos's team described how they developed the biosensor for production of the biofuels isobutanol and isopentanol in yeast. Both are alcohols with a higher energy content than ethanol, which is the dominant biofuel now used in the United States. Like ethanol, isobutanol and isopentanol are produced by Brewer's yeast (Saccharomyces cerevisiae), a single-celled fungus commonly used in making bread, beer and other alcoholic beverages. However, these advanced biofuels have much higher compatibility with existing gasoline infrastructure, allowing them to replace more fossil fuel, and can easily be upgraded to jet fuel. \"Scientists, engineers and regulators are still examining them, but these alcohols could be completely compatible with our current gasoline infrastructure,\" said Avalos, the paper's senior author. \"Most cars couldn't use gasoline with ethanol concentrations higher than 10 or 15 percent. However, they could use gasoline with much higher concentrations of isobutanol. So that means you could replace more gasoline with these advanced fuels.\" The current research began with the challenge of speeding up the development of yeast strains for isobutanol and isopentanol production. The rate at which scientists can introduce genetic diversity in yeast greatly outpaces the rate at which they can screen each strain to find those with increased biofuel production. Researchers thus had to figure out which genes to turn on or off and what enzymes or proteins were beneficial to the process using very slow, laborious and expensive methods. \"There are millions of ways to try this until you finally find the best way that works,\" said Jeremy Cortez, a graduate student in molecular biology and one of the paper's authors. \"It would be great if we could just tap into the cell—listen to the metabolic 'talks' the various components within the cell are having among themselves—and have the biosensor tell us it's making a lot of the product, rather than having us go through these long procedures.\" The researchers accomplished this by genetically engineering the cells to produce a fluorescent protein when they were making chemicals for biofuels. Scientists could then use the fluorescence as a sensor to look for production. \"We essentially harnessed this transcription factor so that when the cell is producing more biofuel, it also turns on production of a fluorescent protein,\" said Avalos. \"It's doing what it normally does, but now we can see the cell respond to enhanced metabolic activity. We are no longer blind.\" Ultimately, use of the biosensor provided the researchers the breakthrough they were looking for, one that could hasten the production of advanced biofuels and possibly help phase out the use of carbon-emitting fossil fuels. Avalos said that biofuels can serve as a critical step as the world moves to lower carbon energy. He noted that it will be extremely difficult to electrify cars fast enough to meet the Paris Agreement goal of limiting global warming to 1.5 degrees Celsius above pre-industrial levels. Also, aircraft and some other transportation modes are hard to electrify. Isobutanol can also be used to make jet fuel with a lower carbon footprint. \"The gap between how quickly we need to eliminate fossil fuels and how quickly we can electrify our fleets can be filled with biofuels,\" Avalos said. \"Indeed, it must be done with biofuels if we hope to meet this target.\" This theme of urgency is echoed by Cortez. \"Climate change is happening,\" he said. \"If biosensors can save us time, which they do, then that's the best outcome.\" ", "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 Branched-chain amino acid (BCAA) metabolism fulfills numerous physiological roles and can be harnessed to produce valuable chemicals. However, the lack of eukaryotic biosensors specific for BCAA-derived products has limited the ability to develop high-throughput screens for strain engineering and metabolic studies. Here, we harness the transcriptional regulator Leu3p from Saccharomyces cerevisiae to develop a genetically encoded biosensor for BCAA metabolism. In one configuration, we use the biosensor to monitor yeast production of isobutanol, an alcohol derived from valine degradation. Small modifications allow us to redeploy Leu3p in another biosensor configuration that monitors production of the leucine-derived alcohol, isopentanol. These biosensor configurations are effective at isolating high-producing strains and identifying enzymes with enhanced activity from screens for branched-chain higher alcohol (BCHA) biosynthesis in mitochondria as well as cytosol. Furthermore, this biosensor has the potential to assist in metabolic studies involving BCAA pathways, and offers a blueprint to develop biosensors for other products derived from BCAA metabolism. Introduction The metabolism of branched chain amino acids (BCAAs), including valine, leucine, and isoleucine is central to microbial production of many valuable products 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . Among microbial hosts that produce BCAAs and BCAA-derived compounds, the yeast Saccharomyces cerevisiae is a favored industrial organism due to its genetic tractability, resistance to phage contamination, and ability to grow at low pH and high alcohol concentrations 9 . However, the rate at which genetic diversity can be introduced in strains greatly outpaces the rate at which they can be screened for production; and, unfortunately, there are currently no eukaryotic biosensors specific for individual BCAAs and their derived products, which could be used to develop high-throughput screens and accelerate strain development 10 , 11 , 12 , 13 , 14 , 15 . BCAA and BCAA-derived product biosynthesis originates from mitochondrial pyruvate 16 (Supplementary Fig. 1 ). In the biosynthesis of valine and leucine, an acetolactate synthase (ALS, encoded by ILV2 ) first catalyzes the condensation of two pyruvate molecules to produce acetolactate. The subsequent activities of a ketol-acid reductoisomerase (KARI, encoded by ILV5 ), and a dehydroxyacid dehydratase (DHAD, encoded by ILV3 ) yield α-ketoisovalerate (α-KIV), the precursor to valine. Next, α-KIV is acetylated in either mitochondria or the cytosol by α-isopropylmalate (α-IPM) synthases (encoded by LEU4 and LEU9 ) to produce α-IPM. In the cytosol, α-IPM is converted by isopropylmalate isomerase (encoded by LEU1 ) and β-isopropylmalate dehydrogenase (encoded by LEU2 ) to α-ketoisocaproate (α-KIC), the precursor to leucine. Isoleucine biosynthesis resembles that of valine; however for isoleucine, Ilv2p condenses pyruvate with α-ketobutyrate derived from threonine. Subsequent Ilv5p and Ilv3p activity produces α-keto-3-methylvalerate (α-K3MV), the precursor to isoleucine. Finally, the three α-ketoacid precursors (α-KIV, α-KIC, and α-K3MV) are transaminated by branched-chain amino acid aminotransferases in mitochondria (encoded by BAT1 ) and cytosol (encoded by BAT2 ) to produce valine, leucine, and isoleucine, respectively 16 (Supplementary Fig. 1 ). Many biosensors are based on transcription factors (TFs) that activate expression of a reporter gene, such as green fluorescent protein (GFP), in response to elevated concentrations of a specific molecule, which may be a product of interest, by-product, or precursor 12 , 13 , 17 , 18 , 19 . Leu3p is a yeast TF that regulates several genes in BCAA biosynthesis in response to selectively binding to α-IPM, acting as an activator in the presence of α-IPM and a repressor in its absence 20 , 21 , 22 . Because α-IPM is a by-product of valine biosynthesis and an intermediate of leucine biosynthesis (Supplementary Fig. 1 ), its levels are correlated to the activity of both pathways. This makes Leu3p an ideal TF to use in a biosensor for BCAA metabolic activity, which could enable high-throughput screens for production of BCAA-derived products such as branched-chain higher alcohols (BCHAs). There is great interest in producing BCHAs, as they are among the top ten advanced biofuels identified by the U.S. Department of Energy for their potential to boost gasoline engine efficiency 23 , 24 , and can be upgraded to renewable jet fuel 25 . BCHA production can be enhanced by overexpressing enzymes from the Ehrlich degradation pathway 26 . In this pathway, α-ketoacid decarboxylases (α-KDCs) and alcohol dehydrogenases (ADHs) convert the α-ketoacid precursors α-KIV, α-KIC, and α-K3MV to isobutanol, isopentanol, and 2-methyl-1-butanol, respectively (Supplementary Fig. 1 ). Here, we report the development and application of a genetically encoded biosensor for eukaryotic BCAA metabolism and BCHA biosynthesis. The biosensor is based on the α-IPM-dependent function of Leu3p to control expression of GFP. Two biosensor configurations enable high-throughput screening for improved isobutanol or isopentanol production. These two configurations differ mechanistically, by monitoring α-IPM as either a by-product of isobutanol or a precursor of isopentanol. We apply the biosensor to isolate high-producing strains, identify mutant enzymes with enhanced activity, and construct biosynthetic pathways for production of isobutanol and isopentanol in both mitochondria and cytosol. This biosensor has the potential to accelerate the development of yeast strains to produce BCHAs as well as other products derived from BCAA metabolism. Results Design and construction of a biosensor for branched-chain higher alcohol biosynthesis To construct a biosensor for BCHAs, isobutanol and isopentanol, we introduced a copy of yeast-enhanced green fluorescent protein (yEGFP) under the control of the Leu3p-regulated LEU1 promoter (P LEU1 ) and a constitutively expressed leucine-insensitive Leu4p mutant. We tested 8 different biosensor constructs using 4 different Leu4p variants, and the yEGFP tagged or untagged with a proline-glutamate-serine-threonine-rich (PEST) protein degradation tag 27 to test different stability levels of the reporter. We compared the change in fluorescence caused by overexpressing the BCHA biosynthetic pathway in strains with or without a LEU2 deletion, which respectively favors isobutanol or isopentanol production, in a total of 16 different strains (Supplementary Note 1 ). When LEU2 is deleted, the construct using a Leu4p variant with a truncated leucine regulatory domain (Leu4 1–410 ) and a PEST-tagged yEGFP gives the largest change in fluorescence (Supplementary Fig. 2a ). The better performance of the<|im_end|> <|im_start|>assistant Deploying a technique that promises to supercharge the development of biofuels, researchers at Princeton University have found a way to make yeast cultures glow when producing next generation fuels that could power cars and airplanes. The glowing cultures address a major challenge that has slowed biofuel production: developing yeast strains that produce valuable chemicals and separating them from less productive strains of yeast. Before the development of this new technique, evaluating the performance of yeast was a slow, laborious process. Researchers had to grow separate yeast strains and independently evaluate each strain's ability to produce fuel and other chemicals. This process could take days for each strain. "The way we'd have to find better strains would be to take a few colonies, grow them overnight in cultures, and then start a fermentation process that would take between 24 and 48 hours," said lead researcher José Avalos, assistant professor of chemical and biological engineering. "Now, we're measuring hundreds of thousands of strains per minute. This is a several-orders-of-magnitude faster way to identify better strains." In a paper published Jan. 12 in Nature Communications, Avalos's team described how they developed the biosensor for production of the biofuels isobutanol and isopentanol in yeast. Both are alcohols with a higher energy content than ethanol, which is the dominant biofuel now used in the United States. Like ethanol, isobutanol and isopentanol are produced by Brewer's yeast (Saccharomyces cerevisiae), a single-celled fungus commonly used in making bread, beer and other alcoholic beverages. However, these advanced biofuels have much higher compatibility with existing gasoline infrastructure, allowing them to replace more fossil fuel, and can easily be upgraded to jet fuel. "Scientists, engineers and regulators are still examining them, but these alcohols could be completely compatible with our current gasoline infrastructure," said Avalos, the paper's senior author. "Most cars couldn't use gasoline with ethanol concentrations higher than 10 or 15 percent. However, they could use gasoline with much higher concentrations of isobutanol. So that means you could replace more gasoline with these advanced fuels." The current research began with the challenge of speeding up the development of yeast strains for isobutanol and isopentanol production. The rate at which scientists can introduce genetic diversity in yeast greatly outpaces the rate at which they can screen each strain to find those with increased biofuel production. Researchers thus had to figure out which genes to turn on or off and what enzymes or proteins were beneficial to the process using very slow, laborious and expensive methods. "There are millions of ways to try this until you finally find the best way that works," said Jeremy Cortez, a graduate student in molecular biology and one of the paper's authors. "It would be great if we could just tap into the cell—listen to the metabolic 'talks' the various components within the cell are having among themselves—and have the biosensor tell us it's making a lot of the product, rather than having us go through these long procedures." The researchers accomplished this by genetically engineering the cells to produce a fluorescent protein when they were making chemicals for biofuels. Scientists could then use the fluorescence as a sensor to look for production. "We essentially harnessed this transcription factor so that when the cell is producing more biofuel, it also turns on production of a fluorescent protein," said Avalos. "It's doing what it normally does, but now we can see the cell respond to enhanced metabolic activity. We are no longer blind." Ultimately, use of the biosensor provided the researchers the breakthrough they were looking for, one that could hasten the production of advanced biofuels and possibly help phase out the use of carbon-emitting fossil fuels. Avalos said that biofuels can serve as a critical step as the world moves to lower carbon energy. He noted that it will be extremely difficult to electrify cars fast enough to meet the Paris Agreement goal of limiting global warming to 1.5 degrees Celsius above pre-industrial levels. Also, aircraft and some other transportation modes are hard to electrify. Isobutanol can also be used to make jet fuel with a lower carbon footprint. "The gap between how quickly we need to eliminate fossil fuels and how quickly we can electrify our fleets can be filled with biofuels," Avalos said. "Indeed, it must be done with biofuels if we hope to meet this target." This theme of urgency is echoed by Cortez. "Climate change is happening," he said. "If biosensors can save us time, which they do, then that's the best outcome." <|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 Increasingly large proportions of tropical forests are anthropogenically disturbed. Where natural regeneration is possible at all, it requires the input of plant seeds through seed dispersal from the forest matrix. Zoochorous seed dispersal – the major seed dispersal mode for woody plants in tropical forests – is particularly important for natural regeneration. In this study, covering a period of more than 20 years, we show that small New World primates, the tamarins Saguinus mystax and Leontocebus nigrifrons , increase their use of an anthropogenically disturbed area over time and disperse seeds from primary forest tree species into this area. Through monitoring the fate of seeds and through parentage analyses of seedlings of the legume Parkia panurensis from the disturbed area and candidate parents from the primary forest matrix, we show that tamarin seed dispersal is effective and contributes to the natural regeneration of the disturbed area. Introduction The extent of tropical forests is declining worldwide 1 and in the Neotropics, moist forests suffer the strongest net loss 2 . Where forests are not irreversibly destroyed (through construction of hydroelectric dams, roads etc.) or converted into permanent agricultural areas, deforested areas may regenerate into old-growth forest through various phases of secondary growth 3 , 4 . This regeneration process is promoted by seed dispersal into deforested areas 5 , 6 with the importance of zoochorous dispersal by frugivorous animals increasing with the age of the regenerating area 7 , 8 . In early stages of regeneration, flying vertebrates – bats and birds – may drop seeds in defecations while flying over the area or roosting in remnant trees 9 , 10 . With increasing tree cover, arboreal mammals like primates can visit and disperse seeds into regenerating areas. Tamarins, small Neotropical primates from the family Callitrichidae, are tolerant to high levels of forest disturbance. They use, persist in or might even prefer secondary forest 11 , 12 , 13 , 14 . Tamarins are highly frugivorous, disperse seeds from a broad spectrum of plant species 15 , 16 , 17 , and also disperse seeds into secondary forests 18 , 19 . While there is evidence for seasonality in the use of secondary forests 19 , 20 , long-term trends or patterns in tamarins’ use of secondary forest, particularly in early stages of regeneration have not been examined. This is, however, relevant for evaluating the contribution they can make to natural regeneration of such areas. Therefore, in this study we examine (1) how the use of an anthropogenically degraded (clear-cut for buffalo pasture), but regenerating area (in the following we use the term “secondary forest” for this area) by tamarins changes over time; (2) which plant species attract tamarins to the secondary forest; and (3) whether seed dispersal into the secondary forest contributes to natural regeneration. We use long-term ranging and feeding data from a population of two sympatric tamarin species, Leontocebus nigrifrons (previously Saguinus fuscicollis nigrifrons ; see 21 , 22 and Saguinus mystax , for examining the first and second question. The third question is tackled by (a) following the fate of tamarin-dispersed seeds from a diversity of plant species in the secondary forest; and (b) genotyping seedlings of a tamarin-dispersed tree species, Parkia panurensis , growing in the secondary forest and from adults growing the adjacent primary forest and subsequent parentage analyses. This plant species is particularly suitable for examining the role of tamarins for regeneration, as these primates are the exclusive seed dispersers of P. panurensis at our study site. Results Temporal patterns in the use of the secondary forest Tamarins were first observed to enter the secondary forest in 2000, i.e. the year in which the pasture was abandoned. Between 2000 and 2003, they spent generally <1.5% of the yearly activity period in secondary forest; thereafter, time in the secondary forest strongly increased but showed fluctuations with pronounced peaks in 2006 and 2012 and lows in 2008 and 2009 (Fig. 1a ). Although time in the secondary forest tended to be higher from June to November (Fig. 1b ), monthly variation was not significant (ANOVA: F 1,11 = 1.022, n.s.). The proportion of time in the secondary forest was on average two times higher in months with <250 mm compared to months with ≥250 mm rainfall (Fig. 2 ), but the difference was only marginally significant (t 78 = −1.951, p = 0.055). Figure 1 Temporal patterns of secondary forest use by the tamarins. ( a ) Long-term pattern (yearly means), corrected for uneven representation of months and potential seasonal variation. ( b ) Yearly pattern ( ● : monthly means; whiskers: monthly minima and maxima). Blue dots: months with ≥250 mm of rainfall; orange dots: months with <250 mm of rainfall. Full size image Figure 2 Use of secondary forest in months with ≥250 mm of rainfall and <250 mm of rainfall. ● : means; ○ : outliers; *extremes. Full size image Feeding patterns in the secondary forest A total of 31 plant species were exploited for fruit in the secondary forest (Supplementary Information [Supplementary Table 1 ]). This corresponded to ca. 10% of the total number of plant species exploited by tamarins for fruit, nectar or exudate. While in 2000 only one fruit species was consumed in the secondary forest ( Miconia ternatifolia ), the six fruit species were consumed in 2005 (4 observation months), 12 in 2006 (8 observation months), 16 in 2007 (7 observation months), and 19 in 2008 (6 observation months). Seedling recruitment in the secondary forest We followed the fate of 487 identified seeds for at least one year; 47 seeds (9.6%) were dispersed from primary into secondary forest. Of these 47, 15 (31.9%) seeds dispersed into secondary forest survived for at least one year and germinated. In comparison, 82 out of 440 (18.6%) seeds dispersed in primary forest recruited and survived for at least one year. Recruited seedlings in secondary forest belonged to eight species: Inga acrocephala, Inga lopadadenia, Inga umbellifera, Parkia panurensis (all Fabaceae); Dicranostyles aff. scandens", "role": "user" }, { "content": "Tropical rainforests store large quantities of carbon dioxide, produce oxygen and provide habitats for many animal and plant species. If these ecosystems, which are so important for the global climate and biodiversity, are destroyed, they will recover very slowly, if at all. Scientists from the German Primate Center (DPZ) - Leibniz Institute for Primate Research, the University Estadual Paulista, Brazil, and the University of Marburg have conducted a long-term study on the role monkeys play in the regeneration of degraded rainforests. For over 20 years, they observed two tamarin species in the rainforest of Peru. These animals feed on fruits and void the seeds undigested with their faeces. The researchers have studied the dispersal and germination of seeds as well as the growth and genetic origin of various plants in a forest that had emerged from a former pasture. For the first time, they were able to prove that monkeys have a decisive influence on the dispersal of seeds from the original primary forest to the regenerating secondary forest (Scientific Reports). The study was carried out in the Peruvian Amazon rainforest at the Estación Biológica Quebrada Blanco research station of the German Primate Center. Near the station there is an area of about four hectares which was cleared and used as pasture for water buffalo between 1990 and 2000. After the grazing was abandoned, rainforest slowly developed again. The researchers around Eckhard W. Heymann, scientist at the German Primate Center and head of the study, observed that moustached and black-fronted tamarins were temporarily in the early secondary forest. Tamarins feed mainly on fruits and disperse the seeds of many different tropical trees and lianas over their faeces. \"We wanted to find out whether the seed dispersal by monkeys has a demonstrable effect on the natural regeneration of forests,\" says Heymann. To investigate which seeds were dispersed from the primary forest to the secondary forest, the researchers identified seeds from the monkeys' faeces and observed their development in the secondary forest. Around ten per cent of these seeds stem from plants growing in the primary forest and were dispersed into the secondary forest. A part of these seeds germinated and the resulting seedlings survived for at least one year. These seedlings could be assigned to eight different plant species. Seven of these species could only be found as adult plants in the nearby primary forest. A secondary forest growing on a former water buffalo pasture. The regenerating forest consists of young, smaller trees and a dense herb layer, as more light reaches the ground. Credit: Eckhard W. Heymann, German Primate Center, Germany In order to genetically verify the results, the scientists analyzed seedlings and young plants of the neotropic tree Parkia panurensis. The seeds of this tree are dispersed exclusively by tamarins in the area around the DPZ research station. The researchers extracted the DNA from leaves of seedlings and young plants growing in the secondary forest and compared the genotype with those of adult Parkia trees in the primary forest. Half of these seedlings and young plants could be matched to eleven parent trees in the primary forest. The distances between young and parent plants were exactly in the range over which the tamarins disperse Parkia seeds. \"Our data show for the first time that the moustached and black-fronted tamarins effectively disperse seeds from primary forest into secondary forest,\" says Heymann. \"We were able to prove that the seeds germinate and form young plants, thus increasing the diversity of species in the secondary forest. The tamarins have been shown to contribute to the natural regeneration of areas destroyed by humans.\" The study included data collected at the DPZ research station since 1994, but not initially against the background of the current issue. \"At that time, we did not expect the cleared forest area to ever recover,\" emphasizes Heymann. \"However, the study shows how important data collection and investigations over a very long period of time are in order to be able to make reliable statements about slowly developing ecological processes.\" ", "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 Increasingly large proportions of tropical forests are anthropogenically disturbed. Where natural regeneration is possible at all, it requires the input of plant seeds through seed dispersal from the forest matrix. Zoochorous seed dispersal – the major seed dispersal mode for woody plants in tropical forests – is particularly important for natural regeneration. In this study, covering a period of more than 20 years, we show that small New World primates, the tamarins Saguinus mystax and Leontocebus nigrifrons , increase their use of an anthropogenically disturbed area over time and disperse seeds from primary forest tree species into this area. Through monitoring the fate of seeds and through parentage analyses of seedlings of the legume Parkia panurensis from the disturbed area and candidate parents from the primary forest matrix, we show that tamarin seed dispersal is effective and contributes to the natural regeneration of the disturbed area. Introduction The extent of tropical forests is declining worldwide 1 and in the Neotropics, moist forests suffer the strongest net loss 2 . Where forests are not irreversibly destroyed (through construction of hydroelectric dams, roads etc.) or converted into permanent agricultural areas, deforested areas may regenerate into old-growth forest through various phases of secondary growth 3 , 4 . This regeneration process is promoted by seed dispersal into deforested areas 5 , 6 with the importance of zoochorous dispersal by frugivorous animals increasing with the age of the regenerating area 7 , 8 . In early stages of regeneration, flying vertebrates – bats and birds – may drop seeds in defecations while flying over the area or roosting in remnant trees 9 , 10 . With increasing tree cover, arboreal mammals like primates can visit and disperse seeds into regenerating areas. Tamarins, small Neotropical primates from the family Callitrichidae, are tolerant to high levels of forest disturbance. They use, persist in or might even prefer secondary forest 11 , 12 , 13 , 14 . Tamarins are highly frugivorous, disperse seeds from a broad spectrum of plant species 15 , 16 , 17 , and also disperse seeds into secondary forests 18 , 19 . While there is evidence for seasonality in the use of secondary forests 19 , 20 , long-term trends or patterns in tamarins’ use of secondary forest, particularly in early stages of regeneration have not been examined. This is, however, relevant for evaluating the contribution they can make to natural regeneration of such areas. Therefore, in this study we examine (1) how the use of an anthropogenically degraded (clear-cut for buffalo pasture), but regenerating area (in the following we use the term “secondary forest” for this area) by tamarins changes over time; (2) which plant species attract tamarins to the secondary forest; and (3) whether seed dispersal into the secondary forest contributes to natural regeneration. We use long-term ranging and feeding data from a population of two sympatric tamarin species, Leontocebus nigrifrons (previously Saguinus fuscicollis nigrifrons ; see 21 , 22 and Saguinus mystax , for examining the first and second question. The third question is tackled by (a) following the fate of tamarin-dispersed seeds from a diversity of plant species in the secondary forest; and (b) genotyping seedlings of a tamarin-dispersed tree species, Parkia panurensis , growing in the secondary forest and from adults growing the adjacent primary forest and subsequent parentage analyses. This plant species is particularly suitable for examining the role of tamarins for regeneration, as these primates are the exclusive seed dispersers of P. panurensis at our study site. Results Temporal patterns in the use of the secondary forest Tamarins were first observed to enter the secondary forest in 2000, i.e. the year in which the pasture was abandoned. Between 2000 and 2003, they spent generally <1.5% of the yearly activity period in secondary forest; thereafter, time in the secondary forest strongly increased but showed fluctuations with pronounced peaks in 2006 and 2012 and lows in 2008 and 2009 (Fig. 1a ). Although time in the secondary forest tended to be higher from June to November (Fig. 1b ), monthly variation was not significant (ANOVA: F 1,11 = 1.022, n.s.). The proportion of time in the secondary forest was on average two times higher in months with <250 mm compared to months with ≥250 mm rainfall (Fig. 2 ), but the difference was only marginally significant (t 78 = −1.951, p = 0.055). Figure 1 Temporal patterns of secondary forest use by the tamarins. ( a ) Long-term pattern (yearly means), corrected for uneven representation of months and potential seasonal variation. ( b ) Yearly pattern ( ● : monthly means; whiskers: monthly minima and maxima). Blue dots: months with ≥250 mm of rainfall; orange dots: months with <250 mm of rainfall. Full size image Figure 2 Use of secondary forest in months with ≥250 mm of rainfall and <250 mm of rainfall. ● : means; ○ : outliers; *extremes. Full size image Feeding patterns in the secondary forest A total of 31 plant species were exploited for fruit in the secondary forest (Supplementary Information [Supplementary Table 1 ]). This corresponded to ca. 10% of the total number of plant species exploited by tamarins for fruit, nectar or exudate. While in 2000 only one fruit species was consumed in the secondary forest ( Miconia ternatifolia ), the six fruit species were consumed in 2005 (4 observation months), 12 in 2006 (8 observation months), 16 in 2007 (7 observation months), and 19 in 2008 (6 observation months). Seedling recruitment in the secondary forest We followed the fate of 487 identified seeds for at least one year; 47 seeds (9.6%) were dispersed from primary into secondary forest. Of these 47, 15 (31.9%) seeds dispersed into secondary forest survived for at least one year and germinated. In comparison, 82 out of 440 (18.6%) seeds dispersed in primary forest recruited and survived for at least one year. Recruited seedlings in secondary forest belonged to eight species: Inga acrocephala, Inga lopadadenia, Inga umbellifera, Parkia panurensis (all Fabaceae); Dicranostyles aff. scandens<|im_end|> <|im_start|>assistant Tropical rainforests store large quantities of carbon dioxide, produce oxygen and provide habitats for many animal and plant species. If these ecosystems, which are so important for the global climate and biodiversity, are destroyed, they will recover very slowly, if at all. Scientists from the German Primate Center (DPZ) - Leibniz Institute for Primate Research, the University Estadual Paulista, Brazil, and the University of Marburg have conducted a long-term study on the role monkeys play in the regeneration of degraded rainforests. For over 20 years, they observed two tamarin species in the rainforest of Peru. These animals feed on fruits and void the seeds undigested with their faeces. The researchers have studied the dispersal and germination of seeds as well as the growth and genetic origin of various plants in a forest that had emerged from a former pasture. For the first time, they were able to prove that monkeys have a decisive influence on the dispersal of seeds from the original primary forest to the regenerating secondary forest (Scientific Reports). The study was carried out in the Peruvian Amazon rainforest at the Estación Biológica Quebrada Blanco research station of the German Primate Center. Near the station there is an area of about four hectares which was cleared and used as pasture for water buffalo between 1990 and 2000. After the grazing was abandoned, rainforest slowly developed again. The researchers around Eckhard W. Heymann, scientist at the German Primate Center and head of the study, observed that moustached and black-fronted tamarins were temporarily in the early secondary forest. Tamarins feed mainly on fruits and disperse the seeds of many different tropical trees and lianas over their faeces. "We wanted to find out whether the seed dispersal by monkeys has a demonstrable effect on the natural regeneration of forests," says Heymann. To investigate which seeds were dispersed from the primary forest to the secondary forest, the researchers identified seeds from the monkeys' faeces and observed their development in the secondary forest. Around ten per cent of these seeds stem from plants growing in the primary forest and were dispersed into the secondary forest. A part of these seeds germinated and the resulting seedlings survived for at least one year. These seedlings could be assigned to eight different plant species. Seven of these species could only be found as adult plants in the nearby primary forest. A secondary forest growing on a former water buffalo pasture. The regenerating forest consists of young, smaller trees and a dense herb layer, as more light reaches the ground. Credit: Eckhard W. Heymann, German Primate Center, Germany In order to genetically verify the results, the scientists analyzed seedlings and young plants of the neotropic tree Parkia panurensis. The seeds of this tree are dispersed exclusively by tamarins in the area around the DPZ research station. The researchers extracted the DNA from leaves of seedlings and young plants growing in the secondary forest and compared the genotype with those of adult Parkia trees in the primary forest. Half of these seedlings and young plants could be matched to eleven parent trees in the primary forest. The distances between young and parent plants were exactly in the range over which the tamarins disperse Parkia seeds. "Our data show for the first time that the moustached and black-fronted tamarins effectively disperse seeds from primary forest into secondary forest," says Heymann. "We were able to prove that the seeds germinate and form young plants, thus increasing the diversity of species in the secondary forest. The tamarins have been shown to contribute to the natural regeneration of areas destroyed by humans." The study included data collected at the DPZ research station since 1994, but not initially against the background of the current issue. "At that time, we did not expect the cleared forest area to ever recover," emphasizes Heymann. "However, the study shows how important data collection and investigations over a very long period of time are in order to be able to make reliable statements about slowly developing ecological processes." <|im_end|>

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311, 387, 3025, 311, 1304, 15062, 12518, 922, 14297, 11469, 50953, 11618, 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 To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability. Main Microcephalic primordial dwarfism (MPD) is the collective term for a group of human disorders characterized by intra-uterine and postnatal growth delay alongside marked microcephaly 1 , and it includes disorders such as microcephalic osteodysplastic primordial dwarfism type 2 (MOPD 2), ATR–Seckel syndrome (SCKL1) and Meier–Gorlin syndrome. Mutations in genes encoding either components of the DNA replication machinery (replisome) or proteins involved in genome stability are a frequent cause of microcephalic dwarfism 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 . During the course of normal DNA replication, a subset of replication forks may stall, causing 'replication stress' 15 . This stalling can be caused by endogenous or exogenous sources, such as collision of the replisome with DNA lesions or the transcriptional machinery, or by the replication of difficult-to-replicate genomic regions. To facilitate efficient genome duplication, stalled replication forks must be stabilized and protected from collapse. Multiple factors safeguard replication fork stability, many of which function within the ATR–CHK1-dependent replication stress response 16 , 17 , 18 . This pathway ensures that fork stabilization is tightly coordinated with a global reduction in DNA synthesis, allowing stalled or damaged forks to be repaired and restarted 19 , 20 . Exome-sequencing analysis of patients with microcephalic dwarfism has identified several previously unknown factors that regulate replication and/or the replication stress response. Using this strategy, we recently identified mutations in TRAIP in individuals with MPD 5 and demonstrated that TRAIP is required for the response to replication-blocking DNA lesions. To identify similar disease-associated genes, we performed whole-exome sequencing (WES) of genetically uncharacterized patients with microcephaly. Here we report the identification of DONSON as a new gene involved in microcephalic dwarfism, and demonstrate that DONSON is a previously unrecognized replisome component that maintains genome stability by protecting stalled or damaged replication forks. Results Mutations in DONSON in patients with microcephalic dwarfism We performed WES on 26 patients with microcephaly and reduced stature. After aligning the WES reads to the reference genome, variant-calling and filtering for rare variants (minor-allele frequency < 0.005), we performed analysis under a recessive model of inheritance and identified rare biallelic mutations in the DONSON gene in nine affected individuals from seven families. Sanger capillary sequencing confirmed the presence of these mutations in the patients (P1-1 to P3, P6, and P9 to P11; Table 1 ). Subsequent resequencing of an additional 230 patients with primary microcephaly, microcephaly with reduced stature or MPD identified five additional families with compound heterozygous mutations in DONSON (P4, P5, P7, P8 and P12; Table 1 ). All of the variants segregated among family members in a manner consistent with an autosomal recessive trait and were present at a frequency of <0.5% in the ExAC database 21 . Table 1 Biallelic DONSON mutations identified in 29 individuals Full size table Two other concurrent molecular genetic studies provided further independent evidence to support the identification of DONSON as a previously uncharacterized gene involved in human disease. First, we performed exome sequencing on a consanguineous Palestinian family that was previously reported to have a Fanconi anemia–like disorder 22 . These patients presented with microcephaly, short stature, slow growth, and forearm and thumb dysplasia, although none of the individuals had hematological evidence of bone marrow failure. This WES analysis identified a deleterious homozygous transition, c.1337T>C, which resulted in substitution of a highly conserved residue (p.M446T) in all three affected individuals (P13-1, P13-2 and P13-3; Supplementary Fig. 1 and Table 1 ). Second, we studied five consanguineous families in Saudi Arabia with extreme microcephaly and short stature and mapped a 1.6-Mb haplotype on chromosome 21 that contained DONSON , which was shared by all five families (combined multipoint logarithm-of-the-odds score ( Z ) = 8.0). Whole-exome and genome sequencing identified a single rare variant at this locus in DONSON , c.786-22A>G. Capillary sequencing confirmed this intronic variant to be homozygous in all seven affected individuals from this study (P14 to P18-3; Table 1 ), and identical to that detected in two individuals from Saudi Arabia who were present within the first study described above (P11, P12). Subsequently, we identified five more individuals from three different families with DONSON mutations from additional patients with MPD who were recruited to two of the genetic studies described above (P19 to P21-2; Table 1 ). Mutations in DONSON lead to microcephaly and short stature Despite their identification in separate studies, all of the patients with DONSON mutations had similar clinical phenotypes. Marked microcephaly was present (occipital frontal circumference (OFC) –7.5 ± 2.4 s.d.), with a substantial reduction in cerebral cortical size, along with decreased gyral folding that was evident by neuroimaging ( Fig. 1a and Supplementary Fig. 2 ), similar to that previously reported for other patients with primary microcephaly and microcephalic dwarfism 5 , 23 , 24 , 25 . Height was reduced (–3.2 ± 1.4 s.d.), although much less so than head circumference ( Fig. 1a ), and to a lesser degree", "role": "user" }, { "content": "A new study shows how errors in a specific gene can cause growth defects associated with a rare type of dwarfism. During the study, published today in Nature Genetics, an international team of scientists led by the University of Birmingham looked at genetic information from more than 250 people around the world with microcephalic dwarfism, a group of disorders characterised by short stature and reduced head size. They found that 29 of the individuals had faulty versions of a gene called DONSON. Tests on cells growing in the laboratory revealed that this gene plays a crucial role in ensuring DNA is copied correctly when cells divide and grow. Cells from patients with mutations in the DONSON gene had difficulty in efficiently replicating their DNA and protecting it from uncontrolled damage, ultimately leading to the growth defects typical of microcephalic dwarfism. This research raises the potential of more accurate diagnoses for patients with genetic microcephaly, in addition to providing an insight into how similar rare hereditary diseases are caused. Professor Grant Stewart, from the Institute of Cancer and Genomic Sciences at the University of Birmingham, says: 'Despite DNA replication being a process that is fundamental to life, there is still a lot we don't know. This research sheds new light on the mechanisms underlying DNA replication, and the effect on human health when this process goes wrong.' Professor Andrew Jackson, of the University of Edinburgh's Institute for Genetics and Molecular Medicine, says: 'Identification of DONSON as a microcephaly gene has given us new insights into how the genome is protected during DNA replication, and has only been possible through the close collaboration and contributions of families, clinicians and scientists from many countries around the world.' Professor Christopher Mathew, from the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' and King's College London, adds: 'This is a good example of how unravelling the genetics of rare human disorders can provide profound insight into basic biological processes.' Professor Fowzan Alkuraya, from the King Faisal Specialist Hospital and Research Center, also adds: 'The DONSON story is a remarkable example of how loss of a very basic cellular function can result in a phenotype that ranges from embryonic lethal to one characterized by growth deficiency of brain and body depending on the severity of the mutation. It is also a reminder of the contribution of tricky deep splicing mutations to human 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 To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability. Main Microcephalic primordial dwarfism (MPD) is the collective term for a group of human disorders characterized by intra-uterine and postnatal growth delay alongside marked microcephaly 1 , and it includes disorders such as microcephalic osteodysplastic primordial dwarfism type 2 (MOPD 2), ATR–Seckel syndrome (SCKL1) and Meier–Gorlin syndrome. Mutations in genes encoding either components of the DNA replication machinery (replisome) or proteins involved in genome stability are a frequent cause of microcephalic dwarfism 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 . During the course of normal DNA replication, a subset of replication forks may stall, causing 'replication stress' 15 . This stalling can be caused by endogenous or exogenous sources, such as collision of the replisome with DNA lesions or the transcriptional machinery, or by the replication of difficult-to-replicate genomic regions. To facilitate efficient genome duplication, stalled replication forks must be stabilized and protected from collapse. Multiple factors safeguard replication fork stability, many of which function within the ATR–CHK1-dependent replication stress response 16 , 17 , 18 . This pathway ensures that fork stabilization is tightly coordinated with a global reduction in DNA synthesis, allowing stalled or damaged forks to be repaired and restarted 19 , 20 . Exome-sequencing analysis of patients with microcephalic dwarfism has identified several previously unknown factors that regulate replication and/or the replication stress response. Using this strategy, we recently identified mutations in TRAIP in individuals with MPD 5 and demonstrated that TRAIP is required for the response to replication-blocking DNA lesions. To identify similar disease-associated genes, we performed whole-exome sequencing (WES) of genetically uncharacterized patients with microcephaly. Here we report the identification of DONSON as a new gene involved in microcephalic dwarfism, and demonstrate that DONSON is a previously unrecognized replisome component that maintains genome stability by protecting stalled or damaged replication forks. Results Mutations in DONSON in patients with microcephalic dwarfism We performed WES on 26 patients with microcephaly and reduced stature. After aligning the WES reads to the reference genome, variant-calling and filtering for rare variants (minor-allele frequency < 0.005), we performed analysis under a recessive model of inheritance and identified rare biallelic mutations in the DONSON gene in nine affected individuals from seven families. Sanger capillary sequencing confirmed the presence of these mutations in the patients (P1-1 to P3, P6, and P9 to P11; Table 1 ). Subsequent resequencing of an additional 230 patients with primary microcephaly, microcephaly with reduced stature or MPD identified five additional families with compound heterozygous mutations in DONSON (P4, P5, P7, P8 and P12; Table 1 ). All of the variants segregated among family members in a manner consistent with an autosomal recessive trait and were present at a frequency of <0.5% in the ExAC database 21 . Table 1 Biallelic DONSON mutations identified in 29 individuals Full size table Two other concurrent molecular genetic studies provided further independent evidence to support the identification of DONSON as a previously uncharacterized gene involved in human disease. First, we performed exome sequencing on a consanguineous Palestinian family that was previously reported to have a Fanconi anemia–like disorder 22 . These patients presented with microcephaly, short stature, slow growth, and forearm and thumb dysplasia, although none of the individuals had hematological evidence of bone marrow failure. This WES analysis identified a deleterious homozygous transition, c.1337T>C, which resulted in substitution of a highly conserved residue (p.M446T) in all three affected individuals (P13-1, P13-2 and P13-3; Supplementary Fig. 1 and Table 1 ). Second, we studied five consanguineous families in Saudi Arabia with extreme microcephaly and short stature and mapped a 1.6-Mb haplotype on chromosome 21 that contained DONSON , which was shared by all five families (combined multipoint logarithm-of-the-odds score ( Z ) = 8.0). Whole-exome and genome sequencing identified a single rare variant at this locus in DONSON , c.786-22A>G. Capillary sequencing confirmed this intronic variant to be homozygous in all seven affected individuals from this study (P14 to P18-3; Table 1 ), and identical to that detected in two individuals from Saudi Arabia who were present within the first study described above (P11, P12). Subsequently, we identified five more individuals from three different families with DONSON mutations from additional patients with MPD who were recruited to two of the genetic studies described above (P19 to P21-2; Table 1 ). Mutations in DONSON lead to microcephaly and short stature Despite their identification in separate studies, all of the patients with DONSON mutations had similar clinical phenotypes. Marked microcephaly was present (occipital frontal circumference (OFC) –7.5 ± 2.4 s.d.), with a substantial reduction in cerebral cortical size, along with decreased gyral folding that was evident by neuroimaging ( Fig. 1a and Supplementary Fig. 2 ), similar to that previously reported for other patients with primary microcephaly and microcephalic dwarfism 5 , 23 , 24 , 25 . Height was reduced (–3.2 ± 1.4 s.d.), although much less so than head circumference ( Fig. 1a ), and to a lesser degree<|im_end|> <|im_start|>assistant A new study shows how errors in a specific gene can cause growth defects associated with a rare type of dwarfism. During the study, published today in Nature Genetics, an international team of scientists led by the University of Birmingham looked at genetic information from more than 250 people around the world with microcephalic dwarfism, a group of disorders characterised by short stature and reduced head size. They found that 29 of the individuals had faulty versions of a gene called DONSON. Tests on cells growing in the laboratory revealed that this gene plays a crucial role in ensuring DNA is copied correctly when cells divide and grow. Cells from patients with mutations in the DONSON gene had difficulty in efficiently replicating their DNA and protecting it from uncontrolled damage, ultimately leading to the growth defects typical of microcephalic dwarfism. This research raises the potential of more accurate diagnoses for patients with genetic microcephaly, in addition to providing an insight into how similar rare hereditary diseases are caused. Professor Grant Stewart, from the Institute of Cancer and Genomic Sciences at the University of Birmingham, says: 'Despite DNA replication being a process that is fundamental to life, there is still a lot we don't know. This research sheds new light on the mechanisms underlying DNA replication, and the effect on human health when this process goes wrong.' Professor Andrew Jackson, of the University of Edinburgh's Institute for Genetics and Molecular Medicine, says: 'Identification of DONSON as a microcephaly gene has given us new insights into how the genome is protected during DNA replication, and has only been possible through the close collaboration and contributions of families, clinicians and scientists from many countries around the world.' Professor Christopher Mathew, from the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' and King's College London, adds: 'This is a good example of how unravelling the genetics of rare human disorders can provide profound insight into basic biological processes.' Professor Fowzan Alkuraya, from the King Faisal Specialist Hospital and Research Center, also adds: 'The DONSON story is a remarkable example of how loss of a very basic cellular function can result in a phenotype that ranges from embryonic lethal to one characterized by growth deficiency of brain and body depending on the severity of the mutation. It is also a reminder of the contribution of tricky deep splicing mutations to human 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 The epigenome is established and maintained by the site-specific recruitment of chromatin-modifying enzymes and their cofactors. Identifying the cis elements that regulate epigenomic modification is critical for understanding the regulatory mechanisms that control gene expression patterns. We present Epigram, an analysis pipeline that predicts histone modification and DNA methylation patterns from DNA motifs. The identified cis elements represent interactions with the site-specific DNA-binding factors that establish and maintain epigenomic modifications. We cataloged the cis elements in embryonic stem cells and four derived lineages and found numerous motifs that have location preference, such as at the center of H3K27ac or at the edges of H3K4me3 and H3K9me3, which provides mechanistic insight about the shaping of the epigenome. The Epigram pipeline and predictive motifs are at . Main Epigenomic modifications, including histone modifications and DNA methylation, play critical roles in development and other key biological processes. The establishment and maintenance of specific epigenomic patterns are regulated by many factors. But how exactly these mechanisms collectively regulate the epigenome, and the importance of cis -regulatory motifs, remains unclear. The genome sequence is unchanged between an individual's different cell types; but the expression and activity of chromatin-modifying enzymes and their cofactors vary between cell types and cellular conditions ( Fig. 1a ). Epigenomic regulatory mechanisms use combinations of enzymes and cofactors to read a cis -regulatory code that defines locus-specific modification patterns. Therefore, given a particular epigenomic state, it is possible to identify the cis elements that interact with epigenomic modifications and are responsible for their establishment and/or maintenance ( Fig. 1b ). A global picture of the cis -regulatory code that regulates the epigenome may emerge from surveying a diversity of cell types and conditions. Indeed, evidence supporting the importance of cis -regulatory code in shaping the epigenome is rapidly accumulating 1 . For example: (G+C)-rich sequences are strongly correlated with trimethylation of histone 3 lysine 27 (H3K27me3; ref. 2 ) and H3K4me3 (ref. 3 ); (G+C)-rich motifs establish H3K27me3 by recruiting the Polycomb repressive complex 2 (PRC2) through interaction with long noncoding RNAs 4 , 5 ; the CpG-binding protein, CFP1, recruits the H3K4 methyltransferase SETD1 to (G+C)-rich motifs 3 ; and another H3K4me3 methyltransferase, PRDM9, has a sequence-specific binding motif that directs it to meiotic recombination hotspots 6 . Figure 1: Identifying motifs that are predicative of epigenomic modifications. ( a ) Site-specific DNA-binding factors regulate the epigenome. The blue section shows three regulatory levels of the cell type–specific state: (i) gene regulatory network, (ii) site-specific DNA-binding factors and (iii) epigenomic regulation of gene expression. The green square represents non-cell-type–specific DNA sequence regulatory influences over the epigenome. The purple box shows stimuli that influence the cell type–specific state. ( b ) Overview of the cis -element cataloging process. ( c ) Schematic showing H1 human embryonic stem cells and the other four cell types that were derived through in vitro differentiation. The table lists the analyzed epigenomic modifications. ( d ) Flow chart of the key stages in our analysis pipeline. ( e ) Effect of sequence-set balancing (SSB) on sequences sets. The bar plot shows the number of regions in a set before and after SSB. Violin plots show the distribution of region G+C content and length before and after SSB. Full size image Despite these suggestive observations, methods to systematically catalog the epigenome's cis -regulatory program are lacking. Studies of nucleosome positioning 7 have identified an ∼ 10-bp periodicity of A+T dinucleotides that oscillates out of phase with the dinucleotide G+C 8 , 9 , 10 and poly(dA-dT) tracks that inhibit nucleosome formation 11 , 12 , 13 . However, the involvement of DNA sequence in nucleosome positioning remains controversial 14 . Nevertheless, these studies did not intend to predict histone modifications from DNA sequence. Enrichment of transcription factor (TF) binding and sequence features in various chromatin states have been examined 15 , but DNA motifs were not used to predict epigenomic modification. Recently, DNA 6-mers were used to predict the presence of H3K4me3 with reasonable accuracy but failed to find sequence features associated with other histone modifications 16 ; notably, this study did not focus on DNA motifs, which are recognized by DNA-binding factors. Herein, we used our analysis pipeline, Epigram, to capture the cis elements that interact with the dynamic regulatory program to shape the epigenome ( Fig. 1b ). By surveying various cell types, we revealed mark-specific motifs, which may be universally recognized by chromatin-modifying enzymes, and motifs with cell type–specific interplay, which may be recognized by cell type–specific cofactors. We applied this approach to predicting the placement of six histone modifications and DNA methylation valleys (DMVs) in five cell types 17 : human embryonic stem cells (H1), neural progenitor cells (NPC), trophoblast-like cells (TBL), mesendoderm cells (ME) and mesenchymal stem cells (MSC) ( Fig. 1c ). To tease out the cis elements that are recognized by epigenomic regulatory factors, we removed simple sequence biases such as G+C content during analysis. We observed that motifs have location preferences within modified regions, such as the center of H3K27ac or the edge of H3K4me3 or H3K9me3. Furthermore, we demonstrated the importance of Epigram motifs in the regulation of histone modification through the significant correlation between their disruption and inter-individual H3K27ac variation. Our study provides a catalog of cis elements that play important roles in shaping the epigenomic modifications, which is useful for designing new epigenome-editing tools. Results Predicting the epigenome from DNA motifs We first examined whether DNA motifs could distinguish genomic regions that possess modified histones from regions that do not possess any modified histones. For the sake of discussion, we refer to this as the 'single-mark analysis'. We started by correcting a potential bias in the chromatin immunoprecipitation–sequencing (ChIP-seq) data that can be caused by the preferential sequencing of (G+C)-rich genomic fragments 18 , 19 ( Fig. 1d ). To identify regions that were enriched with a histone modification from ChIP-seq, we called two types of peaks: tight for H3K27ac, H3K4me1and H3K4me3; broad for H3K27me3,", "role": "user" }, { "content": "Biochemists working at the University of California, San Diego, have developed a program that predicts the placement of chemical marks that control the activity of genes based on sequences of DNA. They describe their analysis and report results from its application to human embryonic cells in a paper published in Nature Methods online September 21. \"All of our cells have the same blueprint, the same DNA, although they serve separate functions,\" said John Whitaker, lead author of the report. \"Skin cells protect, nerve cells send signals, and these differences emerge because different subsets of genes are active or silent within particular kinds of cells.\" These patterns of activity are controlled by modifications of the DNA that do not alter its sequence—chemical tags that influence which genes are read and which are skipped within a particular cell. By comparing sequences with and without epigenomic modification, the researchers identified DNA patterns associated with the changes. They call this novel analysis pipeline Epigram and have made both the program and the DNA motifs they identified openly available to other scientists. \"The interplay between genetic and epigenomic regulation has only begun to be deciphered,\" said Wei Wang, professor of chemistry and biochemistry who directed the work. \"This study revealed that there are specific DNA sequences that are recognized by DNA-binding proteins,\" which specify exactly where other enzymes place epigenomic marks. The epigenome guides the development of complex organisms from single fertilized eggs. The researchers analyzed epigenomic patterns in human embryonic stem cells and four cell lineages derived from them to catalogue genetic elements that shape the epigenome during development. Damage to the epigenome not only disrupts development, but can happen at any point in our lives and sometimes leads to illness. Identification of the DNA sequences that guide the placement of epigenomic could guide experimental analysis, the authors say. By editing DNA sequences that control epigenomic modifications, scientists could probe their functions and perhaps in the future mend epigenomic mistakes that cause harm. —Susan Brown ", "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 epigenome is established and maintained by the site-specific recruitment of chromatin-modifying enzymes and their cofactors. Identifying the cis elements that regulate epigenomic modification is critical for understanding the regulatory mechanisms that control gene expression patterns. We present Epigram, an analysis pipeline that predicts histone modification and DNA methylation patterns from DNA motifs. The identified cis elements represent interactions with the site-specific DNA-binding factors that establish and maintain epigenomic modifications. We cataloged the cis elements in embryonic stem cells and four derived lineages and found numerous motifs that have location preference, such as at the center of H3K27ac or at the edges of H3K4me3 and H3K9me3, which provides mechanistic insight about the shaping of the epigenome. The Epigram pipeline and predictive motifs are at . Main Epigenomic modifications, including histone modifications and DNA methylation, play critical roles in development and other key biological processes. The establishment and maintenance of specific epigenomic patterns are regulated by many factors. But how exactly these mechanisms collectively regulate the epigenome, and the importance of cis -regulatory motifs, remains unclear. The genome sequence is unchanged between an individual's different cell types; but the expression and activity of chromatin-modifying enzymes and their cofactors vary between cell types and cellular conditions ( Fig. 1a ). Epigenomic regulatory mechanisms use combinations of enzymes and cofactors to read a cis -regulatory code that defines locus-specific modification patterns. Therefore, given a particular epigenomic state, it is possible to identify the cis elements that interact with epigenomic modifications and are responsible for their establishment and/or maintenance ( Fig. 1b ). A global picture of the cis -regulatory code that regulates the epigenome may emerge from surveying a diversity of cell types and conditions. Indeed, evidence supporting the importance of cis -regulatory code in shaping the epigenome is rapidly accumulating 1 . For example: (G+C)-rich sequences are strongly correlated with trimethylation of histone 3 lysine 27 (H3K27me3; ref. 2 ) and H3K4me3 (ref. 3 ); (G+C)-rich motifs establish H3K27me3 by recruiting the Polycomb repressive complex 2 (PRC2) through interaction with long noncoding RNAs 4 , 5 ; the CpG-binding protein, CFP1, recruits the H3K4 methyltransferase SETD1 to (G+C)-rich motifs 3 ; and another H3K4me3 methyltransferase, PRDM9, has a sequence-specific binding motif that directs it to meiotic recombination hotspots 6 . Figure 1: Identifying motifs that are predicative of epigenomic modifications. ( a ) Site-specific DNA-binding factors regulate the epigenome. The blue section shows three regulatory levels of the cell type–specific state: (i) gene regulatory network, (ii) site-specific DNA-binding factors and (iii) epigenomic regulation of gene expression. The green square represents non-cell-type–specific DNA sequence regulatory influences over the epigenome. The purple box shows stimuli that influence the cell type–specific state. ( b ) Overview of the cis -element cataloging process. ( c ) Schematic showing H1 human embryonic stem cells and the other four cell types that were derived through in vitro differentiation. The table lists the analyzed epigenomic modifications. ( d ) Flow chart of the key stages in our analysis pipeline. ( e ) Effect of sequence-set balancing (SSB) on sequences sets. The bar plot shows the number of regions in a set before and after SSB. Violin plots show the distribution of region G+C content and length before and after SSB. Full size image Despite these suggestive observations, methods to systematically catalog the epigenome's cis -regulatory program are lacking. Studies of nucleosome positioning 7 have identified an ∼ 10-bp periodicity of A+T dinucleotides that oscillates out of phase with the dinucleotide G+C 8 , 9 , 10 and poly(dA-dT) tracks that inhibit nucleosome formation 11 , 12 , 13 . However, the involvement of DNA sequence in nucleosome positioning remains controversial 14 . Nevertheless, these studies did not intend to predict histone modifications from DNA sequence. Enrichment of transcription factor (TF) binding and sequence features in various chromatin states have been examined 15 , but DNA motifs were not used to predict epigenomic modification. Recently, DNA 6-mers were used to predict the presence of H3K4me3 with reasonable accuracy but failed to find sequence features associated with other histone modifications 16 ; notably, this study did not focus on DNA motifs, which are recognized by DNA-binding factors. Herein, we used our analysis pipeline, Epigram, to capture the cis elements that interact with the dynamic regulatory program to shape the epigenome ( Fig. 1b ). By surveying various cell types, we revealed mark-specific motifs, which may be universally recognized by chromatin-modifying enzymes, and motifs with cell type–specific interplay, which may be recognized by cell type–specific cofactors. We applied this approach to predicting the placement of six histone modifications and DNA methylation valleys (DMVs) in five cell types 17 : human embryonic stem cells (H1), neural progenitor cells (NPC), trophoblast-like cells (TBL), mesendoderm cells (ME) and mesenchymal stem cells (MSC) ( Fig. 1c ). To tease out the cis elements that are recognized by epigenomic regulatory factors, we removed simple sequence biases such as G+C content during analysis. We observed that motifs have location preferences within modified regions, such as the center of H3K27ac or the edge of H3K4me3 or H3K9me3. Furthermore, we demonstrated the importance of Epigram motifs in the regulation of histone modification through the significant correlation between their disruption and inter-individual H3K27ac variation. Our study provides a catalog of cis elements that play important roles in shaping the epigenomic modifications, which is useful for designing new epigenome-editing tools. Results Predicting the epigenome from DNA motifs We first examined whether DNA motifs could distinguish genomic regions that possess modified histones from regions that do not possess any modified histones. For the sake of discussion, we refer to this as the 'single-mark analysis'. We started by correcting a potential bias in the chromatin immunoprecipitation–sequencing (ChIP-seq) data that can be caused by the preferential sequencing of (G+C)-rich genomic fragments 18 , 19 ( Fig. 1d ). To identify regions that were enriched with a histone modification from ChIP-seq, we called two types of peaks: tight for H3K27ac, H3K4me1and H3K4me3; broad for H3K27me3,<|im_end|> <|im_start|>assistant Biochemists working at the University of California, San Diego, have developed a program that predicts the placement of chemical marks that control the activity of genes based on sequences of DNA. They describe their analysis and report results from its application to human embryonic cells in a paper published in Nature Methods online September 21. "All of our cells have the same blueprint, the same DNA, although they serve separate functions," said John Whitaker, lead author of the report. "Skin cells protect, nerve cells send signals, and these differences emerge because different subsets of genes are active or silent within particular kinds of cells." These patterns of activity are controlled by modifications of the DNA that do not alter its sequence—chemical tags that influence which genes are read and which are skipped within a particular cell. By comparing sequences with and without epigenomic modification, the researchers identified DNA patterns associated with the changes. They call this novel analysis pipeline Epigram and have made both the program and the DNA motifs they identified openly available to other scientists. "The interplay between genetic and epigenomic regulation has only begun to be deciphered," said Wei Wang, professor of chemistry and biochemistry who directed the work. "This study revealed that there are specific DNA sequences that are recognized by DNA-binding proteins," which specify exactly where other enzymes place epigenomic marks. The epigenome guides the development of complex organisms from single fertilized eggs. The researchers analyzed epigenomic patterns in human embryonic stem cells and four cell lineages derived from them to catalogue genetic elements that shape the epigenome during development. Damage to the epigenome not only disrupts development, but can happen at any point in our lives and sometimes leads to illness. Identification of the DNA sequences that guide the placement of epigenomic could guide experimental analysis, the authors say. By editing DNA sequences that control epigenomic modifications, scientists could probe their functions and perhaps in the future mend epigenomic mistakes that cause harm. —Susan Brown <|im_end|>

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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 Excitation–contraction coupling, the process that regulates contractions by skeletal muscles, transduces changes in membrane voltage by activating release of Ca 2+ from internal stores to initiate muscle contraction. Defects in excitation–contraction coupling are associated with muscle diseases. Here we identify Stac3 as a novel component of the excitation–contraction coupling machinery. Using a zebrafish genetic screen, we generate a locomotor mutation that is mapped to stac3 . We provide electrophysiological, Ca 2+ imaging, immunocytochemical and biochemical evidence that Stac3 participates in excitation–contraction coupling in muscles. Furthermore, we reveal that a mutation in human STAC3 is the genetic basis of the debilitating Native American myopathy (NAM). Analysis of NAM stac3 in zebrafish shows that the NAM mutation decreases excitation–contraction coupling. These findings enhance our understanding of both excitation–contraction coupling and the pathology of myopathies. Introduction Muscle contractions are initiated by depolarization of the voltage across the plasma membrane resulting from synaptic release at the neuromuscular junction (NMJ). Excitation–contraction (EC) coupling is responsible for transducing the shift in the membrane voltage to increase cytosolic levels of Ca 2+ that leads to contraction. Genetic defects in EC coupling components are associated with numerous congenital myopathies 1 that appear in infancy and are characterized by a variety of symptoms that include muscle weakness, difficulty with breathing and feeding, slower development, muscle cramps, stiffness and spasm, and in some cases susceptibility to malignant hyperthermia, which is an adverse reaction to general anaesthesia that can be fatal. Despite the debilitating nature of congenital myopathies, their pathology is for the most part poorly understood. Congenital myopathies are highly heterogenous, and the genetic basis of many disorders are unknown. In skeletal muscles, EC coupling occurs at triads. Triads are junctions of the transverse tubules that are infoldings of the sarcomembrane and the sarcoplasmic reticulum (SR), an internal Ca 2+ store. Changes in the membrane voltage of the transverse tubules are detected by the dihydropyridine receptor (DHPR), an L-type Ca 2+ channel located in the transverse tubule membrane at triads 2 , 3 , 4 , 5 . DHPR is composed of the principal α1s subunit also called Ca V 1.1 that contains the pore and several accessory subunits. Activated DHPR, in turn, is thought to directly activate ryanodine receptor 1 (RyR1) Ca 2+ release channels in the SR membrane side of the triadic junctions 6 , 7 , 8 , 9 . In mammalian skeletal muscles, the DHPR also conducts extracellular Ca 2+ to the cytosol but this is not required for EC coupling 10 . Interestingly, in teleost skeletal muscles EC coupling is similarly independent of Ca 2+ influx from the exterior and the DHPR appears to have evolved so that it no longer conducts Ca 2+ (ref. 11 ). Activation of RyR1 leads to release of Ca 2+ from the SR to the cytosol and subsequently to contraction mediated by the contractile machinery. EC coupling involves a complex of proteins localized to triads that include DHPR and RyR1. Although DHPR and RyR1 are well studied, the identity and roles of other components of the complex, how EC coupling is regulated and how the triadic molecular complex is established are poorly understood. Some of the other components of the triadic complex include FKBP12, triadin, junctin and calsequestrin. Triadin, junctin and calsequestrin are SR proteins that regulate RyR1 from the luminal side of SR 12 , 13 , 14 . FKBP12 is an immunophilin, an immunosuppressive drug-binding protein, that copurifies and co-immunoprecipitates with RyR1 in striated muscles 15 , and stabilize RyRs in their open state in vitro 16 . Two other cytosolic proteins that interact with EC components are SepN1 and calmodulin (CaM). SepN1 is a selenoprotein that co-immunoprecipitates with RyR1a and is associated with myopathy 17 and is required for formation of slow twitch muscles in zebrafish 18 . CaM can bind RyR and DHPR, and modify EC coupling 19 . Despite the identification of these factors, the mechanisms for how they regulate EC coupling is poorly understood. These analyses illustrate the complexity of the EC coupling complex and its regulation, and suggest that a forward genetic strategy might be useful for identification of novel components for EC coupling. Zebrafish have been useful for the analysis of a myriad of biological processes both because they are amenable to forward genetic screens and in vivo manipulations 20 , 21 . Pertinent to a genetic analysis of EC coupling, zebrafish muscles can also be analysed in vivo with electrophysiology and live imaging 22 , 23 . We took advantage of these features to identify a zebrafish mutation in which EC coupling was defective. The gene responsible for the mutant phenotype encoded for Stac3, a putative muscle-specific adaptor protein. Finally, we found that a missense mutation in human STAC3 is responsible for the debilitating, congenital Native American myopathy (NAM) 24 , 25 . Results The mi34 zebrafish mutant is defective in EC coupling To identify new genes involved in the regulation of EC coupling, a forward genetic screen in the zebrafish was performed to isolate motor behaviour mutants 26 , 27 , 28 , 29 , 30 . One mutation, mi34 , was autosomal recessive with mutants dying as larvae and exhibiting defective motor behaviours at early stages of development. Normally zebrafish embryos exhibited spontaneous slow coiling of the body starting at 17 h post fertilization (hpf), touch-induced escape contractions of the body at 22 hpf and touch-induced swimming by 28 hpf (ref. 31 ). Mutants were defective in all three motor behaviours with reduced amplitude of spontaneous coiling, decreased touch-induced escape contractions and ineffective swimming ( Supplementary Movies S1–6 ; Fig. 1a ). Figure 1: mi34 mutant zebrafish exhibit defective swimming but CNS output is normal. ( a ) Touch evoked swimming in wt but not stac3 mi34 embryos (48 hpf). Panels show superimposed frames (30 Hz) of swimming motion from wt sibling and stac3 mi34 embryos with heads embedded in agar. ( b ) Voltage recordings with 6-mM curare showing that touch-evoked synaptic responses of slow twitch", "role": "user" }, { "content": "Zebrafish with very weak muscles helped scientists decode the elusive genetic mutation responsible for Native American myopathy, a rare, hereditary muscle disease that afflicts Native Americans in North Carolina. Scientists led by John Kuwada, professor of molecular, cellular and developmental biology at the University of Michigan, and Hiromi Hirata of the National Institute of Genetics in Japan originally identified the gene in mutant zebrafish that exhibited severe muscle weakness. Native American myopathy causes muscle weakness from birth and other severe problems that can lead to death before adulthood. The findings appear in the journal Nature Communications. The responsible gene encodes for a muscle protein called Stac3, which in turn regulates a physiological process required for muscle contraction. The muscles of zebrafish and people with the genetic mutation don't make normal Stac3 protein and the muscles don't contract effectively. Scientists established the importance of Stac3 for muscle function in zebrafish by studying the small fish physiologically and genetically. Scientists then looked at the human version of the gene, and found that the gene was mutated in people suffering from Native American myopathy. For many degenerative muscle diseases few drugs help, largely because scientists don't know the genes responsible for many of these muscle diseases, making it difficult to develop drugs and other therapies that target the condition. The discovery of the gene for Native American myopathy, however, may help develop drugs to treat the myopathy, as well as other related muscle diseases. ", "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 Excitation–contraction coupling, the process that regulates contractions by skeletal muscles, transduces changes in membrane voltage by activating release of Ca 2+ from internal stores to initiate muscle contraction. Defects in excitation–contraction coupling are associated with muscle diseases. Here we identify Stac3 as a novel component of the excitation–contraction coupling machinery. Using a zebrafish genetic screen, we generate a locomotor mutation that is mapped to stac3 . We provide electrophysiological, Ca 2+ imaging, immunocytochemical and biochemical evidence that Stac3 participates in excitation–contraction coupling in muscles. Furthermore, we reveal that a mutation in human STAC3 is the genetic basis of the debilitating Native American myopathy (NAM). Analysis of NAM stac3 in zebrafish shows that the NAM mutation decreases excitation–contraction coupling. These findings enhance our understanding of both excitation–contraction coupling and the pathology of myopathies. Introduction Muscle contractions are initiated by depolarization of the voltage across the plasma membrane resulting from synaptic release at the neuromuscular junction (NMJ). Excitation–contraction (EC) coupling is responsible for transducing the shift in the membrane voltage to increase cytosolic levels of Ca 2+ that leads to contraction. Genetic defects in EC coupling components are associated with numerous congenital myopathies 1 that appear in infancy and are characterized by a variety of symptoms that include muscle weakness, difficulty with breathing and feeding, slower development, muscle cramps, stiffness and spasm, and in some cases susceptibility to malignant hyperthermia, which is an adverse reaction to general anaesthesia that can be fatal. Despite the debilitating nature of congenital myopathies, their pathology is for the most part poorly understood. Congenital myopathies are highly heterogenous, and the genetic basis of many disorders are unknown. In skeletal muscles, EC coupling occurs at triads. Triads are junctions of the transverse tubules that are infoldings of the sarcomembrane and the sarcoplasmic reticulum (SR), an internal Ca 2+ store. Changes in the membrane voltage of the transverse tubules are detected by the dihydropyridine receptor (DHPR), an L-type Ca 2+ channel located in the transverse tubule membrane at triads 2 , 3 , 4 , 5 . DHPR is composed of the principal α1s subunit also called Ca V 1.1 that contains the pore and several accessory subunits. Activated DHPR, in turn, is thought to directly activate ryanodine receptor 1 (RyR1) Ca 2+ release channels in the SR membrane side of the triadic junctions 6 , 7 , 8 , 9 . In mammalian skeletal muscles, the DHPR also conducts extracellular Ca 2+ to the cytosol but this is not required for EC coupling 10 . Interestingly, in teleost skeletal muscles EC coupling is similarly independent of Ca 2+ influx from the exterior and the DHPR appears to have evolved so that it no longer conducts Ca 2+ (ref. 11 ). Activation of RyR1 leads to release of Ca 2+ from the SR to the cytosol and subsequently to contraction mediated by the contractile machinery. EC coupling involves a complex of proteins localized to triads that include DHPR and RyR1. Although DHPR and RyR1 are well studied, the identity and roles of other components of the complex, how EC coupling is regulated and how the triadic molecular complex is established are poorly understood. Some of the other components of the triadic complex include FKBP12, triadin, junctin and calsequestrin. Triadin, junctin and calsequestrin are SR proteins that regulate RyR1 from the luminal side of SR 12 , 13 , 14 . FKBP12 is an immunophilin, an immunosuppressive drug-binding protein, that copurifies and co-immunoprecipitates with RyR1 in striated muscles 15 , and stabilize RyRs in their open state in vitro 16 . Two other cytosolic proteins that interact with EC components are SepN1 and calmodulin (CaM). SepN1 is a selenoprotein that co-immunoprecipitates with RyR1a and is associated with myopathy 17 and is required for formation of slow twitch muscles in zebrafish 18 . CaM can bind RyR and DHPR, and modify EC coupling 19 . Despite the identification of these factors, the mechanisms for how they regulate EC coupling is poorly understood. These analyses illustrate the complexity of the EC coupling complex and its regulation, and suggest that a forward genetic strategy might be useful for identification of novel components for EC coupling. Zebrafish have been useful for the analysis of a myriad of biological processes both because they are amenable to forward genetic screens and in vivo manipulations 20 , 21 . Pertinent to a genetic analysis of EC coupling, zebrafish muscles can also be analysed in vivo with electrophysiology and live imaging 22 , 23 . We took advantage of these features to identify a zebrafish mutation in which EC coupling was defective. The gene responsible for the mutant phenotype encoded for Stac3, a putative muscle-specific adaptor protein. Finally, we found that a missense mutation in human STAC3 is responsible for the debilitating, congenital Native American myopathy (NAM) 24 , 25 . Results The mi34 zebrafish mutant is defective in EC coupling To identify new genes involved in the regulation of EC coupling, a forward genetic screen in the zebrafish was performed to isolate motor behaviour mutants 26 , 27 , 28 , 29 , 30 . One mutation, mi34 , was autosomal recessive with mutants dying as larvae and exhibiting defective motor behaviours at early stages of development. Normally zebrafish embryos exhibited spontaneous slow coiling of the body starting at 17 h post fertilization (hpf), touch-induced escape contractions of the body at 22 hpf and touch-induced swimming by 28 hpf (ref. 31 ). Mutants were defective in all three motor behaviours with reduced amplitude of spontaneous coiling, decreased touch-induced escape contractions and ineffective swimming ( Supplementary Movies S1–6 ; Fig. 1a ). Figure 1: mi34 mutant zebrafish exhibit defective swimming but CNS output is normal. ( a ) Touch evoked swimming in wt but not stac3 mi34 embryos (48 hpf). Panels show superimposed frames (30 Hz) of swimming motion from wt sibling and stac3 mi34 embryos with heads embedded in agar. ( b ) Voltage recordings with 6-mM curare showing that touch-evoked synaptic responses of slow twitch<|im_end|> <|im_start|>assistant Zebrafish with very weak muscles helped scientists decode the elusive genetic mutation responsible for Native American myopathy, a rare, hereditary muscle disease that afflicts Native Americans in North Carolina. Scientists led by John Kuwada, professor of molecular, cellular and developmental biology at the University of Michigan, and Hiromi Hirata of the National Institute of Genetics in Japan originally identified the gene in mutant zebrafish that exhibited severe muscle weakness. Native American myopathy causes muscle weakness from birth and other severe problems that can lead to death before adulthood. The findings appear in the journal Nature Communications. The responsible gene encodes for a muscle protein called Stac3, which in turn regulates a physiological process required for muscle contraction. The muscles of zebrafish and people with the genetic mutation don't make normal Stac3 protein and the muscles don't contract effectively. Scientists established the importance of Stac3 for muscle function in zebrafish by studying the small fish physiologically and genetically. Scientists then looked at the human version of the gene, and found that the gene was mutated in people suffering from Native American myopathy. For many degenerative muscle diseases few drugs help, largely because scientists don't know the genes responsible for many of these muscle diseases, making it difficult to develop drugs and other therapies that target the condition. The discovery of the gene for Native American myopathy, however, may help develop drugs to treat the myopathy, as well as other related muscle diseases. <|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 During metazoan development, immune surveillance and cancer dissemination, cells migrate in complex three-dimensional microenvironments 1 , 2 , 3 . These spaces are crowded by cells and extracellular matrix, generating mazes with differently sized gaps that are typically smaller than the diameter of the migrating cell 4 , 5 . Most mesenchymal and epithelial cells and some—but not all—cancer cells actively generate their migratory path using pericellular tissue proteolysis 6 . By contrast, amoeboid cells such as leukocytes use non-destructive strategies of locomotion 7 , raising the question how these extremely fast cells navigate through dense tissues. Here we reveal that leukocytes sample their immediate vicinity for large pore sizes, and are thereby able to choose the path of least resistance. This allows them to circumnavigate local obstacles while effectively following global directional cues such as chemotactic gradients. Pore-size discrimination is facilitated by frontward positioning of the nucleus, which enables the cells to use their bulkiest compartment as a mechanical gauge. Once the nucleus and the closely associated microtubule organizing centre pass the largest pore, cytoplasmic protrusions still lingering in smaller pores are retracted. These retractions are coordinated by dynamic microtubules; when microtubules are disrupted, migrating cells lose coherence and frequently fragment into migratory cytoplasmic pieces. As nuclear positioning in front of the microtubule organizing centre is a typical feature of amoeboid migration, our findings link the fundamental organization of cellular polarity to the strategy of locomotion. Main During development and immune surveillance, trafficking cells typically follow chemotactic cues, which globally prescribe direction and destination of migration 8 . At the same time, cells have to negotiate the local physical environment 9 and traverse or circumnavigate obstacles within inhomogeneous tissues 4 , 5 . Rapidly migrating cells such as leukocytes rarely cause permanent tissue defects by proteolysis or rearrangement of the extracellular matrix 7 , 10 , which suggests that they are able to adapt their migratory path to the physical constraints of their immediate environment. As a model system for rapid amoeboid migration of leukocytes in 3D microenvironments, we imaged dendritic cells (DCs) that express LifeAct–GFP, embedded in fluorescent 3D collagen gels, by light-sheet microscopy with isotropic, subcellular 3D resolution 11 . Collagen fibres assembled into a 3D network with pore diameters that ranged between 1 μm and 5 μm (Extended Data Fig. 1a–c , Supplementary Video 1 ) into which DCs inserted multiple actin-rich protrusions (Fig. 1a, b , Extended Data Fig. 1d , Supplementary Video 1 ). To investigate how single cells respond to differential pore-size regimes, we spiked collagen gels with islands of higher network density and established gradients of the chemokine CCL19, which chemoattracts mature DCs (Fig. 1c–e ). When chemotaxing DCs approached a dense island head-on (thus encountering a broad area of denser matrix), they steadily transited from the low-density matrix to the high-density matrix (Fig. 1c , Supplementary Video 2 ). Following this transition, they decelerated but continued to migrate towards the chemokine source (Fig. 1c , Extended Data Fig. 1e ). By contrast, cells that approached a dense island on more tangential trajectories preferentially remained in regions of lower collagen density, thus deviating from the direct path as prescribed by the chemotactic gradient (Fig. 1c , Supplementary Video 2 ). These findings suggest that DCs follow the path of least resistance: whenever the option is available, they circumnavigate local areas of high matrix density, thereby trading the shortest path for migratory speed. Fig. 1: Migrating cells are selective for pore size. a , A DC (LifeAct–GFP-labelled) embedded in a 3D collagen matrix (Alexa Fluor 568-labelled) and imaged by light-sheet microscopy with isotropic, subcellular 3D resolution. Colouring on the DC surface indicates regions of large positive and negative curvature in red and blue, respectively. Image representative of 24 cells from 5 experiments. b , Subvolume of the collagen matrix surrounding the DC depicted in a . Image representative of 24 cells from 5 experiments. c , Migratory tracks (velocity colour coding) of DCs along a CCL19 chemokine gradient in a collagen matrix spiked with a region of higher collagen density (three experiments). d , Confocal reflection microscopy of the same collagen matrix shown in b (three experiments). Scale bar, 100 μm. e , Enlargement of regions in boxes 1, 2 and 3 in c , exemplifying regions of higher (top) and lower (middle and bottom) collagen densities. Scale bar, 10 μm. f , Protrusion dynamics of the leading edge of a DC, labelled with LifeAct–GFP, during migration in microchannels through a junction (decision point) with four differently sized pores (2-, 3-, 4- and 5-μm wide (4-μm height)). Arrows highlight early establishment of cell-front protrusions into all different pore sizes (three experiments). g , Quantification of pore-size preference of DCs treated as in f , with (left; 7 experiments, 119 cells; one-way ANOVA with Tukey’s test; **** P < 0.0001, ** P = 0.0029, * P = 0.0225) or without (right; 3 experiments, 81 cells; one-way ANOVA with Tukey’s test; ** P = 0.0049) a CCL19 chemokine gradient. Pooled data from two devices with differently ordered sequences of pore size (2, 3, 4 and 5 μm or 4, 2, 5 and 3 μm, respectively). h , Migration of T cells, LMR7.5 hybridoma T cells and neutrophils in microchannels through a decision point of four differently sized pores of 2-, 3- ,4- and 5-μm wide (T cells, LMR7.5, 4-μm height; neutrophils, 2-μm height), and quantification of pore-size preference along a chemokine gradient (T cells (CCL19): 3 experiments, 68 cells; LMR7.5: 3 experiments, 40 cells; neutrophils (fMLP): 3 experiments, 46 cells; one-way ANOVA with Tukey’s test; **** P < 0.0001, *** P = 0.0007, ** P = 0.0043, * P = 0.0193). Pooled data from two devices with differently ordered sequences of pore size (2, 3, 4 and 5 μm or 4, 2, 5 and 3 μm, respectively). Data in g and h are mean ± s.d. Time is indicated as h:min.s. Full size image To test the mechanistic basis of local pathfinding, we established", "role": "user" }, { "content": "How do mobile cell types like leukocytes or metastatic cancer cells reach their place of action during immune surveillance or cancer dissemination, respectively? The research group around Michael Sixt at IST Austria has now shown that leukocytes use their nucleus as a ruler to screen their surroundings for the largest pores—and thereby find the path of least resistance. Certain cell types continuously crawl through the body to reach their place of action. For instance, all leukocytes—the white blood cells of the immune system, cover a cumulative distance of more than 100,000 km per hour. On their journey, these migratory cells have to find their way through a three-dimensional maze crowded with other cells and extracellular matrix. Certain cell types—mesenchymal cells like fibroblasts—move forward by digesting the tissue they come up against, thus leaving behind a tunnel as a wake of devastation. Leukocytes, on the other hand, show an amoeboid way of movement that allows them to move around 100 times faster. Also, they do not digest or remodel their environment (if they did, they would perforate the body with more than 2 million kilometers of tunnels per day). How these extremely fast cells navigate through the dense meshwork of interstitial connective tissue fibers without harming other cells has been of great interest to cell biologists. Professor Michael Sixt and his team—including first author Jörg Renkawitz, have now determined how leukocytes manage to choose the path of least resistance when navigating through complex environments. A leukocyte in a collagen maze finding its path of least resistance (nucleus in blue); imaged by Jörg Renkawitz, IST Austria Credit: IST Austria/Jörg Renkawitz Nucleus measures pore size and helps leukocytes to move full speed ahead To understand the mechanism behind this selective form of cell movement, the researchers built an obstacle course for leukocytes in reconstituted tissue in which the cells could choose between differently sized pores while following global directional cues such as chemotactic gradients. What they observed was that whenever the amoeboid cells had a choice, they used the bigger pores, i.e. the path of least resistance. In further tests, the scientists found that the cells facilitate this active directional movement by pushing their nucleus very much to the front of the cell so it can serve as a kind of mechanical gauge or ruler. In other words, as the cell is moving forward, it applies cytoskeletal forces to insert its nucleus into several adjacent pores to measure pore sizes. Michael Sixt says, \"The usual organelle to steer a cell is the actin-rich leading front, which explores the environment. Unexpectedly, we found that this is not what determines the path of a leukocyte. Instead, it is the nucleus that guides the cell through the bigger pores. This makes sense, as the nucleus is the most bulky part of the cell, and also sensitive to damage.\" Microtubules make sure that cells are not fragmented when passing through pores Whenever the cells successfully push their nucleus through a pore, they have to retract the nucleus-free protrusions, which are still inserted in the other pores, to avoid becoming entangled or even fragmented. To tell the protrusions to retract, the microtubules disappear from these protrusions as soon as the microtubule organizing center (which always follows the nucleus) passes through a pore. This disappearance of the microtubules triggers actomyosin contraction, and the cell finally retracts the remaining protrusions. When the researchers actively destroyed the microtubules, the cells entangled because the supernumerary protrusions had not retracted, kept moving forward through other pores and migrated in many directions. Ultimately, the cell fractured into pieces and died. \"Our findings are based on the analysis of leukocytes. Yet, most probably, the mechanisms are the same for any other amoeboid cell types involved in developmental, immunity or regeneration processes. Also, the mechanism might help to explain how cancer cells move from one part of the body to another to form metastases and, most importantly, how to stop them from doing so,\" Michael Sixt concludes. The results of this study are reported in 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 During metazoan development, immune surveillance and cancer dissemination, cells migrate in complex three-dimensional microenvironments 1 , 2 , 3 . These spaces are crowded by cells and extracellular matrix, generating mazes with differently sized gaps that are typically smaller than the diameter of the migrating cell 4 , 5 . Most mesenchymal and epithelial cells and some—but not all—cancer cells actively generate their migratory path using pericellular tissue proteolysis 6 . By contrast, amoeboid cells such as leukocytes use non-destructive strategies of locomotion 7 , raising the question how these extremely fast cells navigate through dense tissues. Here we reveal that leukocytes sample their immediate vicinity for large pore sizes, and are thereby able to choose the path of least resistance. This allows them to circumnavigate local obstacles while effectively following global directional cues such as chemotactic gradients. Pore-size discrimination is facilitated by frontward positioning of the nucleus, which enables the cells to use their bulkiest compartment as a mechanical gauge. Once the nucleus and the closely associated microtubule organizing centre pass the largest pore, cytoplasmic protrusions still lingering in smaller pores are retracted. These retractions are coordinated by dynamic microtubules; when microtubules are disrupted, migrating cells lose coherence and frequently fragment into migratory cytoplasmic pieces. As nuclear positioning in front of the microtubule organizing centre is a typical feature of amoeboid migration, our findings link the fundamental organization of cellular polarity to the strategy of locomotion. Main During development and immune surveillance, trafficking cells typically follow chemotactic cues, which globally prescribe direction and destination of migration 8 . At the same time, cells have to negotiate the local physical environment 9 and traverse or circumnavigate obstacles within inhomogeneous tissues 4 , 5 . Rapidly migrating cells such as leukocytes rarely cause permanent tissue defects by proteolysis or rearrangement of the extracellular matrix 7 , 10 , which suggests that they are able to adapt their migratory path to the physical constraints of their immediate environment. As a model system for rapid amoeboid migration of leukocytes in 3D microenvironments, we imaged dendritic cells (DCs) that express LifeAct–GFP, embedded in fluorescent 3D collagen gels, by light-sheet microscopy with isotropic, subcellular 3D resolution 11 . Collagen fibres assembled into a 3D network with pore diameters that ranged between 1 μm and 5 μm (Extended Data Fig. 1a–c , Supplementary Video 1 ) into which DCs inserted multiple actin-rich protrusions (Fig. 1a, b , Extended Data Fig. 1d , Supplementary Video 1 ). To investigate how single cells respond to differential pore-size regimes, we spiked collagen gels with islands of higher network density and established gradients of the chemokine CCL19, which chemoattracts mature DCs (Fig. 1c–e ). When chemotaxing DCs approached a dense island head-on (thus encountering a broad area of denser matrix), they steadily transited from the low-density matrix to the high-density matrix (Fig. 1c , Supplementary Video 2 ). Following this transition, they decelerated but continued to migrate towards the chemokine source (Fig. 1c , Extended Data Fig. 1e ). By contrast, cells that approached a dense island on more tangential trajectories preferentially remained in regions of lower collagen density, thus deviating from the direct path as prescribed by the chemotactic gradient (Fig. 1c , Supplementary Video 2 ). These findings suggest that DCs follow the path of least resistance: whenever the option is available, they circumnavigate local areas of high matrix density, thereby trading the shortest path for migratory speed. Fig. 1: Migrating cells are selective for pore size. a , A DC (LifeAct–GFP-labelled) embedded in a 3D collagen matrix (Alexa Fluor 568-labelled) and imaged by light-sheet microscopy with isotropic, subcellular 3D resolution. Colouring on the DC surface indicates regions of large positive and negative curvature in red and blue, respectively. Image representative of 24 cells from 5 experiments. b , Subvolume of the collagen matrix surrounding the DC depicted in a . Image representative of 24 cells from 5 experiments. c , Migratory tracks (velocity colour coding) of DCs along a CCL19 chemokine gradient in a collagen matrix spiked with a region of higher collagen density (three experiments). d , Confocal reflection microscopy of the same collagen matrix shown in b (three experiments). Scale bar, 100 μm. e , Enlargement of regions in boxes 1, 2 and 3 in c , exemplifying regions of higher (top) and lower (middle and bottom) collagen densities. Scale bar, 10 μm. f , Protrusion dynamics of the leading edge of a DC, labelled with LifeAct–GFP, during migration in microchannels through a junction (decision point) with four differently sized pores (2-, 3-, 4- and 5-μm wide (4-μm height)). Arrows highlight early establishment of cell-front protrusions into all different pore sizes (three experiments). g , Quantification of pore-size preference of DCs treated as in f , with (left; 7 experiments, 119 cells; one-way ANOVA with Tukey’s test; **** P < 0.0001, ** P = 0.0029, * P = 0.0225) or without (right; 3 experiments, 81 cells; one-way ANOVA with Tukey’s test; ** P = 0.0049) a CCL19 chemokine gradient. Pooled data from two devices with differently ordered sequences of pore size (2, 3, 4 and 5 μm or 4, 2, 5 and 3 μm, respectively). h , Migration of T cells, LMR7.5 hybridoma T cells and neutrophils in microchannels through a decision point of four differently sized pores of 2-, 3- ,4- and 5-μm wide (T cells, LMR7.5, 4-μm height; neutrophils, 2-μm height), and quantification of pore-size preference along a chemokine gradient (T cells (CCL19): 3 experiments, 68 cells; LMR7.5: 3 experiments, 40 cells; neutrophils (fMLP): 3 experiments, 46 cells; one-way ANOVA with Tukey’s test; **** P < 0.0001, *** P = 0.0007, ** P = 0.0043, * P = 0.0193). Pooled data from two devices with differently ordered sequences of pore size (2, 3, 4 and 5 μm or 4, 2, 5 and 3 μm, respectively). Data in g and h are mean ± s.d. Time is indicated as h:min.s. Full size image To test the mechanistic basis of local pathfinding, we established<|im_end|> <|im_start|>assistant How do mobile cell types like leukocytes or metastatic cancer cells reach their place of action during immune surveillance or cancer dissemination, respectively? The research group around Michael Sixt at IST Austria has now shown that leukocytes use their nucleus as a ruler to screen their surroundings for the largest pores—and thereby find the path of least resistance. Certain cell types continuously crawl through the body to reach their place of action. For instance, all leukocytes—the white blood cells of the immune system, cover a cumulative distance of more than 100,000 km per hour. On their journey, these migratory cells have to find their way through a three-dimensional maze crowded with other cells and extracellular matrix. Certain cell types—mesenchymal cells like fibroblasts—move forward by digesting the tissue they come up against, thus leaving behind a tunnel as a wake of devastation. Leukocytes, on the other hand, show an amoeboid way of movement that allows them to move around 100 times faster. Also, they do not digest or remodel their environment (if they did, they would perforate the body with more than 2 million kilometers of tunnels per day). How these extremely fast cells navigate through the dense meshwork of interstitial connective tissue fibers without harming other cells has been of great interest to cell biologists. Professor Michael Sixt and his team—including first author Jörg Renkawitz, have now determined how leukocytes manage to choose the path of least resistance when navigating through complex environments. A leukocyte in a collagen maze finding its path of least resistance (nucleus in blue); imaged by Jörg Renkawitz, IST Austria Credit: IST Austria/Jörg Renkawitz Nucleus measures pore size and helps leukocytes to move full speed ahead To understand the mechanism behind this selective form of cell movement, the researchers built an obstacle course for leukocytes in reconstituted tissue in which the cells could choose between differently sized pores while following global directional cues such as chemotactic gradients. What they observed was that whenever the amoeboid cells had a choice, they used the bigger pores, i.e. the path of least resistance. In further tests, the scientists found that the cells facilitate this active directional movement by pushing their nucleus very much to the front of the cell so it can serve as a kind of mechanical gauge or ruler. In other words, as the cell is moving forward, it applies cytoskeletal forces to insert its nucleus into several adjacent pores to measure pore sizes. Michael Sixt says, "The usual organelle to steer a cell is the actin-rich leading front, which explores the environment. Unexpectedly, we found that this is not what determines the path of a leukocyte. Instead, it is the nucleus that guides the cell through the bigger pores. This makes sense, as the nucleus is the most bulky part of the cell, and also sensitive to damage." Microtubules make sure that cells are not fragmented when passing through pores Whenever the cells successfully push their nucleus through a pore, they have to retract the nucleus-free protrusions, which are still inserted in the other pores, to avoid becoming entangled or even fragmented. To tell the protrusions to retract, the microtubules disappear from these protrusions as soon as the microtubule organizing center (which always follows the nucleus) passes through a pore. This disappearance of the microtubules triggers actomyosin contraction, and the cell finally retracts the remaining protrusions. When the researchers actively destroyed the microtubules, the cells entangled because the supernumerary protrusions had not retracted, kept moving forward through other pores and migrated in many directions. Ultimately, the cell fractured into pieces and died. "Our findings are based on the analysis of leukocytes. Yet, most probably, the mechanisms are the same for any other amoeboid cell types involved in developmental, immunity or regeneration processes. Also, the mechanism might help to explain how cancer cells move from one part of the body to another to form metastases and, most importantly, how to stop them from doing so," Michael Sixt concludes. The results of this study are reported in Nature. <|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 Objectives To examine the recruitment, retention, and preliminary effects of a Christmas themed physical activity intervention designed to increase participation in physical activity and decrease sedentary behaviour in inactive adults. Design Pilot randomised controlled trial. Setting Recruitment from social medial platforms, workplaces, and community groups in the UK. Participants 107 inactive adults (who did not meet the UK guidelines for physical activity) aged 18-75 years. Interventions The intervention consisted of an email sent to participants each day of Advent (1-24 December 2021), which contained a Christmas themed physical activity idea to be completed that day. Each physical activity idea was presented in three intensity formats, including Easy Elf (light intensity), Moderate Mrs Claus (moderate intensity), and Strenuous Santa (vigorous intensity). The comparator group received a leaflet about healthy living on the 1 December. Main outcome measures Participants were randomly assigned (2:1) to either the intervention or control and were masked to group allocation before randomisation. Primary outcomes were recruitment rate, retention, and weekly minutes of participation in self-reported moderate-to-vigorous intensity physical activity by use of the exercise vital signs questionnaire. Primary analysis compared change in minutes of moderate-to-vigorous intensity physical activity from baseline to weeks one, two, and three during the Active Advent intervention. Secondary outcomes were participation in muscle strengthening based physical activity (days per week), accelerometer measured moderate-to-vigorous intensity physical activity, light intensity physical activity, total physical activity, and sedentary time (minutes per day), and enjoyment of and adherence to the intervention. Results 323 individuals expressed interest in participating in the trial and 107 were randomly assigned to the intervention (n=71) or the comparator (n=36) group. The recruitment target (n=105) was reached within 19 days of starting recruitment. 23 (21%) of 107 participants were lost to follow-up. On average, the groups reported participation in similar minutes of moderate-to-vigorous intensity physical activity in weeks one and two. At week three, the adjusted mean difference between groups was 20.6 minutes of participation in moderate-to-vigorous intensity physical activity per week (95% confidence interval −29.7 to 70.9) in favour of the intervention group. Accelerometer data showed that the intervention group spent fewer minutes sedentary per day than comparators (mean difference −58.6 (−113.5 to −3.8)). Overall, 42 (70%) of 60 participants in the intervention group reported that they liked the intervention and 41 (69%) of 59 reported that they completed the Active Advent intervention ideas each day. Conclusions The public were interested to participate in a Christmas themed physical activity intervention during Advent, which might increase physical activity and reduce time sedentary. Enjoyment of, and adherence to the intervention shows the potential benefit that Christmas themed physical activity campaigns/initiatives might have for improving public health. Trial registration ISRCTN12415556 . Introduction Physical activity is known to be a key factor in the prevention and management of non-communicable diseases 1 2 and in reducing the risk of all-cause mortality. 3 Based on self-reported data, about 60% of adults meet the recommended level of participation in moderate-to-vigorous physical activity; however, these estimates reduce greatly to around 25% when participation in muscle strengthening activity is included. 4 Despite multiple iterations of national and international guidelines for physical activity, activity levels have remained low. These statistics highlight the importance of testing innovative interventions that can be delivered at scale to help the public to become more physically active and to ensure optimal health. Recognising the context in which health interventions are implemented is likely to affect their success. The Christmas period is a time characterised by public holidays, social occasions, overconsumption of festive foods and drinks, along with a decrease in physical activity and an increase in sedentary behaviours, such as sitting and screen time. 5 In many countries, the Christmas holidays are also the winter period of the year and we know that physical activity decreases and people are more sedentary during colder weather. 6 Physical inactivity also contributes to weight gain and evidence has shown that the population gain around 0.4-0.9 kg of weight over the Christmas holiday season. 7 8 9 The Christmas holidays are a high risk period for physical inactivity and weight gain, therefore, we aimed to test the recruitment, retention, and preliminary effects of a Christmas themed physical activity intervention during Advent designed to increase participation in physical activity and decrease sedentary time in adults. Methods Trial design The study was a pilot randomised controlled trial with a 2:1 randomisation favouring the intervention group. Recruitment and baseline data collection took place between 11 and 30 November 2021. The last assessment of follow-up data took place on 18 January 2022. This study is reported according to the CONSORT statement for pilot randomised controlled trials and was preregistered at the ISRCTN registry. Participants and randomisation Participants were recruited through social media (Twitter, Facebook, and Instagram), a range of workplaces (eg, Loughborough University and local councils), and local community groups (eg, sports, leisure, and hobby groups). Individuals interested in taking part completed a short online expression of interest form, which included questions to screen for the study inclusion and exclusion criteria. Participants were eligible if they were aged 18-75 years, had access to email, lived in the UK, self-reported completing less than 150 minutes of moderate-to-vigorous intensity physical activity per week, and were considered physically able to participate (determined by the American College of Sports Medicine exercise preparticipation health screening questionnaire for exercise professionals 10 ). All participants provided written informed consent before completing the baseline measures and thereafter were randomly assigned a group. A 2:1 randomisation ratio was adopted so that the Active Advent intervention could be experienced and evaluated by more participants in the time available to conduct the study. The random allocation sequence was generated by an independent member of the research team who had no other involvement in the study. We randomly assigned participants using a computer-generated list, which was concealed from the other members of the research team. Participants were randomised to the Active Advent intervention or the comparator group. Participants were masked to the specific details of each", "role": "user" }, { "content": "A Christmas themed physical activity intervention during Advent shows promise for increasing physical activity and reducing sedentary time among inactive adults, according to a pilot study published in the Christmas issue of The BMJ. The Active Advent intervention—which included \"abdominal snowman\" sit ups and a \"Christmas deliveries\" walk—was enjoyed by participants, showing that the public would welcome public health campaigns to help them to be more physically active and less sedentary during the holidays, say the researchers. Physical activity is an important way to prevent diseases like heart disease and diabetes, yet activity levels remain low in many countries. The Christmas holidays are a particularly high risk period for physical inactivity and weight gain, with evidence suggesting that people gain around 0.4-0.9 kg of weight over the holiday season. However, it is unclear how feasible it is to implement a holiday based activity intervention. So researchers at Loughborough University carried out a pilot study to test the feasibility and effects of a Christmas themed physical activity intervention during Advent, designed to boost physical activity levels and cut down sedentary time. They recruited 107 inactive adults (who did not meet the UK guidelines for physical activity) from social media platforms, workplaces, and community groups between 11 and 30 November 2021. Most (88%) were women of white ethnicity with an average age of 46 years and 56% were overweight or living with obesity. After collecting baseline data, participants were randomly assigned to either the intervention group (71) or control group (36). Intervention participants received a daily email during Advent (1-24 December 2021) containing a Christmas themed physical activity idea to be completed that day. Examples included \"Star\" jumps, \"Dasher the reindeer\" sprints, \"10 lords-a-leaping\" rope skips, \"Lay the table\" planks and \"Rocking around the Christmas tree\" Christmas song dances. Each idea was offered at three intensity levels: Easy Elf (low intensity), Moderate Mrs. Claus (moderate intensity), and Strenuous Santa (high intensity). Participants were free to choose the intensity level of their physical activity each day. Control participants received a leaflet about healthy living on December 1. All participants used an online questionnaire to report how many minutes they spent doing moderate-to-vigorous intensity physical activity per week and how many days they performed muscle-strengthening exercises per week. Around half of participants in both groups were asked to wear an accelerometer (a gadget that tracks the volume and intensity of physical activity) on their wrist 24 hours a day for the duration of the study. Intervention participants were also asked to rate their enjoyment of the activity ideas and recount which activity at which intensity they completed each day. The researchers acknowledge that this was a brief intervention that generated relatively small changes in behavior and being a pilot study, they were unable to report on effectiveness. However, the intervention was safe, inexpensive, and designed to be easily scaled up, and evidence suggests it might have the potential to change health behaviors in the longer term. Some of the pilot results were that on average, the groups reported similar minutes of participation in moderate-to-vigorous intensity physical activity in week one and two. At week three, the intervention group reported participating in about 21 more minutes of moderate-to-vigorous intensity physical activity per week and just over half a day more muscle-strengthening exercises per week than the control group. Accelerometer data showed that the intervention group participated in similar, although marginally more, minutes per day of moderate-to-vigorous intensity physical activity (15 minutes), light intensity physical activity (22 minutes), and total physical activity (37 minutes), than the control group over the intervention period. On average, people in the intervention group also spent fewer (59 minutes) sedentary per day during the intervention than did people in the control group. Overall, 42 (70%) of 60 participants in the intervention group reported that they liked the intervention and 41 (69%) of 59 reported that they completed the Active Advent intervention ideas each day. Of these, 18 (30%) completed Easy Elf, 12 (21%) completed Moderate Mrs. Claus, and 11 (18%) completed Strenuous Santa. There were no reported safety concerns, although the study was not designed to evaluate this definitively. \"The public were interested to engage in a Christmas themed physical activity intervention, which also reduced sedentary time and showed promise for increasing participation in physical activity,\" write the authors. \"Enjoyment of, and adherence to the intervention shows that the public would welcome public health campaigns to help them become more physically active and less sedentary during the holiday season,\" they conclude. ", "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 Objectives To examine the recruitment, retention, and preliminary effects of a Christmas themed physical activity intervention designed to increase participation in physical activity and decrease sedentary behaviour in inactive adults. Design Pilot randomised controlled trial. Setting Recruitment from social medial platforms, workplaces, and community groups in the UK. Participants 107 inactive adults (who did not meet the UK guidelines for physical activity) aged 18-75 years. Interventions The intervention consisted of an email sent to participants each day of Advent (1-24 December 2021), which contained a Christmas themed physical activity idea to be completed that day. Each physical activity idea was presented in three intensity formats, including Easy Elf (light intensity), Moderate Mrs Claus (moderate intensity), and Strenuous Santa (vigorous intensity). The comparator group received a leaflet about healthy living on the 1 December. Main outcome measures Participants were randomly assigned (2:1) to either the intervention or control and were masked to group allocation before randomisation. Primary outcomes were recruitment rate, retention, and weekly minutes of participation in self-reported moderate-to-vigorous intensity physical activity by use of the exercise vital signs questionnaire. Primary analysis compared change in minutes of moderate-to-vigorous intensity physical activity from baseline to weeks one, two, and three during the Active Advent intervention. Secondary outcomes were participation in muscle strengthening based physical activity (days per week), accelerometer measured moderate-to-vigorous intensity physical activity, light intensity physical activity, total physical activity, and sedentary time (minutes per day), and enjoyment of and adherence to the intervention. Results 323 individuals expressed interest in participating in the trial and 107 were randomly assigned to the intervention (n=71) or the comparator (n=36) group. The recruitment target (n=105) was reached within 19 days of starting recruitment. 23 (21%) of 107 participants were lost to follow-up. On average, the groups reported participation in similar minutes of moderate-to-vigorous intensity physical activity in weeks one and two. At week three, the adjusted mean difference between groups was 20.6 minutes of participation in moderate-to-vigorous intensity physical activity per week (95% confidence interval −29.7 to 70.9) in favour of the intervention group. Accelerometer data showed that the intervention group spent fewer minutes sedentary per day than comparators (mean difference −58.6 (−113.5 to −3.8)). Overall, 42 (70%) of 60 participants in the intervention group reported that they liked the intervention and 41 (69%) of 59 reported that they completed the Active Advent intervention ideas each day. Conclusions The public were interested to participate in a Christmas themed physical activity intervention during Advent, which might increase physical activity and reduce time sedentary. Enjoyment of, and adherence to the intervention shows the potential benefit that Christmas themed physical activity campaigns/initiatives might have for improving public health. Trial registration ISRCTN12415556 . Introduction Physical activity is known to be a key factor in the prevention and management of non-communicable diseases 1 2 and in reducing the risk of all-cause mortality. 3 Based on self-reported data, about 60% of adults meet the recommended level of participation in moderate-to-vigorous physical activity; however, these estimates reduce greatly to around 25% when participation in muscle strengthening activity is included. 4 Despite multiple iterations of national and international guidelines for physical activity, activity levels have remained low. These statistics highlight the importance of testing innovative interventions that can be delivered at scale to help the public to become more physically active and to ensure optimal health. Recognising the context in which health interventions are implemented is likely to affect their success. The Christmas period is a time characterised by public holidays, social occasions, overconsumption of festive foods and drinks, along with a decrease in physical activity and an increase in sedentary behaviours, such as sitting and screen time. 5 In many countries, the Christmas holidays are also the winter period of the year and we know that physical activity decreases and people are more sedentary during colder weather. 6 Physical inactivity also contributes to weight gain and evidence has shown that the population gain around 0.4-0.9 kg of weight over the Christmas holiday season. 7 8 9 The Christmas holidays are a high risk period for physical inactivity and weight gain, therefore, we aimed to test the recruitment, retention, and preliminary effects of a Christmas themed physical activity intervention during Advent designed to increase participation in physical activity and decrease sedentary time in adults. Methods Trial design The study was a pilot randomised controlled trial with a 2:1 randomisation favouring the intervention group. Recruitment and baseline data collection took place between 11 and 30 November 2021. The last assessment of follow-up data took place on 18 January 2022. This study is reported according to the CONSORT statement for pilot randomised controlled trials and was preregistered at the ISRCTN registry. Participants and randomisation Participants were recruited through social media (Twitter, Facebook, and Instagram), a range of workplaces (eg, Loughborough University and local councils), and local community groups (eg, sports, leisure, and hobby groups). Individuals interested in taking part completed a short online expression of interest form, which included questions to screen for the study inclusion and exclusion criteria. Participants were eligible if they were aged 18-75 years, had access to email, lived in the UK, self-reported completing less than 150 minutes of moderate-to-vigorous intensity physical activity per week, and were considered physically able to participate (determined by the American College of Sports Medicine exercise preparticipation health screening questionnaire for exercise professionals 10 ). All participants provided written informed consent before completing the baseline measures and thereafter were randomly assigned a group. A 2:1 randomisation ratio was adopted so that the Active Advent intervention could be experienced and evaluated by more participants in the time available to conduct the study. The random allocation sequence was generated by an independent member of the research team who had no other involvement in the study. We randomly assigned participants using a computer-generated list, which was concealed from the other members of the research team. Participants were randomised to the Active Advent intervention or the comparator group. Participants were masked to the specific details of each<|im_end|> <|im_start|>assistant A Christmas themed physical activity intervention during Advent shows promise for increasing physical activity and reducing sedentary time among inactive adults, according to a pilot study published in the Christmas issue of The BMJ. The Active Advent intervention—which included "abdominal snowman" sit ups and a "Christmas deliveries" walk—was enjoyed by participants, showing that the public would welcome public health campaigns to help them to be more physically active and less sedentary during the holidays, say the researchers. Physical activity is an important way to prevent diseases like heart disease and diabetes, yet activity levels remain low in many countries. The Christmas holidays are a particularly high risk period for physical inactivity and weight gain, with evidence suggesting that people gain around 0.4-0.9 kg of weight over the holiday season. However, it is unclear how feasible it is to implement a holiday based activity intervention. So researchers at Loughborough University carried out a pilot study to test the feasibility and effects of a Christmas themed physical activity intervention during Advent, designed to boost physical activity levels and cut down sedentary time. They recruited 107 inactive adults (who did not meet the UK guidelines for physical activity) from social media platforms, workplaces, and community groups between 11 and 30 November 2021. Most (88%) were women of white ethnicity with an average age of 46 years and 56% were overweight or living with obesity. After collecting baseline data, participants were randomly assigned to either the intervention group (71) or control group (36). Intervention participants received a daily email during Advent (1-24 December 2021) containing a Christmas themed physical activity idea to be completed that day. Examples included "Star" jumps, "Dasher the reindeer" sprints, "10 lords-a-leaping" rope skips, "Lay the table" planks and "Rocking around the Christmas tree" Christmas song dances. Each idea was offered at three intensity levels: Easy Elf (low intensity), Moderate Mrs. Claus (moderate intensity), and Strenuous Santa (high intensity). Participants were free to choose the intensity level of their physical activity each day. Control participants received a leaflet about healthy living on December 1. All participants used an online questionnaire to report how many minutes they spent doing moderate-to-vigorous intensity physical activity per week and how many days they performed muscle-strengthening exercises per week. Around half of participants in both groups were asked to wear an accelerometer (a gadget that tracks the volume and intensity of physical activity) on their wrist 24 hours a day for the duration of the study. Intervention participants were also asked to rate their enjoyment of the activity ideas and recount which activity at which intensity they completed each day. The researchers acknowledge that this was a brief intervention that generated relatively small changes in behavior and being a pilot study, they were unable to report on effectiveness. However, the intervention was safe, inexpensive, and designed to be easily scaled up, and evidence suggests it might have the potential to change health behaviors in the longer term. Some of the pilot results were that on average, the groups reported similar minutes of participation in moderate-to-vigorous intensity physical activity in week one and two. At week three, the intervention group reported participating in about 21 more minutes of moderate-to-vigorous intensity physical activity per week and just over half a day more muscle-strengthening exercises per week than the control group. Accelerometer data showed that the intervention group participated in similar, although marginally more, minutes per day of moderate-to-vigorous intensity physical activity (15 minutes), light intensity physical activity (22 minutes), and total physical activity (37 minutes), than the control group over the intervention period. On average, people in the intervention group also spent fewer (59 minutes) sedentary per day during the intervention than did people in the control group. Overall, 42 (70%) of 60 participants in the intervention group reported that they liked the intervention and 41 (69%) of 59 reported that they completed the Active Advent intervention ideas each day. Of these, 18 (30%) completed Easy Elf, 12 (21%) completed Moderate Mrs. Claus, and 11 (18%) completed Strenuous Santa. There were no reported safety concerns, although the study was not designed to evaluate this definitively. "The public were interested to engage in a Christmas themed physical activity intervention, which also reduced sedentary time and showed promise for increasing participation in physical activity," write the authors. "Enjoyment of, and adherence to the intervention shows that the public would welcome public health campaigns to help them become more physically active and less sedentary during the holiday season," they conclude. <|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 Physical activity and sleep duration are established risk factors for many diseases, but their aetiology is poorly understood, partly due to relying on self-reported evidence. Here we report a genome-wide association study (GWAS) of device-measured physical activity and sleep duration in 91,105 UK Biobank participants, finding 14 significant loci (7 novel). These loci account for 0.06% of activity and 0.39% of sleep duration variation. Genome-wide estimates of ~ 15% phenotypic variation indicate high polygenicity. Heritability is higher in women than men for overall activity (23 vs. 20%, p = 1.5 × 10 −4 ) and sedentary behaviours (18 vs. 15%, p = 9.7 × 10 −4 ). Heritability partitioning, enrichment and pathway analyses indicate the central nervous system plays a role in activity behaviours. Two-sample Mendelian randomisation suggests that increased activity might causally lower diastolic blood pressure (beta mmHg/SD: −0.91, SE = 0.18, p = 8.2 × 10 −7 ), and odds of hypertension (Odds ratio/SD: 0.84, SE = 0.03, p = 4.9 × 10 −8 ). Our results advocate the value of physical activity for reducing blood pressure. Introduction Physical inactivity is a global public health threat and is estimated to cost health-care systems ~$50 billion per year worldwide 1 , 2 . It is associated with a range of common diseases including multiple cardiometabolic outcomes such as obesity, type 2 diabetes, and cardiovascular diseases 3 . Alterations in sleep duration also associate with negative health outcomes, including cardiometabolic diseases 4 and psychiatric disorders 5 . In response, recent Canadian public health guidelines recommend how much physical activity and sleep duration youths should engage in for health benefit 6 . Twin and family studies have shown that self-reported daily physical activity is heritable, but with a large degree of heterogeneity in measurement methods and sample size ( h 2 range: 0–78%) 7 . Recent GWAS studies have indicated a genetic contribution to physical activity, finding three variants 8 associated with standard UK Biobank activity metrics 9 . Recent GWAS have also reported common variants that are associated with sleep duration in UK Biobank 10 , 11 , 12 . However, GWAS of behavioural traits such as physical activity and sleep have mostly relied on self-reported data that are prone to measurement error and thus have limited statistical power. It is also possible that self-reported measures capture how well individuals perceive what they do, rather than what they actually do. Consequently, our understanding of the genes and biological pathways that underpin physical activity and sleep behaviours is still limited. Here, we report a GWAS in 91,105 UK Biobank participants who were asked to wear activity trackers over a 7-day period. Our use of statistical machine learning, to derive objective measures of physical activity and sleep duration from raw device data, helps identify 14 genetic loci. The associated loci reveal pathways in the central nervous system that are associated with sleep duration and activity behaviours. We also show that physical activity might causally lower diastolic blood pressure and odds of hypertension. Results Statistical machine learning of behaviours from sensor data We examined data from 101,307 UK Biobank participants who agreed to wear a wrist-worn accelerometer for 7 days 9 and additionally underwent genome-wide genotyping and imputation 13 . As part of the UK Biobank Accelerometer Working Group, we generated a continuous phenotype representing overall activity time 9 (Methods). Additionally, we applied a machine-learning model, using balanced random forests with Markov confusion matrices 14 , to identify which one of four activity states {sleep, sedentary, walking, moderate intensity} an individual was in at any given time (Supplementary Data 1 ). We trained and evaluated the model in 153 free-living individuals (mean age = 42, female n = 100) to distinguish between activity states, evaluated against reference wearable camera, time-use, and sleep diary information sources 14 . Our model achieved an overall classification score of kappa = 0.68 in correctly predicting what activity state an individual is in for any given 30-s time period (Supplementary Table 1 ). As detailed in a previous publication 14 this model was considered suitable for population inference in UK Biobank as the performance was not materially affected by age and sex characteristics (difference in kappa score: sex < 0.0001; age < 0.05). Therefore, our model was applied to over 100,000 UK Biobank participants (Fig. 1 ), where the machine-learned phenotypes demonstrated face validity 14 with clear and expected differences in sleep duration by self-reported chronotype status (Supplementary Fig. 1 ). These machine-learned phenotypes provided orthogonal information to the traditional overall activity time phenotype (Supplementary Fig. 2 ). Fig. 1 Genome-wide significant (5 × 10 −9 ) loci associated with accelerometer-measured variation in sleep duration and physical activity behaviours in 91,105 UK Biobank participants Full size image Loci associated with physical activity and sleep duration After quality control, 91,105 participants of European descent and 9,926,106 single-nucleotide polymorphisms (SNPs) remained for subsequent genetic association analysis (Methods). To maximise statistical power, we performed our analyses using the BOLT-LMM software tool 15 , which applies a linear mixed model to the data, allowing for inclusion of related individuals and those of varying genetic ancestry 16 . We additionally included assessment centre, genotyping array, age, age squared, and season of wear as covariates. Our analysis identified 14 significant loci ( p < 5 × 10 −9 ) that were separated by at least 400 kilobases (kb) (Table 1 , Fig. 1 , and Supplementary Fig. 3 ). We empirically derived this threshold ( p < 5 × 10 −9 ) for genome-wide significance that considers multiple testing in densely imputed data 17 . Seven loci were novel and these include: one for overall activity (rs564819152 near SKIDA1 , p = 1.9 × 10 −9 ); two for sleep duration (rs2416963 near MAPKAP1 , p = 2.3 × 10 −10 ; and rs2006810 near AUTS2 , p = 3.9 × 10 −9 ); four for sedentary time (rs26579 near MEF2C-AS2 , p = 2.6 × 10 −9 ; rs25981 near EFNA5 ,", "role": "user" }, { "content": "Time spent sitting, sleeping and moving is determined in part by our genes, University of Oxford researchers have shown. In one of the most detailed projects of its kind, the scientists studied the activity of 91,105 UK Biobank participants who had previously worn an activity monitor on their wrist for a week. The scientists taught machines to identify active and sedentary behavior from the huge amounts of activity monitor data. They then combined this data with UK Biobank genetic information to reveal 14 genetic regions related to activity, seven new to science, they report in Nature Communications today. The work paves the way for better understanding of sleep, physical activity, and their health consequences. Further analysis of the human genetic data showed for the first time that increased physical activity causally lowers blood pressure. Physical inactivity is a global public health threat and is associated with a range of common diseases including obesity, diabetes and heart disease. Changes in sleep duration are linked to heart and metabolic diseases and psychiatric disorders. The genetic analysis also showed overlap with neurodegenerative diseases, mental health wellbeing and brain structure, showing an important role for the central nervous system with respect to physical activity and sleep. Dr. Aiden Doherty, who led the work and is based at the Big Data Institute, University of Oxford, said: \"How and why we move isn't all about genes, but understanding the role genes play will help improve our understanding of the causes and consequences of physical inactivity. \"It is only by being able to study large amounts of data, such as those provided by UK Biobank, that we are able to understand the complex genetic basis of even some of the most basic human functions like moving, resting and sleeping.\" The study was funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, and the British Heart Foundation Centre of Research Excellence at Oxford. The study was collaborative, and performed by a multidisciplinary team of scientists from a diverse set of fields, including machine learning, genetics, statistics, and epidemiology. The use of machine learning in big healthcare datasets is advancing quickly, and having a profound effect on the sorts of studies that can be carried out, Dr. Karl Smith-Byrne, one of the lead analysts of the study said. \"We have carefully developed machine learning models to teach machines how to analyse complex functions like activity,\" he said. \"These models provide exciting new insights into human movement behaviours in large studies such as UK Biobank with its half a million participants.\" Professor Michael Holmes, a BHF Intermediate Clinical Research Fellow, said: \"This provides scientists with a wonderful opportunity to learn much more about how genes and environment interact in our daily lives, causing us to move as we do, and possibly putting us at increased risk of disease. For instance, it might help us determine whether inactivity is a cause or a consequence of obesity.\" To help identify the types of activity recorded on the wrist monitors, the researchers turned to 200 volunteers who wore a special camera that captured their activity every 20 seconds over two days. The images were compared with the activity data captured by the wrist worn monitors, providing a guide to interpreting the data. ", "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 Physical activity and sleep duration are established risk factors for many diseases, but their aetiology is poorly understood, partly due to relying on self-reported evidence. Here we report a genome-wide association study (GWAS) of device-measured physical activity and sleep duration in 91,105 UK Biobank participants, finding 14 significant loci (7 novel). These loci account for 0.06% of activity and 0.39% of sleep duration variation. Genome-wide estimates of ~ 15% phenotypic variation indicate high polygenicity. Heritability is higher in women than men for overall activity (23 vs. 20%, p = 1.5 × 10 −4 ) and sedentary behaviours (18 vs. 15%, p = 9.7 × 10 −4 ). Heritability partitioning, enrichment and pathway analyses indicate the central nervous system plays a role in activity behaviours. Two-sample Mendelian randomisation suggests that increased activity might causally lower diastolic blood pressure (beta mmHg/SD: −0.91, SE = 0.18, p = 8.2 × 10 −7 ), and odds of hypertension (Odds ratio/SD: 0.84, SE = 0.03, p = 4.9 × 10 −8 ). Our results advocate the value of physical activity for reducing blood pressure. Introduction Physical inactivity is a global public health threat and is estimated to cost health-care systems ~$50 billion per year worldwide 1 , 2 . It is associated with a range of common diseases including multiple cardiometabolic outcomes such as obesity, type 2 diabetes, and cardiovascular diseases 3 . Alterations in sleep duration also associate with negative health outcomes, including cardiometabolic diseases 4 and psychiatric disorders 5 . In response, recent Canadian public health guidelines recommend how much physical activity and sleep duration youths should engage in for health benefit 6 . Twin and family studies have shown that self-reported daily physical activity is heritable, but with a large degree of heterogeneity in measurement methods and sample size ( h 2 range: 0–78%) 7 . Recent GWAS studies have indicated a genetic contribution to physical activity, finding three variants 8 associated with standard UK Biobank activity metrics 9 . Recent GWAS have also reported common variants that are associated with sleep duration in UK Biobank 10 , 11 , 12 . However, GWAS of behavioural traits such as physical activity and sleep have mostly relied on self-reported data that are prone to measurement error and thus have limited statistical power. It is also possible that self-reported measures capture how well individuals perceive what they do, rather than what they actually do. Consequently, our understanding of the genes and biological pathways that underpin physical activity and sleep behaviours is still limited. Here, we report a GWAS in 91,105 UK Biobank participants who were asked to wear activity trackers over a 7-day period. Our use of statistical machine learning, to derive objective measures of physical activity and sleep duration from raw device data, helps identify 14 genetic loci. The associated loci reveal pathways in the central nervous system that are associated with sleep duration and activity behaviours. We also show that physical activity might causally lower diastolic blood pressure and odds of hypertension. Results Statistical machine learning of behaviours from sensor data We examined data from 101,307 UK Biobank participants who agreed to wear a wrist-worn accelerometer for 7 days 9 and additionally underwent genome-wide genotyping and imputation 13 . As part of the UK Biobank Accelerometer Working Group, we generated a continuous phenotype representing overall activity time 9 (Methods). Additionally, we applied a machine-learning model, using balanced random forests with Markov confusion matrices 14 , to identify which one of four activity states {sleep, sedentary, walking, moderate intensity} an individual was in at any given time (Supplementary Data 1 ). We trained and evaluated the model in 153 free-living individuals (mean age = 42, female n = 100) to distinguish between activity states, evaluated against reference wearable camera, time-use, and sleep diary information sources 14 . Our model achieved an overall classification score of kappa = 0.68 in correctly predicting what activity state an individual is in for any given 30-s time period (Supplementary Table 1 ). As detailed in a previous publication 14 this model was considered suitable for population inference in UK Biobank as the performance was not materially affected by age and sex characteristics (difference in kappa score: sex < 0.0001; age < 0.05). Therefore, our model was applied to over 100,000 UK Biobank participants (Fig. 1 ), where the machine-learned phenotypes demonstrated face validity 14 with clear and expected differences in sleep duration by self-reported chronotype status (Supplementary Fig. 1 ). These machine-learned phenotypes provided orthogonal information to the traditional overall activity time phenotype (Supplementary Fig. 2 ). Fig. 1 Genome-wide significant (5 × 10 −9 ) loci associated with accelerometer-measured variation in sleep duration and physical activity behaviours in 91,105 UK Biobank participants Full size image Loci associated with physical activity and sleep duration After quality control, 91,105 participants of European descent and 9,926,106 single-nucleotide polymorphisms (SNPs) remained for subsequent genetic association analysis (Methods). To maximise statistical power, we performed our analyses using the BOLT-LMM software tool 15 , which applies a linear mixed model to the data, allowing for inclusion of related individuals and those of varying genetic ancestry 16 . We additionally included assessment centre, genotyping array, age, age squared, and season of wear as covariates. Our analysis identified 14 significant loci ( p < 5 × 10 −9 ) that were separated by at least 400 kilobases (kb) (Table 1 , Fig. 1 , and Supplementary Fig. 3 ). We empirically derived this threshold ( p < 5 × 10 −9 ) for genome-wide significance that considers multiple testing in densely imputed data 17 . Seven loci were novel and these include: one for overall activity (rs564819152 near SKIDA1 , p = 1.9 × 10 −9 ); two for sleep duration (rs2416963 near MAPKAP1 , p = 2.3 × 10 −10 ; and rs2006810 near AUTS2 , p = 3.9 × 10 −9 ); four for sedentary time (rs26579 near MEF2C-AS2 , p = 2.6 × 10 −9 ; rs25981 near EFNA5 ,<|im_end|> <|im_start|>assistant Time spent sitting, sleeping and moving is determined in part by our genes, University of Oxford researchers have shown. In one of the most detailed projects of its kind, the scientists studied the activity of 91,105 UK Biobank participants who had previously worn an activity monitor on their wrist for a week. The scientists taught machines to identify active and sedentary behavior from the huge amounts of activity monitor data. They then combined this data with UK Biobank genetic information to reveal 14 genetic regions related to activity, seven new to science, they report in Nature Communications today. The work paves the way for better understanding of sleep, physical activity, and their health consequences. Further analysis of the human genetic data showed for the first time that increased physical activity causally lowers blood pressure. Physical inactivity is a global public health threat and is associated with a range of common diseases including obesity, diabetes and heart disease. Changes in sleep duration are linked to heart and metabolic diseases and psychiatric disorders. The genetic analysis also showed overlap with neurodegenerative diseases, mental health wellbeing and brain structure, showing an important role for the central nervous system with respect to physical activity and sleep. Dr. Aiden Doherty, who led the work and is based at the Big Data Institute, University of Oxford, said: "How and why we move isn't all about genes, but understanding the role genes play will help improve our understanding of the causes and consequences of physical inactivity. "It is only by being able to study large amounts of data, such as those provided by UK Biobank, that we are able to understand the complex genetic basis of even some of the most basic human functions like moving, resting and sleeping." The study was funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, and the British Heart Foundation Centre of Research Excellence at Oxford. The study was collaborative, and performed by a multidisciplinary team of scientists from a diverse set of fields, including machine learning, genetics, statistics, and epidemiology. The use of machine learning in big healthcare datasets is advancing quickly, and having a profound effect on the sorts of studies that can be carried out, Dr. Karl Smith-Byrne, one of the lead analysts of the study said. "We have carefully developed machine learning models to teach machines how to analyse complex functions like activity," he said. "These models provide exciting new insights into human movement behaviours in large studies such as UK Biobank with its half a million participants." Professor Michael Holmes, a BHF Intermediate Clinical Research Fellow, said: "This provides scientists with a wonderful opportunity to learn much more about how genes and environment interact in our daily lives, causing us to move as we do, and possibly putting us at increased risk of disease. For instance, it might help us determine whether inactivity is a cause or a consequence of obesity." To help identify the types of activity recorded on the wrist monitors, the researchers turned to 200 volunteers who wore a special camera that captured their activity every 20 seconds over two days. The images were compared with the activity data captured by the wrist worn monitors, providing a guide to interpreting the data. <|im_end|>

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78348, 6382, 11, 892, 25700, 11, 323, 6212, 47242, 2038, 8336, 220, 975, 662, 5751, 1646, 17427, 459, 8244, 24790, 5573, 315, 85095, 284, 220, 15, 13, 2614, 304, 12722, 52997, 1148, 5820, 1614, 459, 3927, 374, 304, 369, 904, 2728, 220, 966, 1355, 892, 4261, 320, 10254, 67082, 6771, 220, 16, 7609, 1666, 11944, 304, 264, 3766, 17009, 220, 975, 420, 1646, 574, 6646, 14791, 369, 7187, 45478, 304, 6560, 12371, 677, 1201, 439, 279, 5178, 574, 539, 90694, 11754, 555, 4325, 323, 1877, 17910, 320, 60351, 304, 85095, 5573, 25, 1877, 366, 220, 15, 13, 931, 16, 26, 4325, 366, 220, 15, 13, 2304, 570, 15636, 11, 1057, 1646, 574, 9435, 311, 927, 220, 1041, 11, 931, 6560, 12371, 677, 1201, 13324, 320, 30035, 13, 220, 16, 7026, 1405, 279, 5780, 12, 12964, 291, 14345, 22583, 21091, 3663, 32939, 220, 975, 449, 2867, 323, 3685, 12062, 304, 6212, 8250, 555, 659, 85296, 27076, 4249, 2704, 320, 10254, 67082, 23966, 13, 220, 16, 7609, 4314, 5780, 12, 12964, 291, 14345, 22583, 3984, 95680, 2038, 311, 279, 8776, 8244, 5820, 892, 82423, 320, 10254, 67082, 23966, 13, 220, 17, 7609, 23966, 13, 220, 16, 82917, 25480, 5199, 320, 20, 25800, 220, 605, 25173, 24, 883, 1353, 72, 5938, 449, 97848, 35073, 40412, 23851, 304, 6212, 8250, 323, 7106, 5820, 71177, 304, 220, 5925, 11, 6550, 6560, 12371, 677, 1201, 13324, 8797, 1404, 2217, 445, 2168, 5938, 449, 7106, 5820, 323, 6212, 8250, 4740, 4367, 2585, 11, 220, 5925, 11, 6550, 13324, 315, 7665, 38052, 323, 220, 24, 11, 26026, 11, 7461, 3254, 5392, 22935, 69044, 46033, 16751, 13978, 320, 19503, 21051, 8, 14958, 369, 17876, 19465, 15360, 6492, 320, 18337, 570, 2057, 31127, 1082, 29564, 2410, 11, 584, 10887, 1057, 29060, 1701, 279, 426, 36420, 8288, 8195, 3241, 5507, 220, 868, 1174, 902, 17208, 264, 13790, 9709, 1646, 311, 279, 828, 11, 10923, 369, 28286, 315, 5552, 7931, 323, 1884, 315, 29865, 19465, 66004, 220, 845, 662, 1226, 37938, 5343, 15813, 12541, 11, 4173, 67247, 1358, 11, 4325, 11, 4325, 53363, 11, 323, 3280, 315, 10051, 439, 22590, 2850, 988, 13, 5751, 6492, 11054, 220, 975, 5199, 1353, 72, 320, 281, 366, 220, 20, 25800, 220, 605, 25173, 24, 883, 430, 1051, 19180, 555, 520, 3325, 220, 3443, 15395, 677, 2315, 320, 22016, 8, 320, 2620, 220, 16, 1174, 23966, 13, 220, 16, 1174, 323, 99371, 23966, 13, 220, 18, 7609, 1226, 38969, 2740, 14592, 420, 12447, 320, 281, 366, 220, 20, 25800, 220, 605, 25173, 24, 883, 369, 33869, 25480, 26431, 430, 32238, 5361, 7649, 304, 97617, 737, 19849, 828, 220, 1114, 662, 31048, 1353, 72, 1051, 11775, 323, 1521, 2997, 25, 832, 369, 8244, 5820, 320, 5544, 22210, 18831, 9756, 3221, 12343, 52271, 16, 1174, 281, 284, 220, 16, 13, 24, 25800, 220, 605, 25173, 24, 7048, 1403, 369, 6212, 8250, 320, 5544, 13341, 23578, 18, 3221, 28322, 42, 2599, 16, 1174, 281, 284, 220, 17, 13, 18, 25800, 220, 605, 25173, 605, 2652, 323, 10242, 1049, 25091, 15, 3221, 54741, 50, 17, 1174, 281, 284, 220, 18, 13, 24, 25800, 220, 605, 25173, 24, 7048, 3116, 369, 11163, 306, 661, 892, 320, 5544, 14374, 4643, 3221, 386, 15229, 17, 34, 12, 1950, 17, 1174, 281, 284, 220, 17, 13, 21, 25800, 220, 605, 25173, 24, 2652, 10242, 15537, 5932, 3221, 45090, 7476, 20, 1174, 128257, 198, 128256, 78191, 198, 1489, 7543, 11961, 11, 21811, 323, 7366, 374, 11075, 304, 961, 555, 1057, 21389, 11, 3907, 315, 26275, 12074, 617, 6982, 13, 763, 832, 315, 279, 1455, 11944, 7224, 315, 1202, 3169, 11, 279, 14248, 20041, 279, 5820, 315, 220, 5925, 11, 6550, 6560, 12371, 677, 1201, 13324, 889, 1047, 8767, 24634, 459, 5820, 8891, 389, 872, 33271, 369, 264, 2046, 13, 578, 14248, 15972, 12933, 311, 10765, 4642, 323, 11163, 306, 661, 7865, 505, 279, 6908, 15055, 315, 5820, 8891, 828, 13, 2435, 1243, 11093, 420, 828, 449, 6560, 12371, 677, 1201, 19465, 2038, 311, 16805, 220, 975, 19465, 13918, 5552, 311, 5820, 11, 8254, 502, 311, 8198, 11, 814, 1934, 304, 22037, 26545, 3432, 13, 578, 990, 281, 4798, 279, 1648, 369, 2731, 8830, 315, 6212, 11, 7106, 5820, 11, 323, 872, 2890, 16296, 13, 15903, 6492, 315, 279, 3823, 19465, 828, 8710, 369, 279, 1176, 892, 430, 7319, 7106, 5820, 25540, 750, 73115, 6680, 7410, 13, 28479, 304, 7323, 374, 264, 3728, 586, 2890, 6023, 323, 374, 5938, 449, 264, 2134, 315, 4279, 19338, 2737, 33048, 11, 20335, 323, 4851, 8624, 13, 29240, 304, 6212, 8250, 527, 10815, 311, 4851, 323, 41861, 19338, 323, 47657, 24673, 13, 578, 19465, 6492, 1101, 8710, 28347, 449, 18247, 451, 7642, 1413, 19338, 11, 10723, 2890, 57930, 323, 8271, 6070, 11, 9204, 459, 3062, 3560, 369, 279, 8792, 23418, 1887, 449, 5201, 311, 7106, 5820, 323, 6212, 13, 2999, 13, 362, 12770, 423, 2319, 1368, 11, 889, 6197, 279, 990, 323, 374, 3196, 520, 279, 6295, 2956, 10181, 11, 3907, 315, 26275, 11, 1071, 25, 330, 4438, 323, 3249, 584, 3351, 4536, 956, 682, 922, 21389, 11, 719, 8830, 279, 3560, 21389, 1514, 690, 1520, 7417, 1057, 8830, 315, 279, 11384, 323, 16296, 315, 7106, 304, 7323, 13, 330, 2181, 374, 1193, 555, 1694, 3025, 311, 4007, 3544, 15055, 315, 828, 11, 1778, 439, 1884, 3984, 555, 6560, 12371, 677, 1201, 11, 430, 584, 527, 3025, 311, 3619, 279, 6485, 19465, 8197, 315, 1524, 1063, 315, 279, 1455, 6913, 3823, 5865, 1093, 7366, 11, 41219, 323, 21811, 1210, 578, 4007, 574, 24853, 555, 279, 5165, 10181, 369, 6401, 8483, 320, 15259, 17526, 8, 26275, 12371, 61860, 8483, 14821, 11, 323, 279, 8013, 18449, 5114, 14821, 315, 8483, 58240, 520, 26275, 13, 578, 4007, 574, 40806, 11, 323, 10887, 555, 264, 64486, 3510, 44550, 2128, 315, 14248, 505, 264, 17226, 743, 315, 5151, 11, 2737, 5780, 6975, 11, 56104, 11, 13443, 11, 323, 62057, 2508, 13, 578, 1005, 315, 5780, 6975, 304, 2466, 18985, 30525, 374, 44169, 6288, 11, 323, 3515, 264, 28254, 2515, 389, 279, 21522, 315, 7978, 430, 649, 387, 11953, 704, 11, 2999, 13, 35131, 9259, 12, 1383, 67020, 11, 832, 315, 279, 3063, 31499, 315, 279, 4007, 1071, 13, 330, 1687, 617, 15884, 8040, 5780, 6975, 4211, 311, 4639, 12933, 1268, 311, 49586, 6485, 5865, 1093, 5820, 1359, 568, 1071, 13, 330, 9673, 4211, 3493, 13548, 502, 26793, 1139, 3823, 7351, 71177, 304, 3544, 7978, 1778, 439, 6560, 12371, 677, 1201, 449, 1202, 4376, 264, 3610, 13324, 1210, 17054, 8096, 40401, 11, 264, 426, 50816, 61748, 33135, 8483, 37946, 11, 1071, 25, 330, 2028, 5825, 14248, 449, 264, 11364, 6776, 311, 4048, 1790, 810, 922, 1268, 21389, 323, 4676, 16681, 304, 1057, 7446, 6439, 11, 14718, 603, 311, 3351, 439, 584, 656, 11, 323, 11000, 10917, 603, 520, 7319, 5326, 315, 8624, 13, 1789, 2937, 11, 433, 2643, 1520, 603, 8417, 3508, 304, 7323, 374, 264, 5353, 477, 264, 29774, 315, 33048, 1210, 2057, 1520, 10765, 279, 4595, 315, 5820, 12715, 389, 279, 33271, 37577, 11, 279, 12074, 6656, 311, 220, 1049, 23872, 889, 28670, 264, 3361, 6382, 430, 17439, 872, 5820, 1475, 220, 508, 6622, 927, 1403, 2919, 13, 578, 5448, 1051, 7863, 449, 279, 5820, 828, 17439, 555, 279, 33271, 24634, 37577, 11, 8405, 264, 8641, 311, 66744, 279, 828, 13, 220, 128257, 198 ]

2,097

[ { "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: Air pollution is a known trigger for exacerbations among individuals with asthma, but its role in the development of new-onset asthma is unclear. We compared the rate of new asthma cases in Sarnia, a city with high pollution levels, with the rates in 2 neighbouring regions in southwestern Ontario, Canada. Methods: Using a population-based birth cohort design and linked health administrative data, we compared the hazard of incident asthma among children 0 to 10 years of age between those born in Lambton (Sarnia) and those born in Windsor and London–Middlesex, for the period Apr. 1, 1993, to Mar. 31, 2009. We used Cox proportional hazards models to adjust for year of birth and exposure to air pollutants (nitrogen dioxide, sulphur dioxide [SO 2 ], ozone and small particulate matter [PM 2.5 ]), as well as maternal, geographic and socioeconomic factors. Results: Among 114 427 children, the highest incidence of asthma was in Lambton, followed by Windsor and London–Middlesex (30.3, 24.4 and 19.8 per 1000 person-years, respectively; p < 0.001). Relative to Lambton, the hazard of asthma, adjusted for socioeconomic and perinatal factors, was lower in Windsor (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.67–0.77) and London–Middlesex (HR 0.65, 95% CI 0.61–0.69). Inclusion of air pollutants attenuated this relative difference in both Windsor (HR 0.79, 95% CI 0.62–1.01) and London–Middlesex (HR 0.89, 95% CI 0.64–1.24). Interpretation We identified a higher incidence of asthma among children born in Lambton (Sarnia) relative to 2 other regions in southwestern Ontario. Higher levels of air pollution (particularly SO 2 and PM 2.5 ) in this region, as experienced by children in their first year of life, may be contributory. Asthma is the most common chronic disease in children, with a Canadian prevalence of 15% to 25%. 1 Asthma exacerbations reduce quality of life and are a leading cause of emergency department visits and hospital admissions. 2 Whereas numerous risk factors for asthma exacerbations are known, 3 – 12 identifying new, modifiable risk factors for onset of this condition could lead to primary prevention. There is a clear association between asthma exacerbations and air pollution in those with previously diagnosed asthma 13 – 17 but less certainty as to whether air pollution might contribute to new-onset asthma. 18 – 21 This association has been challenging to study because of inadequate attribution of air pollution exposure, owing to population mobility and difficulties in differentiating between workplace and residential exposures. Furthermore, most research has focused on adults, 22 , 23 whereas asthma likely develops during gestation or within the first year of life. 24 , 25 As such, it is necessary to elucidate the influence of exposure to pollution on development of asthma in children. A recent systematic review of the relation between incident asthma in children and exposure to air pollution was inconclusive. 26 In the province of Ontario, Canada, a spatial analysis of asthma prevalence between 2002 and 2006 identified a cluster of high rates among children 10 to 14 years of age in and around the city of Sarnia. 27 Sarnia, in southwestern Ontario, is home to the “Chemical Valley,” which accounts for 40% of Canada’s chemical processing facilities. These facilities produce a wide range of products, such as plastics, industrial materials and a variety of consumer goods. 28 , 29 This region has been recorded as having the worst air quality in the country, 30 with measurements above the limits recommended by the World Health Organization. 31 In recent years, this region has received media and government attention because of revelations of unreported toxic emissions and high levels of morbidity as a result of exposure to pollutants. 18 , 32 , 33 We aimed to clarify the link between exposure to air pollution and incident asthma in a subset of Canadian children. Using a population-based birth cohort design, we compared the rate of new asthma cases in Sarnia with rates in 2 neighbouring regions in southwestern Ontario, with adjustment for various factors, including year of birth; maternal, geographic and socioeconomic factors; and exposure to air pollutants. We also examined whether the hazard of incident asthma was attenuated by the reduction in air pollution levels in more recent years. Methods Design and setting We conducted a longitudinal birth cohort study spanning 25 years (Apr. 1, 1993, to Mar. 31, 2018) using linked health administrative databases available at ICES. We chose this period because it had good data availability and because it overlaps with an observed change in asthma trends in Ontario. 34 We compared the incidence of asthma among children born between Apr. 1, 1993, and Mar. 31, 2009, in 3 neighbouring urban regions in southwestern Ontario. The reporting of this study follows the Reporting of Studies Conducted Using Observational Routinely Collected Health Data (RECORD) guidelines for observational studies. 35 , 36 Data sources In the province of Ontario (population 14 million), more than 99% of residents are eligible for government-funded health insurance through the Ontario Health Insurance Plan (OHIP). We used encoded identifiers based on the OHIP number to link individuals to multiple health administrative data sets, including the OHIP data set, which contains information on all physician outpatient visits; the Ontario Registered Persons Database, which provides basic demographic information; and the Canadian Institute for Health Information Discharge Abstract Database (CIHI-DAD), which details all hospital admissions. The MOMBABY data set is derived from the CIHI-DAD and includes records for all mothers linked to their Ontario-born children. The Ontario Marginalization Index 37 , 38 is a geographically based marker of socioeconomic status, consisting of 4 dimensions: residential instability, material deprivation, dependency and ethnic concentration. We linked these data sets using the unique encoded identifiers and analyzed them at ICES (Appendix 1, Table S1, available at ). For data on air quality, we used Ontario Ministry of Environment air quality data 39 and Environment Canada’s National Air Pollution Surveillance data. 40 These publicly available data sets provide information about air pollution across the province. Participants We included all live in-hospital births that occurred", "role": "user" }, { "content": "New findings from Ontario have shown that children born in Sarnia have a higher risk of developing asthma compared to neighboring cities. A research team from Lawson Health Research Institute and Western University, using provincial data from ICES, found that higher air pollution exposure in the first year of life very likely contributed to this higher risk. Their results are published today in CMAJ Open. \"It's known that cities in Southwestern Ontario have varied levels of air pollution because of differences in industry and traffic. For example, Sarnia is home to the 'Chemical Valley' where numerous chemical plants and oil refineries are clustered,\" says Dr. Dhenuka Radhakrishnan, an Adjunct ICES Scientist, formerly working out of ICES Western in London, and Pediatric Respirologist at CHEO. \"We wanted to see if children born in three cities—London, Windsor and Sarnia—had a different risk of developing asthma due to the differing air pollution levels in the three regions, even though the people living in these cities are otherwise comparable in many ways.\" The researchers followed 114,427 children born in these cities between 1993 and 2009 for 10 years, and found that those in Sarnia were at the highest risk of developing asthma. The researchers found that by the age of 10, nearly 24 per cent of children in Sarnia were diagnosed with asthma, compared to 21 per cent in Windsor and 17 per cent in London. The differences were also present after accounting for many risk factors associated with asthma, such as sex, socioeconomic status and urban versus rural setting. The findings were most apparent in the first two years of life, but persistent beyond the age of six. \"Reassuringly, we found the asthma risk for children has reduced in more recent years as pollution levels have also decreased,\" adds Dr. Radhakrishnan. Asthma is the most common chronic disease in Canadian children and has significant impact on quality of life. Asthma is the leading cause of emergency department visits and hospital admissions in this age group. \"It's important to find strategies to prevent asthma development and this study suggests that reducing air pollution exposure, including environmental causes, might reduce the number of children who suffer from asthma,\" explains Dr. Salimah Shariff, Associate Scientist at Lawson, Adjunct Professor at Western and Scientist at ICES Western. There is also growing evidence that exposure during pregnancy can influence development of asthma in children. \"We need to carefully examine how reducing air pollution exposures within a geographic area translates to reductions in asthma development. Understanding the amount of air pollution that a mother and infant are exposed to, and how this impacts their personal risk, could enable regions to target safer levels for their residents,\" adds Dr. Shariff. Wednesday, May 5 is World Asthma Day (WAD). Recognizing symptoms of asthma early is the best a parent can do to improve the health of their child, so they can be diagnosed quickly and start appropriate treatments. If a parent notices their child has wheezing, persistent cough or difficulty with exercise, they are encouraged to bring this to the attention of a health care provider. ", "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: Air pollution is a known trigger for exacerbations among individuals with asthma, but its role in the development of new-onset asthma is unclear. We compared the rate of new asthma cases in Sarnia, a city with high pollution levels, with the rates in 2 neighbouring regions in southwestern Ontario, Canada. Methods: Using a population-based birth cohort design and linked health administrative data, we compared the hazard of incident asthma among children 0 to 10 years of age between those born in Lambton (Sarnia) and those born in Windsor and London–Middlesex, for the period Apr. 1, 1993, to Mar. 31, 2009. We used Cox proportional hazards models to adjust for year of birth and exposure to air pollutants (nitrogen dioxide, sulphur dioxide [SO 2 ], ozone and small particulate matter [PM 2.5 ]), as well as maternal, geographic and socioeconomic factors. Results: Among 114 427 children, the highest incidence of asthma was in Lambton, followed by Windsor and London–Middlesex (30.3, 24.4 and 19.8 per 1000 person-years, respectively; p < 0.001). Relative to Lambton, the hazard of asthma, adjusted for socioeconomic and perinatal factors, was lower in Windsor (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.67–0.77) and London–Middlesex (HR 0.65, 95% CI 0.61–0.69). Inclusion of air pollutants attenuated this relative difference in both Windsor (HR 0.79, 95% CI 0.62–1.01) and London–Middlesex (HR 0.89, 95% CI 0.64–1.24). Interpretation We identified a higher incidence of asthma among children born in Lambton (Sarnia) relative to 2 other regions in southwestern Ontario. Higher levels of air pollution (particularly SO 2 and PM 2.5 ) in this region, as experienced by children in their first year of life, may be contributory. Asthma is the most common chronic disease in children, with a Canadian prevalence of 15% to 25%. 1 Asthma exacerbations reduce quality of life and are a leading cause of emergency department visits and hospital admissions. 2 Whereas numerous risk factors for asthma exacerbations are known, 3 – 12 identifying new, modifiable risk factors for onset of this condition could lead to primary prevention. There is a clear association between asthma exacerbations and air pollution in those with previously diagnosed asthma 13 – 17 but less certainty as to whether air pollution might contribute to new-onset asthma. 18 – 21 This association has been challenging to study because of inadequate attribution of air pollution exposure, owing to population mobility and difficulties in differentiating between workplace and residential exposures. Furthermore, most research has focused on adults, 22 , 23 whereas asthma likely develops during gestation or within the first year of life. 24 , 25 As such, it is necessary to elucidate the influence of exposure to pollution on development of asthma in children. A recent systematic review of the relation between incident asthma in children and exposure to air pollution was inconclusive. 26 In the province of Ontario, Canada, a spatial analysis of asthma prevalence between 2002 and 2006 identified a cluster of high rates among children 10 to 14 years of age in and around the city of Sarnia. 27 Sarnia, in southwestern Ontario, is home to the “Chemical Valley,” which accounts for 40% of Canada’s chemical processing facilities. These facilities produce a wide range of products, such as plastics, industrial materials and a variety of consumer goods. 28 , 29 This region has been recorded as having the worst air quality in the country, 30 with measurements above the limits recommended by the World Health Organization. 31 In recent years, this region has received media and government attention because of revelations of unreported toxic emissions and high levels of morbidity as a result of exposure to pollutants. 18 , 32 , 33 We aimed to clarify the link between exposure to air pollution and incident asthma in a subset of Canadian children. Using a population-based birth cohort design, we compared the rate of new asthma cases in Sarnia with rates in 2 neighbouring regions in southwestern Ontario, with adjustment for various factors, including year of birth; maternal, geographic and socioeconomic factors; and exposure to air pollutants. We also examined whether the hazard of incident asthma was attenuated by the reduction in air pollution levels in more recent years. Methods Design and setting We conducted a longitudinal birth cohort study spanning 25 years (Apr. 1, 1993, to Mar. 31, 2018) using linked health administrative databases available at ICES. We chose this period because it had good data availability and because it overlaps with an observed change in asthma trends in Ontario. 34 We compared the incidence of asthma among children born between Apr. 1, 1993, and Mar. 31, 2009, in 3 neighbouring urban regions in southwestern Ontario. The reporting of this study follows the Reporting of Studies Conducted Using Observational Routinely Collected Health Data (RECORD) guidelines for observational studies. 35 , 36 Data sources In the province of Ontario (population 14 million), more than 99% of residents are eligible for government-funded health insurance through the Ontario Health Insurance Plan (OHIP). We used encoded identifiers based on the OHIP number to link individuals to multiple health administrative data sets, including the OHIP data set, which contains information on all physician outpatient visits; the Ontario Registered Persons Database, which provides basic demographic information; and the Canadian Institute for Health Information Discharge Abstract Database (CIHI-DAD), which details all hospital admissions. The MOMBABY data set is derived from the CIHI-DAD and includes records for all mothers linked to their Ontario-born children. The Ontario Marginalization Index 37 , 38 is a geographically based marker of socioeconomic status, consisting of 4 dimensions: residential instability, material deprivation, dependency and ethnic concentration. We linked these data sets using the unique encoded identifiers and analyzed them at ICES (Appendix 1, Table S1, available at ). For data on air quality, we used Ontario Ministry of Environment air quality data 39 and Environment Canada’s National Air Pollution Surveillance data. 40 These publicly available data sets provide information about air pollution across the province. Participants We included all live in-hospital births that occurred<|im_end|> <|im_start|>assistant New findings from Ontario have shown that children born in Sarnia have a higher risk of developing asthma compared to neighboring cities. A research team from Lawson Health Research Institute and Western University, using provincial data from ICES, found that higher air pollution exposure in the first year of life very likely contributed to this higher risk. Their results are published today in CMAJ Open. "It's known that cities in Southwestern Ontario have varied levels of air pollution because of differences in industry and traffic. For example, Sarnia is home to the 'Chemical Valley' where numerous chemical plants and oil refineries are clustered," says Dr. Dhenuka Radhakrishnan, an Adjunct ICES Scientist, formerly working out of ICES Western in London, and Pediatric Respirologist at CHEO. "We wanted to see if children born in three cities—London, Windsor and Sarnia—had a different risk of developing asthma due to the differing air pollution levels in the three regions, even though the people living in these cities are otherwise comparable in many ways." The researchers followed 114,427 children born in these cities between 1993 and 2009 for 10 years, and found that those in Sarnia were at the highest risk of developing asthma. The researchers found that by the age of 10, nearly 24 per cent of children in Sarnia were diagnosed with asthma, compared to 21 per cent in Windsor and 17 per cent in London. The differences were also present after accounting for many risk factors associated with asthma, such as sex, socioeconomic status and urban versus rural setting. The findings were most apparent in the first two years of life, but persistent beyond the age of six. "Reassuringly, we found the asthma risk for children has reduced in more recent years as pollution levels have also decreased," adds Dr. Radhakrishnan. Asthma is the most common chronic disease in Canadian children and has significant impact on quality of life. Asthma is the leading cause of emergency department visits and hospital admissions in this age group. "It's important to find strategies to prevent asthma development and this study suggests that reducing air pollution exposure, including environmental causes, might reduce the number of children who suffer from asthma," explains Dr. Salimah Shariff, Associate Scientist at Lawson, Adjunct Professor at Western and Scientist at ICES Western. There is also growing evidence that exposure during pregnancy can influence development of asthma in children. "We need to carefully examine how reducing air pollution exposures within a geographic area translates to reductions in asthma development. Understanding the amount of air pollution that a mother and infant are exposed to, and how this impacts their personal risk, could enable regions to target safer levels for their residents," adds Dr. Shariff. Wednesday, May 5 is World Asthma Day (WAD). Recognizing symptoms of asthma early is the best a parent can do to improve the health of their child, so they can be diagnosed quickly and start appropriate treatments. If a parent notices their child has wheezing, persistent cough or difficulty with exercise, they are encouraged to bring this to the attention of a health care provider. <|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 first stars that formed after the Big Bang were probably massive 1 , and they provided the Universe with the first elements heavier than helium (‘metals’), which were incorporated into low-mass stars that have survived to the present 2 , 3 . Eight stars in the oldest globular cluster in the Galaxy, NGC 6522, were found to have surface abundances consistent with the gas from which they formed being enriched by massive stars 4 (that is, with higher α-element/Fe and Eu/Fe ratios than those of the Sun). However, the same stars have anomalously high abundances of Ba and La with respect to Fe 4 , which usually arises through nucleosynthesis in low-mass stars 5 (via the slow-neutron-capture process, or s-process). Recent theory suggests that metal-poor fast-rotating massive stars are able to boost the s-process yields by up to four orders of magnitude 6 , which might provide a solution to this contradiction. Here we report a reanalysis of the earlier spectra, which reveals that Y and Sr are also overabundant with respect to Fe, showing a large scatter similar to that observed in extremely metal-poor stars 7 , whereas C abundances are not enhanced. This pattern is best explained as originating in metal-poor fast-rotating massive stars, which might point to a common property of the first stellar generations and even of the ‘first stars’. Main NGC 6522 has been confirmed to be older than any halo globular cluster, despite its metallicity being a tenth that of the Sun 4 , and is therefore a witness of the early phases of the chemical enrichment of the Universe. Consistent with the age of this cluster, its stars show a chemical pattern typical of an interstellar medium enriched by core-collapse supernovae (in which thermonuclear supernovae of type Ia and low- and intermediate-mass stars did not have time to contribute to the chemical enrichment). However, the large [Ba/Eu] ratios found 4 in five of the eight stars of NGC 6522 studied ( Table 1 ) shows that the excess in Ba cannot be attributed to the rapid-neutron-capture (r) process, and so the s-process must be invoked 4 , 5 (see Supplementary Information ). Table 1 Abundances of the eight stars in NGC 6522. Full size table There are only two ways to explain the high Ba and La found in NGC 6522, namely: (1) the original gas from which the globular cluster formed had been pre-enriched in s-process elements by previous generations of massive stars, or (2) the original composition of the stars formed in the globular cluster was lately modified by mass-transfer episodes taking place in binary systems involving low-mass asymptotic giant branch (AGB) stars within NGC 6522. From re-inspection of the spectra of NGC 6522 (ref. 4 ), we were able to obtain the Y abundances for eight giant stars, and estimate the Sr abundances for six of them ( Table 1 and the Supplementary Information ). We find large overabundances of Y (and Sr) with respect to Fe and Ba in the NGC 6522 stars, with a similar scatter to that observed in extremely metal-poor halo stars 7 , but now also observed for bulge stars with [Fe/H] = −1, a result not seen previously (see Fig. 1 ). In addition, from the C 2 band-head (see Supplementary Information ), we were able to estimate upper limits for the [C/Fe] ratio. We found that all studied stars have [C/Fe] ≲ 0.0, and hence are not enriched in C, as is the case in a significant fraction of very-metal-poor halo stars 8 . Figure 1: The [Y/Ba] scatter observed in the early Universe. Observed [Y/Ba] scatter in the NGC 6522 stars, which have a metallicity of around [Fe/H] = −1 (ref. 4 ) (red circles with s.d. error bars) compared to that observed in extremely metal-poor halo stars 7 (with [Fe/H] < −3). The two yellow shaded areas mark the ‘early Universe phase’ sampled by halo and Bulge stars. We note the similar scatter in [Y/Ba] between the most metal-poor halo stars and our Bulge stars (compare the scatter inside the two yellow zones). Also shown is the [Y/Ba] scatter predicted for the very earliest phases of the chemical enrichment owing to ‘spinstars’ (indicated by the blue column). The dashed line indicates the [Y/Ba] ratio predicted from pure r-process 5 . Finally, the curves show the predictions for the [Y/Ba] ratio by recent AGB models 14 , at different metallicities. The lowest 13 C-pocket efficiency model considered here 14 is ‘ST/12’ (where ST is for standard, and ST/12 means the efficiency of the standard case reduced by a factor of 12; the 13 C-pocket is a tiny radiative layer of material in the He-rich region just below the H shell, responsible for most of the s-process in AGB stars). We do not consider AGB models with lower efficiencies (showing higher [Y/Ba] ratios) because the corresponding [Ba/Fe] and [Y/Fe] ratios would be too low 14 (approximately solar) compared to the large enhancements observed in the NGC 6522 stars ( Table 1 ). Finally, we note that whereas AGB mass-transfer and ‘spinstar’ models can explain stars with slightly sub-solar [Y/Ba] ratios (−1 < [Y/Ba] < 0), both scenarios have difficulties in explaining stars with [Y/Ba] ratios below −1. Gyr, billion year; M ⊙ , solar mass. PowerPoint slide Full size image Extremely metal-poor environments can produce noticeable effects on the properties of massive stars (more details can be found in the Supplementary Information ). At very low metallicities, stars rotate faster 9 . Models of fast-rotating massive stars (hereafter ‘spinstars’) at very low metallicities 10 , 11 , 12 have shown that rotational mixing transports 12 C from He-burning core into H-rich layers where it is transformed to 14 N and 13 C. This primary 14 N is then transported back to the He-burning core where it is converted into 22 Ne, the main neutron source in massive stars for the s-process beyond Fe. Hence, the amount of 22 Ne and of", "role": "user" }, { "content": "The first stars that dotted the universe were not only immense, but probably also fast-spinning, according to a new study that sheds light on the nature of stellar evolution. Astronomers using data from the Very Large Telescope (VLT) of the European Southern Observatory (ESO) have spotted the remains of some of the Universe's very first stars in the Milky Way. The gas cloud left behind when the stars exploded billions of years ago contains elements in proportions different to those found in new stars, shedding light on the 'missing links' between the Big Bang and today's Universe. Even with the most powerful telescopes, it is not possible to observe these stars directly. They are so old that only the most massive, with eight times or more the mass of our sun, would have had the time to die and pollute the gas from which they were formed with elements heavier than helium. These stars lived fast and died young, after no more than 30 million years. 'We think that the first generations of massive stars were very fast rotators - that's why we called them spinstars', explains Christina Chiappini from the Leibniz Institute for Astrophysics Potsdam (AIP) in Germany and the Istituto Nazionale di Astrofisica (INAF) in Italy, who led the study published in the journal Nature. Dr Chiappini and her colleagues have found the remains of these stars in the oldest known globular cluster in our Galaxy, the 12-billion-year-old NGC 6522 which probably witnessed the early phases of the seeding of heavy elements across the Universe. Professor Georges Meynet, from the University of Geneva in Switzerland, explains that it is like trying 'to reveal the character of a cook from the taste of his dishes'. The researchers discovered eight old stars with strangely high levels of the rare elements strontium and yttrium. They also calculated that the stars would have whirled with a surface speed of 1.8 million kilometres per hour. By comparison, massive stars in the Milky Way typically spin at about 360,000 kilometres per hour. This high rate of spin would cause overlap between inner and outer gas layers of the stars that would not otherwise mix. The resulting cascade of nuclear reactions would generate radioactive neon, which in turn would emit neutrons that would collide with iron and other heavy atoms to create strontium and yttrium. After the spinstars' death, these elements made their way into new star-forming clouds and eventually into the stars of NGC 6522. These findings suggest that these fast spinners may have changed the face of the Universe in dramatic ways. For instance, their fast spinning could have led them to create and disperse heavy elements across the Universe much earlier than previously thought. It could also have led to a greater-than-expected number of gamma ray bursts, the most powerful explosions known in the Universe. However, 'alternative scenarios cannot yet be discarded, but we show that if the first generations of massive stars were spinstars, this would offer a very elegant explanation to this puzzle!', says Cristina Chiappini. Therefore, Urs Frischknecht, a PhD student at the University of Basel in Switzerland, is currently working on further testing the proposed scenario. ", "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 first stars that formed after the Big Bang were probably massive 1 , and they provided the Universe with the first elements heavier than helium (‘metals’), which were incorporated into low-mass stars that have survived to the present 2 , 3 . Eight stars in the oldest globular cluster in the Galaxy, NGC 6522, were found to have surface abundances consistent with the gas from which they formed being enriched by massive stars 4 (that is, with higher α-element/Fe and Eu/Fe ratios than those of the Sun). However, the same stars have anomalously high abundances of Ba and La with respect to Fe 4 , which usually arises through nucleosynthesis in low-mass stars 5 (via the slow-neutron-capture process, or s-process). Recent theory suggests that metal-poor fast-rotating massive stars are able to boost the s-process yields by up to four orders of magnitude 6 , which might provide a solution to this contradiction. Here we report a reanalysis of the earlier spectra, which reveals that Y and Sr are also overabundant with respect to Fe, showing a large scatter similar to that observed in extremely metal-poor stars 7 , whereas C abundances are not enhanced. This pattern is best explained as originating in metal-poor fast-rotating massive stars, which might point to a common property of the first stellar generations and even of the ‘first stars’. Main NGC 6522 has been confirmed to be older than any halo globular cluster, despite its metallicity being a tenth that of the Sun 4 , and is therefore a witness of the early phases of the chemical enrichment of the Universe. Consistent with the age of this cluster, its stars show a chemical pattern typical of an interstellar medium enriched by core-collapse supernovae (in which thermonuclear supernovae of type Ia and low- and intermediate-mass stars did not have time to contribute to the chemical enrichment). However, the large [Ba/Eu] ratios found 4 in five of the eight stars of NGC 6522 studied ( Table 1 ) shows that the excess in Ba cannot be attributed to the rapid-neutron-capture (r) process, and so the s-process must be invoked 4 , 5 (see Supplementary Information ). Table 1 Abundances of the eight stars in NGC 6522. Full size table There are only two ways to explain the high Ba and La found in NGC 6522, namely: (1) the original gas from which the globular cluster formed had been pre-enriched in s-process elements by previous generations of massive stars, or (2) the original composition of the stars formed in the globular cluster was lately modified by mass-transfer episodes taking place in binary systems involving low-mass asymptotic giant branch (AGB) stars within NGC 6522. From re-inspection of the spectra of NGC 6522 (ref. 4 ), we were able to obtain the Y abundances for eight giant stars, and estimate the Sr abundances for six of them ( Table 1 and the Supplementary Information ). We find large overabundances of Y (and Sr) with respect to Fe and Ba in the NGC 6522 stars, with a similar scatter to that observed in extremely metal-poor halo stars 7 , but now also observed for bulge stars with [Fe/H] = −1, a result not seen previously (see Fig. 1 ). In addition, from the C 2 band-head (see Supplementary Information ), we were able to estimate upper limits for the [C/Fe] ratio. We found that all studied stars have [C/Fe] ≲ 0.0, and hence are not enriched in C, as is the case in a significant fraction of very-metal-poor halo stars 8 . Figure 1: The [Y/Ba] scatter observed in the early Universe. Observed [Y/Ba] scatter in the NGC 6522 stars, which have a metallicity of around [Fe/H] = −1 (ref. 4 ) (red circles with s.d. error bars) compared to that observed in extremely metal-poor halo stars 7 (with [Fe/H] < −3). The two yellow shaded areas mark the ‘early Universe phase’ sampled by halo and Bulge stars. We note the similar scatter in [Y/Ba] between the most metal-poor halo stars and our Bulge stars (compare the scatter inside the two yellow zones). Also shown is the [Y/Ba] scatter predicted for the very earliest phases of the chemical enrichment owing to ‘spinstars’ (indicated by the blue column). The dashed line indicates the [Y/Ba] ratio predicted from pure r-process 5 . Finally, the curves show the predictions for the [Y/Ba] ratio by recent AGB models 14 , at different metallicities. The lowest 13 C-pocket efficiency model considered here 14 is ‘ST/12’ (where ST is for standard, and ST/12 means the efficiency of the standard case reduced by a factor of 12; the 13 C-pocket is a tiny radiative layer of material in the He-rich region just below the H shell, responsible for most of the s-process in AGB stars). We do not consider AGB models with lower efficiencies (showing higher [Y/Ba] ratios) because the corresponding [Ba/Fe] and [Y/Fe] ratios would be too low 14 (approximately solar) compared to the large enhancements observed in the NGC 6522 stars ( Table 1 ). Finally, we note that whereas AGB mass-transfer and ‘spinstar’ models can explain stars with slightly sub-solar [Y/Ba] ratios (−1 < [Y/Ba] < 0), both scenarios have difficulties in explaining stars with [Y/Ba] ratios below −1. Gyr, billion year; M ⊙ , solar mass. PowerPoint slide Full size image Extremely metal-poor environments can produce noticeable effects on the properties of massive stars (more details can be found in the Supplementary Information ). At very low metallicities, stars rotate faster 9 . Models of fast-rotating massive stars (hereafter ‘spinstars’) at very low metallicities 10 , 11 , 12 have shown that rotational mixing transports 12 C from He-burning core into H-rich layers where it is transformed to 14 N and 13 C. This primary 14 N is then transported back to the He-burning core where it is converted into 22 Ne, the main neutron source in massive stars for the s-process beyond Fe. Hence, the amount of 22 Ne and of<|im_end|> <|im_start|>assistant The first stars that dotted the universe were not only immense, but probably also fast-spinning, according to a new study that sheds light on the nature of stellar evolution. Astronomers using data from the Very Large Telescope (VLT) of the European Southern Observatory (ESO) have spotted the remains of some of the Universe's very first stars in the Milky Way. The gas cloud left behind when the stars exploded billions of years ago contains elements in proportions different to those found in new stars, shedding light on the 'missing links' between the Big Bang and today's Universe. Even with the most powerful telescopes, it is not possible to observe these stars directly. They are so old that only the most massive, with eight times or more the mass of our sun, would have had the time to die and pollute the gas from which they were formed with elements heavier than helium. These stars lived fast and died young, after no more than 30 million years. 'We think that the first generations of massive stars were very fast rotators - that's why we called them spinstars', explains Christina Chiappini from the Leibniz Institute for Astrophysics Potsdam (AIP) in Germany and the Istituto Nazionale di Astrofisica (INAF) in Italy, who led the study published in the journal Nature. Dr Chiappini and her colleagues have found the remains of these stars in the oldest known globular cluster in our Galaxy, the 12-billion-year-old NGC 6522 which probably witnessed the early phases of the seeding of heavy elements across the Universe. Professor Georges Meynet, from the University of Geneva in Switzerland, explains that it is like trying 'to reveal the character of a cook from the taste of his dishes'. The researchers discovered eight old stars with strangely high levels of the rare elements strontium and yttrium. They also calculated that the stars would have whirled with a surface speed of 1.8 million kilometres per hour. By comparison, massive stars in the Milky Way typically spin at about 360,000 kilometres per hour. This high rate of spin would cause overlap between inner and outer gas layers of the stars that would not otherwise mix. The resulting cascade of nuclear reactions would generate radioactive neon, which in turn would emit neutrons that would collide with iron and other heavy atoms to create strontium and yttrium. After the spinstars' death, these elements made their way into new star-forming clouds and eventually into the stars of NGC 6522. These findings suggest that these fast spinners may have changed the face of the Universe in dramatic ways. For instance, their fast spinning could have led them to create and disperse heavy elements across the Universe much earlier than previously thought. It could also have led to a greater-than-expected number of gamma ray bursts, the most powerful explosions known in the Universe. However, 'alternative scenarios cannot yet be discarded, but we show that if the first generations of massive stars were spinstars, this would offer a very elegant explanation to this puzzle!', says Cristina Chiappini. Therefore, Urs Frischknecht, a PhD student at the University of Basel in Switzerland, is currently working on further testing the proposed scenario. <|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 Screening programs must balance the benefit of early detection with the cost of overscreening. Here, we introduce a novel reinforcement learning-based framework for personalized screening, Tempo, and demonstrate its efficacy in the context of breast cancer. We trained our risk-based screening policies on a large screening mammography dataset from Massachusetts General Hospital (MGH; USA) and validated this dataset in held-out patients from MGH and external datasets from Emory University (Emory; USA), Karolinska Institute (Karolinska; Sweden) and Chang Gung Memorial Hospital (CGMH; Taiwan). Across all test sets, we find that the Tempo policy combined with an image-based artificial intelligence (AI) risk model is significantly more efficient than current regimens used in clinical practice in terms of simulated early detection per screen frequency. Moreover, we show that the same Tempo policy can be easily adapted to a wide range of possible screening preferences, allowing clinicians to select their desired trade-off between early detection and screening costs without training new policies. Finally, we demonstrate that Tempo policies based on AI-based risk models outperform Tempo policies based on less accurate clinical risk models. Altogether, our results show that pairing AI-based risk models with agile AI-designed screening policies has the potential to improve screening programs by advancing early detection while reducing overscreening. Main For multiple diseases, early detection significantly improves patient outcomes 1 , 2 . This motivates considerable investments in population-wide screening programs 3 , 4 such as mammography for breast cancer. To be effective and economically viable, these programs must find the right balance between early detection and overscreening. This capacity builds on two complementary technologies: (1) the ability to accurately assess patient risk at a given time point and (2) the ability to design screening regimens based on this risk. With recent advances in deep learning, imaging and genetics, risk assessment technologies are rapidly improving 5 , 6 . However, our ability to utilize these predictions to personalize screening regimens lags behind. This deficiency is particularly apparent when the screening system has limited throughput. In this paper, we focus on the design of screening regimens attuned to the increased capacity of the modern risk assessment models. The need for new methods to personalize screening is motivated by a substantial change in risk assessment algorithms. Traditional risk assessment models rely on a number of categorical variables encoding patient demographics and clinical history combined with traditional statistical models to predict risk 7 , 8 . These scores are relatively static throughout a patient’s lifetime, with changes typically driven by the patient’s age. Moreover, the limited predictive capacity of these risk models restricts the scope of recommendations they support and, consequently, their impact on the screening regimen. Current guidelines divide the population into a few large groups, most often discriminating predicted high-risk patients from the rest, and recommend the same screening frequency to all the members of that cohort 9 , 10 , 11 . As a result, there remain large opportunities to further personalize care. The power of novel, AI-driven risk models 6 , 12 , 13 , 14 has given us an opportunity to fundamentally transform population screening. Deep learning algorithms enable these risk models to operate over raw patient data, such as imaging, in addition to traditional expert-specified categorical variables. Moreover, these models can detect highly complex dependencies, which further strengthens their predictive capacity relative to traditional methods. One distinctive feature of these risk models is that their predictions may fluctuate over time as the patient’s raw data evolve. This feature suggests that screening regimens need to be flexibly adjusted with changes in risk and optimized over a patient’s lifetime. We hypothesize that by pairing AI-based risk models and agile AI-based screening regimens, we can improve early detection while lowering the overall cost of screening. This article presents empirical findings that support this hypothesis in the area of breast cancer screening. The core methodology is applicable to other disease areas and other types of risk models beyond imaging. Results Overview of the algorithm In computational terms, we can view breast cancer screening as a sequential decision task, where we wish to develop a policy (i.e., screening guideline) that predicts a follow-up recommendation for each patient to maximize their chance for early detection while minimizing screening costs. Intuitively, such a policy should recommend infrequent screenings for low-risk patients while prescribing a higher frequency of screenings for patients at increased risk. The question is how to personalize screening intervals based on a patient’s risk profile. More formally, we can cast the screening problem as a Markov decision process, where a patient’s state is their risk assessment, the possible actions are different follow-up recommendations (e.g., 6 months or 2 years) and rewards are a combination of expected early detection benefits and screening costs. This formulation enables us to find the best possible policy for this Markov decision process with reinforcement learning (RL) algorithms 15 , 16 . RL algorithms train policies (i.e., machine learning models) to make a sequence of decisions that maximize future reward (e.g., early detection benefits) without explicit guidance on the right decision at intermediate steps. Policies are initialized randomly, and through a mix of random exploration and utilization of current knowledge, RL algorithms iteratively improve policies. We show how to leverage RL methods of determining effective cancer screening policies from retrospective screening data. Applying RL in this context poses a unique challenge, namely the estimation of patient trajectories from retrospective data. The training data pertaining to individual patients only contain information about their risk at the time points when the mammogram was taken. However, to determine whether the algorithm makes the correct recommendation, we need to know the risk assessment at intermediate points. Therefore, we design an algorithm that learns to extrapolate a patient’s risk at unobserved time points from the observed screenings. This estimation evolves as new mammograms of the patient become available. With access to these predictions, we can guide our reinforcement learner to adjust its actions according to the estimated risk. Using the retrospective trajectories as our", "role": "user" }, { "content": "While mammograms are currently the gold standard in breast cancer screening, swirls of controversy exist: advocates argue for the ability to save lives, (women aged 60 to 69 had a 33 percent lower risk of dying compared to those who didn't get mammograms), and another camp argues about costly and potentially traumatic false positives (a meta-analysis of three randomized trials found a 19 percent over-diagnosis rate from mammography). Even with some saved lives, and some overtreatment and overscreening, current guidelines are still a catch all: women aged 45 to 54 should get mammograms every year. While personalized screening has long been thought of as the answer, tools that can leverage the troves of data to do this lag behind. This led scientists from MIT's Computer Science and Artificial Intelligence Laboratory (CSAIL) and Jameel Clinic for Machine Learning and Health to ask: Can we use machine learning to provide personalized screening? Out of this came Tempo, a technology for creating risk-based screening guidelines. Using an AI-based risk model that looks at who was screened and when they got diagnosed, Tempo will recommend a patient return for a mammogram at a specific time point in the future, like six months or three years. The same Tempo policy can be easily adapted to a wide range of possible screening preferences, which would let clinicians pick their desired early detection to screening cost trade-off, without training new policies. The model was trained on a large screening mammography dataset from Massachusetts General Hospital (MGH), and was tested on held-out patients from MGH as well as external datasets from Emory, Karolinska Sweden and Chang Gung Memorial Hospitals. Using the team's previously developed risk-assessment algorithm Mirai, Tempo obtained better early detection than annual screening while requiring twenty five percent less mammograms overall at Karolinska. At MGH, it recommended roughly a mammogram a year, and obtained a simulated early detection benefit of roughly four and half months better. \"By tailoring the screening to the patient's individual risk, we can improve patient outcomes, reduce over treatment and eliminate health disparities,\" says Adam Yala, MIT CSAIL Ph.D. student and lead researcher. Given the massive scale of breast cancer screening, with tens of millions of women getting mammograms every year, improvements to our guidelines are immensely important.\" Deep medicine Early uses of AI in medicine stem back to the 1960's, where many refer to the Dendral experiments as kicking off the field. Researchers created a software system that was considered the first expert kind that automated the decision-making and problem-solving behavior of organic chemists. Sixty years later, deep medicine has greatly evolved drug diagnostics, predictive medicine, and patient care. \"Current guidelines divide the population into a few large groups, like younger or older than 55, and recommend the same screening frequency to all the members of a cohort. The development of AI based risk models that operate over raw patient data give us an opportunity to transform screening, giving more frequent screens to those who need it and sparing the rest,\" says Yala. \"A key aspect of these models is that their predictions can evolve over time as a patient's raw data changes, suggesting that screening policies need to be attuned to changes in risk and be optimized over long periods of patient data.\" Tempo uses reinforcement learning, a machine learning method widely known for success in games like Chess and Go, to develop a \"policy\" that predicts a followup recommendation for each patient. The training data here only had information about a patient's risk at the time points when their mammogram was taken (when they were 50, or 55, for example). The team needed the risk assessment at intermediate points, so they designed their algorithm to learn a patient's risk at unobserved time points from their observed screenings, which evolved as new mammograms of the patient became available. The team first trained a neural network to predict future risk assessments given previous ones. This model then estimates patient risk at unobserved timepoints, and it enables simulation of the risk-based screening policies. Next, they trained that policy, (also a neural network), to maximize the reward (for example, the combination of early detection and screening cost) to the retrospective training set. Eventually, you'd get a recommendation for when to return for the next screen, ranging from six months to three years in the future, in multiples of six months—the standard is only one or two years. Let's say patient A comes in for their first mammogram, and eventually gets diagnosed at year four. In year two, there's nothing, so they don't come back for another two years, but then at year four they get a diagnosis. Now there's been two years of gap between the last screen, where a tumor could have grown. Using Tempo, at that first mammogram, year zero, the recommendation might have been to come back in two years. And then at year two, it might have seen that risk is high, and recommended that the patient come back in six months, and in the best case, it would be detectable. The model is dynamically changing the patient's screening frequency, based on how the risk profile is changing. Tempo uses a simple metric for early detection, which assumes that cancer can be caught up to 18 months in advance. While Tempo outperformed current guidelines across different settings of this assumption (six months, twelve months), none of these assumptions are perfect as the early detection potential of a tumor depends on that tumor's characteristics. The team suggested that follow up work using tumor growth models could address this issue. Also, the screening cost metric, which counts the total screening volume recommended by Tempo, doesn't provide a full analysis of the entire future cost because it does not explicitly quantify false positive risks or additional screening harms. There are many future directions that can further improve personalized screening algorithms. The team says one avenue would be to build on the metrics used to estimate early detection and screening costs from retrospective data, which would result in more refined guidelines. Tempo could also be adapted to include different types of screening recommendations, such as leveraging MRI or mammograms, and future work could separately model the costs and benefits of each. With better screening policies, recalculating the earliest and latest age that screening is still cost-effective for a patient might be feasible. \"Our framework is flexible and can be readily utilized for other diseases, other forms of risk models, and other definitions of early detection benefit or screening cost. We expect the utility of Tempo to continue to improve as risk models and outcome metrics are further refined. We're excited to work with hospital partners to prospectively study this technology and help us further improve personalized cancer screening,\" says Yala. ", "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 Screening programs must balance the benefit of early detection with the cost of overscreening. Here, we introduce a novel reinforcement learning-based framework for personalized screening, Tempo, and demonstrate its efficacy in the context of breast cancer. We trained our risk-based screening policies on a large screening mammography dataset from Massachusetts General Hospital (MGH; USA) and validated this dataset in held-out patients from MGH and external datasets from Emory University (Emory; USA), Karolinska Institute (Karolinska; Sweden) and Chang Gung Memorial Hospital (CGMH; Taiwan). Across all test sets, we find that the Tempo policy combined with an image-based artificial intelligence (AI) risk model is significantly more efficient than current regimens used in clinical practice in terms of simulated early detection per screen frequency. Moreover, we show that the same Tempo policy can be easily adapted to a wide range of possible screening preferences, allowing clinicians to select their desired trade-off between early detection and screening costs without training new policies. Finally, we demonstrate that Tempo policies based on AI-based risk models outperform Tempo policies based on less accurate clinical risk models. Altogether, our results show that pairing AI-based risk models with agile AI-designed screening policies has the potential to improve screening programs by advancing early detection while reducing overscreening. Main For multiple diseases, early detection significantly improves patient outcomes 1 , 2 . This motivates considerable investments in population-wide screening programs 3 , 4 such as mammography for breast cancer. To be effective and economically viable, these programs must find the right balance between early detection and overscreening. This capacity builds on two complementary technologies: (1) the ability to accurately assess patient risk at a given time point and (2) the ability to design screening regimens based on this risk. With recent advances in deep learning, imaging and genetics, risk assessment technologies are rapidly improving 5 , 6 . However, our ability to utilize these predictions to personalize screening regimens lags behind. This deficiency is particularly apparent when the screening system has limited throughput. In this paper, we focus on the design of screening regimens attuned to the increased capacity of the modern risk assessment models. The need for new methods to personalize screening is motivated by a substantial change in risk assessment algorithms. Traditional risk assessment models rely on a number of categorical variables encoding patient demographics and clinical history combined with traditional statistical models to predict risk 7 , 8 . These scores are relatively static throughout a patient’s lifetime, with changes typically driven by the patient’s age. Moreover, the limited predictive capacity of these risk models restricts the scope of recommendations they support and, consequently, their impact on the screening regimen. Current guidelines divide the population into a few large groups, most often discriminating predicted high-risk patients from the rest, and recommend the same screening frequency to all the members of that cohort 9 , 10 , 11 . As a result, there remain large opportunities to further personalize care. The power of novel, AI-driven risk models 6 , 12 , 13 , 14 has given us an opportunity to fundamentally transform population screening. Deep learning algorithms enable these risk models to operate over raw patient data, such as imaging, in addition to traditional expert-specified categorical variables. Moreover, these models can detect highly complex dependencies, which further strengthens their predictive capacity relative to traditional methods. One distinctive feature of these risk models is that their predictions may fluctuate over time as the patient’s raw data evolve. This feature suggests that screening regimens need to be flexibly adjusted with changes in risk and optimized over a patient’s lifetime. We hypothesize that by pairing AI-based risk models and agile AI-based screening regimens, we can improve early detection while lowering the overall cost of screening. This article presents empirical findings that support this hypothesis in the area of breast cancer screening. The core methodology is applicable to other disease areas and other types of risk models beyond imaging. Results Overview of the algorithm In computational terms, we can view breast cancer screening as a sequential decision task, where we wish to develop a policy (i.e., screening guideline) that predicts a follow-up recommendation for each patient to maximize their chance for early detection while minimizing screening costs. Intuitively, such a policy should recommend infrequent screenings for low-risk patients while prescribing a higher frequency of screenings for patients at increased risk. The question is how to personalize screening intervals based on a patient’s risk profile. More formally, we can cast the screening problem as a Markov decision process, where a patient’s state is their risk assessment, the possible actions are different follow-up recommendations (e.g., 6 months or 2 years) and rewards are a combination of expected early detection benefits and screening costs. This formulation enables us to find the best possible policy for this Markov decision process with reinforcement learning (RL) algorithms 15 , 16 . RL algorithms train policies (i.e., machine learning models) to make a sequence of decisions that maximize future reward (e.g., early detection benefits) without explicit guidance on the right decision at intermediate steps. Policies are initialized randomly, and through a mix of random exploration and utilization of current knowledge, RL algorithms iteratively improve policies. We show how to leverage RL methods of determining effective cancer screening policies from retrospective screening data. Applying RL in this context poses a unique challenge, namely the estimation of patient trajectories from retrospective data. The training data pertaining to individual patients only contain information about their risk at the time points when the mammogram was taken. However, to determine whether the algorithm makes the correct recommendation, we need to know the risk assessment at intermediate points. Therefore, we design an algorithm that learns to extrapolate a patient’s risk at unobserved time points from the observed screenings. This estimation evolves as new mammograms of the patient become available. With access to these predictions, we can guide our reinforcement learner to adjust its actions according to the estimated risk. Using the retrospective trajectories as our<|im_end|> <|im_start|>assistant While mammograms are currently the gold standard in breast cancer screening, swirls of controversy exist: advocates argue for the ability to save lives, (women aged 60 to 69 had a 33 percent lower risk of dying compared to those who didn't get mammograms), and another camp argues about costly and potentially traumatic false positives (a meta-analysis of three randomized trials found a 19 percent over-diagnosis rate from mammography). Even with some saved lives, and some overtreatment and overscreening, current guidelines are still a catch all: women aged 45 to 54 should get mammograms every year. While personalized screening has long been thought of as the answer, tools that can leverage the troves of data to do this lag behind. This led scientists from MIT's Computer Science and Artificial Intelligence Laboratory (CSAIL) and Jameel Clinic for Machine Learning and Health to ask: Can we use machine learning to provide personalized screening? Out of this came Tempo, a technology for creating risk-based screening guidelines. Using an AI-based risk model that looks at who was screened and when they got diagnosed, Tempo will recommend a patient return for a mammogram at a specific time point in the future, like six months or three years. The same Tempo policy can be easily adapted to a wide range of possible screening preferences, which would let clinicians pick their desired early detection to screening cost trade-off, without training new policies. The model was trained on a large screening mammography dataset from Massachusetts General Hospital (MGH), and was tested on held-out patients from MGH as well as external datasets from Emory, Karolinska Sweden and Chang Gung Memorial Hospitals. Using the team's previously developed risk-assessment algorithm Mirai, Tempo obtained better early detection than annual screening while requiring twenty five percent less mammograms overall at Karolinska. At MGH, it recommended roughly a mammogram a year, and obtained a simulated early detection benefit of roughly four and half months better. "By tailoring the screening to the patient's individual risk, we can improve patient outcomes, reduce over treatment and eliminate health disparities," says Adam Yala, MIT CSAIL Ph.D. student and lead researcher. Given the massive scale of breast cancer screening, with tens of millions of women getting mammograms every year, improvements to our guidelines are immensely important." Deep medicine Early uses of AI in medicine stem back to the 1960's, where many refer to the Dendral experiments as kicking off the field. Researchers created a software system that was considered the first expert kind that automated the decision-making and problem-solving behavior of organic chemists. Sixty years later, deep medicine has greatly evolved drug diagnostics, predictive medicine, and patient care. "Current guidelines divide the population into a few large groups, like younger or older than 55, and recommend the same screening frequency to all the members of a cohort. The development of AI based risk models that operate over raw patient data give us an opportunity to transform screening, giving more frequent screens to those who need it and sparing the rest," says Yala. "A key aspect of these models is that their predictions can evolve over time as a patient's raw data changes, suggesting that screening policies need to be attuned to changes in risk and be optimized over long periods of patient data." Tempo uses reinforcement learning, a machine learning method widely known for success in games like Chess and Go, to develop a "policy" that predicts a followup recommendation for each patient. The training data here only had information about a patient's risk at the time points when their mammogram was taken (when they were 50, or 55, for example). The team needed the risk assessment at intermediate points, so they designed their algorithm to learn a patient's risk at unobserved time points from their observed screenings, which evolved as new mammograms of the patient became available. The team first trained a neural network to predict future risk assessments given previous ones. This model then estimates patient risk at unobserved timepoints, and it enables simulation of the risk-based screening policies. Next, they trained that policy, (also a neural network), to maximize the reward (for example, the combination of early detection and screening cost) to the retrospective training set. Eventually, you'd get a recommendation for when to return for the next screen, ranging from six months to three years in the future, in multiples of six months—the standard is only one or two years. Let's say patient A comes in for their first mammogram, and eventually gets diagnosed at year four. In year two, there's nothing, so they don't come back for another two years, but then at year four they get a diagnosis. Now there's been two years of gap between the last screen, where a tumor could have grown. Using Tempo, at that first mammogram, year zero, the recommendation might have been to come back in two years. And then at year two, it might have seen that risk is high, and recommended that the patient come back in six months, and in the best case, it would be detectable. The model is dynamically changing the patient's screening frequency, based on how the risk profile is changing. Tempo uses a simple metric for early detection, which assumes that cancer can be caught up to 18 months in advance. While Tempo outperformed current guidelines across different settings of this assumption (six months, twelve months), none of these assumptions are perfect as the early detection potential of a tumor depends on that tumor's characteristics. The team suggested that follow up work using tumor growth models could address this issue. Also, the screening cost metric, which counts the total screening volume recommended by Tempo, doesn't provide a full analysis of the entire future cost because it does not explicitly quantify false positive risks or additional screening harms. There are many future directions that can further improve personalized screening algorithms. The team says one avenue would be to build on the metrics used to estimate early detection and screening costs from retrospective data, which would result in more refined guidelines. Tempo could also be adapted to include different types of screening recommendations, such as leveraging MRI or mammograms, and future work could separately model the costs and benefits of each. With better screening policies, recalculating the earliest and latest age that screening is still cost-effective for a patient might be feasible. "Our framework is flexible and can be readily utilized for other diseases, other forms of risk models, and other definitions of early detection benefit or screening cost. We expect the utility of Tempo to continue to improve as risk models and outcome metrics are further refined. We're excited to work with hospital partners to prospectively study this technology and help us further improve personalized cancer screening," says Yala. <|im_end|>

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2,605

[ { "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 inability of conventional electronic architectures to efficiently solve large combinatorial problems motivates the development of novel computational hardware. There has been much effort toward developing application-specific hardware across many different fields of engineering, such as integrated circuits, memristors, and photonics. However, unleashing the potential of such architectures requires the development of algorithms which optimally exploit their fundamental properties. Here, we present the Photonic Recurrent Ising Sampler (PRIS), a heuristic method tailored for parallel architectures allowing fast and efficient sampling from distributions of arbitrary Ising problems. Since the PRIS relies on vector-to-fixed matrix multiplications, we suggest the implementation of the PRIS in photonic parallel networks, which realize these operations at an unprecedented speed. The PRIS provides sample solutions to the ground state of Ising models, by converging in probability to their associated Gibbs distribution. The PRIS also relies on intrinsic dynamic noise and eigenvalue dropout to find ground states more efficiently. Our work suggests speedups in heuristic methods via photonic implementations of the PRIS. Introduction Heuristic methods—probabilistic algorithms with stochastic components—are a cornerstone of both numerical methods in statistical physics 1 and NP-Hard optimization 2 . Broad classes of problems in statistical physics, such as growth patterns in clusters 3 , percolation 4 , heterogeneity in lipid membranes 5 , and complex networks 6 , can be described by heuristic methods. These methods have proven instrumental for predicting phase transitions and the critical exponents of various universality classes – families of physical systems exhibiting similar scaling properties near their critical temperature 1 . These heuristic algorithms have become popular, as they typically outperform exact algorithms at solving real-world problems 7 . Heuristic methods are usually tailored for conventional electronic hardware; however, a number of optical machines have recently been shown to solve the well-known Ising 8 , 9 and Traveling Salesman problems 10 , 11 . For computationally demanding problems, these methods can benefit from parallelization speedups 1 , 12 , but the determination of an efficient parallelization approach is highly problem-specific 1 . Half a century before the contemporary Machine Learning Renaissance 13 , the Little 14 and then the Hopfield 15 , 16 networks were considered as early architectures of recurrent neural networks (RNN). The latter was suggested as an algorithm to solve combinatorially hard problems, as it was shown to deterministically converge to local minima of arbitrary quadratic Hamiltonians of the form $${H}^{(K)}=-\\frac{1}{2}\\sum _{1\\le i,j\\le N}{\\sigma }_{i}{K}_{ij}{\\sigma }_{j},$$ (1) which is the most general form of an Ising Hamiltonian in the absence of an external magnetic field 17 . In Eq. ( 1 ), we equivalently denote the set of spins as σ ∈ {−1, 1} N or S ∈ {0, 1} N (with σ = 2 S −1), and K is a N × N real symmetric matrix. In the context of physics, Ising models describe the interaction of many particles in terms of the coupling matrix K . These systems are observed in a particular spin configuration σ with a probability given by the Gibbs distribution \$p(\\sigma )\\propto \\exp (-\\beta {H}^{(K)}(\\sigma ))\$ , where β = 1/( k B T ), with k B the Boltzmann constant and T the temperature. At low temperature, when β → ∞ , the Gibbs probability of observing the system in its ground state approaches 1, thus naturally minimizing the quadratic function in Eq. ( 1 ). As similar optimization problems are often encountered in computer science 2 , 7 , a natural idea is to engineer physical systems with dynamics governed by an equivalent Hamiltonian. Then, by sampling the physical system, one can generate candidate solutions to the optimization problem. This analogy between statistical physics and computer science has nurtured a great variety of concepts in both fields 18 , for instance, the analogy between neural networks and spin glasses 15 , 19 . Many complex systems can be formulated using the Ising model 20 —such as ferromagnets 17 , 21 , liquid-vapor transitions 22 , lipid membranes 5 , brain functions 23 , random photonics 24 , and strongly-interacting systems in quantum chromodynamics 25 . From the perspective of optimization, finding the spin distribution minimizing H ( K ) for an arbitrary matrix K belongs to the class of NP-hard problems 26 . Hopfield networks deterministically converge to a local minimum, thus making it impossible to scale such networks to deterministically find the global minimum 27 —thus jeopardizing any electronic 16 or optical 28 implementation of these algorithms. As a result, these early RNN architectures were soon superseded by heuristic (such as Metropolis-Hastings (MH)) and metaheuristic methods (such as simulated annealing (SA) 29 , parallel tempering 30 , genetic algorithms 31 , Tabu search 32 and local-search-based algorithms 33 ), usually tailored for conventional electronic hardware. Even still, heuristic methods struggle to solve large problems, and could benefit from nanophotonic hardware demonstrating parallel, low-energy, and high-speed computations 34 , 35 , 36 . Here, we propose a photonic implementation of a passive RNN, which models the arbitrary Ising-type Hamiltonian in Eq. ( 1 ). We propose a fast and efficient heuristic method for photonic analog computing platforms, relying essentially on iterative matrix multiplications. Our heuristic approach also takes advantage of optical passivity and dynamic noise to find ground states of arbitrary Ising problems and probe their critical behaviors, yielding accurate predictions of critical exponents of the universality classes of conventional Ising models. Our algorithm presents attractive scaling properties when benchmarked against conventional algorithms, such as MH. Our findings suggest a novel approach to heuristic methods for efficient optimization and sampling by leveraging the potential of matrix-to-vector accelerators, such as parallel photonic networks 34 . We also hint at a broader class of (meta)heuristic algorithms derived from the PRIS, such as combined simulated annealing on the noise and eigenvalue dropout levels. Our algorithm can also be implemented in a competitive manner on fast parallel electronic hardware, such as FPGAs and ASICs. Results Photonic computational architecture The proposed architecture of our photonic network is shown in Fig. 1", "role": "user" }, { "content": "Many of the most challenging optimization problems encountered in various disciplines of science and engineering, from biology and drug discovery to routing and scheduling can be reduced to NP-complete problems. Intuitively speaking, NP-complete problems are \"hard to solve\" because the number of operations that must be performed in order to find the solution grows exponentially with the problem size. The ubiquity of NP-complete problems has led to the development of dedicated hardware (such as optical annealing and quantum annealing machines like \"D-Wave\") and special algorithms (heuristic algorithms like simulated annealing). Recently, there has been a growing interest in solving these hard combinatorial problems by designing optical machines. These optical machines consist of a set of optical transformations imparted to an optical signal, so that the optical signal will encode the solution to the problem after some amount of computation. Such machines could benefit from the fundamental advantages of optical hardware integrated into silicon photonics, such as low-loss, parallel processing, optical passivity at low optical powers and robust scalability enabled by the development of fabrication processes by the industry. However, the development of compact and fast photonic hardware with dedicated algorithms which optimally utilize the capability of this hardware, has been lacking. Today, the path to solving NP-complete problems with integrated photonics is open due to the work of Charles Roques-Carmes, Dr. Yichen Shen, Cristian Zanoci, Mihika Prabhu, Fadi Atieh, Dr. Li Jing, Dr. Tena Dubček, Chenkai Mao, Miles Johnson, Prof. Vladimir Čeperić, Prof. Dirk Englund, Prof. John Joannopoulos, and Prof. Marin Soljačić from MIT and the Institute for Soldier Nanotechnologies, published in Nature Communications. In this work, the MIT team developed an algorithm dedicated to solving the well-known NP-complete Ising problem with photonics hardware. Originally proposed to model magnetic systems, the Ising model describes a network of spins that can point only up or down. Each spin's energy depends on its interaction with neighboring spins—in a ferromagnet, for instance, the positive interaction between nearest neighbors will incentivize each spin to align with its closest neighbors. An Ising machine will tend to find the spin configuration that minimizes the total energy of the spin network. This solution can then be translated into the solution of other optimization problem. Heuristic Ising machines, like the one developed by the MIT team, only yields a candidate solution to the problem (which is, on average, close to the optimal solution). However, algorithms that always find the exact solution to the problem are difficult to apply to large problem sizes, as they would often have to run for hours, if not days, to terminate. Therefore, heuristic algorithms are an alternative to exact algorithms, since they provide fast and cheap solutions to hard problems. The researchers were guided by their knowledge of fundamental photonics. Professor Marin Soljačić from MIT explains: \"Optical computing is a very old field of research. Therefore, we had to identify which recent advances in photonic hardware could make a difference. In other words, we had to identify the value proposition of modern photonics.\" Graduate student Charles Roques-Carmes adds: \"We identified this value proposition to be: (a) performing fast and cheap fixed matrix multiplication and; (b) performing noisy computation, which means that the result of the computation slightly varies from one run to the other, a little bit like flipping a coin. Therefore, these two elements are the building blocks of our work.\" While developing this algorithm and benchmarking it on various problems, the researchers discovered a variety of related algorithms that could also be implemented in photonics to find solutions even faster. Postdoctoral associate Dr. Yichen Shen is enthusiastic about the prospect of this work: \"The field of enhancing computing capability with integrated photonics is currently booming, and we believe this work can be part of it. Since the algorithm we developed optimally leverages the strengths and weaknesses of photonic hardware, we hope it could find some short-term application.\" The MIT research team is currently working in collaboration with others towards realizing proof-of-concept experiments and benchmarking their algorithm on photonic hardware, versus other photonic machines and conventional algorithms running on computers. ", "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 inability of conventional electronic architectures to efficiently solve large combinatorial problems motivates the development of novel computational hardware. There has been much effort toward developing application-specific hardware across many different fields of engineering, such as integrated circuits, memristors, and photonics. However, unleashing the potential of such architectures requires the development of algorithms which optimally exploit their fundamental properties. Here, we present the Photonic Recurrent Ising Sampler (PRIS), a heuristic method tailored for parallel architectures allowing fast and efficient sampling from distributions of arbitrary Ising problems. Since the PRIS relies on vector-to-fixed matrix multiplications, we suggest the implementation of the PRIS in photonic parallel networks, which realize these operations at an unprecedented speed. The PRIS provides sample solutions to the ground state of Ising models, by converging in probability to their associated Gibbs distribution. The PRIS also relies on intrinsic dynamic noise and eigenvalue dropout to find ground states more efficiently. Our work suggests speedups in heuristic methods via photonic implementations of the PRIS. Introduction Heuristic methods—probabilistic algorithms with stochastic components—are a cornerstone of both numerical methods in statistical physics 1 and NP-Hard optimization 2 . Broad classes of problems in statistical physics, such as growth patterns in clusters 3 , percolation 4 , heterogeneity in lipid membranes 5 , and complex networks 6 , can be described by heuristic methods. These methods have proven instrumental for predicting phase transitions and the critical exponents of various universality classes – families of physical systems exhibiting similar scaling properties near their critical temperature 1 . These heuristic algorithms have become popular, as they typically outperform exact algorithms at solving real-world problems 7 . Heuristic methods are usually tailored for conventional electronic hardware; however, a number of optical machines have recently been shown to solve the well-known Ising 8 , 9 and Traveling Salesman problems 10 , 11 . For computationally demanding problems, these methods can benefit from parallelization speedups 1 , 12 , but the determination of an efficient parallelization approach is highly problem-specific 1 . Half a century before the contemporary Machine Learning Renaissance 13 , the Little 14 and then the Hopfield 15 , 16 networks were considered as early architectures of recurrent neural networks (RNN). The latter was suggested as an algorithm to solve combinatorially hard problems, as it was shown to deterministically converge to local minima of arbitrary quadratic Hamiltonians of the form $${H}^{(K)}=-\frac{1}{2}\sum _{1\le i,j\le N}{\sigma }_{i}{K}_{ij}{\sigma }_{j},$$ (1) which is the most general form of an Ising Hamiltonian in the absence of an external magnetic field 17 . In Eq. ( 1 ), we equivalently denote the set of spins as σ ∈ {−1, 1} N or S ∈ {0, 1} N (with σ = 2 S −1), and K is a N × N real symmetric matrix. In the context of physics, Ising models describe the interaction of many particles in terms of the coupling matrix K . These systems are observed in a particular spin configuration σ with a probability given by the Gibbs distribution $p(\sigma )\propto \exp (-\beta {H}^{(K)}(\sigma ))$ , where β = 1/( k B T ), with k B the Boltzmann constant and T the temperature. At low temperature, when β → ∞ , the Gibbs probability of observing the system in its ground state approaches 1, thus naturally minimizing the quadratic function in Eq. ( 1 ). As similar optimization problems are often encountered in computer science 2 , 7 , a natural idea is to engineer physical systems with dynamics governed by an equivalent Hamiltonian. Then, by sampling the physical system, one can generate candidate solutions to the optimization problem. This analogy between statistical physics and computer science has nurtured a great variety of concepts in both fields 18 , for instance, the analogy between neural networks and spin glasses 15 , 19 . Many complex systems can be formulated using the Ising model 20 —such as ferromagnets 17 , 21 , liquid-vapor transitions 22 , lipid membranes 5 , brain functions 23 , random photonics 24 , and strongly-interacting systems in quantum chromodynamics 25 . From the perspective of optimization, finding the spin distribution minimizing H ( K ) for an arbitrary matrix K belongs to the class of NP-hard problems 26 . Hopfield networks deterministically converge to a local minimum, thus making it impossible to scale such networks to deterministically find the global minimum 27 —thus jeopardizing any electronic 16 or optical 28 implementation of these algorithms. As a result, these early RNN architectures were soon superseded by heuristic (such as Metropolis-Hastings (MH)) and metaheuristic methods (such as simulated annealing (SA) 29 , parallel tempering 30 , genetic algorithms 31 , Tabu search 32 and local-search-based algorithms 33 ), usually tailored for conventional electronic hardware. Even still, heuristic methods struggle to solve large problems, and could benefit from nanophotonic hardware demonstrating parallel, low-energy, and high-speed computations 34 , 35 , 36 . Here, we propose a photonic implementation of a passive RNN, which models the arbitrary Ising-type Hamiltonian in Eq. ( 1 ). We propose a fast and efficient heuristic method for photonic analog computing platforms, relying essentially on iterative matrix multiplications. Our heuristic approach also takes advantage of optical passivity and dynamic noise to find ground states of arbitrary Ising problems and probe their critical behaviors, yielding accurate predictions of critical exponents of the universality classes of conventional Ising models. Our algorithm presents attractive scaling properties when benchmarked against conventional algorithms, such as MH. Our findings suggest a novel approach to heuristic methods for efficient optimization and sampling by leveraging the potential of matrix-to-vector accelerators, such as parallel photonic networks 34 . We also hint at a broader class of (meta)heuristic algorithms derived from the PRIS, such as combined simulated annealing on the noise and eigenvalue dropout levels. Our algorithm can also be implemented in a competitive manner on fast parallel electronic hardware, such as FPGAs and ASICs. Results Photonic computational architecture The proposed architecture of our photonic network is shown in Fig. 1<|im_end|> <|im_start|>assistant Many of the most challenging optimization problems encountered in various disciplines of science and engineering, from biology and drug discovery to routing and scheduling can be reduced to NP-complete problems. Intuitively speaking, NP-complete problems are "hard to solve" because the number of operations that must be performed in order to find the solution grows exponentially with the problem size. The ubiquity of NP-complete problems has led to the development of dedicated hardware (such as optical annealing and quantum annealing machines like "D-Wave") and special algorithms (heuristic algorithms like simulated annealing). Recently, there has been a growing interest in solving these hard combinatorial problems by designing optical machines. These optical machines consist of a set of optical transformations imparted to an optical signal, so that the optical signal will encode the solution to the problem after some amount of computation. Such machines could benefit from the fundamental advantages of optical hardware integrated into silicon photonics, such as low-loss, parallel processing, optical passivity at low optical powers and robust scalability enabled by the development of fabrication processes by the industry. However, the development of compact and fast photonic hardware with dedicated algorithms which optimally utilize the capability of this hardware, has been lacking. Today, the path to solving NP-complete problems with integrated photonics is open due to the work of Charles Roques-Carmes, Dr. Yichen Shen, Cristian Zanoci, Mihika Prabhu, Fadi Atieh, Dr. Li Jing, Dr. Tena Dubček, Chenkai Mao, Miles Johnson, Prof. Vladimir Čeperić, Prof. Dirk Englund, Prof. John Joannopoulos, and Prof. Marin Soljačić from MIT and the Institute for Soldier Nanotechnologies, published in Nature Communications. In this work, the MIT team developed an algorithm dedicated to solving the well-known NP-complete Ising problem with photonics hardware. Originally proposed to model magnetic systems, the Ising model describes a network of spins that can point only up or down. Each spin's energy depends on its interaction with neighboring spins—in a ferromagnet, for instance, the positive interaction between nearest neighbors will incentivize each spin to align with its closest neighbors. An Ising machine will tend to find the spin configuration that minimizes the total energy of the spin network. This solution can then be translated into the solution of other optimization problem. Heuristic Ising machines, like the one developed by the MIT team, only yields a candidate solution to the problem (which is, on average, close to the optimal solution). However, algorithms that always find the exact solution to the problem are difficult to apply to large problem sizes, as they would often have to run for hours, if not days, to terminate. Therefore, heuristic algorithms are an alternative to exact algorithms, since they provide fast and cheap solutions to hard problems. The researchers were guided by their knowledge of fundamental photonics. Professor Marin Soljačić from MIT explains: "Optical computing is a very old field of research. Therefore, we had to identify which recent advances in photonic hardware could make a difference. In other words, we had to identify the value proposition of modern photonics." Graduate student Charles Roques-Carmes adds: "We identified this value proposition to be: (a) performing fast and cheap fixed matrix multiplication and; (b) performing noisy computation, which means that the result of the computation slightly varies from one run to the other, a little bit like flipping a coin. Therefore, these two elements are the building blocks of our work." While developing this algorithm and benchmarking it on various problems, the researchers discovered a variety of related algorithms that could also be implemented in photonics to find solutions even faster. Postdoctoral associate Dr. Yichen Shen is enthusiastic about the prospect of this work: "The field of enhancing computing capability with integrated photonics is currently booming, and we believe this work can be part of it. Since the algorithm we developed optimally leverages the strengths and weaknesses of photonic hardware, we hope it could find some short-term application." The MIT research team is currently working in collaboration with others towards realizing proof-of-concept experiments and benchmarking their algorithm on photonic hardware, versus other photonic machines and conventional algorithms running on computers. <|im_end|>

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2,236

[ { "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 pathology of familial Alzheimer’s disease, which is caused by dominant mutations in the gene that encodes amyloid-beta precursor protein (APP) and in those that encode presenilin 1 and presenilin 2, is characterized by extracellular amyloid plaques and intracellular neurofibrillary tangles in multiple brain regions. Here we show that the brain-wide selective disruption of a mutated APP allele in transgenic mouse models carrying the human APP Swedish mutation alleviates amyloid-beta-associated pathologies for at least six months after a single intrahippocampal administration of an adeno-associated virus that encodes both Cas9 and a single-guide RNA that targets the mutation. We also show that the deposition of amyloid-beta, as well as microgliosis, neurite dystrophy and the impairment of cognitive performance, can all be ameliorated when the CRISPR–Cas9 construct is delivered intravenously via a modified adeno-associated virus that can cross the blood–brain barrier. Brain-wide disease-modifying genome editing could represent a viable strategy for the treatment of familial Alzheimer’s disease and other monogenic diseases that affect multiple brain regions. Main Alzheimer’s disease (AD)—one of the most prevalent neurodegenerative diseases—is characterized by the deposition of amyloid-beta (Aβ) peptides and the presence of neurofibrillary tangles composed of hyperphosphorylated tau protein. Although the inherited forms of AD, termed familial AD, account for 3–5% of AD cases 1 , 2 , 3 , their prevalence is comparable to that of other neurological diseases such as Huntington’s disease 4 and amyotrophic lateral sclerosis 5 . Familial AD is caused by fully penetrant and autosomal dominant mutations in the genes that encode APP as well as in those that encode catalytic components of the γ-secretase complex: presenilin 1 (PS1) and presenilin 2 (PS2) 2 . Dysregulated processing of APP by γ-secretase causes the accumulation of Aβ peptides, which is a major factor in the disease pathogenesis 6 . Despite considerable advances in our understanding of the genetic causes of familial AD, there are currently no effective disease-modifying treatments. Clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9)-mediated genome editing is a powerful tool that is potentially capable of targeting specific mutations 7 . However, the development of CRISPR–Cas9 as a targeted genome-editing approach for disease-modifying familial AD therapies requires addressing the needs of widespread genome editing in the brain. Like most brain disorders, AD affects multiple brain regions including the cortex and the hippocampus 8 , 9 . Current genome-editing strategies for brain disorders are delivered via intraparenchymal injection 10 , which affects limited brain regions with restricted beneficial outcomes. Therefore, an efficient and global genome-editing method that can be used in the adult brain is urgently needed. Modified adeno-associated virus (AAV) variants that can cross the blood–brain barrier (BBB) have recently been developed, enabling widespread transduction in the central nervous system after intravenous delivery 11 , 12 , 13 , 14 . Concordantly, brain-wide overexpression of a protein delivered via a BBB-crossing virus has been shown to promote recovery after ischaemic stroke in aged mice 14 . Therefore, modifying the expression of disease-modifier gene(s) in the central nervous system by administration of a BBB-crossing virus has potential for development as a therapeutic strategy for diseases such as familial AD. However, the ability of such a virus to deliver CRISPR–Cas9 genome-editing components to ameliorate the disease phenotypes has not yet been tested in vivo. Given that most cases of familial AD are caused by monogenic mutations, CRISPR–Cas9-mediated genome editing has been used to disrupt or correct familial AD mutations and decrease Aβ production in vitro 15 , 16 . Most patients with familial AD have a heterozygous disease-causing mutation 2 , and humans that naturally carry one copy of APP , PSEN1 (which encodes PS1) or PSEN2 (which encodes PS2) do not exhibit obvious neurological symptoms 17 , 18 . Thus, disruption of the disease-causing allele in patients with familial AD at the adult stage is a rational and feasible disease-modifying strategy for the treatment of familial AD. Among the familial APP mutations, the APP Swedish ( APP swe ) mutation (K670N/M671L) is located at the sequence that encodes the β-secretase cleavage site of APP; it makes the mutant APP more accessible for enzymatic cleavage, which results in higher Aβ production 19 , 20 , 21 . Although a recent study reports the feasibility of using genome editing to disrupt the APP swe mutation in transgenic mice carrying mutations on this gene, the low genome-editing efficiency of less than 3% prohibits the evaluation of the potential disease-modifying effect of disrupting this mutation 16 . In this Article, we show that the AAV-mediated delivery of Cas9 and single-guide RNA (sgRNA) specifically targeting the APP swe mutation into the adult hippocampus generates efficient genome editing and alleviates multiple Aβ-associated pathologies in transgenic mouse models of Aβ deposition. Notably, this CRISPR-mediated beneficial effect persists for at least 6 months in the transgenic mice. Furthermore, a single systemic administration of a BBB-crossing AAV-Cas9 vector that targets the APP swe mutation ameliorates Aβ pathologies throughout the brain. Our results therefore demonstrate that systemic AAV administered in a single dose is a promising approach for the development of disease-modifying therapeutic interventions for familial AD. Moreover, such a strategy could be applicable to other disorders of the central nervous system that are caused by autosomal dominant mutations and affect multiple brain regions. Results CRISPR–Cas9-mediated genome editing specifically disrupts APP swe allele We first targeted the APP swe double-base mutation (K670N/M671L) by designing two sgRNAs—SW1 and SW2—that place the mutation site within the first eight nucleotides immediately adjacent to the protospacer-adjacent motif (PAM) sequence (5′-NNGRRT-3′) of Cas9 from Staphylococcus aureus ( Sa Cas9) (Fig. 1a ); this region is considered to be the ‘seed sequence’ region that is important for the recognition of Cas9-sgRNA 22 . Because mismatches between the sgRNAs and the wild-type (WT) sequence located in the seed sequence are poorly tolerated by Cas9 23 , we expected SW1 and SW2 to distinguish the mutant APP sequence from the WT sequence. We validated the targeting specificities of the sgRNAs by using an EGxxFP reporter system", "role": "user" }, { "content": "An international research team led by scientists from the Hong Kong University of Science and Technology (HKUST) has developed a novel strategy using brain-wide genome-editing technology that can reduce Alzheimer's disease (AD) pathologies in genetically modified AD mouse models. This advanced technology offers immense potential to be translated as a novel long-acting therapeutic treatment for AD patients. In China alone, over 500,000 patients are estimated to be living with a hereditary form of AD—familial Alzheimer's disease (FAD), which is a congenital form of AD highly associated with family history. Although FAD has a clear genetic cause and can be diagnosed before cognitive problems occur, no effective treatment currently exists. There is enormous potential in the use of genome-editing technology as therapeutic strategies for diseases caused by inherited mutations, such as FAD. It is especially useful for correcting disease-causing genetic mutations before symptoms appear, for which it is considered a \"once-and-for-all\" treatment as its effects can last a lifetime. However, several hurdles have prevented its clinical development and application—most notably the lack of an effective, efficient, and non-invasive means to deliver genome-editing agents into the brain. Furthermore, existing genome-editing technologies are unable to generate beneficial outcomes throughout the whole brain. Recently, a team led by Prof. Nancy Ip, Vice-President for Research and Development at HKUST, developed a new genome-editing system that not only crosses the blood–brain barrier, but also delivers an optimized genome-editing tool to the entire brain. Using a newly engineered delivery vehicle for genome-editing, this strategy achieves efficient brain-wide genome editing through a single non-invasive intravenous administration. This effectively disrupts FAD-inflicted mutations in AD mouse models and ameliorates AD pathologies throughout the entire brain, paving the way to novel therapeutic development for the disease. Genome editing of the familial mutation in AD mice improves their memory performance. Credit: HKUST Meanwhile, the research team also found in the mouse models that the level of amyloid, a protein thought to drive neurodegeneration in AD, remained low for 6 months post-treatment (about 1/3 of their normal lifespan), demonstrating that this single-shot genome-editing strategy has lasting effects. More importantly, no side effects were detected so far in the mice. \"As the first demonstration of efficient brain-wide genome editing to alleviate Alzheimer's disease pathology throughout the whole brain, this is really an exciting development,\" said Prof. Ip, who is also the Morningside Professor of Life Science and Director of the State Key Laboratory of Molecular Neuroscience at HKUST. \"Our work is an important milestone for the use of genome editing in treating hereditary brain diseases, and contributes to the development of precision medicine for inherited forms of neurodegenerative diseases.\" This research was a collaborative effort among scientists from HKUST; the California Institute of Technology; and the Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences. The results were recently published in Nature Biomedical Engineering. ", "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 pathology of familial Alzheimer’s disease, which is caused by dominant mutations in the gene that encodes amyloid-beta precursor protein (APP) and in those that encode presenilin 1 and presenilin 2, is characterized by extracellular amyloid plaques and intracellular neurofibrillary tangles in multiple brain regions. Here we show that the brain-wide selective disruption of a mutated APP allele in transgenic mouse models carrying the human APP Swedish mutation alleviates amyloid-beta-associated pathologies for at least six months after a single intrahippocampal administration of an adeno-associated virus that encodes both Cas9 and a single-guide RNA that targets the mutation. We also show that the deposition of amyloid-beta, as well as microgliosis, neurite dystrophy and the impairment of cognitive performance, can all be ameliorated when the CRISPR–Cas9 construct is delivered intravenously via a modified adeno-associated virus that can cross the blood–brain barrier. Brain-wide disease-modifying genome editing could represent a viable strategy for the treatment of familial Alzheimer’s disease and other monogenic diseases that affect multiple brain regions. Main Alzheimer’s disease (AD)—one of the most prevalent neurodegenerative diseases—is characterized by the deposition of amyloid-beta (Aβ) peptides and the presence of neurofibrillary tangles composed of hyperphosphorylated tau protein. Although the inherited forms of AD, termed familial AD, account for 3–5% of AD cases 1 , 2 , 3 , their prevalence is comparable to that of other neurological diseases such as Huntington’s disease 4 and amyotrophic lateral sclerosis 5 . Familial AD is caused by fully penetrant and autosomal dominant mutations in the genes that encode APP as well as in those that encode catalytic components of the γ-secretase complex: presenilin 1 (PS1) and presenilin 2 (PS2) 2 . Dysregulated processing of APP by γ-secretase causes the accumulation of Aβ peptides, which is a major factor in the disease pathogenesis 6 . Despite considerable advances in our understanding of the genetic causes of familial AD, there are currently no effective disease-modifying treatments. Clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9)-mediated genome editing is a powerful tool that is potentially capable of targeting specific mutations 7 . However, the development of CRISPR–Cas9 as a targeted genome-editing approach for disease-modifying familial AD therapies requires addressing the needs of widespread genome editing in the brain. Like most brain disorders, AD affects multiple brain regions including the cortex and the hippocampus 8 , 9 . Current genome-editing strategies for brain disorders are delivered via intraparenchymal injection 10 , which affects limited brain regions with restricted beneficial outcomes. Therefore, an efficient and global genome-editing method that can be used in the adult brain is urgently needed. Modified adeno-associated virus (AAV) variants that can cross the blood–brain barrier (BBB) have recently been developed, enabling widespread transduction in the central nervous system after intravenous delivery 11 , 12 , 13 , 14 . Concordantly, brain-wide overexpression of a protein delivered via a BBB-crossing virus has been shown to promote recovery after ischaemic stroke in aged mice 14 . Therefore, modifying the expression of disease-modifier gene(s) in the central nervous system by administration of a BBB-crossing virus has potential for development as a therapeutic strategy for diseases such as familial AD. However, the ability of such a virus to deliver CRISPR–Cas9 genome-editing components to ameliorate the disease phenotypes has not yet been tested in vivo. Given that most cases of familial AD are caused by monogenic mutations, CRISPR–Cas9-mediated genome editing has been used to disrupt or correct familial AD mutations and decrease Aβ production in vitro 15 , 16 . Most patients with familial AD have a heterozygous disease-causing mutation 2 , and humans that naturally carry one copy of APP , PSEN1 (which encodes PS1) or PSEN2 (which encodes PS2) do not exhibit obvious neurological symptoms 17 , 18 . Thus, disruption of the disease-causing allele in patients with familial AD at the adult stage is a rational and feasible disease-modifying strategy for the treatment of familial AD. Among the familial APP mutations, the APP Swedish ( APP swe ) mutation (K670N/M671L) is located at the sequence that encodes the β-secretase cleavage site of APP; it makes the mutant APP more accessible for enzymatic cleavage, which results in higher Aβ production 19 , 20 , 21 . Although a recent study reports the feasibility of using genome editing to disrupt the APP swe mutation in transgenic mice carrying mutations on this gene, the low genome-editing efficiency of less than 3% prohibits the evaluation of the potential disease-modifying effect of disrupting this mutation 16 . In this Article, we show that the AAV-mediated delivery of Cas9 and single-guide RNA (sgRNA) specifically targeting the APP swe mutation into the adult hippocampus generates efficient genome editing and alleviates multiple Aβ-associated pathologies in transgenic mouse models of Aβ deposition. Notably, this CRISPR-mediated beneficial effect persists for at least 6 months in the transgenic mice. Furthermore, a single systemic administration of a BBB-crossing AAV-Cas9 vector that targets the APP swe mutation ameliorates Aβ pathologies throughout the brain. Our results therefore demonstrate that systemic AAV administered in a single dose is a promising approach for the development of disease-modifying therapeutic interventions for familial AD. Moreover, such a strategy could be applicable to other disorders of the central nervous system that are caused by autosomal dominant mutations and affect multiple brain regions. Results CRISPR–Cas9-mediated genome editing specifically disrupts APP swe allele We first targeted the APP swe double-base mutation (K670N/M671L) by designing two sgRNAs—SW1 and SW2—that place the mutation site within the first eight nucleotides immediately adjacent to the protospacer-adjacent motif (PAM) sequence (5′-NNGRRT-3′) of Cas9 from Staphylococcus aureus ( Sa Cas9) (Fig. 1a ); this region is considered to be the ‘seed sequence’ region that is important for the recognition of Cas9-sgRNA 22 . Because mismatches between the sgRNAs and the wild-type (WT) sequence located in the seed sequence are poorly tolerated by Cas9 23 , we expected SW1 and SW2 to distinguish the mutant APP sequence from the WT sequence. We validated the targeting specificities of the sgRNAs by using an EGxxFP reporter system<|im_end|> <|im_start|>assistant An international research team led by scientists from the Hong Kong University of Science and Technology (HKUST) has developed a novel strategy using brain-wide genome-editing technology that can reduce Alzheimer's disease (AD) pathologies in genetically modified AD mouse models. This advanced technology offers immense potential to be translated as a novel long-acting therapeutic treatment for AD patients. In China alone, over 500,000 patients are estimated to be living with a hereditary form of AD—familial Alzheimer's disease (FAD), which is a congenital form of AD highly associated with family history. Although FAD has a clear genetic cause and can be diagnosed before cognitive problems occur, no effective treatment currently exists. There is enormous potential in the use of genome-editing technology as therapeutic strategies for diseases caused by inherited mutations, such as FAD. It is especially useful for correcting disease-causing genetic mutations before symptoms appear, for which it is considered a "once-and-for-all" treatment as its effects can last a lifetime. However, several hurdles have prevented its clinical development and application—most notably the lack of an effective, efficient, and non-invasive means to deliver genome-editing agents into the brain. Furthermore, existing genome-editing technologies are unable to generate beneficial outcomes throughout the whole brain. Recently, a team led by Prof. Nancy Ip, Vice-President for Research and Development at HKUST, developed a new genome-editing system that not only crosses the blood–brain barrier, but also delivers an optimized genome-editing tool to the entire brain. Using a newly engineered delivery vehicle for genome-editing, this strategy achieves efficient brain-wide genome editing through a single non-invasive intravenous administration. This effectively disrupts FAD-inflicted mutations in AD mouse models and ameliorates AD pathologies throughout the entire brain, paving the way to novel therapeutic development for the disease. Genome editing of the familial mutation in AD mice improves their memory performance. Credit: HKUST Meanwhile, the research team also found in the mouse models that the level of amyloid, a protein thought to drive neurodegeneration in AD, remained low for 6 months post-treatment (about 1/3 of their normal lifespan), demonstrating that this single-shot genome-editing strategy has lasting effects. More importantly, no side effects were detected so far in the mice. "As the first demonstration of efficient brain-wide genome editing to alleviate Alzheimer's disease pathology throughout the whole brain, this is really an exciting development," said Prof. Ip, who is also the Morningside Professor of Life Science and Director of the State Key Laboratory of Molecular Neuroscience at HKUST. "Our work is an important milestone for the use of genome editing in treating hereditary brain diseases, and contributes to the development of precision medicine for inherited forms of neurodegenerative diseases." This research was a collaborative effort among scientists from HKUST; the California Institute of Technology; and the Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences. The results were recently published in Nature Biomedical Engineering. <|im_end|>

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2,070

[ { "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 spin resonance (ESR) spectroscopy is a crucial tool, through spin labelling, in investigations of the chemical structure of materials and of the electronic structure of materials associated with unpaired spins. ESR spectra measured in molecular systems, however, are established on large ensembles of spins and usually require a complicated structural analysis. Recently, the combination of scanning tunnelling microscopy with ESR has proved to be a powerful tool to image and coherently control individual atomic spins on surfaces. Here we extend this technique to single coordination complexes—iron phthalocyanines (FePc)—and investigate the magnetic interactions between their molecular spin with either another molecular spin (in FePc–FePc dimers) or an atomic spin (in FePc–Ti pairs). We show that the molecular spin density of FePc is both localized at the central Fe atom and also distributed to the ligands (Pc), which yields a strongly molecular-geometry-dependent exchange coupling. Main Chemical engineering and fabrication of single molecular spins is of vital importance in molecule-based quantum devices 1 . There are various approaches to detect and control single molecular spins, such as the optical detection of diluted molecular spins 2 , 3 , 4 , magnetic resonance force microscopy 5 , nitrogen-vacancy magnetometry 6 and break-junction-based molecular devices 7 , 8 , 9 . Nevertheless, these systems typically require embedding the molecule in a solid-state host and lack the flexibility to locate and access individual spins or harness intra- and intermolecular spin–spin interactions. Conventional electron spin resonance (ESR) studies on chemical ensembles 10 , 11 are a very useful tool to elucidate the chemical structures at the molecular level, but they rely on the order of ~10 10 spins and often require complementary analysis techniques or theoretical calculations. The recent development of scanning tunnelling microscopy (STM) combined with ESR provides the advantage to investigate single molecular spins with atomic resolution. ESR–STM introduces a radio frequency electric field at the tunnelling junction, which can coherently drive individual atomic spins on surfaces 12 , 13 , 14 . The change in spin state is read out by a spin-polarized tip through tunnelling magnetoresistance. This combined ESR–STM approach enables a precise atom manipulation and imaging in subnanometre scale with a submicroelectronvolt (~10 MHz) energy resolution. Previous ESR–STM studies focused on the spins of single transition metal adatoms 12 , 14 , 15 , 16 rather than those of single molecules, other than early attempts on the organic molecule α,γ-bisdiphenylene β-phenylallyl at room temperature and in ambient conditions 17 . Coordination compounds, in particular, often have non-trivial spin distribution owing to the ligands 18 , which gives a unique opportunity to tune the spin distribution on the ligands to engineer a spin–spin interaction with atomic resolution. Metal phthalocyanines with various substitutional central metal atoms have been extensively employed as model systems in many-body quantum physics 18 , 19 and spin-dependent transport 20 . Here we explore a system of spin-1/2 iron phthalocyanine (FePc) molecules, iron (Fe) atoms and titanium (Ti) atoms adsorbed on a bilayer magnesium oxide (MgO), itself grown atop a Ag(100) surface. We performed ESR on individual FePc molecules and characterized the effects of Pc ligand orientations on the spin–spin interactions in FePc–FePc dimers and FePc–Ti pairs. This enabled us to visualize the electronic configuration of molecular orbitals and characterize the role of the ligands using nearby atoms as sensors to measure the magnetic dipolar and exchange coupling between the molecular spin and ESR-active species (FePc and Ti). Density functional theory (DFT) calculations, in good agreement with the experimental results, suggest that the spin density of the compound mainly located on the Fe centre spreads to the Pc ligands. These findings highlight the role of non-localized spins in the transfer of magnetic interactions, which can be crucial to fabricate molecular devices 21 . Results and discussion Single-molecule ESR Individual FePc molecules, Fe atoms and Ti atoms were deposited in a stepwise manner onto a bilayer (two monolayers (MLs)) MgO surface on a Ag(100) substrate and all the measurements were performed at a temperature of 2 K in a commercial STM with vector magnetic fields. The molecules and atoms were well isolated from each other at a low coverage and were distinguished readily by their topographical appearance, as shown in Fig. 1a . Individual FePc molecules appear as a cross-like shape and lattice analysis indicated that the central Fe atom of the FePc molecule sits atop an oxygen atom of MgO. The molecular axes were rotated by approximately 27° with respect to the underlying oxygen rows (inset of Fig. 1a ). The Ti atoms in our experiment were mainly found on oxygen–oxygen bridge sites (marked as Ti B ) and appeared taller than the Fe atoms atop the oxygen site 22 , 23 . Fig. 1: [FePc] – molecules adsorbed on MgO/Ag(100) and ESR measurements with varied tip fields. a , STM images of [FePc] – molecules (light grey crosses), Fe (smaller white dots) and Ti B (larger white dots) atoms adsorbed on the MgO surface (dark grey background). A naturally formed [FePc] – –[FePc] – dimer is circled in white. Inset: magnified view of [FePc] – molecules and Fe and Ti B atoms. The blue grid indicates oxygen sites of the underlying MgO surface. Black arrows describe the molecular axes that point to the benzene rings and show an azimuthal angle of 26.6° with respect to the oxygen rows. Scanning conditions: V = 200 mV, I set = 12 pA for the main image and I set = 10 pA for the inset. b , Left: isosurface representation (in red) of the frontier orbital (isovalue, 10 –5 ) of a [FePc] – molecule adsorbed on a MgO/Ag(100) surface, which corresponds to the molecular frontier orbital ( a 1 g in the inset). Inset: electron occupancy and d -orbital components (%) of the molecular frontier orbitals, d π = 0.5( d zx + d zy ). Notably, the a 1 u orbital has no contribution from the d component. Right: structure of the FePc complex, which becomes negatively charged", "role": "user" }, { "content": "Scaling down information devices to the atomic scale has brought the interest of using individual spins as a basic unit for data storage. This requires precise detection and control of spin states and a better understanding of spin-spin interactions. For the first time ever, scientists at the IBS Center for Quantum Nanoscience at Ewha Womans University (QNS) have imaged the spin of an individual molecule using electron spin resonance in a scanning tunneling microscope. This achievement, published this month in Nature Chemistry, harnessed the power of synthetic chemistry to control the electron spin of a molecule. A scanning tunneling microscope (STM) has the ability to see exact atomic structures, atom by atom, at a level that is not possible with other techniques. This study uses an electric microwave applied to the STM tip to drive electron spin resonance (ESR) on single molecules and investigate the magnetic interaction between two molecules using this technique. \"Employing single molecules in atomic-scale quantum-control studies is always of high interest and importance. This work sheds light on some intriguing magnetic interactions between non-localized spins, which is crucial for developing molecule-based spintronic devices,\" says the paper's first author, Dr. Xue Zhang. Fe, Ti atoms, and FePc molecules were co-deposited on the surface of a thin magnesium oxide film grown on a silver substrate. They were then imaged and probed using an STM equipped with ESR capabilities. This work has extended the ESR experimental platform from single atoms to a much broader class of matter—magnetic molecules, which brings many more possibilities to perform quantum control on single magnetic molecules. Electron spin resonance is widely employed in biology and chemistry to determine the structure of unknown molecules and to measure the dynamic properties of spins in these molecules. ESR is a cousin of magnetic resonance imaging (MRI) that most people are familiar with from hospital visits. ESR is also an essential tool in the emerging research field of quantum-coherent nanoscience, where the quantum properties of spins are utilized for quantum computation and quantum information science. \"It is impressive to see that the intermolecular interaction can be investigated with an energy resolution in the nano-electron volt precision. Certainly, we should explore more unknowns with this fantastic ESR-STM technique,\" says Yu Wang of QNS. ", "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 spin resonance (ESR) spectroscopy is a crucial tool, through spin labelling, in investigations of the chemical structure of materials and of the electronic structure of materials associated with unpaired spins. ESR spectra measured in molecular systems, however, are established on large ensembles of spins and usually require a complicated structural analysis. Recently, the combination of scanning tunnelling microscopy with ESR has proved to be a powerful tool to image and coherently control individual atomic spins on surfaces. Here we extend this technique to single coordination complexes—iron phthalocyanines (FePc)—and investigate the magnetic interactions between their molecular spin with either another molecular spin (in FePc–FePc dimers) or an atomic spin (in FePc–Ti pairs). We show that the molecular spin density of FePc is both localized at the central Fe atom and also distributed to the ligands (Pc), which yields a strongly molecular-geometry-dependent exchange coupling. Main Chemical engineering and fabrication of single molecular spins is of vital importance in molecule-based quantum devices 1 . There are various approaches to detect and control single molecular spins, such as the optical detection of diluted molecular spins 2 , 3 , 4 , magnetic resonance force microscopy 5 , nitrogen-vacancy magnetometry 6 and break-junction-based molecular devices 7 , 8 , 9 . Nevertheless, these systems typically require embedding the molecule in a solid-state host and lack the flexibility to locate and access individual spins or harness intra- and intermolecular spin–spin interactions. Conventional electron spin resonance (ESR) studies on chemical ensembles 10 , 11 are a very useful tool to elucidate the chemical structures at the molecular level, but they rely on the order of ~10 10 spins and often require complementary analysis techniques or theoretical calculations. The recent development of scanning tunnelling microscopy (STM) combined with ESR provides the advantage to investigate single molecular spins with atomic resolution. ESR–STM introduces a radio frequency electric field at the tunnelling junction, which can coherently drive individual atomic spins on surfaces 12 , 13 , 14 . The change in spin state is read out by a spin-polarized tip through tunnelling magnetoresistance. This combined ESR–STM approach enables a precise atom manipulation and imaging in subnanometre scale with a submicroelectronvolt (~10 MHz) energy resolution. Previous ESR–STM studies focused on the spins of single transition metal adatoms 12 , 14 , 15 , 16 rather than those of single molecules, other than early attempts on the organic molecule α,γ-bisdiphenylene β-phenylallyl at room temperature and in ambient conditions 17 . Coordination compounds, in particular, often have non-trivial spin distribution owing to the ligands 18 , which gives a unique opportunity to tune the spin distribution on the ligands to engineer a spin–spin interaction with atomic resolution. Metal phthalocyanines with various substitutional central metal atoms have been extensively employed as model systems in many-body quantum physics 18 , 19 and spin-dependent transport 20 . Here we explore a system of spin-1/2 iron phthalocyanine (FePc) molecules, iron (Fe) atoms and titanium (Ti) atoms adsorbed on a bilayer magnesium oxide (MgO), itself grown atop a Ag(100) surface. We performed ESR on individual FePc molecules and characterized the effects of Pc ligand orientations on the spin–spin interactions in FePc–FePc dimers and FePc–Ti pairs. This enabled us to visualize the electronic configuration of molecular orbitals and characterize the role of the ligands using nearby atoms as sensors to measure the magnetic dipolar and exchange coupling between the molecular spin and ESR-active species (FePc and Ti). Density functional theory (DFT) calculations, in good agreement with the experimental results, suggest that the spin density of the compound mainly located on the Fe centre spreads to the Pc ligands. These findings highlight the role of non-localized spins in the transfer of magnetic interactions, which can be crucial to fabricate molecular devices 21 . Results and discussion Single-molecule ESR Individual FePc molecules, Fe atoms and Ti atoms were deposited in a stepwise manner onto a bilayer (two monolayers (MLs)) MgO surface on a Ag(100) substrate and all the measurements were performed at a temperature of 2 K in a commercial STM with vector magnetic fields. The molecules and atoms were well isolated from each other at a low coverage and were distinguished readily by their topographical appearance, as shown in Fig. 1a . Individual FePc molecules appear as a cross-like shape and lattice analysis indicated that the central Fe atom of the FePc molecule sits atop an oxygen atom of MgO. The molecular axes were rotated by approximately 27° with respect to the underlying oxygen rows (inset of Fig. 1a ). The Ti atoms in our experiment were mainly found on oxygen–oxygen bridge sites (marked as Ti B ) and appeared taller than the Fe atoms atop the oxygen site 22 , 23 . Fig. 1: [FePc] – molecules adsorbed on MgO/Ag(100) and ESR measurements with varied tip fields. a , STM images of [FePc] – molecules (light grey crosses), Fe (smaller white dots) and Ti B (larger white dots) atoms adsorbed on the MgO surface (dark grey background). A naturally formed [FePc] – –[FePc] – dimer is circled in white. Inset: magnified view of [FePc] – molecules and Fe and Ti B atoms. The blue grid indicates oxygen sites of the underlying MgO surface. Black arrows describe the molecular axes that point to the benzene rings and show an azimuthal angle of 26.6° with respect to the oxygen rows. Scanning conditions: V = 200 mV, I set = 12 pA for the main image and I set = 10 pA for the inset. b , Left: isosurface representation (in red) of the frontier orbital (isovalue, 10 –5 ) of a [FePc] – molecule adsorbed on a MgO/Ag(100) surface, which corresponds to the molecular frontier orbital ( a 1 g in the inset). Inset: electron occupancy and d -orbital components (%) of the molecular frontier orbitals, d π = 0.5( d zx + d zy ). Notably, the a 1 u orbital has no contribution from the d component. Right: structure of the FePc complex, which becomes negatively charged<|im_end|> <|im_start|>assistant Scaling down information devices to the atomic scale has brought the interest of using individual spins as a basic unit for data storage. This requires precise detection and control of spin states and a better understanding of spin-spin interactions. For the first time ever, scientists at the IBS Center for Quantum Nanoscience at Ewha Womans University (QNS) have imaged the spin of an individual molecule using electron spin resonance in a scanning tunneling microscope. This achievement, published this month in Nature Chemistry, harnessed the power of synthetic chemistry to control the electron spin of a molecule. A scanning tunneling microscope (STM) has the ability to see exact atomic structures, atom by atom, at a level that is not possible with other techniques. This study uses an electric microwave applied to the STM tip to drive electron spin resonance (ESR) on single molecules and investigate the magnetic interaction between two molecules using this technique. "Employing single molecules in atomic-scale quantum-control studies is always of high interest and importance. This work sheds light on some intriguing magnetic interactions between non-localized spins, which is crucial for developing molecule-based spintronic devices," says the paper's first author, Dr. Xue Zhang. Fe, Ti atoms, and FePc molecules were co-deposited on the surface of a thin magnesium oxide film grown on a silver substrate. They were then imaged and probed using an STM equipped with ESR capabilities. This work has extended the ESR experimental platform from single atoms to a much broader class of matter—magnetic molecules, which brings many more possibilities to perform quantum control on single magnetic molecules. Electron spin resonance is widely employed in biology and chemistry to determine the structure of unknown molecules and to measure the dynamic properties of spins in these molecules. ESR is a cousin of magnetic resonance imaging (MRI) that most people are familiar with from hospital visits. ESR is also an essential tool in the emerging research field of quantum-coherent nanoscience, where the quantum properties of spins are utilized for quantum computation and quantum information science. "It is impressive to see that the intermolecular interaction can be investigated with an energy resolution in the nano-electron volt precision. Certainly, we should explore more unknowns with this fantastic ESR-STM technique," says Yu Wang of QNS. <|im_end|>

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16, 14, 17, 11245, 1343, 31392, 511, 8503, 483, 320, 6251, 47, 66, 8, 35715, 11, 11245, 320, 6251, 8, 33299, 323, 71404, 320, 46451, 8, 33299, 14058, 269, 2788, 389, 264, 20934, 1155, 61933, 51180, 320, 44, 70, 46, 705, 5196, 15042, 47088, 264, 4701, 7, 1041, 8, 7479, 13, 1226, 10887, 469, 14899, 389, 3927, 3926, 47, 66, 35715, 323, 32971, 279, 6372, 315, 89933, 29413, 438, 89935, 389, 279, 12903, 4235, 42682, 22639, 304, 3926, 47, 66, 4235, 6251, 47, 66, 5213, 388, 323, 3926, 47, 66, 4235, 46451, 13840, 13, 1115, 9147, 603, 311, 51187, 279, 14683, 6683, 315, 31206, 27605, 1147, 323, 70755, 279, 3560, 315, 279, 29413, 2914, 1701, 14373, 33299, 439, 26148, 311, 6767, 279, 24924, 24522, 7569, 323, 9473, 59086, 1990, 279, 31206, 12903, 323, 469, 14899, 32344, 9606, 320, 6251, 47, 66, 323, 23126, 570, 73710, 16003, 10334, 320, 35, 4082, 8, 29217, 11, 304, 1695, 9306, 449, 279, 22772, 3135, 11, 4284, 430, 279, 12903, 17915, 315, 279, 24549, 14918, 7559, 389, 279, 3926, 12541, 43653, 311, 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25776, 1051, 46720, 555, 13489, 220, 1544, 11877, 449, 5201, 311, 279, 16940, 24463, 7123, 320, 258, 751, 315, 23966, 13, 220, 16, 64, 7609, 578, 23126, 33299, 304, 1057, 9526, 1051, 14918, 1766, 389, 24463, 4235, 78, 19472, 14497, 6732, 320, 47462, 439, 23126, 426, 883, 323, 9922, 51009, 1109, 279, 3926, 33299, 47088, 279, 24463, 2816, 220, 1313, 1174, 220, 1419, 662, 23966, 13, 220, 16, 25, 510, 6251, 47, 66, 60, 1389, 35715, 14058, 269, 2788, 389, 73693, 46, 14, 9219, 7, 1041, 8, 323, 469, 14899, 22323, 449, 28830, 11813, 5151, 13, 264, 1174, 48273, 5448, 315, 510, 6251, 47, 66, 60, 1389, 35715, 320, 4238, 20366, 50535, 705, 3926, 320, 9181, 261, 4251, 32094, 8, 323, 23126, 426, 320, 27995, 261, 4251, 32094, 8, 33299, 14058, 269, 2788, 389, 279, 73693, 46, 7479, 320, 23449, 20366, 4092, 570, 362, 18182, 14454, 510, 6251, 47, 66, 60, 1389, 1389, 58, 6251, 47, 66, 60, 1389, 294, 3212, 374, 4319, 839, 304, 4251, 13, 763, 751, 25, 8622, 1908, 1684, 315, 510, 6251, 47, 66, 60, 1389, 35715, 323, 3926, 323, 23126, 426, 33299, 13, 578, 6437, 5950, 15151, 24463, 6732, 315, 279, 16940, 73693, 46, 7479, 13, 5348, 38057, 7664, 279, 31206, 25776, 430, 1486, 311, 279, 72046, 1994, 25562, 323, 1501, 459, 93060, 278, 9392, 315, 220, 1627, 13, 21, 11877, 449, 5201, 311, 279, 24463, 7123, 13, 2522, 6073, 4787, 25, 650, 284, 220, 1049, 296, 53, 11, 358, 743, 284, 220, 717, 281, 32, 369, 279, 1925, 2217, 323, 358, 743, 284, 220, 605, 281, 32, 369, 279, 55959, 13, 293, 1174, 14043, 25, 374, 437, 10730, 13340, 320, 258, 2579, 8, 315, 279, 49100, 65691, 320, 285, 869, 542, 11, 220, 605, 1389, 20, 883, 315, 264, 510, 6251, 47, 66, 60, 1389, 43030, 14058, 269, 2788, 389, 264, 73693, 46, 14, 9219, 7, 1041, 8, 7479, 11, 902, 34310, 311, 279, 31206, 49100, 65691, 320, 264, 220, 16, 342, 304, 279, 55959, 570, 763, 751, 25, 17130, 66419, 323, 294, 482, 30986, 2223, 6956, 35055, 315, 279, 31206, 49100, 27605, 1147, 11, 294, 52845, 284, 220, 15, 13, 20, 7, 294, 72422, 489, 294, 1167, 88, 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520, 264, 2237, 430, 374, 539, 3284, 449, 1023, 12823, 13, 1115, 4007, 5829, 459, 9249, 42374, 9435, 311, 279, 48273, 11813, 311, 6678, 17130, 12903, 58081, 320, 1600, 49, 8, 389, 3254, 35715, 323, 19874, 279, 24924, 16628, 1990, 1403, 35715, 1701, 420, 15105, 13, 330, 37132, 287, 3254, 35715, 304, 25524, 13230, 31228, 4565, 7978, 374, 2744, 315, 1579, 2802, 323, 12939, 13, 1115, 990, 77039, 3177, 389, 1063, 41765, 24924, 22639, 1990, 2536, 41160, 1534, 45858, 11, 902, 374, 16996, 369, 11469, 43030, 6108, 12903, 376, 14338, 7766, 1359, 2795, 279, 5684, 596, 1176, 3229, 11, 2999, 13, 1630, 361, 37120, 13, 3926, 11, 23126, 33299, 11, 323, 3926, 47, 66, 35715, 1051, 1080, 6953, 981, 1639, 389, 279, 7479, 315, 264, 15792, 61933, 51180, 4632, 15042, 389, 264, 15310, 54057, 13, 2435, 1051, 1243, 737, 3359, 323, 463, 2788, 1701, 459, 48273, 19167, 449, 469, 14899, 17357, 13, 1115, 990, 706, 11838, 279, 469, 14899, 22772, 5452, 505, 3254, 33299, 311, 264, 1790, 27927, 538, 315, 5030, 2345, 76, 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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 pathogenesis of ulcerative colitis (UC), a major type of inflammatory bowel disease, remains unknown. No model exists that adequately recapitulates the complexity of clinical UC. Here, we take advantage of induced pluripotent stem cells (iPSCs) to develop an induced human UC-derived organoid (iHUCO) model and compared it with the induced human normal organoid model (iHNO). Notably, iHUCOs recapitulated histological and functional features of primary colitic tissues, including the absence of acidic mucus secretion and aberrant adherens junctions in the epithelial barrier both in vitro and in vivo. We demonstrate that the CXCL8/CXCR1 axis was overexpressed in iHUCO but not in iHNO. As proof-of-principle, we show that inhibition of CXCL8 receptor by the small-molecule non-competitive inhibitor repertaxin attenuated the progression of UC phenotypes in vitro and in vivo. This patient-derived organoid model, containing both epithelial and stromal compartments, will generate new insights into the underlying pathogenesis of UC while offering opportunities to tailor interventions to the individual patient. Introduction Ulcerative colitis (UC) is one of the two principal types of inflammatory bowel disease (IBD) and is a debilitating inflammatory condition of the colon that usually begins in young adulthood 1 . Although the precise pathogenesis is unknown, the lack of mucus secretion, elevated concentrations of soluble inflammatory mediators secreted by the stroma, wounding, and epithelial barrier permeability are thought to play essential early roles in the development and progression of UC 2 , 3 , 4 , 5 . Clinical UC is heterogeneous, ranging from acute to chronic inflammation of the colon. As the pathogenesis is unknown, medical interventions are nonspecific, resulting in inconsistent treatment responses 6 , 7 . Patients with poor response to these therapies develop severe symptoms, ultimately leading to resection of the colon and rectum 8 , 9 . Because patient-based predictive models, which capture individual heterogeneity, are lacking, a more complete experimental model is essential. Pluripotent stem cell (PSC)-derived human intestinal organoids have been developed for the normal mid/hind gut 10 , 11 and colon 12 , 13 and have distinct advantages in advancing precision medicine 14 . These organoids can be derived from the individual patient and exhibit recapitulation of physiological responses both in vitro and in vivo 10 , 12 , 15 . Besides the unique characteristics of PSCs, induced PSC-derived (iPSC) organoids retain the phenotype and genetic background of the individual donor as reported by recent studies modeling both normal and pathological organs 16 , 17 , 18 . In this study, we provide evidence linking recent advances in stem cell biology 19 with intestinal development 10 , 11 , 12 , 15 , 20 , 21 , 22 to reprogram colonic fibroblasts isolated from UC patients to iPSCs, followed by directed differentiation to induced human UC organoids (iHUCOs). Notably, iHUCOs have both epithelial and stromal compartments, preserving the colitic phenotype of their tissue of origin, such as responding to wounding by aberrant proliferation, a lack of goblet cells, and having compromised cellular tight junctions in their epithelial barrier. High-resolution transcriptome-wide analysis of iHUCOs and UC parental fibroblasts revealed pathways and inflammatory mediators in common between both groups compared with their controls, induced human normal organoids (iHNOs) and normal fibroblasts. Specifically, the roles of the inflammatory chemokine CXCL8 and chemotactic cytokine CXCL1 were highlighted in the transcriptome and mesenchymal secretome of iHUCOs and their parental fibroblasts. As proof-of-principle, we studied the iHUCO functional response to the CXCL8 receptor antagonist, repertaxin, and demonstrated the attenuation of colitic features in iHUCOs both in vitro and in a xenograft model in vivo. Mice have no homolog for human CXCL8. Therefore, this axis is not present in genetic or chemically induced murine models, emphasizing the essential utility of patient-derived UC models. Results Patterning of induced organoids recapitulates in vitro their primary tissues Fresh surgical specimens from colitic and healthy colons were obtained (Fig. 1a ), and fibroblasts were isolated 23 (Fig. 1b ). We reprogrammed UC fibroblasts to iPSCs; UC fibroblasts were isolated from 6 patients with established chronic colitis along with samples from 4 participants with normal colonic fibroblasts and one from a commercially available source (Supplementary Table 1 , Supplementary Fig. 1a , 1b ). Pluripotency of the generated iPSCs was confirmed (Supplementary Fig. 1c – l ). Next, we applied an established protocol for intestinal organoid generation 11 to direct differentiation of the iPSCs into definitive endoderm (DE), validated by SOX17 and FOXA2 protein expression (Fig. 1a, d ), followed by intestinal spheroid formation (SPH, validated by CDX2 expression, Fig. 1a, e ). Normal and UC spheroids were then cultured in Matrigel for 21 days to develop induced human normal organoids (iHNOs), and iHUCOs, respectively. Representative immunofluorescent (IF) staining of iHUCOs including epithelium (stained for CK19) and mesenchyme (stained for VIM) is shown in Fig. 1f . Fig. 1: Patterning of induced organoids recapitulates in vitro their primary tissues. a Schematic representation of induced human ulcerative colitis organoid (iHUCO) generation protocol followed by immunofluorescence (IF) staining of key proteins at each stage of development. b Fibroblasts (FB) express α-SMA (green) and lack CK19 expression (red). c Induced pluripotent stem cells (iPSCs) express Tra-1-60 (green) and Oct-4 (red). d Definitive endoderm (DE) expresses SOX17 (green) and FOXA2 (red). e Spheroids (SPH) express CDX2 (green), confirming the intestinal identity. f iHUCO expresses CK19 (red) in epithelium and vimentin (green) in the mesenchyme. Nuclei in all IF images are counterstained with DAPI (blue). g1–g4 Representative H&E-stained induced human normal organoid (iHNO) with simple columnar epithelium and iHUCO with stratified epithelium corresponding to the primary tissues. h Summarized percentages for epithelial structure—columnar, pseudostratified, or stratified—in iHNO and iHUCO. The median value is indicated in the center of the box plot. The whiskers above and below the plot represent 1 standard deviation (SD) above and below the mean of the data, respectively. For the columnar and stratified epithelial, P < 0.0001. For the pseudo-stratified epithelium, P = 0.22. i1–i4 Representative immunohistochemistry (IHC) for Ki67 in iHNO, iHUCO, and their primary tissues. j Percentage distribution of the cells", "role": "user" }, { "content": "As reported in Nature Communications, researchers from Cleveland Clinic's Lerner Research Institute have developed a novel, patient-derived model of ulcerative colitis, which will help advance studies into new treatments for the chronic inflammatory bowel disease. The team used the model to identify a promising target that could be inhibited to slow disease progression.Ulcerative colitis is characterized by abnormal reactions of the immune system that lead to inflammation and ulcers on the inner lining of the large intestines. It is a highly heterogeneous condition, both in terms of patients' symptoms and disease pathology. Suppressing the overactive immune response with anti-inflammatory drugs is the current mainstay treatment for inflammatory bowel diseases, although these therapies have limited long-term efficacy in ulcerative colitis patients. Research suggests that elements of both the immune system and the ulcerative colitis microenvironment (the surrounding, less diseased cellular components) interact to drive disease development and progression. Considering that immune-suppressing drugs have demonstrated limited success in treating ulcerative colitis, researchers are interested to learn whether targeting elements of the microenvironment—including components of the intestinal lining (called the epithelium) and stem cell-like cells called stromal cells—may be a better or complementary treatment approach. \"Gaining a more comprehensive understanding of the complex interplay between immune and other cell types will be critical to developing new and more effective ulcerative colitis therapies and tailored, patient-specific treatment approaches,\" said Emina Huang, MD, staff in the Departments of Cancer Biology and Colorectal Surgery, and the study's lead author. Dr. Huang, who is also a practicing colorectal surgeon, and her team developed their model using tissue samples from patients with ulcerative colitis who underwent surgery at Cleveland Clinic. They isolated a specific type of cell (called fibroblasts) that can be \"reprogrammed\" to develop into all-purpose, undifferentiated cells called induced pluripotent stem cells, which have emerged as a growing research priority. The researchers then grew the stem cells in the lab into tiny, three-dimensional tissues that mimic actual organs (called organoids). They found that compared to healthy colon organoids, the diseased organoids reflected histological and functional features commonly observed in ulcerative colitis patients, including reduced mucus secretions, faulty barrier integrity of the intestinal lining and overexpression of select proteins (including one called CXCL8). \"Our in vitro model accurately mirrors what we observe in patients in the clinic and is much more dynamic than current models. For example, other organoid models only focus on the contributions of the epithelium, where ours reflects the contributions of other microenvironment components, too, like the stroma,\" said Dr. Huang. After developing the model, the team was able to rapidly identify novel drug targets and candidates. They showed that inhibiting CXCL8 expression with a small molecule called repertaxin helped to slow disease progression. \"We look forward to further exploring repertaxin's potential benefit in other preclinical and eventual clinical studies,\" said Dr. Huang. \"We are hopeful that others will also find this model useful in identifying other potential anti-ulcerative colitis drugs.\" She also noted that the approach used to develop this new ulcerative colitis model may also be used to model other complex diseases. ", "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 pathogenesis of ulcerative colitis (UC), a major type of inflammatory bowel disease, remains unknown. No model exists that adequately recapitulates the complexity of clinical UC. Here, we take advantage of induced pluripotent stem cells (iPSCs) to develop an induced human UC-derived organoid (iHUCO) model and compared it with the induced human normal organoid model (iHNO). Notably, iHUCOs recapitulated histological and functional features of primary colitic tissues, including the absence of acidic mucus secretion and aberrant adherens junctions in the epithelial barrier both in vitro and in vivo. We demonstrate that the CXCL8/CXCR1 axis was overexpressed in iHUCO but not in iHNO. As proof-of-principle, we show that inhibition of CXCL8 receptor by the small-molecule non-competitive inhibitor repertaxin attenuated the progression of UC phenotypes in vitro and in vivo. This patient-derived organoid model, containing both epithelial and stromal compartments, will generate new insights into the underlying pathogenesis of UC while offering opportunities to tailor interventions to the individual patient. Introduction Ulcerative colitis (UC) is one of the two principal types of inflammatory bowel disease (IBD) and is a debilitating inflammatory condition of the colon that usually begins in young adulthood 1 . Although the precise pathogenesis is unknown, the lack of mucus secretion, elevated concentrations of soluble inflammatory mediators secreted by the stroma, wounding, and epithelial barrier permeability are thought to play essential early roles in the development and progression of UC 2 , 3 , 4 , 5 . Clinical UC is heterogeneous, ranging from acute to chronic inflammation of the colon. As the pathogenesis is unknown, medical interventions are nonspecific, resulting in inconsistent treatment responses 6 , 7 . Patients with poor response to these therapies develop severe symptoms, ultimately leading to resection of the colon and rectum 8 , 9 . Because patient-based predictive models, which capture individual heterogeneity, are lacking, a more complete experimental model is essential. Pluripotent stem cell (PSC)-derived human intestinal organoids have been developed for the normal mid/hind gut 10 , 11 and colon 12 , 13 and have distinct advantages in advancing precision medicine 14 . These organoids can be derived from the individual patient and exhibit recapitulation of physiological responses both in vitro and in vivo 10 , 12 , 15 . Besides the unique characteristics of PSCs, induced PSC-derived (iPSC) organoids retain the phenotype and genetic background of the individual donor as reported by recent studies modeling both normal and pathological organs 16 , 17 , 18 . In this study, we provide evidence linking recent advances in stem cell biology 19 with intestinal development 10 , 11 , 12 , 15 , 20 , 21 , 22 to reprogram colonic fibroblasts isolated from UC patients to iPSCs, followed by directed differentiation to induced human UC organoids (iHUCOs). Notably, iHUCOs have both epithelial and stromal compartments, preserving the colitic phenotype of their tissue of origin, such as responding to wounding by aberrant proliferation, a lack of goblet cells, and having compromised cellular tight junctions in their epithelial barrier. High-resolution transcriptome-wide analysis of iHUCOs and UC parental fibroblasts revealed pathways and inflammatory mediators in common between both groups compared with their controls, induced human normal organoids (iHNOs) and normal fibroblasts. Specifically, the roles of the inflammatory chemokine CXCL8 and chemotactic cytokine CXCL1 were highlighted in the transcriptome and mesenchymal secretome of iHUCOs and their parental fibroblasts. As proof-of-principle, we studied the iHUCO functional response to the CXCL8 receptor antagonist, repertaxin, and demonstrated the attenuation of colitic features in iHUCOs both in vitro and in a xenograft model in vivo. Mice have no homolog for human CXCL8. Therefore, this axis is not present in genetic or chemically induced murine models, emphasizing the essential utility of patient-derived UC models. Results Patterning of induced organoids recapitulates in vitro their primary tissues Fresh surgical specimens from colitic and healthy colons were obtained (Fig. 1a ), and fibroblasts were isolated 23 (Fig. 1b ). We reprogrammed UC fibroblasts to iPSCs; UC fibroblasts were isolated from 6 patients with established chronic colitis along with samples from 4 participants with normal colonic fibroblasts and one from a commercially available source (Supplementary Table 1 , Supplementary Fig. 1a , 1b ). Pluripotency of the generated iPSCs was confirmed (Supplementary Fig. 1c – l ). Next, we applied an established protocol for intestinal organoid generation 11 to direct differentiation of the iPSCs into definitive endoderm (DE), validated by SOX17 and FOXA2 protein expression (Fig. 1a, d ), followed by intestinal spheroid formation (SPH, validated by CDX2 expression, Fig. 1a, e ). Normal and UC spheroids were then cultured in Matrigel for 21 days to develop induced human normal organoids (iHNOs), and iHUCOs, respectively. Representative immunofluorescent (IF) staining of iHUCOs including epithelium (stained for CK19) and mesenchyme (stained for VIM) is shown in Fig. 1f . Fig. 1: Patterning of induced organoids recapitulates in vitro their primary tissues. a Schematic representation of induced human ulcerative colitis organoid (iHUCO) generation protocol followed by immunofluorescence (IF) staining of key proteins at each stage of development. b Fibroblasts (FB) express α-SMA (green) and lack CK19 expression (red). c Induced pluripotent stem cells (iPSCs) express Tra-1-60 (green) and Oct-4 (red). d Definitive endoderm (DE) expresses SOX17 (green) and FOXA2 (red). e Spheroids (SPH) express CDX2 (green), confirming the intestinal identity. f iHUCO expresses CK19 (red) in epithelium and vimentin (green) in the mesenchyme. Nuclei in all IF images are counterstained with DAPI (blue). g1–g4 Representative H&E-stained induced human normal organoid (iHNO) with simple columnar epithelium and iHUCO with stratified epithelium corresponding to the primary tissues. h Summarized percentages for epithelial structure—columnar, pseudostratified, or stratified—in iHNO and iHUCO. The median value is indicated in the center of the box plot. The whiskers above and below the plot represent 1 standard deviation (SD) above and below the mean of the data, respectively. For the columnar and stratified epithelial, P < 0.0001. For the pseudo-stratified epithelium, P = 0.22. i1–i4 Representative immunohistochemistry (IHC) for Ki67 in iHNO, iHUCO, and their primary tissues. j Percentage distribution of the cells<|im_end|> <|im_start|>assistant As reported in Nature Communications, researchers from Cleveland Clinic's Lerner Research Institute have developed a novel, patient-derived model of ulcerative colitis, which will help advance studies into new treatments for the chronic inflammatory bowel disease. The team used the model to identify a promising target that could be inhibited to slow disease progression.Ulcerative colitis is characterized by abnormal reactions of the immune system that lead to inflammation and ulcers on the inner lining of the large intestines. It is a highly heterogeneous condition, both in terms of patients' symptoms and disease pathology. Suppressing the overactive immune response with anti-inflammatory drugs is the current mainstay treatment for inflammatory bowel diseases, although these therapies have limited long-term efficacy in ulcerative colitis patients. Research suggests that elements of both the immune system and the ulcerative colitis microenvironment (the surrounding, less diseased cellular components) interact to drive disease development and progression. Considering that immune-suppressing drugs have demonstrated limited success in treating ulcerative colitis, researchers are interested to learn whether targeting elements of the microenvironment—including components of the intestinal lining (called the epithelium) and stem cell-like cells called stromal cells—may be a better or complementary treatment approach. "Gaining a more comprehensive understanding of the complex interplay between immune and other cell types will be critical to developing new and more effective ulcerative colitis therapies and tailored, patient-specific treatment approaches," said Emina Huang, MD, staff in the Departments of Cancer Biology and Colorectal Surgery, and the study's lead author. Dr. Huang, who is also a practicing colorectal surgeon, and her team developed their model using tissue samples from patients with ulcerative colitis who underwent surgery at Cleveland Clinic. They isolated a specific type of cell (called fibroblasts) that can be "reprogrammed" to develop into all-purpose, undifferentiated cells called induced pluripotent stem cells, which have emerged as a growing research priority. The researchers then grew the stem cells in the lab into tiny, three-dimensional tissues that mimic actual organs (called organoids). They found that compared to healthy colon organoids, the diseased organoids reflected histological and functional features commonly observed in ulcerative colitis patients, including reduced mucus secretions, faulty barrier integrity of the intestinal lining and overexpression of select proteins (including one called CXCL8). "Our in vitro model accurately mirrors what we observe in patients in the clinic and is much more dynamic than current models. For example, other organoid models only focus on the contributions of the epithelium, where ours reflects the contributions of other microenvironment components, too, like the stroma," said Dr. Huang. After developing the model, the team was able to rapidly identify novel drug targets and candidates. They showed that inhibiting CXCL8 expression with a small molecule called repertaxin helped to slow disease progression. "We look forward to further exploring repertaxin's potential benefit in other preclinical and eventual clinical studies," said Dr. Huang. "We are hopeful that others will also find this model useful in identifying other potential anti-ulcerative colitis drugs." She also noted that the approach used to develop this new ulcerative colitis model may also be used to model other complex diseases. <|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 Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10 −15 ), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10 −16 ), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10 −14 ), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10 −11 ), and DPM2 – FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10 −12 ). We also confirmed significant association at three previously described loci ( P < 5 × 10 −8 for each sentinel SNP at PLEKHA7 , COL11A1 , and PCMTD1 – ST18 ) 1 , providing new insights into the biology of PACG. Main Glaucoma is the most common cause of irreversible blindness worldwide 2 . The main forms of glaucoma are primary open angle glaucoma (POAG), PACG, and exfoliation glaucoma. All three forms of glaucoma show familial clustering, suggesting a substantial genetic component in pathogenesis. Recent genetic studies have implicated several distinct loci associated with each of these types of glaucoma 1 , 3 , 4 , 5 , 6 . For PACG, the epidemiological risk factors include advancing age, female sex, and East Asian ancestry 7 , 8 . Up to 80% of the estimated 15 million people afflicted with PACG live in Asia 9 , where the disease is responsible for a high proportion of blindness 10 , 11 , 12 , 13 . Patients either present with acute primary angle closure (APAC) or have PACG upon presentation ( Supplementary Note ). We previously performed a GWAS of PACG susceptibility on 1,854 PACG cases and 9,608 controls with replication in 1,917 cases and 8,943 controls, identifying three susceptibility loci 1 . We now expand the study to perform a discovery-stage GWAS on a combined total of 6,525 PACG cases and 19,929 controls, which were enrolled from 15 countries spanning East Asia, South Asia, Europe, and South America ( Fig. 1 and Supplementary Table 1 ). We applied routine quality control checks for SNPs and samples as is usually done for GWAS analyses (Online Methods ). SNPs at ten distinct loci surpassed P < 1 × 10 −6 ( Supplementary Table 2 ), a threshold we took to be indicative of suggestive evidence of association with disease 14 . Three of these loci have previously been reported ( Fig. 2 and Supplementary Table 3 ) 1 . We then subjected the ten sentinel SNPs representing each of the ten independent loci to replication genotyping in a further 3,978 cases and 9,638 controls from 14 countries ( Supplementary Table 1 ). Significant replication was observed at eight distinct loci ( Table 1 and Supplementary Table 2 ; the initial associations observed at FNDC3B rs16856870 on chromosome 3 and SLC38A6 rs10483730 on chromosome 14 did not replicate), and meta-analysis of all discovery and replication samples totaling 10,503 PACG cases and 29,567 controls showed genome-wide significant evidence of association for the eight loci with PACG ( Fig. 2 and Table 1 ). This two-stage study design is powered to detect effect sizes as low as 1.15 with minor allele frequencies (MAFs) as low as 0.15 at genome-wide significance ( Supplementary Table 4 ). Figure 1: Distribution of PACG cases and controls from the GWAS discovery stage, which encompassed collections from 15 countries. Cases and controls are projected onto the top two principal components of genetic stratification, with cases on the left and controls on the right. Principal-component comparisons for each of the East Asian countries are shown in Supplementary Figure 10 . Full size image Figure 2: Results of the discovery GWAS meta-analysis. The three previously reported loci are underlined. FNDC3B did not replicate in the replication collections. SNPs at EPDR1 , GLIS3 , DPM2 – FAM102A , CHAT , and FERMT2 represent new genome-wide significant associations. Full size image Table 1 Results for the eight genome-wide significant loci upon meta-analysis of all PACG case–control collections Full size table We next asked whether heterogeneity in genetic effect sizes exists across ancestry groups and geographical locations and found that only EPDR1 rs3816415 showed discernable evidence of heterogeneity in the overall meta-analysis ( P het = 0.0072, I 2 index = 43.0%). Closer scrutiny showed that effect sizes were consistently larger in Europeans (OR = 1.42) than in Asians (OR = 1.21) ( Fig. 3 and Table 1 ), despite similar risk allele frequencies across the ancestry groups ( Supplementary Table 5 ). This discrepancy could be due either to more unreliable estimation in Europeans because of the smaller sample size in comparison to Asians ( n = 1,105 European PACG cases versus 9,398 Asian PACG cases) or to a genuine difference in effect between Asians and Europeans 15 , 16 , 17 . We did not observe significant heterogeneity in effect sizes at the other four loci ( Fig. 3 and Table 1 ). Imputation-based fine-mapping and regional association analysis showed that each SNP locus mapped distinctly among its nearest genes, mostly framed by recombination events ( Supplementary Fig. 1 ). However, as the GWAS approach assays mostly common, representative genetic variants across the human genome, we are unable to exclude the possibility that the identified SNPs at each locus could be tagging functional variants that are exerting control on distant gene targets in a position- and orientation-independent manner 18 , 19 . Figure 3: Forest plots for the five new genome-wide significant loci. Point estimates for each locus are denoted as risk allele odds ratios, accompanied by horizontal lines representing the 95% confidence interval for each point estimate. Diamonds represent meta-analyses for the GWAS discovery stage, replication stage, all", "role": "user" }, { "content": "Scientists have discovered new genetic areas linked to an increased risk of glaucoma - the leading cause of irreversible blindness worldwide. The investigation studied the genetic make up of about 40,000 people and identified five previously unknown genetic areas linked to an increased risk of primary angle closure glaucoma (PACG). Co-author of the study Professor Jamie Craig from Flinders University in South Australia said PACG symptoms occurred quickly and required immediate medical attention. \"This new discovery provides a handle, to gain an understanding of the mechanisms of the disease. This will help to work out who is at risk of developing angle closure glaucoma so they can have preventative laser treatment before an emergency situation develops,\" Prof Craig said. \"We also expect in time, that the improved understanding of the pathways of this disease to lead to new ways to more effectively prevent and treat this serious condition, so that permanent loss of vision does not occur.\" The genetic analysis is by far the largest genome wide association study to date on this condition. It used a combined total of 10,404 cases of angle closure glaucoma and 29,343 normal controls to identify five novel glaucoma markers. Researchers at Flinders University, using the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG), led by Prof Craig guided international research across 23 countries in Asia, Australia, Europe and the Americas to make the discovery. Up to 80 per cent of the estimated 15 million people afflicted with PACG live in Asia, where the disease is responsible for a high proportion of blindness. Glaucoma generally develops later in life, initially causes loss of peripheral vision and can lead to complete blindness if untreated. Angle closure glaucoma is a less common form of the disease than open angle glaucoma. It is caused by blocked drainage canals in the eye and is characterised by a narrow angle between the iris and cornea. \"With (PACG) it comes on quite rapidly, so they are aware something is happening. But if something is not done quickly, they can lose their vision,\" Prof Craig said. \"All types of glaucoma have a strong hereditary or family influence and if there are any cases of glaucoma in the family, then people should be checked every two years from the age of 40.\" The study on angle closure glaucoma is published in Nature Genetics and was completed in association with the University of Melbourne, the University of Sydney and the Genome Institute of Singapore. ", "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 Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10 −15 ), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10 −16 ), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10 −14 ), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10 −11 ), and DPM2 – FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10 −12 ). We also confirmed significant association at three previously described loci ( P < 5 × 10 −8 for each sentinel SNP at PLEKHA7 , COL11A1 , and PCMTD1 – ST18 ) 1 , providing new insights into the biology of PACG. Main Glaucoma is the most common cause of irreversible blindness worldwide 2 . The main forms of glaucoma are primary open angle glaucoma (POAG), PACG, and exfoliation glaucoma. All three forms of glaucoma show familial clustering, suggesting a substantial genetic component in pathogenesis. Recent genetic studies have implicated several distinct loci associated with each of these types of glaucoma 1 , 3 , 4 , 5 , 6 . For PACG, the epidemiological risk factors include advancing age, female sex, and East Asian ancestry 7 , 8 . Up to 80% of the estimated 15 million people afflicted with PACG live in Asia 9 , where the disease is responsible for a high proportion of blindness 10 , 11 , 12 , 13 . Patients either present with acute primary angle closure (APAC) or have PACG upon presentation ( Supplementary Note ). We previously performed a GWAS of PACG susceptibility on 1,854 PACG cases and 9,608 controls with replication in 1,917 cases and 8,943 controls, identifying three susceptibility loci 1 . We now expand the study to perform a discovery-stage GWAS on a combined total of 6,525 PACG cases and 19,929 controls, which were enrolled from 15 countries spanning East Asia, South Asia, Europe, and South America ( Fig. 1 and Supplementary Table 1 ). We applied routine quality control checks for SNPs and samples as is usually done for GWAS analyses (Online Methods ). SNPs at ten distinct loci surpassed P < 1 × 10 −6 ( Supplementary Table 2 ), a threshold we took to be indicative of suggestive evidence of association with disease 14 . Three of these loci have previously been reported ( Fig. 2 and Supplementary Table 3 ) 1 . We then subjected the ten sentinel SNPs representing each of the ten independent loci to replication genotyping in a further 3,978 cases and 9,638 controls from 14 countries ( Supplementary Table 1 ). Significant replication was observed at eight distinct loci ( Table 1 and Supplementary Table 2 ; the initial associations observed at FNDC3B rs16856870 on chromosome 3 and SLC38A6 rs10483730 on chromosome 14 did not replicate), and meta-analysis of all discovery and replication samples totaling 10,503 PACG cases and 29,567 controls showed genome-wide significant evidence of association for the eight loci with PACG ( Fig. 2 and Table 1 ). This two-stage study design is powered to detect effect sizes as low as 1.15 with minor allele frequencies (MAFs) as low as 0.15 at genome-wide significance ( Supplementary Table 4 ). Figure 1: Distribution of PACG cases and controls from the GWAS discovery stage, which encompassed collections from 15 countries. Cases and controls are projected onto the top two principal components of genetic stratification, with cases on the left and controls on the right. Principal-component comparisons for each of the East Asian countries are shown in Supplementary Figure 10 . Full size image Figure 2: Results of the discovery GWAS meta-analysis. The three previously reported loci are underlined. FNDC3B did not replicate in the replication collections. SNPs at EPDR1 , GLIS3 , DPM2 – FAM102A , CHAT , and FERMT2 represent new genome-wide significant associations. Full size image Table 1 Results for the eight genome-wide significant loci upon meta-analysis of all PACG case–control collections Full size table We next asked whether heterogeneity in genetic effect sizes exists across ancestry groups and geographical locations and found that only EPDR1 rs3816415 showed discernable evidence of heterogeneity in the overall meta-analysis ( P het = 0.0072, I 2 index = 43.0%). Closer scrutiny showed that effect sizes were consistently larger in Europeans (OR = 1.42) than in Asians (OR = 1.21) ( Fig. 3 and Table 1 ), despite similar risk allele frequencies across the ancestry groups ( Supplementary Table 5 ). This discrepancy could be due either to more unreliable estimation in Europeans because of the smaller sample size in comparison to Asians ( n = 1,105 European PACG cases versus 9,398 Asian PACG cases) or to a genuine difference in effect between Asians and Europeans 15 , 16 , 17 . We did not observe significant heterogeneity in effect sizes at the other four loci ( Fig. 3 and Table 1 ). Imputation-based fine-mapping and regional association analysis showed that each SNP locus mapped distinctly among its nearest genes, mostly framed by recombination events ( Supplementary Fig. 1 ). However, as the GWAS approach assays mostly common, representative genetic variants across the human genome, we are unable to exclude the possibility that the identified SNPs at each locus could be tagging functional variants that are exerting control on distant gene targets in a position- and orientation-independent manner 18 , 19 . Figure 3: Forest plots for the five new genome-wide significant loci. Point estimates for each locus are denoted as risk allele odds ratios, accompanied by horizontal lines representing the 95% confidence interval for each point estimate. Diamonds represent meta-analyses for the GWAS discovery stage, replication stage, all<|im_end|> <|im_start|>assistant Scientists have discovered new genetic areas linked to an increased risk of glaucoma - the leading cause of irreversible blindness worldwide. The investigation studied the genetic make up of about 40,000 people and identified five previously unknown genetic areas linked to an increased risk of primary angle closure glaucoma (PACG). Co-author of the study Professor Jamie Craig from Flinders University in South Australia said PACG symptoms occurred quickly and required immediate medical attention. "This new discovery provides a handle, to gain an understanding of the mechanisms of the disease. This will help to work out who is at risk of developing angle closure glaucoma so they can have preventative laser treatment before an emergency situation develops," Prof Craig said. "We also expect in time, that the improved understanding of the pathways of this disease to lead to new ways to more effectively prevent and treat this serious condition, so that permanent loss of vision does not occur." The genetic analysis is by far the largest genome wide association study to date on this condition. It used a combined total of 10,404 cases of angle closure glaucoma and 29,343 normal controls to identify five novel glaucoma markers. Researchers at Flinders University, using the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG), led by Prof Craig guided international research across 23 countries in Asia, Australia, Europe and the Americas to make the discovery. Up to 80 per cent of the estimated 15 million people afflicted with PACG live in Asia, where the disease is responsible for a high proportion of blindness. Glaucoma generally develops later in life, initially causes loss of peripheral vision and can lead to complete blindness if untreated. Angle closure glaucoma is a less common form of the disease than open angle glaucoma. It is caused by blocked drainage canals in the eye and is characterised by a narrow angle between the iris and cornea. "With (PACG) it comes on quite rapidly, so they are aware something is happening. But if something is not done quickly, they can lose their vision," Prof Craig said. "All types of glaucoma have a strong hereditary or family influence and if there are any cases of glaucoma in the family, then people should be checked every two years from the age of 40." The study on angle closure glaucoma is published in Nature Genetics and was completed in association with the University of Melbourne, the University of Sydney and the Genome Institute of Singapore. <|im_end|>

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1,960

[ { "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 goal of the National Cancer Institute’s (NCI’s) Genomic Data Commons (GDC) is to provide the cancer research community with a data repository of uniformly processed genomic and associated clinical data that enables data sharing and collaborative analysis in the support of precision medicine. The initial GDC dataset include genomic, epigenomic, proteomic, clinical and other data from the NCI TCGA and TARGET programs. Data production for the GDC started in June, 2015 using an OpenStack-based private cloud. By June of 2016, the GDC had analyzed more than 50,000 raw sequencing data inputs, as well as multiple other data types. Using the latest human genome reference build GRCh38, the GDC generated a variety of data types from aligned reads to somatic mutations, gene expression, miRNA expression, DNA methylation status, and copy number variation. In this paper, we describe the pipelines and workflows used to process and harmonize the data in the GDC. The generated data, as well as the original input files from TCGA and TARGET, are available for download and exploratory analysis at the GDC Data Portal and Legacy Archive ( ). Introduction The National Cancer Institute’s (NCI’s) Genomic Data Commons (GDC) 1 , 2 currently contains NCI-generated data from some of the largest and most comprehensive cancer genomic datasets, including The Cancer Genome Atlas (TCGA, ) and Therapeutically Applicable Research to Generate Effective Therapies (TARGET, ). Each of these projects contains a variety of processed and unprocessed molecular data types, including genomics, epigenomics, proteomics, imaging, clinical, and others. These data, as well as data from future projects, are often generated using different methods, so that joint analysis of multiple datasets are often confounded by batch effects. Based on the lessons learned from TCGA, one of the major goals of the GDC is to create a uniform set of molecular datasets that minimize batch effects due to differences in reference genomes, gene models, analytical algorithms, and processing pipelines. In the GDC, this process is called harmonization and is broken up into two stages: alignment and higher level data generation. In the alignment stage, reads from Next Generation Sequencing (NGS) data are extracted and aligned, or re-aligned, to a single human reference genome sequence using a single pipeline for that particular data type. In the second stage, different higher level data generation pipelines utilize the GDC aligned data to derive summary results, such as somatic mutations or gene expression. Data production started with processing of Whole Exome Sequencing (WXS) alignment and somatic mutation calling, Whole Genome Sequencing (WGS) alignment, mRNA-Seq alignment and gene/exon level quantification, miRNA-Seq alignment and quantification, TCGA Affymetrix Genome-Wide Human SNP Array 6.0 array copy number segmentation, and Illumina Infinium HumanMethylation450/27 methylation array re-annotation. By the end of May 2016, we had successfully processed more than 56,168 BAM files and FASTQ bundles, including 27,594 WXS, 4691 WGS, 11,969 RNA-Seq and 11,914 miRNA-Seq, from 12,487 patients with a total input file size of 1001.7 TB. From GDC harmonized BAMs, more than 100,000 higher level derived data files have been generated. A total of more than 1400 TB of generated data, including intermediate files, have been produced by GDC data processing pipelines, and stored in GDC storage. Many of them have been imported into the GDC database (described in a companion submission), and have become queryable and downloadable from the GDC Data Portal ( ) and API. Users are able to get the up-to-date file summary directly from data repository facet view. In this work, we discuss the general considerations, implementation details and quality comparisons of a large-scale uniform genomics data analysis that was used by the NCI’s Genomic Data Commons for processing and harmonizing the cancer genomics data that it shares with its users. Results Reference genome and gene model The GDC chose GRCh38 as the reference human genome build for all data analyses, because of its improved coverage and accuracy over the previous major build GRCh37 3 . The GRCh38 major human genome assembly was released by Genome Reference Consortium (GRC) on Dec 2013 with GenBank assembly accession GCA_000001405.15. The complete assembly downloaded from NCBI contains 456 sequences, including 25 continuous chromosomal and mitochondrial sequences, 42 unlocalized scaffolds, 127 unplaced scaffolds, 261 alternative scaffolds, and 1 EBV decoy sequence. At the time of the development of the GDC pipelines, there was a lack of tool support for alternative scaffolds analysis. As a result, the GDC excluded alternative contigs from the GDC reference sequence, and used GCA_000001405.15_GRCh38_no_alt_analysis_set from the NCBI ftp site as a modified GCA_000001405.15 reference contig set without alternative loci and patches. In addition to the continuous chromosomal and mitochondrial sequences, unlocalized and unplaced scaffolds described above, the GDC reference sequence also includes 2385 human decoy sequences, together named hs38d1 with GenBank assembly accession GCA_000786075.2. These human decoy sequences are additional unlocalized sequences not officially recognized by GRC at the time of reference release, and having them in the GDC reference helps to reduce false alignments of such reads in other regions 4 . Similar to the idea of improving alignment quality with human decoy sequence, we collected genomic sequences from ten types (200 subtypes) of cancer related viruses in the reference genome, together called “virus decoy” as a collection. The additional benefit of having such virus sequences in the reference genome is to give users the opportunity to directly identify virus genome derived reads. These viruses include Human Cytomegalovirus (CMV, HHV-5), Epstein-Barr virus (EBV, HHV-4), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human immunodeficiency virus (HIV), Human herpesvirus 8 (KSHV, HHV-8), Human T-lymphotropic virus 1 (HTLV-1), Merkel cell polyomavirus (MCV), Simian vacuolating virus 40 (SV40), and Human papillomavirus (HPV) (Table 1 ). All HPV sequences were obtained from The PapillomaVirus Episteme (PaVE, ) instead of NCBI, because this group updated the sequences as new information is confirmed 5 . The GDC reference including all human and viral decoys can be downloaded from the GDC at the following link ( ). Table 1 Virus Sequences included in the GDC reference genome a . Full size", "role": "user" }, { "content": "The National Cancer Institute's Genomic Data Commons (GDC), launched in 2016 by then-Vice President Joseph Biden and hosted at the University of Chicago, has become one of the largest and most widely used resources in cancer genomics, with more than 3.3 petabytes of data from more than 65 projects and over 84,000 anonymized patient cases, serving more than 50,000 unique users each month. In new papers published Feb. 22 in Nature Communications and Nature Genetics, the UChicago-based research team shares new details about the GDC, which is funded by the National Cancer Institute (NCI), via subcontract with the Frederick National Laboratory for Cancer Research, currently operated by Leidos Biomedical Research, Inc. One of the papers describes the design and operation of the GDC. The other describes the pipelines used by the GDC for the harmonization of data submitted to the GDC and the generation of datasets used by the GDC research community. The goal of the GDC is to provide the cancer research community with a data repository of uniformly processed genomic and associated clinical data that enables data sharing and collaborative analysis in the support of precision medicine. Data production for what would become the GDC began in June 2015 using a private cloud. After just a year, the GDC had analyzed more than 50,000 raw sequencing data inputs. The GDC includes genomic, transcriptomic, epigenomic, proteomic, clinical, and imaging data. The processing pipelines described in the Nature paper have produced more than 1,660 TB of data on more than two dozen types of primary cancers. These data are stored within the GDC Data Portal, where they are available for viewing and downloading. Along with the data portal, the GDC also offers additional user resources, including the GDC Data Analysis, Visualization, and Exploration (DAVE) Tools for interactive exploration of data by genomic variant or specific alteration; the GDC Data Submission Portal for submitting data; the GDC Data Transfer Tool (DTT) for downloading large genomic datasets; and the GDC data harmonization system, which allows users to run data submitted to the GDC through the harmonizing processing pipelines. \"These data have a critical role to play,\" said Robert Grossman, Ph.D., principal investigator for the GDC and director of the Center for Translational Data Science at UChicago. \"As data accumulates, new signals will become easier to identify as important targets for understanding cancer biology. In addition, the data-sharing infrastructure can serve to inform research studies, providing new insight into genetic variation between individuals and how it may affect cancer patient outcomes.\" ", "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 goal of the National Cancer Institute’s (NCI’s) Genomic Data Commons (GDC) is to provide the cancer research community with a data repository of uniformly processed genomic and associated clinical data that enables data sharing and collaborative analysis in the support of precision medicine. The initial GDC dataset include genomic, epigenomic, proteomic, clinical and other data from the NCI TCGA and TARGET programs. Data production for the GDC started in June, 2015 using an OpenStack-based private cloud. By June of 2016, the GDC had analyzed more than 50,000 raw sequencing data inputs, as well as multiple other data types. Using the latest human genome reference build GRCh38, the GDC generated a variety of data types from aligned reads to somatic mutations, gene expression, miRNA expression, DNA methylation status, and copy number variation. In this paper, we describe the pipelines and workflows used to process and harmonize the data in the GDC. The generated data, as well as the original input files from TCGA and TARGET, are available for download and exploratory analysis at the GDC Data Portal and Legacy Archive ( ). Introduction The National Cancer Institute’s (NCI’s) Genomic Data Commons (GDC) 1 , 2 currently contains NCI-generated data from some of the largest and most comprehensive cancer genomic datasets, including The Cancer Genome Atlas (TCGA, ) and Therapeutically Applicable Research to Generate Effective Therapies (TARGET, ). Each of these projects contains a variety of processed and unprocessed molecular data types, including genomics, epigenomics, proteomics, imaging, clinical, and others. These data, as well as data from future projects, are often generated using different methods, so that joint analysis of multiple datasets are often confounded by batch effects. Based on the lessons learned from TCGA, one of the major goals of the GDC is to create a uniform set of molecular datasets that minimize batch effects due to differences in reference genomes, gene models, analytical algorithms, and processing pipelines. In the GDC, this process is called harmonization and is broken up into two stages: alignment and higher level data generation. In the alignment stage, reads from Next Generation Sequencing (NGS) data are extracted and aligned, or re-aligned, to a single human reference genome sequence using a single pipeline for that particular data type. In the second stage, different higher level data generation pipelines utilize the GDC aligned data to derive summary results, such as somatic mutations or gene expression. Data production started with processing of Whole Exome Sequencing (WXS) alignment and somatic mutation calling, Whole Genome Sequencing (WGS) alignment, mRNA-Seq alignment and gene/exon level quantification, miRNA-Seq alignment and quantification, TCGA Affymetrix Genome-Wide Human SNP Array 6.0 array copy number segmentation, and Illumina Infinium HumanMethylation450/27 methylation array re-annotation. By the end of May 2016, we had successfully processed more than 56,168 BAM files and FASTQ bundles, including 27,594 WXS, 4691 WGS, 11,969 RNA-Seq and 11,914 miRNA-Seq, from 12,487 patients with a total input file size of 1001.7 TB. From GDC harmonized BAMs, more than 100,000 higher level derived data files have been generated. A total of more than 1400 TB of generated data, including intermediate files, have been produced by GDC data processing pipelines, and stored in GDC storage. Many of them have been imported into the GDC database (described in a companion submission), and have become queryable and downloadable from the GDC Data Portal ( ) and API. Users are able to get the up-to-date file summary directly from data repository facet view. In this work, we discuss the general considerations, implementation details and quality comparisons of a large-scale uniform genomics data analysis that was used by the NCI’s Genomic Data Commons for processing and harmonizing the cancer genomics data that it shares with its users. Results Reference genome and gene model The GDC chose GRCh38 as the reference human genome build for all data analyses, because of its improved coverage and accuracy over the previous major build GRCh37 3 . The GRCh38 major human genome assembly was released by Genome Reference Consortium (GRC) on Dec 2013 with GenBank assembly accession GCA_000001405.15. The complete assembly downloaded from NCBI contains 456 sequences, including 25 continuous chromosomal and mitochondrial sequences, 42 unlocalized scaffolds, 127 unplaced scaffolds, 261 alternative scaffolds, and 1 EBV decoy sequence. At the time of the development of the GDC pipelines, there was a lack of tool support for alternative scaffolds analysis. As a result, the GDC excluded alternative contigs from the GDC reference sequence, and used GCA_000001405.15_GRCh38_no_alt_analysis_set from the NCBI ftp site as a modified GCA_000001405.15 reference contig set without alternative loci and patches. In addition to the continuous chromosomal and mitochondrial sequences, unlocalized and unplaced scaffolds described above, the GDC reference sequence also includes 2385 human decoy sequences, together named hs38d1 with GenBank assembly accession GCA_000786075.2. These human decoy sequences are additional unlocalized sequences not officially recognized by GRC at the time of reference release, and having them in the GDC reference helps to reduce false alignments of such reads in other regions 4 . Similar to the idea of improving alignment quality with human decoy sequence, we collected genomic sequences from ten types (200 subtypes) of cancer related viruses in the reference genome, together called “virus decoy” as a collection. The additional benefit of having such virus sequences in the reference genome is to give users the opportunity to directly identify virus genome derived reads. These viruses include Human Cytomegalovirus (CMV, HHV-5), Epstein-Barr virus (EBV, HHV-4), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human immunodeficiency virus (HIV), Human herpesvirus 8 (KSHV, HHV-8), Human T-lymphotropic virus 1 (HTLV-1), Merkel cell polyomavirus (MCV), Simian vacuolating virus 40 (SV40), and Human papillomavirus (HPV) (Table 1 ). All HPV sequences were obtained from The PapillomaVirus Episteme (PaVE, ) instead of NCBI, because this group updated the sequences as new information is confirmed 5 . The GDC reference including all human and viral decoys can be downloaded from the GDC at the following link ( ). Table 1 Virus Sequences included in the GDC reference genome a . Full size<|im_end|> <|im_start|>assistant The National Cancer Institute's Genomic Data Commons (GDC), launched in 2016 by then-Vice President Joseph Biden and hosted at the University of Chicago, has become one of the largest and most widely used resources in cancer genomics, with more than 3.3 petabytes of data from more than 65 projects and over 84,000 anonymized patient cases, serving more than 50,000 unique users each month. In new papers published Feb. 22 in Nature Communications and Nature Genetics, the UChicago-based research team shares new details about the GDC, which is funded by the National Cancer Institute (NCI), via subcontract with the Frederick National Laboratory for Cancer Research, currently operated by Leidos Biomedical Research, Inc. One of the papers describes the design and operation of the GDC. The other describes the pipelines used by the GDC for the harmonization of data submitted to the GDC and the generation of datasets used by the GDC research community. The goal of the GDC is to provide the cancer research community with a data repository of uniformly processed genomic and associated clinical data that enables data sharing and collaborative analysis in the support of precision medicine. Data production for what would become the GDC began in June 2015 using a private cloud. After just a year, the GDC had analyzed more than 50,000 raw sequencing data inputs. The GDC includes genomic, transcriptomic, epigenomic, proteomic, clinical, and imaging data. The processing pipelines described in the Nature paper have produced more than 1,660 TB of data on more than two dozen types of primary cancers. These data are stored within the GDC Data Portal, where they are available for viewing and downloading. Along with the data portal, the GDC also offers additional user resources, including the GDC Data Analysis, Visualization, and Exploration (DAVE) Tools for interactive exploration of data by genomic variant or specific alteration; the GDC Data Submission Portal for submitting data; the GDC Data Transfer Tool (DTT) for downloading large genomic datasets; and the GDC data harmonization system, which allows users to run data submitted to the GDC through the harmonizing processing pipelines. "These data have a critical role to play," said Robert Grossman, Ph.D., principal investigator for the GDC and director of the Center for Translational Data Science at UChicago. "As data accumulates, new signals will become easier to identify as important targets for understanding cancer biology. In addition, the data-sharing infrastructure can serve to inform research studies, providing new insight into genetic variation between individuals and how it may affect cancer patient outcomes." <|im_end|>

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2,040

[ { "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 emergence of the “4th Industrial Revolution,” i.e. the convergence of artificial intelligence, the Internet of Things, advanced materials, and bioengineering technologies, could accelerate socioeconomic insecurities and anxieties or provide beneficial alternatives to the status quo. In the post-Covid-19 era, the entities that are best positioned to capitalize on these innovations are large firms, which use digital platforms and big data to orchestrate vast ecosystems of users and extract market share across industry sectors. Nonetheless, these technologies also have the potential to democratize ownership, broaden political-economic participation, and reduce environmental harms. We articulate the potential sociotechnical pathways in this high-stakes crossroads by analyzing cellular agriculture, an exemplary 4th Industrial Revolution technology that synergizes computer science, biopharma, tissue engineering, and food science to grow cultured meat, dairy, and egg products from cultured cells and/or genetically modified yeast. Our exploration of this space involved multi-sited ethnographic research in both (a) the cellular agriculture community and (b) alternative economic organizations devoted to open source licensing, member-owned cooperatives, social financing, and platform business models. Upon discussing how these latter approaches could potentially facilitate alternative sociotechnical pathways in cellular agriculture, we reflect upon the broader implications of this work with respect to the 4th Industrial Revolution and the enduring need for public policy reform. Working on a manuscript? Avoid the common mistakes Introduction Emerging “4th Industrial Revolution” (4IR) technologies that fuse the “physical, digital, and biological worlds” (Schwab 2016 , p. 1) could help to revitalize the contemporary agri-food system, improve social equity, and reduce environmental degradation. They could also do the opposite. Cellular agriculture, a 4IR technology that uses animal cells—or, in some cases, genetically modified yeast—to grow meat, dairy, egg, seafood, and plant components in vitro is an exemplar of this existential tension. Although it is not yet widely available as a consumer product, its proponents portray a best-case scenario in which cellular agriculture could reduce land, water, and chemical inputs, minimize greenhouse gas emissions, improve food safety, optimize nutritional attributes, and obviate the need to raise and slaughter animals for food (Cameron and O’Neill 2019 ; Datar et al. 2016 ; Specht et al. 2018 ). However, cellular agriculture could also concentrate ownership and power in the global food system, namely by displacing ranchers, farmers, fishers, and ancillary industries, while also falling short of its environmental promises (Broad 2019 ; Cosgrove 2017 ; Hines et al. 2018 ; Lynch and Pierrehumbert 2019 ; Tuomisto 2019 ). Over the past decade, scholars have explored a broad spectrum of socioeconomic and ethical questions pertaining to this technology (see Chiles 2013 ; Guthman and Biltekoff 2020 ; Hocquette et al. 2015 ; Jönsson 2016 ; Laestadius 2015 ; Slade 2018 ; Broad 2019 ). However, this scholarship has done little to engage with concepts related to inclusive innovation (Juma 2016 ; Stilgoe et al. 2013 ), and therefore has yet to identify mechanisms that might facilitate more (or less) just and equitable development in this sector. Scholarship in the political economy of agriculture provides a logical starting point for such an inquiry, as it has demonstrated how supply chain configurations, public and private governance systems, and the social construction of technology affect consumption patterns and livelihoods. Perhaps above all, this literature showcases the importance of understanding food-system ownership and stakeholder participation at a structural level (Howard 2016 ). However, as noted by Gibson-Graham ( 2006 ), there is a tendency for many political economy scholars to portray the capitalist economy as monolithic and incessant. Large transnational firms have gained powerful oligopolistic market control with global influence that will likely persist. However, their continued dominance is not a foregone conclusion, as there are alternative social organizations of economic activities that could become more prominent alongside 4IR innovations. This is important because, as previous industrial revolutions have revealed, the potential socioeconomic and ecological benefits of technological innovations are contingent on the social organization of their production and distribution. Industrial revolutions thus present the possibility for social reorganization that could democratize ownership, broaden political-economic participation, and reduce environmental harms (McCarthy and Zald 1977 ; Rifkin 2014 ; Schwab 2016 ). We explore these issues by investigating how alternative economic models might facilitate a process of inclusive innovation in cellular agriculture, and by extension, provide a template for other 4IR technologies. In what follows, we first engage with and extend the political economy of agriculture literature by examining how digitalization is reshaping traditional forms of ownership and participation in the agri-food system. We then discuss our empirical investigation of this phenomenon, which has been guided by two basic research questions: (I) How do players in the cellular agriculture community understand its current economic trajectory? (II) What types of alternative sociotechnical pathways could be used to develop cellular agriculture? Our approach to these questions involved multi-sited ethnographic research of the cellular agriculture community and alternative economic organization events. After reviewing our findings from these two respective areas of inquiry, we synthesize our results by discussing a unique sociotechnical pathway that could facilitate inclusive innovation in this field. We conclude the paper by reflecting upon the broader implications of this work, specifically with respect to the 4IR, alternative food movements, food tech justice, and public policy. The 4th Industrial Revolution and cellular agriculture in political-economic context Historically, while the appropriation and substitution of raw natural materials for industrial products has resulted in innovative solutions for agricultural challenges (Lusk 2016 ), it has also concentrated political and economic power in the hands of the largest farmers, input providers, processors, and retailers (Goodman et al. 1987 ; Howard 2016 ). Horizontal/vertical integration, intellectual property rights, financialization, and private governance have further squeezed market share from small producers (Carlson 2018 ; Lawrence 2017 ; Marsden et al. 2019 ; Patel and Moore 2017 ; Pimbert et al. 2001 ). Proprietary-driven innovation strategies have become so prominent that even public universities have sought to attract more private investments and intellectual property protections (Brandl and Glenna 2017 ). Agricultural scientists and large agribusiness actors have", "role": "user" }, { "content": "Depending on how it occurs, the development of cellular agriculture—food grown in factories from cells or yeast—has the potential to either accelerate socioeconomic inequality or provide beneficial alternatives to the status quo. That's the conclusion of a new study led by Penn State researchers, who assessed the potential trajectories for a new technology that synergizes computer science, biopharma, tissue engineering and food science to grow cultured meat, dairy and egg products from animal cells and/or genetically modified yeast. The entities that currently are best positioned to capitalize on these innovations are large companies, according to researcher Robert Chiles, assistant professor of rural sociology, College of Agricultural Sciences. \"Nonetheless, new technologies such as artificial intelligence, smart agriculture, bioengineering, synthetic biology and 3D printers are also being used to decentralize and personalize food manufacturing,\" he said. \"They have the potential to democratize ownership and mobilize alternative economic organizations devoted to open-source licensing, member-owned cooperatives, social financing and platform business models.\" Although cellular meat is not yet widely available to consumers, its proponents believe that cellular agriculture could reduce land, water and chemical inputs, minimize greenhouse gas emissions, improve food safety, optimize nutrition, and eliminate the need to raise and slaughter large numbers of animals for food. However, cellular agriculture could also concentrate ownership and power in the global food system, namely by displacing ranchers, farmers, fishermen and ancillary industries. The latter possibility has led to widespread concern that cellular agriculture could accelerate the concentration of wealth and diminish public participation in agriculture—all while offering fewer environmental and nutritional benefits than promised. Over the past decade, scholars have explored a broad spectrum of socioeconomic and ethical questions pertaining to this technological approach, noted Chiles, who is a research associate at Penn State's Rock Ethics Institute. However, he explained, this scholarship has done little to explore the types of mechanisms that might facilitate a more just and equitable development of this sector. To assess cellular agriculture's potential trajectories, Chiles and colleagues attended 11 cellular agriculture and alternative economic organization events held around the United States over two years, interviewing key experts at those conferences and summits, asking how they think the industry will develop and should develop. Likewise, the researchers collected data from an additional 21 conferences online. The study's findings, published in Agriculture and Human Values, affirm the argument for increased public investments in open-source research and education on cellular agriculture, particularly for community and household-level production. The paper is publicly available through open access. The jury is still out on how cellular agriculture will develop in the U.S. and around the world, Chiles pointed out. This research—which engaged innovators and early adopters in the field in conversation about whether this emerging technology will further concentrate wealth and power in the global food system—yielded valuable clues, he said. \"Government investments in publicly accessible digital infrastructures could help to facilitate a more just transition, as could public policies that protect workers' rights and consumer privacy,\" Chiles added. \"Stakeholders who are concerned about the justice and equity implications of cellular agriculture may ultimately find more success by engaging with how these technologies are being developed rather than avoiding them or trying to eradicate 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 The emergence of the “4th Industrial Revolution,” i.e. the convergence of artificial intelligence, the Internet of Things, advanced materials, and bioengineering technologies, could accelerate socioeconomic insecurities and anxieties or provide beneficial alternatives to the status quo. In the post-Covid-19 era, the entities that are best positioned to capitalize on these innovations are large firms, which use digital platforms and big data to orchestrate vast ecosystems of users and extract market share across industry sectors. Nonetheless, these technologies also have the potential to democratize ownership, broaden political-economic participation, and reduce environmental harms. We articulate the potential sociotechnical pathways in this high-stakes crossroads by analyzing cellular agriculture, an exemplary 4th Industrial Revolution technology that synergizes computer science, biopharma, tissue engineering, and food science to grow cultured meat, dairy, and egg products from cultured cells and/or genetically modified yeast. Our exploration of this space involved multi-sited ethnographic research in both (a) the cellular agriculture community and (b) alternative economic organizations devoted to open source licensing, member-owned cooperatives, social financing, and platform business models. Upon discussing how these latter approaches could potentially facilitate alternative sociotechnical pathways in cellular agriculture, we reflect upon the broader implications of this work with respect to the 4th Industrial Revolution and the enduring need for public policy reform. Working on a manuscript? Avoid the common mistakes Introduction Emerging “4th Industrial Revolution” (4IR) technologies that fuse the “physical, digital, and biological worlds” (Schwab 2016 , p. 1) could help to revitalize the contemporary agri-food system, improve social equity, and reduce environmental degradation. They could also do the opposite. Cellular agriculture, a 4IR technology that uses animal cells—or, in some cases, genetically modified yeast—to grow meat, dairy, egg, seafood, and plant components in vitro is an exemplar of this existential tension. Although it is not yet widely available as a consumer product, its proponents portray a best-case scenario in which cellular agriculture could reduce land, water, and chemical inputs, minimize greenhouse gas emissions, improve food safety, optimize nutritional attributes, and obviate the need to raise and slaughter animals for food (Cameron and O’Neill 2019 ; Datar et al. 2016 ; Specht et al. 2018 ). However, cellular agriculture could also concentrate ownership and power in the global food system, namely by displacing ranchers, farmers, fishers, and ancillary industries, while also falling short of its environmental promises (Broad 2019 ; Cosgrove 2017 ; Hines et al. 2018 ; Lynch and Pierrehumbert 2019 ; Tuomisto 2019 ). Over the past decade, scholars have explored a broad spectrum of socioeconomic and ethical questions pertaining to this technology (see Chiles 2013 ; Guthman and Biltekoff 2020 ; Hocquette et al. 2015 ; Jönsson 2016 ; Laestadius 2015 ; Slade 2018 ; Broad 2019 ). However, this scholarship has done little to engage with concepts related to inclusive innovation (Juma 2016 ; Stilgoe et al. 2013 ), and therefore has yet to identify mechanisms that might facilitate more (or less) just and equitable development in this sector. Scholarship in the political economy of agriculture provides a logical starting point for such an inquiry, as it has demonstrated how supply chain configurations, public and private governance systems, and the social construction of technology affect consumption patterns and livelihoods. Perhaps above all, this literature showcases the importance of understanding food-system ownership and stakeholder participation at a structural level (Howard 2016 ). However, as noted by Gibson-Graham ( 2006 ), there is a tendency for many political economy scholars to portray the capitalist economy as monolithic and incessant. Large transnational firms have gained powerful oligopolistic market control with global influence that will likely persist. However, their continued dominance is not a foregone conclusion, as there are alternative social organizations of economic activities that could become more prominent alongside 4IR innovations. This is important because, as previous industrial revolutions have revealed, the potential socioeconomic and ecological benefits of technological innovations are contingent on the social organization of their production and distribution. Industrial revolutions thus present the possibility for social reorganization that could democratize ownership, broaden political-economic participation, and reduce environmental harms (McCarthy and Zald 1977 ; Rifkin 2014 ; Schwab 2016 ). We explore these issues by investigating how alternative economic models might facilitate a process of inclusive innovation in cellular agriculture, and by extension, provide a template for other 4IR technologies. In what follows, we first engage with and extend the political economy of agriculture literature by examining how digitalization is reshaping traditional forms of ownership and participation in the agri-food system. We then discuss our empirical investigation of this phenomenon, which has been guided by two basic research questions: (I) How do players in the cellular agriculture community understand its current economic trajectory? (II) What types of alternative sociotechnical pathways could be used to develop cellular agriculture? Our approach to these questions involved multi-sited ethnographic research of the cellular agriculture community and alternative economic organization events. After reviewing our findings from these two respective areas of inquiry, we synthesize our results by discussing a unique sociotechnical pathway that could facilitate inclusive innovation in this field. We conclude the paper by reflecting upon the broader implications of this work, specifically with respect to the 4IR, alternative food movements, food tech justice, and public policy. The 4th Industrial Revolution and cellular agriculture in political-economic context Historically, while the appropriation and substitution of raw natural materials for industrial products has resulted in innovative solutions for agricultural challenges (Lusk 2016 ), it has also concentrated political and economic power in the hands of the largest farmers, input providers, processors, and retailers (Goodman et al. 1987 ; Howard 2016 ). Horizontal/vertical integration, intellectual property rights, financialization, and private governance have further squeezed market share from small producers (Carlson 2018 ; Lawrence 2017 ; Marsden et al. 2019 ; Patel and Moore 2017 ; Pimbert et al. 2001 ). Proprietary-driven innovation strategies have become so prominent that even public universities have sought to attract more private investments and intellectual property protections (Brandl and Glenna 2017 ). Agricultural scientists and large agribusiness actors have<|im_end|> <|im_start|>assistant Depending on how it occurs, the development of cellular agriculture—food grown in factories from cells or yeast—has the potential to either accelerate socioeconomic inequality or provide beneficial alternatives to the status quo. That's the conclusion of a new study led by Penn State researchers, who assessed the potential trajectories for a new technology that synergizes computer science, biopharma, tissue engineering and food science to grow cultured meat, dairy and egg products from animal cells and/or genetically modified yeast. The entities that currently are best positioned to capitalize on these innovations are large companies, according to researcher Robert Chiles, assistant professor of rural sociology, College of Agricultural Sciences. "Nonetheless, new technologies such as artificial intelligence, smart agriculture, bioengineering, synthetic biology and 3D printers are also being used to decentralize and personalize food manufacturing," he said. "They have the potential to democratize ownership and mobilize alternative economic organizations devoted to open-source licensing, member-owned cooperatives, social financing and platform business models." Although cellular meat is not yet widely available to consumers, its proponents believe that cellular agriculture could reduce land, water and chemical inputs, minimize greenhouse gas emissions, improve food safety, optimize nutrition, and eliminate the need to raise and slaughter large numbers of animals for food. However, cellular agriculture could also concentrate ownership and power in the global food system, namely by displacing ranchers, farmers, fishermen and ancillary industries. The latter possibility has led to widespread concern that cellular agriculture could accelerate the concentration of wealth and diminish public participation in agriculture—all while offering fewer environmental and nutritional benefits than promised. Over the past decade, scholars have explored a broad spectrum of socioeconomic and ethical questions pertaining to this technological approach, noted Chiles, who is a research associate at Penn State's Rock Ethics Institute. However, he explained, this scholarship has done little to explore the types of mechanisms that might facilitate a more just and equitable development of this sector. To assess cellular agriculture's potential trajectories, Chiles and colleagues attended 11 cellular agriculture and alternative economic organization events held around the United States over two years, interviewing key experts at those conferences and summits, asking how they think the industry will develop and should develop. Likewise, the researchers collected data from an additional 21 conferences online. The study's findings, published in Agriculture and Human Values, affirm the argument for increased public investments in open-source research and education on cellular agriculture, particularly for community and household-level production. The paper is publicly available through open access. The jury is still out on how cellular agriculture will develop in the U.S. and around the world, Chiles pointed out. This research—which engaged innovators and early adopters in the field in conversation about whether this emerging technology will further concentrate wealth and power in the global food system—yielded valuable clues, he said. "Government investments in publicly accessible digital infrastructures could help to facilitate a more just transition, as could public policies that protect workers' rights and consumer privacy," Chiles added. "Stakeholders who are concerned about the justice and equity implications of cellular agriculture may ultimately find more success by engaging with how these technologies are being developed rather than avoiding them or trying to eradicate them." <|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 existence of bound states of elementary spin waves (magnons) in one-dimensional quantum magnets was predicted almost 80 years ago 1 . Identifying signatures of magnon bound states has so far remained the subject of intense theoretical research 2 , 3 , 4 , 5 , and their detection has proved challenging for experiments. Ultracold atoms offer an ideal setting in which to find such bound states by tracking the spin dynamics with single-spin and single-site resolution 6 , 7 following a local excitation 8 . Here we use in situ correlation measurements to observe two-magnon bound states directly in a one-dimensional Heisenberg spin chain comprising ultracold bosonic atoms in an optical lattice. We observe the quantum dynamics of free and bound magnon states through time-resolved measurements of two spin impurities. The increased effective mass of the compound magnon state results in slower spin dynamics as compared to single-magnon excitations. We also determine the decay time of bound magnons, which is probably limited by scattering on thermal fluctuations in the system. Our results provide a new way of studying fundamental properties of quantum magnets and, more generally, properties of interacting impurities in quantum many-body systems. Main The study of non-equilibrium processes in quantum spin models can provide fundamental insight into elementary aspects of magnetism. Magnons are the basic quasiparticle excitations around the ground state of ferromagnets and govern their low-temperature physics 9 , 10 . Owing to the ferromagnetic interaction, two spin excitations can remain bound together, forming a so-called two-magnon bound state 1 , 9 , 11 . In one and two dimensions, bound states exist for all centre-of-mass momenta, which prohibits the description of low-energy properties in terms of free magnon states 9 . In the classical limit, magnon bound states can be regarded as the basic building blocks of magnetic solitons 12 , 13 . The study of non-equilibrium dynamics in quantum spin chains is also important for a variety of applications. The evolution of two localized spin excitations realizes an interacting quantum walk 14 , 15 in the spin domain, which can be a versatile tool for the study of complex many-body systems 16 . It is also of importance in the context of quantum information 17 , where transport properties in a one-dimensional chain of qubits can be strongly influenced by magnon bound states 18 . The spin-1/2 Heisenberg model is one of the foundational models of interacting quantum spins. The corresponding Hamiltonian was solved analytically in one dimension in the early 1930s by Bethe, who used a systematic Ansatz for the form of the eigenvectors 1 . Later, the Bethe Ansatz proved to be far more general and allowed the solving of many more one-dimensional problems, such as the Lieb–Liniger model or the fermionic Hubbard model 19 . Recent powerful extensions of this approach include the investigation of the dynamics of one-dimensional quantum many-body systems. One of the first results of Bethe’s analysis was the prediction of magnon bound states. Experimentally, spectroscopic studies of solid-state materials provided the first evidence for the existence of such states 20 , 21 , 22 . For ultracold atoms in optical lattices, high-energy bound states have been observed in the form of repulsively bound atom pairs 23 , 24 . Optical lattice systems can also be used to realize the Heisenberg model with (in principle) tunable anisotropy 25 , 26 , where bound states occur as low-energy excitations of the many-body system. Recent technological advances even allow for the in situ control and detection of atomic spins in these experiments 6 , 7 , 27 . In our system, we make use of a one-dimensional chain of bosonic atoms in an optical lattice. Starting from an initial Mott insulating state and a fully magnetized chain, we flip two neighbouring spins in the centre of the chain (see Fig. 1 and ref. 28 ). Making use of our detection technique, which has single-site and single-spin resolution 7 , we are able to observe individual magnons and their bound states directly and to identify them by correlation measurements after letting the system evolve. Figure 1: Schematic representation of magnon propagation. a – c , Initially prepared state of ‘up’ spins (blue) with the two flipped ‘down’ spins shown in red ( a ), and its decomposition into bound magnons ( b ) and free magnons ( c ) propagating through the lattice. d , Numerical results obtained from exact diagonalization, showing the probability of finding a flipped spin at a given lattice site following the initial state preparation. Two different wavefronts corresponding to bound and free magnons can be identified (insets). Note that the maximum probability was clipped in the graph for clarity. PowerPoint slide Full size image The system is described by the one-dimensional two-species single-band Bose–Hubbard Hamiltonian at unity filling. In the strong coupling limit, where the on-site interaction energy is much larger than the tunnelling matrix element, this Hamiltonian can be mapped onto the ferromagnetic spin-1/2 Heisenberg chain (also known as the XXZ spin-1/2 chain) 25 , 26 : where J ex is the superexchange coupling and Δ is the anisotropy between the transverse and longitudinal spin couplings. The pseudo-spin operators are defined in terms of creation and annihilation operators for a boson on site i with spin σ = ↑, ↓: , and , where the number operators count the bosons of the respective spin states on each lattice site. The transverse coupling (the first term of equation (1)) corresponds to the spin exchange between two neighbouring sites and results in the propagation of spin excitations, or magnons 28 , 29 . The longitudinal coupling describes a nearest-neighbour interaction between the spins, which favours ferromagnetic order for J ex Δ > 0. This term is the origin of the magnon bound states: two flipped spins can lower their energy when located on neighbouring sites. For our scattering parameters, the Heisenberg interactions are almost isotropic; that is, Δ ≈ 1 (see Methods). We note that the", "role": "user" }, { "content": "Simulating solid state properties with precisely controlled quantum systems is an important goal of the Quantum Many-Body Systems Division at MPQ. Now the team around Professor Immanuel Bloch (Chair for Experimental Physics at the Ludwig-Maximilians-Universität Munich and Director at MPQ) has come again a step closer to it – to be precise, to the understanding of processes in ferromagnetic solid state crystals in which elementary excitations, so-called magnons, can emerge. About 80 years ago the German physicist Hans Bethe deduced from a theoretical model that in one-dimensional ferromagnets two of those elementary magnetic excitations can form a bound state. Like two tiny bar magnets, two atoms can stick together and form a new particle that propagates in the crystal. The MPQ team has now succeeded to observe these most elementary mobile magnetic domains, the two-magnon states, directly and to resolve their dynamics with time-resolved measurements. This study complements conventional spectroscopy in solid state crystals which yields information on momentum and frequency of the magnetic excitations. Bound states of excitations can influence the thermal conductance properties of low-dimensional ferromagnets or the propagation speed of quantum information in magnetic wires. The magnetic properties of certain materials have been known for centuries, and they have been used for a variety of applications almost quite as long. Today, this behaviour is very well understood at the microscopic level: magnetism goes back to the angular momentum – the spin – of the electrons in the outer shell of the atoms that build up a solid state crystal. In ferromagnetic matter these spins are aligned within the so-called \"Weiss\" domains. Similar conditions can be prepared in quantum crystals if the atoms have a defined spin. To this end a cloud of extremely cold (i.e. extremely slow) rubidium atoms is loaded into an optical lattice, generated by crosswise superposition of standing laser waves. The periodically arranged bright patches of the lattice are the sites on which the atoms are allowed to settle down. The dark areas act as barriers, the height of which is determined by the intensity of the laser light. As long as the lattice is comparably shallow, the atoms are able to \"tunnel\" through the barrier to their neighbouring site. In the experiment described here, the scientists restrict their motion to one direction. As a result the atoms are arranged in ten decoupled one-dimensional \"tubes\" of more or less the same length. In the beginning the laser intensity is rather high, and the quantum crystal forms a so-called \"Mott-insulator\": each lattice site is occupied with exactly one atom, fixed in space. The atoms are thereby lined up like pearls on a chain with all spins pointing in the same direction – in other words the chain represents a perfect ferromagnetic quantum magnet. A couple of months ago, in a similar experimental set-up, the Bloch group were able to change the spin-direction of one individual atom and to track the propagation of the resulting spin wave throughout the quantum magnet. Now they went one step further: by precise addressing and application of microwave pulses they flipped the spins of two neighbouring atoms in the centre of each fully magnetized atomic chain. The two spin excitations can propagate as individual, free magnons along the quantum magnet. But due to the ferromagnetic interaction between them, they can also stick together forming an elementary mobile magnetic domain with about the same probability. Two technical achievements make it possible to both observe the bound state directly and to track its dynamical evolution. On the one hand the group has developed a method of imaging individual atoms on their individual lattice sites. With a special kind of a microscope the scientists can distinguish atoms with a flipped spin from the unflipped ones. On the other hand, they can trigger precisely at which moment the particles start to move. This is done by lowering the lattice height, which enhances the magnetic interactions between the atoms. When the lattice height is raised again after a certain time interval, the magnetic interaction is turned off again and the spin orientation of the atoms is \"frozen out\". By taking snapshots of the actual spin patterns for a series of different evolution times the propagation of the ferromagnetic excitations can be measured with high resolution in space and time. \"With this method we can unambiguously separate states with bound magnons from those with free excitations,\" Dr. Christian Groß, project leader at the experiment, explains. \"In the first case, the two adjacent flipped spins stay together on their walk along the quantum magnet. In the second, the free magnons show anti-bunching in their motion. This means, if one spin excitation has travelled three lattice sites to the right the other one has moved the same distance in the opposite direction. Bound states usually don't hold forever – this is as valid in the quantum world as it is in real life. \"According to our observation the number of magnon pairs decreases for long observation times,\" Dr. Takeshi Fukuhara points out. \"One possible reason for this is that the fragile spin waves couple to some extent to thermal excitations. At present we are working on a model which will describe the decay of bound states both quantitatively and qualitatively.\" The observation of elementary quantum magnetic phenomena helps to understand fundamental magnetic processes in solid state crystals. But the investigation of the dynamics of spin waves in one-dimensional quantum magnets is also relevant for potential applications. For example, the transport of quantum information along a chain of qubits can be strongly influenced by the formation of bound two-magnon states. ", "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 existence of bound states of elementary spin waves (magnons) in one-dimensional quantum magnets was predicted almost 80 years ago 1 . Identifying signatures of magnon bound states has so far remained the subject of intense theoretical research 2 , 3 , 4 , 5 , and their detection has proved challenging for experiments. Ultracold atoms offer an ideal setting in which to find such bound states by tracking the spin dynamics with single-spin and single-site resolution 6 , 7 following a local excitation 8 . Here we use in situ correlation measurements to observe two-magnon bound states directly in a one-dimensional Heisenberg spin chain comprising ultracold bosonic atoms in an optical lattice. We observe the quantum dynamics of free and bound magnon states through time-resolved measurements of two spin impurities. The increased effective mass of the compound magnon state results in slower spin dynamics as compared to single-magnon excitations. We also determine the decay time of bound magnons, which is probably limited by scattering on thermal fluctuations in the system. Our results provide a new way of studying fundamental properties of quantum magnets and, more generally, properties of interacting impurities in quantum many-body systems. Main The study of non-equilibrium processes in quantum spin models can provide fundamental insight into elementary aspects of magnetism. Magnons are the basic quasiparticle excitations around the ground state of ferromagnets and govern their low-temperature physics 9 , 10 . Owing to the ferromagnetic interaction, two spin excitations can remain bound together, forming a so-called two-magnon bound state 1 , 9 , 11 . In one and two dimensions, bound states exist for all centre-of-mass momenta, which prohibits the description of low-energy properties in terms of free magnon states 9 . In the classical limit, magnon bound states can be regarded as the basic building blocks of magnetic solitons 12 , 13 . The study of non-equilibrium dynamics in quantum spin chains is also important for a variety of applications. The evolution of two localized spin excitations realizes an interacting quantum walk 14 , 15 in the spin domain, which can be a versatile tool for the study of complex many-body systems 16 . It is also of importance in the context of quantum information 17 , where transport properties in a one-dimensional chain of qubits can be strongly influenced by magnon bound states 18 . The spin-1/2 Heisenberg model is one of the foundational models of interacting quantum spins. The corresponding Hamiltonian was solved analytically in one dimension in the early 1930s by Bethe, who used a systematic Ansatz for the form of the eigenvectors 1 . Later, the Bethe Ansatz proved to be far more general and allowed the solving of many more one-dimensional problems, such as the Lieb–Liniger model or the fermionic Hubbard model 19 . Recent powerful extensions of this approach include the investigation of the dynamics of one-dimensional quantum many-body systems. One of the first results of Bethe’s analysis was the prediction of magnon bound states. Experimentally, spectroscopic studies of solid-state materials provided the first evidence for the existence of such states 20 , 21 , 22 . For ultracold atoms in optical lattices, high-energy bound states have been observed in the form of repulsively bound atom pairs 23 , 24 . Optical lattice systems can also be used to realize the Heisenberg model with (in principle) tunable anisotropy 25 , 26 , where bound states occur as low-energy excitations of the many-body system. Recent technological advances even allow for the in situ control and detection of atomic spins in these experiments 6 , 7 , 27 . In our system, we make use of a one-dimensional chain of bosonic atoms in an optical lattice. Starting from an initial Mott insulating state and a fully magnetized chain, we flip two neighbouring spins in the centre of the chain (see Fig. 1 and ref. 28 ). Making use of our detection technique, which has single-site and single-spin resolution 7 , we are able to observe individual magnons and their bound states directly and to identify them by correlation measurements after letting the system evolve. Figure 1: Schematic representation of magnon propagation. a – c , Initially prepared state of ‘up’ spins (blue) with the two flipped ‘down’ spins shown in red ( a ), and its decomposition into bound magnons ( b ) and free magnons ( c ) propagating through the lattice. d , Numerical results obtained from exact diagonalization, showing the probability of finding a flipped spin at a given lattice site following the initial state preparation. Two different wavefronts corresponding to bound and free magnons can be identified (insets). Note that the maximum probability was clipped in the graph for clarity. PowerPoint slide Full size image The system is described by the one-dimensional two-species single-band Bose–Hubbard Hamiltonian at unity filling. In the strong coupling limit, where the on-site interaction energy is much larger than the tunnelling matrix element, this Hamiltonian can be mapped onto the ferromagnetic spin-1/2 Heisenberg chain (also known as the XXZ spin-1/2 chain) 25 , 26 : where J ex is the superexchange coupling and Δ is the anisotropy between the transverse and longitudinal spin couplings. The pseudo-spin operators are defined in terms of creation and annihilation operators for a boson on site i with spin σ = ↑, ↓: , and , where the number operators count the bosons of the respective spin states on each lattice site. The transverse coupling (the first term of equation (1)) corresponds to the spin exchange between two neighbouring sites and results in the propagation of spin excitations, or magnons 28 , 29 . The longitudinal coupling describes a nearest-neighbour interaction between the spins, which favours ferromagnetic order for J ex Δ > 0. This term is the origin of the magnon bound states: two flipped spins can lower their energy when located on neighbouring sites. For our scattering parameters, the Heisenberg interactions are almost isotropic; that is, Δ ≈ 1 (see Methods). We note that the<|im_end|> <|im_start|>assistant Simulating solid state properties with precisely controlled quantum systems is an important goal of the Quantum Many-Body Systems Division at MPQ. Now the team around Professor Immanuel Bloch (Chair for Experimental Physics at the Ludwig-Maximilians-Universität Munich and Director at MPQ) has come again a step closer to it – to be precise, to the understanding of processes in ferromagnetic solid state crystals in which elementary excitations, so-called magnons, can emerge. About 80 years ago the German physicist Hans Bethe deduced from a theoretical model that in one-dimensional ferromagnets two of those elementary magnetic excitations can form a bound state. Like two tiny bar magnets, two atoms can stick together and form a new particle that propagates in the crystal. The MPQ team has now succeeded to observe these most elementary mobile magnetic domains, the two-magnon states, directly and to resolve their dynamics with time-resolved measurements. This study complements conventional spectroscopy in solid state crystals which yields information on momentum and frequency of the magnetic excitations. Bound states of excitations can influence the thermal conductance properties of low-dimensional ferromagnets or the propagation speed of quantum information in magnetic wires. The magnetic properties of certain materials have been known for centuries, and they have been used for a variety of applications almost quite as long. Today, this behaviour is very well understood at the microscopic level: magnetism goes back to the angular momentum – the spin – of the electrons in the outer shell of the atoms that build up a solid state crystal. In ferromagnetic matter these spins are aligned within the so-called "Weiss" domains. Similar conditions can be prepared in quantum crystals if the atoms have a defined spin. To this end a cloud of extremely cold (i.e. extremely slow) rubidium atoms is loaded into an optical lattice, generated by crosswise superposition of standing laser waves. The periodically arranged bright patches of the lattice are the sites on which the atoms are allowed to settle down. The dark areas act as barriers, the height of which is determined by the intensity of the laser light. As long as the lattice is comparably shallow, the atoms are able to "tunnel" through the barrier to their neighbouring site. In the experiment described here, the scientists restrict their motion to one direction. As a result the atoms are arranged in ten decoupled one-dimensional "tubes" of more or less the same length. In the beginning the laser intensity is rather high, and the quantum crystal forms a so-called "Mott-insulator": each lattice site is occupied with exactly one atom, fixed in space. The atoms are thereby lined up like pearls on a chain with all spins pointing in the same direction – in other words the chain represents a perfect ferromagnetic quantum magnet. A couple of months ago, in a similar experimental set-up, the Bloch group were able to change the spin-direction of one individual atom and to track the propagation of the resulting spin wave throughout the quantum magnet. Now they went one step further: by precise addressing and application of microwave pulses they flipped the spins of two neighbouring atoms in the centre of each fully magnetized atomic chain. The two spin excitations can propagate as individual, free magnons along the quantum magnet. But due to the ferromagnetic interaction between them, they can also stick together forming an elementary mobile magnetic domain with about the same probability. Two technical achievements make it possible to both observe the bound state directly and to track its dynamical evolution. On the one hand the group has developed a method of imaging individual atoms on their individual lattice sites. With a special kind of a microscope the scientists can distinguish atoms with a flipped spin from the unflipped ones. On the other hand, they can trigger precisely at which moment the particles start to move. This is done by lowering the lattice height, which enhances the magnetic interactions between the atoms. When the lattice height is raised again after a certain time interval, the magnetic interaction is turned off again and the spin orientation of the atoms is "frozen out". By taking snapshots of the actual spin patterns for a series of different evolution times the propagation of the ferromagnetic excitations can be measured with high resolution in space and time. "With this method we can unambiguously separate states with bound magnons from those with free excitations," Dr. Christian Groß, project leader at the experiment, explains. "In the first case, the two adjacent flipped spins stay together on their walk along the quantum magnet. In the second, the free magnons show anti-bunching in their motion. This means, if one spin excitation has travelled three lattice sites to the right the other one has moved the same distance in the opposite direction. Bound states usually don't hold forever – this is as valid in the quantum world as it is in real life. "According to our observation the number of magnon pairs decreases for long observation times," Dr. Takeshi Fukuhara points out. "One possible reason for this is that the fragile spin waves couple to some extent to thermal excitations. At present we are working on a model which will describe the decay of bound states both quantitatively and qualitatively." The observation of elementary quantum magnetic phenomena helps to understand fundamental magnetic processes in solid state crystals. But the investigation of the dynamics of spin waves in one-dimensional quantum magnets is also relevant for potential applications. For example, the transport of quantum information along a chain of qubits can be strongly influenced by the formation of bound two-magnon states. <|im_end|>

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2,470

[ { "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 Glacial lakes are increasing in number and extent under a warming climate. Despite demand for lake monitoring and understanding outburst mechanisms, studies of large outburst events are sparse. Here we report an outburst of Lago Greve, a large proglacial lake in Chilean Patagonia. During the event in April–July 2020, the lake level dropped by 18.3 ± 1.2 m and the area decreased by 14.5 ± 0.02 km 2 . The total water discharge was 3.7 ± 0.2 km 3 , which is one of the largest glacial lake outbursts ever reported in satellite era. Satellite data indicated the collapse of a bump near the lake outlet triggered the event, by initiating erosion of the bank and bed of the outlet stream. Satellite gravimetry captured a signal of the event, although the magnitude of the corresponding mass change was inconsistent with the drained water mass. Our study demonstrated the potential for observing lake outburst using satellite imagery, altimetry, photogrammetry, and gravimetry. Introduction As a consequence of glacier retreat under a warming climate, the number, area, and volume of glacial lakes has increased in recent decades 1 . In particular, rapid increase has been observed in Patagonia 2 , Alaska 3 , Himalaya 4 , and Greenland 5 . Glacial lakes affect ice dynamics, frontal ablation, and hence the evolution of glaciers terminating in the lakes 6 , 7 , 8 , 9 . Because of the lake influences, freshwater calving glaciers experience more rapid retreat and greater mass-loss than glaciers terminating on land 10 . In Patagonia, freshwater calving glaciers are rapidly retreating and thinning 11 , 12 , 13 , 14 , which causes rapid mass loss of the Southern and Northern Patagonia Icefields 15 . As a result of the glacier retreat, glacial lakes in the regions are expanding at the greatest rate in the world 1 . Freshwater calving is important also because glaciers affect lake environments via nutrient-rich meltwater discharge 16 , 17 , sedimentation and water circulation 18 , 19 , which play critical roles in the ecosystems of the lakes 20 . Further, glacial lake outburst flood (GLOF) has a strong impact on physical and biological environments downstream 21 . For example, large-scale GLOFs during the deglaciation of past ice sheets affected ocean current and hence regional climate by discharging a large amount of freshwater into the ocean 22 , 23 . Monitoring glacial lakes is thus important for understanding future changes of freshwater calving glaciers and the surrounding environment. GLOF occurs when a moraine-, glacier-, or bedrock-dam is breached. Tsunami and seiche waves generated by e.g., calving, landslide, or rockfall trigger outburst by initiating lakewater overflow and subsequent erosion of the dam 24 , 25 . Seepage of lakewater through a moraine dam and uplift of an ice dam due to flotation are other mechanisms that trigger lake outburst 26 , 27 . GLOF also occurs when a moraine dam spontaneously collapses after deglaciation, a process so called “self-destruction” of a dam 28 . Sudden release of a large amount of water has the potential to cause serious damage to communities and infrastructure downstream 29 . Several thousand deaths due to GLOFs have been reported during the last hundred years 30 . The actual number of fatalities is most likely greater because the inventory of lake outburst is incomplete 31 . Under the influence of formation and expansion of glacial lakes 1 , 2 , 3 , 4 , 5 , the frequency of GLOFs possibly increases in the 21st century 32 . Therefore, further understanding of outburst mechanism and long-term monitoring of glacial lakes are required to manage hazards in mountainous regions. Satellite remote sensing techniques are powerful tools to monitor glacial lakes. For example, satellite images have been used to map glacial lakes and measure aerial changes all over the world 1 . Satellite observations were utilized to quantify the changes in Himalayan glacial lakes from 1990 to 2015 with temporal resolution of 5 years 33 . Lake surface elevations have been measured by satellite laser/radar altimetry 34 , 35 as well as digital elevation models (DEMs) 36 . Data series of Gravity Recovery And Climate Experiment (GRACE) and GRACE-FO (follow-on) have been combined with laser and radar altimeter measurement to quantify the water mass change of ordinary lakes 37 , 38 . Yi et al. 39 demonstrated an ability of the GRACE data to identify the change of 13.0 Gt of water of a reservoir. Nevertheless, GRACE has never been applied to GLOFs. In April 2020, we observed a sudden retreat of the shoreline of Lago Greve, an extraordinarily large proglacial lake in Patagonia (Fig. 1 ). Additional analyses with several types of satellite data indicated the release of a large amount of water within a short time period. In this paper, we report changes in the lake area, water level, and volume during the event, as well as its impact on the gravity field. We also investigate the mechanism of drainage based on satellite imagery and DEMs. The data illustrates the details of a largest glacial lake outburst event observed by satellite to date. Fig. 1: Study site. Satellite image of Lago Greve (Sentinel-2 MSI image on 1st November 2020). The inset shows the location of the study site in South America. The area which turned from lake to land surface from 8 April to 1st November 2020 are highlighted in yellow. Areas highlighted in orange and cyan indicate advance and retreat of glacier calving fronts during the same period. Blue curves indicate glacier boundaries from RGI 6.0 inventory 69 (based on satellite imagery in 2000–2003), with glacier frontal margins delineated in this study. The red box in the upper left corner indicates the location of the lake outlet and the area shown in Fig. 4 . The magenta boxes indicate the areas shown in Fig. 3 . Full size image Study site Lago Greve (49.0°S, 73.9°W) is a glacier-fed lake situated on the western side of the Southern", "role": "user" }, { "content": "Only satellites were watching when the world's fourth-largest proglacial lake suddenly drained in 2020. Hokkaido University researchers have now uncovered the event and analyzed the cause—the collapse of a sediment bump at the outlet of the lake. Proglacial lakes form when meltwater from retreating glaciers is trapped by ice or by a moraine left behind by the same or another glacier. A warming climate contributes to the recent global increase in the number and volume of these lakes, and they also themselves contribute to glaciers melting even faster. However, these lakes can drain very quickly when the dams that contain them fail for one of various reasons. Such a catastrophic event not only poses a direct safety risk for humans, but also influences ecosystems downstream due to the sudden influx of a large amount of freshwater. It is therefore important to monitor proglacial lakes and study their interactions with their surroundings. Unfortunately, this is difficult due to their often remote location. Hokkaido University glacier scientist Shin Sugiyama and doctoral student Shuntaro Hata were studying glacier fluctuations in Chilean Patagonia using satellite images, when they noticed that the proglacial lake Lago Greve had shrunk significantly in the short time between April and July of 2020. In their publication of these findings in the journal Communications Earth & Environment, they add further analysis of the available data confirming that the lake's water level dropped by 18 meters, which translates to a loss of 3.7 cubic kilometers (or, giga-tons) of water—the largest such event observed by a satellite to date. This huge loss of water even measurably changed the gravity field of Earth, as recorded by GRACE satellites, even though quantitative data from these satellites is inconsistent with the actual amount of water drained. Finally, careful analysis of the satellite imagery and topographic data from before and after the event enabled them to deduce that the cause of the release probably was the collapse of a sediment bump close to the outlet of the lake. Satellite image of Lago Greve (Greve Lake), Chile and surrounding landmarks. The area which turned from lake to land surface from 8 April to 1st November 2020 are highlighted in yellow. Areas highlighted in orange and cyan indicate advance and retreat of glacier calving fronts during the same period. The red box (top right) indicates the location of the lake outlet (Shuntaro Hata, Shin Sugiyama, Kosuke Heki. Communications Earth & Environment. August 26, 2022). Credit: Shuntaro Hata, Shin Sugiyama, Kosuke Heki. Communications Earth & Environment. August 26, 2022 This study opens up many interesting aspects. For one, it points the way for future research on glacial dynamics. Sugiyama explains, \"These results provide detailed information on large-scale glacial lake outburst floods, which occur very rarely, and are important for understanding disasters caused by glacial lake failures.\" It also highlights the possibility and the current limitations of using GRACE satellite data for observing such events. The researchers write, \"The importance of GRACE measurements in studying such events would be increased if the calculation of the gravity field readings is adapted for localized events.\" And finally, the study provides concrete data that can be used to better understand the dynamics of the interactions between glaciers and the lakes they form, as \"the observed changes in the water level of glacial lakes can be used to predict changes in the glacier inflow into the lakes.\" ", "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 Glacial lakes are increasing in number and extent under a warming climate. Despite demand for lake monitoring and understanding outburst mechanisms, studies of large outburst events are sparse. Here we report an outburst of Lago Greve, a large proglacial lake in Chilean Patagonia. During the event in April–July 2020, the lake level dropped by 18.3 ± 1.2 m and the area decreased by 14.5 ± 0.02 km 2 . The total water discharge was 3.7 ± 0.2 km 3 , which is one of the largest glacial lake outbursts ever reported in satellite era. Satellite data indicated the collapse of a bump near the lake outlet triggered the event, by initiating erosion of the bank and bed of the outlet stream. Satellite gravimetry captured a signal of the event, although the magnitude of the corresponding mass change was inconsistent with the drained water mass. Our study demonstrated the potential for observing lake outburst using satellite imagery, altimetry, photogrammetry, and gravimetry. Introduction As a consequence of glacier retreat under a warming climate, the number, area, and volume of glacial lakes has increased in recent decades 1 . In particular, rapid increase has been observed in Patagonia 2 , Alaska 3 , Himalaya 4 , and Greenland 5 . Glacial lakes affect ice dynamics, frontal ablation, and hence the evolution of glaciers terminating in the lakes 6 , 7 , 8 , 9 . Because of the lake influences, freshwater calving glaciers experience more rapid retreat and greater mass-loss than glaciers terminating on land 10 . In Patagonia, freshwater calving glaciers are rapidly retreating and thinning 11 , 12 , 13 , 14 , which causes rapid mass loss of the Southern and Northern Patagonia Icefields 15 . As a result of the glacier retreat, glacial lakes in the regions are expanding at the greatest rate in the world 1 . Freshwater calving is important also because glaciers affect lake environments via nutrient-rich meltwater discharge 16 , 17 , sedimentation and water circulation 18 , 19 , which play critical roles in the ecosystems of the lakes 20 . Further, glacial lake outburst flood (GLOF) has a strong impact on physical and biological environments downstream 21 . For example, large-scale GLOFs during the deglaciation of past ice sheets affected ocean current and hence regional climate by discharging a large amount of freshwater into the ocean 22 , 23 . Monitoring glacial lakes is thus important for understanding future changes of freshwater calving glaciers and the surrounding environment. GLOF occurs when a moraine-, glacier-, or bedrock-dam is breached. Tsunami and seiche waves generated by e.g., calving, landslide, or rockfall trigger outburst by initiating lakewater overflow and subsequent erosion of the dam 24 , 25 . Seepage of lakewater through a moraine dam and uplift of an ice dam due to flotation are other mechanisms that trigger lake outburst 26 , 27 . GLOF also occurs when a moraine dam spontaneously collapses after deglaciation, a process so called “self-destruction” of a dam 28 . Sudden release of a large amount of water has the potential to cause serious damage to communities and infrastructure downstream 29 . Several thousand deaths due to GLOFs have been reported during the last hundred years 30 . The actual number of fatalities is most likely greater because the inventory of lake outburst is incomplete 31 . Under the influence of formation and expansion of glacial lakes 1 , 2 , 3 , 4 , 5 , the frequency of GLOFs possibly increases in the 21st century 32 . Therefore, further understanding of outburst mechanism and long-term monitoring of glacial lakes are required to manage hazards in mountainous regions. Satellite remote sensing techniques are powerful tools to monitor glacial lakes. For example, satellite images have been used to map glacial lakes and measure aerial changes all over the world 1 . Satellite observations were utilized to quantify the changes in Himalayan glacial lakes from 1990 to 2015 with temporal resolution of 5 years 33 . Lake surface elevations have been measured by satellite laser/radar altimetry 34 , 35 as well as digital elevation models (DEMs) 36 . Data series of Gravity Recovery And Climate Experiment (GRACE) and GRACE-FO (follow-on) have been combined with laser and radar altimeter measurement to quantify the water mass change of ordinary lakes 37 , 38 . Yi et al. 39 demonstrated an ability of the GRACE data to identify the change of 13.0 Gt of water of a reservoir. Nevertheless, GRACE has never been applied to GLOFs. In April 2020, we observed a sudden retreat of the shoreline of Lago Greve, an extraordinarily large proglacial lake in Patagonia (Fig. 1 ). Additional analyses with several types of satellite data indicated the release of a large amount of water within a short time period. In this paper, we report changes in the lake area, water level, and volume during the event, as well as its impact on the gravity field. We also investigate the mechanism of drainage based on satellite imagery and DEMs. The data illustrates the details of a largest glacial lake outburst event observed by satellite to date. Fig. 1: Study site. Satellite image of Lago Greve (Sentinel-2 MSI image on 1st November 2020). The inset shows the location of the study site in South America. The area which turned from lake to land surface from 8 April to 1st November 2020 are highlighted in yellow. Areas highlighted in orange and cyan indicate advance and retreat of glacier calving fronts during the same period. Blue curves indicate glacier boundaries from RGI 6.0 inventory 69 (based on satellite imagery in 2000–2003), with glacier frontal margins delineated in this study. The red box in the upper left corner indicates the location of the lake outlet and the area shown in Fig. 4 . The magenta boxes indicate the areas shown in Fig. 3 . Full size image Study site Lago Greve (49.0°S, 73.9°W) is a glacier-fed lake situated on the western side of the Southern<|im_end|> <|im_start|>assistant Only satellites were watching when the world's fourth-largest proglacial lake suddenly drained in 2020. Hokkaido University researchers have now uncovered the event and analyzed the cause—the collapse of a sediment bump at the outlet of the lake. Proglacial lakes form when meltwater from retreating glaciers is trapped by ice or by a moraine left behind by the same or another glacier. A warming climate contributes to the recent global increase in the number and volume of these lakes, and they also themselves contribute to glaciers melting even faster. However, these lakes can drain very quickly when the dams that contain them fail for one of various reasons. Such a catastrophic event not only poses a direct safety risk for humans, but also influences ecosystems downstream due to the sudden influx of a large amount of freshwater. It is therefore important to monitor proglacial lakes and study their interactions with their surroundings. Unfortunately, this is difficult due to their often remote location. Hokkaido University glacier scientist Shin Sugiyama and doctoral student Shuntaro Hata were studying glacier fluctuations in Chilean Patagonia using satellite images, when they noticed that the proglacial lake Lago Greve had shrunk significantly in the short time between April and July of 2020. In their publication of these findings in the journal Communications Earth & Environment, they add further analysis of the available data confirming that the lake's water level dropped by 18 meters, which translates to a loss of 3.7 cubic kilometers (or, giga-tons) of water—the largest such event observed by a satellite to date. This huge loss of water even measurably changed the gravity field of Earth, as recorded by GRACE satellites, even though quantitative data from these satellites is inconsistent with the actual amount of water drained. Finally, careful analysis of the satellite imagery and topographic data from before and after the event enabled them to deduce that the cause of the release probably was the collapse of a sediment bump close to the outlet of the lake. Satellite image of Lago Greve (Greve Lake), Chile and surrounding landmarks. The area which turned from lake to land surface from 8 April to 1st November 2020 are highlighted in yellow. Areas highlighted in orange and cyan indicate advance and retreat of glacier calving fronts during the same period. The red box (top right) indicates the location of the lake outlet (Shuntaro Hata, Shin Sugiyama, Kosuke Heki. Communications Earth & Environment. August 26, 2022). Credit: Shuntaro Hata, Shin Sugiyama, Kosuke Heki. Communications Earth & Environment. August 26, 2022 This study opens up many interesting aspects. For one, it points the way for future research on glacial dynamics. Sugiyama explains, "These results provide detailed information on large-scale glacial lake outburst floods, which occur very rarely, and are important for understanding disasters caused by glacial lake failures." It also highlights the possibility and the current limitations of using GRACE satellite data for observing such events. The researchers write, "The importance of GRACE measurements in studying such events would be increased if the calculation of the gravity field readings is adapted for localized events." And finally, the study provides concrete data that can be used to better understand the dynamics of the interactions between glaciers and the lakes they form, as "the observed changes in the water level of glacial lakes can be used to predict changes in the glacier inflow into the lakes." <|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 Axonal plasticity allows neurons to control their output, which critically determines the flow of information in the brain. Axon diameter can be regulated by activity, yet how morphological changes in an axon impact its function remains poorly understood. Axonal swellings have been found on Purkinje cell axons in the cerebellum both in healthy development and in neurodegenerative diseases, and computational models predicts that axonal swellings impair axonal function. Here we report that in young Purkinje cells, axons with swellings propagated action potentials with higher fidelity than those without, and that axonal swellings form when axonal failures are high. Furthermore, we observed that healthy young adult mice with more axonal swellings learn better on cerebellar-related tasks than mice with fewer swellings. Our findings suggest that axonal swellings underlie a form of axonal plasticity that optimizes the fidelity of action potential propagation in axons, resulting in enhanced learning. Introduction Information is transmitted in the nervous system primarily by action potentials traveling along axons. This means that a neuron’s ability to maintain high-fidelity axonal propagation is of fundamental importance for its function 1 . Indeed, instances when axonal propagation is delayed or interrupted can produce devastating consequences. For example, in multiple sclerosis (MS), axonal impairments resulting from the breakdown of myelin that surrounds axons lead to severe sensory and motor symptoms. Conversely, alterations in axonal structure can also be adaptive: for example, neurons respond to elevated levels of activity by restructuring their axon initial segment (AIS) to homeostatically regulate their excitability 2 . Since Purkinje cell axons carry information out of the cerebellar cortex, changes in the structure of their axons could impact cerebellar function dramatically. Purkinje cell axonal swellings appear transiently during cerebellar development 3 , 4 and are observed during normal aging 5 , including in healthy human samples 6 , 7 . These data suggest that axonal swellings play a physiological role in the brain. However, similar axonal swellings have also been associated with axon dysfunction in several neurodegenerative diseases 8 , 9 , 10 , 11 , indicating that at least in some cases, axonal swellings may be implicated in pathological function. Whether axonal swellings serve different roles in different contexts remains to be determined. Computational modeling has proposed that axonal swellings serve a pathophysiological role, as models predict that action potentials will be delayed, filtered, or fail when propagating across an axonal swelling 12 , 13 , 14 . To determine the impact of axonal swellings on Purkinje cell axonal function, we performed visually-targeted dual recordings from the soma and axon of individual Purkinje cells from young mice, and found that Purkinje cell axonal failures were reduced in axons with swellings. Axonal propagation was more reliable in axons with swellings when axon failures were induced by driving the neuron to fire at near-maximal firing rates. Pharmacologically mimicking high levels of axonal failures led to the formation of focal axonal swellings, and we uncovered that their formation is Ca 2+ -dependent and requires Ca 2+ entry through voltage-gated Ca 2+ channels. Finally, by examining cerebellar-related behavior, we observed that mice exhibiting higher levels of cerebellar learning had higher numbers of axonal swellings. These data suggest that the enhancement of action potential propagation associated with axonal swellings in healthy young animals positively impacts behavior. Results Action potential propagation is enhanced in axons with swellings Purkinje cell axonal swellings are present in healthy developing rodents 4 and are also observed in several neurodegenerative diseases 8 , 9 , 10 , 11 . However, functional measurements of the impact of axonal swellings on axons have been lacking. We used dual targeted loose-patch recordings with fluorescently-tagged Quantum dot-coated glass electrodes 15 to measure action potentials simultaneously in Purkinje cell somata and axons (Fig. 1a ) in acute brain slices prepared from the cerebellar vermis of juvenile, healthy transgenic mice expressing GFP in Purkinje cells, including in their axons 16 , 17 . Since computational models suggest that axonal swellings increase axonal failure rates 13 , we monitored action potential failures in Purkinje cells with and without focal axonal swellings (Fig. 1b ). Approximately 30% of axons display swellings at this age 4 , and the vast majority of these were single swellings within the granule cell layer (98.7%; Supplementary Fig. 1 ), which we targeted for our recordings of axonal swellings. Axons without swellings were recorded as control axons at similar distances from the soma (Supplementary Fig. 2 and Supplementary Table 1 ). Surprisingly, we found that the axonal failure rate in Purkinje cells with swellings was significantly lower than that in Purkinje cells without axonal swellings (Control Axon: 6.07 ± 1.36 per 1000 spike; n = 11; Axon with Swelling: 1.12 ± 0.41 per 1000 spike; n = 9; Mann–Whitney U -test, P = 0.001; Fig. 1c ). A large proportion of axons with swellings propagated action potentials with very high fidelity (having very few axonal failures), whereas only the occasional axon without a swelling propagated with similar fidelity (9.1% of control axons were high-fidelity; 55.5% of axons with swellings were high-fidelity; Mann–Whitney U -test, P = 0.05; Fig. 1d ). We found no differences in the axosomatic delay between recordings in axons with swelling and control axons (Fig. 1e and Supplementary Fig. 2 ), suggesting that swellings do not change the propagation speed of action potentials, or at least not over the relatively short distances that we have measured (Supplementary Fig. 2 and Supplementary Table 1 ). Taken together, these data argue that axonal swellings enhance rather than impair axonal propagation. Fig. 1: Axonal swellings are associated with improved axonal propagation of action potentials. a Representative images of a Purkinje cell with placement of electrodes showing simultaneous dual recording from Purkinje cells soma (left electrode) and axon (right electrode) from a control axon (top) and an axon with a swelling (bottom; asterisk indicates swelling). Images were acquired after each simultaneous dual recording. Scale bar, 25 μm. b Representative traces of dual recordings from soma (black) and axon corresponding to Purkinje", "role": "user" }, { "content": "Researchers at McGill University have shown that a brain cell structure previously thought to be pathological in fact enhances cells' ability to transmit information and correlates with better learning on certain tasks. In a study published in Nature Communications, the team investigated swellings that occur in the axons of Purkinje cells in the cerebellum. In results that contradict established expectations, they found that axons with swellings did a better job of conducting electrical signals than those without. \"These are the kind of results where you really scratch your head and think, \"Let's check that again,'\" says senior author Alanna Watt, an Associate Professor in the Department of Biology. \"We really thought when we started this that we were going to characterize and measure how an axon fails—and that's not at all what we saw.\" Experimental data confounds expectations Swellings in axons—the long, slender fibers through which nerve cells transmit information to other cells—are observed in normal development and in disease. Increased numbers of axonal swellings are seen in various neurodegenerative disorders, which has led scientists to believe swellings have a negative impact on axon function. While computer modeling lends some support to this view, the McGill research team was the first to test the theory with measurements on actual nerve cells. Using a technically challenging combination of two-photon microscopy and electrophysiology to measure electrical activity simultaneously at different locations within cells, the researchers demonstrated that the presence of axonal swellings in mouse Purkinje cells had no detrimental impact on the rate at which those cells produced signals (the firing rate) or on the speed at which axons transmitted the signals. Remarkably, the experiments also showed that at peak firing rates axons with swellings were less likely to fail than those without. Role in neurodegenerative disease called into question In a surprising twist, the McGill researchers found that they were able to stimulate the formation of axonal swellings by introducing a pharmaceutical that blocked the transmission of electrical signals in nerve cells, especially in the axons. Seeing axonal swellings form within a matter of hours when the axon of a nerve cell had been compromised in this way challenges previous assumptions about the role of axonal swellings in neurodegenerative disorders. As Watt explains, the discovery leaves room for the possibility that swellings represent a self-repair mechanism rather than a deterioration caused by disease. \"Transmitting information by way of electrical signals is the most important thing that an axon does,\" she says. \"If it starts to fail at that job, it makes sense that there's a mechanism that tries to prevent that.\" Behavioral analysis confirms swellings' positive impact In addition to their investigations at the cellular level, the researchers sought to determine the impact of axonal swellings on overall brain function. The team used three tests designed to assess motor learning and coordination, which are among the cerebellum's most important roles. Supported by modeling to account for the natural variation between individual learning abilities, the results revealed a positive correlation between the abundance of axonal swellings in cerebellar Purkinje cells and motor learning abilities. \"We think the link is probably an indirect one,\" Watt explains. \"The learning is probably happening somewhere else, but the information is being relayed more reliably and therefore we see an improvement.\" ", "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 Axonal plasticity allows neurons to control their output, which critically determines the flow of information in the brain. Axon diameter can be regulated by activity, yet how morphological changes in an axon impact its function remains poorly understood. Axonal swellings have been found on Purkinje cell axons in the cerebellum both in healthy development and in neurodegenerative diseases, and computational models predicts that axonal swellings impair axonal function. Here we report that in young Purkinje cells, axons with swellings propagated action potentials with higher fidelity than those without, and that axonal swellings form when axonal failures are high. Furthermore, we observed that healthy young adult mice with more axonal swellings learn better on cerebellar-related tasks than mice with fewer swellings. Our findings suggest that axonal swellings underlie a form of axonal plasticity that optimizes the fidelity of action potential propagation in axons, resulting in enhanced learning. Introduction Information is transmitted in the nervous system primarily by action potentials traveling along axons. This means that a neuron’s ability to maintain high-fidelity axonal propagation is of fundamental importance for its function 1 . Indeed, instances when axonal propagation is delayed or interrupted can produce devastating consequences. For example, in multiple sclerosis (MS), axonal impairments resulting from the breakdown of myelin that surrounds axons lead to severe sensory and motor symptoms. Conversely, alterations in axonal structure can also be adaptive: for example, neurons respond to elevated levels of activity by restructuring their axon initial segment (AIS) to homeostatically regulate their excitability 2 . Since Purkinje cell axons carry information out of the cerebellar cortex, changes in the structure of their axons could impact cerebellar function dramatically. Purkinje cell axonal swellings appear transiently during cerebellar development 3 , 4 and are observed during normal aging 5 , including in healthy human samples 6 , 7 . These data suggest that axonal swellings play a physiological role in the brain. However, similar axonal swellings have also been associated with axon dysfunction in several neurodegenerative diseases 8 , 9 , 10 , 11 , indicating that at least in some cases, axonal swellings may be implicated in pathological function. Whether axonal swellings serve different roles in different contexts remains to be determined. Computational modeling has proposed that axonal swellings serve a pathophysiological role, as models predict that action potentials will be delayed, filtered, or fail when propagating across an axonal swelling 12 , 13 , 14 . To determine the impact of axonal swellings on Purkinje cell axonal function, we performed visually-targeted dual recordings from the soma and axon of individual Purkinje cells from young mice, and found that Purkinje cell axonal failures were reduced in axons with swellings. Axonal propagation was more reliable in axons with swellings when axon failures were induced by driving the neuron to fire at near-maximal firing rates. Pharmacologically mimicking high levels of axonal failures led to the formation of focal axonal swellings, and we uncovered that their formation is Ca 2+ -dependent and requires Ca 2+ entry through voltage-gated Ca 2+ channels. Finally, by examining cerebellar-related behavior, we observed that mice exhibiting higher levels of cerebellar learning had higher numbers of axonal swellings. These data suggest that the enhancement of action potential propagation associated with axonal swellings in healthy young animals positively impacts behavior. Results Action potential propagation is enhanced in axons with swellings Purkinje cell axonal swellings are present in healthy developing rodents 4 and are also observed in several neurodegenerative diseases 8 , 9 , 10 , 11 . However, functional measurements of the impact of axonal swellings on axons have been lacking. We used dual targeted loose-patch recordings with fluorescently-tagged Quantum dot-coated glass electrodes 15 to measure action potentials simultaneously in Purkinje cell somata and axons (Fig. 1a ) in acute brain slices prepared from the cerebellar vermis of juvenile, healthy transgenic mice expressing GFP in Purkinje cells, including in their axons 16 , 17 . Since computational models suggest that axonal swellings increase axonal failure rates 13 , we monitored action potential failures in Purkinje cells with and without focal axonal swellings (Fig. 1b ). Approximately 30% of axons display swellings at this age 4 , and the vast majority of these were single swellings within the granule cell layer (98.7%; Supplementary Fig. 1 ), which we targeted for our recordings of axonal swellings. Axons without swellings were recorded as control axons at similar distances from the soma (Supplementary Fig. 2 and Supplementary Table 1 ). Surprisingly, we found that the axonal failure rate in Purkinje cells with swellings was significantly lower than that in Purkinje cells without axonal swellings (Control Axon: 6.07 ± 1.36 per 1000 spike; n = 11; Axon with Swelling: 1.12 ± 0.41 per 1000 spike; n = 9; Mann–Whitney U -test, P = 0.001; Fig. 1c ). A large proportion of axons with swellings propagated action potentials with very high fidelity (having very few axonal failures), whereas only the occasional axon without a swelling propagated with similar fidelity (9.1% of control axons were high-fidelity; 55.5% of axons with swellings were high-fidelity; Mann–Whitney U -test, P = 0.05; Fig. 1d ). We found no differences in the axosomatic delay between recordings in axons with swelling and control axons (Fig. 1e and Supplementary Fig. 2 ), suggesting that swellings do not change the propagation speed of action potentials, or at least not over the relatively short distances that we have measured (Supplementary Fig. 2 and Supplementary Table 1 ). Taken together, these data argue that axonal swellings enhance rather than impair axonal propagation. Fig. 1: Axonal swellings are associated with improved axonal propagation of action potentials. a Representative images of a Purkinje cell with placement of electrodes showing simultaneous dual recording from Purkinje cells soma (left electrode) and axon (right electrode) from a control axon (top) and an axon with a swelling (bottom; asterisk indicates swelling). Images were acquired after each simultaneous dual recording. Scale bar, 25 μm. b Representative traces of dual recordings from soma (black) and axon corresponding to Purkinje<|im_end|> <|im_start|>assistant Researchers at McGill University have shown that a brain cell structure previously thought to be pathological in fact enhances cells' ability to transmit information and correlates with better learning on certain tasks. In a study published in Nature Communications, the team investigated swellings that occur in the axons of Purkinje cells in the cerebellum. In results that contradict established expectations, they found that axons with swellings did a better job of conducting electrical signals than those without. "These are the kind of results where you really scratch your head and think, "Let's check that again,'" says senior author Alanna Watt, an Associate Professor in the Department of Biology. "We really thought when we started this that we were going to characterize and measure how an axon fails—and that's not at all what we saw." Experimental data confounds expectations Swellings in axons—the long, slender fibers through which nerve cells transmit information to other cells—are observed in normal development and in disease. Increased numbers of axonal swellings are seen in various neurodegenerative disorders, which has led scientists to believe swellings have a negative impact on axon function. While computer modeling lends some support to this view, the McGill research team was the first to test the theory with measurements on actual nerve cells. Using a technically challenging combination of two-photon microscopy and electrophysiology to measure electrical activity simultaneously at different locations within cells, the researchers demonstrated that the presence of axonal swellings in mouse Purkinje cells had no detrimental impact on the rate at which those cells produced signals (the firing rate) or on the speed at which axons transmitted the signals. Remarkably, the experiments also showed that at peak firing rates axons with swellings were less likely to fail than those without. Role in neurodegenerative disease called into question In a surprising twist, the McGill researchers found that they were able to stimulate the formation of axonal swellings by introducing a pharmaceutical that blocked the transmission of electrical signals in nerve cells, especially in the axons. Seeing axonal swellings form within a matter of hours when the axon of a nerve cell had been compromised in this way challenges previous assumptions about the role of axonal swellings in neurodegenerative disorders. As Watt explains, the discovery leaves room for the possibility that swellings represent a self-repair mechanism rather than a deterioration caused by disease. "Transmitting information by way of electrical signals is the most important thing that an axon does," she says. "If it starts to fail at that job, it makes sense that there's a mechanism that tries to prevent that." Behavioral analysis confirms swellings' positive impact In addition to their investigations at the cellular level, the researchers sought to determine the impact of axonal swellings on overall brain function. The team used three tests designed to assess motor learning and coordination, which are among the cerebellum's most important roles. Supported by modeling to account for the natural variation between individual learning abilities, the results revealed a positive correlation between the abundance of axonal swellings in cerebellar Purkinje cells and motor learning abilities. "We think the link is probably an indirect one," Watt explains. "The learning is probably happening somewhere else, but the information is being relayed more reliably and therefore we see an improvement." <|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 Proton transport plays an important role in many biological processes due to the ability of protons to rapidly translocate along chains of hydrogen-bonded water molecules. Molecular dynamics simulations have predicted that confinement in hydrophobic nanochannels should enhance the rate of proton transport. Here, we show that 0.8-nm-diameter carbon nanotube porins, which promote the formation of one-dimensional water wires, can support proton transport rates exceeding those of bulk water by an order of magnitude. The transport rates in these narrow nanotube pores also exceed those of biological channels and Nafion. With larger 1.5-nm-diameter nanotube porins, proton transport rates comparable to bulk water are observed. We also show that the proton conductance of these channels can be modulated by the presence of Ca 2+ ions. Our results illustrate the potential of small-diameter carbon nanotube porins as a proton conductor material and suggest that strong spatial confinement is a key factor in enabling efficient proton transport. Main In 1806, Theodor von Grotthuss had the brilliant insight that water decomposes into charged particles that move quickly along chains of water molecules 1 . Two centuries after this seminal discovery, the Grotthuss ‘hop-turn’ mechanism, which involves fast proton hopping along hydrogen-bonded water molecule chains followed by the reorientation of water molecules, is still accepted as the dominant mechanism that gives protons in aqueous solutions a diffusion coefficient that is an order of magnitude greater than any other ion 2 . Such high mobility undoubtedly contributes to the significant role that protons and proton channels play in biological processes. For instance, the proton motive force is a major factor in energy production and energy storage in bacteria 3 , proton channels are activated during respiratory bursts in phagocytes 4 , proton conductance is required during spreading of neutrophils 5 and proton channels are expressed at high density in alveolar epithelial cells, contributing to the elimination of CO 2 by the lungs 6 . Some of the mediators for biological proton flux include Gramicidin A (gramA) 7 , the M2 proton channel of the influenza A virus 8 , the MotA flagellar motor torque generator 9 and the F 0 sector of ATPase 10 . Although these proteins have markedly different structures and functionality, they often translocate protons along hydrogen-bonded chains of water molecules. Despite the clear prominence of the Grotthuss mechanism in biological systems, and the importance of proton transport in applications such as proton-exchange fuel cells 11 , the implementation of efficient proton transport in artificial systems has not been very successful. So far, highly hydrated Nafion membranes remain one of the most efficient man-made proton conductors, yet their intrinsic proton conductivity is still lower than that of gramA 12 . One of the major reasons why synthetic proton conductors have lagged behind their biological counterparts is the difficulty of forming and maintaining the structured one-dimensional (1D) water chains that enable proton hopping. In Nafion the water molecules are retained by interactions with the highly charged surface groups of the polymer, which is a less efficient way to form hydrogen-bonded water chains than confining water in sub-1-nm pores, as in biological proton wires. Of all of the man-made materials, the narrow hydrophobic inner pores of carbon nanotubes (CNTs) hold the most promise to deliver the level of confinement and weak interaction with water molecules that facilitate the formation of 1D hydrogen-bonded water chains 13 , 14 . The electrophoretic proton transport rates in long 1.5-nm-diameter CNTs have been investigated, and reported to be just below those of gramA 15 . Notably, molecular dynamics (MD) simulations 16 showed that water in 0.8-nm-diameter (6,6) CNTs would create such 1D wires and these channels are predicted to exhibit proton transport rates much faster than those of bulk water 17 . Despite significant effort in CNT transport studies 18 , 19 , these predictions have proven to be hard to validate, mainly because of the difficulties in measuring transport through sub-1-nm diameter CNT pores. We have recently reported a simple and versatile experimental system for studying transport in CNT porins (CNTPs)—short carbon nanotubes embedded in the lipid membrane that mimic biological ion channels ( Fig. 1a ) 20 . Figure 1: Sub-1-nm CNTPs. a , Schematics showing CNTPs inserted into a liposome. b , c , Molecular models showing water molecules in the inner pores of two CNTPs of different diameters: 1.5 nm ( b ), and 0.8 nm ( c ). d , e , 3D fluorescence spectra of the uncut ( d ) and cut ( e ) 0.8-nm-diameter CNTs showing predominance of (8,4) CNT species after sonication cutting. f , Histogram showing the lengths of the CNTPs inserted into liposomes as measured from cryogenic TEM images. The red solid line indicates a fit to a log-normal distribution (mean value: 10.6 ± 0.9 nm). The insets show representative cryogenic TEM images of CNTPs in liposomes. Red frames outline locations of CNTPs. g , Raman spectrum of the CNTP/lipid suspension after 16 h of sonication-assisted cutting for 0.8-nm-diameter porins. The broad DOPC lipid signal peak between 1,000–3,000 cm –1 indicates that CNTPs are sufficiently solubilized by the lipid. Inset: Magnified view of the radial breathing mode (RBM) region of the spectrum (100–350 cm –1 ). Full size image In this report, we focus our efforts on studying proton diffusion through CNTPs of two different pore diameters. The smaller porins with diameters of only 0.8 nm show extraordinarily fast proton transport rates, exceeding those of bulk water by an order of magnitude and matching the predictions of MD simulations. Notably, we did not observe significant enhancement in the larger 1.5-nm-diameter pores, indicating that enhanced proton transport requires strong water confinement. We also show that, similar to biological systems, the proton conductance of these channels can be modulated by the presence of Ca 2+ ions, making these channels promising biomimetic artificial proton conductors. Synthesis of sub-1-nm CNTPs Although 1.5-nm-diameter CNTPs provide some degree of confinement (as we reported previously 20 ) they are not narrow enough to form 1D", "role": "user" }, { "content": "For the first time, Lawrence Livermore National Laboratory (LLNL) researchers have shown that carbon nanotubes as small as eight-tenths of a nanometer in diameter can transport protons faster than bulk water, by an order of magnitude. The research validates a 200-year old mechanism of proton transport. A nanometer is one billionth of a meter. By comparison, the diameter of a human hair is 20,000 nanometers. The transport rates in these nanotube pores, which form one-dimensional water wires, also exceed those of biological channels and man-made proton conductors, making carbon nanotubes the fastest known proton conductor. The research appears in the April 4 advanced online edition of the journal Nature Nanotechnology. Practical applications include proton exchange membranes, proton-based signaling in biological systems and the emerging field of proton bioelectronics (protonics). \"The cool thing about our results is that we found that when you squeeze water into the nanotube, protons move through that water even faster than through normal (bulk) water,\" said Aleksandr Noy, an LLNL biophysicist and a lead author of the paper. (Bulk water is similar to what you would find in a cup of water that is much bigger than the size of a single water molecule). The idea that protons travel fast in solutions by hopping along chains of hydrogen-bonded water molecules dates back 200 years to the work of Theodore von Grotthuss and still remains the foundation of the scientific understanding of proton transport. In the new research, LLNL researchers used carbon nanotube pores to line up water molecules into perfect one-dimensional chains and showed that they allow proton transport rates to approach the ultimate limits for the Grotthuss transport mechanism. \"The possibility to achieve fast proton transport by changing the degree of water confinement is exciting,\" Noy said. \"So far, the man-made proton conductors, such as polymer Nafion, use a different principle to enhance the proton transport. We have mimicked the way biological systems enhance the proton transport, took it to the extreme, and now our system realizes the ultimate limit of proton conductivity in a nanopore.\" Of all man-made materials, the narrow hydrophobic inner pores of carbon nanotubes (CNT) hold the most promise to deliver the level of confinement and weak interactions with water molecules that facilitate the formation of one-dimensional hydrogen-bonded water chains that enhance proton transport. Earlier molecular dynamic simulations showed that water in 0.8 nm diameter carbon nanotubes would create such water wires and predicted that these channels would exhibit proton transport rates that would be much faster than those of bulk water. Ramya Tunuguntla, an LLNL postdoctoral researcher and the first author on the paper, said that despite significant efforts in carbon nanotube transport studies, these predictions proved to be hard to validate, mainly because of the difficulties in creating sub-1-nm diameter CNT pores. However, the Lawrence Livermore team along with colleagues from the Lawrence Berkeley National Lab and UC Berkeley was able to create a simple and versatile experimental system for studying transport in ultra-narrow CNT pores. They used carbon nanotube porins (CNTPs), a technology they developed earlier at LLNL, which uses carbon nanotubes embedded in the lipid membrane to mimic biological ion channel functionality. The key breakthrough was the creation of nanotube porins with a diameter of less than 1 nm, which allowed researchers for the first time to achieve true one-dimensional water confinement. ", "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 Proton transport plays an important role in many biological processes due to the ability of protons to rapidly translocate along chains of hydrogen-bonded water molecules. Molecular dynamics simulations have predicted that confinement in hydrophobic nanochannels should enhance the rate of proton transport. Here, we show that 0.8-nm-diameter carbon nanotube porins, which promote the formation of one-dimensional water wires, can support proton transport rates exceeding those of bulk water by an order of magnitude. The transport rates in these narrow nanotube pores also exceed those of biological channels and Nafion. With larger 1.5-nm-diameter nanotube porins, proton transport rates comparable to bulk water are observed. We also show that the proton conductance of these channels can be modulated by the presence of Ca 2+ ions. Our results illustrate the potential of small-diameter carbon nanotube porins as a proton conductor material and suggest that strong spatial confinement is a key factor in enabling efficient proton transport. Main In 1806, Theodor von Grotthuss had the brilliant insight that water decomposes into charged particles that move quickly along chains of water molecules 1 . Two centuries after this seminal discovery, the Grotthuss ‘hop-turn’ mechanism, which involves fast proton hopping along hydrogen-bonded water molecule chains followed by the reorientation of water molecules, is still accepted as the dominant mechanism that gives protons in aqueous solutions a diffusion coefficient that is an order of magnitude greater than any other ion 2 . Such high mobility undoubtedly contributes to the significant role that protons and proton channels play in biological processes. For instance, the proton motive force is a major factor in energy production and energy storage in bacteria 3 , proton channels are activated during respiratory bursts in phagocytes 4 , proton conductance is required during spreading of neutrophils 5 and proton channels are expressed at high density in alveolar epithelial cells, contributing to the elimination of CO 2 by the lungs 6 . Some of the mediators for biological proton flux include Gramicidin A (gramA) 7 , the M2 proton channel of the influenza A virus 8 , the MotA flagellar motor torque generator 9 and the F 0 sector of ATPase 10 . Although these proteins have markedly different structures and functionality, they often translocate protons along hydrogen-bonded chains of water molecules. Despite the clear prominence of the Grotthuss mechanism in biological systems, and the importance of proton transport in applications such as proton-exchange fuel cells 11 , the implementation of efficient proton transport in artificial systems has not been very successful. So far, highly hydrated Nafion membranes remain one of the most efficient man-made proton conductors, yet their intrinsic proton conductivity is still lower than that of gramA 12 . One of the major reasons why synthetic proton conductors have lagged behind their biological counterparts is the difficulty of forming and maintaining the structured one-dimensional (1D) water chains that enable proton hopping. In Nafion the water molecules are retained by interactions with the highly charged surface groups of the polymer, which is a less efficient way to form hydrogen-bonded water chains than confining water in sub-1-nm pores, as in biological proton wires. Of all of the man-made materials, the narrow hydrophobic inner pores of carbon nanotubes (CNTs) hold the most promise to deliver the level of confinement and weak interaction with water molecules that facilitate the formation of 1D hydrogen-bonded water chains 13 , 14 . The electrophoretic proton transport rates in long 1.5-nm-diameter CNTs have been investigated, and reported to be just below those of gramA 15 . Notably, molecular dynamics (MD) simulations 16 showed that water in 0.8-nm-diameter (6,6) CNTs would create such 1D wires and these channels are predicted to exhibit proton transport rates much faster than those of bulk water 17 . Despite significant effort in CNT transport studies 18 , 19 , these predictions have proven to be hard to validate, mainly because of the difficulties in measuring transport through sub-1-nm diameter CNT pores. We have recently reported a simple and versatile experimental system for studying transport in CNT porins (CNTPs)—short carbon nanotubes embedded in the lipid membrane that mimic biological ion channels ( Fig. 1a ) 20 . Figure 1: Sub-1-nm CNTPs. a , Schematics showing CNTPs inserted into a liposome. b , c , Molecular models showing water molecules in the inner pores of two CNTPs of different diameters: 1.5 nm ( b ), and 0.8 nm ( c ). d , e , 3D fluorescence spectra of the uncut ( d ) and cut ( e ) 0.8-nm-diameter CNTs showing predominance of (8,4) CNT species after sonication cutting. f , Histogram showing the lengths of the CNTPs inserted into liposomes as measured from cryogenic TEM images. The red solid line indicates a fit to a log-normal distribution (mean value: 10.6 ± 0.9 nm). The insets show representative cryogenic TEM images of CNTPs in liposomes. Red frames outline locations of CNTPs. g , Raman spectrum of the CNTP/lipid suspension after 16 h of sonication-assisted cutting for 0.8-nm-diameter porins. The broad DOPC lipid signal peak between 1,000–3,000 cm –1 indicates that CNTPs are sufficiently solubilized by the lipid. Inset: Magnified view of the radial breathing mode (RBM) region of the spectrum (100–350 cm –1 ). Full size image In this report, we focus our efforts on studying proton diffusion through CNTPs of two different pore diameters. The smaller porins with diameters of only 0.8 nm show extraordinarily fast proton transport rates, exceeding those of bulk water by an order of magnitude and matching the predictions of MD simulations. Notably, we did not observe significant enhancement in the larger 1.5-nm-diameter pores, indicating that enhanced proton transport requires strong water confinement. We also show that, similar to biological systems, the proton conductance of these channels can be modulated by the presence of Ca 2+ ions, making these channels promising biomimetic artificial proton conductors. Synthesis of sub-1-nm CNTPs Although 1.5-nm-diameter CNTPs provide some degree of confinement (as we reported previously 20 ) they are not narrow enough to form 1D<|im_end|> <|im_start|>assistant For the first time, Lawrence Livermore National Laboratory (LLNL) researchers have shown that carbon nanotubes as small as eight-tenths of a nanometer in diameter can transport protons faster than bulk water, by an order of magnitude. The research validates a 200-year old mechanism of proton transport. A nanometer is one billionth of a meter. By comparison, the diameter of a human hair is 20,000 nanometers. The transport rates in these nanotube pores, which form one-dimensional water wires, also exceed those of biological channels and man-made proton conductors, making carbon nanotubes the fastest known proton conductor. The research appears in the April 4 advanced online edition of the journal Nature Nanotechnology. Practical applications include proton exchange membranes, proton-based signaling in biological systems and the emerging field of proton bioelectronics (protonics). "The cool thing about our results is that we found that when you squeeze water into the nanotube, protons move through that water even faster than through normal (bulk) water," said Aleksandr Noy, an LLNL biophysicist and a lead author of the paper. (Bulk water is similar to what you would find in a cup of water that is much bigger than the size of a single water molecule). The idea that protons travel fast in solutions by hopping along chains of hydrogen-bonded water molecules dates back 200 years to the work of Theodore von Grotthuss and still remains the foundation of the scientific understanding of proton transport. In the new research, LLNL researchers used carbon nanotube pores to line up water molecules into perfect one-dimensional chains and showed that they allow proton transport rates to approach the ultimate limits for the Grotthuss transport mechanism. "The possibility to achieve fast proton transport by changing the degree of water confinement is exciting," Noy said. "So far, the man-made proton conductors, such as polymer Nafion, use a different principle to enhance the proton transport. We have mimicked the way biological systems enhance the proton transport, took it to the extreme, and now our system realizes the ultimate limit of proton conductivity in a nanopore." Of all man-made materials, the narrow hydrophobic inner pores of carbon nanotubes (CNT) hold the most promise to deliver the level of confinement and weak interactions with water molecules that facilitate the formation of one-dimensional hydrogen-bonded water chains that enhance proton transport. Earlier molecular dynamic simulations showed that water in 0.8 nm diameter carbon nanotubes would create such water wires and predicted that these channels would exhibit proton transport rates that would be much faster than those of bulk water. Ramya Tunuguntla, an LLNL postdoctoral researcher and the first author on the paper, said that despite significant efforts in carbon nanotube transport studies, these predictions proved to be hard to validate, mainly because of the difficulties in creating sub-1-nm diameter CNT pores. However, the Lawrence Livermore team along with colleagues from the Lawrence Berkeley National Lab and UC Berkeley was able to create a simple and versatile experimental system for studying transport in ultra-narrow CNT pores. They used carbon nanotube porins (CNTPs), a technology they developed earlier at LLNL, which uses carbon nanotubes embedded in the lipid membrane to mimic biological ion channel functionality. The key breakthrough was the creation of nanotube porins with a diameter of less than 1 nm, which allowed researchers for the first time to achieve true one-dimensional water confinement. <|im_end|>

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2,157

[ { "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 over half a century, worldwide growth in affluence has continuously increased resource use and pollutant emissions far more rapidly than these have been reduced through better technology. The affluent citizens of the world are responsible for most environmental impacts and are central to any future prospect of retreating to safer environmental conditions. We summarise the evidence and present possible solution approaches. Any transition towards sustainability can only be effective if far-reaching lifestyle changes complement technological advancements. However, existing societies, economies and cultures incite consumption expansion and the structural imperative for growth in competitive market economies inhibits necessary societal change. Introduction Recent scientists’ warnings confirm alarming trends of environmental degradation from human activity, leading to profound changes in essential life-sustaining functions of planet Earth 1 , 2 , 3 . The warnings surmise that humanity has failed to find lasting solutions to these changes that pose existential threats to natural systems, economies and societies and call for action by governments and individuals. The warnings aptly describe the problems, identify population, economic growth and affluence as drivers of unsustainable trends and acknowledge that humanity needs to reassess the role of growth-oriented economies and the pursuit of affluence 1 , 2 . However, they fall short of clearly identifying the underlying forces of overconsumption and of spelling out the measures that are needed to tackle the overwhelming power of consumption and the economic growth paradigm 4 . This perspective synthesises existing knowledge and recommendations from the scientific community. We provide evidence from the literature that consumption of affluent households worldwide is by far the strongest determinant and the strongest accelerator of increases of global environmental and social impacts. We describe the systemic drivers of affluent overconsumption and synthesise the literature that provides possible solutions by reforming or changing economic systems. These solution approaches range from reformist to radical ideas, including degrowth, eco-socialism and eco-anarchism. Based on these insights, we distil recommendations for further research in the final section. Affluence as a driver of environmental and social impacts The link between consumption and impacts There exists a large body of literature in which the relationship between environmental, resource and social impacts on one hand, and possible explanatory variables on the other, is investigated. We review and summarise those studies that holistically assess the impact of human activities, in the sense that impacts are not restricted to the home, city, or territory of the individuals, but instead are counted irrespective of where they occur. Such an assessment perspective is usually referred to as consumption-based accounting, or footprinting 5 . Allocating environmental impacts to consumers is consistent with the perspective that consumers are the ultimate drivers of production, with their purchasing decisions setting in motion a series of trade transactions and production activities, rippling along complex international supply-chain networks 5 . However, allocating impacts to consumers does not necessarily imply a systemic causal understanding of which actor should be held most responsible for these impacts. Responsibility may lie with the consumer or with an external actor, like the state, or in structural relations between actors. Scholars of sustainable consumption have shown that consumers often have little control over environmentally damaging decisions along supply chains 6 , however they often do have control over making a consumption decision in the first place. Whilst in Keynesian-type economics consumer demand drives production, Marxian political economics as well as environmental sociology views the economy as supply dominated 7 . In this paper, we highlight the measurement of environmental impacts of consumption, while noting that multiple actors bear responsibility. Holistic studies of the environmental or social consequences of consumption usually involve the use of life-cycle assessment or input-output analysis that do not only account for direct (on-site, within-territory) but importantly also include indirect impacts occurring along global and complete supply chains 8 , 9 . The use of such methods is important, because failing to detect the outsourcing of indirect impacts (also called spill overs or leakage) has the potential to seriously undermine global environmental abatement efforts, e.g. on climate change 10 . A significant proportionality between consumption and impact exists for a large range of environmental, resource and social indicators. The implications of consumption on scarce energy resources emerged already in the 1970s and was confirmed by many consumption-based analyses on indicators as varied as CO 2 emissions, raw materials, air pollution, biodiversity, nitrogen emissions, scarce water use or energy 5 , 11 . Many of these studies employed multiple regression or similar techniques, yielding clear evidence for our first finding: that consumption is by far the strongest determinant of global impacts, dwarfing other socio-economic–demographic factors such as age, household size, qualification or dwelling structure 12 , 13 , 14 , 15 . Whilst the strength of the proportionality between consumption and impact decreases slightly towards higher incomes (measured by so-called elasticities), consumption was found to be a consistently positive driver. In other words, the impact intensity of consumption decreases, but absolute impacts increase towards higher consumption. Absolute decoupling, let alone an inverted-U-type Kuznets relationship, does not occur from a consumption-based accounting perspective 11 , 16 , 17 . For some social indicators, causal associations between consumption and impact are weak or non-existent. For example, withdrawing consumption from countries with unequal wages, child labour, corruption or severe occupational hazards may not influence those conditions, and might even exacerbate social problems. Footprint studies on these indicators nevertheless characterise consumers of commodities from socially problematic origins as being implicated with detrimental impacts 9 , 18 , 19 , 20 . Trends Many indicators of global environmental and social impacts have been monitored over time, and time series data exist 5 . Numerous global studies decomposing time series of footprints of consumption into drivers of trends have been carried out over the past decades, for example on greenhouse-gas emissions, energy use, water use, materials or mercury emissions. These studies routinely decompose global impact trends into effects due to changes in a number of factors, such as technology, the input structure of", "role": "user" }, { "content": "A group of researchers, led by a UNSW sustainability scientist, have reviewed existing academic discussions on the link between wealth, economy and associated impacts, reaching a clear conclusion: technology will only get us so far when working towards sustainability—we need far-reaching lifestyle changes and different economic paradigms. In their review, published today in Nature Communications and entitled Scientists' Warning on Affluence, the researchers have summarized the available evidence, identifying possible solution approaches. \"Recent scientists' warnings have done a great job at describing the many perils our natural world is facing through crises in climate, biodiversity and food systems, to name but a few,\" says lead author Professor Tommy Wiedmann from UNSW Engineering. \"However, none of these warnings has explicitly considered the role of growth-oriented economies and the pursuit of affluence. In our scientists' warning, we identify the underlying forces of overconsumption and spell out the measures that are needed to tackle the overwhelming 'power' of consumption and the economic growth paradigm—that's the gap we fill. \"The key conclusion from our review is that we cannot rely on technology alone to solve existential environmental problems—like climate change, biodiversity loss and pollution—but that we also have to change our affluent lifestyles and reduce overconsumption, in combination with structural change.\" During the past 40 years, worldwide wealth growth has continuously outpaced any efficiency gains. \"Technology can help us to consume more efficiently, i.e. to save energy and resources, but these technological improvements cannot keep pace with our ever-increasing levels of consumption,\" Prof Wiedmann says. Reducing overconsumption in the world's richest Co-author Julia Steinberger, Professor of Ecological Economics at the University of Leeds, says affluence is often portrayed as something to aspire to. \"But our paper has shown that it's actually dangerous and leads to planetary-scale destruction. To protect ourselves from the worsening climate crisis, we must reduce inequality and challenge the notion that riches, and those who possess them, are inherently good.\" In fact, the researchers say the world's affluent citizens are responsible for most environmental impacts and are central to any future prospect of retreating to safer conditions. \"Consumption of affluent households worldwide is by far the strongest determinant—and the strongest accelerator—of increased global environmental and social impacts,\" co-author Lorenz Keysser from ETH Zurich says. \"Current discussions on how to address the ecological crises within science, policy making and social movements need to recognize the responsibility of the most affluent for these crises.\" The researchers say overconsumption and affluence need to be addressed through lifestyle changes. \"It's hardly ever acknowledged, but any transition towards sustainability can only be effective if technological advancements are complemented by far-reaching lifestyle changes,\" says co-author Manfred Lenzen, Professor of Sustainability Research at the University of Sydney. \"I am often asked to explain this issue at social gatherings. Usually I say that what we see or associate with our current environmental issues (cars, power, planes) is just the tip of our personal iceberg. It's all the stuff we consume and the environmental destruction embodied in that stuff that forms the iceberg's submerged part. Unfortunately, once we understand this, the implications for our lifestyle are often so confronting that denial kicks in.\" No level of growth is sustainable However, the scientists say responsibility for change doesn't just sit with individuals—broader structural changes are needed. \"Individuals' attempts at such lifestyle transitions may be doomed to fail, because existing societies, economies and cultures incentivise consumption expansion,\" Prof Wiedmann says. A change in economic paradigms is therefore sorely needed. \"The structural imperative for growth in competitive market economies leads to decision makers being locked into bolstering economic growth, and inhibiting necessary societal changes,\" Prof Wiedmann says. \"So, we have to get away from our obsession with economic growth—we really need to start managing our economies in a way that protects our climate and natural resources, even if this means less, no or even negative growth. \"In Australia, this discussion isn't happening at all—economic growth is the one and only mantra preached by both main political parties. It's very different in New Zealand—their Wellbeing Budget 2019 is one example of how government investment can be directed in a more sustainable direction, by transforming the economy rather than growing it.\" The researchers say that \"green growth\" or \"sustainable growth\" is a myth. \"As long as there is growth—both economically and in population—technology cannot keep up with reducing impacts, the overall environmental impacts with only increase,\" Prof Wiedmann says. One way to enforce these lifestyle changes could be to reduce overconsumption by the super-rich, e.g. through taxation policies. \"'Degrowth' proponents go a step further and suggest a more radical social change that leads away from capitalism to other forms of economic and social governance,\" Prof Wiedmann says. \"Policies may include, for example, eco-taxes, green investments, wealth redistribution through taxation and a maximum income, a guaranteed basic income and reduced working hours.\" Modeling an alternative future Prof Wiedmann's team now wants to model scenarios for sustainable transformations—that means exploring different pathways of development with a computer model to see what we need to do to achieve the best possible outcome. \"We have already started doing this with a recent piece of research that showed a fairer, greener and more prosperous Australia is possible—so long as political leaders don't focus just on economic growth. \"We hope that this review shows a different perspective on what matters, and supports us in overcoming deeply entrenched views on how humans have to dominate nature, and on how our economies have to grow ever more. We can't keep behaving as if we had a spare planet available.\" ", "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 over half a century, worldwide growth in affluence has continuously increased resource use and pollutant emissions far more rapidly than these have been reduced through better technology. The affluent citizens of the world are responsible for most environmental impacts and are central to any future prospect of retreating to safer environmental conditions. We summarise the evidence and present possible solution approaches. Any transition towards sustainability can only be effective if far-reaching lifestyle changes complement technological advancements. However, existing societies, economies and cultures incite consumption expansion and the structural imperative for growth in competitive market economies inhibits necessary societal change. Introduction Recent scientists’ warnings confirm alarming trends of environmental degradation from human activity, leading to profound changes in essential life-sustaining functions of planet Earth 1 , 2 , 3 . The warnings surmise that humanity has failed to find lasting solutions to these changes that pose existential threats to natural systems, economies and societies and call for action by governments and individuals. The warnings aptly describe the problems, identify population, economic growth and affluence as drivers of unsustainable trends and acknowledge that humanity needs to reassess the role of growth-oriented economies and the pursuit of affluence 1 , 2 . However, they fall short of clearly identifying the underlying forces of overconsumption and of spelling out the measures that are needed to tackle the overwhelming power of consumption and the economic growth paradigm 4 . This perspective synthesises existing knowledge and recommendations from the scientific community. We provide evidence from the literature that consumption of affluent households worldwide is by far the strongest determinant and the strongest accelerator of increases of global environmental and social impacts. We describe the systemic drivers of affluent overconsumption and synthesise the literature that provides possible solutions by reforming or changing economic systems. These solution approaches range from reformist to radical ideas, including degrowth, eco-socialism and eco-anarchism. Based on these insights, we distil recommendations for further research in the final section. Affluence as a driver of environmental and social impacts The link between consumption and impacts There exists a large body of literature in which the relationship between environmental, resource and social impacts on one hand, and possible explanatory variables on the other, is investigated. We review and summarise those studies that holistically assess the impact of human activities, in the sense that impacts are not restricted to the home, city, or territory of the individuals, but instead are counted irrespective of where they occur. Such an assessment perspective is usually referred to as consumption-based accounting, or footprinting 5 . Allocating environmental impacts to consumers is consistent with the perspective that consumers are the ultimate drivers of production, with their purchasing decisions setting in motion a series of trade transactions and production activities, rippling along complex international supply-chain networks 5 . However, allocating impacts to consumers does not necessarily imply a systemic causal understanding of which actor should be held most responsible for these impacts. Responsibility may lie with the consumer or with an external actor, like the state, or in structural relations between actors. Scholars of sustainable consumption have shown that consumers often have little control over environmentally damaging decisions along supply chains 6 , however they often do have control over making a consumption decision in the first place. Whilst in Keynesian-type economics consumer demand drives production, Marxian political economics as well as environmental sociology views the economy as supply dominated 7 . In this paper, we highlight the measurement of environmental impacts of consumption, while noting that multiple actors bear responsibility. Holistic studies of the environmental or social consequences of consumption usually involve the use of life-cycle assessment or input-output analysis that do not only account for direct (on-site, within-territory) but importantly also include indirect impacts occurring along global and complete supply chains 8 , 9 . The use of such methods is important, because failing to detect the outsourcing of indirect impacts (also called spill overs or leakage) has the potential to seriously undermine global environmental abatement efforts, e.g. on climate change 10 . A significant proportionality between consumption and impact exists for a large range of environmental, resource and social indicators. The implications of consumption on scarce energy resources emerged already in the 1970s and was confirmed by many consumption-based analyses on indicators as varied as CO 2 emissions, raw materials, air pollution, biodiversity, nitrogen emissions, scarce water use or energy 5 , 11 . Many of these studies employed multiple regression or similar techniques, yielding clear evidence for our first finding: that consumption is by far the strongest determinant of global impacts, dwarfing other socio-economic–demographic factors such as age, household size, qualification or dwelling structure 12 , 13 , 14 , 15 . Whilst the strength of the proportionality between consumption and impact decreases slightly towards higher incomes (measured by so-called elasticities), consumption was found to be a consistently positive driver. In other words, the impact intensity of consumption decreases, but absolute impacts increase towards higher consumption. Absolute decoupling, let alone an inverted-U-type Kuznets relationship, does not occur from a consumption-based accounting perspective 11 , 16 , 17 . For some social indicators, causal associations between consumption and impact are weak or non-existent. For example, withdrawing consumption from countries with unequal wages, child labour, corruption or severe occupational hazards may not influence those conditions, and might even exacerbate social problems. Footprint studies on these indicators nevertheless characterise consumers of commodities from socially problematic origins as being implicated with detrimental impacts 9 , 18 , 19 , 20 . Trends Many indicators of global environmental and social impacts have been monitored over time, and time series data exist 5 . Numerous global studies decomposing time series of footprints of consumption into drivers of trends have been carried out over the past decades, for example on greenhouse-gas emissions, energy use, water use, materials or mercury emissions. These studies routinely decompose global impact trends into effects due to changes in a number of factors, such as technology, the input structure of<|im_end|> <|im_start|>assistant A group of researchers, led by a UNSW sustainability scientist, have reviewed existing academic discussions on the link between wealth, economy and associated impacts, reaching a clear conclusion: technology will only get us so far when working towards sustainability—we need far-reaching lifestyle changes and different economic paradigms. In their review, published today in Nature Communications and entitled Scientists' Warning on Affluence, the researchers have summarized the available evidence, identifying possible solution approaches. "Recent scientists' warnings have done a great job at describing the many perils our natural world is facing through crises in climate, biodiversity and food systems, to name but a few," says lead author Professor Tommy Wiedmann from UNSW Engineering. "However, none of these warnings has explicitly considered the role of growth-oriented economies and the pursuit of affluence. In our scientists' warning, we identify the underlying forces of overconsumption and spell out the measures that are needed to tackle the overwhelming 'power' of consumption and the economic growth paradigm—that's the gap we fill. "The key conclusion from our review is that we cannot rely on technology alone to solve existential environmental problems—like climate change, biodiversity loss and pollution—but that we also have to change our affluent lifestyles and reduce overconsumption, in combination with structural change." During the past 40 years, worldwide wealth growth has continuously outpaced any efficiency gains. "Technology can help us to consume more efficiently, i.e. to save energy and resources, but these technological improvements cannot keep pace with our ever-increasing levels of consumption," Prof Wiedmann says. Reducing overconsumption in the world's richest Co-author Julia Steinberger, Professor of Ecological Economics at the University of Leeds, says affluence is often portrayed as something to aspire to. "But our paper has shown that it's actually dangerous and leads to planetary-scale destruction. To protect ourselves from the worsening climate crisis, we must reduce inequality and challenge the notion that riches, and those who possess them, are inherently good." In fact, the researchers say the world's affluent citizens are responsible for most environmental impacts and are central to any future prospect of retreating to safer conditions. "Consumption of affluent households worldwide is by far the strongest determinant—and the strongest accelerator—of increased global environmental and social impacts," co-author Lorenz Keysser from ETH Zurich says. "Current discussions on how to address the ecological crises within science, policy making and social movements need to recognize the responsibility of the most affluent for these crises." The researchers say overconsumption and affluence need to be addressed through lifestyle changes. "It's hardly ever acknowledged, but any transition towards sustainability can only be effective if technological advancements are complemented by far-reaching lifestyle changes," says co-author Manfred Lenzen, Professor of Sustainability Research at the University of Sydney. "I am often asked to explain this issue at social gatherings. Usually I say that what we see or associate with our current environmental issues (cars, power, planes) is just the tip of our personal iceberg. It's all the stuff we consume and the environmental destruction embodied in that stuff that forms the iceberg's submerged part. Unfortunately, once we understand this, the implications for our lifestyle are often so confronting that denial kicks in." No level of growth is sustainable However, the scientists say responsibility for change doesn't just sit with individuals—broader structural changes are needed. "Individuals' attempts at such lifestyle transitions may be doomed to fail, because existing societies, economies and cultures incentivise consumption expansion," Prof Wiedmann says. A change in economic paradigms is therefore sorely needed. "The structural imperative for growth in competitive market economies leads to decision makers being locked into bolstering economic growth, and inhibiting necessary societal changes," Prof Wiedmann says. "So, we have to get away from our obsession with economic growth—we really need to start managing our economies in a way that protects our climate and natural resources, even if this means less, no or even negative growth. "In Australia, this discussion isn't happening at all—economic growth is the one and only mantra preached by both main political parties. It's very different in New Zealand—their Wellbeing Budget 2019 is one example of how government investment can be directed in a more sustainable direction, by transforming the economy rather than growing it." The researchers say that "green growth" or "sustainable growth" is a myth. "As long as there is growth—both economically and in population—technology cannot keep up with reducing impacts, the overall environmental impacts with only increase," Prof Wiedmann says. One way to enforce these lifestyle changes could be to reduce overconsumption by the super-rich, e.g. through taxation policies. "'Degrowth' proponents go a step further and suggest a more radical social change that leads away from capitalism to other forms of economic and social governance," Prof Wiedmann says. "Policies may include, for example, eco-taxes, green investments, wealth redistribution through taxation and a maximum income, a guaranteed basic income and reduced working hours." Modeling an alternative future Prof Wiedmann's team now wants to model scenarios for sustainable transformations—that means exploring different pathways of development with a computer model to see what we need to do to achieve the best possible outcome. "We have already started doing this with a recent piece of research that showed a fairer, greener and more prosperous Australia is possible—so long as political leaders don't focus just on economic growth. "We hope that this review shows a different perspective on what matters, and supports us in overcoming deeply entrenched views on how humans have to dominate nature, and on how our economies have to grow ever more. We can't keep behaving as if we had a spare planet available." <|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 A class of multilayered functional materials has recently emerged in which the component atomic layers are held together by weak van der Waals forces that preserve the structural integrity and physical properties of each layer. An exemplar of such a structure is a transistor device in which relativistic Dirac fermions can resonantly tunnel through a boron nitride barrier, a few atomic layers thick, sandwiched between two graphene electrodes. An applied magnetic field quantizes graphene’s gapless conduction and valence band states into discrete Landau levels, allowing us to resolve individual inter-Landau-level transitions and thereby demonstrate that the energy, momentum and chiral properties of the electrons are conserved in the tunnelling process. We also demonstrate that the change in the semiclassical cyclotron trajectories, following an inter-layer tunnelling event, is analogous to the case of intra-layer Klein tunnelling. Main An electron moving through the hexagonal crystal structure of graphene is not only quasi-relativistic but also exhibits chirality 1 . The chirality originates from the diatomic unit cell of the graphene crystal lattice and means that the amplitude of the electron wavefunction is intrinsically coupled to the direction of motion. This gives rise to the phenomenon of Klein tunnelling, whereby an electron can pass with unity transmission through a potential barrier formed in the graphene layer 2 , 3 . In principle, chirality should also affect the properties of devices in which electrons tunnel between graphene layers. To investigate this effect, we focus on a van der Waals heterostructure 4 in which Dirac fermions can resonantly tunnel between two graphene electrodes separated by a hexagonal boron nitride tunnel barrier 5 , 6 , 7 , 8 . Recent work has demonstrated that even a small misalignment of the crystalline lattices of the two graphene electrodes lowers the translation symmetry in the plane of the tunnel barrier and gives rise to an impulse which modifies the dynamics of the tunnelling electron 6 , 7 , 9 , 10 , 11 , 12 . By applying a magnetic field perpendicular to the layers we show that electron tunnelling is governed by the laws of conservation of energy and in-plane momentum, as was demonstrated for the case of inter-Landau-level (inter-LL) tunnelling between two quantum wells in III–V semiconductor heterostructures 13 , 14 . Here, our measurements on electron tunnelling between two graphene layers reveal an additional phenomenon, namely, chirality, and its enhancement by the quantizing magnetic field. Our device, with bias, V b , and gate, V g , voltages applied, is shown schematically in Fig. 1a . It consists of a four-layer thick ( d = 1.4 nm) hexagonal boron nitride (hBN) tunnel barrier 15 sandwiched between two high-purity crystalline graphene electrodes. The active area of the device, in which tunnelling occurs, is 100 μm 2 . The lower graphene electrode sits on an atomically flat hBN layer (lower yellow region in Fig. 1a ), directly above a SiO 2 /n-Si substrate, in which the doped Si layer acts as the gate electrode and the oxide thickness is 300 nm. Our device is thus a graphene–boron nitride analogue of an independently contacted GaAs/AlGaAs double quantum well structure with back gate 13 . The device fabrication is described in the methods section of ref. 6 . The two graphene lattices are intentionally aligned to within an angle of 1° (see ref. 6 for details). However, even this slight misalignment, or ‘twist angle’, θ , leads to a significant k -space displacement of magnitude Δ K = | ΔK ± | = | K b ± − K t ± | = 2sin( θ /2) | K b ± | of the Dirac cones at the Brillouin zone corners 16 , 17 , 18 , 19 (see Figs 1b and 2a , insets). This displacement induces an impulse on a tunnelling electron and has a large effect on the measured current–voltage characteristics and their magnetic field dependence. Figure 1: Device structure and misaligned Brillouin zones. a , Schematic of the device showing the two misaligned graphene lattices (bottom, red and top, blue) separated by a boron nitride tunnel barrier (upper yellow region). An optical micrograph is shown in Supplementary Fig. 1 . b , Dashed black lines show the Brillouin zone boundary for electrons in the bottom graphene layer. Red arrows show the vector positions of the Dirac points K b ± (red circles) relative to the Γ point. Blue arrows show the positions of the Dirac points in the top layer, K t ± (blue circles), misoriented at an angle θ to the bottom layer. Full size image Figure 2: Magnetic field-induced resonances in the conductance. a , I ( V b ) curves measured when V g = 0 for B = 0 (black dashed) and 4 T (red solid), the latter offset by 7.5 μA for clarity. Insets i and ii show the relative energies of the Dirac cones, displaced by Δ K , in the bottom (red) and top (blue) electrodes at the voltages V 1 and V 2 marked by the labelled vertical arrows. The intersections of the cones are shown by the thick yellow curves. The Fermi circles of the two layers are shown in white. b , Differential conductance, G ( V b ), measured at V g = −40 V (blue lower curve), V g = 0 V (red middle curve), and V g = 40 V (green upper curve) when B = 4 T and temperature T = 4 K. Red and green curves are offset by 250 μS and 350 μS, respectively (that is, dotted lines mark G = 0 for the three curves). Red horizontal bars in a , b mark the V b > 0 region where conductance peaks can be observed when V g = 0. Full size image Figure 2a (black dashed curve) shows the measured current–voltage curve, I ( V b ), at V g = 0 in the absence of a magnetic field. The current increases at a threshold bias voltage", "role": "user" }, { "content": "(Phys.org)—A team of researches affiliated with several institutions in the U.K. and Russia has found that chirality in graphene impacts current flow. In their paper published in the journal Nature Physics, the team describes how they developed a method for both detecting and measuring the impact of chirality in graphene and why they believe it could lead to better tunneling electronics devices. Electrons and other particles have a property that is called chirality, where they exist as being either left or right-handed. In addition, when they exist in an electronic state, it can also be defined as chiral. In this new experiment, the researchers found that the chirality of electrons can have an impact on current flow—they made this discovery by creating a small testing material made of a sheet of four atom thick boron nitride placed between two sheets of graphene. This setup allowed for creating a very controllable type of current flow—when voltage was applied to one of the sheets of graphene, it tunneled its way through the boron nitride to the other graphene sheet where it could be removed. That allowed for noting the right or left-handedness of the electrons as they tunneled through the borone nitride sheet and the states they ended up in. The researchers note that right-handed electrons tended to prefer to make it to right-hand states and vice-versa for the left-handed electrons. By applying voltage, the team was able to \"see\" the chirality of the tunneling electrons and its impact on current flow. They also found that applying a magnetic field at a ninety degree angle to the material allowed for seeing the impact even better—doing so served to quantize the motion of the electron, which showed up on a measuring device as energy levels that were unequally spaced apart—a ladder effect. Doing so allowed them to demonstrate that spin, energy and momentum were all conserved in the tunneling process, as was their chirality. The researchers suggest their findings could lead to efforts that are involved in making better tunneling electronic devices and perhaps to a whole new class of chiralitic electronics. ", "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 class of multilayered functional materials has recently emerged in which the component atomic layers are held together by weak van der Waals forces that preserve the structural integrity and physical properties of each layer. An exemplar of such a structure is a transistor device in which relativistic Dirac fermions can resonantly tunnel through a boron nitride barrier, a few atomic layers thick, sandwiched between two graphene electrodes. An applied magnetic field quantizes graphene’s gapless conduction and valence band states into discrete Landau levels, allowing us to resolve individual inter-Landau-level transitions and thereby demonstrate that the energy, momentum and chiral properties of the electrons are conserved in the tunnelling process. We also demonstrate that the change in the semiclassical cyclotron trajectories, following an inter-layer tunnelling event, is analogous to the case of intra-layer Klein tunnelling. Main An electron moving through the hexagonal crystal structure of graphene is not only quasi-relativistic but also exhibits chirality 1 . The chirality originates from the diatomic unit cell of the graphene crystal lattice and means that the amplitude of the electron wavefunction is intrinsically coupled to the direction of motion. This gives rise to the phenomenon of Klein tunnelling, whereby an electron can pass with unity transmission through a potential barrier formed in the graphene layer 2 , 3 . In principle, chirality should also affect the properties of devices in which electrons tunnel between graphene layers. To investigate this effect, we focus on a van der Waals heterostructure 4 in which Dirac fermions can resonantly tunnel between two graphene electrodes separated by a hexagonal boron nitride tunnel barrier 5 , 6 , 7 , 8 . Recent work has demonstrated that even a small misalignment of the crystalline lattices of the two graphene electrodes lowers the translation symmetry in the plane of the tunnel barrier and gives rise to an impulse which modifies the dynamics of the tunnelling electron 6 , 7 , 9 , 10 , 11 , 12 . By applying a magnetic field perpendicular to the layers we show that electron tunnelling is governed by the laws of conservation of energy and in-plane momentum, as was demonstrated for the case of inter-Landau-level (inter-LL) tunnelling between two quantum wells in III–V semiconductor heterostructures 13 , 14 . Here, our measurements on electron tunnelling between two graphene layers reveal an additional phenomenon, namely, chirality, and its enhancement by the quantizing magnetic field. Our device, with bias, V b , and gate, V g , voltages applied, is shown schematically in Fig. 1a . It consists of a four-layer thick ( d = 1.4 nm) hexagonal boron nitride (hBN) tunnel barrier 15 sandwiched between two high-purity crystalline graphene electrodes. The active area of the device, in which tunnelling occurs, is 100 μm 2 . The lower graphene electrode sits on an atomically flat hBN layer (lower yellow region in Fig. 1a ), directly above a SiO 2 /n-Si substrate, in which the doped Si layer acts as the gate electrode and the oxide thickness is 300 nm. Our device is thus a graphene–boron nitride analogue of an independently contacted GaAs/AlGaAs double quantum well structure with back gate 13 . The device fabrication is described in the methods section of ref. 6 . The two graphene lattices are intentionally aligned to within an angle of 1° (see ref. 6 for details). However, even this slight misalignment, or ‘twist angle’, θ , leads to a significant k -space displacement of magnitude Δ K = | ΔK ± | = | K b ± − K t ± | = 2sin( θ /2) | K b ± | of the Dirac cones at the Brillouin zone corners 16 , 17 , 18 , 19 (see Figs 1b and 2a , insets). This displacement induces an impulse on a tunnelling electron and has a large effect on the measured current–voltage characteristics and their magnetic field dependence. Figure 1: Device structure and misaligned Brillouin zones. a , Schematic of the device showing the two misaligned graphene lattices (bottom, red and top, blue) separated by a boron nitride tunnel barrier (upper yellow region). An optical micrograph is shown in Supplementary Fig. 1 . b , Dashed black lines show the Brillouin zone boundary for electrons in the bottom graphene layer. Red arrows show the vector positions of the Dirac points K b ± (red circles) relative to the Γ point. Blue arrows show the positions of the Dirac points in the top layer, K t ± (blue circles), misoriented at an angle θ to the bottom layer. Full size image Figure 2: Magnetic field-induced resonances in the conductance. a , I ( V b ) curves measured when V g = 0 for B = 0 (black dashed) and 4 T (red solid), the latter offset by 7.5 μA for clarity. Insets i and ii show the relative energies of the Dirac cones, displaced by Δ K , in the bottom (red) and top (blue) electrodes at the voltages V 1 and V 2 marked by the labelled vertical arrows. The intersections of the cones are shown by the thick yellow curves. The Fermi circles of the two layers are shown in white. b , Differential conductance, G ( V b ), measured at V g = −40 V (blue lower curve), V g = 0 V (red middle curve), and V g = 40 V (green upper curve) when B = 4 T and temperature T = 4 K. Red and green curves are offset by 250 μS and 350 μS, respectively (that is, dotted lines mark G = 0 for the three curves). Red horizontal bars in a , b mark the V b > 0 region where conductance peaks can be observed when V g = 0. Full size image Figure 2a (black dashed curve) shows the measured current–voltage curve, I ( V b ), at V g = 0 in the absence of a magnetic field. The current increases at a threshold bias voltage<|im_end|> <|im_start|>assistant (Phys.org)—A team of researches affiliated with several institutions in the U.K. and Russia has found that chirality in graphene impacts current flow. In their paper published in the journal Nature Physics, the team describes how they developed a method for both detecting and measuring the impact of chirality in graphene and why they believe it could lead to better tunneling electronics devices. Electrons and other particles have a property that is called chirality, where they exist as being either left or right-handed. In addition, when they exist in an electronic state, it can also be defined as chiral. In this new experiment, the researchers found that the chirality of electrons can have an impact on current flow—they made this discovery by creating a small testing material made of a sheet of four atom thick boron nitride placed between two sheets of graphene. This setup allowed for creating a very controllable type of current flow—when voltage was applied to one of the sheets of graphene, it tunneled its way through the boron nitride to the other graphene sheet where it could be removed. That allowed for noting the right or left-handedness of the electrons as they tunneled through the borone nitride sheet and the states they ended up in. The researchers note that right-handed electrons tended to prefer to make it to right-hand states and vice-versa for the left-handed electrons. By applying voltage, the team was able to "see" the chirality of the tunneling electrons and its impact on current flow. They also found that applying a magnetic field at a ninety degree angle to the material allowed for seeing the impact even better—doing so served to quantize the motion of the electron, which showed up on a measuring device as energy levels that were unequally spaced apart—a ladder effect. Doing so allowed them to demonstrate that spin, energy and momentum were all conserved in the tunneling process, as was their chirality. The researchers suggest their findings could lead to efforts that are involved in making better tunneling electronic devices and perhaps to a whole new class of chiralitic electronics. <|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 Palaeospondylus gunni , from the Middle Devonian period, is one of the most enigmatic fossil vertebrates, and its phylogenetic position has remained unclear since its discovery in Scotland in 1890 (ref. 1 ). The fossil’s strange set of morphological features has made comparisons with known vertebrate morphotype diversity difficult. Here we use synchrotron radiation X-ray micro-computed tomography to show that Palaeospondylus was a sarcopterygian, and most probably a stem-tetrapod. The skeleton of Palaeospondylus consisted solely of endoskeletal elements in which hypertrophied chondrocyte cell lacunae, osteoids and a small fraction of perichondral bones developed. Despite the complete lack of teeth and dermal bones, the neurocranium of Palaeospondylus resembles those of stem-tetrapod Eusthenopteron 2 and Panderichthys 3 , and phylogenetic analyses place Palaeospondylus in between them. Because the unique features of Palaeospondylus , such as the cartilaginous skeleton and the absence of paired appendages, are present in the larva of crown tetrapods, our study highlights an unanticipated heterochronic evolution at the root of tetrapods. Main Though mysterious, Palaeospondylus is the most abundant vertebrate in the Achanarras fish bed, Eifelian age deep lacustrine deposits, where at least 13 vertebrate genera including the lungfish Dipterus , acanthodian Mesacanthus and antiarch Pterichthyodes co-occur 4 . For more than 130 years since the discovery of Palaeospondylus , many researchers have tried to identify homologies between it and various known taxa from both gnathostomes and cyclostomes ( Supplementary Information , Supplementary Fig. 1 ). Thousands of Palaeospondylus specimens have been collected, but they led to only one common understanding—that the fossilized skeletal elements are endoskeletal components—underscoring the uniqueness of Palaeospondylus skeletal morphology. To explain the non-preservation of teeth and dermal bones in Palaeospondylus fossils, one theory assumed a preservational difference between enameloids and calcified cartilage 5 . However, preserved teeth and dermal bones have often been found for fossil fishes co-occurring in the same strata 4 , 6 (for example, Mesacanthus , Pterichthyodes , Coccosteus , and Dipterus ), suggesting that this assumption is unlikely to be true. Data on the cranial skeleton of Palaeospondylus have not been substantially enhanced since the early work 5 , 7 , 8 of 120 years ago, despite improvements in techniques of morphological and histological analyses. Indeed, a reconstruction based on high-resolution CT scanning 9 was almost the same as the wax-based reconstruction 5 . Also, unlike the histological features of exoskeletal elements in gnathostomes 10 , those of endoskeletal elements in Palaeospondylus 11 gave insufficient phylogenetic signals. Thus, it is important to clarify the homology correspondences (or ‘primary homology’ as described in ref. 12 ) of cranial skeletal elements to a certain higher taxon for phylogenetic analyses of Palaeospondylus . Nevertheless, we still lack clear evidence for articulations or boundaries between cranial skeletal elements of Palaeospondylus , making it impossible to conclusively identify such homology correspondences. To overcome this difficulty, we analysed Palaeospondylus cranial skeletons at the histological level three-dimensionally by using synchrotron radiation X-ray micro-computed tomography (SRXµCT; Fig. 1 ), and separated cranial skeletal elements on the basis of the distribution of cell lacunae (Fig. 2 ). The boundaries between separate skeletal elements of Palaeospondylus clarified their morphologies (Fig. 1 , Supplementary Videos 1 , 2 ). Unlike previous studies, we studied specimens whose cranial skeletons are completely embedded intact within the matrices (Fig. 1 , Extended Data Fig. 1 ), such that no fossilized cranial parts fell away during the preparation. It should be noted that the identification of separate skeletal elements in this study is consistent with modes of postmortem disarticulations of Palaeospondylus reported previously 13 . Fig. 1: Cranial skeleton of P. gunni , NSMPV 24679. a , Position of the cranial skeleton (arrowhead) embedded intact within the matrix. b , c , Dorsal ( b ) and ventral ( c ) views of the cranial skeleton. d , Separate skeletal portions in left oblique lateral view. arp, arcual plate; aup1, autopalatinum 1; aup2, autopalatinum 2; bscf, basicranial fenestra; bspp, basipterygoid process; epp, epipterygoid; hym, hyomandibula; ltc, lateral commissure; mc, Meckel's cartilage; mtp, metapterygoid; nac, nasal capsule; nas, nasal septum; ocpa, occipital arches (basioccipital portion of the neurocranium); prop, prootic process; qua, quadrate; r1, rib 1; vt1–3, vertebral segments 1–3. Scale bars, 1 mm. Full size image Fig. 2: Skeletal histology of P. gunni (NSMPV 24679) in comparison with the extant sarcopterygian Neoceratodus forsteri . a , b , Sections at the left autopalatinum 1 ( a ) and at the left otic capsule ( b ) in P. gunni ( n = 1). c , Three-dimensional model of histology at the right autopalatinum 1 in P. gunni . d , Interpretation of the skeletal tissues of P. gunni . e , Section at the left palatoquadrate in a stage 47 larva of the Australian lungfish, N. forsteri ( n = 1). f , Section at the right ceratohyal in a stage 48 larva of N. forsteri ( n = 1). Note that in N. forsteri sections, the cell lacuna was shown as an ellipsoid in dark colour surrounding a cell nucleus in white. es, ethmosphenoid; lac, cell lacuna; mu, muscle; nu, cell nucleus; os, osteoid; pcb, perichondral bone; pq, palatoquadrate. Arrowheads in c and e denote boundaries between separate skeletal elements, where cell lacunae are absent. Scale bars, 100 µm. Full size image Within the cranial skeleton of Palaeospondylus , separate oval spherical cell lacunae are present, surrounded by a skeletal matrix (Fig. 2 , Extended Data Fig. 2 , Supplementary Video 3 ). The size of cell lacunae (up to 40 µm in the direction of the major axis) is consistent with the feature of hypertrophied cartilage of extant osteichthyan endochondral bones, as previously reported 11 . The periphery of the skeletal tissue is bordered by a 5- to 7-µm-thick convoluted margin with low X-ray absorption (in particular, on images with voxel size of 1.46 µm; Fig. 2a, b ), probably representing an osteoid secreted by a perichondrium. A fraction of the margins accompanies a tissue with high X-ray absorption, which is about", "role": "user" }, { "content": "The Evolutionary Morphology Laboratory led by Shigeru Kuratani at the RIKEN Cluster for Pioneering Research (CPR) in Japan, along with collaborators, has found evidence that the mysterious ancient fish-like vertebrate Palaeospondylus was likely one of the earliest ancestors of four-limbed animals, including humans. Published May 25 in the scientific journal Nature, the study unmasks this strange animal from the deep past and sets its position on the evolutionary tree. Palaeospondylus was a small fish-like vertebrate, about 5 cm long, which had an eel-like body and lived in the Devonian period about 390 million years ago. Although fossils are abundant, its small size and the poor quality of cranial reconstructions—by both CT scan and wax models—have made placing it on the evolutionary tree difficult ever since its discovery in 1890. It's been thought to share features with both jawed and jawless fish and its body has presented evolutionary scientists as a mystery. Among several unusual features, the most perplexing is the lack of teeth or dermal bones in the fossil record. To resolve some of these issues, the researchers used the extremely powerful RIKEN SPring-8 synchrotron to generate high-resolution micro-CT scans using synchrotron radiation X-rays. Additionally, unlike most studies that have used excavated fossil heads, the new study used carefully selected fossils in which the heads remained completely embedded in the rock. \"Choosing the best specimens for the micro-CT scans and carefully trimming away the rock surrounding the fossilized skull allowed us to improve the resolution of the scans,\" says lead author Tatsuya Hirasawa. \"Although not quite cutting-edge technology, these preparations were certainly keys to our achievement.\" The high-resolution scans revealed several important features. First, researchers found three semi-circular canals, clearly indicating an inner-ear morphology of jawed vertebrates. This resolved an issue because previous studies suggested that Palaeospondylus was evolutionarily closer to primitive jawless vertebrates. Next, they found key cranial features that place Palaeospondylus into the tetrapodomorph category, which is made from tetrapods—four-limbed animals—and their closest ancient relatives. Several analyses showed that Palaeospondylus was more closely related to limbed tetrapods than to many other known tetrapodomorphs that still retained fins. However, unlike tetrapodomorphs in general, teeth, dermal bones, and paired appendages have never been associated with Palaeospondylus fossils, although these features are readily found in fossils of other animals that lived around the same time and in the same place in the Achanarras fish bed in Scotland. The lack of these features can be explained by the splitting of a set of developmental features, resulting in a larval-like body. \"Whether these features were evolutionarily lost or whether normal development froze half-way in fossils might never be known,\" says Hirasawa. \"Nevertheless, this heterochronic evolution might have facilitated the development of new features like limbs.\" Kuratani and his research group do not limit their study of early vertebrate evolution to the fossil record. They also use molecular biology and genetics to study developing embryos of key modern vertebrates. \"The strange morphology of Palaeospondylus, which is comparable to that of tetrapod larvae, is very interesting from a developmental genetic point of view,\" says Hirasawa. \"Taking this into consideration, we will continue to study the developmental genetics that brought about this and other morphological changes that occurred at the water-to-land transition in vertebrate history.\" ", "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 Palaeospondylus gunni , from the Middle Devonian period, is one of the most enigmatic fossil vertebrates, and its phylogenetic position has remained unclear since its discovery in Scotland in 1890 (ref. 1 ). The fossil’s strange set of morphological features has made comparisons with known vertebrate morphotype diversity difficult. Here we use synchrotron radiation X-ray micro-computed tomography to show that Palaeospondylus was a sarcopterygian, and most probably a stem-tetrapod. The skeleton of Palaeospondylus consisted solely of endoskeletal elements in which hypertrophied chondrocyte cell lacunae, osteoids and a small fraction of perichondral bones developed. Despite the complete lack of teeth and dermal bones, the neurocranium of Palaeospondylus resembles those of stem-tetrapod Eusthenopteron 2 and Panderichthys 3 , and phylogenetic analyses place Palaeospondylus in between them. Because the unique features of Palaeospondylus , such as the cartilaginous skeleton and the absence of paired appendages, are present in the larva of crown tetrapods, our study highlights an unanticipated heterochronic evolution at the root of tetrapods. Main Though mysterious, Palaeospondylus is the most abundant vertebrate in the Achanarras fish bed, Eifelian age deep lacustrine deposits, where at least 13 vertebrate genera including the lungfish Dipterus , acanthodian Mesacanthus and antiarch Pterichthyodes co-occur 4 . For more than 130 years since the discovery of Palaeospondylus , many researchers have tried to identify homologies between it and various known taxa from both gnathostomes and cyclostomes ( Supplementary Information , Supplementary Fig. 1 ). Thousands of Palaeospondylus specimens have been collected, but they led to only one common understanding—that the fossilized skeletal elements are endoskeletal components—underscoring the uniqueness of Palaeospondylus skeletal morphology. To explain the non-preservation of teeth and dermal bones in Palaeospondylus fossils, one theory assumed a preservational difference between enameloids and calcified cartilage 5 . However, preserved teeth and dermal bones have often been found for fossil fishes co-occurring in the same strata 4 , 6 (for example, Mesacanthus , Pterichthyodes , Coccosteus , and Dipterus ), suggesting that this assumption is unlikely to be true. Data on the cranial skeleton of Palaeospondylus have not been substantially enhanced since the early work 5 , 7 , 8 of 120 years ago, despite improvements in techniques of morphological and histological analyses. Indeed, a reconstruction based on high-resolution CT scanning 9 was almost the same as the wax-based reconstruction 5 . Also, unlike the histological features of exoskeletal elements in gnathostomes 10 , those of endoskeletal elements in Palaeospondylus 11 gave insufficient phylogenetic signals. Thus, it is important to clarify the homology correspondences (or ‘primary homology’ as described in ref. 12 ) of cranial skeletal elements to a certain higher taxon for phylogenetic analyses of Palaeospondylus . Nevertheless, we still lack clear evidence for articulations or boundaries between cranial skeletal elements of Palaeospondylus , making it impossible to conclusively identify such homology correspondences. To overcome this difficulty, we analysed Palaeospondylus cranial skeletons at the histological level three-dimensionally by using synchrotron radiation X-ray micro-computed tomography (SRXµCT; Fig. 1 ), and separated cranial skeletal elements on the basis of the distribution of cell lacunae (Fig. 2 ). The boundaries between separate skeletal elements of Palaeospondylus clarified their morphologies (Fig. 1 , Supplementary Videos 1 , 2 ). Unlike previous studies, we studied specimens whose cranial skeletons are completely embedded intact within the matrices (Fig. 1 , Extended Data Fig. 1 ), such that no fossilized cranial parts fell away during the preparation. It should be noted that the identification of separate skeletal elements in this study is consistent with modes of postmortem disarticulations of Palaeospondylus reported previously 13 . Fig. 1: Cranial skeleton of P. gunni , NSMPV 24679. a , Position of the cranial skeleton (arrowhead) embedded intact within the matrix. b , c , Dorsal ( b ) and ventral ( c ) views of the cranial skeleton. d , Separate skeletal portions in left oblique lateral view. arp, arcual plate; aup1, autopalatinum 1; aup2, autopalatinum 2; bscf, basicranial fenestra; bspp, basipterygoid process; epp, epipterygoid; hym, hyomandibula; ltc, lateral commissure; mc, Meckel's cartilage; mtp, metapterygoid; nac, nasal capsule; nas, nasal septum; ocpa, occipital arches (basioccipital portion of the neurocranium); prop, prootic process; qua, quadrate; r1, rib 1; vt1–3, vertebral segments 1–3. Scale bars, 1 mm. Full size image Fig. 2: Skeletal histology of P. gunni (NSMPV 24679) in comparison with the extant sarcopterygian Neoceratodus forsteri . a , b , Sections at the left autopalatinum 1 ( a ) and at the left otic capsule ( b ) in P. gunni ( n = 1). c , Three-dimensional model of histology at the right autopalatinum 1 in P. gunni . d , Interpretation of the skeletal tissues of P. gunni . e , Section at the left palatoquadrate in a stage 47 larva of the Australian lungfish, N. forsteri ( n = 1). f , Section at the right ceratohyal in a stage 48 larva of N. forsteri ( n = 1). Note that in N. forsteri sections, the cell lacuna was shown as an ellipsoid in dark colour surrounding a cell nucleus in white. es, ethmosphenoid; lac, cell lacuna; mu, muscle; nu, cell nucleus; os, osteoid; pcb, perichondral bone; pq, palatoquadrate. Arrowheads in c and e denote boundaries between separate skeletal elements, where cell lacunae are absent. Scale bars, 100 µm. Full size image Within the cranial skeleton of Palaeospondylus , separate oval spherical cell lacunae are present, surrounded by a skeletal matrix (Fig. 2 , Extended Data Fig. 2 , Supplementary Video 3 ). The size of cell lacunae (up to 40 µm in the direction of the major axis) is consistent with the feature of hypertrophied cartilage of extant osteichthyan endochondral bones, as previously reported 11 . The periphery of the skeletal tissue is bordered by a 5- to 7-µm-thick convoluted margin with low X-ray absorption (in particular, on images with voxel size of 1.46 µm; Fig. 2a, b ), probably representing an osteoid secreted by a perichondrium. A fraction of the margins accompanies a tissue with high X-ray absorption, which is about<|im_end|> <|im_start|>assistant The Evolutionary Morphology Laboratory led by Shigeru Kuratani at the RIKEN Cluster for Pioneering Research (CPR) in Japan, along with collaborators, has found evidence that the mysterious ancient fish-like vertebrate Palaeospondylus was likely one of the earliest ancestors of four-limbed animals, including humans. Published May 25 in the scientific journal Nature, the study unmasks this strange animal from the deep past and sets its position on the evolutionary tree. Palaeospondylus was a small fish-like vertebrate, about 5 cm long, which had an eel-like body and lived in the Devonian period about 390 million years ago. Although fossils are abundant, its small size and the poor quality of cranial reconstructions—by both CT scan and wax models—have made placing it on the evolutionary tree difficult ever since its discovery in 1890. It's been thought to share features with both jawed and jawless fish and its body has presented evolutionary scientists as a mystery. Among several unusual features, the most perplexing is the lack of teeth or dermal bones in the fossil record. To resolve some of these issues, the researchers used the extremely powerful RIKEN SPring-8 synchrotron to generate high-resolution micro-CT scans using synchrotron radiation X-rays. Additionally, unlike most studies that have used excavated fossil heads, the new study used carefully selected fossils in which the heads remained completely embedded in the rock. "Choosing the best specimens for the micro-CT scans and carefully trimming away the rock surrounding the fossilized skull allowed us to improve the resolution of the scans," says lead author Tatsuya Hirasawa. "Although not quite cutting-edge technology, these preparations were certainly keys to our achievement." The high-resolution scans revealed several important features. First, researchers found three semi-circular canals, clearly indicating an inner-ear morphology of jawed vertebrates. This resolved an issue because previous studies suggested that Palaeospondylus was evolutionarily closer to primitive jawless vertebrates. Next, they found key cranial features that place Palaeospondylus into the tetrapodomorph category, which is made from tetrapods—four-limbed animals—and their closest ancient relatives. Several analyses showed that Palaeospondylus was more closely related to limbed tetrapods than to many other known tetrapodomorphs that still retained fins. However, unlike tetrapodomorphs in general, teeth, dermal bones, and paired appendages have never been associated with Palaeospondylus fossils, although these features are readily found in fossils of other animals that lived around the same time and in the same place in the Achanarras fish bed in Scotland. The lack of these features can be explained by the splitting of a set of developmental features, resulting in a larval-like body. "Whether these features were evolutionarily lost or whether normal development froze half-way in fossils might never be known," says Hirasawa. "Nevertheless, this heterochronic evolution might have facilitated the development of new features like limbs." Kuratani and his research group do not limit their study of early vertebrate evolution to the fossil record. They also use molecular biology and genetics to study developing embryos of key modern vertebrates. "The strange morphology of Palaeospondylus, which is comparable to that of tetrapod larvae, is very interesting from a developmental genetic point of view," says Hirasawa. "Taking this into consideration, we will continue to study the developmental genetics that brought about this and other morphological changes that occurred at the water-to-land transition in vertebrate history." <|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 Mafic enclaves preserve a record of deep differentiation of primitive magmas in arc settings. We analyze the petrology and geochemistry of mafic enclaves from Shiveluch volcano in the Kamchatka peninsula to determine the differentiation histories of primitive magmas and to estimate their pressures, temperatures, and water contents. Amphibole inclusions in high forsterite olivine suggest that the primitive melt was superhydrous (i.e., > 8 wt% H 2 O) and was fractionating amphibole and olivine early on its liquid line of descent. We find that the hydrous primitive melt had liquidus temperatures of 1062 ± 48 °C and crystallized high Mg# amphibole at depths of 23.6–28.8 km and water contents of 10–14 wt% H 2 O. The major and trace element whole-rock chemistry of enclaves and of published analyses of andesites suggest that they are related through fractionation of amphibole-bearing assemblages. Quantitative models fractionating olivine, clinopyroxene, and amphibole reproduce geochemical trends defined by enclaves and andesites in variation diagrams. These models estimate 0.2–12.2% amphibole fractionated from the melt to reproduce the full range of enclave compositions, which overlaps with estimates of the amount of amphibole fractionated from parental melts based on whole-rock dysprosium contents. This contribution extends the published model of shallow processes at Shiveluch to greater depths. It provides evidence that primitive magmas feeding arc volcanoes may be more hydrous than estimated from other methods, and that amphibole is an important early fractionating phase on the liquid line of descent of superhydrous, primitive mantle-derived melts. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Mafic enclaves are often intermixed with andesites at arc volcanoes and record magmatic processes that are largely “overwritten” by fractionation, assimilation, and mixing processes affecting the host andesite (e.g., Eichelberger et al. 2000 ; Izbekov et al. 2004 ; Browne et al. 2006 ; Halama et al. 2006 ; Plail et al. 2014 , 2018 ). The presence of mafic enclaves in an andesite is a physical piece of evidence that mafic magma was involved in magma mixing (e.g., Eichelberger 1975 ; Bacon 1986 ). Studies of mafic enclaves themselves have revealed details about both shallow and deep mixing processes (e.g., Browne et al. 2006 ; Ruprecht et al. 2012 ; Plail et al. 2014 ), the role of mafic recharge in eruption catalysis (e.g., Martin et al. 2006 , 2008 ; Ruprecht and Bachmann 2010 ; Plail et al. 2018 ), and the structure of magmatic plumbing systems at depth (e.g., Ruprecht et al. 2012 ; Davydova et al. 2017 ), thus complementing the information from host magmas. In this study, we examine the petrology and geochemistry of mafic enclaves recently erupted from Shiveluch volcano in Kamchatka. We use a combination of mineral chemistry and bulk rock major and trace element analyses to estimate the pressures, temperatures, and magmatic water contents of primitive Shiveluch magmas. Holocene Shiveluch eruptions are dominated by andesites, and amphibole phenocrysts in the erupted andesites preserve a complex history of recharge by partially crystalline basaltic magmas in a shallow magma reservoir (e.g., Volynets et al. 1997 ; Dirksen et al. 2006 ; Humphreys et al. 2006 , 2008 ; Ponomareva et al. 2007b ; Ferlito 2011 ; Gorbach and Portnyagin, 2011 ; Gorbach et al. 2013 , 2016 ). Shiveluch is of particular interest because its magmas are thought to be extremely hydrous (e.g., Portnyagin et al. 2007 ), with some estimates of water content as high as 6 wt% H 2 O (Gavrilenko et al. 2016a ), making it one of the most hydrous volcanoes in the world, comparable to Mt. Shasta in the Cascade Arc. (e.g., Baker et al. 1994 ; Grove et al. 2003 , 2005 ). In this study, we present a model of lower crustal magmatism at Shiveluch before magmatic differentiation to andesite and show that fractional crystallization of olivine, clinopyroxene, and amphibole from a basaltic andesite parental melt reproduces the composition of enclaves and andesites erupted from Shiveluch. We conclude that high magmatic water contents are required to produce the mafic enclaves and their mineralogy. We estimate that differentiation processes occurring in the mid to lower crust require water contents of 10–14 wt%. Geologic background Shiveluch volcano is an eruptive center in the Kamchatka peninsula in Far Eastern Russia. The Kamchatka arc is located at the junction of the North American, Okhotsk, and Pacific plates (e.g., Bird 2003 ). Shiveluch is part of the northernmost segment of the arc called the Central Kamchatka Depression (CKD; e.g., Portnyagin et al. 2007 ). Volcanoes in the CKD are some of the most productive arc volcanoes on Earth (Fedotov 1991 ). Volcanic rocks along the CKD compositionally range from high-Mg basalts to dacites or rhyolites, although rhyolites are rare and basalts and andesites are the most frequently erupted in the CKD (e.g., Volynets 1991 ; Ponomareva et al. 2007a ; Portnyagin et al. 2007 ; Churikova et al. 2013 ). Shiveluch is the northernmost active volcano in the CKD. It is composed of two overlapping eruptive centers: Old Shiveluch (3283 m a.s.l; Ponomareva et al. 2007b ) and Young Shiveluch (2800 m a.s.l; Ponomareva et al. 2007b ; Fig. 1 ). Old Shiveluch is a Pleistocene-age stratovolcano inferred to have collapsed in a catastrophic eruption in the Late Pleistocene (Gorbach et al. 2013 ). The Young Shiveluch volcanic center is located within the crater formed by the catastrophic collapse of Old Shiveluch. Young Shiveluch has been active since the early Holocene (e.g., Volynets et al. 1997 ; Belousov et al. 1999 ; Gorbach and Portnyagin 2011 ; Ponomareva et al. 2015 ). Volcanism at Young Shiveluch includes 60 large Plinian eruptions throughout its history and frequent dome collapses followed by periods of regrowth (e.g., Belousov et al. 1999 ; Ponomareva et al. 2007a , 2015 ). The volcano normally erupts andesite, but throughout its history, there have been at least two instances of Mg-rich basaltic to basaltic-andesite eruptions identified in tephra deposits dated to 3959 (basaltic) and", "role": "user" }, { "content": "There isn't much in Kamchatka, a remote peninsula in northeastern Russia just across the Bering Sea from Alaska, besides an impressive population of brown bears and the most explosive volcano in the world. Kamchatka's Shiveluch volcano has had more than 40 violent eruptions over the last 10,000 years. The last gigantic blast occurred in 1964, creating a new crater and covering an area of nearly 100 square kilometers with pyroclastic flows. But Shiveluch is actually currently erupting, as it has been for over 20 years. So why would anyone risk venturing too close? Researchers from Washington University in St. Louis, including Michael Krawczynski, assistant professor of earth and planetary sciences in Arts & Sciences and graduate student Andrea Goltz, brave the harsh conditions on Kamchatka because understanding what makes Shiveluch tick could help scientists understand the global water cycle and gain insights into the plumbing systems of other volcanoes. In a recent study published in the journal Contributions to Mineralogy and Petrology, researchers from the Krawczynski lab looked at small nodules of primitive magma that were erupted and preserved amid other materials. \"The minerals in these nodules retain the signatures of what was happening early in the magma's evolution, deep in Earth's crust,\" said Goltz, the lead author of the paper. The researchers found that the conditions inside Shiveluch include roughly 10%-14% water by weight (wt%). Most volcanoes have less than 1% water. For subduction zone volcanoes, the average is usually 4%, rarely exceeding 8 wt%, which is considered superhydrous. Of particular interest is a mineral called amphibole, which acts as a proxy or fingerprint for high water content at known temperature and pressure. The unique chemistry of the mineral tells researchers how much water is present deep underneath Shiveluch. \"When you convert the chemistry of these two minerals, amphibole and olivine, into temperatures and water contents as we do in this paper, the results are remarkable both in terms of how much water and how low a temperature we're recording,\" Krawczynski said. \"The only way to get primitive, pristine materials at low temperatures is to add lots and lots of water,\" he said. \"Adding water to rock has the same effect as adding salt to ice; you're lowering the melting point. In this case, there is so much water that the temperature is reduced to a point where amphiboles can crystallize.\" ", "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 Mafic enclaves preserve a record of deep differentiation of primitive magmas in arc settings. We analyze the petrology and geochemistry of mafic enclaves from Shiveluch volcano in the Kamchatka peninsula to determine the differentiation histories of primitive magmas and to estimate their pressures, temperatures, and water contents. Amphibole inclusions in high forsterite olivine suggest that the primitive melt was superhydrous (i.e., > 8 wt% H 2 O) and was fractionating amphibole and olivine early on its liquid line of descent. We find that the hydrous primitive melt had liquidus temperatures of 1062 ± 48 °C and crystallized high Mg# amphibole at depths of 23.6–28.8 km and water contents of 10–14 wt% H 2 O. The major and trace element whole-rock chemistry of enclaves and of published analyses of andesites suggest that they are related through fractionation of amphibole-bearing assemblages. Quantitative models fractionating olivine, clinopyroxene, and amphibole reproduce geochemical trends defined by enclaves and andesites in variation diagrams. These models estimate 0.2–12.2% amphibole fractionated from the melt to reproduce the full range of enclave compositions, which overlaps with estimates of the amount of amphibole fractionated from parental melts based on whole-rock dysprosium contents. This contribution extends the published model of shallow processes at Shiveluch to greater depths. It provides evidence that primitive magmas feeding arc volcanoes may be more hydrous than estimated from other methods, and that amphibole is an important early fractionating phase on the liquid line of descent of superhydrous, primitive mantle-derived melts. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Mafic enclaves are often intermixed with andesites at arc volcanoes and record magmatic processes that are largely “overwritten” by fractionation, assimilation, and mixing processes affecting the host andesite (e.g., Eichelberger et al. 2000 ; Izbekov et al. 2004 ; Browne et al. 2006 ; Halama et al. 2006 ; Plail et al. 2014 , 2018 ). The presence of mafic enclaves in an andesite is a physical piece of evidence that mafic magma was involved in magma mixing (e.g., Eichelberger 1975 ; Bacon 1986 ). Studies of mafic enclaves themselves have revealed details about both shallow and deep mixing processes (e.g., Browne et al. 2006 ; Ruprecht et al. 2012 ; Plail et al. 2014 ), the role of mafic recharge in eruption catalysis (e.g., Martin et al. 2006 , 2008 ; Ruprecht and Bachmann 2010 ; Plail et al. 2018 ), and the structure of magmatic plumbing systems at depth (e.g., Ruprecht et al. 2012 ; Davydova et al. 2017 ), thus complementing the information from host magmas. In this study, we examine the petrology and geochemistry of mafic enclaves recently erupted from Shiveluch volcano in Kamchatka. We use a combination of mineral chemistry and bulk rock major and trace element analyses to estimate the pressures, temperatures, and magmatic water contents of primitive Shiveluch magmas. Holocene Shiveluch eruptions are dominated by andesites, and amphibole phenocrysts in the erupted andesites preserve a complex history of recharge by partially crystalline basaltic magmas in a shallow magma reservoir (e.g., Volynets et al. 1997 ; Dirksen et al. 2006 ; Humphreys et al. 2006 , 2008 ; Ponomareva et al. 2007b ; Ferlito 2011 ; Gorbach and Portnyagin, 2011 ; Gorbach et al. 2013 , 2016 ). Shiveluch is of particular interest because its magmas are thought to be extremely hydrous (e.g., Portnyagin et al. 2007 ), with some estimates of water content as high as 6 wt% H 2 O (Gavrilenko et al. 2016a ), making it one of the most hydrous volcanoes in the world, comparable to Mt. Shasta in the Cascade Arc. (e.g., Baker et al. 1994 ; Grove et al. 2003 , 2005 ). In this study, we present a model of lower crustal magmatism at Shiveluch before magmatic differentiation to andesite and show that fractional crystallization of olivine, clinopyroxene, and amphibole from a basaltic andesite parental melt reproduces the composition of enclaves and andesites erupted from Shiveluch. We conclude that high magmatic water contents are required to produce the mafic enclaves and their mineralogy. We estimate that differentiation processes occurring in the mid to lower crust require water contents of 10–14 wt%. Geologic background Shiveluch volcano is an eruptive center in the Kamchatka peninsula in Far Eastern Russia. The Kamchatka arc is located at the junction of the North American, Okhotsk, and Pacific plates (e.g., Bird 2003 ). Shiveluch is part of the northernmost segment of the arc called the Central Kamchatka Depression (CKD; e.g., Portnyagin et al. 2007 ). Volcanoes in the CKD are some of the most productive arc volcanoes on Earth (Fedotov 1991 ). Volcanic rocks along the CKD compositionally range from high-Mg basalts to dacites or rhyolites, although rhyolites are rare and basalts and andesites are the most frequently erupted in the CKD (e.g., Volynets 1991 ; Ponomareva et al. 2007a ; Portnyagin et al. 2007 ; Churikova et al. 2013 ). Shiveluch is the northernmost active volcano in the CKD. It is composed of two overlapping eruptive centers: Old Shiveluch (3283 m a.s.l; Ponomareva et al. 2007b ) and Young Shiveluch (2800 m a.s.l; Ponomareva et al. 2007b ; Fig. 1 ). Old Shiveluch is a Pleistocene-age stratovolcano inferred to have collapsed in a catastrophic eruption in the Late Pleistocene (Gorbach et al. 2013 ). The Young Shiveluch volcanic center is located within the crater formed by the catastrophic collapse of Old Shiveluch. Young Shiveluch has been active since the early Holocene (e.g., Volynets et al. 1997 ; Belousov et al. 1999 ; Gorbach and Portnyagin 2011 ; Ponomareva et al. 2015 ). Volcanism at Young Shiveluch includes 60 large Plinian eruptions throughout its history and frequent dome collapses followed by periods of regrowth (e.g., Belousov et al. 1999 ; Ponomareva et al. 2007a , 2015 ). The volcano normally erupts andesite, but throughout its history, there have been at least two instances of Mg-rich basaltic to basaltic-andesite eruptions identified in tephra deposits dated to 3959 (basaltic) and<|im_end|> <|im_start|>assistant There isn't much in Kamchatka, a remote peninsula in northeastern Russia just across the Bering Sea from Alaska, besides an impressive population of brown bears and the most explosive volcano in the world. Kamchatka's Shiveluch volcano has had more than 40 violent eruptions over the last 10,000 years. The last gigantic blast occurred in 1964, creating a new crater and covering an area of nearly 100 square kilometers with pyroclastic flows. But Shiveluch is actually currently erupting, as it has been for over 20 years. So why would anyone risk venturing too close? Researchers from Washington University in St. Louis, including Michael Krawczynski, assistant professor of earth and planetary sciences in Arts & Sciences and graduate student Andrea Goltz, brave the harsh conditions on Kamchatka because understanding what makes Shiveluch tick could help scientists understand the global water cycle and gain insights into the plumbing systems of other volcanoes. In a recent study published in the journal Contributions to Mineralogy and Petrology, researchers from the Krawczynski lab looked at small nodules of primitive magma that were erupted and preserved amid other materials. "The minerals in these nodules retain the signatures of what was happening early in the magma's evolution, deep in Earth's crust," said Goltz, the lead author of the paper. The researchers found that the conditions inside Shiveluch include roughly 10%-14% water by weight (wt%). Most volcanoes have less than 1% water. For subduction zone volcanoes, the average is usually 4%, rarely exceeding 8 wt%, which is considered superhydrous. Of particular interest is a mineral called amphibole, which acts as a proxy or fingerprint for high water content at known temperature and pressure. The unique chemistry of the mineral tells researchers how much water is present deep underneath Shiveluch. "When you convert the chemistry of these two minerals, amphibole and olivine, into temperatures and water contents as we do in this paper, the results are remarkable both in terms of how much water and how low a temperature we're recording," Krawczynski said. "The only way to get primitive, pristine materials at low temperatures is to add lots and lots of water," he said. "Adding water to rock has the same effect as adding salt to ice; you're lowering the melting point. In this case, there is so much water that the temperature is reduced to a point where amphiboles can crystallize." <|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 is increasing evidence that coronavirus disease 2019 (COVID-19) produces more severe symptoms and higher mortality among men than among women 1 , 2 , 3 , 4 , 5 . However, whether immune responses against severe acute respiratory syndrome coronavirus (SARS-CoV-2) differ between sexes, and whether such differences correlate with the sex difference in the disease course of COVID-19, is currently unknown. Here we examined sex differences in viral loads, SARS-CoV-2-specific antibody titres, plasma cytokines and blood-cell phenotyping in patients with moderate COVID-19 who had not received immunomodulatory medications. Male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL-18 along with more robust induction of non-classical monocytes. By contrast, female patients had more robust T cell activation than male patients during SARS-CoV-2 infection. Notably, we found that a poor T cell response negatively correlated with patients’ age and was associated with worse disease outcome in male patients, but not in female patients. By contrast, higher levels of innate immune cytokines were associated with worse disease progression in female patients, but not in male patients. These findings provide a possible explanation for the observed sex biases in COVID-19, and provide an important basis for the development of a sex-based approach to the treatment and care of male and female patients with COVID-19. Main SARS-CoV-2 is the novel coronavirus first detected in Wuhan, China, in November 2019 that causes COVID-19 6 . On 11 March 2020, the World Health Organization (WHO) declared COVID-19 a pandemic 7 . A growing body of evidence reveals that male sex is a risk factor for a more severe disease, including death. Globally, approximately 60% of deaths from COVID-19 are reported in men 5 , and a cohort study of 17 million adults in England reported a strong association between male sex and the risk of death from COVID-19 (hazard ratio 1.59, 95% confidence interval 1.53–1.65) 8 . Past studies have shown that sex has a considerable effect on the outcome of infections and has been associated with underlying differences in immune responses to infection 9 , 10 . For example, the prevalence of hepatitis A and tuberculosis are notably higher in men that in women 11 . Viral loads are consistently higher in male patients with hepatitis C virus and human immunodeficiency virus (HIV) 12 , 13 . By contrast, women mount a more robust immune response to vaccines 14 . These findings collectively suggest a more robust ability among women to control infectious agents. However, the mechanism by which SARS-CoV-2 causes more severe disease in male patients than in female patients remains unknown. To determine the immune responses against SARS-CoV-2 infection in male and female patients, we performed detailed analyses on the sex differences in immune phenotypes by the assessment of viral loads, levels of SARS-CoV-2-specific antibodies, plasma cytokines or chemokines, and blood-cell phenotypes. Overview of the study design Patients who were admitted to the Yale-New Haven Hospital between 18 March and 9 May 2020 and were confirmed positive for SARS-CoV-2 by RT–PCR from nasopharyngeal and/or oropharyngeal swabs in CLIA-certified laboratories were enrolled through the IMPACT biorepository study 15 . In the IMPACT study, biospecimens including blood, nasopharyngeal swabs, saliva, urine and stool samples were collected at study enrolment (baseline denotes the first time point) and longitudinally on average every 3 to 7 days (serial time points). The detailed demographics and clinical characteristics of these 98 participants are shown in Extended Data Table 1 . Plasma and peripheral blood mononuclear cells (PBMCs) were isolated from whole blood, and plasma was used for titre measurements of SARS-CoV-2 spike S1 protein-specific IgG and IgM antibodies (anti-S1-IgG and -IgM) and cytokine or chemokine measurements. Freshly isolated PBMCs were stained and analysed by flow cytometry 15 . We obtained longitudinal serial time-point samples from a subset of these 98 study participants ( n = 48; information in Extended Data Table 1 ). To compare the immune phenotypes between sexes, two sets of data analyses were performed in parallel—baseline and longitudinal, as described below. As a control group, healthcare workers (HCWs) from Yale-New Haven Hospital were enrolled who were uninfected with COVID-19. Demographics and background information for the HCW group and the demographics of HCWs for cytokine assays and flow cytometry assays for the primary analyses are in Extended Data Table 1 . Demographic data, time-point information of the samples defined by the days from the symptom onset (DFSO) in each patient, treatment information, and raw data used to generate figures and tables is in Supplementary Table 1 . Baseline analysis The baseline analysis was performed on samples from the first time point of patients who met the following criteria: not in intensive care unit (ICU), had not received tocilizumab, and had not received high doses of corticosteroids (prednisone equivalent of more than 40 mg) before the first sample collection date. This patient group, cohort A, consisted of 39 patients (17 male and 22 female) (Extended Data Tables 1 , 2 ). Intersex and transgender individuals were not represented in this study. Figures 1 – 4 represent analyses of baseline raw values obtained from patients in cohort A. In cohort A patients, male and female patients were matched in terms of age, body mass index (BMI), and DFSO at the first time point sample collection (Extended Data Fig. 1a ). However, there were significant differences in age and BMI between HCW controls and patients (patients had higher age and BMI values) (Extended Data Table 1 ), and therefore an age- and BMI-adjusted difference-in-differences analysis was also performed in parallel (Extended Data Table 3 ). Fig. 1: Comparison of viral RNA concentrations, titres of anti-SARS-CoV-2 antibodies, and plasma cytokines and chemokine levels at the first sampling of cohort A patients. a , Comparison of viral RNA measured from nasopharyngeal (Np) swab and saliva. n = 14 for male and female patients (M_Pt and F_Pt, respectively) for nasopharyngeal samples, and n = 9 and 12, respectively, for saliva samples. Dotted lines indicate the detection limit", "role": "user" }, { "content": "A new study looking at male and female immune responses to the new coronavirus may shed new light on why men are more likely to become seriously ill with COVID-19, researchers said Wednesday. Since early in the pandemic it has been clear that men, particularly older men, are at a far higher risk of dying from the virus than women of a similar age, but scientists have not yet been able to pinpoint exactly why. A new study published in the journal Nature noted that globally men account for about 60 percent of deaths from COVID-19 and looked at whether differences in immune responses could explain why. \"What we found was that men and women indeed develop different types of immune responses to COVID-19,\" said the study's lead author Akiko Iwasaki, a professor at Yale University, in a video. The immunity specialist said \"these differences may underlie heightened disease susceptibility in men\". Researchers collected nasal, saliva, and blood samples from non-infected control subjects and patients with the disease who were treated at Yale New Haven Hospital in the United States. They then monitored patients to look at their immune responses. Researchers found that women mounted a more robust immune response involving T lymphocytes, which are a type of white blood cell that can recognize viruses and eliminate them. This was the case even among older women, the study found. In contrast, older men had weaker T cell activity—the older they were, the weaker the response. Overall men also produced more cytokines, which are inflammatory proteins that form another part of the body's natural immune defence. However, severe cases of COVID-19 have been linked to what is known as a \"cytokine storm\", when the immune system goes into overdrive, which is harmful and potentially deadly. Men who showed high concentrations early on were more likely to have a severe case of the disease, while those women who also showed significant cytokine levels also appeared to fare worse, the study found. According to the authors, this could imply that men and women need different treatments. For men, for example \"we should be enhancing their T cell responses with vaccines\" Iwasaki said, while women could be given treatment to dampen the cytokine response. Treated differently? But the study has limitations. Firstly, the sample size was relatively small, with 98 patients in total. The average age of the patients was also high, at around sixty years. Commenting on the research, Eleanor Riley, a professor at the University of Edinburgh, said some of the divergence noted in the study is \"likely due to differences in age or BMI (the sex differences disappear once these other factors are taken into account)\". BMI measures body fat. She said others could have arisen \"by chance\". \"Importantly, although the average response may differ between men and women, the range of most of the measurements in men and women overlap significantly, meaning that many women have responses that are indistinguishable from those of many men,\" she added. Riley said this is why treatments would be better if they were individually tailored, rather than defined solely on sex. ", "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 is increasing evidence that coronavirus disease 2019 (COVID-19) produces more severe symptoms and higher mortality among men than among women 1 , 2 , 3 , 4 , 5 . However, whether immune responses against severe acute respiratory syndrome coronavirus (SARS-CoV-2) differ between sexes, and whether such differences correlate with the sex difference in the disease course of COVID-19, is currently unknown. Here we examined sex differences in viral loads, SARS-CoV-2-specific antibody titres, plasma cytokines and blood-cell phenotyping in patients with moderate COVID-19 who had not received immunomodulatory medications. Male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL-18 along with more robust induction of non-classical monocytes. By contrast, female patients had more robust T cell activation than male patients during SARS-CoV-2 infection. Notably, we found that a poor T cell response negatively correlated with patients’ age and was associated with worse disease outcome in male patients, but not in female patients. By contrast, higher levels of innate immune cytokines were associated with worse disease progression in female patients, but not in male patients. These findings provide a possible explanation for the observed sex biases in COVID-19, and provide an important basis for the development of a sex-based approach to the treatment and care of male and female patients with COVID-19. Main SARS-CoV-2 is the novel coronavirus first detected in Wuhan, China, in November 2019 that causes COVID-19 6 . On 11 March 2020, the World Health Organization (WHO) declared COVID-19 a pandemic 7 . A growing body of evidence reveals that male sex is a risk factor for a more severe disease, including death. Globally, approximately 60% of deaths from COVID-19 are reported in men 5 , and a cohort study of 17 million adults in England reported a strong association between male sex and the risk of death from COVID-19 (hazard ratio 1.59, 95% confidence interval 1.53–1.65) 8 . Past studies have shown that sex has a considerable effect on the outcome of infections and has been associated with underlying differences in immune responses to infection 9 , 10 . For example, the prevalence of hepatitis A and tuberculosis are notably higher in men that in women 11 . Viral loads are consistently higher in male patients with hepatitis C virus and human immunodeficiency virus (HIV) 12 , 13 . By contrast, women mount a more robust immune response to vaccines 14 . These findings collectively suggest a more robust ability among women to control infectious agents. However, the mechanism by which SARS-CoV-2 causes more severe disease in male patients than in female patients remains unknown. To determine the immune responses against SARS-CoV-2 infection in male and female patients, we performed detailed analyses on the sex differences in immune phenotypes by the assessment of viral loads, levels of SARS-CoV-2-specific antibodies, plasma cytokines or chemokines, and blood-cell phenotypes. Overview of the study design Patients who were admitted to the Yale-New Haven Hospital between 18 March and 9 May 2020 and were confirmed positive for SARS-CoV-2 by RT–PCR from nasopharyngeal and/or oropharyngeal swabs in CLIA-certified laboratories were enrolled through the IMPACT biorepository study 15 . In the IMPACT study, biospecimens including blood, nasopharyngeal swabs, saliva, urine and stool samples were collected at study enrolment (baseline denotes the first time point) and longitudinally on average every 3 to 7 days (serial time points). The detailed demographics and clinical characteristics of these 98 participants are shown in Extended Data Table 1 . Plasma and peripheral blood mononuclear cells (PBMCs) were isolated from whole blood, and plasma was used for titre measurements of SARS-CoV-2 spike S1 protein-specific IgG and IgM antibodies (anti-S1-IgG and -IgM) and cytokine or chemokine measurements. Freshly isolated PBMCs were stained and analysed by flow cytometry 15 . We obtained longitudinal serial time-point samples from a subset of these 98 study participants ( n = 48; information in Extended Data Table 1 ). To compare the immune phenotypes between sexes, two sets of data analyses were performed in parallel—baseline and longitudinal, as described below. As a control group, healthcare workers (HCWs) from Yale-New Haven Hospital were enrolled who were uninfected with COVID-19. Demographics and background information for the HCW group and the demographics of HCWs for cytokine assays and flow cytometry assays for the primary analyses are in Extended Data Table 1 . Demographic data, time-point information of the samples defined by the days from the symptom onset (DFSO) in each patient, treatment information, and raw data used to generate figures and tables is in Supplementary Table 1 . Baseline analysis The baseline analysis was performed on samples from the first time point of patients who met the following criteria: not in intensive care unit (ICU), had not received tocilizumab, and had not received high doses of corticosteroids (prednisone equivalent of more than 40 mg) before the first sample collection date. This patient group, cohort A, consisted of 39 patients (17 male and 22 female) (Extended Data Tables 1 , 2 ). Intersex and transgender individuals were not represented in this study. Figures 1 – 4 represent analyses of baseline raw values obtained from patients in cohort A. In cohort A patients, male and female patients were matched in terms of age, body mass index (BMI), and DFSO at the first time point sample collection (Extended Data Fig. 1a ). However, there were significant differences in age and BMI between HCW controls and patients (patients had higher age and BMI values) (Extended Data Table 1 ), and therefore an age- and BMI-adjusted difference-in-differences analysis was also performed in parallel (Extended Data Table 3 ). Fig. 1: Comparison of viral RNA concentrations, titres of anti-SARS-CoV-2 antibodies, and plasma cytokines and chemokine levels at the first sampling of cohort A patients. a , Comparison of viral RNA measured from nasopharyngeal (Np) swab and saliva. n = 14 for male and female patients (M_Pt and F_Pt, respectively) for nasopharyngeal samples, and n = 9 and 12, respectively, for saliva samples. Dotted lines indicate the detection limit<|im_end|> <|im_start|>assistant A new study looking at male and female immune responses to the new coronavirus may shed new light on why men are more likely to become seriously ill with COVID-19, researchers said Wednesday. Since early in the pandemic it has been clear that men, particularly older men, are at a far higher risk of dying from the virus than women of a similar age, but scientists have not yet been able to pinpoint exactly why. A new study published in the journal Nature noted that globally men account for about 60 percent of deaths from COVID-19 and looked at whether differences in immune responses could explain why. "What we found was that men and women indeed develop different types of immune responses to COVID-19," said the study's lead author Akiko Iwasaki, a professor at Yale University, in a video. The immunity specialist said "these differences may underlie heightened disease susceptibility in men". Researchers collected nasal, saliva, and blood samples from non-infected control subjects and patients with the disease who were treated at Yale New Haven Hospital in the United States. They then monitored patients to look at their immune responses. Researchers found that women mounted a more robust immune response involving T lymphocytes, which are a type of white blood cell that can recognize viruses and eliminate them. This was the case even among older women, the study found. In contrast, older men had weaker T cell activity—the older they were, the weaker the response. Overall men also produced more cytokines, which are inflammatory proteins that form another part of the body's natural immune defence. However, severe cases of COVID-19 have been linked to what is known as a "cytokine storm", when the immune system goes into overdrive, which is harmful and potentially deadly. Men who showed high concentrations early on were more likely to have a severe case of the disease, while those women who also showed significant cytokine levels also appeared to fare worse, the study found. According to the authors, this could imply that men and women need different treatments. For men, for example "we should be enhancing their T cell responses with vaccines" Iwasaki said, while women could be given treatment to dampen the cytokine response. Treated differently? But the study has limitations. Firstly, the sample size was relatively small, with 98 patients in total. The average age of the patients was also high, at around sixty years. Commenting on the research, Eleanor Riley, a professor at the University of Edinburgh, said some of the divergence noted in the study is "likely due to differences in age or BMI (the sex differences disappear once these other factors are taken into account)". BMI measures body fat. She said others could have arisen "by chance". "Importantly, although the average response may differ between men and women, the range of most of the measurements in men and women overlap significantly, meaning that many women have responses that are indistinguishable from those of many men," she added. Riley said this is why treatments would be better if they were individually tailored, rather than defined solely on sex. <|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 Most ovarian cancers are infiltrated by prognostically relevant activated T cells 1 , 2 , 3 , yet exhibit low response rates to immune checkpoint inhibitors 4 . Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer 5 , 6 , but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors. Main Ovarian cancer is an immunogenic disease in which the pre-established immunoreactive landscape determines the outcome of the patient 1 , 2 , 3 , 7 . However, as monotherapies such as immune checkpoint inhibitors that augment T cell activity have only very modest response rates in patients with advanced disease 4 . Recent studies have suggested that plasma cell and memory B cell infiltrates, including those in tertiary lymphoid structures 8 , are associated with the cytolytic activity of T cells at ovarian cancer beds, resulting in improved survival of patients 5 , 6 . Although these studies suggest that humoral responses may potentiate T cell immune surveillance, the roles of different antibody isotypes in malignant progression are controversial. To characterize the role of B cells in ovarian cancer, we first stained a panel of 534 annotated high-grade serous ovarian cancers (HGSOCs) from 3 independent cohorts with T and B cell markers. As expected, CD19 + B cell infiltrates were associated with improved overall survival (Extended Data Fig. 1a, b ), similar to data from The Cancer Genome Atlas (TCGA) (Extended Data Fig. 1c ), and positively correlated with T cell infiltrates (Extended Data Fig. 1d, e ). In addition, intra-epithelial T cells only predict improved survival 2 when B cells co-infiltrate tumour islets (Extended Data Fig. 1f ). To characterize the isotypes produced by these B cells, we analysed viable single-cell suspensions from 29 freshly dissociated HGSOCs. Intracellular staining of plasma cells and CD19 + CD20 − CD38 high CD27 + cells (defined as plasmablasts) revealed the dominant production of class-switched IgA, followed by IgG; this is consistent with mRNA expression data from TCGA (Fig. 1a , Extended Data Figs. 1 g–i, 2a, b ) and with surface staining of B cells (Fig. 1a , Extended Data Fig. 1g–i ). Fig. 1: IgA–pIgR colocalization is associated with protective immunity in human ovarian cancer. a , Left, percentage of FACS cell counts of IgA + , IgG + or IgM + cells among Ig + B cells or plasmablasts or plasma cells, normalized to 10,000 viable CD45 + cells. B cells, CD45 + CD3 − CD19 + CD20 + cells; plasmablasts, CD45 + CD3 − CD19 + CD20 − CD38 high cells; plasma cells, CD45 + CD3 − CD19 + CD20 − CD138 + and CD45 + CD3 − CD19 − CD20 − CD138 + cells. Each dot represents one tumour ( n = 29). Details of box plots can be found in Methods. P values were obtained by a two-way analysis of variance (ANOVA) followed by Dunnett’s test for multiple comparisons. Supplementary Table 1 provides further details on statistics. Right, bar graphs representing the percentage of each isotype produced by plasma cells (top) or B cells (bottom) in the same tumours, normalized to 10,000 viable CD45 + cells. IC, intracellular. b , IgA-coated CD45 − EpCAM + tumour epithelial cells (mean ± s.e.m., n = 10) in dissociated HGSOC. c , Expression of pIgR protein in independent HGSOC ( n = 27); tumour-free Fallopian tube ( n = 3), ovary ( n = 5) and omental ( n = 4) samples; ovarian tumour cell lines; and K562 leukaemia cells and THP1 monocyte cells (negative controls). Positive control, recombinant human pIgR. Western blots were repeated twice. NSCLC, non-small-cell lung cancer. d , Histograms showing FACS analysis of pIgR, in ovarian surface epithelial (OSE), K562, THP1, wild-type or PIGR -ablated (pIgR CRISPR ) OVCAR3 cells. e , Left, representative ( n = 273) combined staining of IgA, pIgR, IgG, PCK and DAPI. Instances with IgA–pIgR colocalization are indicated with arrows. Scale bar, 50 μm (top left), 20 μm (all other panels). Top right, representative ( n = 137, IgA–pIgR colocalization ≥ median) dot plot showing IgA–pIgR colocalized signal among DAPI + PCK + cells. Bottom right, scattered graph showing number of IgA–pIgR colocalized cells (averaged from duplicated cores) per mm 2 of PCK + (mean ± s.e.m., n = 273). f , Increased numbers of cells with IgA–pIgR colocalization per PCK + tumour islet area (averaged from duplicated cores) are associated with improved outcome (threshold, median; P = 0.0116, H. Lee Moffett Cancer Centre cohort (MCC) (right); P = 0.0002, New England Case–Control study cohort (NECC) (left)). g , Density of IgA-coated cells (averaged from duplicated cores) in tumour islets (cells per mm 2 PCK + area) is associated with improved outcome ( P = 0.0110 for MCC (right) and P = 0.0054 for NECC (left) cohorts). * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001, two-sided log-rank (Mantel–Cox) test. Source data Full size image As previously reported 6 , CD138 + plasma cell", "role": "user" }, { "content": "The prognosis of ovarian cancer is poor, with an estimated five-year survival of only 40% for advanced disease, the stage at which most ovarian carcinomas are diagnosed. These poor outcomes are partly due to the lack of effective therapies for advanced disease and recurrence. Immunotherapies hold promise for many types of cancer; however, studies have shown that patients with ovarian cancer do not have strong responses to existing drugs. In a new article published in Nature, Moffitt Cancer Center researchers demonstrate why some ovarian cancer patients evolve better than others and suggest possible approaches to improve patient outcomes. Immunotherapeutic drugs activate T cells, a type of immune cell, to put up a defense against tumor cells. Immunotherapies are approved to treat several different types of cancer and have greatly changed the standard of care and improved patient outcomes. However, in ovarian cancer, clinical studies using immunotherapies aimed at stimulating T cells resulted in modest response rates. Studies have suggested that cancer patients who have a higher presence of other immune cells, such as plasma and memory B cells, could respond better to immunotherapies, but how these cell types promote better outcomes is unclear. Moffitt researchers wanted to confirm whether antibodies produced by these cells are associated with better outcomes and assess how these cells contribute to the spontaneous anti-tumor immune response against ovarian cancer. The researchers analyzed a panel of 534 samples from ovarian cancer patients and found that patients who had a higher infiltration of B cells or B cell-derived plasma cells had better outcomes. B cells are a type of immune cell that produce antibodies and express one of five types of B cell receptors on their surface: IgM, IgD, IgG, IgE or IgA. These isotypes regulate different B cell signaling pathways and control B cell processes. The surprise came when, upon further analysis of the samples, the Moffitt team discovered that the antibodies produced by B and plasma cells were predominantly of the IgA subtype, followed by IgG. \"We found that the presence of IgA regulated downstream signaling pathways of the ovarian cancer cells. Specifically, IgA resulted in inhibition of the RAS signaling pathway, which is known to contribute to ovarian cancer development,\" said Jose Conejo-Garcia, M.D., Ph.D., chair of Moffitt's Immunology Department. This inhibition of RAS sensitized the tumor cells to T cell mediated cell killing, produced by both novel CAR T cells and tumor-infiltrating lymphocytes. The team also assessed that IgA and IgG secreted by the B cells recognized specific ovarian tumor cell surface markers and stimulated other immune cells called myeloid cells to target ovarian cancer cells for destruction. These data provide new insights into how components of the immune system regulate ovarian cancer progression and offer new opportunities to develop improved targeted agents. This includes a repertoire of tumor-derived antibodies that can be effectively used as novel immunotherapeutic agents. In addition, the study provides a mechanistic rationale for integrated antibody responses in the development of novel immunotherapies, which until now have been based on T cell-centric approaches. \"The findings indicate that immunotherapies that boost both coordinated B and T cell responses against ovarian cancer, an immunogenic disease currently resistant to checkpoint inhibitors, are likely to show superior therapeutic benefit,\" said Subir Biswas, Ph.D., first author and postdoctoral fellow in the Conejo-Garcia lab. ", "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 Most ovarian cancers are infiltrated by prognostically relevant activated T cells 1 , 2 , 3 , yet exhibit low response rates to immune checkpoint inhibitors 4 . Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer 5 , 6 , but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors. Main Ovarian cancer is an immunogenic disease in which the pre-established immunoreactive landscape determines the outcome of the patient 1 , 2 , 3 , 7 . However, as monotherapies such as immune checkpoint inhibitors that augment T cell activity have only very modest response rates in patients with advanced disease 4 . Recent studies have suggested that plasma cell and memory B cell infiltrates, including those in tertiary lymphoid structures 8 , are associated with the cytolytic activity of T cells at ovarian cancer beds, resulting in improved survival of patients 5 , 6 . Although these studies suggest that humoral responses may potentiate T cell immune surveillance, the roles of different antibody isotypes in malignant progression are controversial. To characterize the role of B cells in ovarian cancer, we first stained a panel of 534 annotated high-grade serous ovarian cancers (HGSOCs) from 3 independent cohorts with T and B cell markers. As expected, CD19 + B cell infiltrates were associated with improved overall survival (Extended Data Fig. 1a, b ), similar to data from The Cancer Genome Atlas (TCGA) (Extended Data Fig. 1c ), and positively correlated with T cell infiltrates (Extended Data Fig. 1d, e ). In addition, intra-epithelial T cells only predict improved survival 2 when B cells co-infiltrate tumour islets (Extended Data Fig. 1f ). To characterize the isotypes produced by these B cells, we analysed viable single-cell suspensions from 29 freshly dissociated HGSOCs. Intracellular staining of plasma cells and CD19 + CD20 − CD38 high CD27 + cells (defined as plasmablasts) revealed the dominant production of class-switched IgA, followed by IgG; this is consistent with mRNA expression data from TCGA (Fig. 1a , Extended Data Figs. 1 g–i, 2a, b ) and with surface staining of B cells (Fig. 1a , Extended Data Fig. 1g–i ). Fig. 1: IgA–pIgR colocalization is associated with protective immunity in human ovarian cancer. a , Left, percentage of FACS cell counts of IgA + , IgG + or IgM + cells among Ig + B cells or plasmablasts or plasma cells, normalized to 10,000 viable CD45 + cells. B cells, CD45 + CD3 − CD19 + CD20 + cells; plasmablasts, CD45 + CD3 − CD19 + CD20 − CD38 high cells; plasma cells, CD45 + CD3 − CD19 + CD20 − CD138 + and CD45 + CD3 − CD19 − CD20 − CD138 + cells. Each dot represents one tumour ( n = 29). Details of box plots can be found in Methods. P values were obtained by a two-way analysis of variance (ANOVA) followed by Dunnett’s test for multiple comparisons. Supplementary Table 1 provides further details on statistics. Right, bar graphs representing the percentage of each isotype produced by plasma cells (top) or B cells (bottom) in the same tumours, normalized to 10,000 viable CD45 + cells. IC, intracellular. b , IgA-coated CD45 − EpCAM + tumour epithelial cells (mean ± s.e.m., n = 10) in dissociated HGSOC. c , Expression of pIgR protein in independent HGSOC ( n = 27); tumour-free Fallopian tube ( n = 3), ovary ( n = 5) and omental ( n = 4) samples; ovarian tumour cell lines; and K562 leukaemia cells and THP1 monocyte cells (negative controls). Positive control, recombinant human pIgR. Western blots were repeated twice. NSCLC, non-small-cell lung cancer. d , Histograms showing FACS analysis of pIgR, in ovarian surface epithelial (OSE), K562, THP1, wild-type or PIGR -ablated (pIgR CRISPR ) OVCAR3 cells. e , Left, representative ( n = 273) combined staining of IgA, pIgR, IgG, PCK and DAPI. Instances with IgA–pIgR colocalization are indicated with arrows. Scale bar, 50 μm (top left), 20 μm (all other panels). Top right, representative ( n = 137, IgA–pIgR colocalization ≥ median) dot plot showing IgA–pIgR colocalized signal among DAPI + PCK + cells. Bottom right, scattered graph showing number of IgA–pIgR colocalized cells (averaged from duplicated cores) per mm 2 of PCK + (mean ± s.e.m., n = 273). f , Increased numbers of cells with IgA–pIgR colocalization per PCK + tumour islet area (averaged from duplicated cores) are associated with improved outcome (threshold, median; P = 0.0116, H. Lee Moffett Cancer Centre cohort (MCC) (right); P = 0.0002, New England Case–Control study cohort (NECC) (left)). g , Density of IgA-coated cells (averaged from duplicated cores) in tumour islets (cells per mm 2 PCK + area) is associated with improved outcome ( P = 0.0110 for MCC (right) and P = 0.0054 for NECC (left) cohorts). * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001, two-sided log-rank (Mantel–Cox) test. Source data Full size image As previously reported 6 , CD138 + plasma cell<|im_end|> <|im_start|>assistant The prognosis of ovarian cancer is poor, with an estimated five-year survival of only 40% for advanced disease, the stage at which most ovarian carcinomas are diagnosed. These poor outcomes are partly due to the lack of effective therapies for advanced disease and recurrence. Immunotherapies hold promise for many types of cancer; however, studies have shown that patients with ovarian cancer do not have strong responses to existing drugs. In a new article published in Nature, Moffitt Cancer Center researchers demonstrate why some ovarian cancer patients evolve better than others and suggest possible approaches to improve patient outcomes. Immunotherapeutic drugs activate T cells, a type of immune cell, to put up a defense against tumor cells. Immunotherapies are approved to treat several different types of cancer and have greatly changed the standard of care and improved patient outcomes. However, in ovarian cancer, clinical studies using immunotherapies aimed at stimulating T cells resulted in modest response rates. Studies have suggested that cancer patients who have a higher presence of other immune cells, such as plasma and memory B cells, could respond better to immunotherapies, but how these cell types promote better outcomes is unclear. Moffitt researchers wanted to confirm whether antibodies produced by these cells are associated with better outcomes and assess how these cells contribute to the spontaneous anti-tumor immune response against ovarian cancer. The researchers analyzed a panel of 534 samples from ovarian cancer patients and found that patients who had a higher infiltration of B cells or B cell-derived plasma cells had better outcomes. B cells are a type of immune cell that produce antibodies and express one of five types of B cell receptors on their surface: IgM, IgD, IgG, IgE or IgA. These isotypes regulate different B cell signaling pathways and control B cell processes. The surprise came when, upon further analysis of the samples, the Moffitt team discovered that the antibodies produced by B and plasma cells were predominantly of the IgA subtype, followed by IgG. "We found that the presence of IgA regulated downstream signaling pathways of the ovarian cancer cells. Specifically, IgA resulted in inhibition of the RAS signaling pathway, which is known to contribute to ovarian cancer development," said Jose Conejo-Garcia, M.D., Ph.D., chair of Moffitt's Immunology Department. This inhibition of RAS sensitized the tumor cells to T cell mediated cell killing, produced by both novel CAR T cells and tumor-infiltrating lymphocytes. The team also assessed that IgA and IgG secreted by the B cells recognized specific ovarian tumor cell surface markers and stimulated other immune cells called myeloid cells to target ovarian cancer cells for destruction. These data provide new insights into how components of the immune system regulate ovarian cancer progression and offer new opportunities to develop improved targeted agents. This includes a repertoire of tumor-derived antibodies that can be effectively used as novel immunotherapeutic agents. In addition, the study provides a mechanistic rationale for integrated antibody responses in the development of novel immunotherapies, which until now have been based on T cell-centric approaches. "The findings indicate that immunotherapies that boost both coordinated B and T cell responses against ovarian cancer, an immunogenic disease currently resistant to checkpoint inhibitors, are likely to show superior therapeutic benefit," said Subir Biswas, Ph.D., first author and postdoctoral fellow in the Conejo-Garcia lab. <|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 endosomal sorting complex required for transport (ESCRT)-III mediates membrane fission in fundamental cellular processes, including cytokinesis. ESCRT-III is thought to form persistent filaments that over time increase their curvature to constrict membranes. Unexpectedly, we found that ESCRT-III at the midbody of human cells rapidly turns over subunits with cytoplasmic pools while gradually forming larger assemblies. ESCRT-III turnover depended on the ATPase VPS4, which accumulated at the midbody simultaneously with ESCRT-III subunits, and was required for assembly of functional ESCRT-III structures. In vitro , the Vps2/Vps24 subunits of ESCRT-III formed side-by-side filaments with Snf7 and inhibited further polymerization, but the growth inhibition was alleviated by the addition of Vps4 and ATP. High-speed atomic force microscopy further revealed highly dynamic arrays of growing and shrinking ESCRT-III spirals in the presence of Vps4. Continuous ESCRT-III remodelling by subunit turnover might facilitate shape adaptions to variable membrane geometries, with broad implications for diverse cellular processes. Main The endosomal sorting complex required for transport-III (ESCRT-III) promotes membrane fission from the inner side of membrane necks in various cellular processes 1 , including the biogenesis of multivesicular bodies 2 , cytokinetic abscission 3 , 4 , 5 , 6 , 7 , nuclear envelope sealing 8 , 9 , 10 , 11 , plasma membrane repair 12 , human immunodeficiency virus (HIV) budding 13 , 14 , and exosome or microvesicle shedding 15 , 16 , 17 . ESCRT-III forms polymers that are thought to constrict membrane necks until they split 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , but the mechanism underlying constriction is unknown. ESCRT-III is evolutionarily conserved from humans to archaea, and is composed of four structurally related core subunits with distinct functions 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 . Budding yeast Vps20 (human homologue is CHMP6) functions as a nucleation factor, Snf7 (human homologue CHMP4 has three isoforms, A–C) serves as a main polymer subunit, Vps24 (CHMP3 in humans) and Vps2 (CHMP2A and B isoforms in humans) inhibit Snf7 polymerization 28 , 29 , 30 , 31 , 32 and recruit the ATPase Vps4, which is thought to predominantly disassemble ESCRT-III polymers 30 , 31 , 33 , 34 , 35 , 36 , 37 , 38 . How different ESCRT-III components coordinately assemble and remodel polymer structures has remained unclear. Purified ESCRT-III subunits polymerize into filaments that form spirals on flat membranes or helices on membrane tubes 36 , 39 , 40 , 41 , 42 , 43 , 44 , 45 . ESCRT-III also forms filament spirals and helices in intact cells 44 , 46 , 47 , and it is required for the assembly of large filament helices that constrict the intercellular bridge during cytokinetic abscission 4 . Prevailing models propose that ESCRT-III mediates membrane fission by sequential assembly of distinct subunits 18 , 19 , 20 , 21 , 22 , 23 , 25 , whereby late-binding Vps2/Vps24 (CHMP2/CHMP3) subunits might form a rigid dome-shaped scaffold to guide attached membranes towards the fission site 36 or induce changes in the curvature of pre-assembled Snf7 filament spirals to promote membrane neck constriction 41 . These models rely on the sequential addition of distinct subunits and the persistence of ESCRT-III polymers, yet this has not been directly observed under physiological conditions. We hence set out to systematically quantify the assembly kinetics, dynamics and structure of ESCRT polymers in live human cells and in an in vitro reconstitution system. RESULTS ESCRT-III assemblies continuously turn over their subunits with the cytoplasm To investigate the dynamics of ESCRT-III polymers at the abscission site, we generated stable HeLa cell lines expressing fluorescently tagged subunits. We found that CHMP4B tagged with GFP via a long flexible linker (localization and affinity purification tag, LAP) and expressed close to endogenous levels 4 did not perturb abscission ( Fig. 1a ). To probe the functionality of LAP-tagged CHMP4B, we depleted endogenous CHMP4B in wild-type HeLa cells or in HeLa cells stably expressing short interfering RNA (siRNA)-resistant mouse CHMP4B-LAP ( Supplementary Fig. 1a ). Cytokinetic abscission was substantially perturbed following depletion of endogenous CHMP4B in wild-type HeLa cells, but was not affected in mouse-CHMP4B-LAP-expressing HeLa cells ( Fig. 1a ), validating the functionality of CHMP4B-LAP. Figure 1: ESCRT-III assemblies at the midbody dynamically turn over subunits in early and late abscission stages. ( a ) Validation of mmCHMP4B-LAP functionality by RNAi phenotype rescue. Cumulative histograms indicate duration from complete cleavage furrow ingression until abscission for wild-type HeLa cells and for HeLa cells expressing mmCHMP4B-LAP at 55–80 h after siRNA transfection (3 independent experiments with combined sample numbers of n = 48 cells for wild-type + siControl, n = 38 cells for wild-type + siCHMP4B, n = 60 cells for mmCHMP4B-LAP + siControl, and n = 46 cells for mmCHMP4B-LAP + siCHMP4B). siCHMP4B (hs) targets only endogenous human CHMP4B but not mmCHMP4B-LAP. ( b ) FRAP of mmCHMP4B-LAP at a HeLa cell midbody at early and late abscission stages, stained with SiR-tubulin. The dashed circles indicate the photobleaching region; time 0 indicates the first image after photobleaching. High-resolution example of experiment in c – e . ( c , d ) Fluorescence recovery curves for early abscission ( n = 18 cells from 4 independent experiments) ( c ) or late abscission stages ( n = 17 cells from 4 independent experiments) ( d ). Single exponential function f ( t ) = 1 − e (− k ∗ t ) , or double exponential function f ( t ) = A1 ∗ (1 − e (− k 1 ∗ t ) ) + (1 − A1 ∗ )(1 − e (− k 2 ∗ t ) ) were fitted to the data. The points and shaded areas indicate mean ± s.e.m. of fluorescence; the dashed lines indicate fits of exponential functions. ( e ) Quantification of highly mobile fractions by fitting double exponential functions to data", "role": "user" }, { "content": "Cells multiply by duplicating themselves: they grow, replicate their components, and finally split into two. Many diseases are related to defective cell division; cancer is one of them. Understanding mechanisms conducting this division is therefore essential in the search for cancer treatments. Researchers at the University of Geneva (UNIGE), Switzerland, in collaboration with the IMBA- Institute of Molecular Biotechnology at the Vienna BioCenter (VBC) and the Weill Cornell Medical College in New York, have turned their attention in particular to the role of ESCRT proteins, which are responsible for severing cell membranes. These proteins assemble in spirals that gradually bring about cleavage of the membrane, spirals that are constantly renewing themselves with the help of the Vps4 molecule. Without this molecule the renewal stops, eventually preventing the membrane from being severed. This research, reported in the journal Nature Cell Biology, sheds new light on the fight against cancer and HIV, both of which depend on cell division. In a previous research, the team led by Professor Aurélien Roux of the Department of Biochemistry at the Faculty of Sciences of the UNIGE, discovered that ESCRT proteins assemble in the form of spirals, a structure that is unique amongst the many forms created by the organism's filamentous proteins. Why this unique form? During cell division, the cell contracts at its centre to separate the two daughter cells. At the end of this stage, called cytokinesis, a very thin link remains between the cells, a tube of plasma membrane - the cell's skin - called the \"cytoplasmic bridge\". The spirals formed by ESCRT proteins coil around the inner surface of this tube and constrict it in order to sever it, a stage called abscission. Professor Roux's team showed that these spirals behaved like the springs of a watch, suggesting a scenario wherein the more the ESCRT proteins assembled, the more tightly they were compressed. Research conducted simultaneously in vitro and in vivo After discovering why these molecules assembled in spirals, the UNIGE researchers examined the dynamics of the assembly. Until now scientists have thought that they assembled like Lego blocks, the proteins being added progressively to the structure without ever leaving it. In this new study, biochemists were able to invalidate this hypothesis. To do so they joined forces with the Gerlich group at IMBA, Vienna Biocenter, to conduct the experiment simultaneously in vivo (the Viennese scientists' part) and in vitro (the Genevan scientists' part). \"On our side, we observed the dynamics of the ESCRT proteins by isolating them on a flat artificial membrane that we created using lipids, onto which we placed the ESCRT protein complexes,\" explains Nicolas Chiaruttini, a research scientist at UNIGE. \"And contrary to what we thought, the proteins do not form a rigidly fixed spiral that is compressed; instead there is a constant renewal of proteins, creating supple, mobile spirals in constant motion.\" Using a new imaging technique, the team led by Simon Scheuring in New York, working in collaboration with the UNIGE team, was able to directly visualize the dynamics and flexibility of these spirals. Conducting further research, the biochemists noted that this renewal cannot occur without the Vps4 molecule, which is an integral part of ESCRT protein complexes. \"Vps4 is known for disassembling molecules in polymeric structures,\" says Aurélien Roux. \"So it is the indispensable ingredient for the severing of membranes insofar as it enables the renewal of spirals.\" It is worthwhile noting that the Viennese researchers reached exactly the same conclusions. \"During our observations in the cell in motion, Vps4 was revealed to be necessary for the renewal of spirals,\" explains Beata Mierzwa, a researcher at IMBA-VBC. More importantly, the team observed that the absence or inactivation of Vps4 inhibited cell division in 50% of cases and delayed it significantly in the other 50%. Vps4 and the constant renewal of ESCRTs appear, therefore, to be essential for abscission. \"It is rare to be able to conduct experiments in vivo and in vitro simultaneously, and the fact that the results coincide firmly establishes our study.\" Another way to approach cancer and HIV Cancer is characterized by excessive multiplication of diseased cells. By elucidating the role of the Vps4 molecule in cell division, researchers have decipher mechanisms that could be targeted as new treatments that would, for instance, block ESCRT protein renewal directly, thereby preventing the proliferation of the disease. Similarly, when a cell is infected by the Human Immunodeficiency Virus, virus particles bud from the membrane, then eventually break off from it to infect other cells. The virus must also sever the cell membrane in order to be released and spread the disease—a stage that is also carried out by ESCRT proteins. Here again, targeting the Vps4 molecule could prevent the virus from leaving the infected cell. The primary role of fundamental research is not to find new drugs for cancer or AIDS traitements, but rather, by understanding how ESCRT and Vps4 participate in cell division and virus replication, \"to provide knowledge essential to treat those diseases, and clues about potential interactions between treatments\", concludes Aurélien Roux. ", "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 endosomal sorting complex required for transport (ESCRT)-III mediates membrane fission in fundamental cellular processes, including cytokinesis. ESCRT-III is thought to form persistent filaments that over time increase their curvature to constrict membranes. Unexpectedly, we found that ESCRT-III at the midbody of human cells rapidly turns over subunits with cytoplasmic pools while gradually forming larger assemblies. ESCRT-III turnover depended on the ATPase VPS4, which accumulated at the midbody simultaneously with ESCRT-III subunits, and was required for assembly of functional ESCRT-III structures. In vitro , the Vps2/Vps24 subunits of ESCRT-III formed side-by-side filaments with Snf7 and inhibited further polymerization, but the growth inhibition was alleviated by the addition of Vps4 and ATP. High-speed atomic force microscopy further revealed highly dynamic arrays of growing and shrinking ESCRT-III spirals in the presence of Vps4. Continuous ESCRT-III remodelling by subunit turnover might facilitate shape adaptions to variable membrane geometries, with broad implications for diverse cellular processes. Main The endosomal sorting complex required for transport-III (ESCRT-III) promotes membrane fission from the inner side of membrane necks in various cellular processes 1 , including the biogenesis of multivesicular bodies 2 , cytokinetic abscission 3 , 4 , 5 , 6 , 7 , nuclear envelope sealing 8 , 9 , 10 , 11 , plasma membrane repair 12 , human immunodeficiency virus (HIV) budding 13 , 14 , and exosome or microvesicle shedding 15 , 16 , 17 . ESCRT-III forms polymers that are thought to constrict membrane necks until they split 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , but the mechanism underlying constriction is unknown. ESCRT-III is evolutionarily conserved from humans to archaea, and is composed of four structurally related core subunits with distinct functions 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 . Budding yeast Vps20 (human homologue is CHMP6) functions as a nucleation factor, Snf7 (human homologue CHMP4 has three isoforms, A–C) serves as a main polymer subunit, Vps24 (CHMP3 in humans) and Vps2 (CHMP2A and B isoforms in humans) inhibit Snf7 polymerization 28 , 29 , 30 , 31 , 32 and recruit the ATPase Vps4, which is thought to predominantly disassemble ESCRT-III polymers 30 , 31 , 33 , 34 , 35 , 36 , 37 , 38 . How different ESCRT-III components coordinately assemble and remodel polymer structures has remained unclear. Purified ESCRT-III subunits polymerize into filaments that form spirals on flat membranes or helices on membrane tubes 36 , 39 , 40 , 41 , 42 , 43 , 44 , 45 . ESCRT-III also forms filament spirals and helices in intact cells 44 , 46 , 47 , and it is required for the assembly of large filament helices that constrict the intercellular bridge during cytokinetic abscission 4 . Prevailing models propose that ESCRT-III mediates membrane fission by sequential assembly of distinct subunits 18 , 19 , 20 , 21 , 22 , 23 , 25 , whereby late-binding Vps2/Vps24 (CHMP2/CHMP3) subunits might form a rigid dome-shaped scaffold to guide attached membranes towards the fission site 36 or induce changes in the curvature of pre-assembled Snf7 filament spirals to promote membrane neck constriction 41 . These models rely on the sequential addition of distinct subunits and the persistence of ESCRT-III polymers, yet this has not been directly observed under physiological conditions. We hence set out to systematically quantify the assembly kinetics, dynamics and structure of ESCRT polymers in live human cells and in an in vitro reconstitution system. RESULTS ESCRT-III assemblies continuously turn over their subunits with the cytoplasm To investigate the dynamics of ESCRT-III polymers at the abscission site, we generated stable HeLa cell lines expressing fluorescently tagged subunits. We found that CHMP4B tagged with GFP via a long flexible linker (localization and affinity purification tag, LAP) and expressed close to endogenous levels 4 did not perturb abscission ( Fig. 1a ). To probe the functionality of LAP-tagged CHMP4B, we depleted endogenous CHMP4B in wild-type HeLa cells or in HeLa cells stably expressing short interfering RNA (siRNA)-resistant mouse CHMP4B-LAP ( Supplementary Fig. 1a ). Cytokinetic abscission was substantially perturbed following depletion of endogenous CHMP4B in wild-type HeLa cells, but was not affected in mouse-CHMP4B-LAP-expressing HeLa cells ( Fig. 1a ), validating the functionality of CHMP4B-LAP. Figure 1: ESCRT-III assemblies at the midbody dynamically turn over subunits in early and late abscission stages. ( a ) Validation of mmCHMP4B-LAP functionality by RNAi phenotype rescue. Cumulative histograms indicate duration from complete cleavage furrow ingression until abscission for wild-type HeLa cells and for HeLa cells expressing mmCHMP4B-LAP at 55–80 h after siRNA transfection (3 independent experiments with combined sample numbers of n = 48 cells for wild-type + siControl, n = 38 cells for wild-type + siCHMP4B, n = 60 cells for mmCHMP4B-LAP + siControl, and n = 46 cells for mmCHMP4B-LAP + siCHMP4B). siCHMP4B (hs) targets only endogenous human CHMP4B but not mmCHMP4B-LAP. ( b ) FRAP of mmCHMP4B-LAP at a HeLa cell midbody at early and late abscission stages, stained with SiR-tubulin. The dashed circles indicate the photobleaching region; time 0 indicates the first image after photobleaching. High-resolution example of experiment in c – e . ( c , d ) Fluorescence recovery curves for early abscission ( n = 18 cells from 4 independent experiments) ( c ) or late abscission stages ( n = 17 cells from 4 independent experiments) ( d ). Single exponential function f ( t ) = 1 − e (− k ∗ t ) , or double exponential function f ( t ) = A1 ∗ (1 − e (− k 1 ∗ t ) ) + (1 − A1 ∗ )(1 − e (− k 2 ∗ t ) ) were fitted to the data. The points and shaded areas indicate mean ± s.e.m. of fluorescence; the dashed lines indicate fits of exponential functions. ( e ) Quantification of highly mobile fractions by fitting double exponential functions to data<|im_end|> <|im_start|>assistant Cells multiply by duplicating themselves: they grow, replicate their components, and finally split into two. Many diseases are related to defective cell division; cancer is one of them. Understanding mechanisms conducting this division is therefore essential in the search for cancer treatments. Researchers at the University of Geneva (UNIGE), Switzerland, in collaboration with the IMBA- Institute of Molecular Biotechnology at the Vienna BioCenter (VBC) and the Weill Cornell Medical College in New York, have turned their attention in particular to the role of ESCRT proteins, which are responsible for severing cell membranes. These proteins assemble in spirals that gradually bring about cleavage of the membrane, spirals that are constantly renewing themselves with the help of the Vps4 molecule. Without this molecule the renewal stops, eventually preventing the membrane from being severed. This research, reported in the journal Nature Cell Biology, sheds new light on the fight against cancer and HIV, both of which depend on cell division. In a previous research, the team led by Professor Aurélien Roux of the Department of Biochemistry at the Faculty of Sciences of the UNIGE, discovered that ESCRT proteins assemble in the form of spirals, a structure that is unique amongst the many forms created by the organism's filamentous proteins. Why this unique form? During cell division, the cell contracts at its centre to separate the two daughter cells. At the end of this stage, called cytokinesis, a very thin link remains between the cells, a tube of plasma membrane - the cell's skin - called the "cytoplasmic bridge". The spirals formed by ESCRT proteins coil around the inner surface of this tube and constrict it in order to sever it, a stage called abscission. Professor Roux's team showed that these spirals behaved like the springs of a watch, suggesting a scenario wherein the more the ESCRT proteins assembled, the more tightly they were compressed. Research conducted simultaneously in vitro and in vivo After discovering why these molecules assembled in spirals, the UNIGE researchers examined the dynamics of the assembly. Until now scientists have thought that they assembled like Lego blocks, the proteins being added progressively to the structure without ever leaving it. In this new study, biochemists were able to invalidate this hypothesis. To do so they joined forces with the Gerlich group at IMBA, Vienna Biocenter, to conduct the experiment simultaneously in vivo (the Viennese scientists' part) and in vitro (the Genevan scientists' part). "On our side, we observed the dynamics of the ESCRT proteins by isolating them on a flat artificial membrane that we created using lipids, onto which we placed the ESCRT protein complexes," explains Nicolas Chiaruttini, a research scientist at UNIGE. "And contrary to what we thought, the proteins do not form a rigidly fixed spiral that is compressed; instead there is a constant renewal of proteins, creating supple, mobile spirals in constant motion." Using a new imaging technique, the team led by Simon Scheuring in New York, working in collaboration with the UNIGE team, was able to directly visualize the dynamics and flexibility of these spirals. Conducting further research, the biochemists noted that this renewal cannot occur without the Vps4 molecule, which is an integral part of ESCRT protein complexes. "Vps4 is known for disassembling molecules in polymeric structures," says Aurélien Roux. "So it is the indispensable ingredient for the severing of membranes insofar as it enables the renewal of spirals." It is worthwhile noting that the Viennese researchers reached exactly the same conclusions. "During our observations in the cell in motion, Vps4 was revealed to be necessary for the renewal of spirals," explains Beata Mierzwa, a researcher at IMBA-VBC. More importantly, the team observed that the absence or inactivation of Vps4 inhibited cell division in 50% of cases and delayed it significantly in the other 50%. Vps4 and the constant renewal of ESCRTs appear, therefore, to be essential for abscission. "It is rare to be able to conduct experiments in vivo and in vitro simultaneously, and the fact that the results coincide firmly establishes our study." Another way to approach cancer and HIV Cancer is characterized by excessive multiplication of diseased cells. By elucidating the role of the Vps4 molecule in cell division, researchers have decipher mechanisms that could be targeted as new treatments that would, for instance, block ESCRT protein renewal directly, thereby preventing the proliferation of the disease. Similarly, when a cell is infected by the Human Immunodeficiency Virus, virus particles bud from the membrane, then eventually break off from it to infect other cells. The virus must also sever the cell membrane in order to be released and spread the disease—a stage that is also carried out by ESCRT proteins. Here again, targeting the Vps4 molecule could prevent the virus from leaving the infected cell. The primary role of fundamental research is not to find new drugs for cancer or AIDS traitements, but rather, by understanding how ESCRT and Vps4 participate in cell division and virus replication, "to provide knowledge essential to treat those diseases, and clues about potential interactions between treatments", concludes Aurélien Roux. <|im_end|>

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2,673

[ { "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 T cell antigen receptor (TCR) expressed on thymocytes interacts with self-peptide major histocompatibility complex (pMHC) ligands to signal apoptosis or survival. Here, we found that negative-selection ligands induced thymocytes to exert forces on the TCR and the co-receptor CD8 and formed cooperative TCR–pMHC–CD8 trimolecular ‘catch bonds’, whereas positive-selection ligands induced less sustained thymocyte forces on TCR and CD8 and formed shorter-lived, independent TCR–pMHC and pMHC–CD8 bimolecular ‘slip bonds’. Catch bonds were not intrinsic to either the TCR–pMHC or the pMHC–CD8 arm of the trans (cross-junctional) heterodimer but resulted from coupling of the extracellular pMHC–CD8 interaction to the intracellular interaction of CD8 with TCR–CD3 via associated kinases to form a cis (lateral) heterodimer capable of inside-out signaling. We suggest that the coupled trans–cis heterodimeric interactions form a mechanotransduction loop that reinforces negative-selection signaling that is distinct from positive-selection signaling in the thymus. Main T cell antigen recognition occurs through interactions between TCRs and pMHCs. The invariant co-receptors CD4 or CD8 also bind pMHC class II or I molecules, respectively. This recognition is highly discriminative, because small differences in peptide sequence can induce distinctive phenotypic outcomes in T cells. Extensive studies have been devoted to these molecular interactions 1 . Nonetheless, understanding remains incomplete regarding how the TCR and/or CD4/CD8 interact with pMHC in situ, what measures of these interactions provide the most informative features to predict T cell behavior, how such interactions transmit (and are regulated by) extracellular and intracellular signals, and how they drive T cell function and developmental fate. Existing models of thymocyte selection are based on measurements of TCR kinetics and affinity; for example, the TCR–pMHC dwell time determines the selection outcome 2 , 3 . The differences in TCR dwell times with positive- and negative-selection ligands measured with purified proteins in solution (3D measurements) are very small; however, signaling initiated by these ligands results in the survival or death of thymocytes 2 , 4 . Whereas making in situ measurements with TCRs and co-receptors on live cells (2D measurements) is an important advance in kinetic analysis 5 , 6 , 7 , these measurements are made without externally applied force and assess bond quantity only and may miss key information required to predict all T cell behaviors 8 . Additional information can be found by measuring TCR–pMHC dissociation under force, a method assessing bond quality and revealing TCR dynamic bonds, including catch bonds with agonist pMHCs, in which force prolongs bond lifetime, and slip bonds with antagonist pMHCs, in which force shortens bond lifetime, thereby amplifying the kinetic differences among TCR bonds with different pMHCs 9 , 10 , 11 . Furthermore, T cells exert endogenous forces on the TCR and CD8 in a manner dependent on the ligand and the protein tyrosine kinase Lck, thus supporting the physiological relevance of kinetic measurements under force 12 . To find better predictors of thymocyte-selection outcomes, we made in situ measurements of the affinities, molecular stiffness 13 , and force-dependent lifetimes of the bonds of two panels of pMHCs with two TCRs and/or CD8, and the thymocyte forces exerted on these bonds. Our data suggest that mechanotransduction amplifies the ligand-discriminative power of the TCR, thus allowing for the outcome of thymocyte selection to be determined. Results TCR dynamic bonds distinguish negative- and positive-selection ligands We used a biomembrane force probe (BFP) 9 to measure the force-dependent lifetimes of single pMHC bonds on the surfaces of CD4 + CD8 + double-positive (DP) thymocytes from OT1 TCR transgenic mice. The probe was coated with H2-K b or H2-K b α3A2 (in which the mouse α3 domain was replaced with that of human HLA-A2 to abolish CD8 binding 9 ) to present Q4H7, the strongest positive-selection peptide, or Q4R7, the weakest negative-selection peptide, in a panel of peptides mutated from the ovalbumin (OVA)-derived sequence SIINFEKL, previously identified with fetal thymic organ culture 4 (Fig. 1a ). The OT1 TCR interactions with Q4H7 and Q4R7 presented by H2-K b α3A2 (denoted mQ4R7 and mQ4H7 hereafter) showed comparable slip bonds, in which the mean bond lifetime decreased monotonically with increasing force (Fig. 1b ). CD8 interaction with VSV (RGYVYQGL) presented by H2-K b (denoted wVSV hereafter), a noncognate ligand of the OT1 TCR, showed short-lived slip bonds (Fig. 1b ). We next used H2-K b to present cognate peptides, thus allowing for interaction with TCR, CD8, and both (denoted total interaction hereafter); wQ4R7 formed a catch bond that prolonged lifetime at low forces, then transitioned to a slip bond at >13 pN force, whereas wQ4H7 formed a short-lived slip bond nearly identical to that of mQ4H7 (Fig. 1b ). These data suggest that whether a ligand forms a CD8-dependent catch bond with the TCR at low force determines whether it is a negative-selection ligand. Fig. 1: Lck-dependent dynamic bonds of TCR and/or CD8 with Q4H7 and Q4R7. a , BFP setup (left) and schematic showing the interacting molecules (right). The BFP uses a pressurized red blood cell (RBC) as a force transducer with an attached glass bead to present pMHC. A thymocyte is aspirated by an apposing micropipette and driven to contact the bead. Scale bar, 5 µm. The pMHC on the BFP bead is coupled via biotin–streptavidin (SA) and interacts with the TCR–CD3 complex as well as the CD8 co-receptor on the DP thymocyte. b , c , Untreated ( b ) and Lck-inhibitor- or DMSO-treated ( c ) systems. From left to right, the first and second graphs show data from OT1 thymocytes, and the third and forth graphs show data from OT1.CD8.4 thymocytes. The first and third graphs show data for Q4H7, whereas the second and fourth graphs show data for Q4R7. Data are shown as mean ± s.e.m. of lifetime-versus-force plots of TCR bonds with Q4H7 or Q4R7 presented by H2-K b α3A2 (brown circles), total bonds with either peptide presented by H2-K b (green squares), or CD8 bonds with VSV:H-2K b (black triangles). Open and closed symbols denote untreated and Lck-inhibitor-treated systems, respectively. Open black squares denote", "role": "user" }, { "content": "Ball lands in cup; cup triggers spring; spring clamps lever onto ball and holds it tight. That's a rough description of newly discovered cellular mechanisms that eliminate T cells that may cause autoimmune disorders. Although the mechanisms are intertwined with biochemical processes, they also work mechanically, grasping, tugging and clamping, say researchers at the Georgia Institute of Technology, who, for a new study in the journal Nature Immunology, measured responses to physical force acting upon these elimination mechanisms. The mechanisms' purpose is to make dangerously aggressive developing immune cells called thymocytes kill themselves to keep them from attacking the body, while sparing healthy thymocytes as they mature into T cells. Understanding these selection mechanisms, which ensure T cells aggressively pursue hordes of infectors and cancers but not damage healthy human tissue, could someday lead to new immune-regulating therapies. Two-handed handshake Usually, researchers pursue such mechanisms using chemistry experiments, but Georgia Tech's Cheng Zhu, who led the study, makes atypical discoveries via physical experiments to observe effects of forces between key proteins in living cells. \"Experiments where the proteins are isolated and used in chemical reactions in vitro miss this force dynamic,\" said Zhu, a Regents Professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. \"Before our work, force was not considered as a factor in thymocyte selection and now it is.\" In this study, they discovered a loop of physical signals resembling a double-handed handshake that encourages cell suicide. It is described in more detail below. The medical significance of this field of research was highlighted by the 2018 Nobel Prize in medicine, which was awarded to other researchers at other institutions, James Allison of MD Anderson Cancer Center and Tasuku Honjo of Kyoto University. Allison and Honjo received the prize for their cancer therapies exploiting T cell regulating mechanisms intertwined with those that the Georgia Tech researchers study. Georgia Tech's Zhu and first authors Jinsung Hong and Chenghao Ge published their new research paper on November 12, 2018. The research was funded by the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Institute of Neurological Disorders and Stroke. The agencies are part of the National Institutes of Health. Under the microscope, tiny pipettes tug at living cells to exert forces on their structures, measure those forces and observe the consequences for the cells. Credit: Georgia Tech / Allison Carter Thymocyte death gauntlet Like blood cells, human thymocytes are born in bone marrow, but they travel to the thymus, a small organ just below the neck, where they run a gauntlet of selection tests. Failing any one selection means death by cell suicide; passing all selections promotes thymocytes to T cells that depart the thymus to battle our bodies' foes. One selection checks T cell receptors (TCR), which are on the thymocyte's membrane, to ensure they are properly formed then to see if they recognize self-antigens, i.e. molecules that identify the body's own cells. Then another selection, called negative selection, tests TCRs to make sure they don't react too aggressively to self-antigens. Cells that pass these checks then have TCRs that tolerate self- yet react to enemy antigens. \"You don't want the cells with strongly grabbing receptor sites to turn against the body itself,\" said Zhu, whose study focused on negative selection. Self-antigen shakes In negative selection, other cells extend self-antigens on their membrane to interact with the thymocytes' T cell receptors. Those interactions seal the thymocytes' fate: advance or die. Studying forces in those interactions revealed a new signaling loop with mechanical properties analogous to a two-handed grip and tug by the thymocyte. The first hand would be the T cell receptor itself, and the other cell presenting the self-antigen would be like someone else's hand holding a special ball out to the T cell's first hand. The handshake begins as the self-antigen gives a signal to the T cell receptor. Regents Professor Cheng Zhu in his lab at Georgia Tech stands over a microscope station set up to observe forces researchers exert and measure on structures of living cells. Credit: Georgia Tech / Allison Carter If the TCR reacts too strongly to the self-antigen, the thymocyte adds the second, assisting hand coming in from the side to make a two-handed handshake. The additional hand is a lever called CD8 (cluster of differentiation 8), which connects to key mechanisms inside the thymocyte and is considered part of the TCR site. Suicide handshakes For about two weeks in the thymus, multiple T cell receptor sites engage in one- or two-handed handshakes, which send signals into the thymocyte that make it either mature into a T cell or commit suicide. The researchers found that the two-handedness markedly resisted the force applied to break the grip between the T cell receptor and the self-antigen, thus prolonging the duration of the handshake. A long grip sent signals for the thymocyte to die. \"That's the study's elegant finding,\" Zhu said. \"That the force is significant for the selection to work.\" New signaling loop The researchers also made the novel discovery that CD8's handshake participation constitutes a signal coming from inside the thymocyte back out to the self-antigen in answer to its initial signal. \"The inside-out return signal had not yet been reported for this T cell receptor,\" Zhu said. Together, the outside-in and inside-out signals create a feedback loop that perpetuates the handshake: 1. Self-antigen touches receptor. 2. Receptor fires signal into cell and interacts with self-antigen too aggressively. 3. Inside cell membrane, signal pulls CD8 closer. 4. Outside cell membrane, CD8 strengthens handshake. 5. When the self-antigen slips a bit, the double-handed grip can coax it back into the receptor, kicking off another signal, restarting the signaling cycle again and again. 6. Many feedback loops trigger cell suicide. ", "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 T cell antigen receptor (TCR) expressed on thymocytes interacts with self-peptide major histocompatibility complex (pMHC) ligands to signal apoptosis or survival. Here, we found that negative-selection ligands induced thymocytes to exert forces on the TCR and the co-receptor CD8 and formed cooperative TCR–pMHC–CD8 trimolecular ‘catch bonds’, whereas positive-selection ligands induced less sustained thymocyte forces on TCR and CD8 and formed shorter-lived, independent TCR–pMHC and pMHC–CD8 bimolecular ‘slip bonds’. Catch bonds were not intrinsic to either the TCR–pMHC or the pMHC–CD8 arm of the trans (cross-junctional) heterodimer but resulted from coupling of the extracellular pMHC–CD8 interaction to the intracellular interaction of CD8 with TCR–CD3 via associated kinases to form a cis (lateral) heterodimer capable of inside-out signaling. We suggest that the coupled trans–cis heterodimeric interactions form a mechanotransduction loop that reinforces negative-selection signaling that is distinct from positive-selection signaling in the thymus. Main T cell antigen recognition occurs through interactions between TCRs and pMHCs. The invariant co-receptors CD4 or CD8 also bind pMHC class II or I molecules, respectively. This recognition is highly discriminative, because small differences in peptide sequence can induce distinctive phenotypic outcomes in T cells. Extensive studies have been devoted to these molecular interactions 1 . Nonetheless, understanding remains incomplete regarding how the TCR and/or CD4/CD8 interact with pMHC in situ, what measures of these interactions provide the most informative features to predict T cell behavior, how such interactions transmit (and are regulated by) extracellular and intracellular signals, and how they drive T cell function and developmental fate. Existing models of thymocyte selection are based on measurements of TCR kinetics and affinity; for example, the TCR–pMHC dwell time determines the selection outcome 2 , 3 . The differences in TCR dwell times with positive- and negative-selection ligands measured with purified proteins in solution (3D measurements) are very small; however, signaling initiated by these ligands results in the survival or death of thymocytes 2 , 4 . Whereas making in situ measurements with TCRs and co-receptors on live cells (2D measurements) is an important advance in kinetic analysis 5 , 6 , 7 , these measurements are made without externally applied force and assess bond quantity only and may miss key information required to predict all T cell behaviors 8 . Additional information can be found by measuring TCR–pMHC dissociation under force, a method assessing bond quality and revealing TCR dynamic bonds, including catch bonds with agonist pMHCs, in which force prolongs bond lifetime, and slip bonds with antagonist pMHCs, in which force shortens bond lifetime, thereby amplifying the kinetic differences among TCR bonds with different pMHCs 9 , 10 , 11 . Furthermore, T cells exert endogenous forces on the TCR and CD8 in a manner dependent on the ligand and the protein tyrosine kinase Lck, thus supporting the physiological relevance of kinetic measurements under force 12 . To find better predictors of thymocyte-selection outcomes, we made in situ measurements of the affinities, molecular stiffness 13 , and force-dependent lifetimes of the bonds of two panels of pMHCs with two TCRs and/or CD8, and the thymocyte forces exerted on these bonds. Our data suggest that mechanotransduction amplifies the ligand-discriminative power of the TCR, thus allowing for the outcome of thymocyte selection to be determined. Results TCR dynamic bonds distinguish negative- and positive-selection ligands We used a biomembrane force probe (BFP) 9 to measure the force-dependent lifetimes of single pMHC bonds on the surfaces of CD4 + CD8 + double-positive (DP) thymocytes from OT1 TCR transgenic mice. The probe was coated with H2-K b or H2-K b α3A2 (in which the mouse α3 domain was replaced with that of human HLA-A2 to abolish CD8 binding 9 ) to present Q4H7, the strongest positive-selection peptide, or Q4R7, the weakest negative-selection peptide, in a panel of peptides mutated from the ovalbumin (OVA)-derived sequence SIINFEKL, previously identified with fetal thymic organ culture 4 (Fig. 1a ). The OT1 TCR interactions with Q4H7 and Q4R7 presented by H2-K b α3A2 (denoted mQ4R7 and mQ4H7 hereafter) showed comparable slip bonds, in which the mean bond lifetime decreased monotonically with increasing force (Fig. 1b ). CD8 interaction with VSV (RGYVYQGL) presented by H2-K b (denoted wVSV hereafter), a noncognate ligand of the OT1 TCR, showed short-lived slip bonds (Fig. 1b ). We next used H2-K b to present cognate peptides, thus allowing for interaction with TCR, CD8, and both (denoted total interaction hereafter); wQ4R7 formed a catch bond that prolonged lifetime at low forces, then transitioned to a slip bond at >13 pN force, whereas wQ4H7 formed a short-lived slip bond nearly identical to that of mQ4H7 (Fig. 1b ). These data suggest that whether a ligand forms a CD8-dependent catch bond with the TCR at low force determines whether it is a negative-selection ligand. Fig. 1: Lck-dependent dynamic bonds of TCR and/or CD8 with Q4H7 and Q4R7. a , BFP setup (left) and schematic showing the interacting molecules (right). The BFP uses a pressurized red blood cell (RBC) as a force transducer with an attached glass bead to present pMHC. A thymocyte is aspirated by an apposing micropipette and driven to contact the bead. Scale bar, 5 µm. The pMHC on the BFP bead is coupled via biotin–streptavidin (SA) and interacts with the TCR–CD3 complex as well as the CD8 co-receptor on the DP thymocyte. b , c , Untreated ( b ) and Lck-inhibitor- or DMSO-treated ( c ) systems. From left to right, the first and second graphs show data from OT1 thymocytes, and the third and forth graphs show data from OT1.CD8.4 thymocytes. The first and third graphs show data for Q4H7, whereas the second and fourth graphs show data for Q4R7. Data are shown as mean ± s.e.m. of lifetime-versus-force plots of TCR bonds with Q4H7 or Q4R7 presented by H2-K b α3A2 (brown circles), total bonds with either peptide presented by H2-K b (green squares), or CD8 bonds with VSV:H-2K b (black triangles). Open and closed symbols denote untreated and Lck-inhibitor-treated systems, respectively. Open black squares denote<|im_end|> <|im_start|>assistant Ball lands in cup; cup triggers spring; spring clamps lever onto ball and holds it tight. That's a rough description of newly discovered cellular mechanisms that eliminate T cells that may cause autoimmune disorders. Although the mechanisms are intertwined with biochemical processes, they also work mechanically, grasping, tugging and clamping, say researchers at the Georgia Institute of Technology, who, for a new study in the journal Nature Immunology, measured responses to physical force acting upon these elimination mechanisms. The mechanisms' purpose is to make dangerously aggressive developing immune cells called thymocytes kill themselves to keep them from attacking the body, while sparing healthy thymocytes as they mature into T cells. Understanding these selection mechanisms, which ensure T cells aggressively pursue hordes of infectors and cancers but not damage healthy human tissue, could someday lead to new immune-regulating therapies. Two-handed handshake Usually, researchers pursue such mechanisms using chemistry experiments, but Georgia Tech's Cheng Zhu, who led the study, makes atypical discoveries via physical experiments to observe effects of forces between key proteins in living cells. "Experiments where the proteins are isolated and used in chemical reactions in vitro miss this force dynamic," said Zhu, a Regents Professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. "Before our work, force was not considered as a factor in thymocyte selection and now it is." In this study, they discovered a loop of physical signals resembling a double-handed handshake that encourages cell suicide. It is described in more detail below. The medical significance of this field of research was highlighted by the 2018 Nobel Prize in medicine, which was awarded to other researchers at other institutions, James Allison of MD Anderson Cancer Center and Tasuku Honjo of Kyoto University. Allison and Honjo received the prize for their cancer therapies exploiting T cell regulating mechanisms intertwined with those that the Georgia Tech researchers study. Georgia Tech's Zhu and first authors Jinsung Hong and Chenghao Ge published their new research paper on November 12, 2018. The research was funded by the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Institute of Neurological Disorders and Stroke. The agencies are part of the National Institutes of Health. Under the microscope, tiny pipettes tug at living cells to exert forces on their structures, measure those forces and observe the consequences for the cells. Credit: Georgia Tech / Allison Carter Thymocyte death gauntlet Like blood cells, human thymocytes are born in bone marrow, but they travel to the thymus, a small organ just below the neck, where they run a gauntlet of selection tests. Failing any one selection means death by cell suicide; passing all selections promotes thymocytes to T cells that depart the thymus to battle our bodies' foes. One selection checks T cell receptors (TCR), which are on the thymocyte's membrane, to ensure they are properly formed then to see if they recognize self-antigens, i.e. molecules that identify the body's own cells. Then another selection, called negative selection, tests TCRs to make sure they don't react too aggressively to self-antigens. Cells that pass these checks then have TCRs that tolerate self- yet react to enemy antigens. "You don't want the cells with strongly grabbing receptor sites to turn against the body itself," said Zhu, whose study focused on negative selection. Self-antigen shakes In negative selection, other cells extend self-antigens on their membrane to interact with the thymocytes' T cell receptors. Those interactions seal the thymocytes' fate: advance or die. Studying forces in those interactions revealed a new signaling loop with mechanical properties analogous to a two-handed grip and tug by the thymocyte. The first hand would be the T cell receptor itself, and the other cell presenting the self-antigen would be like someone else's hand holding a special ball out to the T cell's first hand. The handshake begins as the self-antigen gives a signal to the T cell receptor. Regents Professor Cheng Zhu in his lab at Georgia Tech stands over a microscope station set up to observe forces researchers exert and measure on structures of living cells. Credit: Georgia Tech / Allison Carter If the TCR reacts too strongly to the self-antigen, the thymocyte adds the second, assisting hand coming in from the side to make a two-handed handshake. The additional hand is a lever called CD8 (cluster of differentiation 8), which connects to key mechanisms inside the thymocyte and is considered part of the TCR site. Suicide handshakes For about two weeks in the thymus, multiple T cell receptor sites engage in one- or two-handed handshakes, which send signals into the thymocyte that make it either mature into a T cell or commit suicide. The researchers found that the two-handedness markedly resisted the force applied to break the grip between the T cell receptor and the self-antigen, thus prolonging the duration of the handshake. A long grip sent signals for the thymocyte to die. "That's the study's elegant finding," Zhu said. "That the force is significant for the selection to work." New signaling loop The researchers also made the novel discovery that CD8's handshake participation constitutes a signal coming from inside the thymocyte back out to the self-antigen in answer to its initial signal. "The inside-out return signal had not yet been reported for this T cell receptor," Zhu said. Together, the outside-in and inside-out signals create a feedback loop that perpetuates the handshake: 1. Self-antigen touches receptor. 2. Receptor fires signal into cell and interacts with self-antigen too aggressively. 3. Inside cell membrane, signal pulls CD8 closer. 4. Outside cell membrane, CD8 strengthens handshake. 5. When the self-antigen slips a bit, the double-handed grip can coax it back into the receptor, kicking off another signal, restarting the signaling cycle again and again. 6. Many feedback loops trigger cell suicide. <|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 Objectives Systemic lupus erythematosus (SLE) affects the joints in up to 95% of patients. The diagnosis and evaluation of SLE arthritis remain challenging in both practice and clinical trials. Frequency domain optical imaging (FDOI) has been previously used to assess joint involvement in inflammatory arthritis. The objective of this study was to evaluate FDOI in SLE arthritis. Methods Ninety-six proximal interphalangeal (PIP) joints from 16 patients with SLE arthritis and 60 PIP joints from 10 age-matched, gender-matched and race/ethnicity-matched controls were examined. A laser beam with a wavelength of 670 nm, 1 mm in diameter and intensity modulated at 300 MHz and 600 MHz was directed onto the dorsal surface of each joint, scanning across a sagittal plane. The transmitted light intensities and phase shifts were measured with an intensified charge-coupled device camera. The data were analysed using Discriminant Analysis and Support Vector Machine algorithms. Results The amplitude and phase of the transmitted light were significantly different between SLE and control PIPs (p<0.05). Receiver operating characteristic (ROC) analysis of cross-validated models showed an Area Under the ROC Curve (AUC)of 0.89 with corresponding sensitivity of 95%, specificity of 79%, and accuracy of 80%. Conclusion This study is the first evaluation of optical methods in the assessment of SLE arthritis; there was a statistically significant difference in the FDOI signals between patients with SLE and healthy volunteers. The results show that FDOI may have the potential to provide an objective, user-independent, evaluation of SLE PIP joints arthritis. Lupus erythematosus systemic arthritis inflammation Data availability statement Data are available upon reasonable request. Data is available upon reasonable request. Requests may be made to Anca Askanase, MD at [email protected]. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: . googletag.cmd.push(function() { googletag.display(\"dfp-ad-mpu\"); }); Statistics from Altmetric.com See more details Picked up by 1 news outlets Tweeted by 4 On 1 Facebook pages 17 readers on Mendeley Supplementary materials 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 Lupus erythematosus systemic arthritis inflammation Key messages What is already known about this subject? The diagnosis and evaluation of SLE arthritis remain challenging in both clinical practice and research trials. What does this study add? Optical imaging showed a statistically significant difference in the signals between patients with SLE and healthy volunteers. How might this impact on clinical practice or future developments? Optical methods may have the potential to provide an objective, user-independent, evaluation of SLE proximal interphalangeal joints arthritis. Introduction SLE is a chronic autoimmune disease that can affect multiple organs and systems. The prevalence of SLE in the USA is 20 to 150 cases per 100 000 with variations among different racial and ethnic groups. 1–3 Joints are affected in up to 95% of patients with SLE and can be the presenting symptom in 50% of SLE cases. 4 Twelve per cent of patients with lupus develop permanent joint damage. 5 Chronic joint involvement is associated with lower quality of life and functional performance; 19%–40% of patients with arthritis report work disability in the first 5 years of disease onset. 6 7 Lupus-related joint involvement is characterised by a wide heterogeneity in phenotypes and severity, ranging from arthralgia (persistent joint pain without evidence of synovitis) to deforming arthropathy (Jaccoud’s arthropathy) and erosive arthritis. Because of this heterogeneity, it is inconsistently described in classification criteria and activity measures. The 1982 American College of Rheumatology (ACR) criteria 8 defined arthritis as ‘non-erosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion’, while the 2012 SLICC criteria 9 broaden the definition to include ‘arthralgia with stiffness’. The definition of joint involvement varies among lupus disease activity assessment instruments used in observational studies and clinical trials. The Systemic Lupus Erythematous Disease Activity Index (SLEDAI) 10 scores the presence of physician-evaluated arthritis, while British Isles Lupus Assessment Group (BILAG) 11 and European Consensus Lupus Activity Measurement (ECLAM) 12 take into account patient’s report of arthralgia. Furthermore, there is controversy whether tenderness alone is equal to active joint involvement and should be scored as lupus disease activity. Unfortunately, all these inconsistencies in the definition of SLE arthritis impact clinical trial outcomes. Identification of lupus arthritis and assessment of its activity remain a challenge in clinical practice. 13 Evaluations based on traditional joint examination lack precision, due to its subjective nature 14 and accuracy in situations such as obese digits and co-existing fibromyalgia. 15 As such, these examinations have limited ability to render quantitative data about improvement and worsening. The recent application of imaging modalities, especially ultrasound (US) and MRI, has enabled more objective and detailed assessment of articular and periarticular abnormalities with higher sensitivity. 16–18 However, MRI and US are expensive and time-consuming. Furthermore, US has been found to be very operator dependent. Therefore, both modalities are currently not routinely used in practice. There is a clear unmet need for a simple, reliable, non-invasive and low-cost imaging modality that can objectively assess and monitor arthritis progress in patients with lupus . Optical imaging methods have been applied to diagnosing and assessing progression of various diseases, including breast cancer, 19–23 peripheral vascular disease, 24–27 wound healing 28 29 and more. 30–32 In these applications, optical transmission and reflection measurements are used to assess differences in the scatter and absorption of light between patients and healthy controls. At different wavelengths and modulation of the infrared light, tissue components (ie, blood, water and lipid concentrations) absorb light differently, making it possible", "role": "user" }, { "content": "Systemic lupus erythematosus (SLE), commonly referred to as simply \"lupus,\" is an autoimmune disorder where the body's immune system attacks healthy tissue. Lupus affects somewhere between 20 to 150 people per 100,000, with variations among different racial and ethnic groups. The disease often causes arthritic symptoms in the joints, which can be debilitating in some cases. Despite the severity of the disease, identification of lupus arthritis and assessment of its activity remains a challenge in clinical practice. Evaluations based on traditional joint examination lack precision, due to its subjective nature and accuracy in situations such as obese digits and co-existing fibromyalgia. As such, these examinations have limited ability to render quantitative data about improvement and worsening. Recently, imaging technology, especially ultrasound (US) and magnetic resonance imaging (MRI), has enabled more objective and detailed assessment of articular and periarticular abnormalities with higher sensitivity. However, MRI and US are expensive and time-consuming. Furthermore, US has been found to be very operator dependent. Therefore, both modalities are currently not routinely used in practice. There is a clear unmet need for a simple, reliable, non-invasive and low-cost imaging modality that can objectively assess and monitor arthritis progress in patients with lupus. Now, researchers at NYU Tandon in collaboration with Columbia University are exploring optical imaging technology as a reliable way to diagnose patients and assess the progression of the disease. The researchers, including Research Assistant Professor Alessandro Marone and Chair of the Biomedical Engineering Department Andreas H. Hielscher, found that frequency domain optical imaging could reliably identify lupus arthritis, and could be used to track how the disease progressed. The results provide strong evidence that frequency domain optical images could provide objective, accurate insights into SLE that were not possible or economically feasible using other technologies. The light diffusion identified inflammation in the blood vessels around joints, similar to but distinct from the symptoms caused by rheumatoid arthritis. With this technology, caregivers may not have to rely on patient feedback to track the progression of lupus, but can see it in action. Optical imaging methods have been used in studies comparing osteoarthritis, rheumatoid arthritis (RA) and healthy controls. The results of those studies highlighted that patients suffering from RA have higher light absorption in the joint space compared with healthy subjects. This is likely due to the presence of inflammatory synovial fluid that decreases light transmission through the inflamed joints. But these observations have never been used to study lupus before, and these findings could provide a reliable, rapid, and cost-effective method of assessing joint involvement in lupus 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 Objectives Systemic lupus erythematosus (SLE) affects the joints in up to 95% of patients. The diagnosis and evaluation of SLE arthritis remain challenging in both practice and clinical trials. Frequency domain optical imaging (FDOI) has been previously used to assess joint involvement in inflammatory arthritis. The objective of this study was to evaluate FDOI in SLE arthritis. Methods Ninety-six proximal interphalangeal (PIP) joints from 16 patients with SLE arthritis and 60 PIP joints from 10 age-matched, gender-matched and race/ethnicity-matched controls were examined. A laser beam with a wavelength of 670 nm, 1 mm in diameter and intensity modulated at 300 MHz and 600 MHz was directed onto the dorsal surface of each joint, scanning across a sagittal plane. The transmitted light intensities and phase shifts were measured with an intensified charge-coupled device camera. The data were analysed using Discriminant Analysis and Support Vector Machine algorithms. Results The amplitude and phase of the transmitted light were significantly different between SLE and control PIPs (p<0.05). Receiver operating characteristic (ROC) analysis of cross-validated models showed an Area Under the ROC Curve (AUC)of 0.89 with corresponding sensitivity of 95%, specificity of 79%, and accuracy of 80%. Conclusion This study is the first evaluation of optical methods in the assessment of SLE arthritis; there was a statistically significant difference in the FDOI signals between patients with SLE and healthy volunteers. The results show that FDOI may have the potential to provide an objective, user-independent, evaluation of SLE PIP joints arthritis. Lupus erythematosus systemic arthritis inflammation Data availability statement Data are available upon reasonable request. Data is available upon reasonable request. Requests may be made to Anca Askanase, MD at [email protected]. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: . googletag.cmd.push(function() { googletag.display("dfp-ad-mpu"); }); Statistics from Altmetric.com See more details Picked up by 1 news outlets Tweeted by 4 On 1 Facebook pages 17 readers on Mendeley Supplementary materials 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 Lupus erythematosus systemic arthritis inflammation Key messages What is already known about this subject? The diagnosis and evaluation of SLE arthritis remain challenging in both clinical practice and research trials. What does this study add? Optical imaging showed a statistically significant difference in the signals between patients with SLE and healthy volunteers. How might this impact on clinical practice or future developments? Optical methods may have the potential to provide an objective, user-independent, evaluation of SLE proximal interphalangeal joints arthritis. Introduction SLE is a chronic autoimmune disease that can affect multiple organs and systems. The prevalence of SLE in the USA is 20 to 150 cases per 100 000 with variations among different racial and ethnic groups. 1–3 Joints are affected in up to 95% of patients with SLE and can be the presenting symptom in 50% of SLE cases. 4 Twelve per cent of patients with lupus develop permanent joint damage. 5 Chronic joint involvement is associated with lower quality of life and functional performance; 19%–40% of patients with arthritis report work disability in the first 5 years of disease onset. 6 7 Lupus-related joint involvement is characterised by a wide heterogeneity in phenotypes and severity, ranging from arthralgia (persistent joint pain without evidence of synovitis) to deforming arthropathy (Jaccoud’s arthropathy) and erosive arthritis. Because of this heterogeneity, it is inconsistently described in classification criteria and activity measures. The 1982 American College of Rheumatology (ACR) criteria 8 defined arthritis as ‘non-erosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion’, while the 2012 SLICC criteria 9 broaden the definition to include ‘arthralgia with stiffness’. The definition of joint involvement varies among lupus disease activity assessment instruments used in observational studies and clinical trials. The Systemic Lupus Erythematous Disease Activity Index (SLEDAI) 10 scores the presence of physician-evaluated arthritis, while British Isles Lupus Assessment Group (BILAG) 11 and European Consensus Lupus Activity Measurement (ECLAM) 12 take into account patient’s report of arthralgia. Furthermore, there is controversy whether tenderness alone is equal to active joint involvement and should be scored as lupus disease activity. Unfortunately, all these inconsistencies in the definition of SLE arthritis impact clinical trial outcomes. Identification of lupus arthritis and assessment of its activity remain a challenge in clinical practice. 13 Evaluations based on traditional joint examination lack precision, due to its subjective nature 14 and accuracy in situations such as obese digits and co-existing fibromyalgia. 15 As such, these examinations have limited ability to render quantitative data about improvement and worsening. The recent application of imaging modalities, especially ultrasound (US) and MRI, has enabled more objective and detailed assessment of articular and periarticular abnormalities with higher sensitivity. 16–18 However, MRI and US are expensive and time-consuming. Furthermore, US has been found to be very operator dependent. Therefore, both modalities are currently not routinely used in practice. There is a clear unmet need for a simple, reliable, non-invasive and low-cost imaging modality that can objectively assess and monitor arthritis progress in patients with lupus . Optical imaging methods have been applied to diagnosing and assessing progression of various diseases, including breast cancer, 19–23 peripheral vascular disease, 24–27 wound healing 28 29 and more. 30–32 In these applications, optical transmission and reflection measurements are used to assess differences in the scatter and absorption of light between patients and healthy controls. At different wavelengths and modulation of the infrared light, tissue components (ie, blood, water and lipid concentrations) absorb light differently, making it possible<|im_end|> <|im_start|>assistant Systemic lupus erythematosus (SLE), commonly referred to as simply "lupus," is an autoimmune disorder where the body's immune system attacks healthy tissue. Lupus affects somewhere between 20 to 150 people per 100,000, with variations among different racial and ethnic groups. The disease often causes arthritic symptoms in the joints, which can be debilitating in some cases. Despite the severity of the disease, identification of lupus arthritis and assessment of its activity remains a challenge in clinical practice. Evaluations based on traditional joint examination lack precision, due to its subjective nature and accuracy in situations such as obese digits and co-existing fibromyalgia. As such, these examinations have limited ability to render quantitative data about improvement and worsening. Recently, imaging technology, especially ultrasound (US) and magnetic resonance imaging (MRI), has enabled more objective and detailed assessment of articular and periarticular abnormalities with higher sensitivity. However, MRI and US are expensive and time-consuming. Furthermore, US has been found to be very operator dependent. Therefore, both modalities are currently not routinely used in practice. There is a clear unmet need for a simple, reliable, non-invasive and low-cost imaging modality that can objectively assess and monitor arthritis progress in patients with lupus. Now, researchers at NYU Tandon in collaboration with Columbia University are exploring optical imaging technology as a reliable way to diagnose patients and assess the progression of the disease. The researchers, including Research Assistant Professor Alessandro Marone and Chair of the Biomedical Engineering Department Andreas H. Hielscher, found that frequency domain optical imaging could reliably identify lupus arthritis, and could be used to track how the disease progressed. The results provide strong evidence that frequency domain optical images could provide objective, accurate insights into SLE that were not possible or economically feasible using other technologies. The light diffusion identified inflammation in the blood vessels around joints, similar to but distinct from the symptoms caused by rheumatoid arthritis. With this technology, caregivers may not have to rely on patient feedback to track the progression of lupus, but can see it in action. Optical imaging methods have been used in studies comparing osteoarthritis, rheumatoid arthritis (RA) and healthy controls. The results of those studies highlighted that patients suffering from RA have higher light absorption in the joint space compared with healthy subjects. This is likely due to the presence of inflammatory synovial fluid that decreases light transmission through the inflamed joints. But these observations have never been used to study lupus before, and these findings could provide a reliable, rapid, and cost-effective method of assessing joint involvement in lupus 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 As of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA 1 , 2 . Previous studies have found human adenoviruses (HAdVs) in the blood from patients in Europe and the USA 3 , 4 , 5 , 6 , 7 , although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing to analyse samples from 16 HAdV-positive cases from 1 October 2021 to 22 May 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus type 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls ( P < 0.001) and to 0 of 30 patients with hepatitis of defined aetiology ( P < 0.001). In controls, HAdV type 41 was detected in blood from 9 (39.1%) of the 23 patients with acute gastroenteritis (without hepatitis), including 8 of 9 patients with positive stool HAdV testing, but co-infection with AAV2 was observed in only 3 (13.0%) of these 23 patients versus 93% of cases ( P < 0.001). Co-infections by Epstein–Barr virus, human herpesvirus 6 and/or enterovirus A71 were also detected in 12 (85.7%) of 14 cases, with higher herpesvirus detection in cases versus controls ( P < 0.001). Our findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses. Main Viral hepatitis is an inflammation of the liver most commonly caused by one of the main hepatitis viruses (A–E). Since October 2021, clusters of acute non-A–E severe hepatitis of unknown aetiology in children have been reported in 35 countries, including the USA 1 , 2 . As of 17 August 2022, 358 people under investigation have been reported in the USA, of whom 22 (6%) required a liver transplant and 13 (4%) died 8 . HAdVs are non-enveloped, double-stranded DNA viruses that cause a variety of infections in both adults and children, including respiratory tract infection, conjunctivitis and gastroenteritis (mainly from HAdV type 40 (HAdV-40) and HAdV-41) 9 . Although a potentially life-threatening disease in immunocompromised patients 7 , 9 , hepatitis from adenovirus infection has been thought to be rare in immunocompetent children without underlying comorbidities 10 . HAdVs, particularly HAdV-41, have been found in blood from clusters of acute severe hepatitis cases from Scotland, the UK and the USA 3 , 4 , 5 , 6 , 7 , but whether the virus is causative remains unclear. Adeno-associated viruses (AAVs) are small, single-stranded DNA parvoviruses that are considered non-pathogenic in humans and for this reason have been widely used as vectors for gene therapy 11 . Importantly, AAVs require a helper virus, such as a herpesvirus or adenovirus, for productive infection of liver tissue 12 . AAVs have previously been reported in children with acute severe hepatitis in a study of nine patients from the UK 13 , often in association with adenovirus or human herpesvirus 6 (HHV-6) infection 14 . In this study, 27 samples (21 whole blood, 2 plasma, 1 liver tissue, 1 nasopharyngeal swab and 2 stool sample(s)) from 16 children with acute severe hepatitis of unknown aetiology were analysed (Fig. 1 ). All children met the clinical case definition established by the Centers for Disease Control and Prevention, including lack of a confirmed aetiology, liver enzyme levels (aspartate aminotransferase (AST) or alanine aminotransferase (ALT)) >500 U l −1 , age < 10 years and onset on or after 1 October 2021 (refs. 2 , 15 ). Cases were enrolled from six states (Alabama, California, Florida, Illinois, North Carolina, and South Dakota) from 1 October 2021 to 22 May 2022. All 16 cases had positive testing for HAdV from blood, and thus HAdV infection was over-represented compared to the overall affected population, of which HAdV is detected in 45–90% (refs. 3 , 4 , 5 , 6 , 7 ). The median age of affected children was 3 years; 56% were female and 44% male (Table 1 ). Mean elevations in ALT and AST were 2,293 ± 1,486 U l −1 (normal range: 4–36 U l −1 ) and 2,652 ± 1,851 U l −1 (normal range: 8–33 U l −1 ), respectively (Supplementary Table 1 ). A liver biopsy was carried out in eight patients; viral PCR testing of the liver biopsies for HAdVs, herpesviruses, enteroviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was incomplete, but yielded positive results for HAdV in three patients with no other viruses detected (Fig. 2b and Supplementary Table 1 ). Two children underwent liver transplantation, but none died from complications of liver failure. Fig. 1: Epidemiology of cases and controls. Geographic distribution of the 16 acute severe hepatitis cases and 113 controls in the study, showing the hospital or public health laboratory sites providing samples and associated clinical data from cases and/or controls. WB, whole blood; NP, nasopharyngeal. Full size image Table 1 Demographic and clinical characteristics of cases and controls Full size table Fig. 2: Sequencing and molecular-based testing for viruses carried out on cases and controls. a , Analyses carried out on the different sample groups. The specific assays carried out for each group are shown in green whereas assays that were not carried out are shaded in black. WGS, whole-genome sequencing. mNGS, metagenomic next-generation sequencing. b , Graphical chart showing results of sequencing or PCR-based assays for virus detection. Each circle represents a sequenced sample with at least three non-overlapping reads 29 aligning to a viral reference sequence. Circles are colour-coded on the basis of sample type and scaled according to normalized viral read counts. Viral PCR positive and negative results are denoted by plus and minus symbols, respectively. For the HAdV-F PCR, the HAdV subtype identified by hexon sequencing is shown to the left of the viral PCR result. PBV, picobirnavirus; bx, biopsy; ND, not determined. c , Associations between viruses detected in blood and cases of", "role": "user" }, { "content": "A new UC San Francisco-led study brings scientists closer to understanding the causes of a mysterious rash of cases of acute severe hepatitis that began appearing in otherwise healthy children after COVID-19 lockdowns eased in the United States and 34 other countries in the spring of 2022. Pediatric hepatitis is rare, and doctors were alarmed when they started seeing outbreaks of severe unexplained hepatitis. There have been about 1,000 cases to date; 50 of these children needed liver transplants and at least 22 have died. In the study, publishing on March 30 in Nature, researchers linked the disease to co-infections from multiple common viruses, in particular a strain of adeno-associated virus type 2 (AAV2). AAVs are not known to cause hepatitis on their own. They need \"helper\" viruses, such as adenoviruses that cause colds and flus, to replicate in the liver. Once they returned to school, children were more susceptible to infections with these common pathogens. The study suggests that for a small subset of these children, getting more than one infection at the same time may have made them more vulnerable to severe hepatitis. \"We were surprised by the fact that the infections we detected in these children were caused not by an unusual, emerging virus, but by common childhood viral pathogens,\" said Charles Chiu, MD, Ph.D., professor of laboratory medicine and medicine in the Division of Infectious Diseases, director of the UCSF Clinical Microbiology Laboratory, and senior author of the paper. \"That's what led us to speculate that the timing of the outbreak was probably related to the really unusual situations we were going through with COVID-19 related school and daycare closures and social restrictions,\" Chiu said. \"It may have been an unintended consequence of what we have experienced during the last two-to-three years of the pandemic.\" By August 2022, clusters of cases were reported in 35 countries, including the U. S., where 358 cases were under investigation. The Centers for Disease Control and Prevention (CDC) launched an investigation into the causes. Testing for viruses To conduct the study, which was backed by the CDC, researchers used polymerase chain reaction (PCR) along with various metagenomic sequencing and molecular-testing methods to examine plasma, whole blood, nasal swab and stool samples from 16 pediatric cases in six states—Alabama, California, Florida, Illinois, North Carolina and South Dakota—from Oct. 1, 2021, to May 22, 2022. The specimens were compared with 113 control samples. In genotyping the 14 available blood samples, adeno-associated virus 2 (AAV2) was detected in 93% of the cases and human adenoviruses (HAdVs) were found in all the cases; a specific type of adenovirus linked to gastroenteritis (HAdV-41) was found in 11 cases. Additional co-infections with Epstein-Barr, herpes and enterovirus were found in 85.7% of cases. Chiu noted the results mirrored the findings of two concurrent studies conducted in the United Kingdom, which identified the same AAV2 strain. All three studies identified co-infections from multiple viruses, and 75% of the children in the U.S. study had three or four viral infections. Since AAVs are not considered pathogenic on their own, a direct causal link with the severe acute hepatitis has yet to be established. The study notes, however, that children may be especially vulnerable to more severe hepatitis triggered by co-infections. While infections from adeno-associated viruses can occur at any age, the peak is typically between 1 and 5 years old, and the median age of the affected children in the study was 3 years old. The clusters of acute severe hepatitis in children have recently waned, but Chiu said the best way to protect children from this unlikely outcome is by washing hands frequently and staying home when sick. ", "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 of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA 1 , 2 . Previous studies have found human adenoviruses (HAdVs) in the blood from patients in Europe and the USA 3 , 4 , 5 , 6 , 7 , although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing to analyse samples from 16 HAdV-positive cases from 1 October 2021 to 22 May 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus type 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls ( P < 0.001) and to 0 of 30 patients with hepatitis of defined aetiology ( P < 0.001). In controls, HAdV type 41 was detected in blood from 9 (39.1%) of the 23 patients with acute gastroenteritis (without hepatitis), including 8 of 9 patients with positive stool HAdV testing, but co-infection with AAV2 was observed in only 3 (13.0%) of these 23 patients versus 93% of cases ( P < 0.001). Co-infections by Epstein–Barr virus, human herpesvirus 6 and/or enterovirus A71 were also detected in 12 (85.7%) of 14 cases, with higher herpesvirus detection in cases versus controls ( P < 0.001). Our findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses. Main Viral hepatitis is an inflammation of the liver most commonly caused by one of the main hepatitis viruses (A–E). Since October 2021, clusters of acute non-A–E severe hepatitis of unknown aetiology in children have been reported in 35 countries, including the USA 1 , 2 . As of 17 August 2022, 358 people under investigation have been reported in the USA, of whom 22 (6%) required a liver transplant and 13 (4%) died 8 . HAdVs are non-enveloped, double-stranded DNA viruses that cause a variety of infections in both adults and children, including respiratory tract infection, conjunctivitis and gastroenteritis (mainly from HAdV type 40 (HAdV-40) and HAdV-41) 9 . Although a potentially life-threatening disease in immunocompromised patients 7 , 9 , hepatitis from adenovirus infection has been thought to be rare in immunocompetent children without underlying comorbidities 10 . HAdVs, particularly HAdV-41, have been found in blood from clusters of acute severe hepatitis cases from Scotland, the UK and the USA 3 , 4 , 5 , 6 , 7 , but whether the virus is causative remains unclear. Adeno-associated viruses (AAVs) are small, single-stranded DNA parvoviruses that are considered non-pathogenic in humans and for this reason have been widely used as vectors for gene therapy 11 . Importantly, AAVs require a helper virus, such as a herpesvirus or adenovirus, for productive infection of liver tissue 12 . AAVs have previously been reported in children with acute severe hepatitis in a study of nine patients from the UK 13 , often in association with adenovirus or human herpesvirus 6 (HHV-6) infection 14 . In this study, 27 samples (21 whole blood, 2 plasma, 1 liver tissue, 1 nasopharyngeal swab and 2 stool sample(s)) from 16 children with acute severe hepatitis of unknown aetiology were analysed (Fig. 1 ). All children met the clinical case definition established by the Centers for Disease Control and Prevention, including lack of a confirmed aetiology, liver enzyme levels (aspartate aminotransferase (AST) or alanine aminotransferase (ALT)) >500 U l −1 , age < 10 years and onset on or after 1 October 2021 (refs. 2 , 15 ). Cases were enrolled from six states (Alabama, California, Florida, Illinois, North Carolina, and South Dakota) from 1 October 2021 to 22 May 2022. All 16 cases had positive testing for HAdV from blood, and thus HAdV infection was over-represented compared to the overall affected population, of which HAdV is detected in 45–90% (refs. 3 , 4 , 5 , 6 , 7 ). The median age of affected children was 3 years; 56% were female and 44% male (Table 1 ). Mean elevations in ALT and AST were 2,293 ± 1,486 U l −1 (normal range: 4–36 U l −1 ) and 2,652 ± 1,851 U l −1 (normal range: 8–33 U l −1 ), respectively (Supplementary Table 1 ). A liver biopsy was carried out in eight patients; viral PCR testing of the liver biopsies for HAdVs, herpesviruses, enteroviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was incomplete, but yielded positive results for HAdV in three patients with no other viruses detected (Fig. 2b and Supplementary Table 1 ). Two children underwent liver transplantation, but none died from complications of liver failure. Fig. 1: Epidemiology of cases and controls. Geographic distribution of the 16 acute severe hepatitis cases and 113 controls in the study, showing the hospital or public health laboratory sites providing samples and associated clinical data from cases and/or controls. WB, whole blood; NP, nasopharyngeal. Full size image Table 1 Demographic and clinical characteristics of cases and controls Full size table Fig. 2: Sequencing and molecular-based testing for viruses carried out on cases and controls. a , Analyses carried out on the different sample groups. The specific assays carried out for each group are shown in green whereas assays that were not carried out are shaded in black. WGS, whole-genome sequencing. mNGS, metagenomic next-generation sequencing. b , Graphical chart showing results of sequencing or PCR-based assays for virus detection. Each circle represents a sequenced sample with at least three non-overlapping reads 29 aligning to a viral reference sequence. Circles are colour-coded on the basis of sample type and scaled according to normalized viral read counts. Viral PCR positive and negative results are denoted by plus and minus symbols, respectively. For the HAdV-F PCR, the HAdV subtype identified by hexon sequencing is shown to the left of the viral PCR result. PBV, picobirnavirus; bx, biopsy; ND, not determined. c , Associations between viruses detected in blood and cases of<|im_end|> <|im_start|>assistant A new UC San Francisco-led study brings scientists closer to understanding the causes of a mysterious rash of cases of acute severe hepatitis that began appearing in otherwise healthy children after COVID-19 lockdowns eased in the United States and 34 other countries in the spring of 2022. Pediatric hepatitis is rare, and doctors were alarmed when they started seeing outbreaks of severe unexplained hepatitis. There have been about 1,000 cases to date; 50 of these children needed liver transplants and at least 22 have died. In the study, publishing on March 30 in Nature, researchers linked the disease to co-infections from multiple common viruses, in particular a strain of adeno-associated virus type 2 (AAV2). AAVs are not known to cause hepatitis on their own. They need "helper" viruses, such as adenoviruses that cause colds and flus, to replicate in the liver. Once they returned to school, children were more susceptible to infections with these common pathogens. The study suggests that for a small subset of these children, getting more than one infection at the same time may have made them more vulnerable to severe hepatitis. "We were surprised by the fact that the infections we detected in these children were caused not by an unusual, emerging virus, but by common childhood viral pathogens," said Charles Chiu, MD, Ph.D., professor of laboratory medicine and medicine in the Division of Infectious Diseases, director of the UCSF Clinical Microbiology Laboratory, and senior author of the paper. "That's what led us to speculate that the timing of the outbreak was probably related to the really unusual situations we were going through with COVID-19 related school and daycare closures and social restrictions," Chiu said. "It may have been an unintended consequence of what we have experienced during the last two-to-three years of the pandemic." By August 2022, clusters of cases were reported in 35 countries, including the U. S., where 358 cases were under investigation. The Centers for Disease Control and Prevention (CDC) launched an investigation into the causes. Testing for viruses To conduct the study, which was backed by the CDC, researchers used polymerase chain reaction (PCR) along with various metagenomic sequencing and molecular-testing methods to examine plasma, whole blood, nasal swab and stool samples from 16 pediatric cases in six states—Alabama, California, Florida, Illinois, North Carolina and South Dakota—from Oct. 1, 2021, to May 22, 2022. The specimens were compared with 113 control samples. In genotyping the 14 available blood samples, adeno-associated virus 2 (AAV2) was detected in 93% of the cases and human adenoviruses (HAdVs) were found in all the cases; a specific type of adenovirus linked to gastroenteritis (HAdV-41) was found in 11 cases. Additional co-infections with Epstein-Barr, herpes and enterovirus were found in 85.7% of cases. Chiu noted the results mirrored the findings of two concurrent studies conducted in the United Kingdom, which identified the same AAV2 strain. All three studies identified co-infections from multiple viruses, and 75% of the children in the U.S. study had three or four viral infections. Since AAVs are not considered pathogenic on their own, a direct causal link with the severe acute hepatitis has yet to be established. The study notes, however, that children may be especially vulnerable to more severe hepatitis triggered by co-infections. While infections from adeno-associated viruses can occur at any age, the peak is typically between 1 and 5 years old, and the median age of the affected children in the study was 3 years old. The clusters of acute severe hepatitis in children have recently waned, but Chiu said the best way to protect children from this unlikely outcome is by washing hands frequently and staying home when sick. <|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 Clinical trials focusing on therapeutic candidates that modify β-amyloid (Aβ) have repeatedly failed to treat Alzheimer’s disease (AD), suggesting that Aβ may not be the optimal target for treating AD. The evaluation of Aβ, tau, and neurodegenerative (A/T/N) biomarkers has been proposed for classifying AD. However, it remains unclear whether disturbances in each arm of the A/T/N framework contribute equally throughout the progression of AD. Here, using the random forest machine learning method to analyze participants in the Alzheimer’s Disease Neuroimaging Initiative dataset, we show that A/T/N biomarkers show varying importance in predicting AD development, with elevated biomarkers of Aβ and tau better predicting early dementia status, and biomarkers of neurodegeneration, especially glucose hypometabolism, better predicting later dementia status. Our results suggest that AD treatments may also need to be disease stage-oriented with Aβ and tau as targets in early AD and glucose metabolism as a target in later AD. Introduction Alzheimer’s disease (AD) is the most common form of dementia worldwide and is defined biologically as the pathologic deposition of folded β-amyloid (Aβ) plaques, and hyperphosphorylated neurofibrillary tau tangles in the brain leading to neurodegeneration 1 , 2 , 3 . Clinically, AD presents as a syndrome of progressive episodic memory and executive functioning problems across a cognitive continuum ranging through cognitively unimpaired (CU), mild cognitive impairment (MCI), and AD. While there are currently five drugs approved by the FDA to treat the symptoms of AD, there are no disease-modifying therapies that alter the course of the disease. Over the past few decades, the development of treatments for AD has been largely focused on compounds which aim to reduce Aβ plaques, either by directly targeting Aβ itself through antibodies or by targeting the enzymes that cleave amyloid precursor protein (APP) to produce it 4 , 5 . However, clinical trials of drugs targeting Aβ had a 99.6% failure rate between 2002 and 2012 6 , and two more Aβ-focused drug trials failed in phase three in 2019 7 . This failure rate is among the highest of any disease area. The high failure rate for AD drug candidates focused on Aβ indicates that Aβ may not be the optimal therapeutic target to combat AD. Careful analysis of AD biomarkers may give important insights into underlying AD pathogenesis and clues about appropriate AD treatments, since these biomarkers exist as proxies for AD neuropathologic changes. Furthermore, an understanding of how the biomarkers correlate with clinical symptoms of AD could inform clinicians making AD management decisithe ons to improve patient quality of life. The A/T/N biomarker framework promulgated by the National Institute on Aging-Alzheimer’s Association was created to be an unbiased classification scheme for the three arms of biomarkers known to underlie AD pathology, namely neuropathological loads of Aβ (A) and tau (T), and neurodegeneration (N, including hypometabolism and brain atrophy) 8 , 9 . Indeed, some research groups have demonstrated that the distribution of tau tangles 10 and hypometabolism (due to low glucose uptake) are more strongly correlated with cognitive performance than Aβ 11 . Moreover, brain atrophy is also suggested to be highly correlated with AD progression 12 . However, it remains unclear whether disturbances in each arm of the A/T/N framework contribute equally to the progression of AD symptoms or if these factors instead have varying impacts at different stages of AD progression. Understanding this stage-dependent nature of the biomarkers could lead to important clues in preventing and treating AD. In order to determine the nature of the association of AD biomarkers with the progression of AD symptoms, in this study, we assessed the statistical importance of each arm of the A/T/N framework in predicting three progressive clinical statuses of cognitive performance: cognitively unimpaired (CU), late mild cognitive impairment (LMCI), and AD 8 . To do so, we used data from the Alzheimer’s Disease Neuroimaging Initiatives (ADNI) database, relating to four biomarkers: Aβ (assessed from 18 Florbetapir-positron emission tomography (PET)), phosphorylated tau (pTau181, assessed from cerebrospinal fluid), glucose uptake (assessed from 18 fluorodeoxyglucose (FDG)-PET), and volumetric measures (assessed from MRI). We used a random forest machine learning algorithm to rank the importance of each biomarker in predicting clinical dementia status. We chose the random forest machine learning method because it not only has the ability to fit models with high prediction accuracy due to its use of multiple decision trees that combine to yield a consensus prediction, but also is very interpretable due to its ranking capability of the relative importance of predictors used in the classification (AD biomarkers in our case). We also analyzed the relationship between A/T/N biomarkers and memory composite and executive functioning composite scores in order to assess more directly their association with cognitive performance. We show that A/T/N biomarkers have differing contributions in predicting clinical dementia status based on the stage of cognitive impairment, with Aβ and pTau having higher contribution in predicting early cognitive impairment (LMCI vs. CU) and glucose uptake having higher contribution in predicting later cognitive impairment (AD vs. LMCI and AD vs. CU). Our findings could help real-world patient populations by informing clinicians to make AD management decisions according to disease stage based on the expression of the relevant A/T/N biomarkers, and by informing drug development teams to design treatments to target the pathophysiology underlying the expression of the biomarkers at the appropriate stage of disease progression. Results Participant characterizations and data selection Participant data was extracted from the ADNI database for inclusion in the analysis. Participants were required to have baseline Aβ imaging biomarkers (from 18 Florbetapir PET), glucose uptake imaging biomarkers (from 18 FDG PET), brain volume imaging biomarkers (from T1-weighted structural MRI), and cognitive testing to be included in the analysis. Participants with three or more missing values were excluded from the analysis. As tau imaging was not available for most participants in the ADNI database, we used a phosphorylated tau biomarker (pTau) from cerebrospinal fluid (CSF) as a measure of tau levels. These criteria yielded a final sample of 405 participants clinically diagnosed as being", "role": "user" }, { "content": "Alzheimer's disease (AD) is the most common form of dementia among the elderly and currently there is no cure for the disease. The hallmarks of AD are the Aβ plaques and tau tangles found throughout the patient's brain. For the past several decades, much of the work to find a treatment for AD has been focused on eliminating those dreaded Aβ plaques, by assuming that memory could be restored by removing the plaques. \"Unfortunately, clinical trials on this attempt have repeatedly failed,\" said Ai-Ling Lin, associate professor at the University of Kentucky's Sanders-Brown Center on Aging (SBCoA) and UK College of Medicine. Lin and several others at UK worked on a study that was recently published in Communications Biology (Hammond, Xin et al). The study was a collaborative effort between both the College of Medicine and the College of Engineering. In addition to contributions from Lin and the Department of Pharmacology and Nutritional Sciences, Nathan Jacobs with Computer Sciences and Qiang Cheng with Biomedical Informatics played integral parts in the project. Lin says failures of clinical trials focused on eliminating the plaques may not be the optimal target for treating AD. In addition to the plaques and tangles, AD patients also show symptoms of neurodegeneration, which includes shrinkage of the brain size and lost energy support for sustaining brain functions. Due to this, it has been suggested by the National Institutes on Aging and Alzheimer's Association that Aβ (A), tau (T), and neurodegeneration (N) markers all need to be considered to determine the risk of AD. Looking at those biomarkers is what the recent study focused on, by using a machine learning algorithm called \"random forest\" to identify the patterns of the markers that separate AD from cognitively unimpaired and mild cognitive impairment participants with neuroimaging data. \"We found that A/T/N biomarkers show varying importance in predicting AD development, with elevated biomarkers of Aβ and tau better predicting early dementia status, and biomarkers of neurodegeneration, especially brain energy metabolism deficits, better predicting later dementia status,\" Lin said. \"Our findings may partly explain the repeated failures of clinical trials attempting to treat AD by modifying the Aβ load: it may be too late to gain therapeutic benefit from the treatment of Aβ when patients have already progressed to the clinical AD stage,\" explained Lin. Additionally, she says their findings suggest that treatments for AD potentially need to be disease stage oriented—with Aβ and tau as targets in early AD and glucose metabolism as a target in later AD. \"Our findings may influence the thinking in the field regarding AD progression and therapeutics.\" ", "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 Clinical trials focusing on therapeutic candidates that modify β-amyloid (Aβ) have repeatedly failed to treat Alzheimer’s disease (AD), suggesting that Aβ may not be the optimal target for treating AD. The evaluation of Aβ, tau, and neurodegenerative (A/T/N) biomarkers has been proposed for classifying AD. However, it remains unclear whether disturbances in each arm of the A/T/N framework contribute equally throughout the progression of AD. Here, using the random forest machine learning method to analyze participants in the Alzheimer’s Disease Neuroimaging Initiative dataset, we show that A/T/N biomarkers show varying importance in predicting AD development, with elevated biomarkers of Aβ and tau better predicting early dementia status, and biomarkers of neurodegeneration, especially glucose hypometabolism, better predicting later dementia status. Our results suggest that AD treatments may also need to be disease stage-oriented with Aβ and tau as targets in early AD and glucose metabolism as a target in later AD. Introduction Alzheimer’s disease (AD) is the most common form of dementia worldwide and is defined biologically as the pathologic deposition of folded β-amyloid (Aβ) plaques, and hyperphosphorylated neurofibrillary tau tangles in the brain leading to neurodegeneration 1 , 2 , 3 . Clinically, AD presents as a syndrome of progressive episodic memory and executive functioning problems across a cognitive continuum ranging through cognitively unimpaired (CU), mild cognitive impairment (MCI), and AD. While there are currently five drugs approved by the FDA to treat the symptoms of AD, there are no disease-modifying therapies that alter the course of the disease. Over the past few decades, the development of treatments for AD has been largely focused on compounds which aim to reduce Aβ plaques, either by directly targeting Aβ itself through antibodies or by targeting the enzymes that cleave amyloid precursor protein (APP) to produce it 4 , 5 . However, clinical trials of drugs targeting Aβ had a 99.6% failure rate between 2002 and 2012 6 , and two more Aβ-focused drug trials failed in phase three in 2019 7 . This failure rate is among the highest of any disease area. The high failure rate for AD drug candidates focused on Aβ indicates that Aβ may not be the optimal therapeutic target to combat AD. Careful analysis of AD biomarkers may give important insights into underlying AD pathogenesis and clues about appropriate AD treatments, since these biomarkers exist as proxies for AD neuropathologic changes. Furthermore, an understanding of how the biomarkers correlate with clinical symptoms of AD could inform clinicians making AD management decisithe ons to improve patient quality of life. The A/T/N biomarker framework promulgated by the National Institute on Aging-Alzheimer’s Association was created to be an unbiased classification scheme for the three arms of biomarkers known to underlie AD pathology, namely neuropathological loads of Aβ (A) and tau (T), and neurodegeneration (N, including hypometabolism and brain atrophy) 8 , 9 . Indeed, some research groups have demonstrated that the distribution of tau tangles 10 and hypometabolism (due to low glucose uptake) are more strongly correlated with cognitive performance than Aβ 11 . Moreover, brain atrophy is also suggested to be highly correlated with AD progression 12 . However, it remains unclear whether disturbances in each arm of the A/T/N framework contribute equally to the progression of AD symptoms or if these factors instead have varying impacts at different stages of AD progression. Understanding this stage-dependent nature of the biomarkers could lead to important clues in preventing and treating AD. In order to determine the nature of the association of AD biomarkers with the progression of AD symptoms, in this study, we assessed the statistical importance of each arm of the A/T/N framework in predicting three progressive clinical statuses of cognitive performance: cognitively unimpaired (CU), late mild cognitive impairment (LMCI), and AD 8 . To do so, we used data from the Alzheimer’s Disease Neuroimaging Initiatives (ADNI) database, relating to four biomarkers: Aβ (assessed from 18 Florbetapir-positron emission tomography (PET)), phosphorylated tau (pTau181, assessed from cerebrospinal fluid), glucose uptake (assessed from 18 fluorodeoxyglucose (FDG)-PET), and volumetric measures (assessed from MRI). We used a random forest machine learning algorithm to rank the importance of each biomarker in predicting clinical dementia status. We chose the random forest machine learning method because it not only has the ability to fit models with high prediction accuracy due to its use of multiple decision trees that combine to yield a consensus prediction, but also is very interpretable due to its ranking capability of the relative importance of predictors used in the classification (AD biomarkers in our case). We also analyzed the relationship between A/T/N biomarkers and memory composite and executive functioning composite scores in order to assess more directly their association with cognitive performance. We show that A/T/N biomarkers have differing contributions in predicting clinical dementia status based on the stage of cognitive impairment, with Aβ and pTau having higher contribution in predicting early cognitive impairment (LMCI vs. CU) and glucose uptake having higher contribution in predicting later cognitive impairment (AD vs. LMCI and AD vs. CU). Our findings could help real-world patient populations by informing clinicians to make AD management decisions according to disease stage based on the expression of the relevant A/T/N biomarkers, and by informing drug development teams to design treatments to target the pathophysiology underlying the expression of the biomarkers at the appropriate stage of disease progression. Results Participant characterizations and data selection Participant data was extracted from the ADNI database for inclusion in the analysis. Participants were required to have baseline Aβ imaging biomarkers (from 18 Florbetapir PET), glucose uptake imaging biomarkers (from 18 FDG PET), brain volume imaging biomarkers (from T1-weighted structural MRI), and cognitive testing to be included in the analysis. Participants with three or more missing values were excluded from the analysis. As tau imaging was not available for most participants in the ADNI database, we used a phosphorylated tau biomarker (pTau) from cerebrospinal fluid (CSF) as a measure of tau levels. These criteria yielded a final sample of 405 participants clinically diagnosed as being<|im_end|> <|im_start|>assistant Alzheimer's disease (AD) is the most common form of dementia among the elderly and currently there is no cure for the disease. The hallmarks of AD are the Aβ plaques and tau tangles found throughout the patient's brain. For the past several decades, much of the work to find a treatment for AD has been focused on eliminating those dreaded Aβ plaques, by assuming that memory could be restored by removing the plaques. "Unfortunately, clinical trials on this attempt have repeatedly failed," said Ai-Ling Lin, associate professor at the University of Kentucky's Sanders-Brown Center on Aging (SBCoA) and UK College of Medicine. Lin and several others at UK worked on a study that was recently published in Communications Biology (Hammond, Xin et al). The study was a collaborative effort between both the College of Medicine and the College of Engineering. In addition to contributions from Lin and the Department of Pharmacology and Nutritional Sciences, Nathan Jacobs with Computer Sciences and Qiang Cheng with Biomedical Informatics played integral parts in the project. Lin says failures of clinical trials focused on eliminating the plaques may not be the optimal target for treating AD. In addition to the plaques and tangles, AD patients also show symptoms of neurodegeneration, which includes shrinkage of the brain size and lost energy support for sustaining brain functions. Due to this, it has been suggested by the National Institutes on Aging and Alzheimer's Association that Aβ (A), tau (T), and neurodegeneration (N) markers all need to be considered to determine the risk of AD. Looking at those biomarkers is what the recent study focused on, by using a machine learning algorithm called "random forest" to identify the patterns of the markers that separate AD from cognitively unimpaired and mild cognitive impairment participants with neuroimaging data. "We found that A/T/N biomarkers show varying importance in predicting AD development, with elevated biomarkers of Aβ and tau better predicting early dementia status, and biomarkers of neurodegeneration, especially brain energy metabolism deficits, better predicting later dementia status," Lin said. "Our findings may partly explain the repeated failures of clinical trials attempting to treat AD by modifying the Aβ load: it may be too late to gain therapeutic benefit from the treatment of Aβ when patients have already progressed to the clinical AD stage," explained Lin. Additionally, she says their findings suggest that treatments for AD potentially need to be disease stage oriented—with Aβ and tau as targets in early AD and glucose metabolism as a target in later AD. "Our findings may influence the thinking in the field regarding AD progression and therapeutics." <|im_end|>

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1,903

[ { "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 Linker histone H1 is an important structural component of chromatin that stabilizes the nucleosome and compacts the nucleofilament into higher-order structures. The biology of histone H1 remains, however, poorly understood. Here we show that Drosophila histone H1 (dH1) prevents genome instability as indicated by the increased γH2Av (H2AvS137P) content and the high incidence of DNA breaks and sister-chromatid exchanges observed in dH1-depleted cells. Increased γH2Av occurs preferentially at heterochromatic elements, which are upregulated upon dH1 depletion, and is due to the abnormal accumulation of DNA:RNA hybrids (R-loops). R-loops accumulation is readily detectable in G1-phase, whereas γH2Av increases mainly during DNA replication. These defects induce JNK-mediated apoptosis and are specific of dH1 depletion since they are not observed when heterochromatin silencing is relieved by HP1a depletion. Altogether, our results suggest that histone H1 prevents R-loops-induced DNA damage in heterochromatin and unveil its essential contribution to maintenance of genome stability. Introduction Histones are chromosomal proteins that play an important structural function in packaging of the eukaryotic genome into chromatin. Histones H2A, H2B, H3 and H4 form an octameric complex that organizes 146 bp of DNA and constitutes the protein core of the nucleosome, a highly conserved particle that is the basic structural and functional subunit of chromatin. In addition, linker histones H1 bind to the nucleosome core particle and stabilize folding of the nucleofilament into higher-order structures 1 , 2 . Histones are also crucial to the regulation of genomic functions. In recent years, we have become aware of the essential contribution of core histones to the epigenetic regulation of multiple genomic processes from RNA transcription to DNA replication, recombination and repair, chromosome segregation and genome integrity. In comparison, the biology of linker histones H1 remains poorly understood. Histones H1 are less well conserved than core histones and, in metazoa, they generally exist in multiple variants that play partially redundant functions. For instance, deletion of one or two of the seven mouse somatic H1 variants have no detectable effects since mice develop normally and show normal total H1 levels due to the compensatory expression of other variants 3 , 4 . Mice also contain one female and three male germline specific H1 variants 5 . Humans show a similar complexity. In contrast, H1 diversity in Drosophila melanogaster is low since it contains only one somatic (dH1) and a second germline specific (dBigH1) variant 5 , 6 . Note, however, that somatic dH1 is encoded by a multigene family, which is unusual since, in most metazoa, H1 variants are encoded by single-copy genes 6 . Unicellular eukaryotes such as Saccharomyces cerevisiae , Aspergillus nidulans and Tetrahymena termophila also contain a single histone H1-like gene 7 , 8 , 9 . Genetic studies unveiled the essential contribution of histones H1 to metazoan development. In Drosophila , dH1 depletion impairs normal development and causes lethality 10 , 11 . Similarly, triple H1 variants knockout mice fail to compensate total H1 levels and die at early developmental stages 12 . The reason for this lethality is not well understood. On one hand, although they are widely distributed across the genome, histones H1 have a weak contribution to gene expression since depletion of Drosophila dH1 affects expression of <10% of protein-coding genes 11 . Similarly, only a few hundreds of genes are found deregulated in ES-cells derived from triple H1 knockout mice 13 , whose total H1 content is reduced by ∼ 50%. Furthermore, in S . cerevisiae , deletion of the single H1-like gene Hho1 affects expression of only a few genes 14 . In contrast to its weak effect on expression of euchromatic genes, dH1 depletion strongly affects silencing of transposable elements (TE) and other repetitive DNA sequences 11 , 15 , and induces DNA damage 11 . However, the actual molecular mechanisms underlying these defects remain unknown. Here, we show that dH1 depletion induces the accumulation of R-loops in heterochromatin. R-loops are three-stranded structures formed when a newly synthesized RNA forms a DNA:RNA hybrid with the transcribed strand leaving the untranscribed strand single-stranded (ssDNA). R-loops can form naturally during plasmid and mitochondrial DNA replication 16 , 17 , in immunoglobulin class switching 18 or during transcription 19 . However, unregulated R-loops formation is also an important source of genomic instability 20 , 21 , 22 , 23 . In particular, R-loops can stall replication fork progression, which generates double-stranded breaks (DSBs) and induces hyperrecombination 24 , 25 . Our results show that DNA damage, genomic instability and apoptosis induced by dH1 depletion depend on R-loops. We also show that dH1 contribution to R-loops dynamics is specific since HP1a depletion, which strongly relieves heterochromatin silencing too 26 , does not induce R-loops accumulation. Results dH1 depletion induces DNA damage in heterochromatin dH1 depletion in the Drosophila wing imaginal disc was shown to induce DNA damage, as determined by an increased αγH2Av reactivity 11 . However, the underlying molecular mechanisms of this effect remained unknown. Here, to address this question, we performed depletion experiments in cultured Drosophila S2 cells, which constitute a homogeneous cell population amenable to mechanistic studies. As previously observed in the wing imaginal disc, RNAi-induced dH1 depletion in S2 cells significantly increased γH2Av content, as determined by both immunofluorescence (IF) (Fig. 1a ) and western blot (WB) analyses (Fig. 1b ). This increase was not observed in control cells treated with siRNAs against LacZ (Fig. 1a and b ), and it was not associated with increased total H2Av content (Supplementary Fig. 1 ). Concomitant to increased γH2Av, dH1-depleted cells showed a high incidence of DNA breaks (DBs), as determined by the increased tail-moment observed in single-cell electrophoretic analyses performed under alkaline and neutral conditions to detect both single-stranded (SSBs) and double-stranded DNA breaks (DSBs) or only DSBs, respectively (Fig. 1c ). In addition, radiation-induced DNA damage was repaired efficiently in dH1-depleted cells (Fig. 1d ), indicating that DNA repair was not impaired. Triple H1 knockout mouse ES-cells also showed efficient DNA repair 27 . Fig. 1 dH1 depletion induces DNA damage. a", "role": "user" }, { "content": "Scientists headed by Ferran Azorín at the Institute for Research in Biomedicine (IRB Barcelona) have discovered why histone 1 is a major protection factor against genomic instability and a vital protein. Their study of the function of histone 1, the least known of the five histones, has been published in the journal Nature Communications. \"Although histone 1 is key component of chromatin, the form in which DNA is packaged inside the cell nucleus through the action of histones, there are still many questions regarding this molecule,\" says Ferran Azorín. \"Regarding the other histones, which are major proteins in the regulation of gene expression, we know which enzymes modify them, their functions, and how they are regulated. But for some reason, the functions of histone 1 have not been addressed,\" he says. Lethal lesions The study explains for the first time that the suppression of histone 1 causes cell damage and DNA damage. The deregulation of a commonly suppressed region of chromatin, called heterochromatin, leads to defects in information transcription, which in turn gives rise to the accumulation of DNA and RNA hybrids, the so-called R-loops, which are lethal. \"The deregulation of heterochromatin has disastrous consequences,\" says Jordi Bernués, associate researcher in Azorín's group and co-leader of the study. The team also observed that in the presence of histone 1, these problems did not arise in spite of heterochromatin expression. \"Histone 1 not only serves as a repressor but also actively contributes to the removal of R-loops.\" However, the researchers do not know how this function arises. \"The mechanism is what we want to study, how histone 1 prevents the mechanism from causing damage,\" explains IRB Barcelona PhD student Anna Casas-Lamesa, co-author of the article together with Aleix Bayona-Feliu. DNA replication. Red and green: replication regions. Credit: Jordi Bernués, IRB Barcelona. The fruit fly Drosophila melanogaster is crucial in unraveling this function. First, only one variant of this histone is present in the fly, while humans have up to seven, so the research is simplified. Second, the fly allows scientists to remove a protein from a specific place and at a specific time. They removed histone 1 from the precursor structure of wings. They observed that the fly was born alive but without wings; thus, the removal of this molecule caused the death of all cell precursors of this tissue—if histone 1 is completely removed, the embryo dies. A statistical analysis of gene expression allowed the scientists to reject a longstanding hypothesis, namely that histone 1 is a global repressor of expression. \"The effect of removing histone 1 on gene expression is very weak,\" says Bernués. Its expression alters that of only 5 percent of genes. \"It is not a transcriptional regulator,\" says Azorín. Heterochromatin contains genetic information that is not translated for proteins but that comprises repetitive sequences that the cell silences and that is tightly regulated. \"Both R-loops and the information held in heterochromatin have natural functions, but when they are deregulated, they are lethal. \"We have now been able to associate genomic instability with the uncontrolled formation of R-loops caused by the lack of histone 1 and this is completely new,\" says Bernués. Drosophila without wings. The removal of histone 1 causes the death of all cell precursors of this tissue. Credit: Jordi Bernués, IRB Barcelona. Histone 1 and cancer Preliminary experiments in cultured tumour cells confirm that the genomic instability present in these cells is partly caused by histone 1 deficiency. \"But we have to further study the functions of this histone, identify the other proteins with which it is associated, and determine the enzymes that modify it and why, and the cell signaling pathways involved,\" says Bernués. In addition to exploring the mechanisms through which histone 1 keeps heterochromatin in check and prevents R-loop formation, Anna Casas-Lamesa is also addressing the involvement of this molecule in cancer. \"Our preliminary studies are promising,\" explains Azorín. \"But we are still a long way off proposing histone 1 as a target.\" ", "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 Linker histone H1 is an important structural component of chromatin that stabilizes the nucleosome and compacts the nucleofilament into higher-order structures. The biology of histone H1 remains, however, poorly understood. Here we show that Drosophila histone H1 (dH1) prevents genome instability as indicated by the increased γH2Av (H2AvS137P) content and the high incidence of DNA breaks and sister-chromatid exchanges observed in dH1-depleted cells. Increased γH2Av occurs preferentially at heterochromatic elements, which are upregulated upon dH1 depletion, and is due to the abnormal accumulation of DNA:RNA hybrids (R-loops). R-loops accumulation is readily detectable in G1-phase, whereas γH2Av increases mainly during DNA replication. These defects induce JNK-mediated apoptosis and are specific of dH1 depletion since they are not observed when heterochromatin silencing is relieved by HP1a depletion. Altogether, our results suggest that histone H1 prevents R-loops-induced DNA damage in heterochromatin and unveil its essential contribution to maintenance of genome stability. Introduction Histones are chromosomal proteins that play an important structural function in packaging of the eukaryotic genome into chromatin. Histones H2A, H2B, H3 and H4 form an octameric complex that organizes 146 bp of DNA and constitutes the protein core of the nucleosome, a highly conserved particle that is the basic structural and functional subunit of chromatin. In addition, linker histones H1 bind to the nucleosome core particle and stabilize folding of the nucleofilament into higher-order structures 1 , 2 . Histones are also crucial to the regulation of genomic functions. In recent years, we have become aware of the essential contribution of core histones to the epigenetic regulation of multiple genomic processes from RNA transcription to DNA replication, recombination and repair, chromosome segregation and genome integrity. In comparison, the biology of linker histones H1 remains poorly understood. Histones H1 are less well conserved than core histones and, in metazoa, they generally exist in multiple variants that play partially redundant functions. For instance, deletion of one or two of the seven mouse somatic H1 variants have no detectable effects since mice develop normally and show normal total H1 levels due to the compensatory expression of other variants 3 , 4 . Mice also contain one female and three male germline specific H1 variants 5 . Humans show a similar complexity. In contrast, H1 diversity in Drosophila melanogaster is low since it contains only one somatic (dH1) and a second germline specific (dBigH1) variant 5 , 6 . Note, however, that somatic dH1 is encoded by a multigene family, which is unusual since, in most metazoa, H1 variants are encoded by single-copy genes 6 . Unicellular eukaryotes such as Saccharomyces cerevisiae , Aspergillus nidulans and Tetrahymena termophila also contain a single histone H1-like gene 7 , 8 , 9 . Genetic studies unveiled the essential contribution of histones H1 to metazoan development. In Drosophila , dH1 depletion impairs normal development and causes lethality 10 , 11 . Similarly, triple H1 variants knockout mice fail to compensate total H1 levels and die at early developmental stages 12 . The reason for this lethality is not well understood. On one hand, although they are widely distributed across the genome, histones H1 have a weak contribution to gene expression since depletion of Drosophila dH1 affects expression of <10% of protein-coding genes 11 . Similarly, only a few hundreds of genes are found deregulated in ES-cells derived from triple H1 knockout mice 13 , whose total H1 content is reduced by ∼ 50%. Furthermore, in S . cerevisiae , deletion of the single H1-like gene Hho1 affects expression of only a few genes 14 . In contrast to its weak effect on expression of euchromatic genes, dH1 depletion strongly affects silencing of transposable elements (TE) and other repetitive DNA sequences 11 , 15 , and induces DNA damage 11 . However, the actual molecular mechanisms underlying these defects remain unknown. Here, we show that dH1 depletion induces the accumulation of R-loops in heterochromatin. R-loops are three-stranded structures formed when a newly synthesized RNA forms a DNA:RNA hybrid with the transcribed strand leaving the untranscribed strand single-stranded (ssDNA). R-loops can form naturally during plasmid and mitochondrial DNA replication 16 , 17 , in immunoglobulin class switching 18 or during transcription 19 . However, unregulated R-loops formation is also an important source of genomic instability 20 , 21 , 22 , 23 . In particular, R-loops can stall replication fork progression, which generates double-stranded breaks (DSBs) and induces hyperrecombination 24 , 25 . Our results show that DNA damage, genomic instability and apoptosis induced by dH1 depletion depend on R-loops. We also show that dH1 contribution to R-loops dynamics is specific since HP1a depletion, which strongly relieves heterochromatin silencing too 26 , does not induce R-loops accumulation. Results dH1 depletion induces DNA damage in heterochromatin dH1 depletion in the Drosophila wing imaginal disc was shown to induce DNA damage, as determined by an increased αγH2Av reactivity 11 . However, the underlying molecular mechanisms of this effect remained unknown. Here, to address this question, we performed depletion experiments in cultured Drosophila S2 cells, which constitute a homogeneous cell population amenable to mechanistic studies. As previously observed in the wing imaginal disc, RNAi-induced dH1 depletion in S2 cells significantly increased γH2Av content, as determined by both immunofluorescence (IF) (Fig. 1a ) and western blot (WB) analyses (Fig. 1b ). This increase was not observed in control cells treated with siRNAs against LacZ (Fig. 1a and b ), and it was not associated with increased total H2Av content (Supplementary Fig. 1 ). Concomitant to increased γH2Av, dH1-depleted cells showed a high incidence of DNA breaks (DBs), as determined by the increased tail-moment observed in single-cell electrophoretic analyses performed under alkaline and neutral conditions to detect both single-stranded (SSBs) and double-stranded DNA breaks (DSBs) or only DSBs, respectively (Fig. 1c ). In addition, radiation-induced DNA damage was repaired efficiently in dH1-depleted cells (Fig. 1d ), indicating that DNA repair was not impaired. Triple H1 knockout mouse ES-cells also showed efficient DNA repair 27 . Fig. 1 dH1 depletion induces DNA damage. a<|im_end|> <|im_start|>assistant Scientists headed by Ferran Azorín at the Institute for Research in Biomedicine (IRB Barcelona) have discovered why histone 1 is a major protection factor against genomic instability and a vital protein. Their study of the function of histone 1, the least known of the five histones, has been published in the journal Nature Communications. "Although histone 1 is key component of chromatin, the form in which DNA is packaged inside the cell nucleus through the action of histones, there are still many questions regarding this molecule," says Ferran Azorín. "Regarding the other histones, which are major proteins in the regulation of gene expression, we know which enzymes modify them, their functions, and how they are regulated. But for some reason, the functions of histone 1 have not been addressed," he says. Lethal lesions The study explains for the first time that the suppression of histone 1 causes cell damage and DNA damage. The deregulation of a commonly suppressed region of chromatin, called heterochromatin, leads to defects in information transcription, which in turn gives rise to the accumulation of DNA and RNA hybrids, the so-called R-loops, which are lethal. "The deregulation of heterochromatin has disastrous consequences," says Jordi Bernués, associate researcher in Azorín's group and co-leader of the study. The team also observed that in the presence of histone 1, these problems did not arise in spite of heterochromatin expression. "Histone 1 not only serves as a repressor but also actively contributes to the removal of R-loops." However, the researchers do not know how this function arises. "The mechanism is what we want to study, how histone 1 prevents the mechanism from causing damage," explains IRB Barcelona PhD student Anna Casas-Lamesa, co-author of the article together with Aleix Bayona-Feliu. DNA replication. Red and green: replication regions. Credit: Jordi Bernués, IRB Barcelona. The fruit fly Drosophila melanogaster is crucial in unraveling this function. First, only one variant of this histone is present in the fly, while humans have up to seven, so the research is simplified. Second, the fly allows scientists to remove a protein from a specific place and at a specific time. They removed histone 1 from the precursor structure of wings. They observed that the fly was born alive but without wings; thus, the removal of this molecule caused the death of all cell precursors of this tissue—if histone 1 is completely removed, the embryo dies. A statistical analysis of gene expression allowed the scientists to reject a longstanding hypothesis, namely that histone 1 is a global repressor of expression. "The effect of removing histone 1 on gene expression is very weak," says Bernués. Its expression alters that of only 5 percent of genes. "It is not a transcriptional regulator," says Azorín. Heterochromatin contains genetic information that is not translated for proteins but that comprises repetitive sequences that the cell silences and that is tightly regulated. "Both R-loops and the information held in heterochromatin have natural functions, but when they are deregulated, they are lethal. "We have now been able to associate genomic instability with the uncontrolled formation of R-loops caused by the lack of histone 1 and this is completely new," says Bernués. Drosophila without wings. The removal of histone 1 causes the death of all cell precursors of this tissue. Credit: Jordi Bernués, IRB Barcelona. Histone 1 and cancer Preliminary experiments in cultured tumour cells confirm that the genomic instability present in these cells is partly caused by histone 1 deficiency. "But we have to further study the functions of this histone, identify the other proteins with which it is associated, and determine the enzymes that modify it and why, and the cell signaling pathways involved," says Bernués. In addition to exploring the mechanisms through which histone 1 keeps heterochromatin in check and prevents R-loop formation, Anna Casas-Lamesa is also addressing the involvement of this molecule in cancer. "Our preliminary studies are promising," explains Azorín. "But we are still a long way off proposing histone 1 as a target." <|im_end|>

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2,440

[ { "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 The COVID-19 pandemic had clear impacts on mental health. Social media presents an opportunity for assessing mental health at the population level. Objectives 1) Identify and describe language used on social media that is associated with discourse about depression. 2) Describe the associations between identified language and COVID-19 incidence over time across several geographies. Methods We create a word embedding based on the posts in Reddit's /r/Depression and use this word embedding to train representations of active authors. We contrast these authors against a control group and extract keywords that capture differences between the two groups. We filter these keywords for face validity and to match character limits of an information retrieval system, Elasticsearch. We retrieve all geo-tagged posts on Twitter from April 2019 to June 2021 from Seattle, Sydney, Mumbai, and Toronto. The tweets are scored with BM25 using the keywords. We call this score rDD. We compare changes in average score over time with case counts from the pandemic's beginning through June 2021. Results We observe a pattern in rDD across all cities analyzed: There is an increase in rDD near the start of the pandemic which levels off over time. However, in Mumbai we also see an increase aligned with a second wave of cases. Conclusions Our results are concordant with other studies which indicate that the impact of the pandemic on mental health was highest initially and was followed by recovery, largely unchanged by subsequent waves. However, in the Mumbai data we observed a substantial rise in rDD with a large second wave. Our results indicate possible un-captured heterogeneity across geographies, and point to a need for a better understanding of this differential impact on mental health. Introduction The COVID-19 pandemic has had a significant impact on population mental health. For example, a meta-analysis of community-based studies conducted during the early stages of the pandemic indicates there was an increase in the prevalence of depression in various countries from January 2020 to May 2020 [ 1 ]. The reasons for this increase are complex; COVID-19 changed day-to-day life significantly for many people, and the individual burden of public health restrictions is variable. For example, highly individual factors such as living situation, income, and pre-existing mental health conditions all interact with pandemic-unique stressors to constitute mental health burdens [ 2 ]. A study by Daly & Robinson found that psychological distress levels began to decrease following a peak that occurred near the start of the pandemic, and were generally in decline by July 2020 [ 3 ]. As public health efforts continue, being able to describe and understand the population mental health burden imposed by the pandemic is an important part of generating an effective response. Social media can provide a useful source of freely available data for population health monitoring as an adjunct to survey-based methodology. Advantages include its timeliness, lack of recall bias (though other biases may be present), and the fact that it can be retrospectively assessed for its relationships to different events [ 4 ]. Furthermore, social media data permit rapid analysis across a variety of geographic areas that may be challenging for survey-based approaches. Such data have been used to inform a variety of public health domains, including mental health and mental illness, disease surveillance, rapid knowledge dissemination, quantifying community supports, and characterizing misinformation in health communication [ 5 – 9 ]. Using sentiment analysis (a natural language processing technique), social media data have also been used with large social media datasets to quantify population mental health during the pandemic [ 10 ]. However, sentiment analysis can give an incomplete picture of population mental health for three main reasons. First, sentiment and mental health are different constructs. Many sentiments expressed on social media have nothing to do with the author’s mental health, and sentiment analysis techniques are not designed to distinguish between negative sentiment associated with poor mental health and negative sentiment not associated with mental health status [ 11 ]. Second, even if poor mental health is evidenced by negative sentiment, many sentiment analysis methods are based on fixed vocabularies and rule-based annotations that are subject to degrading applicability as language evolves over time [ 12 ]. This can be problematic, as language used to indicate poor mental health can vary widely from individual to individual and across cultures [ 13 ]. Due to nuances in online discourse about mental health, techniques that rely on closed-vocabulary approaches with fixed keyword sets may miss mental health indicators, particularly ones expressed using slang or memetics. Third, language on social media associated with poorer mental health at the population level may not express negative sentiment at all—for example, an increase in positive or supportive posts from “helpers” may be a response to a perceived increase in poor mental health at the population level. Sentiment analysis techniques are not currently designed to detect language that is associated with poor mental health at the population level. Aims Our overall aim is to present a framework for describing population mental health using social media data that uses a transparent, open-vocabulary approach based on discourse in online communities. To illustrate its use, we present a case study that describes keywords associated with online discussion about depression as well as its rise and fall in different geographic regions over the first year of the COVID-19 pandemic. The aims of our case study are as follows: (I) identify and describe language used on social media that is associated with discourse about depression, and (II) describe the associations between the identified language and COVID-19 incidence over time across several geographies. To assess the framework’s suitability for supporting public health practice, we compare to published results not relying on social media such as that of Aknin et al. and Shields et al. [ 14 , 15 ]. Our goal is for the framework to be understandable and for the resulting keywords to be easy to re-purpose so that other practitioners can perform related analyses on other topics and geographies of", "role": "user" }, { "content": "Researchers who analyzed language related to depression on social media during the pandemic say the data suggest people learned to cope as the waves wore on. University of Alberta researcher Alona Fyshe and her collaborators at the University of Western Ontario hypothesized that depression-related language would spike during each wave of COVID-19. But their study shows that wasn't the case. \"There was a big reaction at the beginning and then people sort of found their new normal,\" says Fyshe, an assistant professor of computing science and psychology. \"It's a message of resilience, people figuring out how to keep on keeping on in a pandemic.\" For the study, the researchers turned their attention to online platforms such as Reddit and Twitter. Social media is a useful tool in assessing mental health at the population level, explains Fyshe, a fellow of the Alberta Machine Intelligence Institute and Canada CIFAR AI chair. The researchers first identified keywords by analyzing the type of language posters were using in discussions on Reddit. The self-identification found in those subreddits and forums isn't replicated in many other social media platforms, Fyshe explains. \"Essentially we trained a machine learning model that can differentiate between the language of people who post to a thread on the topic of depression versus people who don't,\" says Fyshe. Using this information and the identified keywords, they turned their attention to Twitter. They analyzed data from four cities—Sydney, Mumbai, Seattle and Toronto—with different waves of COVID-19 so they could determine which changes in language were due to global trends and which were local. They restricted the data to areas with a large percentage of English tweets so they could use the same methodology to analyze all the data. The results were surprising, says Fyshe. In general, spikes in COVID-19 cases and the various waves throughout the pandemic weren't reflected in the data. In fact, the only city with an increase in depression-related language after the first wave was Mumbai, which saw a significant second wave. Fyshe says the machine learning methods used to scrape Reddit subforums to identify keywords and analyze Twitter data could be applied to a wide range of subjects. For example, when examining data in Seattle, they found strong reactions to the Black Lives Matter movement. \"It was indicative of there being a large change to the general mood—what people were talking about and how people were feeling about the world they lived in.\" The research was published in the International Journal of Population Data 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 Introduction The COVID-19 pandemic had clear impacts on mental health. Social media presents an opportunity for assessing mental health at the population level. Objectives 1) Identify and describe language used on social media that is associated with discourse about depression. 2) Describe the associations between identified language and COVID-19 incidence over time across several geographies. Methods We create a word embedding based on the posts in Reddit's /r/Depression and use this word embedding to train representations of active authors. We contrast these authors against a control group and extract keywords that capture differences between the two groups. We filter these keywords for face validity and to match character limits of an information retrieval system, Elasticsearch. We retrieve all geo-tagged posts on Twitter from April 2019 to June 2021 from Seattle, Sydney, Mumbai, and Toronto. The tweets are scored with BM25 using the keywords. We call this score rDD. We compare changes in average score over time with case counts from the pandemic's beginning through June 2021. Results We observe a pattern in rDD across all cities analyzed: There is an increase in rDD near the start of the pandemic which levels off over time. However, in Mumbai we also see an increase aligned with a second wave of cases. Conclusions Our results are concordant with other studies which indicate that the impact of the pandemic on mental health was highest initially and was followed by recovery, largely unchanged by subsequent waves. However, in the Mumbai data we observed a substantial rise in rDD with a large second wave. Our results indicate possible un-captured heterogeneity across geographies, and point to a need for a better understanding of this differential impact on mental health. Introduction The COVID-19 pandemic has had a significant impact on population mental health. For example, a meta-analysis of community-based studies conducted during the early stages of the pandemic indicates there was an increase in the prevalence of depression in various countries from January 2020 to May 2020 [ 1 ]. The reasons for this increase are complex; COVID-19 changed day-to-day life significantly for many people, and the individual burden of public health restrictions is variable. For example, highly individual factors such as living situation, income, and pre-existing mental health conditions all interact with pandemic-unique stressors to constitute mental health burdens [ 2 ]. A study by Daly & Robinson found that psychological distress levels began to decrease following a peak that occurred near the start of the pandemic, and were generally in decline by July 2020 [ 3 ]. As public health efforts continue, being able to describe and understand the population mental health burden imposed by the pandemic is an important part of generating an effective response. Social media can provide a useful source of freely available data for population health monitoring as an adjunct to survey-based methodology. Advantages include its timeliness, lack of recall bias (though other biases may be present), and the fact that it can be retrospectively assessed for its relationships to different events [ 4 ]. Furthermore, social media data permit rapid analysis across a variety of geographic areas that may be challenging for survey-based approaches. Such data have been used to inform a variety of public health domains, including mental health and mental illness, disease surveillance, rapid knowledge dissemination, quantifying community supports, and characterizing misinformation in health communication [ 5 – 9 ]. Using sentiment analysis (a natural language processing technique), social media data have also been used with large social media datasets to quantify population mental health during the pandemic [ 10 ]. However, sentiment analysis can give an incomplete picture of population mental health for three main reasons. First, sentiment and mental health are different constructs. Many sentiments expressed on social media have nothing to do with the author’s mental health, and sentiment analysis techniques are not designed to distinguish between negative sentiment associated with poor mental health and negative sentiment not associated with mental health status [ 11 ]. Second, even if poor mental health is evidenced by negative sentiment, many sentiment analysis methods are based on fixed vocabularies and rule-based annotations that are subject to degrading applicability as language evolves over time [ 12 ]. This can be problematic, as language used to indicate poor mental health can vary widely from individual to individual and across cultures [ 13 ]. Due to nuances in online discourse about mental health, techniques that rely on closed-vocabulary approaches with fixed keyword sets may miss mental health indicators, particularly ones expressed using slang or memetics. Third, language on social media associated with poorer mental health at the population level may not express negative sentiment at all—for example, an increase in positive or supportive posts from “helpers” may be a response to a perceived increase in poor mental health at the population level. Sentiment analysis techniques are not currently designed to detect language that is associated with poor mental health at the population level. Aims Our overall aim is to present a framework for describing population mental health using social media data that uses a transparent, open-vocabulary approach based on discourse in online communities. To illustrate its use, we present a case study that describes keywords associated with online discussion about depression as well as its rise and fall in different geographic regions over the first year of the COVID-19 pandemic. The aims of our case study are as follows: (I) identify and describe language used on social media that is associated with discourse about depression, and (II) describe the associations between the identified language and COVID-19 incidence over time across several geographies. To assess the framework’s suitability for supporting public health practice, we compare to published results not relying on social media such as that of Aknin et al. and Shields et al. [ 14 , 15 ]. Our goal is for the framework to be understandable and for the resulting keywords to be easy to re-purpose so that other practitioners can perform related analyses on other topics and geographies of<|im_end|> <|im_start|>assistant Researchers who analyzed language related to depression on social media during the pandemic say the data suggest people learned to cope as the waves wore on. University of Alberta researcher Alona Fyshe and her collaborators at the University of Western Ontario hypothesized that depression-related language would spike during each wave of COVID-19. But their study shows that wasn't the case. "There was a big reaction at the beginning and then people sort of found their new normal," says Fyshe, an assistant professor of computing science and psychology. "It's a message of resilience, people figuring out how to keep on keeping on in a pandemic." For the study, the researchers turned their attention to online platforms such as Reddit and Twitter. Social media is a useful tool in assessing mental health at the population level, explains Fyshe, a fellow of the Alberta Machine Intelligence Institute and Canada CIFAR AI chair. The researchers first identified keywords by analyzing the type of language posters were using in discussions on Reddit. The self-identification found in those subreddits and forums isn't replicated in many other social media platforms, Fyshe explains. "Essentially we trained a machine learning model that can differentiate between the language of people who post to a thread on the topic of depression versus people who don't," says Fyshe. Using this information and the identified keywords, they turned their attention to Twitter. They analyzed data from four cities—Sydney, Mumbai, Seattle and Toronto—with different waves of COVID-19 so they could determine which changes in language were due to global trends and which were local. They restricted the data to areas with a large percentage of English tweets so they could use the same methodology to analyze all the data. The results were surprising, says Fyshe. In general, spikes in COVID-19 cases and the various waves throughout the pandemic weren't reflected in the data. In fact, the only city with an increase in depression-related language after the first wave was Mumbai, which saw a significant second wave. Fyshe says the machine learning methods used to scrape Reddit subforums to identify keywords and analyze Twitter data could be applied to a wide range of subjects. For example, when examining data in Seattle, they found strong reactions to the Black Lives Matter movement. "It was indicative of there being a large change to the general mood—what people were talking about and how people were feeling about the world they lived in." The research was published in the International Journal of Population Data Science. <|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 Kinesin-8s are dual-activity motor proteins that can move processively on microtubules and depolymerize microtubule plus-ends, but their mechanism of combining these distinct activities remains unclear. We addressed this by obtaining cryo-EM structures (2.6–3.9 Å) of Candida albicans Kip3 in different catalytic states on the microtubule lattice and on a curved microtubule end mimic. We also determined a crystal structure of microtubule-unbound Ca Kip3-ADP (2.0 Å) and analyzed the biochemical activity of Ca Kip3 and kinesin-1 mutants. These data reveal that the microtubule depolymerization activity of kinesin-8 originates from conformational changes of its motor core that are amplified by dynamic contacts between its extended loop-2 and tubulin. On curved microtubule ends, loop-1 inserts into preceding motor domains, forming head-to-tail arrays of kinesin-8s that complement loop-2 contacts with curved tubulin and assist depolymerization. On straight tubulin protofilaments in the microtubule lattice, loop-2-tubulin contacts inhibit conformational changes in the motor core, but in the ADP-Pi state these contacts are relaxed, allowing neck-linker docking for motility. We propose that these tubulin shape-induced alternations between pro-microtubule-depolymerization and pro-motility kinesin states, regulated by loop-2, are the key to the dual activity of kinesin-8 motors. Introduction Members of the kinesin-8 family are unique, as they often integrate the two enzymatic activities of processive microtubule plus-end-directed motility and microtubule depolymerization into a single ~40 kDa motor domain 1 , 2 , 3 , 4 , 5 , 6 , 7 . These activities allow kinesin-8s to localize to the ends of cytoplasmic or spindle microtubules, where they can regulate mitotic spindle size, spindle position, and chromosomal congression 5 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . In many eukaryotes in which these motor proteins have been studied, the motile and depolymerization activities are produced by their N-terminal motor domain, while their C-terminal tail has an additional microtubule-binding site that helps regulate the functions of the motor domain 5 , 17 , 18 , 19 . A lack of high-resolution structures capturing a kinesin-8 motor domain at each major step of its motile and microtubule depolymerization cycles has limited our understanding of the relationship between these two catalytic cycles and the structural elements of the motor domain that control them. At this time, our knowledge of the catalytic cycles of kinesins is limited to motile kinesins that are incapable of microtubule depolymerization, and to microtubule-depolymerizing kinesins that are non-motile. In motile kinesins, such as kinesin-1 and kinesin-3, microtubule lattice binding by one of their two motor domains opens the nucleotide-binding pocket, allowing ADP release 20 , 21 , 22 . Subsequent entry of ATP initiates closing of the nucleotide-binding pocket and docking of a short peptide, known as the neck-linker, along the side of the motor domain. Neck-linker docking in the microtubule-bound motor domain propels the second, microtubule-unbound, motor domain towards the microtubule plus-end, enabling a single stepping event. In the non-motile microtubule-depolymerizing kinesin-13s, which move on microtubules by diffusion 23 , ATP binding does not induce closure of the nucleotide-binding pocket on the microtubule lattice 24 . Only when kinesin-13 is bound to curved αβ-tubulin protofilaments found at microtubule ends does the nucleotide-binding pocket close in the presence of ATP 24 , 25 . In this case, closing the nucleotide-binding pocket allows kinesin-13-specific structural elements to promote further tubulin bending, leading to microtubule depolymerization 26 , 27 . The motility and depolymerization cycles in purely motile and purely depolymerizing kinesins are thus very different. The features of the kinesin-8 cycle that allow their motors to combine both activities remain unknown. An important gap in our understanding of the kinesin-8 depolymerization mechanism is the lack of a kinesin-8 structure bound to curved tubulin. Functional studies of Saccharomyces cerevisiae kinesin-8 Kip3 ( Sc Kip3) have proposed that upon reaching the curved conformation of tubulin at the plus-end, the motor domain experiences a conformational switch that suppresses ATP hydrolysis 28 . As a result, prolonged, tight interactions between kinesin-8 and the microtubule plus-end stabilize protofilament curvature and promote microtubule depolymerization. The suggested mechanism for this tubulin shape-dependent ATPase switch involves formation of an interaction between loop-11 of the motor domain and an aspartate residue on helix-3 of α-tubulin (Asp118—yeast tubulin, Asp116—bovine or porcine tubulin). Subsequent molecular dynamics studies identified an arginine within loop-11 (Arg351– Sc Kip3) as a potential candidate residue that interacts with α-tubulin Asp118/116 in the curved conformation 29 . Studies on the human kinesin-8s KIF18A and KIF19A have also implicated separate regions of the microtubule-binding interface, namely loop-2 and loop-8, as elements that are likely involved in stabilizing curved tubulin protofilaments 30 , 31 , 32 . Ultimately, a structure of a kinesin-8 motor bound to curved tubulin is needed to elucidate how discrete parts of the motor domain contribute to kinesin-8-mediated microtubule depolymerization. Mechanistically, it is well-established that some kinesin-8s operate cooperatively to induce microtubule depolymerization 2 , 3 , 18 , 28 . Both in vitro and in vivo, a build-up of motors at the plus-end is required for effective disassembly of microtubule polymers. As longer microtubules accumulate more motors than shorter microtubules, longer microtubules are depolymerized faster—an effect termed length-dependent depolymerization. The structural basis underlying this cooperative length-dependent microtubule depolymerization is not understood. It is also not clear if and how kinesin-8s physically interact to collectively produce forces needed to dissociate tubulin dimers. To understand the mechanistic basis for the dual-functionality of kinesin-8, we obtained seven cryo-EM structures of Candida albicans Kip3 bound to either the microtubule lattice or curved microtubule end mimics, and a microtubule-unbound Ca Kip3 X-ray structure. We also performed biochemical experiments on Ca Kip3 and human kinesin-1 constructs with their loop-2 region swapped or loop-1 region truncated. On straight protofilaments within the central microtubule lattice, we observed that loop-2 forms extensive contacts with α-tubulin that temporarily restrict the ATP-bound motor in a non-motile, open conformation. Only in the post-ATP-hydrolysis state of microtubule-bound Ca Kip3 are the loop-2-tubulin interactions relaxed enough to allow nucleotide-binding pocket closure and neck-linker docking, producing", "role": "user" }, { "content": "Understanding the busy networks inside our cells can help researchers develop new cancer treatments and prevent dangerous fungal infections. With the help of the Canadian Light Source (CLS) at the University of Saskatchewan, a research team led by John Allingham from Queen's University and Hernando Sosa from the Albert Einstein College of Medicine has shed light on a protein that regulates the intricate microscopic networks that give cells their shape and helps ship important molecules to diverse locations. Using the CMCF beamline at the CLS and the cryo-EM facility at the Simons Electron Microscopy Center (SEMC) at the New York Structural Biology Center, the team found the missing pieces of an important puzzle. In their published work, they are the first group to clearly describe the mechanism of action of a tiny motor protein called Kinesin-8 that enables it to control the structures of microtubule fiber networks inside the cell. \"Our recent paper in Nature Communications, co-first authored by Byron Hunter and Matthieu Benoit, shows how this specific type of kinesin motor protein has developed the ability to use microtubules as tracks for movement, guiding transport of cargo within the cell,\" said Dr. John Allingham, a professor at the Queen's School of Medicine, \"in addition to being able to disassemble these tracks, controlling their length and location in cells.\" The Kinesin-8 proteins ensure that a cell's cargo is in the right place during cellular division and help to regulate cellular networks, making sure the microtubules do not grow too long. This research provides an important strategy for cancer treatment. The team is hopeful that targeting the Kinesin-8 proteins in cancer cells could contribute to anti-cancer treatments. This strategy could also be used to develop a therapy for pathogenic fungal infections that threaten people with compromised immune systems. Allingham said the CLS provides an invaluable training environment for his students, including Ph.D. candidate Byron Hunter who collected the CLS data for their recent work. \"The CLS platform was hugely valuable,\" said Hunter. \"The increase in the quality of data was enormous. We were able to screen a huge number of different crystal samples in a relatively brief period of time.\" ", "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 Kinesin-8s are dual-activity motor proteins that can move processively on microtubules and depolymerize microtubule plus-ends, but their mechanism of combining these distinct activities remains unclear. We addressed this by obtaining cryo-EM structures (2.6–3.9 Å) of Candida albicans Kip3 in different catalytic states on the microtubule lattice and on a curved microtubule end mimic. We also determined a crystal structure of microtubule-unbound Ca Kip3-ADP (2.0 Å) and analyzed the biochemical activity of Ca Kip3 and kinesin-1 mutants. These data reveal that the microtubule depolymerization activity of kinesin-8 originates from conformational changes of its motor core that are amplified by dynamic contacts between its extended loop-2 and tubulin. On curved microtubule ends, loop-1 inserts into preceding motor domains, forming head-to-tail arrays of kinesin-8s that complement loop-2 contacts with curved tubulin and assist depolymerization. On straight tubulin protofilaments in the microtubule lattice, loop-2-tubulin contacts inhibit conformational changes in the motor core, but in the ADP-Pi state these contacts are relaxed, allowing neck-linker docking for motility. We propose that these tubulin shape-induced alternations between pro-microtubule-depolymerization and pro-motility kinesin states, regulated by loop-2, are the key to the dual activity of kinesin-8 motors. Introduction Members of the kinesin-8 family are unique, as they often integrate the two enzymatic activities of processive microtubule plus-end-directed motility and microtubule depolymerization into a single ~40 kDa motor domain 1 , 2 , 3 , 4 , 5 , 6 , 7 . These activities allow kinesin-8s to localize to the ends of cytoplasmic or spindle microtubules, where they can regulate mitotic spindle size, spindle position, and chromosomal congression 5 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . In many eukaryotes in which these motor proteins have been studied, the motile and depolymerization activities are produced by their N-terminal motor domain, while their C-terminal tail has an additional microtubule-binding site that helps regulate the functions of the motor domain 5 , 17 , 18 , 19 . A lack of high-resolution structures capturing a kinesin-8 motor domain at each major step of its motile and microtubule depolymerization cycles has limited our understanding of the relationship between these two catalytic cycles and the structural elements of the motor domain that control them. At this time, our knowledge of the catalytic cycles of kinesins is limited to motile kinesins that are incapable of microtubule depolymerization, and to microtubule-depolymerizing kinesins that are non-motile. In motile kinesins, such as kinesin-1 and kinesin-3, microtubule lattice binding by one of their two motor domains opens the nucleotide-binding pocket, allowing ADP release 20 , 21 , 22 . Subsequent entry of ATP initiates closing of the nucleotide-binding pocket and docking of a short peptide, known as the neck-linker, along the side of the motor domain. Neck-linker docking in the microtubule-bound motor domain propels the second, microtubule-unbound, motor domain towards the microtubule plus-end, enabling a single stepping event. In the non-motile microtubule-depolymerizing kinesin-13s, which move on microtubules by diffusion 23 , ATP binding does not induce closure of the nucleotide-binding pocket on the microtubule lattice 24 . Only when kinesin-13 is bound to curved αβ-tubulin protofilaments found at microtubule ends does the nucleotide-binding pocket close in the presence of ATP 24 , 25 . In this case, closing the nucleotide-binding pocket allows kinesin-13-specific structural elements to promote further tubulin bending, leading to microtubule depolymerization 26 , 27 . The motility and depolymerization cycles in purely motile and purely depolymerizing kinesins are thus very different. The features of the kinesin-8 cycle that allow their motors to combine both activities remain unknown. An important gap in our understanding of the kinesin-8 depolymerization mechanism is the lack of a kinesin-8 structure bound to curved tubulin. Functional studies of Saccharomyces cerevisiae kinesin-8 Kip3 ( Sc Kip3) have proposed that upon reaching the curved conformation of tubulin at the plus-end, the motor domain experiences a conformational switch that suppresses ATP hydrolysis 28 . As a result, prolonged, tight interactions between kinesin-8 and the microtubule plus-end stabilize protofilament curvature and promote microtubule depolymerization. The suggested mechanism for this tubulin shape-dependent ATPase switch involves formation of an interaction between loop-11 of the motor domain and an aspartate residue on helix-3 of α-tubulin (Asp118—yeast tubulin, Asp116—bovine or porcine tubulin). Subsequent molecular dynamics studies identified an arginine within loop-11 (Arg351– Sc Kip3) as a potential candidate residue that interacts with α-tubulin Asp118/116 in the curved conformation 29 . Studies on the human kinesin-8s KIF18A and KIF19A have also implicated separate regions of the microtubule-binding interface, namely loop-2 and loop-8, as elements that are likely involved in stabilizing curved tubulin protofilaments 30 , 31 , 32 . Ultimately, a structure of a kinesin-8 motor bound to curved tubulin is needed to elucidate how discrete parts of the motor domain contribute to kinesin-8-mediated microtubule depolymerization. Mechanistically, it is well-established that some kinesin-8s operate cooperatively to induce microtubule depolymerization 2 , 3 , 18 , 28 . Both in vitro and in vivo, a build-up of motors at the plus-end is required for effective disassembly of microtubule polymers. As longer microtubules accumulate more motors than shorter microtubules, longer microtubules are depolymerized faster—an effect termed length-dependent depolymerization. The structural basis underlying this cooperative length-dependent microtubule depolymerization is not understood. It is also not clear if and how kinesin-8s physically interact to collectively produce forces needed to dissociate tubulin dimers. To understand the mechanistic basis for the dual-functionality of kinesin-8, we obtained seven cryo-EM structures of Candida albicans Kip3 bound to either the microtubule lattice or curved microtubule end mimics, and a microtubule-unbound Ca Kip3 X-ray structure. We also performed biochemical experiments on Ca Kip3 and human kinesin-1 constructs with their loop-2 region swapped or loop-1 region truncated. On straight protofilaments within the central microtubule lattice, we observed that loop-2 forms extensive contacts with α-tubulin that temporarily restrict the ATP-bound motor in a non-motile, open conformation. Only in the post-ATP-hydrolysis state of microtubule-bound Ca Kip3 are the loop-2-tubulin interactions relaxed enough to allow nucleotide-binding pocket closure and neck-linker docking, producing<|im_end|> <|im_start|>assistant Understanding the busy networks inside our cells can help researchers develop new cancer treatments and prevent dangerous fungal infections. With the help of the Canadian Light Source (CLS) at the University of Saskatchewan, a research team led by John Allingham from Queen's University and Hernando Sosa from the Albert Einstein College of Medicine has shed light on a protein that regulates the intricate microscopic networks that give cells their shape and helps ship important molecules to diverse locations. Using the CMCF beamline at the CLS and the cryo-EM facility at the Simons Electron Microscopy Center (SEMC) at the New York Structural Biology Center, the team found the missing pieces of an important puzzle. In their published work, they are the first group to clearly describe the mechanism of action of a tiny motor protein called Kinesin-8 that enables it to control the structures of microtubule fiber networks inside the cell. "Our recent paper in Nature Communications, co-first authored by Byron Hunter and Matthieu Benoit, shows how this specific type of kinesin motor protein has developed the ability to use microtubules as tracks for movement, guiding transport of cargo within the cell," said Dr. John Allingham, a professor at the Queen's School of Medicine, "in addition to being able to disassemble these tracks, controlling their length and location in cells." The Kinesin-8 proteins ensure that a cell's cargo is in the right place during cellular division and help to regulate cellular networks, making sure the microtubules do not grow too long. This research provides an important strategy for cancer treatment. The team is hopeful that targeting the Kinesin-8 proteins in cancer cells could contribute to anti-cancer treatments. This strategy could also be used to develop a therapy for pathogenic fungal infections that threaten people with compromised immune systems. Allingham said the CLS provides an invaluable training environment for his students, including Ph.D. candidate Byron Hunter who collected the CLS data for their recent work. "The CLS platform was hugely valuable," said Hunter. "The increase in the quality of data was enormous. We were able to screen a huge number of different crystal samples in a relatively brief period of time." <|im_end|>

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19581, 2442, 392, 24292, 122241, 8899, 14, 8027, 304, 279, 50264, 390, 1659, 220, 1682, 662, 19241, 389, 279, 3823, 597, 1572, 258, 12, 23, 82, 735, 2843, 972, 32, 323, 735, 2843, 777, 32, 617, 1101, 69702, 8821, 13918, 315, 279, 8162, 83, 392, 1130, 65500, 3834, 11, 32125, 6471, 12, 17, 323, 6471, 12, 23, 11, 439, 5540, 430, 527, 4461, 6532, 304, 27276, 4954, 50264, 15286, 24292, 18940, 12723, 24469, 220, 966, 1174, 220, 2148, 1174, 220, 843, 662, 55106, 11, 264, 6070, 315, 264, 597, 1572, 258, 12, 23, 9048, 6965, 311, 50264, 15286, 24292, 374, 4460, 311, 97298, 349, 1268, 44279, 5596, 315, 279, 9048, 8106, 17210, 311, 597, 1572, 258, 12, 23, 82076, 8162, 83, 392, 1130, 2219, 5849, 1195, 2065, 13, 28901, 38210, 11, 433, 374, 1664, 64868, 430, 1063, 597, 1572, 258, 12, 23, 82, 14816, 22415, 8046, 311, 49853, 8162, 83, 392, 1130, 2219, 5849, 1195, 2065, 220, 17, 1174, 220, 18, 1174, 220, 972, 1174, 220, 1591, 662, 11995, 304, 55004, 323, 304, 41294, 11, 264, 1977, 5352, 315, 38424, 520, 279, 5636, 13368, 374, 2631, 369, 7524, 834, 15343, 315, 8162, 83, 392, 1130, 46033, 388, 13, 1666, 5129, 8162, 83, 392, 2482, 47376, 810, 38424, 1109, 24210, 8162, 83, 392, 2482, 11, 5129, 8162, 83, 392, 2482, 527, 2219, 5849, 1195, 1534, 10819, 85366, 2515, 61937, 3160, 43918, 2219, 5849, 1195, 2065, 13, 578, 24693, 8197, 16940, 420, 48566, 3160, 43918, 8162, 83, 392, 1130, 2219, 5849, 1195, 2065, 374, 539, 16365, 13, 1102, 374, 1101, 539, 2867, 422, 323, 1268, 597, 1572, 258, 12, 23, 82, 22655, 16681, 311, 45925, 8356, 8603, 4460, 311, 91342, 349, 15286, 24292, 5213, 388, 13, 2057, 3619, 279, 7852, 4633, 8197, 369, 279, 19091, 34849, 2786, 315, 597, 1572, 258, 12, 23, 11, 584, 12457, 8254, 16106, 78, 12, 2783, 14726, 315, 94916, 64, 82698, 38473, 735, 575, 18, 6965, 311, 3060, 279, 8162, 83, 392, 1130, 55372, 477, 50264, 8162, 83, 392, 1130, 842, 28003, 1233, 11, 323, 264, 8162, 83, 392, 1130, 20486, 11130, 14751, 735, 575, 18, 1630, 30630, 6070, 13, 1226, 1101, 10887, 93532, 21896, 389, 14751, 735, 575, 18, 323, 3823, 597, 1572, 258, 12, 16, 57327, 449, 872, 6471, 12, 17, 5654, 58050, 477, 6471, 12, 16, 5654, 60856, 13, 1952, 7833, 18940, 12723, 24469, 2949, 279, 8792, 8162, 83, 392, 1130, 55372, 11, 584, 13468, 430, 6471, 12, 17, 7739, 16781, 19015, 449, 19581, 2442, 392, 24292, 430, 28191, 9067, 279, 67656, 50962, 9048, 304, 264, 2536, 1474, 354, 458, 11, 1825, 390, 1659, 13, 8442, 304, 279, 1772, 12, 835, 47, 2902, 68107, 398, 14744, 1614, 315, 8162, 83, 392, 1130, 50962, 14751, 735, 575, 18, 527, 279, 6471, 12, 17, 2442, 392, 24292, 22639, 31467, 3403, 311, 2187, 31484, 69044, 65500, 18301, 22722, 323, 13272, 9142, 261, 89310, 11, 17843, 128257, 198, 128256, 78191, 198, 71251, 279, 13326, 14488, 4871, 1057, 7917, 649, 1520, 12074, 2274, 502, 9572, 22972, 323, 5471, 11660, 95447, 30020, 13, 3161, 279, 1520, 315, 279, 12152, 8828, 8922, 320, 88816, 8, 520, 279, 3907, 315, 66253, 11, 264, 3495, 2128, 6197, 555, 3842, 2052, 24125, 505, 16657, 596, 3907, 323, 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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 Owing to their excellent durability, tunable physical properties, and biofunctionality, block copolymer-based membranes provide a platform for various biotechnological applications. However, conventional approaches for fabricating block copolymer membranes produce only planar or suspended polymersome structures, which limits their utilization. This study is the first to demonstrate that an electric-field-assisted self-assembly technique can allow controllable and scalable fabrication of 3-dimensional block copolymer artificial cell membranes (3DBCPMs) immobilized on predefined locations. Topographically and chemically structured microwell array templates facilitate uniform patterning of block copolymers and serve as reactors for the effective growth of 3DBCPMs. Modulating the concentration of the block copolymer and the amplitude/frequency of the electric field generates 3DBCPMs with diverse shapes, controlled sizes, and high stability (100% survival over 50 days). In vitro protein–membrane assays and mimicking of human intestinal organs highlight the potential of 3DBCPMs for a variety of biological applications such as artificial cells, cell-mimetic biosensors, and bioreactors. Introduction Self-assembly of block copolymers has attracted considerable interest in fundamental research and technical applications because of the exceptional morphological and structural versatility. In the bulk state, block copolymers undergo microphase separation by a driving force that minimizes the free energy of the system to form various structures, such as spheres, cylinders, and lamellae 1 , providing the capability to generate architectural complexity and periodicity that are difficult to achieve with conventional synthetic or lithographic technologies 2 , 3 . This behavior has been widely exploited in 2-dimensional (2D)/3-dimensional (3D) nanoscale patterning for functional devices with high throughput and fine feature sizes 4 , 5 , 6 , porous membranes for molecular separation and water purification 7 , 8 , and other advanced material designs 9 , 10 , 11 . The spin-coating method is widely used to form block copolymer thin films on templates; however, it is restricted in terms of producing patterned areas, which limits its utility in complicated and sophisticated device fabrication. Various methods, such as chemical 12 , 13 or topographical patterning 14 , solvent annealing 15 , and techniques based on electric fields 16 , thermal gradients 17 , and shear forces 18 have been developed to address this issue and provide ordered orientation. However, among these methods, only chemical or topographical patterning is effective in achieving patterned areas with predefined sizes and geometries at the desired locations. Owing to their superior mechanical/chemical stability, adjustable membrane permeability, and various surface functionalities realized through polymer engineering, block copolymer membranes have considerable potential for biological applications. In particular, they are promising alternatives to phospholipid-based membranes as artificial cell membranes for elucidating the underlying mechanical/biological mechanisms of cells and providing a platform for bioreactors and biosensors. However, in aqueous media, block copolymers spontaneously self-assemble into only one type of energetically favorable structure depending on the packing parameter (p = v/a 0 l c , where v and l c are the volume and length of the hydrophobic domain, respectively, and a 0 is the optimal area of the hydrophilic domain) 19 . Moreover, their polymer chains are difficult to rearrange because their molecular weight is greater than that of phospholipids, limiting their applications. Although osmolarity control 20 , chemical addition 21 , liquid-crystalline component incorporation 22 , and deoxyribonucleic acid (DNA)-directed self-assembly 23 have been reported to induce morphological transitions, most approaches produce irreversible shapes under specific conditions or are time-consuming. Therefore, there is a great need to overcome the aforementioned energetic penalties to accomplish a facile, systematic shape transformation. Herein, we demonstrate a method for fabricating 3D block copolymer artificial cell membranes (3DBCPMs) by combining the top-down control of the feature sizes and locations of 3DBCPMs via micro-contact printing and lithographic techniques with the bottom-up control of the diameter/length and shapes of 3DBCPMs via electric field-assisted molecular self-assembly (Fig. 1a ). Topographically and chemically structured microwell array templates not only allow micropatterning of block copolymers but also serve as confined reactors where block copolymers self-assemble and fuse to produce 3DBCPMs. An electric field with controlled amplitude and frequency regulates the morphology of 3DBCPMs over a packing parameter-dependent structure. To date, no method has been reported for the scalable fabrication (~300,000/cm 2 ) of microscale 3D block copolymer structures immobilized on patterned templates with morphological versatility, controlled size, and extremely long lifetime (100% survival over 50 days). Although simple rehydration 24 , sonication 25 , solvent annealing 26 , and electroformation 27 , 28 methods have been adopted to produce 3D block copolymer structures, most of these methods produce only suspended vesicles with large size polydispersity, which are difficult to immobilize onto substrates for further experimentation and observation. Fig. 1: 3D block copolymer artificial cell membranes (3DBCPMs) for versatile biological applications. a Electric-field-assisted self-assembly method for the scalable fabrication of 3DBCPMs with diverse shapes/sizes, high stability, and biofunctionality on silicon (Si) microwell template using a diblock copolymer, namely polybutadiene- b -polyethyleneoxide (PBd-PEO), as a building block and representative biological applications such as protein–membrane assay using prostaglandin E2 receptor 4 (EP4) and artificial intestinal organ using β-galactosidase tagged lipid. The packing parameter, p , is an inherent value of polymers associated with the volume and length of the hydrophobic domain and the optimal area of the hydrophilic domain. b A fluorescence microscopy image of a cilia-like long 3DBCPM array produced from a patterned template. c A cross-sectional transmission electron microscopy (TEM) image of a unilamellar 3DBCPM composed of ~10-nm-thick bilayer membrane. Scale bar: 100 nm. Full size image Results 3D block copolymer structures on Si microwell arrays Figure 1b shows a 3D fluorescence image reconstructed from 2D slices of a representative 3DBCPM comprising an amphiphilic diblock copolymer, polybutadiene- b -polyethyleneoxide (PBd-PEO). It clearly shows extremely long structures with similar shapes, standing along the z-axis of the template. Cross-sectional transmission electron microscopy (TEM) explicitly determined the unilamellar nature of such structures, which was confirmed by the thickness of PBd-PEO bilayer (~10 nm) 29 (Fig. 1c ). This implies that 3DBCPMs exhibit biofunctionality and thus have the potential for various biological applications ranging from drug screening and biological assays to", "role": "user" }, { "content": "The cell membrane, which contains a hydrophilic exterior and a hydrophobic interior, opens and closes ion channels like a water faucet and converts a physicochemical stimulus into an electrical signal that is then transmitted to cells. Until recently, the limited ability of an artificial cell membrane structure to only last a maximum of five days has been a hurdle. The Korea Institute of Science and Technology (KIST, President Seok-Jin Yoon) announced that the research team led by Dr. Tae Song Kim of the Brain Science Institute has succeeded in developing an artificial cell membrane that can be kept stable for over 50 days on a silicon substrate. This is the longest time reported in the field. In addition to creating, in 2018, an artificial cell membrane lasting for five days, Dr. Kim's team demonstrated in 2019 the transfer of a positive ion to the inside of a structure with an artificial cell membrane with a protein attached to the surface, confirming its biosensor application potential. However, durability of at least one month is essential for life science research utilizing artificial cell membranes and the practical commercialization of biosensors. To extend the limit of five days of stability of an artificial cell membrane, the KIST research team focused on a material called block copolymer (BCP). A BCP is a macromolecule consisting of two or more blocks, which can be repeatedly aligned as a long row of blocks of counteracting properties that mimic the hydrophilic and hydrophobic nature of the human cell membrane. Numerous fabricated spherical and tubular structures and a lateral confocal photomicrograph of a single structure. Credit: Korea Institute of Science and Technology Dr. Kim's research team developed a technology that regularly arranges tens of thousands of holes with a diameter of 8 μm on a silicon substrate and inserts a specific amount of BCP solution into each hole through surface treatment, and dries it. Then, a soap bubble-shaped, an elongated oval-shaped, or a thin tubular-shaped BCP double-layer structure is tunably created by applying an electric field between the upper plate electrode of the microfluidic channel and the lower silicon substrate. This process led to the discovery of the possibility of maintaining a structure with a specific shape depending on the concentration of the solution and the applied electric field and frequency. This suggests a means to freely control the size and shape of artificial cell membranes, from a sphere, like a soap bubble, to a cylinder, like a tube. The KIST research team finally created an artificial cell membrane that can be kept stable for over 50 days by filling the outside of a three-dimensional double-layered BCP structure with a porous hydrogel that exhibits excellent elasticity and resilience characteristics similar to that of a human body substance. In addition, an artificial organ structure was produced by replicating an epithelial cell in the small intestine, which consists of thousands of tubular structures (cilia) using a BCP double-layered structure, proving its usage potential as a material for artificial organs through binding with β-galactosidase. Size distribution of each spherical and tubular structure. Credit: Korea Institute of Science and Technology Dr. Kim says that \"while global research on artificial cell membranes has been focusing on placing a two-dimensional planar structure on a silicon substrate, the team has succeeded in extending the stability period of an artificial cell membrane by more than ten times following the development of the first three-dimensional artificial cell membrane structure fabrication technology. The research, which has presented a path for large area array fabrication of artificial cell membranes, is expected to further develop into a platform technology for biological functionality research that identifies the roles of ultra-sensitive biosensors resembling cell functions, drug screening for new drug development, and neurotransmitters and hormones in the brain.\" The research was 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 Owing to their excellent durability, tunable physical properties, and biofunctionality, block copolymer-based membranes provide a platform for various biotechnological applications. However, conventional approaches for fabricating block copolymer membranes produce only planar or suspended polymersome structures, which limits their utilization. This study is the first to demonstrate that an electric-field-assisted self-assembly technique can allow controllable and scalable fabrication of 3-dimensional block copolymer artificial cell membranes (3DBCPMs) immobilized on predefined locations. Topographically and chemically structured microwell array templates facilitate uniform patterning of block copolymers and serve as reactors for the effective growth of 3DBCPMs. Modulating the concentration of the block copolymer and the amplitude/frequency of the electric field generates 3DBCPMs with diverse shapes, controlled sizes, and high stability (100% survival over 50 days). In vitro protein–membrane assays and mimicking of human intestinal organs highlight the potential of 3DBCPMs for a variety of biological applications such as artificial cells, cell-mimetic biosensors, and bioreactors. Introduction Self-assembly of block copolymers has attracted considerable interest in fundamental research and technical applications because of the exceptional morphological and structural versatility. In the bulk state, block copolymers undergo microphase separation by a driving force that minimizes the free energy of the system to form various structures, such as spheres, cylinders, and lamellae 1 , providing the capability to generate architectural complexity and periodicity that are difficult to achieve with conventional synthetic or lithographic technologies 2 , 3 . This behavior has been widely exploited in 2-dimensional (2D)/3-dimensional (3D) nanoscale patterning for functional devices with high throughput and fine feature sizes 4 , 5 , 6 , porous membranes for molecular separation and water purification 7 , 8 , and other advanced material designs 9 , 10 , 11 . The spin-coating method is widely used to form block copolymer thin films on templates; however, it is restricted in terms of producing patterned areas, which limits its utility in complicated and sophisticated device fabrication. Various methods, such as chemical 12 , 13 or topographical patterning 14 , solvent annealing 15 , and techniques based on electric fields 16 , thermal gradients 17 , and shear forces 18 have been developed to address this issue and provide ordered orientation. However, among these methods, only chemical or topographical patterning is effective in achieving patterned areas with predefined sizes and geometries at the desired locations. Owing to their superior mechanical/chemical stability, adjustable membrane permeability, and various surface functionalities realized through polymer engineering, block copolymer membranes have considerable potential for biological applications. In particular, they are promising alternatives to phospholipid-based membranes as artificial cell membranes for elucidating the underlying mechanical/biological mechanisms of cells and providing a platform for bioreactors and biosensors. However, in aqueous media, block copolymers spontaneously self-assemble into only one type of energetically favorable structure depending on the packing parameter (p = v/a 0 l c , where v and l c are the volume and length of the hydrophobic domain, respectively, and a 0 is the optimal area of the hydrophilic domain) 19 . Moreover, their polymer chains are difficult to rearrange because their molecular weight is greater than that of phospholipids, limiting their applications. Although osmolarity control 20 , chemical addition 21 , liquid-crystalline component incorporation 22 , and deoxyribonucleic acid (DNA)-directed self-assembly 23 have been reported to induce morphological transitions, most approaches produce irreversible shapes under specific conditions or are time-consuming. Therefore, there is a great need to overcome the aforementioned energetic penalties to accomplish a facile, systematic shape transformation. Herein, we demonstrate a method for fabricating 3D block copolymer artificial cell membranes (3DBCPMs) by combining the top-down control of the feature sizes and locations of 3DBCPMs via micro-contact printing and lithographic techniques with the bottom-up control of the diameter/length and shapes of 3DBCPMs via electric field-assisted molecular self-assembly (Fig. 1a ). Topographically and chemically structured microwell array templates not only allow micropatterning of block copolymers but also serve as confined reactors where block copolymers self-assemble and fuse to produce 3DBCPMs. An electric field with controlled amplitude and frequency regulates the morphology of 3DBCPMs over a packing parameter-dependent structure. To date, no method has been reported for the scalable fabrication (~300,000/cm 2 ) of microscale 3D block copolymer structures immobilized on patterned templates with morphological versatility, controlled size, and extremely long lifetime (100% survival over 50 days). Although simple rehydration 24 , sonication 25 , solvent annealing 26 , and electroformation 27 , 28 methods have been adopted to produce 3D block copolymer structures, most of these methods produce only suspended vesicles with large size polydispersity, which are difficult to immobilize onto substrates for further experimentation and observation. Fig. 1: 3D block copolymer artificial cell membranes (3DBCPMs) for versatile biological applications. a Electric-field-assisted self-assembly method for the scalable fabrication of 3DBCPMs with diverse shapes/sizes, high stability, and biofunctionality on silicon (Si) microwell template using a diblock copolymer, namely polybutadiene- b -polyethyleneoxide (PBd-PEO), as a building block and representative biological applications such as protein–membrane assay using prostaglandin E2 receptor 4 (EP4) and artificial intestinal organ using β-galactosidase tagged lipid. The packing parameter, p , is an inherent value of polymers associated with the volume and length of the hydrophobic domain and the optimal area of the hydrophilic domain. b A fluorescence microscopy image of a cilia-like long 3DBCPM array produced from a patterned template. c A cross-sectional transmission electron microscopy (TEM) image of a unilamellar 3DBCPM composed of ~10-nm-thick bilayer membrane. Scale bar: 100 nm. Full size image Results 3D block copolymer structures on Si microwell arrays Figure 1b shows a 3D fluorescence image reconstructed from 2D slices of a representative 3DBCPM comprising an amphiphilic diblock copolymer, polybutadiene- b -polyethyleneoxide (PBd-PEO). It clearly shows extremely long structures with similar shapes, standing along the z-axis of the template. Cross-sectional transmission electron microscopy (TEM) explicitly determined the unilamellar nature of such structures, which was confirmed by the thickness of PBd-PEO bilayer (~10 nm) 29 (Fig. 1c ). This implies that 3DBCPMs exhibit biofunctionality and thus have the potential for various biological applications ranging from drug screening and biological assays to<|im_end|> <|im_start|>assistant The cell membrane, which contains a hydrophilic exterior and a hydrophobic interior, opens and closes ion channels like a water faucet and converts a physicochemical stimulus into an electrical signal that is then transmitted to cells. Until recently, the limited ability of an artificial cell membrane structure to only last a maximum of five days has been a hurdle. The Korea Institute of Science and Technology (KIST, President Seok-Jin Yoon) announced that the research team led by Dr. Tae Song Kim of the Brain Science Institute has succeeded in developing an artificial cell membrane that can be kept stable for over 50 days on a silicon substrate. This is the longest time reported in the field. In addition to creating, in 2018, an artificial cell membrane lasting for five days, Dr. Kim's team demonstrated in 2019 the transfer of a positive ion to the inside of a structure with an artificial cell membrane with a protein attached to the surface, confirming its biosensor application potential. However, durability of at least one month is essential for life science research utilizing artificial cell membranes and the practical commercialization of biosensors. To extend the limit of five days of stability of an artificial cell membrane, the KIST research team focused on a material called block copolymer (BCP). A BCP is a macromolecule consisting of two or more blocks, which can be repeatedly aligned as a long row of blocks of counteracting properties that mimic the hydrophilic and hydrophobic nature of the human cell membrane. Numerous fabricated spherical and tubular structures and a lateral confocal photomicrograph of a single structure. Credit: Korea Institute of Science and Technology Dr. Kim's research team developed a technology that regularly arranges tens of thousands of holes with a diameter of 8 μm on a silicon substrate and inserts a specific amount of BCP solution into each hole through surface treatment, and dries it. Then, a soap bubble-shaped, an elongated oval-shaped, or a thin tubular-shaped BCP double-layer structure is tunably created by applying an electric field between the upper plate electrode of the microfluidic channel and the lower silicon substrate. This process led to the discovery of the possibility of maintaining a structure with a specific shape depending on the concentration of the solution and the applied electric field and frequency. This suggests a means to freely control the size and shape of artificial cell membranes, from a sphere, like a soap bubble, to a cylinder, like a tube. The KIST research team finally created an artificial cell membrane that can be kept stable for over 50 days by filling the outside of a three-dimensional double-layered BCP structure with a porous hydrogel that exhibits excellent elasticity and resilience characteristics similar to that of a human body substance. In addition, an artificial organ structure was produced by replicating an epithelial cell in the small intestine, which consists of thousands of tubular structures (cilia) using a BCP double-layered structure, proving its usage potential as a material for artificial organs through binding with β-galactosidase. Size distribution of each spherical and tubular structure. Credit: Korea Institute of Science and Technology Dr. Kim says that "while global research on artificial cell membranes has been focusing on placing a two-dimensional planar structure on a silicon substrate, the team has succeeded in extending the stability period of an artificial cell membrane by more than ten times following the development of the first three-dimensional artificial cell membrane structure fabrication technology. The research, which has presented a path for large area array fabrication of artificial cell membranes, is expected to further develop into a platform technology for biological functionality research that identifies the roles of ultra-sensitive biosensors resembling cell functions, drug screening for new drug development, and neurotransmitters and hormones in the brain." The research was published in 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 Parkinson’s disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles 1 , 2 . An early-onset form of Parkinson’s disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes 3 . PINK1 and Parkin (encoded by PRKN ) are involved in the clearance of damaged mitochondria in cultured cells 4 , but recent evidence obtained using knockout and knockin mouse models have led to contradictory results regarding the contributions of PINK1 and Parkin to mitophagy in vivo 5 , 6 , 7 , 8 . It has previously been shown that PINK1 and Parkin have a key role in adaptive immunity by repressing presentation of mitochondrial antigens 9 , which suggests that autoimmune mechanisms participate in the aetiology of Parkinson’s disease. Here we show that intestinal infection with Gram-negative bacteria in Pink1 −/− mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8 + T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with l -DOPA. These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson’s disease, which highlights the relevance of the gut–brain axis in the disease 10 . Main Although mutations in PINK1 and Parkin in patients with Parkinson’s disease lead to disease progression with near 100% penetrance, Pink1 −/− and Prkn −/− mice are generally healthy and display little—if any—motor impairment reminiscent of Parkinson’s disease 11 . Thus, factors other than the loss of function of these proteins are likely to be required to trigger Parkinson’s disease pathophysiology. We showed that in the absence of PINK1 and/or Parkin, the bacterial endotoxin lipopolysaccharide (LPS) activates the formation of mitochondria-derived vesicles and the presentation of mitochondrial antigens on major histocompatibility complex (MHC) class I molecules at the surface of antigen-presenting cells 9 . We hypothesized that bacterial infection with Gram-negative bacteria (LPS + ) could trigger mitochondrial antigen presentation (MitAP) and elicit the establishment of mitochondria-specific autoreactive CD8 + T cells. To test this hypothesis, we used the mouse macrophage-like cell line RAW 264.7, which was transfected to express the antigenic reporter protein glycoprotein B (gB) from herpes virus in the mitochondrial matrix, and infected the cells with a panel of bacteria to identify activators of MitAP. In this assay, a gB-specific CD8 + T cell hybridoma detects the presentation of the gB 498–505 12 peptide on MHC class I molecules at the surface of antigen-presenting cells. All Gram-negative—but not Gram-positive—bacteria that we tested induced MitAP (Fig. 1a ), with the highest level obtained with enteropathogenic Escherichia coli (EPEC) and Novosphingobium aromaticivorans . The latter is suspected to be the causative agent of the liver autoimmune disease primary biliary cholangitis, which is associated with the presentation of mitochondrial antigens including the matrix protein 2-oxoglutarate dehydrogenase (OGDH) 13 . To study how bacteria trigger MitAP, we focused on EPEC, a human pathogen for which a mouse model of infection exists 14 . As seen with LPS 9 , EPEC infection in RAW macrophages induced MitAP within 8 h (Fig. 1b ), and this was dependent on the sorting nexin SNX9 and repressed by Parkin (Fig. 1c ). By contrast, the presentation of gB expressed in the cytoplasm was not inhibited in the absence of SNX9 or the presence of Parkin (Fig. 1d ). Exposure to heat-killed EPEC also induced MitAP, which rules out the possibility that bacterial effectors injected in host cells by the type III secretion system are required to trigger this pathway (Fig. 1e ). EPEC infection induced the release of gB from mitochondria in vesicular-like structures within a 60–120-min time period (Fig. 1f, g ). PINK1 also repressed the presentation of a mitochondria-derived peptide from OGDH in primary dendritic cells (Fig. 1h ). EPEC infection of RAW macrophages did not induce marked degradation of mitochondrial proteins or alter the levels of the autophagy protein LC3, which suggests that mitophagy is not involved in presentation (Extended Data Fig. 1 ). Fig. 1: Gram-negative infection induces MitAP in vitro. a , MitAP was measured as the fold induction compared with uninfected controls in RAW cells expressing the Herpes simplex gB in the mitochondrial matrix, infected with Gram-negative (2–7) or Gram-positive (8 and 9) bacteria for 8 h. P values are compared with the control condition (1). EHEC, enterohaemmorhagic E. coli . b , MitAP in RAW cells expressing gB in the mitochondrial matrix infected with EPEC. c , MitAP in RAW cells expressing gB in the mitochondrial matrix ectopically expressing non-specific scrambled short hairpin RNA (shRNA), Snx9 shRNA or Parkin, and infected with EPEC. KD, knockdown. d , RAW cells expressing gB in the cytoplasm were infected with EPEC and the presentation of cytoplasmic gB was measured. e , MitAP in RAW cells expressing gB in the mitochondrial matrix after exposure to heat-killed (HK) EPEC (1:1 ratio) after 8 h. f , Representative images of infected and control cells stained for gB (red) and the outer membrane protein TOM20 (green). Scale bar, 10 μm. g , Quantification of co-localization between TOM20 and gB determined by Mander’s coefficient at the indicated time points ( n = 5 cells imaged). h , MitAP in bone-marrow-derived dendritic cells isolated from wild-type or Pink1 −/− mice, infected in vitro with EPEC or heat-killed EPEC, or treated with LPS for 8 h. P values were determined by analysis of variance (ANOVA) at a 95% confidence interval followed by Dunnett’s multiple comparison’s test ( a – e , g ), or two-way ANOVA at a 95% confidence interval followed by Sidak’s multiple comparison’s", "role": "user" }, { "content": "A new study by Montreal scientists published today in Nature demonstrates that a gut infection can lead to a pathology resembling Parkinson's disease (PD) in a mouse model lacking a gene linked to the human disease. This discovery extends recent work by the same group suggesting that PD has a major immune component, providing new avenues for therapeutic strategies. The collaborative study was the work of a joint team of scientists led by Michel Desjardins and Louis-Eric Trudeau of Université de Montréal, Heidi McBride at the Montreal Neurological Institute, and Samantha Gruenheid at McGill University. The number of PD patients in the world more than doubled between 1990 and 2016, from 2.5 million to 6.1 million. A relatively conservative projected doubling of the number of patients over the next 30 years would yield more than 12 million patients worldwide by about 2050. About 10 per cent of cases of PD are due to mutations in genes coding for proteins such as PINK1 and Parkin, which have been linked to mitochondria (the organelle in cells that produces energy). Patients with these mutations develop PD at a much earlier age. However, in mouse models, the same mutations do not generate disease symptoms, leading many researchers to conclude that mice may not be suitable for the study of PD. Trudeau and McBride, two specialists in the field of PD research, argue that the findings in this new study may explain this disparity: these animals are normally kept in germ-free facilities, conditions not representative of those encountered by human beings who are constantly exposed to infectious microorganisms. Gruenheid, a microbiologist, is confident that the link between infection and PD will stimulate further study of the immune response linked to the initiation of the disease, allowing researchers to develop and test novel therapeutic approaches. PD is caused by the progressive death of a subset of neurons in the brain, called dopaminergic neurons. This loss of neurons is responsible for the typical motor symptoms observed in PD patients, including tremors and rigidity. What causes the death of the dopaminergic neurons is still unknown. \"Most of the current models of PD are based on the belief that neurons die due to toxic elements accumulating inside them,\" said Trudeau, a neuroscientist. \"This does not explain, however, the fact that PD pathology is initiated in patients several years before the emergence of the motor impairment and any noticeable loss of neurons.\" The reason for this is believed to be explained by the results of the present study. The Montreal team has shown that in mice lacking a gene linked to PD, infection with bacteria that cause mild intestinal symptoms in young mice was sufficient to trigger PD-like symptoms in these animals later in life. The Parkinson's-like symptoms could be temporarily reversed by the administration of L-DOPA, a drug used to treat Parkinson's patients. Desjardins and Diana Matheoud, an immunologist the University of Montreal Hospital Research Centre (CRCHUM), point out that in normal mice, the immune system responded properly to the gut infection; however, in mice lacking the gene PINK1 related to Parkinson's, the immune system overreacted and triggered \"auto-immunity\", a process that leads the immune system to attack healthy cells in the organism. The results published today suggest that rather than dying from toxin accumulation, the killing of dopaminergic neurons involves immune cells. In the infected mutant mice, autoreactive toxic T lymphocytes were shown to be present in the brain and able to attack healthy neurons in culture dishes. The co-first authors of the published article, Matheoud and Tyler Cannon, a graduate student in microbiology, emphasize the fact that these results strongly suggest that some forms of PD are an autoimmune disease likely to start in the gut several years before patients notice any motor symptoms, highlighting the fact that a window of time exists for preventive treatment. ", "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 Parkinson’s disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles 1 , 2 . An early-onset form of Parkinson’s disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes 3 . PINK1 and Parkin (encoded by PRKN ) are involved in the clearance of damaged mitochondria in cultured cells 4 , but recent evidence obtained using knockout and knockin mouse models have led to contradictory results regarding the contributions of PINK1 and Parkin to mitophagy in vivo 5 , 6 , 7 , 8 . It has previously been shown that PINK1 and Parkin have a key role in adaptive immunity by repressing presentation of mitochondrial antigens 9 , which suggests that autoimmune mechanisms participate in the aetiology of Parkinson’s disease. Here we show that intestinal infection with Gram-negative bacteria in Pink1 −/− mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8 + T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with l -DOPA. These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson’s disease, which highlights the relevance of the gut–brain axis in the disease 10 . Main Although mutations in PINK1 and Parkin in patients with Parkinson’s disease lead to disease progression with near 100% penetrance, Pink1 −/− and Prkn −/− mice are generally healthy and display little—if any—motor impairment reminiscent of Parkinson’s disease 11 . Thus, factors other than the loss of function of these proteins are likely to be required to trigger Parkinson’s disease pathophysiology. We showed that in the absence of PINK1 and/or Parkin, the bacterial endotoxin lipopolysaccharide (LPS) activates the formation of mitochondria-derived vesicles and the presentation of mitochondrial antigens on major histocompatibility complex (MHC) class I molecules at the surface of antigen-presenting cells 9 . We hypothesized that bacterial infection with Gram-negative bacteria (LPS + ) could trigger mitochondrial antigen presentation (MitAP) and elicit the establishment of mitochondria-specific autoreactive CD8 + T cells. To test this hypothesis, we used the mouse macrophage-like cell line RAW 264.7, which was transfected to express the antigenic reporter protein glycoprotein B (gB) from herpes virus in the mitochondrial matrix, and infected the cells with a panel of bacteria to identify activators of MitAP. In this assay, a gB-specific CD8 + T cell hybridoma detects the presentation of the gB 498–505 12 peptide on MHC class I molecules at the surface of antigen-presenting cells. All Gram-negative—but not Gram-positive—bacteria that we tested induced MitAP (Fig. 1a ), with the highest level obtained with enteropathogenic Escherichia coli (EPEC) and Novosphingobium aromaticivorans . The latter is suspected to be the causative agent of the liver autoimmune disease primary biliary cholangitis, which is associated with the presentation of mitochondrial antigens including the matrix protein 2-oxoglutarate dehydrogenase (OGDH) 13 . To study how bacteria trigger MitAP, we focused on EPEC, a human pathogen for which a mouse model of infection exists 14 . As seen with LPS 9 , EPEC infection in RAW macrophages induced MitAP within 8 h (Fig. 1b ), and this was dependent on the sorting nexin SNX9 and repressed by Parkin (Fig. 1c ). By contrast, the presentation of gB expressed in the cytoplasm was not inhibited in the absence of SNX9 or the presence of Parkin (Fig. 1d ). Exposure to heat-killed EPEC also induced MitAP, which rules out the possibility that bacterial effectors injected in host cells by the type III secretion system are required to trigger this pathway (Fig. 1e ). EPEC infection induced the release of gB from mitochondria in vesicular-like structures within a 60–120-min time period (Fig. 1f, g ). PINK1 also repressed the presentation of a mitochondria-derived peptide from OGDH in primary dendritic cells (Fig. 1h ). EPEC infection of RAW macrophages did not induce marked degradation of mitochondrial proteins or alter the levels of the autophagy protein LC3, which suggests that mitophagy is not involved in presentation (Extended Data Fig. 1 ). Fig. 1: Gram-negative infection induces MitAP in vitro. a , MitAP was measured as the fold induction compared with uninfected controls in RAW cells expressing the Herpes simplex gB in the mitochondrial matrix, infected with Gram-negative (2–7) or Gram-positive (8 and 9) bacteria for 8 h. P values are compared with the control condition (1). EHEC, enterohaemmorhagic E. coli . b , MitAP in RAW cells expressing gB in the mitochondrial matrix infected with EPEC. c , MitAP in RAW cells expressing gB in the mitochondrial matrix ectopically expressing non-specific scrambled short hairpin RNA (shRNA), Snx9 shRNA or Parkin, and infected with EPEC. KD, knockdown. d , RAW cells expressing gB in the cytoplasm were infected with EPEC and the presentation of cytoplasmic gB was measured. e , MitAP in RAW cells expressing gB in the mitochondrial matrix after exposure to heat-killed (HK) EPEC (1:1 ratio) after 8 h. f , Representative images of infected and control cells stained for gB (red) and the outer membrane protein TOM20 (green). Scale bar, 10 μm. g , Quantification of co-localization between TOM20 and gB determined by Mander’s coefficient at the indicated time points ( n = 5 cells imaged). h , MitAP in bone-marrow-derived dendritic cells isolated from wild-type or Pink1 −/− mice, infected in vitro with EPEC or heat-killed EPEC, or treated with LPS for 8 h. P values were determined by analysis of variance (ANOVA) at a 95% confidence interval followed by Dunnett’s multiple comparison’s test ( a – e , g ), or two-way ANOVA at a 95% confidence interval followed by Sidak’s multiple comparison’s<|im_end|> <|im_start|>assistant A new study by Montreal scientists published today in Nature demonstrates that a gut infection can lead to a pathology resembling Parkinson's disease (PD) in a mouse model lacking a gene linked to the human disease. This discovery extends recent work by the same group suggesting that PD has a major immune component, providing new avenues for therapeutic strategies. The collaborative study was the work of a joint team of scientists led by Michel Desjardins and Louis-Eric Trudeau of Université de Montréal, Heidi McBride at the Montreal Neurological Institute, and Samantha Gruenheid at McGill University. The number of PD patients in the world more than doubled between 1990 and 2016, from 2.5 million to 6.1 million. A relatively conservative projected doubling of the number of patients over the next 30 years would yield more than 12 million patients worldwide by about 2050. About 10 per cent of cases of PD are due to mutations in genes coding for proteins such as PINK1 and Parkin, which have been linked to mitochondria (the organelle in cells that produces energy). Patients with these mutations develop PD at a much earlier age. However, in mouse models, the same mutations do not generate disease symptoms, leading many researchers to conclude that mice may not be suitable for the study of PD. Trudeau and McBride, two specialists in the field of PD research, argue that the findings in this new study may explain this disparity: these animals are normally kept in germ-free facilities, conditions not representative of those encountered by human beings who are constantly exposed to infectious microorganisms. Gruenheid, a microbiologist, is confident that the link between infection and PD will stimulate further study of the immune response linked to the initiation of the disease, allowing researchers to develop and test novel therapeutic approaches. PD is caused by the progressive death of a subset of neurons in the brain, called dopaminergic neurons. This loss of neurons is responsible for the typical motor symptoms observed in PD patients, including tremors and rigidity. What causes the death of the dopaminergic neurons is still unknown. "Most of the current models of PD are based on the belief that neurons die due to toxic elements accumulating inside them," said Trudeau, a neuroscientist. "This does not explain, however, the fact that PD pathology is initiated in patients several years before the emergence of the motor impairment and any noticeable loss of neurons." The reason for this is believed to be explained by the results of the present study. The Montreal team has shown that in mice lacking a gene linked to PD, infection with bacteria that cause mild intestinal symptoms in young mice was sufficient to trigger PD-like symptoms in these animals later in life. The Parkinson's-like symptoms could be temporarily reversed by the administration of L-DOPA, a drug used to treat Parkinson's patients. Desjardins and Diana Matheoud, an immunologist the University of Montreal Hospital Research Centre (CRCHUM), point out that in normal mice, the immune system responded properly to the gut infection; however, in mice lacking the gene PINK1 related to Parkinson's, the immune system overreacted and triggered "auto-immunity", a process that leads the immune system to attack healthy cells in the organism. The results published today suggest that rather than dying from toxin accumulation, the killing of dopaminergic neurons involves immune cells. In the infected mutant mice, autoreactive toxic T lymphocytes were shown to be present in the brain and able to attack healthy neurons in culture dishes. The co-first authors of the published article, Matheoud and Tyler Cannon, a graduate student in microbiology, emphasize the fact that these results strongly suggest that some forms of PD are an autoimmune disease likely to start in the gut several years before patients notice any motor symptoms, highlighting the fact that a window of time exists for preventive treatment. <|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 Epigenetic aberrations are widespread in cancer, yet the underlying mechanisms and causality remain poorly understood 1 , 2 , 3 . A subset of gastrointestinal stromal tumours (GISTs) lack canonical kinase mutations but instead have succinate dehydrogenase (SDH) deficiency and global DNA hyper-methylation 4 , 5 . Here, we associate this hyper-methylation with changes in genome topology that activate oncogenic programs. To investigate epigenetic alterations systematically, we mapped DNA methylation, CTCF insulators, enhancers, and chromosome topology in KIT -mutant, PDGFRA -mutant and SDH-deficient GISTs. Although these respective subtypes shared similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on a disrupted insulator that normally partitions a core GIST super-enhancer from the FGF4 oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancer and oncogene. CRISPR-mediated excision of the corresponding CTCF motifs in an SDH-intact GIST model disrupted the boundary between enhancer and oncogene, and strongly upregulated FGF4 expression. We also identified a second recurrent insulator loss event near the KIT oncogene, which is also highly expressed across SDH-deficient GISTs. Finally, we established a patient-derived xenograft (PDX) from an SDH-deficient GIST that faithfully maintains the epigenetics of the parental tumour, including hypermethylation and insulator defects. This PDX model is highly sensitive to FGF receptor (FGFR) inhibition, and more so to combined FGFR and KIT inhibition, validating the functional significance of the underlying epigenetic lesions. Our study reveals how epigenetic alterations can drive oncogenic programs in the absence of canonical kinase mutations, with implications for mechanistic targeting of aberrant pathways in cancers. Main The human genome is partitioned into physical domains, often termed topologically associated domains (TADs), by chromosomal boundaries established by the DNA-binding insulator protein CTCF and cohesin 6 , 7 , 8 , 9 . Many proto-oncogenes and master regulators are isolated in such domains and thus protected from promiscuous enhancer interactions 10 . Mutations of tricarboxylic-acid-cycle-related enzymes, including SDH and isocitrate dehydrogenase (IDH), are initiating events in many tumour types 1 , 4 , 5 . These lesions cause accumulation of succinate and 2-hydroxyglutarate, respectively, which inhibit demethylases and are associated with DNA hypermethylation and other epigenetic alterations 5 , 11 , 12 . The CTCF insulator is methylation-sensitive and may be displaced by DNA methylation 13 , 14 , 15 . We previously showed that the PDGFRA oncogene is aberrantly activated by insulator defects in IDH -mutant glioma 16 . We hypothesized that SDH deficiency alters chromosome topology to drive GIST tumorigenesis (Fig. 1a ). GISTs are the most common gastrointestinal tract sarcoma. They are typically caused by gain-of-function mutations of the KIT or PDGFRA oncogenes that render these receptor tyrosine kinases (RTKs) active and ligand-independent 17 . However, approximately 15% of GISTs lack these defining mutations, and have instead lost SDH expression due to mutation or transcriptional silencing of SDH subunit genes ( SDHA–D ) 18 . We collected an initial cohort of clinically defined specimens, including 11 KIT -mutant, 2 PDGFRA- mutant and 8 SDH-deficient tumours (Supplementary Table 1 ). We used hybrid-selection bisulfite sequencing to profile DNA methylation of over 160,000 CTCF sites and representative promoters in 17 of these tumours and 2 normal stomach muscle samples (see Methods ). Consistent with previous reports 5 , SDH-deficient GISTs exhibited CpG island hypermethylation (Fig. 1b ). In addition, a substantial fraction of CTCF sites were methylated in this GIST subtype (Fig. 1b ). Fig. 1: Insulator dysfunction in SDH-deficient GISTs. a , Proposed mechanism of epigenetic oncogene activation. Left, oncogene shielded from super-enhancer by CTCF insulator, which creates a topological boundary. Right, CTCF insulator displaced by DNA methylation, allowing the super-enhancer to contact and induce the oncogene. b , Violin plots depict DNA methylation levels over the 10,000 most variable CpG island promoters (top) and CTCF sites (bottom) in normal stomach muscle (NSM; n = 2), and KIT mutant ( n = 9), PDGFRA mutant (P; n = 2) and SDH-deficient GISTs ( n = 6). Yellow bars indicate mean. c , Volcano plot depicts differential CTCF occupancy between SDH-deficient ( n = 6) and SDH-intact ( n = 8) GISTs. Sites that gain DNA methylation in SDH-deficient GISTs are indicated in red (>25% increase, two-sided t -test false discovery rate (FDR) <5%). d , Plot depicts H3K27ac peaks near lost CTCF insulators ( y axis) rank ordered by signal strength. e , Scatter plot depicts genes (points) separated from a super-enhancer by a CTCF loop anchor that is lost in SDH-deficient GIST. Genes are positioned according to their relative ( y axis) and absolute median expression ( x axis) in SDH-deficient GISTs. Potentially deregulated gene targets (outliers) include oncogenes FGF3 , FGF4 and KIT (red); see also Supplementary Information. TPM, transcripts per million. f , Box plot depicts average expression of MAPK signature genes in RNA-seq data for normal stomach ( n = 262), and KIT mutant ( n = 10), PDGFRA mutant ( n = 3) and SDH-deficient GISTs ( n = 8). Boxes depict 25th, 50th and 75th percentiles, and whiskers depict extreme values. g , Radial phylogenetic tree depicts tyrosine kinase gene expression in SDH-deficient GISTs. Each branch is one tyrosine kinase, arranged by similarity, and with major families depicted by colour. The area of each red circle is proportional to the average expression of the kinase. h , Scatter plot depicts average expression of FGF ligands in SDH-intact ( x axis) and SDH-deficient ( y axis) GISTs. FGF3 and FGF4 are highly expressed in SDH-deficient GISTs (bold). For all panels, n values indicate number of biologically independent specimens. Full size image We next identified candidate insulators and enhancers in these tumours by mapping CTCF and histone H3 acetylated at lysine 27 (H3K27ac) by chromatin immunoprecipitation and sequencing (ChIP–seq). Overall patterns of enhancer acetylation were largely consistent across GISTs, relative to gastrointestinal carcinomas (Extended Data Fig. 1a ). By contrast, comparison of genome-wide CTCF binding profiles revealed that approximately 5% of sites", "role": "user" }, { "content": "Most cases of gastrointestinal stromal tumor (GIST), a type of soft-tissue cancer (sarcoma), are caused by mutations in genes that can be effectively targeted with drugs that inhibit the activity of rogue cancer-promoting enzymes. But an estimated 10% to 20% of GISTs have no identifiable or targetable mutations. Now, investigators in a Boston-area cancer research collaboration have clarified mechanisms that allow these hard-to-treat cancers to develop, and in lab experiments have identified strategies that could lead to effective new therapies. The research, a joint effort of investigators at Massachusetts General Hospital (MGH), the Broad Institute of MIT and Harvard, Dana-Farber Cancer Institute (DFCI) and the Ludwig Center at Harvard Medical School (HMS), is published in the journal Nature. Importantly, the investigators show how \"epigenetic\" changes—changes in how the code of genes is read by tumor cells that are not caused by genetic mutations—can lead to the development of GISTs and other cancers, and how it may be possible to short-circuit the cancer-causing machinery. \"Your genome consists of about 6 feet of DNA wrapped very carefully to fit into microscopic cells. One of the tricks that the cell uses to compact all of this DNA is to tie it up into little loops,\" says senior co-author Bradley E. Bernstein, MD, Ph.D., of MGH, Broad Institute and the Ludwig Center at Harvard. He likens the process to shoelaces, in which each carefully tied loop is separated by a knot. The \"knot\" in the cells is called an \"insulator\" in scientific parlance. He and his colleagues found that one of these insulators normally keeps a cancer-causing gene, FGF4, from coming into contact with a stretch of DNA with a powerful switch that turns on an unrelated gene. In normal cells, the cancer-causing gene and the switch are in separate loops and never come into contact with one another. However, in some forms of GIST, the insulator is not functional, the loops merge into one, and the on-switch mistakenly activates the cancer-causing FGF4 gene. The investigators were studying a form of GIST that lacks typical cancer-causing mutations but has instead lost the function of an enzyme complex called SDH, which normally is key to energy generation in the cell. How SDH deficiency contributed to this malignancy was a mystery, but an interesting clue was that a process called DNA methylation, which adds small chemical 'tags' to the DNA, was abnormally revved up in SDH-deficient tumors. The team found that the excess methylation destroyed many insulators in these tumors, leading to abnormal contacts between on-switches and oncogenes. In addition to the disrupted insulator that activated the FGF4 oncogene, they identified a second disrupted insulator near a normal gene called KIT—the gene that is abnormally activated by a mutation in most other GISTs. To validate their findings, the investigators then transplanted a human GIST tumor into a mouse to create an experimental model or 'mouse avatar'. They showed that their model \"faithfully maintains the epigenetics of the parental tumor\" including the supercharged DNA methylation and defective insulators. Finally, the investigators showed that growth of the model tumors could be suppressed with a class of drugs known as fibroblast growth factor receptor (FGFR) inhibitors, either alone or in combination with an enzyme-inhibiting targeted therapy called sunitinib (Sutent), a drug FDA-approved for treatment of GIST. \"Although some targeted therapies can help SDH-deficient GIST patients, the children and young adults who typically get this form of GIST generally develop resistance rapidly to the standard targeted drugs. The insights from our collaborative research can open new avenues for testing combinations of new therapies in this subset of GIST and other cancers,\" said George Demetri MD, senior co-author from the Dana-Farber Cancer Institute and the Ludwig Center at Harvard. Bernstein adds that \"the FDA approved the first FGFR-inhibitor drug for treatment of metastatic bladder cancer earlier this year, and it may be possible to re-purpose this or similar drugs in development to treat SDH-deficient GIST.\" ", "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 Epigenetic aberrations are widespread in cancer, yet the underlying mechanisms and causality remain poorly understood 1 , 2 , 3 . A subset of gastrointestinal stromal tumours (GISTs) lack canonical kinase mutations but instead have succinate dehydrogenase (SDH) deficiency and global DNA hyper-methylation 4 , 5 . Here, we associate this hyper-methylation with changes in genome topology that activate oncogenic programs. To investigate epigenetic alterations systematically, we mapped DNA methylation, CTCF insulators, enhancers, and chromosome topology in KIT -mutant, PDGFRA -mutant and SDH-deficient GISTs. Although these respective subtypes shared similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on a disrupted insulator that normally partitions a core GIST super-enhancer from the FGF4 oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancer and oncogene. CRISPR-mediated excision of the corresponding CTCF motifs in an SDH-intact GIST model disrupted the boundary between enhancer and oncogene, and strongly upregulated FGF4 expression. We also identified a second recurrent insulator loss event near the KIT oncogene, which is also highly expressed across SDH-deficient GISTs. Finally, we established a patient-derived xenograft (PDX) from an SDH-deficient GIST that faithfully maintains the epigenetics of the parental tumour, including hypermethylation and insulator defects. This PDX model is highly sensitive to FGF receptor (FGFR) inhibition, and more so to combined FGFR and KIT inhibition, validating the functional significance of the underlying epigenetic lesions. Our study reveals how epigenetic alterations can drive oncogenic programs in the absence of canonical kinase mutations, with implications for mechanistic targeting of aberrant pathways in cancers. Main The human genome is partitioned into physical domains, often termed topologically associated domains (TADs), by chromosomal boundaries established by the DNA-binding insulator protein CTCF and cohesin 6 , 7 , 8 , 9 . Many proto-oncogenes and master regulators are isolated in such domains and thus protected from promiscuous enhancer interactions 10 . Mutations of tricarboxylic-acid-cycle-related enzymes, including SDH and isocitrate dehydrogenase (IDH), are initiating events in many tumour types 1 , 4 , 5 . These lesions cause accumulation of succinate and 2-hydroxyglutarate, respectively, which inhibit demethylases and are associated with DNA hypermethylation and other epigenetic alterations 5 , 11 , 12 . The CTCF insulator is methylation-sensitive and may be displaced by DNA methylation 13 , 14 , 15 . We previously showed that the PDGFRA oncogene is aberrantly activated by insulator defects in IDH -mutant glioma 16 . We hypothesized that SDH deficiency alters chromosome topology to drive GIST tumorigenesis (Fig. 1a ). GISTs are the most common gastrointestinal tract sarcoma. They are typically caused by gain-of-function mutations of the KIT or PDGFRA oncogenes that render these receptor tyrosine kinases (RTKs) active and ligand-independent 17 . However, approximately 15% of GISTs lack these defining mutations, and have instead lost SDH expression due to mutation or transcriptional silencing of SDH subunit genes ( SDHA–D ) 18 . We collected an initial cohort of clinically defined specimens, including 11 KIT -mutant, 2 PDGFRA- mutant and 8 SDH-deficient tumours (Supplementary Table 1 ). We used hybrid-selection bisulfite sequencing to profile DNA methylation of over 160,000 CTCF sites and representative promoters in 17 of these tumours and 2 normal stomach muscle samples (see Methods ). Consistent with previous reports 5 , SDH-deficient GISTs exhibited CpG island hypermethylation (Fig. 1b ). In addition, a substantial fraction of CTCF sites were methylated in this GIST subtype (Fig. 1b ). Fig. 1: Insulator dysfunction in SDH-deficient GISTs. a , Proposed mechanism of epigenetic oncogene activation. Left, oncogene shielded from super-enhancer by CTCF insulator, which creates a topological boundary. Right, CTCF insulator displaced by DNA methylation, allowing the super-enhancer to contact and induce the oncogene. b , Violin plots depict DNA methylation levels over the 10,000 most variable CpG island promoters (top) and CTCF sites (bottom) in normal stomach muscle (NSM; n = 2), and KIT mutant ( n = 9), PDGFRA mutant (P; n = 2) and SDH-deficient GISTs ( n = 6). Yellow bars indicate mean. c , Volcano plot depicts differential CTCF occupancy between SDH-deficient ( n = 6) and SDH-intact ( n = 8) GISTs. Sites that gain DNA methylation in SDH-deficient GISTs are indicated in red (>25% increase, two-sided t -test false discovery rate (FDR) <5%). d , Plot depicts H3K27ac peaks near lost CTCF insulators ( y axis) rank ordered by signal strength. e , Scatter plot depicts genes (points) separated from a super-enhancer by a CTCF loop anchor that is lost in SDH-deficient GIST. Genes are positioned according to their relative ( y axis) and absolute median expression ( x axis) in SDH-deficient GISTs. Potentially deregulated gene targets (outliers) include oncogenes FGF3 , FGF4 and KIT (red); see also Supplementary Information. TPM, transcripts per million. f , Box plot depicts average expression of MAPK signature genes in RNA-seq data for normal stomach ( n = 262), and KIT mutant ( n = 10), PDGFRA mutant ( n = 3) and SDH-deficient GISTs ( n = 8). Boxes depict 25th, 50th and 75th percentiles, and whiskers depict extreme values. g , Radial phylogenetic tree depicts tyrosine kinase gene expression in SDH-deficient GISTs. Each branch is one tyrosine kinase, arranged by similarity, and with major families depicted by colour. The area of each red circle is proportional to the average expression of the kinase. h , Scatter plot depicts average expression of FGF ligands in SDH-intact ( x axis) and SDH-deficient ( y axis) GISTs. FGF3 and FGF4 are highly expressed in SDH-deficient GISTs (bold). For all panels, n values indicate number of biologically independent specimens. Full size image We next identified candidate insulators and enhancers in these tumours by mapping CTCF and histone H3 acetylated at lysine 27 (H3K27ac) by chromatin immunoprecipitation and sequencing (ChIP–seq). Overall patterns of enhancer acetylation were largely consistent across GISTs, relative to gastrointestinal carcinomas (Extended Data Fig. 1a ). By contrast, comparison of genome-wide CTCF binding profiles revealed that approximately 5% of sites<|im_end|> <|im_start|>assistant Most cases of gastrointestinal stromal tumor (GIST), a type of soft-tissue cancer (sarcoma), are caused by mutations in genes that can be effectively targeted with drugs that inhibit the activity of rogue cancer-promoting enzymes. But an estimated 10% to 20% of GISTs have no identifiable or targetable mutations. Now, investigators in a Boston-area cancer research collaboration have clarified mechanisms that allow these hard-to-treat cancers to develop, and in lab experiments have identified strategies that could lead to effective new therapies. The research, a joint effort of investigators at Massachusetts General Hospital (MGH), the Broad Institute of MIT and Harvard, Dana-Farber Cancer Institute (DFCI) and the Ludwig Center at Harvard Medical School (HMS), is published in the journal Nature. Importantly, the investigators show how "epigenetic" changes—changes in how the code of genes is read by tumor cells that are not caused by genetic mutations—can lead to the development of GISTs and other cancers, and how it may be possible to short-circuit the cancer-causing machinery. "Your genome consists of about 6 feet of DNA wrapped very carefully to fit into microscopic cells. One of the tricks that the cell uses to compact all of this DNA is to tie it up into little loops," says senior co-author Bradley E. Bernstein, MD, Ph.D., of MGH, Broad Institute and the Ludwig Center at Harvard. He likens the process to shoelaces, in which each carefully tied loop is separated by a knot. The "knot" in the cells is called an "insulator" in scientific parlance. He and his colleagues found that one of these insulators normally keeps a cancer-causing gene, FGF4, from coming into contact with a stretch of DNA with a powerful switch that turns on an unrelated gene. In normal cells, the cancer-causing gene and the switch are in separate loops and never come into contact with one another. However, in some forms of GIST, the insulator is not functional, the loops merge into one, and the on-switch mistakenly activates the cancer-causing FGF4 gene. The investigators were studying a form of GIST that lacks typical cancer-causing mutations but has instead lost the function of an enzyme complex called SDH, which normally is key to energy generation in the cell. How SDH deficiency contributed to this malignancy was a mystery, but an interesting clue was that a process called DNA methylation, which adds small chemical 'tags' to the DNA, was abnormally revved up in SDH-deficient tumors. The team found that the excess methylation destroyed many insulators in these tumors, leading to abnormal contacts between on-switches and oncogenes. In addition to the disrupted insulator that activated the FGF4 oncogene, they identified a second disrupted insulator near a normal gene called KIT—the gene that is abnormally activated by a mutation in most other GISTs. To validate their findings, the investigators then transplanted a human GIST tumor into a mouse to create an experimental model or 'mouse avatar'. They showed that their model "faithfully maintains the epigenetics of the parental tumor" including the supercharged DNA methylation and defective insulators. Finally, the investigators showed that growth of the model tumors could be suppressed with a class of drugs known as fibroblast growth factor receptor (FGFR) inhibitors, either alone or in combination with an enzyme-inhibiting targeted therapy called sunitinib (Sutent), a drug FDA-approved for treatment of GIST. "Although some targeted therapies can help SDH-deficient GIST patients, the children and young adults who typically get this form of GIST generally develop resistance rapidly to the standard targeted drugs. The insights from our collaborative research can open new avenues for testing combinations of new therapies in this subset of GIST and other cancers," said George Demetri MD, senior co-author from the Dana-Farber Cancer Institute and the Ludwig Center at Harvard. Bernstein adds that "the FDA approved the first FGFR-inhibitor drug for treatment of metastatic bladder cancer earlier this year, and it may be possible to re-purpose this or similar drugs in development to treat SDH-deficient GIST." <|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 pseudogap is a partial gap in the electronic density of states that opens in the normal (non-superconducting) state of cuprate superconductors and whose origin is a long-standing puzzle. Its connection to the Mott insulator phase at low doping (hole concentration, p ) remains ambiguous 1 and its relation to the charge order 2 , 3 , 4 that reconstructs the Fermi surface 5 , 6 at intermediate doping is still unclear 7 , 8 , 9 , 10 . Here we use measurements of the Hall coefficient in magnetic fields up to 88 tesla to show that Fermi-surface reconstruction by charge order in the cuprate YBa 2 Cu 3 O y ends sharply at a critical doping p = 0.16 that is distinctly lower than the pseudogap critical point p * = 0.19 (ref. 11 ). This shows that the pseudogap and charge order are separate phenomena. We find that the change in carrier density n from n = 1 + p in the conventional metal at high doping (ref. 12 ) to n = p at low doping (ref. 13 ) starts at the pseudogap critical point. This shows that the pseudogap and the antiferromagnetic Mott insulator are linked. Main Electrons in cuprate materials go from a correlated metallic state at high p to a Mott insulator at p = 0. How the system evolves from one state to the other remains a fundamental question. At high doping, the Fermi surface of cuprates is well established. It is a large hole-like cylinder whose volume yields a carrier density n = 1 + p , as measured, for example, by quantum oscillations 14 , in agreement with band structure calculations. The carrier density can also be measured using the Hall coefficient R H , because in the limit of T = 0 the Hall number n H of a single-band metal is such that n H = n . Indeed, in the cuprate Tl 2 Ba 2 CuO 6+ δ (Tl-2201), the normal-state Hall coefficient R H at p ≈ 0.3, measured at T → 0 in magnetic fields large enough to suppress superconductivity, is such that n H = V /( eR H ) ≈ 1 + p , where e is the electron charge and V the volume per Cu atom in the CuO 2 planes 12 , 15 . By contrast, at low doping, measurements of R H in La 2− x Sr x CuO 4 (LSCO) (ref. 13 ) and YBa 2 Cu 3 O y (YBCO) (ref. 16 ) yield n H ≈ p , below p ≈ 0.08. Having a carrier density equal to the hole concentration, n = p , is known to be an experimental signature of the lightly doped cuprates. The question is: at what doping does the transition between those two limiting regimes take place? Specifically, does the transition from n = 1 + p to n = p occur at p *, the critical doping for the onset of the pseudogap phase? The pseudogap is a partial gap in the normal-state density of states that appears below p * ≈ 0.19 (ref. 11 ), and whose origin is a central puzzle in the physics of correlated electrons and the subject of much debate. To answer this question using Hall measurements, one needs to reach low temperatures, which requires the use of large magnetic fields to suppress superconductivity. The only prior high-field study of cuprates that goes across p * was performed on LSCO (ref. 17 ), a cuprate superconductor with a relatively low critical temperature ( T c < 40 K) and critical field ( H c2 < 60 T). For mainly two reasons, studies on LSCO were inconclusive on the transition from n = 1 + p to n = p . First, the Fermi surface of overdoped LSCO undergoes a Lifshitz transition from a hole-like to an electron-like surface as its band structure crosses a saddle-point van Hove singularity at p ≈ 0.2 (ref. 18 ). This transition causes large changes in R H ( T ) (ref. 15 ) that can mask the effect of the pseudogap onset at p * ≈ 0.19. The second reason is the ill-defined impact of the charge-density-wave (CDW) modulations that develop at low temperature in a doping range near p ≈ 0.12 (ref. 19 ). Such CDW modulations should cause a reconstruction of the Fermi surface, and hence change R H at low temperature 6 . Therefore, the anomalies in n H versus p observed below 60 K in LSCO (ref. 17 )—and in Bi 2 La 2− x Sr x CuO 6+ δ (ref. 20 )—between p ≈ 0.1 and p ≈ 0.2 are most likely to be the combined result of three effects that have yet to be disentangled: Lifshitz transition, Fermi-surface reconstruction (FSR) and pseudogap. Here we turn to YBCO, a cuprate material with several advantages. First, it is one of the cleanest and best ordered of all cuprates, thereby ensuring a homogeneous doping ideal for distinguishing nearby critical points. Second, the location of the pseudogap critical point is well established in YBCO, at p * = 0.19 ± 0.01 (ref. 11 ). Third, the Lifshitz transition in YBCO occurs at p > 0.29 (ref. 21 ), well above p *. Fourth, the CDW modulations in YBCO have been thoroughly characterized. They are detected by X-ray diffraction (XRD) between p ≈ 0.08 and p ≈ 0.16 (refs 22 , 23 ), below a temperature T XRD ( Fig. 1a ). Above a threshold magnetic field, CDW order is detected by NMR (refs 2 , 24 ) below a temperature T NMR ( Fig. 1b ). Fifth, the FSR caused by the CDW modulations has a well-defined signature in the Hall effect of YBCO: R H ( T ) decreases smoothly to become negative at low temperature 6 —the signature of an electron pocket in the reconstructed Fermi surface. Prior Hall measurements in magnetic fields up", "role": "user" }, { "content": "Physicists have zoomed in on the transition that could explain why copper-oxides have such impressive superconducting powers. Settling a 20-year debate in the field, they found that a mysterious quantum phase transition associated with the termination of a regime called the \"pseudogap\" causes a sharp drop in the number of conducting electrons available to pair up for superconductivity. The team hypothesizes that whatever is happening at this point is probably the reason that cuprates support superconductivity at much higher temperatures than other materials—about half way to room temperature. \"It's very likely that the reason superconductivity grows in the first place, and the reason it grows so strongly, is because of that critical point,\" CIFAR Senior Fellow Louis Taillefer (Université de Sherbrooke) says. The new findings are published in Nature. Taillefer, the director of CIFAR's program in Quantum Materials, collaborated with his team and CIFAR Cyril Proust (Laboratoire National des Champs Magnétiques Intenses), Doug Bonn, Walter Hardy and Ruixing Liang (all three University of British Columbia). The study combined the University of British Columbia's expertise in making copper-oxide materials known as cuprates, the Université de Sherbrooke's expertise at probing them, and the powerful magnetic fields produced at the Toulouse lab. Their work is part of a global effort to harness superconductivity—the transmission of electricity with zero resistance in certain materials—to greatly improve power efficiency in many technologies. Cuprates are the most promising materials for that purpose right now, but the community is faced with a formidable physics problem: understanding the mysterious \"pseudogap\" phase. \"That's been the debate for 20 years—what is going on in the pseudogap phase?\" says Taillefer. The mystery has remained unsolved for so long mainly because when superconductivity kicks in, it becomes difficult to study what behaviours are taking place beneath it. With a magnetic field two million times that of the Earth's, the team of scientists managed to wipe out superconductivity in cuprate samples and look closely into the pseudogap phase at temperatures near absolute zero (- 273 C). At the point of instability where the pseudogap sets in, the electronic structure of cuprates undergoes a radical change. The number of available electrons plummets six-fold. This marks a quantum phase transition—a fundamental change of behaviour within the material. The scientists believe this new work will create a major shift in the focus of future research, and will lead to a new understanding of the properties of superconductors. Taillefer says this finding points the way to discovering the nature of the critical point and its fluctuations, and then exploring how to make superconductivity work at room temperature. The discovery follows intense research on the pseudogap mystery, after the same group of CIFAR researchers discovered the first signs of strange behaviour by observing quantum oscillations in 2007. \"The development at Toulouse of very low noise measurements, crucial for the discovery of quantum oscillations in 2007, and now recently the design and construction of our 90 T magnet, together opened up a new window of capability, allowing us to look directly at the pseudogap critical point,\" says Cyril Proust. CIFAR Associate Fellow Subir Sachdev (Harvard University) says the findings validate some of his recent theoretical research and set a clearer direction for future investigation that zooms in on this critical point. \"This gets me very excited about working on the theory of such a critical state,\" Sachdev says. \"The new experiments really sharpen the picture.\" Taillefer says the research would not have been possible without CIFAR fostering collaboration on quantum materials within Canada and internationally. \"It's really a pure CIFAR story,\" he says. Bonn adds that CIFAR's long-term support of collaborations on materials development and many experimental techniques to study the materials has advanced the field. \"The UBC-Sherbrooke collaboration is a particularly successful and long-running example, with each new experimental discovery pushing harder on further development of the materials samples used in the experiments,\" he says. \"This breakthrough is an example of how sustained, global collaboration that brings together diverse expertise from across the world is the most powerful way to advance science and address important sustainability challenges,\" says CIFAR President and CEO Dr. Alan Bernstein. \"This discovery proves once more the extremely high quality of Prof. Taillefer's research. He and his team have contributed to our success in the inaugural competition of the Canada First Research Excellence Fund. This success is consolidated by the recent creation of the Quantum Institute,\" states Prof. Jacques Beauvais, Vice-President, Research, Innovation and Entrepreneurship. The Université de Sherbrooke and the University of British Columbia received a total of $100 million from the Canada First Research Excellence Fund last year to support research on quantum materials and quantum technologies. ", "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 pseudogap is a partial gap in the electronic density of states that opens in the normal (non-superconducting) state of cuprate superconductors and whose origin is a long-standing puzzle. Its connection to the Mott insulator phase at low doping (hole concentration, p ) remains ambiguous 1 and its relation to the charge order 2 , 3 , 4 that reconstructs the Fermi surface 5 , 6 at intermediate doping is still unclear 7 , 8 , 9 , 10 . Here we use measurements of the Hall coefficient in magnetic fields up to 88 tesla to show that Fermi-surface reconstruction by charge order in the cuprate YBa 2 Cu 3 O y ends sharply at a critical doping p = 0.16 that is distinctly lower than the pseudogap critical point p * = 0.19 (ref. 11 ). This shows that the pseudogap and charge order are separate phenomena. We find that the change in carrier density n from n = 1 + p in the conventional metal at high doping (ref. 12 ) to n = p at low doping (ref. 13 ) starts at the pseudogap critical point. This shows that the pseudogap and the antiferromagnetic Mott insulator are linked. Main Electrons in cuprate materials go from a correlated metallic state at high p to a Mott insulator at p = 0. How the system evolves from one state to the other remains a fundamental question. At high doping, the Fermi surface of cuprates is well established. It is a large hole-like cylinder whose volume yields a carrier density n = 1 + p , as measured, for example, by quantum oscillations 14 , in agreement with band structure calculations. The carrier density can also be measured using the Hall coefficient R H , because in the limit of T = 0 the Hall number n H of a single-band metal is such that n H = n . Indeed, in the cuprate Tl 2 Ba 2 CuO 6+ δ (Tl-2201), the normal-state Hall coefficient R H at p ≈ 0.3, measured at T → 0 in magnetic fields large enough to suppress superconductivity, is such that n H = V /( eR H ) ≈ 1 + p , where e is the electron charge and V the volume per Cu atom in the CuO 2 planes 12 , 15 . By contrast, at low doping, measurements of R H in La 2− x Sr x CuO 4 (LSCO) (ref. 13 ) and YBa 2 Cu 3 O y (YBCO) (ref. 16 ) yield n H ≈ p , below p ≈ 0.08. Having a carrier density equal to the hole concentration, n = p , is known to be an experimental signature of the lightly doped cuprates. The question is: at what doping does the transition between those two limiting regimes take place? Specifically, does the transition from n = 1 + p to n = p occur at p *, the critical doping for the onset of the pseudogap phase? The pseudogap is a partial gap in the normal-state density of states that appears below p * ≈ 0.19 (ref. 11 ), and whose origin is a central puzzle in the physics of correlated electrons and the subject of much debate. To answer this question using Hall measurements, one needs to reach low temperatures, which requires the use of large magnetic fields to suppress superconductivity. The only prior high-field study of cuprates that goes across p * was performed on LSCO (ref. 17 ), a cuprate superconductor with a relatively low critical temperature ( T c < 40 K) and critical field ( H c2 < 60 T). For mainly two reasons, studies on LSCO were inconclusive on the transition from n = 1 + p to n = p . First, the Fermi surface of overdoped LSCO undergoes a Lifshitz transition from a hole-like to an electron-like surface as its band structure crosses a saddle-point van Hove singularity at p ≈ 0.2 (ref. 18 ). This transition causes large changes in R H ( T ) (ref. 15 ) that can mask the effect of the pseudogap onset at p * ≈ 0.19. The second reason is the ill-defined impact of the charge-density-wave (CDW) modulations that develop at low temperature in a doping range near p ≈ 0.12 (ref. 19 ). Such CDW modulations should cause a reconstruction of the Fermi surface, and hence change R H at low temperature 6 . Therefore, the anomalies in n H versus p observed below 60 K in LSCO (ref. 17 )—and in Bi 2 La 2− x Sr x CuO 6+ δ (ref. 20 )—between p ≈ 0.1 and p ≈ 0.2 are most likely to be the combined result of three effects that have yet to be disentangled: Lifshitz transition, Fermi-surface reconstruction (FSR) and pseudogap. Here we turn to YBCO, a cuprate material with several advantages. First, it is one of the cleanest and best ordered of all cuprates, thereby ensuring a homogeneous doping ideal for distinguishing nearby critical points. Second, the location of the pseudogap critical point is well established in YBCO, at p * = 0.19 ± 0.01 (ref. 11 ). Third, the Lifshitz transition in YBCO occurs at p > 0.29 (ref. 21 ), well above p *. Fourth, the CDW modulations in YBCO have been thoroughly characterized. They are detected by X-ray diffraction (XRD) between p ≈ 0.08 and p ≈ 0.16 (refs 22 , 23 ), below a temperature T XRD ( Fig. 1a ). Above a threshold magnetic field, CDW order is detected by NMR (refs 2 , 24 ) below a temperature T NMR ( Fig. 1b ). Fifth, the FSR caused by the CDW modulations has a well-defined signature in the Hall effect of YBCO: R H ( T ) decreases smoothly to become negative at low temperature 6 —the signature of an electron pocket in the reconstructed Fermi surface. Prior Hall measurements in magnetic fields up<|im_end|> <|im_start|>assistant Physicists have zoomed in on the transition that could explain why copper-oxides have such impressive superconducting powers. Settling a 20-year debate in the field, they found that a mysterious quantum phase transition associated with the termination of a regime called the "pseudogap" causes a sharp drop in the number of conducting electrons available to pair up for superconductivity. The team hypothesizes that whatever is happening at this point is probably the reason that cuprates support superconductivity at much higher temperatures than other materials—about half way to room temperature. "It's very likely that the reason superconductivity grows in the first place, and the reason it grows so strongly, is because of that critical point," CIFAR Senior Fellow Louis Taillefer (Université de Sherbrooke) says. The new findings are published in Nature. Taillefer, the director of CIFAR's program in Quantum Materials, collaborated with his team and CIFAR Cyril Proust (Laboratoire National des Champs Magnétiques Intenses), Doug Bonn, Walter Hardy and Ruixing Liang (all three University of British Columbia). The study combined the University of British Columbia's expertise in making copper-oxide materials known as cuprates, the Université de Sherbrooke's expertise at probing them, and the powerful magnetic fields produced at the Toulouse lab. Their work is part of a global effort to harness superconductivity—the transmission of electricity with zero resistance in certain materials—to greatly improve power efficiency in many technologies. Cuprates are the most promising materials for that purpose right now, but the community is faced with a formidable physics problem: understanding the mysterious "pseudogap" phase. "That's been the debate for 20 years—what is going on in the pseudogap phase?" says Taillefer. The mystery has remained unsolved for so long mainly because when superconductivity kicks in, it becomes difficult to study what behaviours are taking place beneath it. With a magnetic field two million times that of the Earth's, the team of scientists managed to wipe out superconductivity in cuprate samples and look closely into the pseudogap phase at temperatures near absolute zero (- 273 C). At the point of instability where the pseudogap sets in, the electronic structure of cuprates undergoes a radical change. The number of available electrons plummets six-fold. This marks a quantum phase transition—a fundamental change of behaviour within the material. The scientists believe this new work will create a major shift in the focus of future research, and will lead to a new understanding of the properties of superconductors. Taillefer says this finding points the way to discovering the nature of the critical point and its fluctuations, and then exploring how to make superconductivity work at room temperature. The discovery follows intense research on the pseudogap mystery, after the same group of CIFAR researchers discovered the first signs of strange behaviour by observing quantum oscillations in 2007. "The development at Toulouse of very low noise measurements, crucial for the discovery of quantum oscillations in 2007, and now recently the design and construction of our 90 T magnet, together opened up a new window of capability, allowing us to look directly at the pseudogap critical point," says Cyril Proust. CIFAR Associate Fellow Subir Sachdev (Harvard University) says the findings validate some of his recent theoretical research and set a clearer direction for future investigation that zooms in on this critical point. "This gets me very excited about working on the theory of such a critical state," Sachdev says. "The new experiments really sharpen the picture." Taillefer says the research would not have been possible without CIFAR fostering collaboration on quantum materials within Canada and internationally. "It's really a pure CIFAR story," he says. Bonn adds that CIFAR's long-term support of collaborations on materials development and many experimental techniques to study the materials has advanced the field. "The UBC-Sherbrooke collaboration is a particularly successful and long-running example, with each new experimental discovery pushing harder on further development of the materials samples used in the experiments," he says. "This breakthrough is an example of how sustained, global collaboration that brings together diverse expertise from across the world is the most powerful way to advance science and address important sustainability challenges," says CIFAR President and CEO Dr. Alan Bernstein. "This discovery proves once more the extremely high quality of Prof. Taillefer's research. He and his team have contributed to our success in the inaugural competition of the Canada First Research Excellence Fund. This success is consolidated by the recent creation of the Quantum Institute," states Prof. Jacques Beauvais, Vice-President, Research, Innovation and Entrepreneurship. The Université de Sherbrooke and the University of British Columbia received a total of $100 million from the Canada First Research Excellence Fund last year to support research on quantum materials and quantum technologies. <|im_end|>

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1148, 71177, 527, 4737, 2035, 24923, 433, 13, 3161, 264, 24924, 2115, 1403, 3610, 3115, 430, 315, 279, 9420, 596, 11, 279, 2128, 315, 14248, 9152, 311, 40194, 704, 2307, 77752, 1968, 304, 10747, 7853, 10688, 323, 1427, 15499, 1139, 279, 51743, 540, 391, 10474, 520, 20472, 3221, 10973, 7315, 10505, 220, 15451, 356, 570, 2468, 279, 1486, 315, 56399, 1405, 279, 51743, 540, 391, 7437, 304, 11, 279, 14683, 6070, 315, 10747, 67585, 37771, 288, 264, 18336, 2349, 13, 578, 1396, 315, 2561, 57678, 628, 27054, 1441, 4848, 24325, 13, 1115, 15785, 264, 31228, 10474, 9320, 29096, 16188, 2349, 315, 17432, 2949, 279, 3769, 13, 578, 14248, 4510, 420, 502, 990, 690, 1893, 264, 3682, 6541, 304, 279, 5357, 315, 3938, 3495, 11, 323, 690, 3063, 311, 264, 502, 8830, 315, 279, 6012, 315, 2307, 77752, 1105, 13, 37179, 273, 809, 2795, 420, 9455, 3585, 279, 1648, 311, 42687, 279, 7138, 315, 279, 9200, 1486, 323, 1202, 65649, 11, 323, 1243, 24919, 1268, 311, 1304, 2307, 77752, 1968, 990, 520, 3130, 9499, 13, 578, 18841, 11263, 19428, 3495, 389, 279, 51743, 540, 391, 23347, 11, 1306, 279, 1890, 1912, 315, 98690, 946, 12074, 11352, 279, 1176, 12195, 315, 15234, 17432, 555, 46071, 31228, 43524, 811, 304, 220, 1049, 22, 13, 330, 791, 4500, 520, 350, 67730, 315, 1633, 3428, 12248, 22323, 11, 16996, 369, 279, 18841, 315, 31228, 43524, 811, 304, 220, 1049, 22, 11, 323, 1457, 6051, 279, 2955, 323, 8246, 315, 1057, 220, 1954, 350, 33297, 11, 3871, 9107, 709, 264, 502, 3321, 315, 23099, 11, 10923, 603, 311, 1427, 6089, 520, 279, 51743, 540, 391, 9200, 1486, 1359, 2795, 95805, 393, 583, 267, 13, 98690, 946, 33468, 37946, 3804, 404, 38437, 3667, 320, 27588, 22329, 3907, 8, 2795, 279, 14955, 9788, 1063, 315, 813, 3293, 32887, 3495, 323, 743, 264, 49479, 5216, 369, 3938, 8990, 430, 15932, 82, 304, 389, 420, 9200, 1486, 13, 330, 2028, 5334, 757, 1633, 12304, 922, 3318, 389, 279, 10334, 315, 1778, 264, 9200, 1614, 1359, 38437, 3667, 2795, 13, 330, 791, 502, 21896, 2216, 57463, 279, 6945, 1210, 37179, 273, 809, 2795, 279, 3495, 1053, 539, 617, 1027, 3284, 2085, 98690, 946, 86644, 20632, 389, 31228, 7384, 2949, 7008, 323, 37545, 13, 330, 2181, 596, 2216, 264, 10748, 98690, 946, 3446, 1359, 568, 2795, 13, 13789, 77, 11621, 430, 98690, 946, 596, 1317, 9860, 1862, 315, 83663, 389, 7384, 4500, 323, 1690, 22772, 12823, 311, 4007, 279, 7384, 706, 11084, 279, 2115, 13, 330, 791, 549, 5002, 6354, 1964, 15222, 4845, 20632, 374, 264, 8104, 6992, 323, 1317, 54589, 3187, 11, 449, 1855, 502, 22772, 18841, 17919, 16127, 389, 4726, 4500, 315, 279, 7384, 10688, 1511, 304, 279, 21896, 1359, 568, 2795, 13, 330, 2028, 42445, 374, 459, 3187, 315, 1268, 29759, 11, 3728, 20632, 430, 12716, 3871, 17226, 19248, 505, 4028, 279, 1917, 374, 279, 1455, 8147, 1648, 311, 12178, 8198, 323, 2686, 3062, 41329, 11774, 1359, 2795, 98690, 946, 4900, 323, 12432, 2999, 13, 26349, 82415, 13, 330, 2028, 18841, 36862, 3131, 810, 279, 9193, 1579, 4367, 315, 8626, 13, 37179, 273, 809, 596, 3495, 13, 1283, 323, 813, 2128, 617, 20162, 311, 1057, 2450, 304, 279, 54559, 10937, 315, 279, 7008, 5629, 8483, 58240, 13492, 13, 1115, 2450, 374, 60391, 555, 279, 3293, 9886, 315, 279, 56413, 10181, 1359, 5415, 8626, 13, 64850, 80327, 100063, 11, 23270, 86481, 11, 8483, 11, 38710, 323, 69102, 5383, 13, 578, 15915, 13109, 409, 17530, 15222, 4845, 323, 279, 3907, 315, 8013, 19326, 4036, 264, 2860, 315, 400, 1041, 3610, 505, 279, 7008, 5629, 8483, 58240, 13492, 1566, 1060, 311, 1862, 3495, 389, 31228, 7384, 323, 31228, 14645, 13, 220, 128257, 198 ]

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