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 A superconductor is a material that can conduct electricity without resistance below a superconducting transition temperature, T c . The highest T c that has been achieved to date is in the copper oxide system 1 : 133 kelvin at ambient pressure 2 and 164 kelvin at high pressures 3 . As the nature of superconductivity in these materials is still not fully understood (they are not conventional superconductors), the prospects for achieving still higher transition temperatures by this route are not clear. In contrast, the Bardeen–Cooper–Schrieffer theory of conventional superconductivity gives a guide for achieving high T c with no theoretical upper bound—all that is needed is a favourable combination of high-frequency phonons, strong electron–phonon coupling, and a high density of states 4 . These conditions can in principle be fulfilled for metallic hydrogen and covalent compounds dominated by hydrogen 5 , 6 , as hydrogen atoms provide the necessary high-frequency phonon modes as well as the strong electron–phonon coupling. Numerous calculations support this idea and have predicted transition temperatures in the range 50–235 kelvin for many hydrides 7 , but only a moderate T c of 17 kelvin has been observed experimentally 8 . Here we investigate sulfur hydride 9 , where a T c of 80 kelvin has been predicted 10 . We find that this system transforms to a metal at a pressure of approximately 90 gigapascals. On cooling, we see signatures of superconductivity: a sharp drop of the resistivity to zero and a decrease of the transition temperature with magnetic field, with magnetic susceptibility measurements confirming a T c of 203 kelvin. Moreover, a pronounced isotope shift of T c in sulfur deuteride is suggestive of an electron–phonon mechanism of superconductivity that is consistent with the Bardeen–Cooper–Schrieffer scenario. We argue that the phase responsible for high- T c superconductivity in this system is likely to be H 3 S, formed from H 2 S by decomposition under pressure. These findings raise hope for the prospects for achieving room-temperature superconductivity in other hydrogen-based materials. Main A search for high- (room)-temperature conventional superconductivity is likely to be fruitful, as the Bardeen–Cooper–Schrieffer (BCS) theory in the Eliashberg formulation puts no apparent limits on T c . Materials with light elements are especially favourable as they provide high frequencies in the phonon spectrum. Indeed, many superconductive materials have been found in this way, but only a moderately high T c = 39 K has been found in this search (in MgB 2 ; ref. 11 ). Ashcroft 5 turned attention to hydrogen, which has very high vibrational frequencies due to the light hydrogen atom and provides a strong electron–phonon interaction. Further calculations showed that metallic hydrogen should be a superconductor with a very high T c of about 100–240 K for molecular hydrogen, and of 300–350 K in the atomic phase at 500 GPa (ref. 12 ). However, superconductivity in pure hydrogen has not yet been found, even though a conductive and probably semimetallic state of hydrogen has been recently produced 13 . Hydrogen-dominated materials such as covalent hydrides SiH 4 , SnH 4 , and so on might also be good candidates for showing high- T c superconductivity 6 . Similarly to pure hydrogen, they have high Debye temperatures. Moreover, heavier elements might be beneficial as they contribute to the low frequencies that enhance electron–phonon coupling. Importantly, lower pressures are required to metallize hydrides in comparison to pure hydrogen. Ashcroft’s general idea was supported in numerous calculations 7 , 10 predicting high values of T c for many hydrides. So far only a low T c ( ∼ 17 K) has been observed experimentally 8 . For the present study we selected H 2 S, because it is relatively easy to handle and is predicted to transform to a metal and a superconductor at a low pressure P ≈ 100 GPa with a high T c ≈ 80 K (ref. 10 ). Experimentally, H 2 S is known as a typical molecular compound with a rich phase diagram 14 . At about 96 GPa, hydrogen sulphide transforms to a metal 15 . The transformation is complicated by the partial dissociation of H 2 S and the appearance of elemental sulfur at P > 27 GPa at room temperature, and at higher pressures at lower temperatures 14 . Therefore, the metallization of hydrogen sulphide can be explained by elemental sulfur, which is known to become metallic above 95 GPa (ref. 16 ). No experimental studies of hydrogen sulphide are known above 100 GPa. In a typical experiment, we performed loading and the initial pressure increase at temperatures of ∼ 200 K; this is essential for obtaining a good sample (Methods). The Raman spectra of H 2 S and D 2 S were measured as the pressure was increased, and were in general agreement with the literature data 17 , 18 ( Extended Data Fig. 1 ). The sample starts to conduct at P ≈ 50 GPa. At this pressure it is a semiconductor, as shown by the temperature dependence of the resistance and pronounced photoconductivity. At 90–100 GPa the resistance drops further, and the temperature dependence becomes metallic. No photoconductive response is observed in this state. It is a poor metal—its resistivity at ∼ 100 K is ρ ≈ 3 × 10 −5 ohm m at 110 GPa and ρ ≈ 3 × 10 −7 ohm m at ∼ 200 GPa. During the cooling of the metal at pressures of about 100 GPa ( Fig. 1a ) the resistance abruptly drops by three to four orders of magnitude, indicating a transition to the superconducting state. At the next increase of pressure at low temperatures of T < 100 K, T c steadily increases with pressure. However, at pressures of >160 GPa, T c increases sharply ( Fig. 1b ). As higher temperatures of 150–250 K were involved in this pressure range, we supposed that the increase of T c and the decrease of sample resistance during warming (", "role": "user" }, { "content": "(Phys.org)—A combined team of researchers from the Max Planck Institute and Johannes Gutenberg-Universität Mainz has set a new warmth record for a superconductor. In their paper published in the journal Nature, the team describes the process they followed that led to the record and why it gives them optimism regarding the possibility of ever finding a superconductor that works at room temperature. Igor Mazin, with the Naval Research Laboratory in Washington, offers a News & Views piece on the work done by the team in the same journal issue, suggesting that the new record is causing some disbelievers to become more optimistic that the holy grail of superconductors will someday soon be found. During normal electrical conduction, electrons run into ions causing a ricochet and loss of energy. But scientists have also noted that such collisions also lead to the generation of small clusters of positive charge, which can lead to the formation of Cooper's pairs—that is a good thing, because such pairs are less likely to be part of future collisions. The net result is better efficiency. But, sadly, such pairings are weak, which means they are easily knocked apart by thermal energy—thus, colder temperatures allow for longer lasting Cooper's pairs and better efficiency, and that is why superconductors work at cold temperatures. But scientists are hopeful that one day a material will be found that allows for super-conduction at room temperature. In this new effort, the researchers have taken the science one step further. They put a specimen of hydrogen sulphide into a diamond anvil to pressurize it to approximately 1.6 million times that of atmospheric pressure and then cooled it down to just -70 °C—under such conditions hydrogen sulphide becomes a metal, and in this case, one that is superconducting. What is exciting about this latest record is that the temperature used in the experiment, actually occurs naturally on the surface of our planet sometimes—in Antarctica. That gives researchers the feeling that the next team of record breakers (perhaps using another hydrogen compound) is liable to get even closer, and that eventually, specimens will not have to be cooled at all. Theoretically, the team notes, there is nothing that forbids their existence. ", "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 superconductor is a material that can conduct electricity without resistance below a superconducting transition temperature, T c . The highest T c that has been achieved to date is in the copper oxide system 1 : 133 kelvin at ambient pressure 2 and 164 kelvin at high pressures 3 . As the nature of superconductivity in these materials is still not fully understood (they are not conventional superconductors), the prospects for achieving still higher transition temperatures by this route are not clear. In contrast, the Bardeen–Cooper–Schrieffer theory of conventional superconductivity gives a guide for achieving high T c with no theoretical upper bound—all that is needed is a favourable combination of high-frequency phonons, strong electron–phonon coupling, and a high density of states 4 . These conditions can in principle be fulfilled for metallic hydrogen and covalent compounds dominated by hydrogen 5 , 6 , as hydrogen atoms provide the necessary high-frequency phonon modes as well as the strong electron–phonon coupling. Numerous calculations support this idea and have predicted transition temperatures in the range 50–235 kelvin for many hydrides 7 , but only a moderate T c of 17 kelvin has been observed experimentally 8 . Here we investigate sulfur hydride 9 , where a T c of 80 kelvin has been predicted 10 . We find that this system transforms to a metal at a pressure of approximately 90 gigapascals. On cooling, we see signatures of superconductivity: a sharp drop of the resistivity to zero and a decrease of the transition temperature with magnetic field, with magnetic susceptibility measurements confirming a T c of 203 kelvin. Moreover, a pronounced isotope shift of T c in sulfur deuteride is suggestive of an electron–phonon mechanism of superconductivity that is consistent with the Bardeen–Cooper–Schrieffer scenario. We argue that the phase responsible for high- T c superconductivity in this system is likely to be H 3 S, formed from H 2 S by decomposition under pressure. These findings raise hope for the prospects for achieving room-temperature superconductivity in other hydrogen-based materials. Main A search for high- (room)-temperature conventional superconductivity is likely to be fruitful, as the Bardeen–Cooper–Schrieffer (BCS) theory in the Eliashberg formulation puts no apparent limits on T c . Materials with light elements are especially favourable as they provide high frequencies in the phonon spectrum. Indeed, many superconductive materials have been found in this way, but only a moderately high T c = 39 K has been found in this search (in MgB 2 ; ref. 11 ). Ashcroft 5 turned attention to hydrogen, which has very high vibrational frequencies due to the light hydrogen atom and provides a strong electron–phonon interaction. Further calculations showed that metallic hydrogen should be a superconductor with a very high T c of about 100–240 K for molecular hydrogen, and of 300–350 K in the atomic phase at 500 GPa (ref. 12 ). However, superconductivity in pure hydrogen has not yet been found, even though a conductive and probably semimetallic state of hydrogen has been recently produced 13 . Hydrogen-dominated materials such as covalent hydrides SiH 4 , SnH 4 , and so on might also be good candidates for showing high- T c superconductivity 6 . Similarly to pure hydrogen, they have high Debye temperatures. Moreover, heavier elements might be beneficial as they contribute to the low frequencies that enhance electron–phonon coupling. Importantly, lower pressures are required to metallize hydrides in comparison to pure hydrogen. Ashcroft’s general idea was supported in numerous calculations 7 , 10 predicting high values of T c for many hydrides. So far only a low T c ( ∼ 17 K) has been observed experimentally 8 . For the present study we selected H 2 S, because it is relatively easy to handle and is predicted to transform to a metal and a superconductor at a low pressure P ≈ 100 GPa with a high T c ≈ 80 K (ref. 10 ). Experimentally, H 2 S is known as a typical molecular compound with a rich phase diagram 14 . At about 96 GPa, hydrogen sulphide transforms to a metal 15 . The transformation is complicated by the partial dissociation of H 2 S and the appearance of elemental sulfur at P > 27 GPa at room temperature, and at higher pressures at lower temperatures 14 . Therefore, the metallization of hydrogen sulphide can be explained by elemental sulfur, which is known to become metallic above 95 GPa (ref. 16 ). No experimental studies of hydrogen sulphide are known above 100 GPa. In a typical experiment, we performed loading and the initial pressure increase at temperatures of ∼ 200 K; this is essential for obtaining a good sample (Methods). The Raman spectra of H 2 S and D 2 S were measured as the pressure was increased, and were in general agreement with the literature data 17 , 18 ( Extended Data Fig. 1 ). The sample starts to conduct at P ≈ 50 GPa. At this pressure it is a semiconductor, as shown by the temperature dependence of the resistance and pronounced photoconductivity. At 90–100 GPa the resistance drops further, and the temperature dependence becomes metallic. No photoconductive response is observed in this state. It is a poor metal—its resistivity at ∼ 100 K is ρ ≈ 3 × 10 −5 ohm m at 110 GPa and ρ ≈ 3 × 10 −7 ohm m at ∼ 200 GPa. During the cooling of the metal at pressures of about 100 GPa ( Fig. 1a ) the resistance abruptly drops by three to four orders of magnitude, indicating a transition to the superconducting state. At the next increase of pressure at low temperatures of T < 100 K, T c steadily increases with pressure. However, at pressures of >160 GPa, T c increases sharply ( Fig. 1b ). As higher temperatures of 150–250 K were involved in this pressure range, we supposed that the increase of T c and the decrease of sample resistance during warming (<|im_end|> <|im_start|>assistant (Phys.org)—A combined team of researchers from the Max Planck Institute and Johannes Gutenberg-Universität Mainz has set a new warmth record for a superconductor. In their paper published in the journal Nature, the team describes the process they followed that led to the record and why it gives them optimism regarding the possibility of ever finding a superconductor that works at room temperature. Igor Mazin, with the Naval Research Laboratory in Washington, offers a News & Views piece on the work done by the team in the same journal issue, suggesting that the new record is causing some disbelievers to become more optimistic that the holy grail of superconductors will someday soon be found. During normal electrical conduction, electrons run into ions causing a ricochet and loss of energy. But scientists have also noted that such collisions also lead to the generation of small clusters of positive charge, which can lead to the formation of Cooper's pairs—that is a good thing, because such pairs are less likely to be part of future collisions. The net result is better efficiency. But, sadly, such pairings are weak, which means they are easily knocked apart by thermal energy—thus, colder temperatures allow for longer lasting Cooper's pairs and better efficiency, and that is why superconductors work at cold temperatures. But scientists are hopeful that one day a material will be found that allows for super-conduction at room temperature. In this new effort, the researchers have taken the science one step further. They put a specimen of hydrogen sulphide into a diamond anvil to pressurize it to approximately 1.6 million times that of atmospheric pressure and then cooled it down to just -70 °C—under such conditions hydrogen sulphide becomes a metal, and in this case, one that is superconducting. What is exciting about this latest record is that the temperature used in the experiment, actually occurs naturally on the surface of our planet sometimes—in Antarctica. That gives researchers the feeling that the next team of record breakers (perhaps using another hydrogen compound) is liable to get even closer, and that eventually, specimens will not have to be cooled at all. Theoretically, the team notes, there is nothing that forbids their existence. <|im_end|>

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1,817

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Resolving ecological-economic trade-offs between biodiversity and yields is a key challenge when addressing the biodiversity crisis in tropical agricultural landscapes. Here, we focused on the relation between seven different taxa (trees, herbaceous plants, birds, amphibians, reptiles, butterflies, and ants) and yields in vanilla agroforests in Madagascar. Agroforests established in forests supported overall 23% fewer species and 47% fewer endemic species than old-growth forests, and 14% fewer endemic species than forest fragments. In contrast, agroforests established on fallows had overall 12% more species and 38% more endemic species than fallows. While yields increased with vanilla vine density and length, non-yield related variables largely determined biodiversity. Nonetheless, trade-offs existed between yields and butterflies as well as reptiles. Vanilla yields were generally unrelated to richness of trees, herbaceous plants, birds, amphibians, reptiles, and ants, opening up possibilities for conservation outside of protected areas and restoring degraded land to benefit farmers and biodiversity alike. Introduction Agricultural expansion and intensification are the main drivers of today’s biodiversity crisis 1 . Increases in agricultural productivity are typically achieved at the cost of biodiversity 2 , 3 . Solutions to the resulting ecological-economic trade-offs are urgently needed, especially in tropical landscapes that undergo rapid transformation 4 . In order to prevent, halt and reverse the degradation of ecosystems, the United Nations has declared the years 2021–2030 as the Decade on Ecosystem Restoration 5 . Restoration is an approach, that can at least partially restore levels of biodiversity and ecosystem services 6 . In this context, degradation represents the decline in biodiversity and ecosystem services, and restoration aims to prevent, halt and reverse the degradation of ecosystems 6 , 7 . Agroforestry opens up promising opportunities for ecosystem restoration 8 , 9 , but more system-specific knowledge is needed for an even wider implementation of win–win solutions. This is of particular importance for degraded land that has much reduced biodiversity and services provisioning 10 , and which makes up large shares of tropical landscapes characterized by subsistence agriculture and shifting cultivation 11 . However, agroforestry may also result in biodiversity losses if established at the expense of forests 12 , 13 . Whether tropical agroforests contribute to halting deforestation or accelerate biodiversity declines thus depends on their land-use history, meaning whether they are established on open land (i.e. cropland, pastures, fallow, or degraded land) or by thinning of forest 14 , 15 . Surprisingly, despite decades of research in agroforestry, land-use history is not considered in most studies on tropical agroforestry 15 . Furthermore, the productivity of agroforestry systems is decisive for their overall biodiversity value, because low-yielding agroforestry systems need more land to meet the same demands as provided by high-yielding monocultures, possibly leading to more forest conversion and biodiversity loss on a landscape-level 16 . Here, we focus on vanilla agroforestry in Madagascar (Supplementary Fig. 1 ), a tropical biodiversity hotspot 17 . Madagascar has exceptionally high rates of endemism 18 but faces great challenges in biodiversity conservation and human development in the face of extreme poverty 19 , 20 . Madagascar is the biggest producer of vanilla worldwide 21 , with a majority produced by smallholders 22 . The high world market price of vanilla over the last years brought great socioeconomic benefits for Malagasy smallholders, incentivizing the expansion of vanilla cultivation 22 , 23 . The hemi-epiphytic vanilla orchid is typically grown in agroforests on support trees in combination with shade trees 24 , 25 . Vanilla agroforests are either established through conversion of forest or on fallow land 15 . In contrast to the degradation of forests caused by forest-derived vanilla agroforestry, conversion of fallow land to vanilla agroforests can partially restore biodiversity and important ecosystem functions such as pest predation 26 , 27 . Fallow land, forming part of the shifting cultivation cycle for hill rice production, has increased in Madagascar 28 and is widespread in northeastern Madagascar 23 , 29 . As a consequence, Madagascar has lost 44% of its old-growth forest within the past six decades 30 , generating a need for land-use solutions aligning conservation with agricultural production 31 . We quantified the effect of vanilla cultivation on multiple taxa including trees, herbaceous plants, birds, amphibians, reptiles, butterflies, and ants, and used yield data from 30 vanilla agroforests, to identify yield-biodiversity trade-offs. We assessed the biodiversity value of forest- and fallow-derived vanilla agroforest and compared it with old-growth forest, forest fragments, and fallow land (Supplementary Fig. 2 ). Here, we focus on the restoration of species richness while addressing also differences in species composition. We differentiate between overall species richness and endemic species richness to account for Madagascar’s high share of endemic species and their vulnerability to land use 32 , 33 . To identify biodiversity-friendly as well as profitable strategies of vanilla cultivation, we assessed environmental and management-related variables as drivers of yields and species richness. Results Biodiversity and vanilla yield Comparing species richness and vanilla yield (kg/ha) in forest- and fallow-derived vanilla agroforests, we found that higher vanilla yields were not associated with a decrease in the overall species richness, nor the richness of endemic species, for trees, herbaceous plants, birds, amphibians, and ants. Notably, the analyzed relationship of yield with biodiversity is likely mediated by underlying variables such as management and land-use history. Moreover, the overall and endemic diversity of all taxa combined (i.e., their mean normalized richness) was also not related to vanilla yields at the plot level (Fig. 1 ; Supplementary Tables 1 and 2 ). We found a negative relationship between vanilla yield and butterfly species richness (Fig. 1G , estimate = −0.179, p -value < 0.001) and endemic butterfly species richness (Fig. 2G , estimate = −0.104, p -value = 0.043), a positive relationship with amphibians (Fig. 1E , estimate = 0.110, p -value = 0.045), and, depending on land-use history, an either positive (Fig. 2F , forest-derived, estimate = 0.289, p -value = 0.028) or negative (Fig. 2F , fallow-derived, estimate = −0.145, p -value = 0.016) relationship with endemic", "role": "user" }, { "content": "How can biodiversity be preserved while securing the economic livelihood of smallholder farmers growing vanilla in Madagascar? There is a way, according to a study by the Universities of Göttingen, Marburg and Hohenheim. The research team shows that vanilla plantations established on fallow land do not differ in terms of yield from those established in the forest. Cultivation on fallow land also increases biodiversity there. The results were published in Nature Communications. In this study, researchers recorded crop yields in vanilla agroforestry systems in northeastern Madagascar, the world's largest vanilla-growing area, which is dominated by smallholder farmers. They related these results to the biodiversity as identified by trees, herbaceous plants, birds, amphibians, reptiles, butterflies and ants. The economic and ecological aspects of cultivation were combined. The main finding: increasing vanilla yields were unrelated to overall biodiversity. In addition, the vanilla harvest on plantations established on fallow land did not differ from the harvest of plantations established in the forest. \"The good news is that farmers do not have to clear land to achieve high yields. In fact, they can add value for biodiversity to fallow land by cultivating vanilla there,\" says first author Dr. Annemarie Wurz, a former Ph.D. student in agroecology at Göttingen University and now a postdoctoral researcher at the University of Marburg. \"In northeastern Madagascar, the export of vanilla is an important source of income for tens of thousands of smallholder farmers and the widespread cultivation is a way to escape from poverty.\" Another argument is biodiversity: vanilla cultivated in the forest instead of on fallow land led to a loss of 23 percent of all species, and endemic species decreased by 47 percent. Vanilla in flower. Credit: University of Göttingen Collecting data on Madagascar. Credit: University of Göttingen If the farmers planted the vanilla more densely or increased the length of the vanilla plants, the harvest was higher, but the number of tree and reptile species decreased. However, this had no negative impact on birds, amphibians, butterflies, ants and herbaceous plants. \"We also observed that species diversity can be increased by high tree cover on plantations and in the landscape,\" says co-author Professor Teja Tscharntke, an agricultural ecologist at Göttingen University. Co-author Professor Ingo Grass, ecologist for tropical agricultural systems at the University of Hohenheim, adds that \"promoting vanilla cultivation on fallow land is ecologically and economically significant. This contributes to the current UN Decade for Ecosystem Restoration. In addition, this study illustrates possibilities for promoting and conserving biodiversity outside protected areas.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Resolving ecological-economic trade-offs between biodiversity and yields is a key challenge when addressing the biodiversity crisis in tropical agricultural landscapes. Here, we focused on the relation between seven different taxa (trees, herbaceous plants, birds, amphibians, reptiles, butterflies, and ants) and yields in vanilla agroforests in Madagascar. Agroforests established in forests supported overall 23% fewer species and 47% fewer endemic species than old-growth forests, and 14% fewer endemic species than forest fragments. In contrast, agroforests established on fallows had overall 12% more species and 38% more endemic species than fallows. While yields increased with vanilla vine density and length, non-yield related variables largely determined biodiversity. Nonetheless, trade-offs existed between yields and butterflies as well as reptiles. Vanilla yields were generally unrelated to richness of trees, herbaceous plants, birds, amphibians, reptiles, and ants, opening up possibilities for conservation outside of protected areas and restoring degraded land to benefit farmers and biodiversity alike. Introduction Agricultural expansion and intensification are the main drivers of today’s biodiversity crisis 1 . Increases in agricultural productivity are typically achieved at the cost of biodiversity 2 , 3 . Solutions to the resulting ecological-economic trade-offs are urgently needed, especially in tropical landscapes that undergo rapid transformation 4 . In order to prevent, halt and reverse the degradation of ecosystems, the United Nations has declared the years 2021–2030 as the Decade on Ecosystem Restoration 5 . Restoration is an approach, that can at least partially restore levels of biodiversity and ecosystem services 6 . In this context, degradation represents the decline in biodiversity and ecosystem services, and restoration aims to prevent, halt and reverse the degradation of ecosystems 6 , 7 . Agroforestry opens up promising opportunities for ecosystem restoration 8 , 9 , but more system-specific knowledge is needed for an even wider implementation of win–win solutions. This is of particular importance for degraded land that has much reduced biodiversity and services provisioning 10 , and which makes up large shares of tropical landscapes characterized by subsistence agriculture and shifting cultivation 11 . However, agroforestry may also result in biodiversity losses if established at the expense of forests 12 , 13 . Whether tropical agroforests contribute to halting deforestation or accelerate biodiversity declines thus depends on their land-use history, meaning whether they are established on open land (i.e. cropland, pastures, fallow, or degraded land) or by thinning of forest 14 , 15 . Surprisingly, despite decades of research in agroforestry, land-use history is not considered in most studies on tropical agroforestry 15 . Furthermore, the productivity of agroforestry systems is decisive for their overall biodiversity value, because low-yielding agroforestry systems need more land to meet the same demands as provided by high-yielding monocultures, possibly leading to more forest conversion and biodiversity loss on a landscape-level 16 . Here, we focus on vanilla agroforestry in Madagascar (Supplementary Fig. 1 ), a tropical biodiversity hotspot 17 . Madagascar has exceptionally high rates of endemism 18 but faces great challenges in biodiversity conservation and human development in the face of extreme poverty 19 , 20 . Madagascar is the biggest producer of vanilla worldwide 21 , with a majority produced by smallholders 22 . The high world market price of vanilla over the last years brought great socioeconomic benefits for Malagasy smallholders, incentivizing the expansion of vanilla cultivation 22 , 23 . The hemi-epiphytic vanilla orchid is typically grown in agroforests on support trees in combination with shade trees 24 , 25 . Vanilla agroforests are either established through conversion of forest or on fallow land 15 . In contrast to the degradation of forests caused by forest-derived vanilla agroforestry, conversion of fallow land to vanilla agroforests can partially restore biodiversity and important ecosystem functions such as pest predation 26 , 27 . Fallow land, forming part of the shifting cultivation cycle for hill rice production, has increased in Madagascar 28 and is widespread in northeastern Madagascar 23 , 29 . As a consequence, Madagascar has lost 44% of its old-growth forest within the past six decades 30 , generating a need for land-use solutions aligning conservation with agricultural production 31 . We quantified the effect of vanilla cultivation on multiple taxa including trees, herbaceous plants, birds, amphibians, reptiles, butterflies, and ants, and used yield data from 30 vanilla agroforests, to identify yield-biodiversity trade-offs. We assessed the biodiversity value of forest- and fallow-derived vanilla agroforest and compared it with old-growth forest, forest fragments, and fallow land (Supplementary Fig. 2 ). Here, we focus on the restoration of species richness while addressing also differences in species composition. We differentiate between overall species richness and endemic species richness to account for Madagascar’s high share of endemic species and their vulnerability to land use 32 , 33 . To identify biodiversity-friendly as well as profitable strategies of vanilla cultivation, we assessed environmental and management-related variables as drivers of yields and species richness. Results Biodiversity and vanilla yield Comparing species richness and vanilla yield (kg/ha) in forest- and fallow-derived vanilla agroforests, we found that higher vanilla yields were not associated with a decrease in the overall species richness, nor the richness of endemic species, for trees, herbaceous plants, birds, amphibians, and ants. Notably, the analyzed relationship of yield with biodiversity is likely mediated by underlying variables such as management and land-use history. Moreover, the overall and endemic diversity of all taxa combined (i.e., their mean normalized richness) was also not related to vanilla yields at the plot level (Fig. 1 ; Supplementary Tables 1 and 2 ). We found a negative relationship between vanilla yield and butterfly species richness (Fig. 1G , estimate = −0.179, p -value < 0.001) and endemic butterfly species richness (Fig. 2G , estimate = −0.104, p -value = 0.043), a positive relationship with amphibians (Fig. 1E , estimate = 0.110, p -value = 0.045), and, depending on land-use history, an either positive (Fig. 2F , forest-derived, estimate = 0.289, p -value = 0.028) or negative (Fig. 2F , fallow-derived, estimate = −0.145, p -value = 0.016) relationship with endemic<|im_end|> <|im_start|>assistant How can biodiversity be preserved while securing the economic livelihood of smallholder farmers growing vanilla in Madagascar? There is a way, according to a study by the Universities of Göttingen, Marburg and Hohenheim. The research team shows that vanilla plantations established on fallow land do not differ in terms of yield from those established in the forest. Cultivation on fallow land also increases biodiversity there. The results were published in Nature Communications. In this study, researchers recorded crop yields in vanilla agroforestry systems in northeastern Madagascar, the world's largest vanilla-growing area, which is dominated by smallholder farmers. They related these results to the biodiversity as identified by trees, herbaceous plants, birds, amphibians, reptiles, butterflies and ants. The economic and ecological aspects of cultivation were combined. The main finding: increasing vanilla yields were unrelated to overall biodiversity. In addition, the vanilla harvest on plantations established on fallow land did not differ from the harvest of plantations established in the forest. "The good news is that farmers do not have to clear land to achieve high yields. In fact, they can add value for biodiversity to fallow land by cultivating vanilla there," says first author Dr. Annemarie Wurz, a former Ph.D. student in agroecology at Göttingen University and now a postdoctoral researcher at the University of Marburg. "In northeastern Madagascar, the export of vanilla is an important source of income for tens of thousands of smallholder farmers and the widespread cultivation is a way to escape from poverty." Another argument is biodiversity: vanilla cultivated in the forest instead of on fallow land led to a loss of 23 percent of all species, and endemic species decreased by 47 percent. Vanilla in flower. Credit: University of Göttingen Collecting data on Madagascar. Credit: University of Göttingen If the farmers planted the vanilla more densely or increased the length of the vanilla plants, the harvest was higher, but the number of tree and reptile species decreased. However, this had no negative impact on birds, amphibians, butterflies, ants and herbaceous plants. "We also observed that species diversity can be increased by high tree cover on plantations and in the landscape," says co-author Professor Teja Tscharntke, an agricultural ecologist at Göttingen University. Co-author Professor Ingo Grass, ecologist for tropical agricultural systems at the University of Hohenheim, adds that "promoting vanilla cultivation on fallow land is ecologically and economically significant. This contributes to the current UN Decade for Ecosystem Restoration. In addition, this study illustrates possibilities for promoting and conserving biodiversity outside protected areas." <|im_end|>

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28118, 1101, 12062, 304, 9606, 18528, 13, 1226, 54263, 1990, 8244, 9606, 90030, 323, 96013, 9606, 90030, 311, 2759, 369, 95728, 753, 1579, 4430, 315, 96013, 9606, 323, 872, 34104, 311, 4363, 1005, 220, 843, 1174, 220, 1644, 662, 2057, 10765, 73119, 22658, 439, 1664, 439, 34235, 15174, 315, 33165, 52129, 11, 584, 32448, 12434, 323, 6373, 14228, 7482, 439, 12050, 315, 36508, 323, 9606, 90030, 13, 18591, 426, 3205, 3050, 323, 33165, 7692, 23611, 287, 9606, 90030, 323, 33165, 7692, 320, 7501, 14, 4317, 8, 304, 13952, 12, 323, 4498, 363, 72286, 33165, 945, 299, 1348, 37379, 11, 584, 1766, 430, 5190, 33165, 36508, 1051, 539, 5938, 449, 264, 18979, 304, 279, 8244, 9606, 90030, 11, 6463, 279, 90030, 315, 96013, 9606, 11, 369, 12690, 11, 39999, 77140, 11012, 11, 20229, 11, 89022, 5493, 11, 323, 61495, 13, 2876, 2915, 11, 279, 30239, 5133, 315, 7692, 449, 73119, 374, 4461, 78926, 555, 16940, 7482, 1778, 439, 6373, 323, 4363, 25700, 3925, 13, 23674, 11, 279, 8244, 323, 96013, 20057, 315, 682, 77314, 11093, 320, 72, 1770, 2637, 872, 3152, 30510, 90030, 8, 574, 1101, 539, 5552, 311, 33165, 36508, 520, 279, 7234, 2237, 320, 30035, 13, 220, 16, 2652, 99371, 43252, 220, 16, 323, 220, 17, 7609, 1226, 1766, 264, 8389, 5133, 1990, 33165, 7692, 323, 56269, 9606, 90030, 320, 30035, 13, 220, 16, 38, 1174, 16430, 284, 25173, 15, 13, 11128, 11, 281, 482, 970, 366, 220, 15, 13, 4119, 8, 323, 96013, 56269, 9606, 90030, 320, 30035, 13, 220, 17, 38, 1174, 16430, 284, 25173, 15, 13, 6849, 11, 281, 482, 970, 284, 220, 15, 13, 17776, 705, 264, 6928, 5133, 449, 89022, 5493, 320, 30035, 13, 220, 16, 36, 1174, 16430, 284, 220, 15, 13, 5120, 11, 281, 482, 970, 284, 220, 15, 13, 23785, 705, 323, 11, 11911, 389, 4363, 25700, 3925, 11, 459, 3060, 6928, 320, 30035, 13, 220, 17, 37, 1174, 13952, 72286, 11, 16430, 284, 220, 15, 13, 17212, 11, 281, 482, 970, 284, 220, 15, 13, 22000, 8, 477, 8389, 320, 30035, 13, 220, 17, 37, 1174, 4498, 363, 72286, 11, 16430, 284, 25173, 15, 13, 9591, 11, 281, 482, 970, 284, 220, 15, 13, 15794, 8, 5133, 449, 96013, 128257, 198, 128256, 78191, 198, 4438, 649, 73119, 387, 34683, 1418, 41577, 279, 7100, 64751, 315, 2678, 4346, 20957, 7982, 33165, 304, 95728, 30, 2684, 374, 264, 1648, 11, 4184, 311, 264, 4007, 555, 279, 75898, 315, 480, 45326, 1303, 268, 11, 2947, 10481, 323, 473, 27538, 21215, 13, 578, 3495, 2128, 5039, 430, 33165, 6136, 811, 9749, 389, 4498, 363, 4363, 656, 539, 1782, 304, 3878, 315, 7692, 505, 1884, 9749, 304, 279, 13952, 13, 26676, 40227, 389, 4498, 363, 4363, 1101, 12992, 73119, 1070, 13, 578, 3135, 1051, 4756, 304, 22037, 26545, 13, 763, 420, 4007, 11, 12074, 12715, 19641, 36508, 304, 33165, 945, 299, 1348, 4720, 6067, 304, 87244, 95728, 11, 279, 1917, 596, 7928, 33165, 56657, 3158, 11, 902, 374, 30801, 555, 2678, 4346, 20957, 13, 2435, 5552, 1521, 3135, 311, 279, 73119, 439, 11054, 555, 12690, 11, 39999, 77140, 11012, 11, 20229, 11, 89022, 5493, 11, 64873, 3742, 11, 81776, 323, 61495, 13, 578, 7100, 323, 50953, 13878, 315, 52129, 1051, 11093, 13, 578, 1925, 9455, 25, 7859, 33165, 36508, 1051, 46305, 311, 8244, 73119, 13, 763, 5369, 11, 279, 33165, 24322, 389, 6136, 811, 9749, 389, 4498, 363, 4363, 1550, 539, 1782, 505, 279, 24322, 315, 6136, 811, 9749, 304, 279, 13952, 13, 330, 791, 1695, 3754, 374, 430, 20957, 656, 539, 617, 311, 2867, 4363, 311, 11322, 1579, 36508, 13, 763, 2144, 11, 814, 649, 923, 907, 369, 73119, 311, 4498, 363, 4363, 555, 99139, 33165, 1070, 1359, 2795, 1176, 3229, 2999, 13, 9489, 336, 67545, 468, 324, 89, 11, 264, 4846, 2405, 920, 13, 5575, 304, 945, 299, 762, 2508, 520, 480, 45326, 1303, 268, 3907, 323, 1457, 264, 1772, 38083, 278, 32185, 520, 279, 3907, 315, 2947, 10481, 13, 330, 644, 87244, 95728, 11, 279, 7637, 315, 33165, 374, 459, 3062, 2592, 315, 8070, 369, 22781, 315, 9214, 315, 2678, 4346, 20957, 323, 279, 24716, 52129, 374, 264, 1648, 311, 12731, 505, 19542, 1210, 13596, 5811, 374, 73119, 25, 33165, 67166, 304, 279, 13952, 4619, 315, 389, 4498, 363, 4363, 6197, 311, 264, 4814, 315, 220, 1419, 3346, 315, 682, 9606, 11, 323, 96013, 9606, 25983, 555, 220, 2618, 3346, 13, 66682, 304, 23153, 13, 16666, 25, 3907, 315, 480, 45326, 1303, 268, 21153, 287, 828, 389, 95728, 13, 16666, 25, 3907, 315, 480, 45326, 1303, 268, 1442, 279, 20957, 39441, 279, 33165, 810, 97617, 477, 7319, 279, 3160, 315, 279, 33165, 11012, 11, 279, 24322, 574, 5190, 11, 719, 279, 1396, 315, 5021, 323, 64873, 458, 9606, 25983, 13, 4452, 11, 420, 1047, 912, 8389, 5536, 389, 20229, 11, 89022, 5493, 11, 81776, 11, 61495, 323, 39999, 77140, 11012, 13, 330, 1687, 1101, 13468, 430, 9606, 20057, 649, 387, 7319, 555, 1579, 5021, 3504, 389, 6136, 811, 323, 304, 279, 18921, 1359, 2795, 1080, 43802, 17054, 2722, 5697, 26132, 1799, 406, 441, 11, 459, 29149, 12208, 16549, 520, 480, 45326, 1303, 268, 3907, 13, 3623, 43802, 17054, 763, 3427, 41046, 11, 12208, 16549, 369, 35148, 29149, 6067, 520, 279, 3907, 315, 473, 27538, 21215, 11, 11621, 430, 330, 25475, 11780, 33165, 52129, 389, 4498, 363, 4363, 374, 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1,966

[ { "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 Characterization of the hafnium–tungsten systematics ( 182 Hf decaying to 182 W and emitting two electrons with a half-life of 8.9 million years) of the lunar mantle will enable better constraints on the timescale and processes involved in the currently accepted giant-impact theory for the formation and evolution of the Moon, and for testing the late-accretion hypothesis. Uniform, terrestrial-mantle-like W isotopic compositions have been reported 1 , 2 among crystallization products of the lunar magma ocean. These observations were interpreted to reflect formation of the Moon and crystallization of the lunar magma ocean after 182 Hf was no longer extant—that is, more than about 60 million years after the Solar System formed. Here we present W isotope data for three lunar samples that are more precise by a factor of ≥4 than those previously reported 1 , 2 . The new data reveal that the lunar mantle has a well-resolved 182 W excess of 20.6 ± 5.1 parts per million (±2 standard deviations), relative to the modern terrestrial mantle. The offset between the mantles of the Moon and the modern Earth is best explained by assuming that the W isotopic compositions of the two bodies were identical immediately following formation of the Moon, and that they then diverged as a result of disproportional late accretion to the Earth and Moon 3 , 4 . One implication of this model is that metal from the core of the Moon-forming impactor must have efficiently stripped the Earth’s mantle of highly siderophile elements on its way to merge with the terrestrial core, requiring a substantial, but still poorly defined, level of metal–silicate equilibration. Main Early applications of Hf–W isotopic system to lunar rocks were hampered by the effects of cosmic rays on 182 W, particularly due to production of 182 W from 181 Ta via neutron capture 5 . Consequently, more-recent studies have focused on the analysis of Ta-free metals extracted from lunar basalts and impact-melt rocks 1 , 6 . Here, we present W isotopic data for metals separated from two KREEP-rich Apollo 16 impact-melt rocks, obtained using new high-precision analytical methods 7 (KREEP indicates rocks rich in potassium (K), rare-earth elements (REE) and phosphorus (P)). In addition to W isotopic compositions and abundances, we determined abundances of Hf and the highly siderophile elements (HSE), as well as 187 Os/ 188 Os ratios, in order to assess the Hf/W ratio of the metal, examine the chemical signature of the impactor that produced the melt rocks, and evaluate potential contributions from meteoritic W. These impact-melt rocks were generated by basin-forming events, possibly during a period of late heavy bombardment about 3.9 Gyr ago 8 . The metal present in these rocks may have been derived from either the crustal target rocks, or the impactor that created the melt rocks. In either case, siderophile elements in the metals probably partially or wholly equilibrated with melt or vapour during the impact 9 . Metal separates from impact-melt rocks 68115,114, 68815,394 and 68815,396 (see Methods for nomenclature) have μ 182 W values (where μ 182 W is the deviation in p.p.m. of the 182 W/ 184 W ratio of the sample from that of the modern terrestrial mantle) of +23.3 ± 3.8 ( n = 3, 2 s.d.), +18.1 ± 2.5 and +20.4 ± 2.9, respectively, which are identical within analytical uncertainty ( Table 1 ). The new data are consistent with the previously published data for the same samples 1 , but are considerably more precise ( Fig. 1 ). Of greatest importance, the W isotopic compositions of the metals are now well resolved from the isotopic composition of the silicate portion of the modern Earth. Table 1 Tungsten isotopic compositions and W and Hf abundances of lunar metals Full size table Figure 1: Values of μ 182 W of lunar metals separated from KREEP-rich impact melts analysed by negative thermal ionization mass spectrometry in this study. The data for 68115,114, 68815,394, and 68815,396 are shown as circles, diamond, and square respectively; error bars for our analysis show internal precision of one single measurement, for which the 2 standard deviations (s.d.) external reproducibility is ∼ 4.5 ppm, as demonstrated by replicated standard measurements over the two year period. The white-dotted circle corresponds to the average of the three replicated analyses of 68115,114 metal; error bars show 2 s.d. of these data. The dark grey area and black dashed line indicates the average μ 182 W = +20.6 ± 5.1 (2 s.d., n = 3) of the three metal separates from Apollo 16 impact melt rocks analysed here. The light grey dashed line corresponds to the W isotope composition of the modern terrestrial mantle, and the light grey area at μ 182 W = 0 corresponds to the 2 standard errors (s.e.) uncertainty for repeated analyses of the Alfa Aesar W standard. PowerPoint slide Full size image The positive W isotopic offset between the Moon and the silicate Earth can be attributed to one of several possible causes, including: (1) cosmogenic exposure effects, (2) contribution of W from the basin-forming impactor that created the melt rocks, (3) radiogenic ingrowth of 182 W in a high-Hf/W domain within the mantle of the Moon or of the giant impactor, or (4) disproportional late accretion to the Earth and Moon. These possibilities are considered below. Cosmic ray exposure effects can be excluded as the cause of the isotopic offset. The Ta/Hf ratio of ∼ 0.11 for KREEP 10 , coupled with the measured Hf/W ratios of the metal separates ( Table 1 ), gives a calculated Ta/W average of ∼ 0.008 for the metals. Based on this ratio and the ∼ 2 Myr exposure ages of the samples 11 , a maximum effect of approximately −0.1 p.p.m. on the W isotopic compositions of the separated metals is estimated. This is well below our current level of analytical uncertainty, so no exposure corrections were applied, and the isotopic compositions of the metal separates are interpreted to have pre-exposure W", "role": "user" }, { "content": "Within the first 150 million years after our solar system formed, a giant body roughly the size of Mars struck and merged with Earth, blasting a huge cloud of rock and debris into space. This cloud would eventually coalesce and form the moon. For almost 30 years, planetary scientists have been quite happy with this explanation—with one major exception. Although this scenario makes sense when you look at the size of the moon and the physics of its orbit around Earth, things start to break down a little when you compare their isotopic compositions—the geological equivalent of a DNA \"fingerprint.\" Specifically, Earth and the moon are too much alike. The expectation has long been that the moon should carry the isotopic \"fingerprint\" of the foreign body, which scientists have named Theia. Because Theia came from elsewhere in the solar system, it probably had a much different isotopic fingerprint than early Earth. Now, a team of scientists at the University of Maryland has generated a new isotopic fingerprint of the moon that could provide the missing piece of the puzzle. By zeroing in on an isotope of Tungsten present in both the moon and Earth, the UMD team is the first to reconcile the accepted model of the moon's formation with the unexpectedly similar isotopic fingerprints of both bodies. The results suggest that the impact of Theia into early Earth was so violent, the resulting debris cloud mixed thoroughly before settling down and forming the moon. The findings appear in the April 8, 2015 advance online edition of the journal Nature. \"The problem is that Earth and the moon are very similar with respect to their isotopic fingerprints, suggesting that they are both ultimately formed from the same material that gathered early in the solar system's history,\" said Richard Walker, a professor of geology at UMD and co-author of the study. \"This is surprising, because the Mars-sized body that created the moon is expected to have been very different. So the conundrum is that Earth and the moon shouldn't be as similar as they are.\" The UMD team examined the tungsten isotopic composition of two moon rocks collected by the Apollo 16 mission, including sample 68815, seen here. When corrected for meteoritic additions to Earth and the moon after formation of the moon, the two bodies were found to have identical Tungsten isotopic compositions. Credit: NASA/JSC Several different theories have emerged over the years to explain the similar fingerprints of Earth and the moon. Perhaps the impact created a huge cloud of debris that mixed thoroughly with the Earth and then later condensed to form the moon. Or Theia could have, coincidentally, been isotopically similar to young Earth. A third possibility is that the moon formed from Earthen materials, rather than from Theia, although this would have been a very unusual type of impact. To tease out an explanation, Walker and his team looked to another well-documented phenomenon in the early history of the solar system. Evidence suggests that both Earth and the moon gathered additional material after the main impact, and that Earth collected more of this debris and dust. This new material contained a lot of Tungsten, but relatively little of this was of a lighter isotope known as Tungsten-182. Taking these two observations together, one would expect that Earth would have less Tungsten-182 than the moon. Sure enough, when comparing rocks from the moon and Earth, Walker and his team found that the moon has a slightly higher proportion of Tungsten-182. The key, however, is how much. \"The small, but significant, difference in the Tungsten isotopic composition between Earth and the moon perfectly corresponds to the different amounts of material gathered by Earth and the moon post-impact,\" Walker said. \"This means that, right after the moon formed, it had exactly the same isotopic composition as Earth's mantle.\" This finding supports the idea that the mass of material created by the impact, which later formed the moon, must have mixed together thoroughly before the moon coalesced and cooled. This would explain both the overall similarities in isotopic fingerprints and the slight differences in Tungsten-182. It also largely rules out the idea that the Mars-sized body was of similar composition, or that the moon formed from material contained in the pre-impact Earth. In both cases, it would be highly unlikely to see such a perfect correlation between Tungsten-182 and the amounts of material gathered by the moon and Earth post-impact. \"This result brings us one step closer to understanding the close familial relationship between Earth and the moon,\" Walker said. \"We still need to work out the details, but it's clear that our early solar system was a very violent place.\" ", "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 Characterization of the hafnium–tungsten systematics ( 182 Hf decaying to 182 W and emitting two electrons with a half-life of 8.9 million years) of the lunar mantle will enable better constraints on the timescale and processes involved in the currently accepted giant-impact theory for the formation and evolution of the Moon, and for testing the late-accretion hypothesis. Uniform, terrestrial-mantle-like W isotopic compositions have been reported 1 , 2 among crystallization products of the lunar magma ocean. These observations were interpreted to reflect formation of the Moon and crystallization of the lunar magma ocean after 182 Hf was no longer extant—that is, more than about 60 million years after the Solar System formed. Here we present W isotope data for three lunar samples that are more precise by a factor of ≥4 than those previously reported 1 , 2 . The new data reveal that the lunar mantle has a well-resolved 182 W excess of 20.6 ± 5.1 parts per million (±2 standard deviations), relative to the modern terrestrial mantle. The offset between the mantles of the Moon and the modern Earth is best explained by assuming that the W isotopic compositions of the two bodies were identical immediately following formation of the Moon, and that they then diverged as a result of disproportional late accretion to the Earth and Moon 3 , 4 . One implication of this model is that metal from the core of the Moon-forming impactor must have efficiently stripped the Earth’s mantle of highly siderophile elements on its way to merge with the terrestrial core, requiring a substantial, but still poorly defined, level of metal–silicate equilibration. Main Early applications of Hf–W isotopic system to lunar rocks were hampered by the effects of cosmic rays on 182 W, particularly due to production of 182 W from 181 Ta via neutron capture 5 . Consequently, more-recent studies have focused on the analysis of Ta-free metals extracted from lunar basalts and impact-melt rocks 1 , 6 . Here, we present W isotopic data for metals separated from two KREEP-rich Apollo 16 impact-melt rocks, obtained using new high-precision analytical methods 7 (KREEP indicates rocks rich in potassium (K), rare-earth elements (REE) and phosphorus (P)). In addition to W isotopic compositions and abundances, we determined abundances of Hf and the highly siderophile elements (HSE), as well as 187 Os/ 188 Os ratios, in order to assess the Hf/W ratio of the metal, examine the chemical signature of the impactor that produced the melt rocks, and evaluate potential contributions from meteoritic W. These impact-melt rocks were generated by basin-forming events, possibly during a period of late heavy bombardment about 3.9 Gyr ago 8 . The metal present in these rocks may have been derived from either the crustal target rocks, or the impactor that created the melt rocks. In either case, siderophile elements in the metals probably partially or wholly equilibrated with melt or vapour during the impact 9 . Metal separates from impact-melt rocks 68115,114, 68815,394 and 68815,396 (see Methods for nomenclature) have μ 182 W values (where μ 182 W is the deviation in p.p.m. of the 182 W/ 184 W ratio of the sample from that of the modern terrestrial mantle) of +23.3 ± 3.8 ( n = 3, 2 s.d.), +18.1 ± 2.5 and +20.4 ± 2.9, respectively, which are identical within analytical uncertainty ( Table 1 ). The new data are consistent with the previously published data for the same samples 1 , but are considerably more precise ( Fig. 1 ). Of greatest importance, the W isotopic compositions of the metals are now well resolved from the isotopic composition of the silicate portion of the modern Earth. Table 1 Tungsten isotopic compositions and W and Hf abundances of lunar metals Full size table Figure 1: Values of μ 182 W of lunar metals separated from KREEP-rich impact melts analysed by negative thermal ionization mass spectrometry in this study. The data for 68115,114, 68815,394, and 68815,396 are shown as circles, diamond, and square respectively; error bars for our analysis show internal precision of one single measurement, for which the 2 standard deviations (s.d.) external reproducibility is ∼ 4.5 ppm, as demonstrated by replicated standard measurements over the two year period. The white-dotted circle corresponds to the average of the three replicated analyses of 68115,114 metal; error bars show 2 s.d. of these data. The dark grey area and black dashed line indicates the average μ 182 W = +20.6 ± 5.1 (2 s.d., n = 3) of the three metal separates from Apollo 16 impact melt rocks analysed here. The light grey dashed line corresponds to the W isotope composition of the modern terrestrial mantle, and the light grey area at μ 182 W = 0 corresponds to the 2 standard errors (s.e.) uncertainty for repeated analyses of the Alfa Aesar W standard. PowerPoint slide Full size image The positive W isotopic offset between the Moon and the silicate Earth can be attributed to one of several possible causes, including: (1) cosmogenic exposure effects, (2) contribution of W from the basin-forming impactor that created the melt rocks, (3) radiogenic ingrowth of 182 W in a high-Hf/W domain within the mantle of the Moon or of the giant impactor, or (4) disproportional late accretion to the Earth and Moon. These possibilities are considered below. Cosmic ray exposure effects can be excluded as the cause of the isotopic offset. The Ta/Hf ratio of ∼ 0.11 for KREEP 10 , coupled with the measured Hf/W ratios of the metal separates ( Table 1 ), gives a calculated Ta/W average of ∼ 0.008 for the metals. Based on this ratio and the ∼ 2 Myr exposure ages of the samples 11 , a maximum effect of approximately −0.1 p.p.m. on the W isotopic compositions of the separated metals is estimated. This is well below our current level of analytical uncertainty, so no exposure corrections were applied, and the isotopic compositions of the metal separates are interpreted to have pre-exposure W<|im_end|> <|im_start|>assistant Within the first 150 million years after our solar system formed, a giant body roughly the size of Mars struck and merged with Earth, blasting a huge cloud of rock and debris into space. This cloud would eventually coalesce and form the moon. For almost 30 years, planetary scientists have been quite happy with this explanation—with one major exception. Although this scenario makes sense when you look at the size of the moon and the physics of its orbit around Earth, things start to break down a little when you compare their isotopic compositions—the geological equivalent of a DNA "fingerprint." Specifically, Earth and the moon are too much alike. The expectation has long been that the moon should carry the isotopic "fingerprint" of the foreign body, which scientists have named Theia. Because Theia came from elsewhere in the solar system, it probably had a much different isotopic fingerprint than early Earth. Now, a team of scientists at the University of Maryland has generated a new isotopic fingerprint of the moon that could provide the missing piece of the puzzle. By zeroing in on an isotope of Tungsten present in both the moon and Earth, the UMD team is the first to reconcile the accepted model of the moon's formation with the unexpectedly similar isotopic fingerprints of both bodies. The results suggest that the impact of Theia into early Earth was so violent, the resulting debris cloud mixed thoroughly before settling down and forming the moon. The findings appear in the April 8, 2015 advance online edition of the journal Nature. "The problem is that Earth and the moon are very similar with respect to their isotopic fingerprints, suggesting that they are both ultimately formed from the same material that gathered early in the solar system's history," said Richard Walker, a professor of geology at UMD and co-author of the study. "This is surprising, because the Mars-sized body that created the moon is expected to have been very different. So the conundrum is that Earth and the moon shouldn't be as similar as they are." The UMD team examined the tungsten isotopic composition of two moon rocks collected by the Apollo 16 mission, including sample 68815, seen here. When corrected for meteoritic additions to Earth and the moon after formation of the moon, the two bodies were found to have identical Tungsten isotopic compositions. Credit: NASA/JSC Several different theories have emerged over the years to explain the similar fingerprints of Earth and the moon. Perhaps the impact created a huge cloud of debris that mixed thoroughly with the Earth and then later condensed to form the moon. Or Theia could have, coincidentally, been isotopically similar to young Earth. A third possibility is that the moon formed from Earthen materials, rather than from Theia, although this would have been a very unusual type of impact. To tease out an explanation, Walker and his team looked to another well-documented phenomenon in the early history of the solar system. Evidence suggests that both Earth and the moon gathered additional material after the main impact, and that Earth collected more of this debris and dust. This new material contained a lot of Tungsten, but relatively little of this was of a lighter isotope known as Tungsten-182. Taking these two observations together, one would expect that Earth would have less Tungsten-182 than the moon. Sure enough, when comparing rocks from the moon and Earth, Walker and his team found that the moon has a slightly higher proportion of Tungsten-182. The key, however, is how much. "The small, but significant, difference in the Tungsten isotopic composition between Earth and the moon perfectly corresponds to the different amounts of material gathered by Earth and the moon post-impact," Walker said. "This means that, right after the moon formed, it had exactly the same isotopic composition as Earth's mantle." This finding supports the idea that the mass of material created by the impact, which later formed the moon, must have mixed together thoroughly before the moon coalesced and cooled. This would explain both the overall similarities in isotopic fingerprints and the slight differences in Tungsten-182. It also largely rules out the idea that the Mars-sized body was of similar composition, or that the moon formed from material contained in the pre-impact Earth. In both cases, it would be highly unlikely to see such a perfect correlation between Tungsten-182 and the amounts of material gathered by the moon and Earth post-impact. "This result brings us one step closer to understanding the close familial relationship between Earth and the moon," Walker said. "We still need to work out the details, but it's clear that our early solar system was a very violent place." <|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 Stereoselective halogenation is a highly useful organic transformation for multistep syntheses because the resulting chiral organohalides can serve as precursors for various medicinally relevant derivatives. Even though decarboxylative halogenation of aliphatic carboxylic acids is a useful and fundamental synthetic method for the preparation of a variety of organohalides, an enantioselective version of this reaction has not been reported. Here we report a highly enantioselective decarboxylative chlorination of β-ketocarboxylic acids to obtain α-chloroketones under mild organocatalytic conditions. The present method is also applicable for the enantioselective synthesis of tertiary α-chloroketones. The conversions of the resulting α-chloroketones into α-aminoketones and α-thio-substituted ketones via S N 2 reactions at the tertiary carbon centres are also demonstrated. These results constitute an efficient approach for the synthesis of chiral organohalides and are expected to enhance the availability of enantiomerically enriched chiral compounds with heteroatom-substituted chiral stereogenic centres. Introduction Organohalides are a fundamentally important class of compounds not only because the carbon-halogen bond is found in many biologically active compounds but also because a broad range of pharmaceutical and agrochemical agents are synthesized from organohalides, owing to the good leaving ability of halogen atoms 1 , 2 , 3 . Chiral halides are especially attractive building blocks because following the enantioselective introduction of the halogen atom onto a chiral carbon atom, subsequent substitution of the halogen atom via an S N 2 reaction, for example, generates a variety of chiral compounds with retained enantiopurity. Decarboxylative halogenation of aliphatic carboxylic acids is a useful organic transformation that directly replaces carboxyl groups with halogen atoms ( Fig. 1a ). Upon the initial discovery of this reaction by Borodine 4 and Hunsdiecker and Hunsdiecker 5 , the transformation required the use of stoichiometric quantities of expensive transition metals. A number of improved methods, including the catalytic activation of carboxylic acids, have been developed over the past few decades 6 , 7 , 8 , 9 , 10 , 11 , 12 . For example, in 1997, Chowdhury and Roy 6 reported the first example of a catalytic decarboxylative halogenation reaction using lithium acetate as the catalyst, but this route was applicable only for cinnamic acid derivatives. In addition, in 2012, Li and colleagues developed a catalytic method for the decarboxylative chlorination and fluorination of general carboxylic acids. The visible-light-promoted decarboxylative halogenation has recently attracted much attention as a mild method to create carbon–halogen bonds 9 , 10 , 11 , 12 . In 2014, Sammis and Paquin initially revealed the visible-light-mediated decarboxylative fluorination of 2-aryloxyacetic acids in the presence of a Ru(II) photoredox catalyst 9 . Subsequently, MacMillan and colleagues succeeded in expanding the substrate scope of this reaction to a wide range of aliphatic carboxylic acids 10 . As these decarboxylative halogenation reactions can efficiently produce highly substituted alkyl halides, it was expected that an enantioselective version could be developed by employing a chiral catalyst in the reaction ( Fig. 1b ). However, to the best of our knowledge, this reaction has not been successfully adapted for asymmetric synthesis even though it was initially discovered over a century and a half ago. In this context, we considered the unique reactivity of β-oxocarboxylic acids, which have an additional carbonyl functionality at the β-position. As these carboxylic acids serve as an enolate equivalent involving the decarboxylation, mediation of decarboxylation step by a chiral catalyst is expected to result in reaction of the formal enolate with electrophiles in an enantioselective manner. Thus several groups have reported the enantioselective decarboxylative aldol-type reactions and 1,4-addition reactions of β-oxocarboxylic acids 13 . An elegant example has recently been reported by Saadi and Wennemers 14 , in which decarboxylative aldol reactions of α-fluorinated malonic acid half thioesters and aldehydes yield the corresponding adducts in high diastereoselectivity and enantioselectivity in the presence of a chiral amine catalyst. Inspired by these previous studies, we envisaged that an enantioselective decarboxylative chlorination could be achieved by the chiral amine-mediated formation of enolates from racemic β-ketocarboxylic acids and subsequent electrophilic chlorination to yield enantiomerically enriched α-chloroketones via the ionic reaction pathway ( Fig. 1c ). This method would therefore be useful as an alternative to the direct α-chlorination of ketones for the synthesis of chiral α-chloroketones. Furthermore, although the development of methods for the enantioselective α-halogenation of carbonyl compounds has progressed rapidly in the past decade 15 , 16 since Hintermann and Togni 17 reported pioneering studies on the enantioselective halogenation of active methine compounds, only a single catalytic method has been reported for the enantioselective chlorination of unactivated ketones 18 , and to the best of our knowledge, no catalytic method is available for asymmetrical ketones 19 . Here we show a highly enantioselective decarboxylative chlorination of β-ketocarboxylic acids to obtain α-chloroketones with a chiral primary amine catalyst. S N 2 reactions of the resulting α-chloroketones at a tertiry carbon are also described 20 , 21 . Figure 1: Decarboxylative halogenation of aliphatic carboxylic acids and development of an enantioselective reaction. ( a ) The general reaction scheme of decarboxylative halogenation (R=unspecified alkyl group, Hal=unspecified halogen atom). ( b ) Desired enantioselective synthesis of non-racemic alkyl halides from racemic carboxylic acids. ( c ) Chiral amine-catalysed enantioselective decarboxylative chlorination of β-ketocarboxylic acids. Full size image Results Reaction optimization Our synthetic study began with the preparation of β-ketocarboxylic acid 1a as the starting material for the subsequent decarboxylative chlorination using known chiral amine catalysts, such as cinchona alkaloid derivatives and diarylprolinol derivatives ( Fig. 2 ). However, although the desired α-chloroketone 2a was obtained in good yield, the resulting enantioselectivity was poor. We also examined the reaction with a chiral Lewis acid catalyst prepared from a spiro pyridyl monooxazoline ligand L1 and copper(II) trifluoromethanesulfonate because it is known to catalyse electrophilic halogenation of β-ketoesters with high enantioselectivity 22 , 23 , 24 . However, the decarboxylative chlorination of 1a using this catalyst also proceeded with poor enantioselectivity. Recently, we have reported the synthesis of a 1,1′-binaphthyl-based chiral amino ester C1 and successfully applied it for enantioselective fluorination of α-branched", "role": "user" }, { "content": "Toyohashi University of Technology researchers led by Associate Professor Shibatomi developed new catalytic reaction to produce chlorine-containing organic molecules in isomerically pure (left- or right-handed) form Molecules don't have hands, but some of them are left- or right-handed. Many chemical compounds display a feature called chirality, where two versions—known as enantiomers—exist for the same molecule. Although their atoms are connected in exactly the same sequence, the two enantiomers are distinct mirror images, like a pair of hands. Enantiomers can have very different properties. For example, only the right-handed form of glucose gives you energy—the left-handed isomer cannot be metabolized, even though it tastes the same. Many pharmaceuticals are also chiral, and often only one enantiomer has a medicinal use. Therefore, chemists working on complex molecules have developed a variety of tricks to guarantee isomer purity. However, for some reactions this remains a challenge. Now, the research team has developed a reaction to produce an important class of compounds in pure left- or right-handed form. Organohalides are molecules in which a halogen, such as chlorine, is bonded to carbon. Many are found in nature, or used in medicine. They can be produced from another family of compounds, carboxylic acids, by simply replacing an acid with a halogen. Unfortunately, if the target compound is chiral, this substitution produces left- and right-handed isomers in equal amounts. The Toyohashi University of Technology research team solved this problem by catalyzing the reaction with a catalyst that is itself chiral. Nowadays, catalysts come in a wide range of shapes and sizes—often rivalling the complexity of the actual target molecule. \"We screened a diverse array of chiral catalysts, such as Lewis acid, Brønsted acid, and Lewis base catalysts,\" study lead author Kazutaka Shibatomi says. \"Finally, we found an amine that gave us organohalides with up to 98% enantiomeric purity - even though our starting material was a 50/50 mixture.\" The chlorinated products, known as chloroketones, are building blocks for more important chiral molecules like pharmaceuticals. Because chlorine is only weakly bonded to carbon, it can be easily substituted by another atom to make a new molecule. Using one of the many compounds produced in enantiomeric purity by their new reaction, the research team synthesized Cathinone, a natural stimulant. \"The substitution proceeds in a simple, classic way,\" Associate Prof. Shibatomi says. \"While chlorine leaves the molecule on one side, the incoming group approaches from the opposite side. The product's chirality just depends on the arrangement of these atoms, so if you begin with a pure enantiomer, you retain that purity. This could open up a whole class of compounds that were previously a major challenge to produce as pure enantiomers.\" ", "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 Stereoselective halogenation is a highly useful organic transformation for multistep syntheses because the resulting chiral organohalides can serve as precursors for various medicinally relevant derivatives. Even though decarboxylative halogenation of aliphatic carboxylic acids is a useful and fundamental synthetic method for the preparation of a variety of organohalides, an enantioselective version of this reaction has not been reported. Here we report a highly enantioselective decarboxylative chlorination of β-ketocarboxylic acids to obtain α-chloroketones under mild organocatalytic conditions. The present method is also applicable for the enantioselective synthesis of tertiary α-chloroketones. The conversions of the resulting α-chloroketones into α-aminoketones and α-thio-substituted ketones via S N 2 reactions at the tertiary carbon centres are also demonstrated. These results constitute an efficient approach for the synthesis of chiral organohalides and are expected to enhance the availability of enantiomerically enriched chiral compounds with heteroatom-substituted chiral stereogenic centres. Introduction Organohalides are a fundamentally important class of compounds not only because the carbon-halogen bond is found in many biologically active compounds but also because a broad range of pharmaceutical and agrochemical agents are synthesized from organohalides, owing to the good leaving ability of halogen atoms 1 , 2 , 3 . Chiral halides are especially attractive building blocks because following the enantioselective introduction of the halogen atom onto a chiral carbon atom, subsequent substitution of the halogen atom via an S N 2 reaction, for example, generates a variety of chiral compounds with retained enantiopurity. Decarboxylative halogenation of aliphatic carboxylic acids is a useful organic transformation that directly replaces carboxyl groups with halogen atoms ( Fig. 1a ). Upon the initial discovery of this reaction by Borodine 4 and Hunsdiecker and Hunsdiecker 5 , the transformation required the use of stoichiometric quantities of expensive transition metals. A number of improved methods, including the catalytic activation of carboxylic acids, have been developed over the past few decades 6 , 7 , 8 , 9 , 10 , 11 , 12 . For example, in 1997, Chowdhury and Roy 6 reported the first example of a catalytic decarboxylative halogenation reaction using lithium acetate as the catalyst, but this route was applicable only for cinnamic acid derivatives. In addition, in 2012, Li and colleagues developed a catalytic method for the decarboxylative chlorination and fluorination of general carboxylic acids. The visible-light-promoted decarboxylative halogenation has recently attracted much attention as a mild method to create carbon–halogen bonds 9 , 10 , 11 , 12 . In 2014, Sammis and Paquin initially revealed the visible-light-mediated decarboxylative fluorination of 2-aryloxyacetic acids in the presence of a Ru(II) photoredox catalyst 9 . Subsequently, MacMillan and colleagues succeeded in expanding the substrate scope of this reaction to a wide range of aliphatic carboxylic acids 10 . As these decarboxylative halogenation reactions can efficiently produce highly substituted alkyl halides, it was expected that an enantioselective version could be developed by employing a chiral catalyst in the reaction ( Fig. 1b ). However, to the best of our knowledge, this reaction has not been successfully adapted for asymmetric synthesis even though it was initially discovered over a century and a half ago. In this context, we considered the unique reactivity of β-oxocarboxylic acids, which have an additional carbonyl functionality at the β-position. As these carboxylic acids serve as an enolate equivalent involving the decarboxylation, mediation of decarboxylation step by a chiral catalyst is expected to result in reaction of the formal enolate with electrophiles in an enantioselective manner. Thus several groups have reported the enantioselective decarboxylative aldol-type reactions and 1,4-addition reactions of β-oxocarboxylic acids 13 . An elegant example has recently been reported by Saadi and Wennemers 14 , in which decarboxylative aldol reactions of α-fluorinated malonic acid half thioesters and aldehydes yield the corresponding adducts in high diastereoselectivity and enantioselectivity in the presence of a chiral amine catalyst. Inspired by these previous studies, we envisaged that an enantioselective decarboxylative chlorination could be achieved by the chiral amine-mediated formation of enolates from racemic β-ketocarboxylic acids and subsequent electrophilic chlorination to yield enantiomerically enriched α-chloroketones via the ionic reaction pathway ( Fig. 1c ). This method would therefore be useful as an alternative to the direct α-chlorination of ketones for the synthesis of chiral α-chloroketones. Furthermore, although the development of methods for the enantioselective α-halogenation of carbonyl compounds has progressed rapidly in the past decade 15 , 16 since Hintermann and Togni 17 reported pioneering studies on the enantioselective halogenation of active methine compounds, only a single catalytic method has been reported for the enantioselective chlorination of unactivated ketones 18 , and to the best of our knowledge, no catalytic method is available for asymmetrical ketones 19 . Here we show a highly enantioselective decarboxylative chlorination of β-ketocarboxylic acids to obtain α-chloroketones with a chiral primary amine catalyst. S N 2 reactions of the resulting α-chloroketones at a tertiry carbon are also described 20 , 21 . Figure 1: Decarboxylative halogenation of aliphatic carboxylic acids and development of an enantioselective reaction. ( a ) The general reaction scheme of decarboxylative halogenation (R=unspecified alkyl group, Hal=unspecified halogen atom). ( b ) Desired enantioselective synthesis of non-racemic alkyl halides from racemic carboxylic acids. ( c ) Chiral amine-catalysed enantioselective decarboxylative chlorination of β-ketocarboxylic acids. Full size image Results Reaction optimization Our synthetic study began with the preparation of β-ketocarboxylic acid 1a as the starting material for the subsequent decarboxylative chlorination using known chiral amine catalysts, such as cinchona alkaloid derivatives and diarylprolinol derivatives ( Fig. 2 ). However, although the desired α-chloroketone 2a was obtained in good yield, the resulting enantioselectivity was poor. We also examined the reaction with a chiral Lewis acid catalyst prepared from a spiro pyridyl monooxazoline ligand L1 and copper(II) trifluoromethanesulfonate because it is known to catalyse electrophilic halogenation of β-ketoesters with high enantioselectivity 22 , 23 , 24 . However, the decarboxylative chlorination of 1a using this catalyst also proceeded with poor enantioselectivity. Recently, we have reported the synthesis of a 1,1′-binaphthyl-based chiral amino ester C1 and successfully applied it for enantioselective fluorination of α-branched<|im_end|> <|im_start|>assistant Toyohashi University of Technology researchers led by Associate Professor Shibatomi developed new catalytic reaction to produce chlorine-containing organic molecules in isomerically pure (left- or right-handed) form Molecules don't have hands, but some of them are left- or right-handed. Many chemical compounds display a feature called chirality, where two versions—known as enantiomers—exist for the same molecule. Although their atoms are connected in exactly the same sequence, the two enantiomers are distinct mirror images, like a pair of hands. Enantiomers can have very different properties. For example, only the right-handed form of glucose gives you energy—the left-handed isomer cannot be metabolized, even though it tastes the same. Many pharmaceuticals are also chiral, and often only one enantiomer has a medicinal use. Therefore, chemists working on complex molecules have developed a variety of tricks to guarantee isomer purity. However, for some reactions this remains a challenge. Now, the research team has developed a reaction to produce an important class of compounds in pure left- or right-handed form. Organohalides are molecules in which a halogen, such as chlorine, is bonded to carbon. Many are found in nature, or used in medicine. They can be produced from another family of compounds, carboxylic acids, by simply replacing an acid with a halogen. Unfortunately, if the target compound is chiral, this substitution produces left- and right-handed isomers in equal amounts. The Toyohashi University of Technology research team solved this problem by catalyzing the reaction with a catalyst that is itself chiral. Nowadays, catalysts come in a wide range of shapes and sizes—often rivalling the complexity of the actual target molecule. "We screened a diverse array of chiral catalysts, such as Lewis acid, Brønsted acid, and Lewis base catalysts," study lead author Kazutaka Shibatomi says. "Finally, we found an amine that gave us organohalides with up to 98% enantiomeric purity - even though our starting material was a 50/50 mixture." The chlorinated products, known as chloroketones, are building blocks for more important chiral molecules like pharmaceuticals. Because chlorine is only weakly bonded to carbon, it can be easily substituted by another atom to make a new molecule. Using one of the many compounds produced in enantiomeric purity by their new reaction, the research team synthesized Cathinone, a natural stimulant. "The substitution proceeds in a simple, classic way," Associate Prof. Shibatomi says. "While chlorine leaves the molecule on one side, the incoming group approaches from the opposite side. The product's chirality just depends on the arrangement of these atoms, so if you begin with a pure enantiomer, you retain that purity. This could open up a whole class of compounds that were previously a major challenge to produce as pure enantiomers." <|im_end|>

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2,337

[ { "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 Interacting proteins tend to have similar functions, influencing the same organismal traits. Interaction networks can be used to expand the list of candidate trait-associated genes from genome-wide association studies. Here, we performed network-based expansion of trait-associated genes for 1,002 human traits showing that this recovers known disease genes or drug targets. The similarity of network expansion scores identifies groups of traits likely to share an underlying genetic and biological process. We identified 73 pleiotropic gene modules linked to multiple traits, enriched in genes involved in processes such as protein ubiquitination and RNA processing. In contrast to gene deletion studies, pleiotropy as defined here captures specifically multicellular-related processes. We show examples of modules linked to human diseases enriched in genes with known pathogenic variants that can be used to map targets of approved drugs for repurposing. Finally, we illustrate the use of network expansion scores to study genes at inflammatory bowel disease genome-wide association study loci, and implicate inflammatory bowel disease-relevant genes with strong functional and genetic support. Main Proteins that interact tend to take part in the same cellular functions and be important for the same organismal traits 1 , 2 . Through a principle of guilt-by-association, it has been shown that molecular networks can be used to predict the function or disease relevance of human genes 3 , 4 , 5 . On the basis of this, protein interaction networks can augment genome-wide association studies (GWAS) by using GWAS-linked genes as seeds in a network to identify additional trait-associated genes 6 , 7 , 8 , 9 . It is well known that GWAS loci are enriched in genes encoding for approved drug targets 10 , 11 and genes linked to a trait by network expansion are similarly enriched, even when excluding genes with direct genetic support 12 . This is an opportune time to revisit the application of network approaches to GWAS interpretation on the basis of recent large improvements in the human molecular networks available, single-nucleotide polymorphism (SNP) approaches to gene mapping and the extent of human traits/diseases mapped by GWAS. In particular, there have been substantial improvements in the identification of likely causal genes within GWAS loci using expression and protein quantitative trait loci analysis 13 , 14 , as well as integrative approaches based on machine learning 11 . The genetic study of large numbers of diverse human traits also opens the door to the study of pleiotropy, which occurs when a single genetic change affects multiple traits. Studying pleiotropy can help in the drug discovery process by either increasing the number of potential indications for a drug or avoiding unwanted side effects. Large-scale investigations of the most pleiotropic cellular processes have relied primarily on gene deletion studies. For example, yeast gene deletion studies have revealed pleiotropic cellular processes that include endocytosis, stress response and protein folding, amino acid biosynthesis and global transcriptional regulation 15 . Identification of these highly pleiotropic cellular systems highlights core conserved processes and the complex interconnections within cell biology. Human GWAS data have been extensively used to quantify pleiotropy at the SNP level 16 , 17 , 18 and although this has shed light on the degree of pleiotropy and the relationship between traits, it has not often led to identification of the molecular mechanisms that underlie their common genetic basis. Here, we augmented GWAS data for 1,002 traits by network expansion with the purpose of studying pleiotropic cellular processes at the level of the human organism. This network expansion recovers known disease genes not associated by GWAS, identifies groups of traits under the influence of the same cellular processes and defines a pleiotropy map of human cell biology. Finally, we illustrate the use of network expansion scores to characterize inflammatory bowel disease (IBD) genes at GWAS loci, and implicate IBD-relevant genes with strong functional and genetic support. Results Systematic augmentation of GWAS with network propagation Recent studies have shown that a comprehensive protein interaction network is critical for network propagation efforts 9 . Here, we combined the International Molecular Exchange physical protein interaction dataset 19 from IntAct (protein–protein interactions) 20 , Reactome (pathways) 21 and SIGNOR (directed signaling pathways) 22 . To facilitate re-use of these data (referred to as ‘OTAR interactome’) we have made the data available via a Neo4j Graph Database ( ftp://ftp.ebi.ac.uk/pub/databases/intact/various/ot_graphdb/current ). The physical interactions were combined with functional associations from the STRING database (v.11) 23 to give a final network containing 571,917 edges connecting 18,410 proteins (nodes) (Fig. 1a ). GWAS trait associations were mapped to genes using the locus-to-gene (L2G) score from Open Targets Genetics, a machine learning approach that integrates features such as SNP fine-mapping, gene distance and molecular quantitative trait locus (QTL) information to identify causal genes (Fig. 1b ) 11 . Genes with L2G scores higher than 0.5 are expected to be causal for the respective trait association in 50% of cases. Fig. 1: Implementation and benchmarking of network-based augmentation of GWAS. a , Edge and node counts of the combined interactome and its components. OTAR is the Open Targets combined physical protein interaction network that is provided via a Neo4j Graph Database. b , Graphic representation of some L2G components: SNP-to-gene distance, data from QTLs and variant effect predictions. The integration of information into the L2G score has been described previously 11 . c , Graphical representation of the network-based approach: network propagation of the initial input, clustering using a random walker to find gene communities and scoring of modules using the distribution of PageRank score. KS, Kolmogorov–Smirnov. d , Number of starting genes linked to traits, grouped in therapeutic areas. In the violin plot, the red dots represent the median, the limits of the thick line correspond to quartiles 1 and 3 (25% and 75% of the distribution) and the limits of the thin line are 1.5× the interquartile range. e , Benchmarking of the method, using as a starting signal genes from the Open Targets Genetics portal with a L2G score >0.5. AUC values are calculated", "role": "user" }, { "content": "Scientists at Open Targets, EMBL's European Bioinformatics Institute (EMBL-EBI), and GSK are revealing the shared basis of diseases using a map of interacting human proteins. By helping to understand how biological processes affect human traits and diseases, this work will prioritize new targets for drug discovery and identify drug repurposing opportunities. Proteins are molecules that do most of the work in our cells and are made following blueprints encoded in genes. They are essential for the structure, function, and regulation of the body's tissues, and are often the target of drugs or therapies. Genome Wide Association Studies (GWAS) help us establish the genetic basis of disease by linking specific genes to diseases. To determine how those genes contribute to disease, we need to understand the function of the proteins they encode and link specific biological processes to diseases. In this new study, published in the journal Nature Genetics, researchers created a network of interacting proteins—or an interactome—combining evidence from different sources, including EMBL-EBI's IntAct database, Reactome, and Signor. Using this interactome, they identified groups of proteins interacting with genes that have been linked through GWAS to over 1,000 human traits from 21 therapeutic areas. Guilt-by-association Proteins that interact with each other will likely be involved in the same biological processes. Therefore, if a protein is known to be involved in a disease, knowing which partners it interacts with provides information about the function it has in a cell. Through \"guilt-by-association,\" the interacting proteins can also sometimes be excellent therapeutic targets. The researchers found 73 clusters of proteins that were linked to more than one trait or disease, a phenomenon known as pleiotropy. Understanding these pleiotropic relationships is invaluable to drug discovery because they indicate opportunities where a therapy for one disease might be effective in another. They can also suggest drug targets to avoid, when targeting them may cause unwanted side effects. \"The interactome identified some known associations, such as cardiovascular diseases and lipoprotein or cholesterol measurements,\" said Inigo Barrio Hernandez, postdoctoral fellow at Open Targets and EMBL-EBI. \"But we also found some unexpected associations. For example, the interactome highlighted three protein clusters shared by ten respiratory and skin immune-related diseases. This is hugely exciting because we now have some biological support to repurpose existing drugs that are proven to be safe to treat related diseases.\" Finding the cause of diseases The network expansion is also a useful tool to assess the relative importance of genes at genomic loci identified through GWAS. GWAS compare points of common variation in the human genome between individuals with a specific trait or disease and control individuals. To identify the likely causative genes and proteins linked to the trait in question, prediction methods such as Open Targets's Locus-to-Gene machine learning score have been developed. This method uses factors such as the distance from the point of common variation to the gene and the structure of the DNA in that location to prioritize the most relevant genes. In the present study, the researchers showed that the interactome could be used to find the proteins most likely to be involved in causing disease, using Inflammatory Bowel Disease (IBD) as an example. IBD is a complex disease with a genetic basis, but for which the disease biology is not well understood. In collaboration with Open Targets researchers who specialize in IBD, Barrio Hernandez demonstrated that the interactome could be used to prioritize a list of proteins most likely involved in the disease, based on their proximity to other IBD-linked proteins in the interactome. \"This work bridges many fields of biology, including statistical genetics, cell biology, and bioinformatics,\" said Pedro Beltrao, Associate Professor at ETH Zurich and former Group Leader at EMBL-EBI. \"It brought together groups from across Open Targets and EMBL-EBI, and highlights the value of collaborations across disciplines.\" \"This is an exciting showcase of one of our Open Targets collaborative informatics projects that has generated an array of new insights for novel target discovery as well as drug repurposing, and informs our understanding of the connection between rare and common diseases through shared biological processes,\" said Ellen McDonagh, Director of Informatics Science at Open Targets. \"This is now being developed further to provide tissue and cell-type specific networks to help further prioritize targets for disease 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 Interacting proteins tend to have similar functions, influencing the same organismal traits. Interaction networks can be used to expand the list of candidate trait-associated genes from genome-wide association studies. Here, we performed network-based expansion of trait-associated genes for 1,002 human traits showing that this recovers known disease genes or drug targets. The similarity of network expansion scores identifies groups of traits likely to share an underlying genetic and biological process. We identified 73 pleiotropic gene modules linked to multiple traits, enriched in genes involved in processes such as protein ubiquitination and RNA processing. In contrast to gene deletion studies, pleiotropy as defined here captures specifically multicellular-related processes. We show examples of modules linked to human diseases enriched in genes with known pathogenic variants that can be used to map targets of approved drugs for repurposing. Finally, we illustrate the use of network expansion scores to study genes at inflammatory bowel disease genome-wide association study loci, and implicate inflammatory bowel disease-relevant genes with strong functional and genetic support. Main Proteins that interact tend to take part in the same cellular functions and be important for the same organismal traits 1 , 2 . Through a principle of guilt-by-association, it has been shown that molecular networks can be used to predict the function or disease relevance of human genes 3 , 4 , 5 . On the basis of this, protein interaction networks can augment genome-wide association studies (GWAS) by using GWAS-linked genes as seeds in a network to identify additional trait-associated genes 6 , 7 , 8 , 9 . It is well known that GWAS loci are enriched in genes encoding for approved drug targets 10 , 11 and genes linked to a trait by network expansion are similarly enriched, even when excluding genes with direct genetic support 12 . This is an opportune time to revisit the application of network approaches to GWAS interpretation on the basis of recent large improvements in the human molecular networks available, single-nucleotide polymorphism (SNP) approaches to gene mapping and the extent of human traits/diseases mapped by GWAS. In particular, there have been substantial improvements in the identification of likely causal genes within GWAS loci using expression and protein quantitative trait loci analysis 13 , 14 , as well as integrative approaches based on machine learning 11 . The genetic study of large numbers of diverse human traits also opens the door to the study of pleiotropy, which occurs when a single genetic change affects multiple traits. Studying pleiotropy can help in the drug discovery process by either increasing the number of potential indications for a drug or avoiding unwanted side effects. Large-scale investigations of the most pleiotropic cellular processes have relied primarily on gene deletion studies. For example, yeast gene deletion studies have revealed pleiotropic cellular processes that include endocytosis, stress response and protein folding, amino acid biosynthesis and global transcriptional regulation 15 . Identification of these highly pleiotropic cellular systems highlights core conserved processes and the complex interconnections within cell biology. Human GWAS data have been extensively used to quantify pleiotropy at the SNP level 16 , 17 , 18 and although this has shed light on the degree of pleiotropy and the relationship between traits, it has not often led to identification of the molecular mechanisms that underlie their common genetic basis. Here, we augmented GWAS data for 1,002 traits by network expansion with the purpose of studying pleiotropic cellular processes at the level of the human organism. This network expansion recovers known disease genes not associated by GWAS, identifies groups of traits under the influence of the same cellular processes and defines a pleiotropy map of human cell biology. Finally, we illustrate the use of network expansion scores to characterize inflammatory bowel disease (IBD) genes at GWAS loci, and implicate IBD-relevant genes with strong functional and genetic support. Results Systematic augmentation of GWAS with network propagation Recent studies have shown that a comprehensive protein interaction network is critical for network propagation efforts 9 . Here, we combined the International Molecular Exchange physical protein interaction dataset 19 from IntAct (protein–protein interactions) 20 , Reactome (pathways) 21 and SIGNOR (directed signaling pathways) 22 . To facilitate re-use of these data (referred to as ‘OTAR interactome’) we have made the data available via a Neo4j Graph Database ( ftp://ftp.ebi.ac.uk/pub/databases/intact/various/ot_graphdb/current ). The physical interactions were combined with functional associations from the STRING database (v.11) 23 to give a final network containing 571,917 edges connecting 18,410 proteins (nodes) (Fig. 1a ). GWAS trait associations were mapped to genes using the locus-to-gene (L2G) score from Open Targets Genetics, a machine learning approach that integrates features such as SNP fine-mapping, gene distance and molecular quantitative trait locus (QTL) information to identify causal genes (Fig. 1b ) 11 . Genes with L2G scores higher than 0.5 are expected to be causal for the respective trait association in 50% of cases. Fig. 1: Implementation and benchmarking of network-based augmentation of GWAS. a , Edge and node counts of the combined interactome and its components. OTAR is the Open Targets combined physical protein interaction network that is provided via a Neo4j Graph Database. b , Graphic representation of some L2G components: SNP-to-gene distance, data from QTLs and variant effect predictions. The integration of information into the L2G score has been described previously 11 . c , Graphical representation of the network-based approach: network propagation of the initial input, clustering using a random walker to find gene communities and scoring of modules using the distribution of PageRank score. KS, Kolmogorov–Smirnov. d , Number of starting genes linked to traits, grouped in therapeutic areas. In the violin plot, the red dots represent the median, the limits of the thick line correspond to quartiles 1 and 3 (25% and 75% of the distribution) and the limits of the thin line are 1.5× the interquartile range. e , Benchmarking of the method, using as a starting signal genes from the Open Targets Genetics portal with a L2G score >0.5. AUC values are calculated<|im_end|> <|im_start|>assistant Scientists at Open Targets, EMBL's European Bioinformatics Institute (EMBL-EBI), and GSK are revealing the shared basis of diseases using a map of interacting human proteins. By helping to understand how biological processes affect human traits and diseases, this work will prioritize new targets for drug discovery and identify drug repurposing opportunities. Proteins are molecules that do most of the work in our cells and are made following blueprints encoded in genes. They are essential for the structure, function, and regulation of the body's tissues, and are often the target of drugs or therapies. Genome Wide Association Studies (GWAS) help us establish the genetic basis of disease by linking specific genes to diseases. To determine how those genes contribute to disease, we need to understand the function of the proteins they encode and link specific biological processes to diseases. In this new study, published in the journal Nature Genetics, researchers created a network of interacting proteins—or an interactome—combining evidence from different sources, including EMBL-EBI's IntAct database, Reactome, and Signor. Using this interactome, they identified groups of proteins interacting with genes that have been linked through GWAS to over 1,000 human traits from 21 therapeutic areas. Guilt-by-association Proteins that interact with each other will likely be involved in the same biological processes. Therefore, if a protein is known to be involved in a disease, knowing which partners it interacts with provides information about the function it has in a cell. Through "guilt-by-association," the interacting proteins can also sometimes be excellent therapeutic targets. The researchers found 73 clusters of proteins that were linked to more than one trait or disease, a phenomenon known as pleiotropy. Understanding these pleiotropic relationships is invaluable to drug discovery because they indicate opportunities where a therapy for one disease might be effective in another. They can also suggest drug targets to avoid, when targeting them may cause unwanted side effects. "The interactome identified some known associations, such as cardiovascular diseases and lipoprotein or cholesterol measurements," said Inigo Barrio Hernandez, postdoctoral fellow at Open Targets and EMBL-EBI. "But we also found some unexpected associations. For example, the interactome highlighted three protein clusters shared by ten respiratory and skin immune-related diseases. This is hugely exciting because we now have some biological support to repurpose existing drugs that are proven to be safe to treat related diseases." Finding the cause of diseases The network expansion is also a useful tool to assess the relative importance of genes at genomic loci identified through GWAS. GWAS compare points of common variation in the human genome between individuals with a specific trait or disease and control individuals. To identify the likely causative genes and proteins linked to the trait in question, prediction methods such as Open Targets's Locus-to-Gene machine learning score have been developed. This method uses factors such as the distance from the point of common variation to the gene and the structure of the DNA in that location to prioritize the most relevant genes. In the present study, the researchers showed that the interactome could be used to find the proteins most likely to be involved in causing disease, using Inflammatory Bowel Disease (IBD) as an example. IBD is a complex disease with a genetic basis, but for which the disease biology is not well understood. In collaboration with Open Targets researchers who specialize in IBD, Barrio Hernandez demonstrated that the interactome could be used to prioritize a list of proteins most likely involved in the disease, based on their proximity to other IBD-linked proteins in the interactome. "This work bridges many fields of biology, including statistical genetics, cell biology, and bioinformatics," said Pedro Beltrao, Associate Professor at ETH Zurich and former Group Leader at EMBL-EBI. "It brought together groups from across Open Targets and EMBL-EBI, and highlights the value of collaborations across disciplines." "This is an exciting showcase of one of our Open Targets collaborative informatics projects that has generated an array of new insights for novel target discovery as well as drug repurposing, and informs our understanding of the connection between rare and common diseases through shared biological processes," said Ellen McDonagh, Director of Informatics Science at Open Targets. "This is now being developed further to provide tissue and cell-type specific networks to help further prioritize targets for disease treatment." <|im_end|>

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323, 8051, 420, 706, 25351, 3177, 389, 279, 8547, 315, 7245, 11345, 18237, 323, 279, 5133, 1990, 25022, 11, 433, 706, 539, 3629, 6197, 311, 22654, 315, 279, 31206, 24717, 430, 1234, 11828, 872, 4279, 19465, 8197, 13, 5810, 11, 584, 57088, 42353, 1950, 828, 369, 220, 16, 11, 6726, 25022, 555, 4009, 14800, 449, 279, 7580, 315, 21630, 7245, 11345, 45036, 35693, 11618, 520, 279, 2237, 315, 279, 3823, 47120, 13, 1115, 4009, 14800, 1421, 9146, 3967, 8624, 21389, 539, 5938, 555, 42353, 1950, 11, 36611, 5315, 315, 25022, 1234, 279, 10383, 315, 279, 1890, 35693, 11618, 323, 19170, 264, 7245, 11345, 18237, 2472, 315, 3823, 2849, 34458, 13, 17830, 11, 584, 41468, 279, 1005, 315, 4009, 14800, 12483, 311, 70755, 47288, 66358, 8624, 320, 3336, 35, 8, 21389, 520, 42353, 1950, 1353, 72, 11, 323, 3242, 49895, 358, 9740, 5621, 8532, 21389, 449, 3831, 16003, 323, 19465, 1862, 13, 18591, 744, 780, 79885, 315, 42353, 1950, 449, 4009, 54743, 35390, 7978, 617, 6982, 430, 264, 16195, 13128, 16628, 4009, 374, 9200, 369, 4009, 54743, 9045, 220, 24, 662, 5810, 11, 584, 11093, 279, 7327, 60825, 19224, 7106, 13128, 16628, 10550, 220, 777, 505, 1357, 2471, 320, 79565, 4235, 79565, 22639, 8, 220, 508, 1174, 3676, 638, 320, 2398, 2336, 8, 220, 1691, 323, 44272, 878, 320, 20384, 291, 43080, 44014, 8, 220, 1313, 662, 2057, 28696, 312, 25700, 315, 1521, 828, 320, 265, 5671, 311, 439, 3451, 1831, 946, 16681, 638, 96206, 584, 617, 1903, 279, 828, 2561, 4669, 264, 41744, 19, 73, 12441, 10199, 320, 46527, 1129, 26124, 1770, 8385, 15761, 15549, 60592, 3529, 24760, 32214, 533, 93246, 1245, 14, 354, 15080, 2042, 75153, 7609, 578, 7106, 22639, 1051, 11093, 449, 16003, 30257, 505, 279, 36355, 4729, 320, 85, 13, 806, 8, 220, 1419, 311, 3041, 264, 1620, 4009, 8649, 220, 22005, 11, 24391, 13116, 21583, 220, 972, 11, 14487, 28896, 320, 20606, 8, 320, 30035, 13, 220, 16, 64, 7609, 42353, 1950, 18027, 30257, 1051, 24784, 311, 21389, 1701, 279, 79257, 4791, 2427, 1994, 320, 43, 17, 38, 8, 5573, 505, 5377, 86047, 84386, 11, 264, 5780, 6975, 5603, 430, 75762, 4519, 1778, 439, 60418, 7060, 1474, 3713, 11, 15207, 6138, 323, 31206, 47616, 18027, 79257, 320, 48, 13778, 8, 2038, 311, 10765, 59557, 21389, 320, 30035, 13, 220, 16, 65, 883, 220, 806, 662, 9500, 288, 449, 445, 17, 38, 12483, 5190, 1109, 220, 15, 13, 20, 527, 3685, 311, 387, 59557, 369, 279, 20081, 18027, 15360, 304, 220, 1135, 4, 315, 5157, 13, 23966, 13, 220, 16, 25, 31913, 323, 29531, 287, 315, 4009, 6108, 79885, 315, 42353, 1950, 13, 264, 1174, 10564, 323, 2494, 14921, 315, 279, 11093, 16681, 638, 323, 1202, 6956, 13, 8775, 946, 374, 279, 5377, 86047, 11093, 7106, 13128, 16628, 4009, 430, 374, 3984, 4669, 264, 41744, 19, 73, 12441, 10199, 13, 293, 1174, 45051, 13340, 315, 1063, 445, 17, 38, 6956, 25, 60418, 4791, 2427, 1994, 6138, 11, 828, 505, 1229, 13778, 82, 323, 11678, 2515, 20492, 13, 578, 18052, 315, 2038, 1139, 279, 445, 17, 38, 5573, 706, 1027, 7633, 8767, 220, 806, 662, 272, 1174, 12441, 950, 13340, 315, 279, 4009, 6108, 5603, 25, 4009, 54743, 315, 279, 2926, 1988, 11, 59454, 1701, 264, 4288, 63624, 311, 1505, 15207, 10977, 323, 20413, 315, 13761, 1701, 279, 8141, 315, 5874, 23366, 5573, 13, 47474, 11, 46615, 76, 540, 269, 869, 4235, 10902, 404, 39142, 13, 294, 1174, 5742, 315, 6041, 21389, 10815, 311, 25022, 11, 41141, 304, 37471, 5789, 13, 763, 279, 63137, 7234, 11, 279, 2579, 32094, 4097, 279, 23369, 11, 279, 13693, 315, 279, 12314, 1584, 8024, 311, 41376, 3742, 220, 16, 323, 220, 18, 320, 914, 4, 323, 220, 2075, 4, 315, 279, 8141, 8, 323, 279, 13693, 315, 279, 15792, 1584, 527, 220, 16, 13, 20, 18028, 279, 958, 447, 472, 458, 2134, 13, 384, 1174, 62722, 287, 315, 279, 1749, 11, 1701, 439, 264, 6041, 8450, 21389, 505, 279, 5377, 86047, 84386, 24007, 449, 264, 445, 17, 38, 5573, 871, 15, 13, 20, 13, 362, 5576, 2819, 527, 16997, 128257, 198, 128256, 78191, 198, 72326, 520, 5377, 86047, 11, 469, 8578, 43, 596, 7665, 24432, 98588, 10181, 320, 2783, 9574, 12, 8428, 40, 705, 323, 480, 16074, 527, 31720, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Spatial and molecular characteristics determine tissue function, yet high-resolution methods to capture both concurrently are lacking. Here, we developed high-definition spatial transcriptomics, which captures RNA from histological tissue sections on a dense, spatially barcoded bead array. Each experiment recovers several hundred thousand transcript-coupled spatial barcodes at 2-μm resolution, as demonstrated in mouse brain and primary breast cancer. This opens the way to high-resolution spatial analysis of cells and tissues. Main Charting cells’ spatial organization and molecular features is essential to understand how they interact in both normal and diseased tissues 1 , 2 . Massively parallel single-cell RNA sequencing (scRNA-Seq) 3 , 4 can profile hundreds of thousands of dissociated individual cells, but does not retain their spatial position, and can introduce biases in cell recovery 5 . Conversely, spatial profiling captures detailed positional information in intact tissue, but current methods require pre-selected markers, rely on nonstandard instrumentation 6 , 7 , 8 , 9 , 10 , 11 or have limited spatial resolution, scalability or applicability. In particular, spatial transcriptomics 12 (ST) is a spatially barcoded RNA-Seq method providing transcriptome-wide coverage in many systems, but at a resolution of 100 μm (3–30 cells). To bridge this gap, we developed high-definition spatial transcriptomics (HDST, Fig. 1a ) and demonstrate its application to large tissue areas in the mouse brain and human tumors in situ. In HDST, we deposit barcoded poly(d)T oligonucleotides into 2-μm wells with a randomly ordered bead array-based fabrication process 13 and decode their positions by a sequential hybridization and error-correcting strategy 13 , 14 . After a frozen tissue section is placed on the decoded slide, stained and imaged, RNA is captured and then profiled by RNA-Seq. Fig. 1: HDST. a , HDST workflow. b , Labeling of morphological layers. HDST H&E image of a MOB and matching HDST ( x , y ) barcodes annotated into nine morphological areas. c , Layer-specific DE patterns in HDST. Shown is the summed normalized expression of positively enriched signature genes significantly (FDR < 0.1, two-sided t -test) associated with each layer as annotated in b . d , e , Nuclei segmentation and binning of HDST as in b . d , Segmented nuclei (sn-like) and lightly binned (sc-like) spatial barcodes assigned (black) to each of two cell types as in b . e , Enrichment of sn- and sc-like spatial barcodes with assigned cell types (columns) to morphological layers (rows) as in b . Color bar represents −log 10 ( P value) (one-sided Fisher’s exact test, Bonferroni adjusted, P < 0.01) and gray tiles are nonsignificant values. OBNBL1, olfactory neuroblasts; OBINH1-3, inhibitory neurons; EPMB and EPEN, astroependymal cells; OEC, olfactory ensheathing cells; VLMC2, vascular cells; SATG2, satellite glia; OBNBL5, GABAergic neuroblasts; OBDOP1, dopaminergic periglomerular neuroblasts; OBNLB2, VGLUT1/2 neuroblasts; SEZ, subependymal zone; ONL, olfactory nerve layer; M/T, mitral layer; IPL, internal plexiform layer; GCL-E, GCL-I and GCL-D, granular layers; GL, glomerular layer; EPL, external plexiform layer. Full size image To produce a high-resolution, high-density bead array, we generated 2,893,865 individual barcoded beads with a split-and-pool approach (Supplementary Fig. 1a ), randomly placed them into a hexagonal array of >1.4 million 2 μm wells and then decoded each bead’s location (Fig. 1a ) 13 , 14 with several hybridization rounds. Each round hybridizes a set of complementary and labeled decoder oligonucleotides (decoders) ( Methods ), records fluorescence across the entire slide area and then strips the decoders. The process is repeated log 3 N times (14 times for the array presented here), where N is the number of sequences to be decoded with three labels used (Supplementary Fig. 1b ). In this way, each bead and barcode receives a unique spatial color address 14 creating a HDST array in ~3 h total processing time. To test HDST, we first profiled the main olfactory bulb (MOB) of the mouse brain, whose neurons have traditionally been defined by the presence of neuronal cell bodies across morphological layers 15 . We assessed whether HDST molecular data can be related to layers and other histological features. We analyzed three replicate sections by HDST and tested its performance in two key tasks: (1) generating high-resolution spatial expression patterns of individual genes, and (2) detecting cell types and assigning them to correct, high-resolution positions. We confirmed that RNA capture was specific and in overall agreement with bulk RNA-Seq controls, despite the relatively low number of transcripts captured per spatial barcode. We first accounted for barcode redundancy (‘clashing’), decoding efficiency and stringent barcode demultiplexing (Supplementary Fig. 2a and Supplementary Table 1 ). Next, we observed that at saturating sequencing depth (Supplementary Fig. 2b ), 85.6 ± 3.3% of all genes detected were located within the area physically covered by the tissue specimen (without using any lower cutoffs), with almost 160,000 barcodes generating spatially mapped transcripts per assay ( n = 3 sections, Supplementary Fig. 2c ). Although there were few unique molecular identifiers (UMIs) per barcode location (7.1 ± 6.0 (mean ± s.d.), n = 3 sections), a very distinct spatial in situ profile followed the tissue boundary (Supplementary Fig. 2d,e ), suggesting detection specificity. Moreover, a combined ‘bulk’ expression profile of each HDST dataset correlated significantly with published MOB bulk RNA-Seq (Supplementary Fig. 3a ; Spearman’s ρ = 0.69 ± 0.02; mean ± s.d.) and across the three replicate experiments (Spearman’s ρ = 0.82 ± 0.06; mean ± s.d.). Most detected genes agreed between the bulk and HDST datasets (Supplementary Fig. 3b ). Finally, comparing the HDST capture per bead to that observed from smFISH for three genes ( Penk , Slc17a7 and Fabp7 ), we estimated HDST capture efficiency at 1.3% per bead ( Methods and Supplementary Table 2 ). Next, supervised analysis of HDST data correctly identified layer-specific expression signatures. We first annotated morphological layers ( Methods ) from the hematoxylin and eosin (H&E) stain of each specimen (Fig. 1b ). We reasoned that 24 neighboring wells ( r = ~6.5 μm) will likely capture transcripts from the same cell. We thus enhanced", "role": "user" }, { "content": "Researchers in Sweden and the U.S. have devised a new method for studying individual cells in human tissue, which could lead to even earlier detection of diseases such as cancer and ALS. The method offers a 1,400-fold increase in spatial resolution. Published in the scientific journal, Nature Methods, the study was performed by researchers from KTH Royal Institute of Technology and the Broad Institute of MIT and Harvard. The technology builds on transcriptomics, or the mapping of the cell's molecular fingerprints. RNA-sequencing provides a tool for studying different functions within tissues but the molecular profile only reveals so much. The cell's position in the tissue also has several stories to tell, including how different diseases occur. Methods for studying active genes in individual cells from tissue have evolved dramatically. At the forefront of this research are various microfluidic systems where researchers have been able to isolate individual cells and then carry out so-called massive parallel RNA-sequencing. This method has enabled the profiling of hundreds of thousands of cells from tissue, but provides no information about the cell's origin in the tissue. At the same time, other spatial and molecular methods that capture detailed information about the position of cells in frozen or solid tissue have been developed. Yet such methods still demand knowledge of which genes—or biomarkers—researchers want to investigate, which in turn requires relatively large and expensive instruments. In addition, it is usually only possible to study hundreds of genes at one time, out of thousands of active ones. \"To solve this, a couple of years ago we developed what is called 'spatial transcriptomics,' which gives a spatial image of all genes, the entire transcriptome, in a tissue,\" says Joakim Lundeberg, professor of genetic engineering at KTH. This in turn has led to the possibility of developing artificial intelligence for analysis of the constituents of a sample. \"The limitation up to now has been that the researchers were only able to study a group of cells and not the individual cell,\" Lundeberg says. The new research effort addressed that challenge, says co-author Sanja Vickovic, a Wallenberg Fellow at the Broad Institute and a KTH Ph.D. graduate. \"In the new study we show that we can study parts of a cell, that is, we have increased the resolution 1,400 times, which allows us to more accurately describe individual cells in a tissue,\" Vickovic says. \"We show this both with samples from brain tissue and breast cancer.\" The researchers call the new method 'high-definition spatial transcriptomics' (HDST), and it opens up entirely new opportunities to create a better understanding of the cell in its natural environment. This can be very important for studies of cancer tumors. One example is cancer where a gene mutation in a single cell sets off the development of a tumor. Diagnostics in use today are based on observing the tissue in a microscope and looking for tumor cells. The fewer cells there are, the harder they are to find. \"This is a process that takes time and is subjective. You can simply miss this important tumor cell,\" Vickovic says. With the HDST method, computers look for cells' gene activity in the data, since each cell has its own gene activity signature without any subjective interpretation, Lundeberg says. \"Before we would look for a tumor cell gene signature in a group of about 20 cells. Now we have improved the technology so we find a single tumor cell, even parts of a tumor cell,\" he says. HDST could become key in treating patients because it enables labs to spot early changes within a single cell, where many diseases originate. \"In later stages of a disease, changes that occur early and are driving the disease are hidden by everything else that is going on,\" he says. The research team underscored that point with a study of ALS which was published last spring. \"We could show very early spatial and molecular changes before illness occurred.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Spatial and molecular characteristics determine tissue function, yet high-resolution methods to capture both concurrently are lacking. Here, we developed high-definition spatial transcriptomics, which captures RNA from histological tissue sections on a dense, spatially barcoded bead array. Each experiment recovers several hundred thousand transcript-coupled spatial barcodes at 2-μm resolution, as demonstrated in mouse brain and primary breast cancer. This opens the way to high-resolution spatial analysis of cells and tissues. Main Charting cells’ spatial organization and molecular features is essential to understand how they interact in both normal and diseased tissues 1 , 2 . Massively parallel single-cell RNA sequencing (scRNA-Seq) 3 , 4 can profile hundreds of thousands of dissociated individual cells, but does not retain their spatial position, and can introduce biases in cell recovery 5 . Conversely, spatial profiling captures detailed positional information in intact tissue, but current methods require pre-selected markers, rely on nonstandard instrumentation 6 , 7 , 8 , 9 , 10 , 11 or have limited spatial resolution, scalability or applicability. In particular, spatial transcriptomics 12 (ST) is a spatially barcoded RNA-Seq method providing transcriptome-wide coverage in many systems, but at a resolution of 100 μm (3–30 cells). To bridge this gap, we developed high-definition spatial transcriptomics (HDST, Fig. 1a ) and demonstrate its application to large tissue areas in the mouse brain and human tumors in situ. In HDST, we deposit barcoded poly(d)T oligonucleotides into 2-μm wells with a randomly ordered bead array-based fabrication process 13 and decode their positions by a sequential hybridization and error-correcting strategy 13 , 14 . After a frozen tissue section is placed on the decoded slide, stained and imaged, RNA is captured and then profiled by RNA-Seq. Fig. 1: HDST. a , HDST workflow. b , Labeling of morphological layers. HDST H&E image of a MOB and matching HDST ( x , y ) barcodes annotated into nine morphological areas. c , Layer-specific DE patterns in HDST. Shown is the summed normalized expression of positively enriched signature genes significantly (FDR < 0.1, two-sided t -test) associated with each layer as annotated in b . d , e , Nuclei segmentation and binning of HDST as in b . d , Segmented nuclei (sn-like) and lightly binned (sc-like) spatial barcodes assigned (black) to each of two cell types as in b . e , Enrichment of sn- and sc-like spatial barcodes with assigned cell types (columns) to morphological layers (rows) as in b . Color bar represents −log 10 ( P value) (one-sided Fisher’s exact test, Bonferroni adjusted, P < 0.01) and gray tiles are nonsignificant values. OBNBL1, olfactory neuroblasts; OBINH1-3, inhibitory neurons; EPMB and EPEN, astroependymal cells; OEC, olfactory ensheathing cells; VLMC2, vascular cells; SATG2, satellite glia; OBNBL5, GABAergic neuroblasts; OBDOP1, dopaminergic periglomerular neuroblasts; OBNLB2, VGLUT1/2 neuroblasts; SEZ, subependymal zone; ONL, olfactory nerve layer; M/T, mitral layer; IPL, internal plexiform layer; GCL-E, GCL-I and GCL-D, granular layers; GL, glomerular layer; EPL, external plexiform layer. Full size image To produce a high-resolution, high-density bead array, we generated 2,893,865 individual barcoded beads with a split-and-pool approach (Supplementary Fig. 1a ), randomly placed them into a hexagonal array of >1.4 million 2 μm wells and then decoded each bead’s location (Fig. 1a ) 13 , 14 with several hybridization rounds. Each round hybridizes a set of complementary and labeled decoder oligonucleotides (decoders) ( Methods ), records fluorescence across the entire slide area and then strips the decoders. The process is repeated log 3 N times (14 times for the array presented here), where N is the number of sequences to be decoded with three labels used (Supplementary Fig. 1b ). In this way, each bead and barcode receives a unique spatial color address 14 creating a HDST array in ~3 h total processing time. To test HDST, we first profiled the main olfactory bulb (MOB) of the mouse brain, whose neurons have traditionally been defined by the presence of neuronal cell bodies across morphological layers 15 . We assessed whether HDST molecular data can be related to layers and other histological features. We analyzed three replicate sections by HDST and tested its performance in two key tasks: (1) generating high-resolution spatial expression patterns of individual genes, and (2) detecting cell types and assigning them to correct, high-resolution positions. We confirmed that RNA capture was specific and in overall agreement with bulk RNA-Seq controls, despite the relatively low number of transcripts captured per spatial barcode. We first accounted for barcode redundancy (‘clashing’), decoding efficiency and stringent barcode demultiplexing (Supplementary Fig. 2a and Supplementary Table 1 ). Next, we observed that at saturating sequencing depth (Supplementary Fig. 2b ), 85.6 ± 3.3% of all genes detected were located within the area physically covered by the tissue specimen (without using any lower cutoffs), with almost 160,000 barcodes generating spatially mapped transcripts per assay ( n = 3 sections, Supplementary Fig. 2c ). Although there were few unique molecular identifiers (UMIs) per barcode location (7.1 ± 6.0 (mean ± s.d.), n = 3 sections), a very distinct spatial in situ profile followed the tissue boundary (Supplementary Fig. 2d,e ), suggesting detection specificity. Moreover, a combined ‘bulk’ expression profile of each HDST dataset correlated significantly with published MOB bulk RNA-Seq (Supplementary Fig. 3a ; Spearman’s ρ = 0.69 ± 0.02; mean ± s.d.) and across the three replicate experiments (Spearman’s ρ = 0.82 ± 0.06; mean ± s.d.). Most detected genes agreed between the bulk and HDST datasets (Supplementary Fig. 3b ). Finally, comparing the HDST capture per bead to that observed from smFISH for three genes ( Penk , Slc17a7 and Fabp7 ), we estimated HDST capture efficiency at 1.3% per bead ( Methods and Supplementary Table 2 ). Next, supervised analysis of HDST data correctly identified layer-specific expression signatures. We first annotated morphological layers ( Methods ) from the hematoxylin and eosin (H&E) stain of each specimen (Fig. 1b ). We reasoned that 24 neighboring wells ( r = ~6.5 μm) will likely capture transcripts from the same cell. We thus enhanced<|im_end|> <|im_start|>assistant Researchers in Sweden and the U.S. have devised a new method for studying individual cells in human tissue, which could lead to even earlier detection of diseases such as cancer and ALS. The method offers a 1,400-fold increase in spatial resolution. Published in the scientific journal, Nature Methods, the study was performed by researchers from KTH Royal Institute of Technology and the Broad Institute of MIT and Harvard. The technology builds on transcriptomics, or the mapping of the cell's molecular fingerprints. RNA-sequencing provides a tool for studying different functions within tissues but the molecular profile only reveals so much. The cell's position in the tissue also has several stories to tell, including how different diseases occur. Methods for studying active genes in individual cells from tissue have evolved dramatically. At the forefront of this research are various microfluidic systems where researchers have been able to isolate individual cells and then carry out so-called massive parallel RNA-sequencing. This method has enabled the profiling of hundreds of thousands of cells from tissue, but provides no information about the cell's origin in the tissue. At the same time, other spatial and molecular methods that capture detailed information about the position of cells in frozen or solid tissue have been developed. Yet such methods still demand knowledge of which genes—or biomarkers—researchers want to investigate, which in turn requires relatively large and expensive instruments. In addition, it is usually only possible to study hundreds of genes at one time, out of thousands of active ones. "To solve this, a couple of years ago we developed what is called 'spatial transcriptomics,' which gives a spatial image of all genes, the entire transcriptome, in a tissue," says Joakim Lundeberg, professor of genetic engineering at KTH. This in turn has led to the possibility of developing artificial intelligence for analysis of the constituents of a sample. "The limitation up to now has been that the researchers were only able to study a group of cells and not the individual cell," Lundeberg says. The new research effort addressed that challenge, says co-author Sanja Vickovic, a Wallenberg Fellow at the Broad Institute and a KTH Ph.D. graduate. "In the new study we show that we can study parts of a cell, that is, we have increased the resolution 1,400 times, which allows us to more accurately describe individual cells in a tissue," Vickovic says. "We show this both with samples from brain tissue and breast cancer." The researchers call the new method 'high-definition spatial transcriptomics' (HDST), and it opens up entirely new opportunities to create a better understanding of the cell in its natural environment. This can be very important for studies of cancer tumors. One example is cancer where a gene mutation in a single cell sets off the development of a tumor. Diagnostics in use today are based on observing the tissue in a microscope and looking for tumor cells. The fewer cells there are, the harder they are to find. "This is a process that takes time and is subjective. You can simply miss this important tumor cell," Vickovic says. With the HDST method, computers look for cells' gene activity in the data, since each cell has its own gene activity signature without any subjective interpretation, Lundeberg says. "Before we would look for a tumor cell gene signature in a group of about 20 cells. Now we have improved the technology so we find a single tumor cell, even parts of a tumor cell," he says. HDST could become key in treating patients because it enables labs to spot early changes within a single cell, where many diseases originate. "In later stages of a disease, changes that occur early and are driving the disease are hidden by everything else that is going on," he says. The research team underscored that point with a study of ALS which was published last spring. "We could show very early spatial and molecular changes before illness occurred." <|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 Electronic devices based on two-dimensional semiconductors suffer from limited electrical stability because charge carriers originating from the semiconductors interact with defects in the surrounding insulators. In field-effect transistors, the resulting trapped charges can lead to large hysteresis and device drifts, particularly when common amorphous gate oxides (such as silicon or hafnium dioxide) are used, hindering stable circuit operation. Here, we show that device stability in graphene-based field-effect transistors with amorphous gate oxides can be improved by Fermi-level tuning. We deliberately tune the Fermi level of the channel to maximize the energy distance between the charge carriers in the channel and the defect bands in the amorphous aluminium gate oxide. Charge trapping is highly sensitive to the energetic alignment of the Fermi level of the channel with the defect band in the insulator, and thus, our approach minimizes the amount of electrically active border traps without the need to reduce the total number of traps in the insulator. Main Two-dimensional (2D) semiconductors are a potential channel material for ultimately scaled field-effect transistors (FETs) 1 . In contrast to silicon, 2D semiconductors retain sizable mobilities at atomic layer thicknesses below 1 nm, a thickness that also helps to suppress short-channel effects in FETs and thus allows for physical channel lengths below 5 nm (ref. 2 ). Furthermore, the integration of 2D materials in van der Waals heterostructures provides design options for energy-efficient transistors that can overcome the limitations of thermal charge-carrier injection. In addition, 2D materials are of potential use in a broad range of applications, including photonics and optoelectronics 3 , neuromorphic computing 4 , nanoelectromechanical systems 5 , and gas and biological sensors 6 . There is, however, currently a lack of low-resistive contacts to 2D semiconductors, which minimize the prevalent Schottky barriers 7 . In addition, there is a lack of suitable gate insulators 8 that can ensure high interface quality, scalability 9 and a minimum of electrically active border traps, the presence of which in the insulator close to the channel limits device stability. These two challenges are major obstacles for the industrial applications of 2D-based nanoelectronics and, being independent from each other, need to be separately addressed. There has been recent progress regarding the formation of low-barrier contacts for 2D semiconductors using contact gating 10 or semimetallic bismuth contacts to achieve ultralow contact resistances 11 . However, the need to find a suitable insulator with a minimum number of electrically active traps remains. Stability studies of 2D FETs typically show a stability that is at least two orders of magnitude worse 12 , 13 compared with silicon-based FETs 14 , 15 . Measurements of FET stability typically evaluate the hysteresis in the transfer characteristics 16 and stability of threshold voltage under prolonged periods of applied elevated gate biases and temperatures (bias temperature instability (BTI)) 14 . Charge trapping inside the gate oxide has been identified as the root cause of BTI 15 , 17 . At elevated gate biases and temperatures, charges are transferred between the channel and gate oxide in a phonon-mediated transition 18 , with charging time constants spanning a wide range, from picoseconds to years 2 , 19 . Border traps in the gate oxide close to the channel determine the long-term stability and reliability of silicon FETs 15 , whereas in 2D-material-based FETs, they typically limit device stability on much shorter timescales 20 . In amorphous oxides, the defect trap levels vary due to the differing surroundings of every instance of atomic defects 18 . In the first approximation, the energy levels of defects follow a normal distribution around the average defect levels, forming defect bands 21 . Consequently, the overall density of border traps and the widths of the corresponding defect bands can be considerably reduced by using crystalline insulators, such as hexagonal boron nitride (hBN) or calcium fluoride 8 (CaF 2 ). However, these insulators are difficult to synthesize and have several technological challenges. For example, current state-of-the-art crystalline hBN can be grown only at temperatures above 1,200 °C (ref. 22 ) and CaF 2 requires a crystalline silicon(111) substrate for growth, allowing only back-gated configurations 23 . In addition, hBN is unsuitable for use as a scaled gate insulator because of its small dielectric constant 9 . In this Article, we show that the stability and reliability of 2D-material-based FETs with amorphous gate oxides can be improved by tuning the Fermi level ( E F ) of the 2D channel material such that it maximizes the energy distance between the charge carriers in the channel and the defect bands in the gate insulator during device operation. This can be achieved via a careful selection of the 2D material and amorphous gate oxide, as well as by doping the 2D layer to shift E F away from the defect bands in the gate insulator. Graphene FETs (GFETs) with aluminium oxide (Al 2 O 3 ) as the top-gate oxide are measured and compared, where one of the device batches uses a p-doped graphene layer. The GFET batch where E F is tuned away from the Al 2 O 3 defect band edge shows reduced hysteresis and BTI. We further verify the approach with technology computer-aided design (TCAD) simulations 24 . In addition, double-gated GFETs are fabricated, where the back gate is used to directly tune the Fermi level in the graphene monolayer via electrostatic doping. This shows that the stability observed for top-gate operation strongly depends on the location of E F . Our approach aims to design a metal–oxide–semiconductor (MOS) system with a minimal amount of electrically active border traps without the need to reduce the total number of traps in the insulator. Fermi-level tuning for increasing stability of 2D FETs Our stability-based design approach is centred on the analysis and design of the band diagram of the MOS system, including the defect bands in the insulator. Fig. 1a shows a top-gated GFET that forms an example MOS system out of aluminium (metal), Al 2 O 3 (oxide) and", "role": "user" }, { "content": "Two-dimensional (2D) semiconductors are a class of semiconducting materials with thicknesses on the atomic scale. These materials have numerous advantageous properties, including good mobilities at thicknesses below 1 nm, which make them particularly promising for the development of field effect transistors (FETs) and other electronic, photonic and optoelectronic components. Despite their advantages, when they are used to build electronic components, these materials often exhibit a limited electrical stability. The main reason for this is that the charge carriers originating from the semiconductors can interact with defects in the insulators that surround the materials inside devices, hindering the devices' stability. Researchers at TU Wien and AMO GmbH have recently demonstrated a strategy that could be used to improve the stability of FETs based on 2D materials. This strategy, introduced in a paper published in Nature Electronics, entails tuning the Fermi Level of the 2D materials, ensuring that it maximizes the energy distance between the charge carriers and defects in the gate insulator while the device is operating. \"In FETs, the resulting trapped charges can lead to large hysteresis and device drifts, particularly when common amorphous gate oxides (such as silicon or hafnium dioxide) are used, hindering stable circuit operation,\" the researchers wrote in their paper. \"We show that device stability in graphene-based field-effect transistors with amorphous gate oxides can be improved by Fermi-level tuning.\" In their experiments, the researchers tested different graphene FETs with aluminum oxide (Al2O3) as the top-gate oxide and compared their performances. One of the device batches they tested also utilized a p-doped graphene layer. \"We deliberately tuned the Fermi level of the channel to maximize the energy distance between the charge carriers in the channel and the defect bands in the amorphous aluminum gate oxide,\" the researchers explained in their paper. Interestingly, the researchers found that their approach improved the stability of the transistors. In fact, the batch of FETs that was Fermi tuned away from the aluminum oxide's defects (i.e., the one that was most p-doped) resulted in lower hysteresis and bias temperature instability, two characteristics typically associated with operational instability. The team verified the effectiveness of their approach further by running a series of technology computer-aided design (TCAD) simulations. These are computer simulations often used to model semiconductor devices and processes. \"Charge trapping is highly sensitive to the energetic alignment of the Fermi level of the channel with the defect band in the insulator, and thus, our approach maximizes the amount of electrically active border traps without the need to reduce the total number of traps in the insulator,\" the researchers added in their paper. The recent work by this team of researchers highlights the need to choose suitable designs for devices based on 2D semiconductors to ensure reliable and stable operation. In the future, the approach introduced in their paper could be used to improve the stability of FETs based on 2D graphene. Moreover, the same strategy could potentially be applicable to a wide range of insulators, including crystalline insulators. In their next studies, the researchers plan to test their proposed strategy further, to determine the levels of stability that it could enable with different material combinations. ", "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 Electronic devices based on two-dimensional semiconductors suffer from limited electrical stability because charge carriers originating from the semiconductors interact with defects in the surrounding insulators. In field-effect transistors, the resulting trapped charges can lead to large hysteresis and device drifts, particularly when common amorphous gate oxides (such as silicon or hafnium dioxide) are used, hindering stable circuit operation. Here, we show that device stability in graphene-based field-effect transistors with amorphous gate oxides can be improved by Fermi-level tuning. We deliberately tune the Fermi level of the channel to maximize the energy distance between the charge carriers in the channel and the defect bands in the amorphous aluminium gate oxide. Charge trapping is highly sensitive to the energetic alignment of the Fermi level of the channel with the defect band in the insulator, and thus, our approach minimizes the amount of electrically active border traps without the need to reduce the total number of traps in the insulator. Main Two-dimensional (2D) semiconductors are a potential channel material for ultimately scaled field-effect transistors (FETs) 1 . In contrast to silicon, 2D semiconductors retain sizable mobilities at atomic layer thicknesses below 1 nm, a thickness that also helps to suppress short-channel effects in FETs and thus allows for physical channel lengths below 5 nm (ref. 2 ). Furthermore, the integration of 2D materials in van der Waals heterostructures provides design options for energy-efficient transistors that can overcome the limitations of thermal charge-carrier injection. In addition, 2D materials are of potential use in a broad range of applications, including photonics and optoelectronics 3 , neuromorphic computing 4 , nanoelectromechanical systems 5 , and gas and biological sensors 6 . There is, however, currently a lack of low-resistive contacts to 2D semiconductors, which minimize the prevalent Schottky barriers 7 . In addition, there is a lack of suitable gate insulators 8 that can ensure high interface quality, scalability 9 and a minimum of electrically active border traps, the presence of which in the insulator close to the channel limits device stability. These two challenges are major obstacles for the industrial applications of 2D-based nanoelectronics and, being independent from each other, need to be separately addressed. There has been recent progress regarding the formation of low-barrier contacts for 2D semiconductors using contact gating 10 or semimetallic bismuth contacts to achieve ultralow contact resistances 11 . However, the need to find a suitable insulator with a minimum number of electrically active traps remains. Stability studies of 2D FETs typically show a stability that is at least two orders of magnitude worse 12 , 13 compared with silicon-based FETs 14 , 15 . Measurements of FET stability typically evaluate the hysteresis in the transfer characteristics 16 and stability of threshold voltage under prolonged periods of applied elevated gate biases and temperatures (bias temperature instability (BTI)) 14 . Charge trapping inside the gate oxide has been identified as the root cause of BTI 15 , 17 . At elevated gate biases and temperatures, charges are transferred between the channel and gate oxide in a phonon-mediated transition 18 , with charging time constants spanning a wide range, from picoseconds to years 2 , 19 . Border traps in the gate oxide close to the channel determine the long-term stability and reliability of silicon FETs 15 , whereas in 2D-material-based FETs, they typically limit device stability on much shorter timescales 20 . In amorphous oxides, the defect trap levels vary due to the differing surroundings of every instance of atomic defects 18 . In the first approximation, the energy levels of defects follow a normal distribution around the average defect levels, forming defect bands 21 . Consequently, the overall density of border traps and the widths of the corresponding defect bands can be considerably reduced by using crystalline insulators, such as hexagonal boron nitride (hBN) or calcium fluoride 8 (CaF 2 ). However, these insulators are difficult to synthesize and have several technological challenges. For example, current state-of-the-art crystalline hBN can be grown only at temperatures above 1,200 °C (ref. 22 ) and CaF 2 requires a crystalline silicon(111) substrate for growth, allowing only back-gated configurations 23 . In addition, hBN is unsuitable for use as a scaled gate insulator because of its small dielectric constant 9 . In this Article, we show that the stability and reliability of 2D-material-based FETs with amorphous gate oxides can be improved by tuning the Fermi level ( E F ) of the 2D channel material such that it maximizes the energy distance between the charge carriers in the channel and the defect bands in the gate insulator during device operation. This can be achieved via a careful selection of the 2D material and amorphous gate oxide, as well as by doping the 2D layer to shift E F away from the defect bands in the gate insulator. Graphene FETs (GFETs) with aluminium oxide (Al 2 O 3 ) as the top-gate oxide are measured and compared, where one of the device batches uses a p-doped graphene layer. The GFET batch where E F is tuned away from the Al 2 O 3 defect band edge shows reduced hysteresis and BTI. We further verify the approach with technology computer-aided design (TCAD) simulations 24 . In addition, double-gated GFETs are fabricated, where the back gate is used to directly tune the Fermi level in the graphene monolayer via electrostatic doping. This shows that the stability observed for top-gate operation strongly depends on the location of E F . Our approach aims to design a metal–oxide–semiconductor (MOS) system with a minimal amount of electrically active border traps without the need to reduce the total number of traps in the insulator. Fermi-level tuning for increasing stability of 2D FETs Our stability-based design approach is centred on the analysis and design of the band diagram of the MOS system, including the defect bands in the insulator. Fig. 1a shows a top-gated GFET that forms an example MOS system out of aluminium (metal), Al 2 O 3 (oxide) and<|im_end|> <|im_start|>assistant Two-dimensional (2D) semiconductors are a class of semiconducting materials with thicknesses on the atomic scale. These materials have numerous advantageous properties, including good mobilities at thicknesses below 1 nm, which make them particularly promising for the development of field effect transistors (FETs) and other electronic, photonic and optoelectronic components. Despite their advantages, when they are used to build electronic components, these materials often exhibit a limited electrical stability. The main reason for this is that the charge carriers originating from the semiconductors can interact with defects in the insulators that surround the materials inside devices, hindering the devices' stability. Researchers at TU Wien and AMO GmbH have recently demonstrated a strategy that could be used to improve the stability of FETs based on 2D materials. This strategy, introduced in a paper published in Nature Electronics, entails tuning the Fermi Level of the 2D materials, ensuring that it maximizes the energy distance between the charge carriers and defects in the gate insulator while the device is operating. "In FETs, the resulting trapped charges can lead to large hysteresis and device drifts, particularly when common amorphous gate oxides (such as silicon or hafnium dioxide) are used, hindering stable circuit operation," the researchers wrote in their paper. "We show that device stability in graphene-based field-effect transistors with amorphous gate oxides can be improved by Fermi-level tuning." In their experiments, the researchers tested different graphene FETs with aluminum oxide (Al2O3) as the top-gate oxide and compared their performances. One of the device batches they tested also utilized a p-doped graphene layer. "We deliberately tuned the Fermi level of the channel to maximize the energy distance between the charge carriers in the channel and the defect bands in the amorphous aluminum gate oxide," the researchers explained in their paper. Interestingly, the researchers found that their approach improved the stability of the transistors. In fact, the batch of FETs that was Fermi tuned away from the aluminum oxide's defects (i.e., the one that was most p-doped) resulted in lower hysteresis and bias temperature instability, two characteristics typically associated with operational instability. The team verified the effectiveness of their approach further by running a series of technology computer-aided design (TCAD) simulations. These are computer simulations often used to model semiconductor devices and processes. "Charge trapping is highly sensitive to the energetic alignment of the Fermi level of the channel with the defect band in the insulator, and thus, our approach maximizes the amount of electrically active border traps without the need to reduce the total number of traps in the insulator," the researchers added in their paper. The recent work by this team of researchers highlights the need to choose suitable designs for devices based on 2D semiconductors to ensure reliable and stable operation. In the future, the approach introduced in their paper could be used to improve the stability of FETs based on 2D graphene. Moreover, the same strategy could potentially be applicable to a wide range of insulators, including crystalline insulators. In their next studies, the researchers plan to test their proposed strategy further, to determine the levels of stability that it could enable with different material combinations. <|im_end|>

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3789, 5353, 315, 21795, 40, 220, 868, 1174, 220, 1114, 662, 2468, 32389, 18618, 50183, 323, 20472, 11, 10405, 527, 23217, 1990, 279, 5613, 323, 18618, 51180, 304, 264, 51923, 263, 82076, 9320, 220, 972, 1174, 449, 23468, 892, 18508, 56886, 264, 7029, 2134, 11, 505, 10532, 76989, 311, 1667, 220, 17, 1174, 220, 777, 662, 14319, 45660, 304, 279, 18618, 51180, 3345, 311, 279, 5613, 8417, 279, 1317, 9860, 20334, 323, 31638, 315, 51692, 435, 1372, 82, 220, 868, 1174, 20444, 304, 220, 17, 35, 68418, 6108, 435, 1372, 82, 11, 814, 11383, 4017, 3756, 20334, 389, 1790, 24210, 3115, 31296, 220, 508, 662, 763, 1097, 16751, 788, 19488, 3422, 11, 279, 23011, 23709, 5990, 13592, 4245, 311, 279, 61469, 40190, 315, 1475, 2937, 315, 25524, 42655, 220, 972, 662, 763, 279, 1176, 57304, 11, 279, 4907, 5990, 315, 42655, 1833, 264, 4725, 8141, 2212, 279, 5578, 23011, 5990, 11, 30164, 23011, 21562, 220, 1691, 662, 53123, 11, 279, 8244, 17915, 315, 3973, 45660, 323, 279, 65511, 315, 279, 12435, 23011, 21562, 649, 387, 33452, 11293, 555, 1701, 64568, 483, 1672, 42391, 11, 1778, 439, 12651, 24346, 32732, 263, 25719, 1425, 320, 71, 15967, 8, 477, 35719, 89230, 220, 23, 320, 23389, 37, 220, 17, 7609, 4452, 11, 1521, 1672, 42391, 527, 5107, 311, 6925, 27985, 323, 617, 3892, 30116, 11774, 13, 1789, 3187, 11, 1510, 1614, 8838, 10826, 38921, 64568, 483, 305, 15967, 649, 387, 15042, 1193, 520, 20472, 3485, 220, 16, 11, 1049, 37386, 34, 320, 1116, 13, 220, 1313, 883, 323, 14751, 37, 220, 17, 7612, 264, 64568, 483, 51692, 7, 5037, 8, 54057, 369, 6650, 11, 10923, 1193, 1203, 2427, 660, 33483, 220, 1419, 662, 763, 5369, 11, 305, 15967, 374, 7120, 86581, 369, 1005, 439, 264, 31790, 18618, 1672, 10733, 1606, 315, 1202, 2678, 2815, 47262, 6926, 220, 24, 662, 763, 420, 13659, 11, 584, 1501, 430, 279, 20334, 323, 31638, 315, 220, 17, 35, 68418, 6108, 435, 1372, 82, 449, 1097, 16751, 788, 18618, 19488, 3422, 649, 387, 13241, 555, 42438, 279, 99362, 72, 2237, 320, 469, 435, 883, 315, 279, 220, 17, 35, 5613, 3769, 1778, 430, 433, 31127, 4861, 279, 4907, 6138, 1990, 279, 6900, 35991, 304, 279, 5613, 323, 279, 23011, 21562, 304, 279, 18618, 1672, 10733, 2391, 3756, 5784, 13, 1115, 649, 387, 17427, 4669, 264, 16994, 6727, 315, 279, 220, 17, 35, 3769, 323, 1097, 16751, 788, 18618, 51180, 11, 439, 1664, 439, 555, 97928, 279, 220, 17, 35, 6324, 311, 6541, 469, 435, 3201, 505, 279, 23011, 21562, 304, 279, 18618, 1672, 10733, 13, 12441, 1994, 435, 1372, 82, 320, 37432, 1372, 82, 8, 449, 55993, 51180, 320, 2149, 220, 17, 507, 220, 18, 883, 439, 279, 1948, 2427, 349, 51180, 527, 17303, 323, 7863, 11, 1405, 832, 315, 279, 3756, 45892, 5829, 264, 281, 1773, 16771, 66192, 6324, 13, 578, 41126, 1372, 7309, 1405, 469, 435, 374, 33519, 3201, 505, 279, 1708, 220, 17, 507, 220, 18, 23011, 7200, 6964, 5039, 11293, 305, 599, 13213, 285, 323, 21795, 40, 13, 1226, 4726, 10356, 279, 5603, 449, 5557, 6500, 12, 3864, 291, 2955, 320, 7905, 1846, 8, 47590, 220, 1187, 662, 763, 5369, 11, 2033, 2427, 660, 41126, 1372, 82, 527, 70554, 11, 1405, 279, 1203, 18618, 374, 1511, 311, 6089, 26306, 279, 99362, 72, 2237, 304, 279, 66192, 1647, 337, 1155, 4669, 25396, 2020, 97928, 13, 1115, 5039, 430, 279, 20334, 13468, 369, 1948, 2427, 349, 5784, 16917, 14117, 389, 279, 3813, 315, 469, 435, 662, 5751, 5603, 22262, 311, 2955, 264, 9501, 4235, 55189, 4235, 7143, 52592, 320, 44, 3204, 8, 1887, 449, 264, 17832, 3392, 315, 9249, 750, 4642, 3973, 45660, 2085, 279, 1205, 311, 8108, 279, 2860, 1396, 315, 45660, 304, 279, 1672, 10733, 13, 99362, 72, 11852, 42438, 369, 7859, 20334, 315, 220, 17, 35, 435, 1372, 82, 5751, 20334, 6108, 2955, 5603, 374, 2960, 1171, 389, 279, 6492, 323, 2955, 315, 279, 7200, 13861, 315, 279, 74174, 1887, 11, 2737, 279, 23011, 21562, 304, 279, 1672, 10733, 13, 23966, 13, 220, 16, 64, 5039, 264, 1948, 2427, 660, 41126, 1372, 430, 7739, 459, 3187, 74174, 1887, 704, 315, 55993, 320, 55108, 705, 1708, 220, 17, 507, 220, 18, 320, 55189, 8, 323, 128257, 198, 128256, 78191, 198, 11874, 33520, 320, 17, 35, 8, 5347, 1965, 1076, 1105, 527, 264, 538, 315, 5347, 1965, 1076, 287, 7384, 449, 26839, 288, 389, 279, 25524, 5569, 13, 4314, 7384, 617, 12387, 76824, 6012, 11, 2737, 1695, 12881, 4396, 520, 26839, 288, 3770, 220, 16, 26807, 11, 902, 1304, 1124, 8104, 26455, 369, 279, 4500, 315, 2115, 2515, 1380, 380, 1105, 320, 37, 1372, 82, 8, 323, 1023, 14683, 11, 4604, 14338, 323, 3469, 4748, 772, 8535, 6956, 13, 18185, 872, 22934, 11, 994, 814, 527, 1511, 311, 1977, 14683, 6956, 11, 1521, 7384, 3629, 31324, 264, 7347, 20314, 20334, 13, 578, 1925, 2944, 369, 420, 374, 430, 279, 6900, 35991, 71373, 505, 279, 5347, 1965, 1076, 1105, 649, 16681, 449, 42655, 304, 279, 1672, 42391, 430, 9172, 279, 7384, 4871, 7766, 11, 48419, 4776, 279, 7766, 6, 20334, 13, 59250, 520, 70514, 99986, 323, 6912, 46, 32577, 617, 6051, 21091, 264, 8446, 430, 1436, 387, 1511, 311, 7417, 279, 20334, 315, 435, 1372, 82, 3196, 389, 220, 17, 35, 7384, 13, 1115, 8446, 11, 11784, 304, 264, 5684, 4756, 304, 22037, 38784, 11, 71204, 42438, 279, 99362, 72, 9580, 315, 279, 220, 17, 35, 7384, 11, 23391, 430, 433, 31127, 4861, 279, 4907, 6138, 1990, 279, 6900, 35991, 323, 42655, 304, 279, 18618, 1672, 10733, 1418, 279, 3756, 374, 10565, 13, 330, 644, 435, 1372, 82, 11, 279, 13239, 31691, 10405, 649, 3063, 311, 3544, 305, 599, 13213, 285, 323, 3756, 34738, 82, 11, 8104, 994, 4279, 1097, 16751, 788, 18618, 19488, 3422, 320, 21470, 439, 51692, 477, 105539, 77, 2411, 40589, 8, 527, 1511, 11, 48419, 4776, 15528, 16622, 5784, 1359, 279, 12074, 6267, 304, 872, 5684, 13, 330, 1687, 1501, 430, 3756, 20334, 304, 66192, 6108, 2115, 23937, 1380, 380, 1105, 449, 1097, 16751, 788, 18618, 19488, 3422, 649, 387, 13241, 555, 99362, 72, 11852, 42438, 1210, 763, 872, 21896, 11, 279, 12074, 12793, 2204, 66192, 435, 1372, 82, 449, 25674, 51180, 320, 2149, 17, 46, 18, 8, 439, 279, 1948, 2427, 349, 51180, 323, 7863, 872, 24601, 13, 3861, 315, 279, 3756, 45892, 814, 12793, 1101, 34716, 264, 281, 1773, 16771, 66192, 6324, 13, 330, 1687, 36192, 33519, 279, 99362, 72, 2237, 315, 279, 5613, 311, 35608, 279, 4907, 6138, 1990, 279, 6900, 35991, 304, 279, 5613, 323, 279, 23011, 21562, 304, 279, 1097, 16751, 788, 25674, 18618, 51180, 1359, 279, 12074, 11497, 304, 872, 5684, 13, 58603, 11, 279, 12074, 1766, 430, 872, 5603, 13241, 279, 20334, 315, 279, 1380, 380, 1105, 13, 763, 2144, 11, 279, 7309, 315, 435, 1372, 82, 430, 574, 99362, 72, 33519, 3201, 505, 279, 25674, 51180, 596, 42655, 320, 72, 1770, 2637, 279, 832, 430, 574, 1455, 281, 1773, 16771, 8, 19543, 304, 4827, 305, 599, 13213, 285, 323, 15837, 9499, 56399, 11, 1403, 17910, 11383, 5938, 449, 25605, 56399, 13, 578, 2128, 24884, 279, 27375, 315, 872, 5603, 4726, 555, 4401, 264, 4101, 315, 5557, 6500, 12, 3864, 291, 2955, 320, 7905, 1846, 8, 47590, 13, 4314, 527, 6500, 47590, 3629, 1511, 311, 1646, 87836, 7766, 323, 11618, 13, 330, 56463, 93669, 374, 7701, 16614, 311, 279, 45955, 17632, 315, 279, 99362, 72, 2237, 315, 279, 5613, 449, 279, 23011, 7200, 304, 279, 1672, 10733, 11, 323, 8617, 11, 1057, 5603, 31127, 4861, 279, 3392, 315, 9249, 750, 4642, 3973, 45660, 2085, 279, 1205, 311, 8108, 279, 2860, 1396, 315, 45660, 304, 279, 1672, 10733, 1359, 279, 12074, 3779, 304, 872, 5684, 13, 578, 3293, 990, 555, 420, 2128, 315, 12074, 22020, 279, 1205, 311, 5268, 14791, 14769, 369, 7766, 3196, 389, 220, 17, 35, 5347, 1965, 1076, 1105, 311, 6106, 15062, 323, 15528, 5784, 13, 763, 279, 3938, 11, 279, 5603, 11784, 304, 872, 5684, 1436, 387, 1511, 311, 7417, 279, 20334, 315, 435, 1372, 82, 3196, 389, 220, 17, 35, 66192, 13, 23674, 11, 279, 1890, 8446, 1436, 13893, 387, 8581, 311, 264, 7029, 2134, 315, 1672, 42391, 11, 2737, 64568, 483, 1672, 42391, 13, 763, 872, 1828, 7978, 11, 279, 12074, 3197, 311, 1296, 872, 11223, 8446, 4726, 11, 311, 8417, 279, 5990, 315, 20334, 430, 433, 1436, 7431, 449, 2204, 3769, 28559, 13, 220, 128257, 198 ]

2,099

[ { "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 Clear cell renal carcinoma has been reported in many research studies as a rather heterogeneous disease. Identification of different subtypes and their molecular characteristics can help in choosing a more effective treatment and predicting a response to it. In this study, using multi-omics clustering of RNA-Seq data of patients with clear cell renal carcinoma from TCGA. Specific genes were identified for the most aggressive ccRCC subtype associated with metastasis and a subtype associated with a more favorable course of the disease. Among them were genes associated with blood clotting ( FGA , FGG ) and genes associated with changes in the immune characteristics of a tumor ( ENAM , IGFBP1 , IL6 ). In addition, an association of hub genes of poor survival ccRCC subtype with the levels of infiltration of endothelial cells, hematopoietic stem cells, T cells NK and mast cells was revealed. It was shown that MFI2 , CP , FGA , and FGG expression can predict the response to sunitinib, while the APOB , ENAM , IGFBP1 , and MFI2 expression predict the response to nivolumab. The results obtained provide insight into the genetic characteristics underlying the aggressive subtype of ccRCC and may help develop new approaches to the treatment of this disease. Introduction Clear cell renal carcinoma (ccRCC) is the most common subtype of renal cancer 1 . The 5-year survival of ccRCC patients is about 60–70% 2 . The available data show an increase in the number of new cases of ccRCC over the past decades 2 . Despite the extensive data accumulated recently, the identification of reliable genes that make it possible to predict and select therapy for ccRCC is still an urgent problem. To date, abundant evidence suggests that ccRCC is a rather heterogeneous type of cancer 3 . In particular, subtypes of metastatic ccRCC have been identified based on their response to sunitinib 4 . Recently, different subtypes of ccRCC have been identified based on the activity of transcription factors 5 . These data show that within the histologic type, ccRCC group of samples can be distinguished by the general unique characteristics. Common TNM classification of samples is often insufficient to prescribe a suitable targeted treatment 6 . It was shown that gene expression depends on the stages of ccRCC, and different stages of ccRCC are characterized by different aberrant regulated pathways, including the coagulation cascade 7 . Early identification of the most aggressive tumors could significantly improve the treatment of ccRCC. The identification of key molecular changes specific to such malignant subtypes can help in the development of effective personalized therapies. Thus, the aim of this work is to reveal major subtypes of ccRCC tumors and to identify key genetic characteristics of these subtypes. Results Clustering of ccRCC samples revealed three subtypes with different survival rates Clustering of ccRCC samples from the TCGA database was carried out by the k-means method with 100 replicates. For the clustering of samples, k = 3 was chosen, since it was previously reported that clustering stability increases from k = 2 to k = 3, but not at k > 3 for the ccRCC samples 3 . For analysis, I selected tumor samples for which no radiotherapy or additional pharmacotherapy was performed. As a result, 456 samples were divided into two large clusters (n = 299 and n = 126) and one smaller (n = 31). Survival analysis revealed that Cluster 2 was associated with worse overall survival, while Cluster 1 was associated with better overall patient survival (Fig. 1 b). At the same time, in Cluster 2, samples with late stages (III and IV) as well as samples with metastases prevail (Fig. 1 c). While in Cluster 1, samples with stage I prevail (Fig. S1 b). In addition, the available data suggests patients from Cluster 1 respond better to treatment than patients from Cluster 2 (Fig. S1 c,d). Figure 1 Clustering by the k-means method of ccRCC samples from the TCGA database (a) . The heat map shows the distribution of 456 samples across three clusters (matrix columns) and the distribution of the 2000 most variable genes in five gene clusters (matrix rows). Survival analysis for the three resulting clusters ( b ). The P -value shows the difference between the three groups according to the Logrank test. Distribution of samples with metastases depending on the cluster ( c ). The blue gradient increases towards a more significant P -value. The difference was considered significant at the P < 0.05. In Cluster 2, samples with the presence of metastases prevail, and in Cluster 1 with the absence of metastases. Full size image For gene clustering, I selected 2000 genes with the most highly variable expression. As a result, the genes were divided into 5 clusters (Fig. 1 a). At the same time, the analysis of gene ontology shows a pronounced cluster associated with ion transport and pH maintenance, an immune response cluster, a cluster associated with an acute-phase response, a cluster associated with transmembrane organic anion transport, and a cluster associated with cell adhesion and organization of the extracellular matrix (Fig. S2 ). Thus, ccRCC subtypes with different survival rates and different responses to treatment were identified. Identification of hub genes specific for the poor prognostic subtype For the detected clusters, I identified differentially expressed genes using the rank sum test (Fig. 2 a,b). The difference was considered significant at P < 0.05, and identified 310 genes for Cluster 2 and 315 genes for Cluster 1. Then, a network of protein–protein interactions (PPI) of Cluster 1 and Cluster 2 was built, taking into account changes in gene expression in ccRCC (Fig. 2 c,d). Figure 2 Identification of marker genes for Cluster 1 and Cluster 2 ( a ) using the rank sum test. Scheme of PPI taking into account changes in gene expression ( b ). Volcano plot of DEGs for Cluster 1 ( a ); volcano plot of DEGs for Cluster 2 ( b ). The dotted line shows the twofold change", "role": "user" }, { "content": "HSE researchers have found genes characteristic of the most aggressive subtype of clear cell renal carcinoma. Having studied data on tumor samples from 456 patients, Grigory Puzanov, research fellow at the HSE Faculty of Computer Science International Laboratory of Bioinformatics, identified cancer subtypes associated with either a favorable or unfavorable course of the disease. The paper is published in Scientific Reports. Clear cell renal carcinoma (ccRCC) is the most common subtype of kidney cancer, with five-year patient survival outcomes ranging from 60% to 70% and the number of new cases on the rise in recent decades. Despite extensive data available on the disease, there is little information on specific human genes which could help predict its clinical course. Findings from Puzanov's study reveal which ccRCC subtypes are more dangerous than others and which human genes appear to be responsible for the progression of the disease. This new information is significant for the early detection of aggressive tumors and for designing personalized treatment plans for ccRCC patients. The author analyzed data from The Cancer Genome Atlas (TCGA) on 456 tumor samples for which no radiotherapy or additional pharmacotherapy was performed. Subtypes with different survival rates were identified using the k-means method for clustering samples into subgroups with similar characteristics. For gene clustering, Puzanov selected 2,000 genes with highly variable expression patterns in ccRCC. Gene expression is the process by which a gene is read and copied to produce a messenger RNA (mRNA) which is then used to synthesize proteins. A bioinformatic algorithm was run 100 times, each time sorting the tumor samples based on similarity of the 2,000 genes' expression patterns. Three clusters (subtypes) with different survival rates were identified. The cluster with the lowest survival rates was associated with metastases and the worst response to subsequent treatment. The study was carried out in several stages. In stage one, each cluster's characteristics were examined for a better understanding of genetic factors which could influence the course of the disease. Then, the study author identified the key genes specific to high and low survival clusters and constructed a network of interactions for proteins whose synthesis is encoded by these genes. Puzanov's analysis determined which genes encoded proteins with the highest number of network connections. The cluster with the poorest survival rates was found to be associated with the MFI2, CP, APOB, and ENAM genes known to be involved in the transport of insulin-like growth factor (a protein similar in structure to insulin) and in post-translational modification of proteins. In addition, specific to the low-survival subtype were the genes encoding fibrinogen and prothrombin associated with blood clotting (FGA, FGG, and F2). \"Some of these key genes may affect the efficacy of anti-tumor therapies. For example, increased activity of the CP, FGA, and FGG genes is associated with poor response to nivolumab, and high expression of APOB and ENAM predicts a lack of response to sunitinib. This knowledge can help in prescribing the most suitable targeted treatments for patients with malignancies,\" says Puzanov. According to the researcher, combined use of conventional anti-tumor agents and anticoagulants (medicines that help prevent blood clots) can increase the effectiveness of cancer treatment. Thus, there is evidence that heparin, which is commonly used to treat thromboembolic events in cancer patients, contributes to patient survival and has anti-metastatic activity. ", "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 Clear cell renal carcinoma has been reported in many research studies as a rather heterogeneous disease. Identification of different subtypes and their molecular characteristics can help in choosing a more effective treatment and predicting a response to it. In this study, using multi-omics clustering of RNA-Seq data of patients with clear cell renal carcinoma from TCGA. Specific genes were identified for the most aggressive ccRCC subtype associated with metastasis and a subtype associated with a more favorable course of the disease. Among them were genes associated with blood clotting ( FGA , FGG ) and genes associated with changes in the immune characteristics of a tumor ( ENAM , IGFBP1 , IL6 ). In addition, an association of hub genes of poor survival ccRCC subtype with the levels of infiltration of endothelial cells, hematopoietic stem cells, T cells NK and mast cells was revealed. It was shown that MFI2 , CP , FGA , and FGG expression can predict the response to sunitinib, while the APOB , ENAM , IGFBP1 , and MFI2 expression predict the response to nivolumab. The results obtained provide insight into the genetic characteristics underlying the aggressive subtype of ccRCC and may help develop new approaches to the treatment of this disease. Introduction Clear cell renal carcinoma (ccRCC) is the most common subtype of renal cancer 1 . The 5-year survival of ccRCC patients is about 60–70% 2 . The available data show an increase in the number of new cases of ccRCC over the past decades 2 . Despite the extensive data accumulated recently, the identification of reliable genes that make it possible to predict and select therapy for ccRCC is still an urgent problem. To date, abundant evidence suggests that ccRCC is a rather heterogeneous type of cancer 3 . In particular, subtypes of metastatic ccRCC have been identified based on their response to sunitinib 4 . Recently, different subtypes of ccRCC have been identified based on the activity of transcription factors 5 . These data show that within the histologic type, ccRCC group of samples can be distinguished by the general unique characteristics. Common TNM classification of samples is often insufficient to prescribe a suitable targeted treatment 6 . It was shown that gene expression depends on the stages of ccRCC, and different stages of ccRCC are characterized by different aberrant regulated pathways, including the coagulation cascade 7 . Early identification of the most aggressive tumors could significantly improve the treatment of ccRCC. The identification of key molecular changes specific to such malignant subtypes can help in the development of effective personalized therapies. Thus, the aim of this work is to reveal major subtypes of ccRCC tumors and to identify key genetic characteristics of these subtypes. Results Clustering of ccRCC samples revealed three subtypes with different survival rates Clustering of ccRCC samples from the TCGA database was carried out by the k-means method with 100 replicates. For the clustering of samples, k = 3 was chosen, since it was previously reported that clustering stability increases from k = 2 to k = 3, but not at k > 3 for the ccRCC samples 3 . For analysis, I selected tumor samples for which no radiotherapy or additional pharmacotherapy was performed. As a result, 456 samples were divided into two large clusters (n = 299 and n = 126) and one smaller (n = 31). Survival analysis revealed that Cluster 2 was associated with worse overall survival, while Cluster 1 was associated with better overall patient survival (Fig. 1 b). At the same time, in Cluster 2, samples with late stages (III and IV) as well as samples with metastases prevail (Fig. 1 c). While in Cluster 1, samples with stage I prevail (Fig. S1 b). In addition, the available data suggests patients from Cluster 1 respond better to treatment than patients from Cluster 2 (Fig. S1 c,d). Figure 1 Clustering by the k-means method of ccRCC samples from the TCGA database (a) . The heat map shows the distribution of 456 samples across three clusters (matrix columns) and the distribution of the 2000 most variable genes in five gene clusters (matrix rows). Survival analysis for the three resulting clusters ( b ). The P -value shows the difference between the three groups according to the Logrank test. Distribution of samples with metastases depending on the cluster ( c ). The blue gradient increases towards a more significant P -value. The difference was considered significant at the P < 0.05. In Cluster 2, samples with the presence of metastases prevail, and in Cluster 1 with the absence of metastases. Full size image For gene clustering, I selected 2000 genes with the most highly variable expression. As a result, the genes were divided into 5 clusters (Fig. 1 a). At the same time, the analysis of gene ontology shows a pronounced cluster associated with ion transport and pH maintenance, an immune response cluster, a cluster associated with an acute-phase response, a cluster associated with transmembrane organic anion transport, and a cluster associated with cell adhesion and organization of the extracellular matrix (Fig. S2 ). Thus, ccRCC subtypes with different survival rates and different responses to treatment were identified. Identification of hub genes specific for the poor prognostic subtype For the detected clusters, I identified differentially expressed genes using the rank sum test (Fig. 2 a,b). The difference was considered significant at P < 0.05, and identified 310 genes for Cluster 2 and 315 genes for Cluster 1. Then, a network of protein–protein interactions (PPI) of Cluster 1 and Cluster 2 was built, taking into account changes in gene expression in ccRCC (Fig. 2 c,d). Figure 2 Identification of marker genes for Cluster 1 and Cluster 2 ( a ) using the rank sum test. Scheme of PPI taking into account changes in gene expression ( b ). Volcano plot of DEGs for Cluster 1 ( a ); volcano plot of DEGs for Cluster 2 ( b ). The dotted line shows the twofold change<|im_end|> <|im_start|>assistant HSE researchers have found genes characteristic of the most aggressive subtype of clear cell renal carcinoma. Having studied data on tumor samples from 456 patients, Grigory Puzanov, research fellow at the HSE Faculty of Computer Science International Laboratory of Bioinformatics, identified cancer subtypes associated with either a favorable or unfavorable course of the disease. The paper is published in Scientific Reports. Clear cell renal carcinoma (ccRCC) is the most common subtype of kidney cancer, with five-year patient survival outcomes ranging from 60% to 70% and the number of new cases on the rise in recent decades. Despite extensive data available on the disease, there is little information on specific human genes which could help predict its clinical course. Findings from Puzanov's study reveal which ccRCC subtypes are more dangerous than others and which human genes appear to be responsible for the progression of the disease. This new information is significant for the early detection of aggressive tumors and for designing personalized treatment plans for ccRCC patients. The author analyzed data from The Cancer Genome Atlas (TCGA) on 456 tumor samples for which no radiotherapy or additional pharmacotherapy was performed. Subtypes with different survival rates were identified using the k-means method for clustering samples into subgroups with similar characteristics. For gene clustering, Puzanov selected 2,000 genes with highly variable expression patterns in ccRCC. Gene expression is the process by which a gene is read and copied to produce a messenger RNA (mRNA) which is then used to synthesize proteins. A bioinformatic algorithm was run 100 times, each time sorting the tumor samples based on similarity of the 2,000 genes' expression patterns. Three clusters (subtypes) with different survival rates were identified. The cluster with the lowest survival rates was associated with metastases and the worst response to subsequent treatment. The study was carried out in several stages. In stage one, each cluster's characteristics were examined for a better understanding of genetic factors which could influence the course of the disease. Then, the study author identified the key genes specific to high and low survival clusters and constructed a network of interactions for proteins whose synthesis is encoded by these genes. Puzanov's analysis determined which genes encoded proteins with the highest number of network connections. The cluster with the poorest survival rates was found to be associated with the MFI2, CP, APOB, and ENAM genes known to be involved in the transport of insulin-like growth factor (a protein similar in structure to insulin) and in post-translational modification of proteins. In addition, specific to the low-survival subtype were the genes encoding fibrinogen and prothrombin associated with blood clotting (FGA, FGG, and F2). "Some of these key genes may affect the efficacy of anti-tumor therapies. For example, increased activity of the CP, FGA, and FGG genes is associated with poor response to nivolumab, and high expression of APOB and ENAM predicts a lack of response to sunitinib. This knowledge can help in prescribing the most suitable targeted treatments for patients with malignancies," says Puzanov. According to the researcher, combined use of conventional anti-tumor agents and anticoagulants (medicines that help prevent blood clots) can increase the effectiveness of cancer treatment. Thus, there is evidence that heparin, which is commonly used to treat thromboembolic events in cancer patients, contributes to patient survival and has anti-metastatic activity. <|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 Turbulence is the major cause of friction losses in transport processes and it is responsible for a drastic drag increase in flows over bounding surfaces. While much effort is invested into developing ways to control and reduce turbulence intensities 1 , 2 , 3 , so far no methods exist to altogether eliminate turbulence if velocities are sufficiently large. We demonstrate for pipe flow that appropriate distortions to the velocity profile lead to a complete collapse of turbulence and subsequently friction losses are reduced by as much as 90%. Counterintuitively, the return to laminar motion is accomplished by initially increasing turbulence intensities or by transiently amplifying wall shear. Since neither the Reynolds number nor the shear stresses decrease (the latter often increase), these measures are not indicative of turbulence collapse. Instead, an amplification mechanism 4 , 5 measuring the interaction between eddies and the mean shear is found to set a threshold below which turbulence is suppressed beyond recovery. Main Flows through pipes and hydraulic networks are generally turbulent and the friction losses encountered in these flows are responsible for approximately 10% of the global electric energy consumption. Here turbulence causes a severe drag increase and consequently much larger forces are needed to maintain desired flow rates. In pipes, both laminar and turbulent states are stable (the former is believed to be linearly stable for all Reynolds number (Re) values; the latter is stable if Re > 2,040 (ref. 6 )), but with increasing speed the laminar state becomes more and more susceptible to small disturbances. Hence, in practice most flows are turbulent at sufficiently large Re. While the stability of laminar flow has been studied in great detail, little attention has been paid to the susceptibility of turbulence, the general assumption being that once turbulence is established it is stable. Many turbulence control strategies have been put forward to reduce the drag encountered in shear flows 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 . Recent strategies employ feedback mechanisms to actively counter selected velocity components or vortices. Such methods usually require knowledge of the full turbulent velocity field. In computer simulations 7 , 8 , it could be demonstrated that under these ideal conditions, flows at a low Re number can even be relaminarized. In experiments, the required detailed manipulation of the time-dependent velocity field is, however, currently impossible to achieve. Other studies employ passive (for example, riblets) or active (oscillations or excitation of travelling waves) methods to interfere with the near-wall turbulence creation. Typically here drag reduction of 10 to 40% has been reported, but often the control cost is substantially higher than the gain, or a net gain can be achieved only in a narrow Re number regime. Instead of attempting to control or counter certain components of the complex fluctuating flow fields, we will show in the following that by appropriately disturbing the mean profile, turbulence can be pushed outside its limit of existence and as a consequence the entire flow relaminarizes. Disturbance schemes are developed with the aid of direct numerical simulations (DNSs) of pipe flow and subsequently implemented and tested in experiments. In the DNS, a flow is simulated in a five-diameter ( D )-long pipe and periodic boundary conditions are applied in the axial direction. Initially we perturb laminar pipe flow by adding fluctuation levels of a fully turbulent velocity field rescaled by a factor ( k ) to a laminar flow field. As shown in Fig. 1a (dark blue curve), for small initial perturbations (that is, small k ), the disturbance eventually decays and the flow remains laminar. For sufficiently large amplitudes ( k of order unity), turbulence is triggered (purple, red and cyan curves). So far, this is the familiar picture of the transition to turbulence in shear flows, where turbulence is triggered only if perturbation amplitudes surpass a certain threshold. However, when increasing the turbulent fluctuations well beyond their usual levels ( k > 2.5), surprisingly the highly turbulent flow almost immediately collapses and returns to laminar (light and dark green curves). Here the initially strong vortical motion leads to a redistribution of shear resulting in an unusually flat velocity profile (black profile in Fig. 1c ). Fig. 1: Perturbing turbulence. a , Direct numerical simulations of pipe flow starting from turbulent initial conditions (taken from a run at Re = 10,000), rescaled by a constant factor k and added to the laminar base flow at Re = 4,000, which was then integrated forward in time (at Re = 4,000). For small initial energies, perturbations die out (dark blue curve). For sufficiently large energies ( k ≈1), transition to turbulence occurs (red, purple and cyan). For even larger energies ( k > 2.5), however, the initially turbulent flow is destabilized and collapses after a short time (light and dark green curves). The six streamwise vorticity isosurface figures show ω z = +/− (red/blue) 7.2, 2.0 and 1.6 U / D respectively at snapshot times t 0 = 0, t 1 = 5 and t 2 = 10 ( D / U ). b , Fully turbulent flow (top panel) at Re = 3,100 is perturbed by vigorously stirring the fluid with four rotors. The more strongly turbulent flow (second panel) eventually relaminarizes as it proceeds downstream (third and fourth panel). c , Temporally and azimuthally averaged velocity fields of modified/perturbed flow fields in simulations and experiments. u z is the streamwise velocity component; the cross-stream components are denoted by u r and u θ . d , Relaminarization of fully turbulent flow in experiments at Re = 3,100. The flow is perturbed by injecting 25 jets of fluid radially through the pipe wall. When actuated, the fluctuation levels in the flow drop (top panel) and the centre line velocity switches from the turbulent level to the laminar value (2 U , where U is the mean velocity in the pipe) (bottom panel). Full size image", "role": "user" }, { "content": "Scientists have assumed that once a flow of a fluid has become turbulent, turbulence would persist. Researchers at the Institute of Science and Technology Austria (IST Austria), including Professor Björn Hof and co-first authors Jakob Kühnen and Baofang Song, have now shown that this is not the case. In their experiments, which they published in Nature Physics, they destabilized turbulence in a pipe so that the flow turned to a laminar (non-turbulent) state, and they observed that the flow remained laminar thereafter. Eliminating turbulence can save as much as 95 percent of the energy required to pump a fluid through a pipe. The amount of energy used by industry to pump fluids through pipes is considerable and corresponds to approximately 10 percent of the global electricity consumption. It therefore does not come as a surprise that researchers worldwide are seeking ways to reduce these costs. The major part of these energy losses is caused by turbulence, a phenomenon that leads to a drastic increase of frictional drag, requiring much more energy to pump the fluid. Previous approaches have aimed to locally reduce turbulence levels. Now, the research group of Björn Hof at IST Austria has taken an entirely new approach, tackling the problem from a different side. Rather than temporarily weakening turbulence, they destabilized existing turbulence so that the flow automatically became laminar. In a so-called laminar flow, a fluid flows in parallel layers which do not mix. The opposite of this is a turbulent flow, which is characterized by vortices and chaotic changes in pressure and velocity within the fluid. Most flows that we can observe in nature and in engineering are turbulent, from the smoke of an extinguished candle to the flow of blood in the left ventricle of our heart. In pipes, both laminar and turbulent flows can, in principle, exist and be stable, but a small disturbance can make a laminar flow turbulent. Turbulence in pipes was until now assumed to be stable, and efforts to save energy costs therefore only focused on reducing its magnitude but not to extinguish it completely. In their proof of principle, Björn Hof and his group have now shown that this assumption was wrong, and that a turbulent flow can, indeed, be transformed to a laminar one. The flow thereafter remains laminar unless it is disturbed again. Turbulent flow (top) compared to laminar flow (bottom). Credit: Jakob Kühnen \"Nobody knew that it was possible to get rid of turbulence in practice. We have now proven that it can be done. This opens up new possibilities to develop applications for pipelines,\" explains Jakob Kühnen. The secret lies in the velocity profile, i.e., in the variation of the flow velocity when looking at different positions in the pipe's cross section. The flow is fastest in the middle of the pipe while it is much slower near the walls. By placing rotors in the flow that reduced the difference between the fluid in the center and that close to the wall, the researchers managed to obtain a \"flatter\" profile. For such flow profiles, the processes that sustain and create turbulent eddies fail and the fluid gradually returns to smooth laminar motion and it remained laminar until it reached the end of the pipe. Another way to obtain the flat velocity profile was to inject liquid from the wall. Yet another implementation of the idea of a flat velocity profile was a moving part of the pipe: by moving the walls quickly over a stretch of the pipe, they also obtained the same flat profile that restored the laminar flow. Turbulent flow (top) compared to laminar flow (bottom). Credit: Jakob Kühnen The group has already registered two patents for their discovery. However, turning this proof of concept experiment into a system that can be used in actual oil or water pipelines all over the world will require some more efforts in development. So far, the concept was proven for relatively small velocities, but for use in pipelines, an application working at larger velocity will be necessary. In computer simulations, however, the flat velocity profile always led to a successful elimination of turbulence, which is very promising for future developments. \"In computer simulations, we have tested the impact of the flat velocity profile for Reynolds numbers up to 100.000, and it has worked absolutely everywhere. The next step is now to make it work also for high speeds in the experiments,\" says Björn Hof. ", "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 Turbulence is the major cause of friction losses in transport processes and it is responsible for a drastic drag increase in flows over bounding surfaces. While much effort is invested into developing ways to control and reduce turbulence intensities 1 , 2 , 3 , so far no methods exist to altogether eliminate turbulence if velocities are sufficiently large. We demonstrate for pipe flow that appropriate distortions to the velocity profile lead to a complete collapse of turbulence and subsequently friction losses are reduced by as much as 90%. Counterintuitively, the return to laminar motion is accomplished by initially increasing turbulence intensities or by transiently amplifying wall shear. Since neither the Reynolds number nor the shear stresses decrease (the latter often increase), these measures are not indicative of turbulence collapse. Instead, an amplification mechanism 4 , 5 measuring the interaction between eddies and the mean shear is found to set a threshold below which turbulence is suppressed beyond recovery. Main Flows through pipes and hydraulic networks are generally turbulent and the friction losses encountered in these flows are responsible for approximately 10% of the global electric energy consumption. Here turbulence causes a severe drag increase and consequently much larger forces are needed to maintain desired flow rates. In pipes, both laminar and turbulent states are stable (the former is believed to be linearly stable for all Reynolds number (Re) values; the latter is stable if Re > 2,040 (ref. 6 )), but with increasing speed the laminar state becomes more and more susceptible to small disturbances. Hence, in practice most flows are turbulent at sufficiently large Re. While the stability of laminar flow has been studied in great detail, little attention has been paid to the susceptibility of turbulence, the general assumption being that once turbulence is established it is stable. Many turbulence control strategies have been put forward to reduce the drag encountered in shear flows 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 . Recent strategies employ feedback mechanisms to actively counter selected velocity components or vortices. Such methods usually require knowledge of the full turbulent velocity field. In computer simulations 7 , 8 , it could be demonstrated that under these ideal conditions, flows at a low Re number can even be relaminarized. In experiments, the required detailed manipulation of the time-dependent velocity field is, however, currently impossible to achieve. Other studies employ passive (for example, riblets) or active (oscillations or excitation of travelling waves) methods to interfere with the near-wall turbulence creation. Typically here drag reduction of 10 to 40% has been reported, but often the control cost is substantially higher than the gain, or a net gain can be achieved only in a narrow Re number regime. Instead of attempting to control or counter certain components of the complex fluctuating flow fields, we will show in the following that by appropriately disturbing the mean profile, turbulence can be pushed outside its limit of existence and as a consequence the entire flow relaminarizes. Disturbance schemes are developed with the aid of direct numerical simulations (DNSs) of pipe flow and subsequently implemented and tested in experiments. In the DNS, a flow is simulated in a five-diameter ( D )-long pipe and periodic boundary conditions are applied in the axial direction. Initially we perturb laminar pipe flow by adding fluctuation levels of a fully turbulent velocity field rescaled by a factor ( k ) to a laminar flow field. As shown in Fig. 1a (dark blue curve), for small initial perturbations (that is, small k ), the disturbance eventually decays and the flow remains laminar. For sufficiently large amplitudes ( k of order unity), turbulence is triggered (purple, red and cyan curves). So far, this is the familiar picture of the transition to turbulence in shear flows, where turbulence is triggered only if perturbation amplitudes surpass a certain threshold. However, when increasing the turbulent fluctuations well beyond their usual levels ( k > 2.5), surprisingly the highly turbulent flow almost immediately collapses and returns to laminar (light and dark green curves). Here the initially strong vortical motion leads to a redistribution of shear resulting in an unusually flat velocity profile (black profile in Fig. 1c ). Fig. 1: Perturbing turbulence. a , Direct numerical simulations of pipe flow starting from turbulent initial conditions (taken from a run at Re = 10,000), rescaled by a constant factor k and added to the laminar base flow at Re = 4,000, which was then integrated forward in time (at Re = 4,000). For small initial energies, perturbations die out (dark blue curve). For sufficiently large energies ( k ≈1), transition to turbulence occurs (red, purple and cyan). For even larger energies ( k > 2.5), however, the initially turbulent flow is destabilized and collapses after a short time (light and dark green curves). The six streamwise vorticity isosurface figures show ω z = +/− (red/blue) 7.2, 2.0 and 1.6 U / D respectively at snapshot times t 0 = 0, t 1 = 5 and t 2 = 10 ( D / U ). b , Fully turbulent flow (top panel) at Re = 3,100 is perturbed by vigorously stirring the fluid with four rotors. The more strongly turbulent flow (second panel) eventually relaminarizes as it proceeds downstream (third and fourth panel). c , Temporally and azimuthally averaged velocity fields of modified/perturbed flow fields in simulations and experiments. u z is the streamwise velocity component; the cross-stream components are denoted by u r and u θ . d , Relaminarization of fully turbulent flow in experiments at Re = 3,100. The flow is perturbed by injecting 25 jets of fluid radially through the pipe wall. When actuated, the fluctuation levels in the flow drop (top panel) and the centre line velocity switches from the turbulent level to the laminar value (2 U , where U is the mean velocity in the pipe) (bottom panel). Full size image<|im_end|> <|im_start|>assistant Scientists have assumed that once a flow of a fluid has become turbulent, turbulence would persist. Researchers at the Institute of Science and Technology Austria (IST Austria), including Professor Björn Hof and co-first authors Jakob Kühnen and Baofang Song, have now shown that this is not the case. In their experiments, which they published in Nature Physics, they destabilized turbulence in a pipe so that the flow turned to a laminar (non-turbulent) state, and they observed that the flow remained laminar thereafter. Eliminating turbulence can save as much as 95 percent of the energy required to pump a fluid through a pipe. The amount of energy used by industry to pump fluids through pipes is considerable and corresponds to approximately 10 percent of the global electricity consumption. It therefore does not come as a surprise that researchers worldwide are seeking ways to reduce these costs. The major part of these energy losses is caused by turbulence, a phenomenon that leads to a drastic increase of frictional drag, requiring much more energy to pump the fluid. Previous approaches have aimed to locally reduce turbulence levels. Now, the research group of Björn Hof at IST Austria has taken an entirely new approach, tackling the problem from a different side. Rather than temporarily weakening turbulence, they destabilized existing turbulence so that the flow automatically became laminar. In a so-called laminar flow, a fluid flows in parallel layers which do not mix. The opposite of this is a turbulent flow, which is characterized by vortices and chaotic changes in pressure and velocity within the fluid. Most flows that we can observe in nature and in engineering are turbulent, from the smoke of an extinguished candle to the flow of blood in the left ventricle of our heart. In pipes, both laminar and turbulent flows can, in principle, exist and be stable, but a small disturbance can make a laminar flow turbulent. Turbulence in pipes was until now assumed to be stable, and efforts to save energy costs therefore only focused on reducing its magnitude but not to extinguish it completely. In their proof of principle, Björn Hof and his group have now shown that this assumption was wrong, and that a turbulent flow can, indeed, be transformed to a laminar one. The flow thereafter remains laminar unless it is disturbed again. Turbulent flow (top) compared to laminar flow (bottom). Credit: Jakob Kühnen "Nobody knew that it was possible to get rid of turbulence in practice. We have now proven that it can be done. This opens up new possibilities to develop applications for pipelines," explains Jakob Kühnen. The secret lies in the velocity profile, i.e., in the variation of the flow velocity when looking at different positions in the pipe's cross section. The flow is fastest in the middle of the pipe while it is much slower near the walls. By placing rotors in the flow that reduced the difference between the fluid in the center and that close to the wall, the researchers managed to obtain a "flatter" profile. For such flow profiles, the processes that sustain and create turbulent eddies fail and the fluid gradually returns to smooth laminar motion and it remained laminar until it reached the end of the pipe. Another way to obtain the flat velocity profile was to inject liquid from the wall. Yet another implementation of the idea of a flat velocity profile was a moving part of the pipe: by moving the walls quickly over a stretch of the pipe, they also obtained the same flat profile that restored the laminar flow. Turbulent flow (top) compared to laminar flow (bottom). Credit: Jakob Kühnen The group has already registered two patents for their discovery. However, turning this proof of concept experiment into a system that can be used in actual oil or water pipelines all over the world will require some more efforts in development. So far, the concept was proven for relatively small velocities, but for use in pipelines, an application working at larger velocity will be necessary. In computer simulations, however, the flat velocity profile always led to a successful elimination of turbulence, which is very promising for future developments. "In computer simulations, we have tested the impact of the flat velocity profile for Reynolds numbers up to 100.000, and it has worked absolutely everywhere. The next step is now to make it work also for high speeds in the experiments," says Björn Hof. <|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 Several Mousterian sites in France have yielded large numbers of small black blocs . The usual interpretation is that these ‘manganese oxides’ were collected for their colouring properties and used in body decoration, potentially for symbolic expression. Neanderthals habitually used fire and if they needed black material for decoration, soot and charcoal were readily available, whereas obtaining manganese oxides would have incurred considerably higher costs. Compositional analyses lead us to infer that late Neanderthals at Pech-de-l’Azé I were deliberately selecting manganese dioxide. Combustion experiments and thermo-gravimetric measurements demonstrate that manganese dioxide reduces wood’s auto-ignition temperature and substantially increases the rate of char combustion, leading us to conclude that the most beneficial use for manganese dioxide was in fire-making. With archaeological evidence for fire places and the conversion of the manganese dioxide to powder, we argue that Neanderthals at Pech-de-l’Azé I used manganese dioxide in fire-making and produced fire on demand. Introduction Whether the Neanderthal archaeological record testifies to the kind of symbolic behaviours that are considered typical for ‘modern’ humans is a highly debated topic within palaeoanthropology, with the use of coloured materials such as ochres and manganese oxides one of the possible indicators of such behaviours 1 , 2 . More than forty Middle Palaeolithic sites in Europe have yielded coloured mineral materials, the majority dating to the end of the Middle Palaeolithic, between 60,000 and 40,000 years ago 3 . Several Mousterian and Châtelperronian sites in France have yielded large numbers of small black blocs ( Fig. 1 and Supplementary Information 1 ) and the usual interpretation is that these are manganese oxides collected for their colouring properties, perhaps for body decoration and potentially for social communication and symbolic expression 3 , 4 , 5 , 6 , 7 . It has been argued that in African Middle Stone Age contexts, ochres were used as a cosmetic pigment in female reproductive strategies 8 but in extending the hypothesis to the European late Middle Palaeolithic sites, the presence of black “manganese” was interpreted as a Neanderthal female aversion to using the colour red during glacial cycles when, it is argued, pair-bond stability would have been critical 8 . Ethnographic data 9 , 10 , 11 as well as other evidence 12 , 13 underline the limitations of exclusive interpretations as pigments and/or their use as symbolic mediators whilst Neanderthal use of ochre more than 200,000 years ago 14 shows that the manipulation of these materials has a significant time depth in the Middle Palaeolithic. In stark contrast with the wide variety of uses documented for iron oxides, the archaeological and ethnographic records contain very limited evidence for the use of manganese oxides 15 , 16 , all associated with decoration. Figure 1 Blocs from Pech-de-l’Azé I - both unmodified (b,d) and with abrasion marks (a,c). ( b ) is MD3 from the excavation spoil of early 20th century excavations and the others were recovered in the 2004 and 2005 field work campaigns. Full size image Thus far, researchers have focused exclusively on the colour properties of manganese oxides, however, decorative use might imply that any black material soft enough to mark and resilient enough for the mark to remain could have been used. Indeed, both carbon-rich materials and black manganese ores were used in the production of Upper Palaeolithic cave art 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 . Neanderthals habitually used fire 25 and if they needed a black material for body decoration, carbon-rich materials such as soot and charcoal were readily available. The use of such carbon-rich materials for body decoration is documented in the ethnographic literature 15 . In contrast to these fire residues, manganese oxides would have had to have been sourced and transported, at considerably higher costs. An explanation of such investments should take into consideration either the possibility of special colouring properties or the chemical properties of manganese oxides, including their oxidising and catalytic properties. In exploring the potential uses, we have studied the Neanderthal site of Pech-de-l’Azé I where several hundred small black blocs ( Fig. 1 ) were uncovered from a Mousterian of Acheulean Tradition layer that was excavated by Bordes in 1954–55 and 1970–71 and more recently by Soressi in 2004–5 26 . The total weight of curated blocs from the site is approximately 0.75 kg. Layer 4, sealed by three metres of undisturbed Middle Palaeolithic deposits, with no Upper Palaeolithic deposit present at the site ( Supplementary Information 1 ), was called “ le niveau de foyer” by Bordes 27 because of the abundant presence of combustion features, also identified in the recent excavations. The clayey sand matrix of this layer contained stone artefacts, faunal remains, a juvenile Neanderthal tooth and the remains of various individual combustion features 26 , 28 . Single grain optically stimulated luminescence dating gave a weighted mean age of 51.4 + /−2.0 thousand years ago 29 . This age is consistent with conventional radiocarbon, electron-spin resonance and coupled electron-spin resonance/uranium-series ages 30 . Pech-de-l’Azé I was occupied by Neanderthals several millennia before the first evidence for anatomically modern humans in Europe 31 . Of the large number of blocs from Pech-de-l’Azé I available for study 26 , a majority show clear facets of use 6 . The facets display striations related to the abrasion of the blocs on a grindstone and part of one sandstone grindstone still covered with black residues was recovered 26 ( Supplementary Information 1 , Fig. 1 ). While the abrasion would have produced powder, some of the blocs may have been used to mark soft materials such as animal or human skin 3 . The majority of the Pech-de-l’Azé I manganese ore finds come from Layer 4, but the upper levels also yielded black blocs 26 . Pech-de-l’Azé I is not unique and Table 1 in Supplementary Information 1 lists other Mousterian sites in France that are reported to have produced ‘manganese ore’ blocs and preserve evidence of combustion features.", "role": "user" }, { "content": "Several Neanderthal sites in France have yielded large numbers of small black blocs. Neanderthals used these 'manganese oxides' in fire-making and not as previously thought for colouring. The usual interpretation is that these 'manganese oxides' were collected for their colouring properties and used in body decoration, potentially for symbolic expression. Neanderthals habitually used fire and if they needed black material for decoration, soot and charcoal were readily available, whereas obtaining manganese oxides would have incurred considerably higher subsistence costs. Combustion A series of compositional analyses has led scientists from Leiden University and Delft University of Technology to infer that late Neanderthals at Pech-de-l'Azé I (Dordogne, SW France) were deliberately selecting manganese dioxide, 50,000 years ago. Statistically designed combustion experiments and thermo- gravimetric (TGA) measurements demonstrate that manganese dioxide reduces wood's auto-ignition temperature and substantially increases the rate of char combustion; in other words manganese dioxide facilitates fire making. (Youtube film showing the difference in combustion, lowering the ignition temperature from 350 to 250 degrees) Archaeological evidence for both fire places and the conversion of manganese dioxide blocs to powder supports the hypothesis that Neanderthals at Pech-de-l'Azé I used manganese dioxide in fire-making. Fire would have provided important subsistence benefits but its social and symbolic significance should not be overlooked. Neanderthal cognitive capabilities The selection and use of manganese dioxide for fire making is unknown from the ethnographic record of recent hunter gatherers. This knowledge had been lost. This unusual behaviour holds potential significance for our understanding of Neanderthal cognitive capabilities through the extent of their knowledge and insights. The actions involved in the preferential selection of a specific, non-combustible material and its use to make fire are not obvious nor intuitive. The knowledge and insights suggested by Neanderthal selection of manganese dioxide and use in fire-making are surprising and qualitatively different from the expertise commonly associated with Neanderthals. Interestingly, whilst Neanderthals may have sourced and used manganese dioxide in fire making 50,000 years ago, manganese dioxide has important uses today in energy storage (batteries) and potentially in future clean energy production systems. Manganese dioxide tolerated more freshly cut 'green' wood Dr Peter Heyes, the first author of the paper, suggests: 'We don't know how Neanderthals made fire but given their skills with lithics, we might start with an assumption they used sparks and tinder. We don't bring it out particularly in the paper but manganese dioxide added to wood shavings or other tinder increases the efficiency with which the tinder captures a spark and lights. Starting a fire using sparks from flint without a metal striker is not as easy as it may seem but manganese dioxide has a significant beneficial effect. Woodsmen typically keep a supply of naturally air-dried wood shavings or other tinder to help light fires. From the evidence of the wear patterns on their lithics, Neanderthals cut and whittled wood. If we assume Neanderthals could keep a supply of air-dried wood shavings, then once they had a small fire established aided by manganese dioxide, it could have been built with twigs and small braches. The growing fire would have tolerated more freshly cut 'green' wood. Finding evidence to support a view on Neanderthal management of wood fuel resources is a very remote possibility. It could nevertheless have been an important aspect of subsistence. If Neanderthals could devote time and resources to collecting manganese dioxide for fire making, it is perhaps not unreasonable to assume they could manage wood fuel resources effectively.' ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Several Mousterian sites in France have yielded large numbers of small black blocs . The usual interpretation is that these ‘manganese oxides’ were collected for their colouring properties and used in body decoration, potentially for symbolic expression. Neanderthals habitually used fire and if they needed black material for decoration, soot and charcoal were readily available, whereas obtaining manganese oxides would have incurred considerably higher costs. Compositional analyses lead us to infer that late Neanderthals at Pech-de-l’Azé I were deliberately selecting manganese dioxide. Combustion experiments and thermo-gravimetric measurements demonstrate that manganese dioxide reduces wood’s auto-ignition temperature and substantially increases the rate of char combustion, leading us to conclude that the most beneficial use for manganese dioxide was in fire-making. With archaeological evidence for fire places and the conversion of the manganese dioxide to powder, we argue that Neanderthals at Pech-de-l’Azé I used manganese dioxide in fire-making and produced fire on demand. Introduction Whether the Neanderthal archaeological record testifies to the kind of symbolic behaviours that are considered typical for ‘modern’ humans is a highly debated topic within palaeoanthropology, with the use of coloured materials such as ochres and manganese oxides one of the possible indicators of such behaviours 1 , 2 . More than forty Middle Palaeolithic sites in Europe have yielded coloured mineral materials, the majority dating to the end of the Middle Palaeolithic, between 60,000 and 40,000 years ago 3 . Several Mousterian and Châtelperronian sites in France have yielded large numbers of small black blocs ( Fig. 1 and Supplementary Information 1 ) and the usual interpretation is that these are manganese oxides collected for their colouring properties, perhaps for body decoration and potentially for social communication and symbolic expression 3 , 4 , 5 , 6 , 7 . It has been argued that in African Middle Stone Age contexts, ochres were used as a cosmetic pigment in female reproductive strategies 8 but in extending the hypothesis to the European late Middle Palaeolithic sites, the presence of black “manganese” was interpreted as a Neanderthal female aversion to using the colour red during glacial cycles when, it is argued, pair-bond stability would have been critical 8 . Ethnographic data 9 , 10 , 11 as well as other evidence 12 , 13 underline the limitations of exclusive interpretations as pigments and/or their use as symbolic mediators whilst Neanderthal use of ochre more than 200,000 years ago 14 shows that the manipulation of these materials has a significant time depth in the Middle Palaeolithic. In stark contrast with the wide variety of uses documented for iron oxides, the archaeological and ethnographic records contain very limited evidence for the use of manganese oxides 15 , 16 , all associated with decoration. Figure 1 Blocs from Pech-de-l’Azé I - both unmodified (b,d) and with abrasion marks (a,c). ( b ) is MD3 from the excavation spoil of early 20th century excavations and the others were recovered in the 2004 and 2005 field work campaigns. Full size image Thus far, researchers have focused exclusively on the colour properties of manganese oxides, however, decorative use might imply that any black material soft enough to mark and resilient enough for the mark to remain could have been used. Indeed, both carbon-rich materials and black manganese ores were used in the production of Upper Palaeolithic cave art 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 . Neanderthals habitually used fire 25 and if they needed a black material for body decoration, carbon-rich materials such as soot and charcoal were readily available. The use of such carbon-rich materials for body decoration is documented in the ethnographic literature 15 . In contrast to these fire residues, manganese oxides would have had to have been sourced and transported, at considerably higher costs. An explanation of such investments should take into consideration either the possibility of special colouring properties or the chemical properties of manganese oxides, including their oxidising and catalytic properties. In exploring the potential uses, we have studied the Neanderthal site of Pech-de-l’Azé I where several hundred small black blocs ( Fig. 1 ) were uncovered from a Mousterian of Acheulean Tradition layer that was excavated by Bordes in 1954–55 and 1970–71 and more recently by Soressi in 2004–5 26 . The total weight of curated blocs from the site is approximately 0.75 kg. Layer 4, sealed by three metres of undisturbed Middle Palaeolithic deposits, with no Upper Palaeolithic deposit present at the site ( Supplementary Information 1 ), was called “ le niveau de foyer” by Bordes 27 because of the abundant presence of combustion features, also identified in the recent excavations. The clayey sand matrix of this layer contained stone artefacts, faunal remains, a juvenile Neanderthal tooth and the remains of various individual combustion features 26 , 28 . Single grain optically stimulated luminescence dating gave a weighted mean age of 51.4 + /−2.0 thousand years ago 29 . This age is consistent with conventional radiocarbon, electron-spin resonance and coupled electron-spin resonance/uranium-series ages 30 . Pech-de-l’Azé I was occupied by Neanderthals several millennia before the first evidence for anatomically modern humans in Europe 31 . Of the large number of blocs from Pech-de-l’Azé I available for study 26 , a majority show clear facets of use 6 . The facets display striations related to the abrasion of the blocs on a grindstone and part of one sandstone grindstone still covered with black residues was recovered 26 ( Supplementary Information 1 , Fig. 1 ). While the abrasion would have produced powder, some of the blocs may have been used to mark soft materials such as animal or human skin 3 . The majority of the Pech-de-l’Azé I manganese ore finds come from Layer 4, but the upper levels also yielded black blocs 26 . Pech-de-l’Azé I is not unique and Table 1 in Supplementary Information 1 lists other Mousterian sites in France that are reported to have produced ‘manganese ore’ blocs and preserve evidence of combustion features.<|im_end|> <|im_start|>assistant Several Neanderthal sites in France have yielded large numbers of small black blocs. Neanderthals used these 'manganese oxides' in fire-making and not as previously thought for colouring. The usual interpretation is that these 'manganese oxides' were collected for their colouring properties and used in body decoration, potentially for symbolic expression. Neanderthals habitually used fire and if they needed black material for decoration, soot and charcoal were readily available, whereas obtaining manganese oxides would have incurred considerably higher subsistence costs. Combustion A series of compositional analyses has led scientists from Leiden University and Delft University of Technology to infer that late Neanderthals at Pech-de-l'Azé I (Dordogne, SW France) were deliberately selecting manganese dioxide, 50,000 years ago. Statistically designed combustion experiments and thermo- gravimetric (TGA) measurements demonstrate that manganese dioxide reduces wood's auto-ignition temperature and substantially increases the rate of char combustion; in other words manganese dioxide facilitates fire making. (Youtube film showing the difference in combustion, lowering the ignition temperature from 350 to 250 degrees) Archaeological evidence for both fire places and the conversion of manganese dioxide blocs to powder supports the hypothesis that Neanderthals at Pech-de-l'Azé I used manganese dioxide in fire-making. Fire would have provided important subsistence benefits but its social and symbolic significance should not be overlooked. Neanderthal cognitive capabilities The selection and use of manganese dioxide for fire making is unknown from the ethnographic record of recent hunter gatherers. This knowledge had been lost. This unusual behaviour holds potential significance for our understanding of Neanderthal cognitive capabilities through the extent of their knowledge and insights. The actions involved in the preferential selection of a specific, non-combustible material and its use to make fire are not obvious nor intuitive. The knowledge and insights suggested by Neanderthal selection of manganese dioxide and use in fire-making are surprising and qualitatively different from the expertise commonly associated with Neanderthals. Interestingly, whilst Neanderthals may have sourced and used manganese dioxide in fire making 50,000 years ago, manganese dioxide has important uses today in energy storage (batteries) and potentially in future clean energy production systems. Manganese dioxide tolerated more freshly cut 'green' wood Dr Peter Heyes, the first author of the paper, suggests: 'We don't know how Neanderthals made fire but given their skills with lithics, we might start with an assumption they used sparks and tinder. We don't bring it out particularly in the paper but manganese dioxide added to wood shavings or other tinder increases the efficiency with which the tinder captures a spark and lights. Starting a fire using sparks from flint without a metal striker is not as easy as it may seem but manganese dioxide has a significant beneficial effect. Woodsmen typically keep a supply of naturally air-dried wood shavings or other tinder to help light fires. From the evidence of the wear patterns on their lithics, Neanderthals cut and whittled wood. If we assume Neanderthals could keep a supply of air-dried wood shavings, then once they had a small fire established aided by manganese dioxide, it could have been built with twigs and small braches. The growing fire would have tolerated more freshly cut 'green' wood. Finding evidence to support a view on Neanderthal management of wood fuel resources is a very remote possibility. It could nevertheless have been an important aspect of subsistence. If Neanderthals could devote time and resources to collecting manganese dioxide for fire making, it is perhaps not unreasonable to assume they could manage wood fuel resources effectively.' <|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 Larvae of flies and gnats (Diptera) form a crucial component of many terrestrial and freshwater ecosystems in the extant biosphere. Larvae of Diptera play a central role in water purification, matter and energy transfer in riparian ecosystems in rivers, carbon cycling in lakes and forests as well as being major decomposers of dead organic matter. Despite all these important roles, dipteran larvae are most often ignored in palaeoecological studies, due to the difficulty of the taxonomic identification of fossil larvae, but also due to the perceived importance of adult dipterans in palaeoentomological and taxonomic studies. Despite that, much information on palaeoecosystems can be gained from studying fossil dipteran larvae, in particular for well preserved specimens from fossil resins (ambers and copals). Since ambers are selectively preserving fauna of trunks and leaf litter, it allows us to learn a lot about xylophages and saprophages of amber forests, such as Eocene Baltic amber forest. Here we present immature stages (larvae and pupae) of the dipteran ingroup Bibionomorpha, from Baltic and Bitterfeld amber forests. We have recorded at least four different larval morphotypes, one with four distinct instars, and at least three pupal morphotypes. One larva is recognised as a new species and can be interpreted either as a representative of a highly derived ingroup of Bibionidae or as a sister species to Bibionidae. Also represented by single larval specimens are the groups Pachyneura (Pachyneuridae) and Sylvicola (Anisopodidae). The majority of the recorded specimens are representatives of the group Mycetobia (Anisopodidae). Due to the abundance of immature stages of Mycetobia , we have been able to reconstruct the number of larval stages (4) and relative growth rate of these fossil dipterans. We discuss implications of these finds. Cite this as Baranov VA, Schädel M, Haug JT. 2019 . Fly palaeo-evo-devo: immature stages of bibionomorphan dipterans in Baltic and Bitterfeld amber . PeerJ 7 : e7843 Main article text Introduction Holometabola is a hyperdiverse group of organisms, representing the dominant part of animal life in terrestrial ecosystems ( Grimaldi & Engel, 2005 ). Representatives of the group such as bees, butterflies, beetles and mosquitoes are therefore the best known forms of Insecta to most people. The dominance of holometabolans has led researchers to consider Holometabola as one of the largest groups of Metazoa ( Grimaldi & Engel, 2005 ; Engel, 2019 ). The evolution of niche differentiation between the larva and the adult (see Haug, in press ) has been interpreted as one of the driving factors of their success. The evolutionary independence of different life stages and phases (see Scholtz, 2005 ) has allowed holometabolans to utilize a very wide spectrum of habitats and ecological niches ( Grimaldi & Engel, 2005 ). Larvae of flies and midges (representatives of the group Diptera) are successful in diverse habitats, from glaciers at the Antarctic mainland to the fast-drying rock pools of central Africa ( Armitage, Pinder & Cranston, 2012 ; Marshall, 2012 ). Due to such variety of habitats occupied, larvae of Diptera have become involved in numerous critical ecosystem functions ( Marshall, 2012 ). Dipteran larvae are crucial saprophages, recycling dead organic matter in both aquatic and terrestrial ecosystems, and therefore heavily influence biogeochemical cycles of matter and energy, for example in riparian ecosystems ( Marshall, 2012 ; McAlister, 2017 ). This ecological role of larval forms of Diptera became especially important about 80 million years ago, in the Upper Cretaceous, when due to the Cretaceous Terrestrial Revolution (CTR) angiosperm plants have become the dominant players in the ecosystem ( Fastovsky et al., 2004 ; McKenna et al., 2015 ). The emergence of angiosperm plants in terrestrial ecosystem probably led to an increased load of dead organic matter into terrestrial and freshwater ecosystems ( Kalugina, 1974a ; Kalugina, 1974b ; McKenna et al., 2015 ). Such a drastic ecosystem change has led to shifts in the communities of various lineages of Insecta ( Kalugina, 1974a ; Kalugina, 1974b ). Such shifts included the extinction or decline of certain systematic and ecological groups. Among them were nectic and benthic oxyphilic forms living in dystrophic lakes. Vice versa, other groups, such as specialized pollinators or saprophages, have experienced an enormous diversification ( Sinichenkova & Zherikhin, 1996 ). Among the groups experiencing a pronounced diversification were many ingroups of Diptera ( Grimaldi & Engel, 2005 ). Numerous groups of dipterans with terrestrial larvae are associated with decaying organic material, such as dead wood, fungal fruit bodies, dead leaves, or animals corpses ( Keilin & Tate, 1940 ; Marshall, 2012 ). Among the most abundant extant saprophagous forms of Diptera (with predominantly terrestrial larvae) are representatives of Bibionomorpha ( Marshall, 2012 ; Ševčík et al., 2016 ). Bibionomorpha includes numerous ingroups diverse representatives. However, larvae of Bibionomorpha are predominantly restricted to terrestrial habitats ( Fig. 1 , modified and simplified from Ševčík et al., 2016 ). Figure 1: Phylogenetic relationship among different lineages of Bibionomorpha sensu lato, modified from Ševčík et al., 2016 . Bayesian hypothesis for relationships among selected taxa of Bibionomorpha based on DNA sequence data (18S, 28S, CAD, 12S, 16S, and COI), 5,018 characters. Position of the Perissommatidae were inferred from comparing phylogeny from ( Marshall, 2012 with Ševčík et al., 2016 ). Download full-size image DOI: 10.7717/peerj.7843/fig-1 Table 1: List of material examined. ID-Number Taxa Specimens Syninclusions Deposited Origin GPIH-Schlee-0024 Dinobibio hoffeinseorum 1 Acalyptrata GPIH Baltic Dip-00642 larvae Sylvicola (?) 1 Plant material+ stellate hairs DEI Baltic PED-4395 Mycetobia connexa male, female, pupal exuvia partial inclusion of an adult beetle PED Baltic BI-2350 Mycetobia larvae 1 none GPIH Bitterfeld GPIH-3706 W Mycetobia larvae 1 Phoridae adult+stellate hairs GPIH Baltic Dip-00639 Mycetobia larvae 1 DEI Baltic PED-4965 Mycetobia larvae 1 PED Baltic PED-4970 Mycetobia larvae 1 PED Baltic PED-5695 Mycetobia larvae 1 Cicadellidae nymph, larva of Coccidoidea, worker ant and non-biting midge female (Diptera: Chironomidae: Tanytarsini) PED Baltic GPIH-L-7592 Mycetobia larvae 2 Fragment of the Diptera Brachycera female, mites, stellate hairs GPIH Baltic Dip-00640 Mycetobia larvae 3 2 males, 1 female Rheosmittia pertenuis DEI", "role": "user" }, { "content": "Scientists at Ludwig-Maximilians-Universitaet (LMU) in Munich have shown that the incidence of midge and fly larvae in amber is far higher than previously thought. The new finds shed light on insect evolution and the ecology in the Baltic amber forest during the Eocene epoch. In the Eocene epoch—between 56 and 33.9 million years ago—much of Northern Europe was covered by a huge forest, now referred to as the Baltic amber forest. The forest was probably dominated by pines and oaks, but also comprised representatives of many other deciduous species and conifers, including tropical taxa. The resins produced by the forest account for all of Europe's amber, including the samples in which the LMU zoologists Viktor Baranov, Mario Schädel and Joachim T. Haug have now discovered many examples of entrapped midge and fly larvae. In a paper published in the online journal PeerJ, they point out that these finds refute the widespread notion that amber is devoid of such fossils. Their analysis also provides new evidence in relation to the ecology of the amber forests of Eocene age, which supports a new interpretation of this habitat as a warm to temperate seasonal humid forest ecosystem. Flies and midges (Diptera) make up one of the most diverse groups of insects found in Germany. Their larval forms are an important element of many ecosystems and play a significant role in, for example, the decomposition and recycling of biomass. In spite of their ecological prominence, little is known about the evolution of dipteran larvae, and the fossilized specimens that have so far come to light—in particular those characteristic of terrestrial ecosystems—have so far been little studied. The authors of the new study have now identified more than 100 larvae in amber inclusions assembled by collectors in Northern Germany. The samples described come from either the Baltic or the Bitterfeld section of the amber forest. Most of the dipterans identified, belong to the group known as Bibionomorpha, whose evolutionary history extends over a period of more than 200 million years. With a total of 35 specimens, the group most frequently represented is the genus Mycetobia, which belongs to the Family Anisopodidae (whose members are commonly known as window gnats). Thanks to the abundance of this material, the researchers were able to reconstruct the relative growth rate of these larvae based on the length and width of the head capsule. The results confirmed that these gnats went through four larval stages, just like the present-day representatives of the same group. In addition, their overall morphology is very similar to that of extant window gnats. \"Since the morphologies of the other fossil bibionomorphan larvae are also very reminiscent of their recent relatives, we can safely assume that they occupied habitats similar to those of our contemporary forms,\" says Baranov, first author of the new paper. The presence of large numbers of Mycetobia larvae among the specimens examined therefore implies that Europe's amber forests were characterized by moist conditions and an abundance of decaying organic matter. Moreover, the researchers also discovered the first fossilized larva that could be assigned to the Pachyneura (Diptera, Pachyneuridae), and recent are associated with dead wood in undisturbed woodland. \"Within the scientific community, a new interpretation of Europe's amber forests is currently emerging. This is based on paleobotanical and isotope evidence which suggests that these woods constituted a warm-to-temperate seasonal ecosystem. Our findings provide further support for this picture,\" Baranov explains. He and his colleagues argue that it is quite conceivable that, under the climatic conditions prevailing in Europe during the Eocene, a subtropical, seasonal forest would have supplied abundant amounts of decaying organic matter in the form of leaf litter and dead plants and animals, as well as bacterial biofilms and fungi. In any case, the dipteran larvae provide an independent source of information that can be used to reconstruct the nature of the paleohabitats. \"Perhaps our most surprising find is a larva which we identified as a representative of a previously unknown group,\" says Baranov. While this larva belongs among the march flies (Diptera, Bibionidae), it exhibits a very unusual combination of morphological characters which finds no parallel among modern representatives of this group.\" In Baranov's opinion, the specimen may document an experimental phase of their evolution, during which different lineages independently \"discovered\" similar sets of morphological traits. ", "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 Larvae of flies and gnats (Diptera) form a crucial component of many terrestrial and freshwater ecosystems in the extant biosphere. Larvae of Diptera play a central role in water purification, matter and energy transfer in riparian ecosystems in rivers, carbon cycling in lakes and forests as well as being major decomposers of dead organic matter. Despite all these important roles, dipteran larvae are most often ignored in palaeoecological studies, due to the difficulty of the taxonomic identification of fossil larvae, but also due to the perceived importance of adult dipterans in palaeoentomological and taxonomic studies. Despite that, much information on palaeoecosystems can be gained from studying fossil dipteran larvae, in particular for well preserved specimens from fossil resins (ambers and copals). Since ambers are selectively preserving fauna of trunks and leaf litter, it allows us to learn a lot about xylophages and saprophages of amber forests, such as Eocene Baltic amber forest. Here we present immature stages (larvae and pupae) of the dipteran ingroup Bibionomorpha, from Baltic and Bitterfeld amber forests. We have recorded at least four different larval morphotypes, one with four distinct instars, and at least three pupal morphotypes. One larva is recognised as a new species and can be interpreted either as a representative of a highly derived ingroup of Bibionidae or as a sister species to Bibionidae. Also represented by single larval specimens are the groups Pachyneura (Pachyneuridae) and Sylvicola (Anisopodidae). The majority of the recorded specimens are representatives of the group Mycetobia (Anisopodidae). Due to the abundance of immature stages of Mycetobia , we have been able to reconstruct the number of larval stages (4) and relative growth rate of these fossil dipterans. We discuss implications of these finds. Cite this as Baranov VA, Schädel M, Haug JT. 2019 . Fly palaeo-evo-devo: immature stages of bibionomorphan dipterans in Baltic and Bitterfeld amber . PeerJ 7 : e7843 Main article text Introduction Holometabola is a hyperdiverse group of organisms, representing the dominant part of animal life in terrestrial ecosystems ( Grimaldi & Engel, 2005 ). Representatives of the group such as bees, butterflies, beetles and mosquitoes are therefore the best known forms of Insecta to most people. The dominance of holometabolans has led researchers to consider Holometabola as one of the largest groups of Metazoa ( Grimaldi & Engel, 2005 ; Engel, 2019 ). The evolution of niche differentiation between the larva and the adult (see Haug, in press ) has been interpreted as one of the driving factors of their success. The evolutionary independence of different life stages and phases (see Scholtz, 2005 ) has allowed holometabolans to utilize a very wide spectrum of habitats and ecological niches ( Grimaldi & Engel, 2005 ). Larvae of flies and midges (representatives of the group Diptera) are successful in diverse habitats, from glaciers at the Antarctic mainland to the fast-drying rock pools of central Africa ( Armitage, Pinder & Cranston, 2012 ; Marshall, 2012 ). Due to such variety of habitats occupied, larvae of Diptera have become involved in numerous critical ecosystem functions ( Marshall, 2012 ). Dipteran larvae are crucial saprophages, recycling dead organic matter in both aquatic and terrestrial ecosystems, and therefore heavily influence biogeochemical cycles of matter and energy, for example in riparian ecosystems ( Marshall, 2012 ; McAlister, 2017 ). This ecological role of larval forms of Diptera became especially important about 80 million years ago, in the Upper Cretaceous, when due to the Cretaceous Terrestrial Revolution (CTR) angiosperm plants have become the dominant players in the ecosystem ( Fastovsky et al., 2004 ; McKenna et al., 2015 ). The emergence of angiosperm plants in terrestrial ecosystem probably led to an increased load of dead organic matter into terrestrial and freshwater ecosystems ( Kalugina, 1974a ; Kalugina, 1974b ; McKenna et al., 2015 ). Such a drastic ecosystem change has led to shifts in the communities of various lineages of Insecta ( Kalugina, 1974a ; Kalugina, 1974b ). Such shifts included the extinction or decline of certain systematic and ecological groups. Among them were nectic and benthic oxyphilic forms living in dystrophic lakes. Vice versa, other groups, such as specialized pollinators or saprophages, have experienced an enormous diversification ( Sinichenkova & Zherikhin, 1996 ). Among the groups experiencing a pronounced diversification were many ingroups of Diptera ( Grimaldi & Engel, 2005 ). Numerous groups of dipterans with terrestrial larvae are associated with decaying organic material, such as dead wood, fungal fruit bodies, dead leaves, or animals corpses ( Keilin & Tate, 1940 ; Marshall, 2012 ). Among the most abundant extant saprophagous forms of Diptera (with predominantly terrestrial larvae) are representatives of Bibionomorpha ( Marshall, 2012 ; Ševčík et al., 2016 ). Bibionomorpha includes numerous ingroups diverse representatives. However, larvae of Bibionomorpha are predominantly restricted to terrestrial habitats ( Fig. 1 , modified and simplified from Ševčík et al., 2016 ). Figure 1: Phylogenetic relationship among different lineages of Bibionomorpha sensu lato, modified from Ševčík et al., 2016 . Bayesian hypothesis for relationships among selected taxa of Bibionomorpha based on DNA sequence data (18S, 28S, CAD, 12S, 16S, and COI), 5,018 characters. Position of the Perissommatidae were inferred from comparing phylogeny from ( Marshall, 2012 with Ševčík et al., 2016 ). Download full-size image DOI: 10.7717/peerj.7843/fig-1 Table 1: List of material examined. ID-Number Taxa Specimens Syninclusions Deposited Origin GPIH-Schlee-0024 Dinobibio hoffeinseorum 1 Acalyptrata GPIH Baltic Dip-00642 larvae Sylvicola (?) 1 Plant material+ stellate hairs DEI Baltic PED-4395 Mycetobia connexa male, female, pupal exuvia partial inclusion of an adult beetle PED Baltic BI-2350 Mycetobia larvae 1 none GPIH Bitterfeld GPIH-3706 W Mycetobia larvae 1 Phoridae adult+stellate hairs GPIH Baltic Dip-00639 Mycetobia larvae 1 DEI Baltic PED-4965 Mycetobia larvae 1 PED Baltic PED-4970 Mycetobia larvae 1 PED Baltic PED-5695 Mycetobia larvae 1 Cicadellidae nymph, larva of Coccidoidea, worker ant and non-biting midge female (Diptera: Chironomidae: Tanytarsini) PED Baltic GPIH-L-7592 Mycetobia larvae 2 Fragment of the Diptera Brachycera female, mites, stellate hairs GPIH Baltic Dip-00640 Mycetobia larvae 3 2 males, 1 female Rheosmittia pertenuis DEI<|im_end|> <|im_start|>assistant Scientists at Ludwig-Maximilians-Universitaet (LMU) in Munich have shown that the incidence of midge and fly larvae in amber is far higher than previously thought. The new finds shed light on insect evolution and the ecology in the Baltic amber forest during the Eocene epoch. In the Eocene epoch—between 56 and 33.9 million years ago—much of Northern Europe was covered by a huge forest, now referred to as the Baltic amber forest. The forest was probably dominated by pines and oaks, but also comprised representatives of many other deciduous species and conifers, including tropical taxa. The resins produced by the forest account for all of Europe's amber, including the samples in which the LMU zoologists Viktor Baranov, Mario Schädel and Joachim T. Haug have now discovered many examples of entrapped midge and fly larvae. In a paper published in the online journal PeerJ, they point out that these finds refute the widespread notion that amber is devoid of such fossils. Their analysis also provides new evidence in relation to the ecology of the amber forests of Eocene age, which supports a new interpretation of this habitat as a warm to temperate seasonal humid forest ecosystem. Flies and midges (Diptera) make up one of the most diverse groups of insects found in Germany. Their larval forms are an important element of many ecosystems and play a significant role in, for example, the decomposition and recycling of biomass. In spite of their ecological prominence, little is known about the evolution of dipteran larvae, and the fossilized specimens that have so far come to light—in particular those characteristic of terrestrial ecosystems—have so far been little studied. The authors of the new study have now identified more than 100 larvae in amber inclusions assembled by collectors in Northern Germany. The samples described come from either the Baltic or the Bitterfeld section of the amber forest. Most of the dipterans identified, belong to the group known as Bibionomorpha, whose evolutionary history extends over a period of more than 200 million years. With a total of 35 specimens, the group most frequently represented is the genus Mycetobia, which belongs to the Family Anisopodidae (whose members are commonly known as window gnats). Thanks to the abundance of this material, the researchers were able to reconstruct the relative growth rate of these larvae based on the length and width of the head capsule. The results confirmed that these gnats went through four larval stages, just like the present-day representatives of the same group. In addition, their overall morphology is very similar to that of extant window gnats. "Since the morphologies of the other fossil bibionomorphan larvae are also very reminiscent of their recent relatives, we can safely assume that they occupied habitats similar to those of our contemporary forms," says Baranov, first author of the new paper. The presence of large numbers of Mycetobia larvae among the specimens examined therefore implies that Europe's amber forests were characterized by moist conditions and an abundance of decaying organic matter. Moreover, the researchers also discovered the first fossilized larva that could be assigned to the Pachyneura (Diptera, Pachyneuridae), and recent are associated with dead wood in undisturbed woodland. "Within the scientific community, a new interpretation of Europe's amber forests is currently emerging. This is based on paleobotanical and isotope evidence which suggests that these woods constituted a warm-to-temperate seasonal ecosystem. Our findings provide further support for this picture," Baranov explains. He and his colleagues argue that it is quite conceivable that, under the climatic conditions prevailing in Europe during the Eocene, a subtropical, seasonal forest would have supplied abundant amounts of decaying organic matter in the form of leaf litter and dead plants and animals, as well as bacterial biofilms and fungi. In any case, the dipteran larvae provide an independent source of information that can be used to reconstruct the nature of the paleohabitats. "Perhaps our most surprising find is a larva which we identified as a representative of a previously unknown group," says Baranov. While this larva belongs among the march flies (Diptera, Bibionidae), it exhibits a very unusual combination of morphological characters which finds no parallel among modern representatives of this group." In Baranov's opinion, the specimen may document an experimental phase of their evolution, during which different lineages independently "discovered" similar sets of morphological traits. <|im_end|>

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2,599

[ { "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 By analyzing the exomes of 12,332 unrelated Swedish individuals, including 4,877 individuals affected with schizophrenia, in ways informed by exome sequences from 45,376 other individuals, we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant among individuals with schizophrenia than among controls ( P = 1.3 × 10 −10 ). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this elevation arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk. Main Schizophrenia is a psychiatric disorder with a lifetime risk of about 0.7% 1 and a heritability of 60–80% 2 , 3 despite greatly reduced reproductive fecundity 4 , 5 . Because individuals affected with schizophrenia have fewer offspring, purifying selection is expected to prevent high-risk alleles from reaching even modest allele frequencies 6 . Indeed, estimates of selection (when based only on the reproductive costs of schizophrenia) may underestimate the actual selective pressure against such alleles given emerging evidence that such alleles have multiple adverse effects: for example, rare copy number variations (CNVs), with penetrances ranging from 2–30% (the latter observed for 22q11.2 deletions), negatively affect cognition and fecundity even in their more-typical presentation without schizophrenia 7 . To the extent that such observations condition expectations for rare single-nucleotide variants, variants with a large effect on schizophrenia risk are likely to be rare in populations, requiring sequencing to find them. Distinguishing those variants that are extremely rare from variants that are segregating in a population is ideally informed by sequencing very-large numbers of individuals from the same population. We therefore analyzed the sequences of 12,332 unrelated individuals (4,946 affected with schizophrenia, 6,242 unaffected controls and 1,144 with other psychiatric illnesses whose analysis is beyond the scope of the current study) from Sweden (Online Methods ). We further informed this analysis with a much larger set of exome sequencing data from 45,376 individuals from multiple non-psychiatric cohorts ascertained by the Exome Aggregation Consortium 8 . This made it possible to identify among the Swedish research participants 244,246 coding-sequence and splice-site URVs that were present in single individuals, a set of variants that is greatly enriched for recent mutations, relative to the vastly larger fraction of heterozygosity that is a result of less-rare variants ( Fig. 1a ). This large set of variants made it possible to identify broad biological patterns among an excess of more than 1,000 protein-damaging URVs that we found in the exomes of 4,877 individuals affected with schizophrenia. Figure 1: URV distribution and association with schizophrenia. ( a , b ) Counts across coding-sequence and splice-site rare variants stratified by minor allele count across exome-sequencing data from 12,332 individuals indicating how many variants were observed in the ExAC cohort ( a ) and how many variants were classified as disruptive, damaging, missense non-damaging and synonymous ( b ). ( c ) Observed enrichment in schizophrenia cases compared with controls for coding-sequence and splice-site URVs across the main four annotation types. Enrichment and P values were computed using a linear regression model (left) and a logistic regression model (right). Horizontal bars indicate 95% confidence intervals. Full size image Results Exome-wide enrichment of URVs We analyzed the protein-coding sequences (the exomes) of 12,332 unrelated Swedish individuals, including 4,946 affected individuals with schizophrenia (2,951 males and 1,995 females), 6,242 unaffected controls (3,182 males and 3,060 females) and 1,144 individuals affected with other disorders (443 males and 701 females, used for population genetic analyses, but not as cases or controls). After removing 119 individuals for quality control reasons (mostly because of divergent ancestry, Online Methods ), we identified 244,246 coding-sequence and splice-site URVs (among 4,877 schizophrenia cases and 6,203 controls) that were present in only 1 of the 12,332 unrelated Swedish exomes analyzed and never seen in the Exome Aggregation Consortium (ExAC) cohort (which numbered 45,376 individuals after excluding the subjects from this cohort and other subjects ascertained for psychiatric disorders). We focused on URVs in most analyses because such variants, although comprising a tiny fraction (less than 0.2%) of the heterozygous sites in an individual, will be greatly enriched for recent mutations, and will therefore have been exposed to fewer generations of purifying selection. The size of the Swedish cohort analyzed, and the additional sequence data from ExAC, allowed us to greatly refine the identification of URVs; for example, among 5,092 (of the 12,332) individuals who were also part of an earlier sequencing study 9 , the additional data allowed us to re-classify ∼ 66% of variants that had been 'singletons' as segregating variants (not URVs in the current analysis). This may have been particularly helpful for refining analyses of challenging-to-interpret missense variants, as we describe below. We classified coding-sequence and splice-site variants into four groups ( Fig. 1b ): synonymous, which were exonic variants not predicted to change the encoded protein (63,230 URVs); missense non-damaging, which were missense variants not predicted to damage protein function (by the criteria below) (134,100 URVs); damaging, which were missense variants predicted (by an algorithm) to compromise protein function (Online Methods ), in-frame indels or variants affecting protein-protein-contact domains (27,390 URVs); and disruptive, which were variants that truncated or abrogated the encoded protein in a way that was readily classified as loss of function 10 or as triggering nonsense-mediated decay (NMD) 11 , including nonsense, frame shift, splice-site and, very rarely, read-through variants. (19,526 URVs). The terms protein-damaging and gene-disruptive refer to predicted effects on individual gene copies and the encoded proteins, rather than to effects on phenotypes; effects on phenotypes can be inferred", "role": "user" }, { "content": "(Medical Xpress)—Two teams of researchers looking to better understand what happens to people born with certain rare genetic mutations have found a link between an increased risk of schizophrenia and how long such people remain in school. In one of the studies, a team made up of researchers from several institutions in the U.S. and Sweden conducted a study of gene mutations in a large group of Swedish people, some of whom had been diagnosed with schizophrenia and compared them with schizophrenia rates. The other group conducted a similar analysis with a large group of people from Finland, Estonia and Sweden looking for a connection between gene mutations and school dropout rates. Both teams have published their results in the journal Nature Neuroscience. In the first study, the researchers looked at protein encoding sequences of DNA, focusing on rare mutations that did not appear in people who had never been diagnosed with a psychiatric illness. In so doing, they were able to see that the mutations were more common in those people that had been diagnosed with schizophrenia. They also found that the mutations were involved in the expression of proteins in the synapses of brain cells. These finding, the researchers suggest, indicate that such mutations play at least some role in the development of schizophrenia. In the other study, the researchers looked at similar rare mutations, but compared them to the amount of time that people stayed in school. They found that one such mutation could be linked with three fewer months of school attendance by those that had it than by students in the general population. For other people who had the rare mutations—specifically in parts of their brains—the researchers found a difference of six months less school attendance. Both teams note that they do not believe a single factor such as a person having a rare mutation is solely responsible for the development of brain disorders such as schizophrenia or for the amount of time a student remains in school—rather, both are suggesting that rare gene mutations may be one of the factors involved, along with other influences such as the environment in which people live. ", "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 By analyzing the exomes of 12,332 unrelated Swedish individuals, including 4,877 individuals affected with schizophrenia, in ways informed by exome sequences from 45,376 other individuals, we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant among individuals with schizophrenia than among controls ( P = 1.3 × 10 −10 ). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this elevation arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk. Main Schizophrenia is a psychiatric disorder with a lifetime risk of about 0.7% 1 and a heritability of 60–80% 2 , 3 despite greatly reduced reproductive fecundity 4 , 5 . Because individuals affected with schizophrenia have fewer offspring, purifying selection is expected to prevent high-risk alleles from reaching even modest allele frequencies 6 . Indeed, estimates of selection (when based only on the reproductive costs of schizophrenia) may underestimate the actual selective pressure against such alleles given emerging evidence that such alleles have multiple adverse effects: for example, rare copy number variations (CNVs), with penetrances ranging from 2–30% (the latter observed for 22q11.2 deletions), negatively affect cognition and fecundity even in their more-typical presentation without schizophrenia 7 . To the extent that such observations condition expectations for rare single-nucleotide variants, variants with a large effect on schizophrenia risk are likely to be rare in populations, requiring sequencing to find them. Distinguishing those variants that are extremely rare from variants that are segregating in a population is ideally informed by sequencing very-large numbers of individuals from the same population. We therefore analyzed the sequences of 12,332 unrelated individuals (4,946 affected with schizophrenia, 6,242 unaffected controls and 1,144 with other psychiatric illnesses whose analysis is beyond the scope of the current study) from Sweden (Online Methods ). We further informed this analysis with a much larger set of exome sequencing data from 45,376 individuals from multiple non-psychiatric cohorts ascertained by the Exome Aggregation Consortium 8 . This made it possible to identify among the Swedish research participants 244,246 coding-sequence and splice-site URVs that were present in single individuals, a set of variants that is greatly enriched for recent mutations, relative to the vastly larger fraction of heterozygosity that is a result of less-rare variants ( Fig. 1a ). This large set of variants made it possible to identify broad biological patterns among an excess of more than 1,000 protein-damaging URVs that we found in the exomes of 4,877 individuals affected with schizophrenia. Figure 1: URV distribution and association with schizophrenia. ( a , b ) Counts across coding-sequence and splice-site rare variants stratified by minor allele count across exome-sequencing data from 12,332 individuals indicating how many variants were observed in the ExAC cohort ( a ) and how many variants were classified as disruptive, damaging, missense non-damaging and synonymous ( b ). ( c ) Observed enrichment in schizophrenia cases compared with controls for coding-sequence and splice-site URVs across the main four annotation types. Enrichment and P values were computed using a linear regression model (left) and a logistic regression model (right). Horizontal bars indicate 95% confidence intervals. Full size image Results Exome-wide enrichment of URVs We analyzed the protein-coding sequences (the exomes) of 12,332 unrelated Swedish individuals, including 4,946 affected individuals with schizophrenia (2,951 males and 1,995 females), 6,242 unaffected controls (3,182 males and 3,060 females) and 1,144 individuals affected with other disorders (443 males and 701 females, used for population genetic analyses, but not as cases or controls). After removing 119 individuals for quality control reasons (mostly because of divergent ancestry, Online Methods ), we identified 244,246 coding-sequence and splice-site URVs (among 4,877 schizophrenia cases and 6,203 controls) that were present in only 1 of the 12,332 unrelated Swedish exomes analyzed and never seen in the Exome Aggregation Consortium (ExAC) cohort (which numbered 45,376 individuals after excluding the subjects from this cohort and other subjects ascertained for psychiatric disorders). We focused on URVs in most analyses because such variants, although comprising a tiny fraction (less than 0.2%) of the heterozygous sites in an individual, will be greatly enriched for recent mutations, and will therefore have been exposed to fewer generations of purifying selection. The size of the Swedish cohort analyzed, and the additional sequence data from ExAC, allowed us to greatly refine the identification of URVs; for example, among 5,092 (of the 12,332) individuals who were also part of an earlier sequencing study 9 , the additional data allowed us to re-classify ∼ 66% of variants that had been 'singletons' as segregating variants (not URVs in the current analysis). This may have been particularly helpful for refining analyses of challenging-to-interpret missense variants, as we describe below. We classified coding-sequence and splice-site variants into four groups ( Fig. 1b ): synonymous, which were exonic variants not predicted to change the encoded protein (63,230 URVs); missense non-damaging, which were missense variants not predicted to damage protein function (by the criteria below) (134,100 URVs); damaging, which were missense variants predicted (by an algorithm) to compromise protein function (Online Methods ), in-frame indels or variants affecting protein-protein-contact domains (27,390 URVs); and disruptive, which were variants that truncated or abrogated the encoded protein in a way that was readily classified as loss of function 10 or as triggering nonsense-mediated decay (NMD) 11 , including nonsense, frame shift, splice-site and, very rarely, read-through variants. (19,526 URVs). The terms protein-damaging and gene-disruptive refer to predicted effects on individual gene copies and the encoded proteins, rather than to effects on phenotypes; effects on phenotypes can be inferred<|im_end|> <|im_start|>assistant (Medical Xpress)—Two teams of researchers looking to better understand what happens to people born with certain rare genetic mutations have found a link between an increased risk of schizophrenia and how long such people remain in school. In one of the studies, a team made up of researchers from several institutions in the U.S. and Sweden conducted a study of gene mutations in a large group of Swedish people, some of whom had been diagnosed with schizophrenia and compared them with schizophrenia rates. The other group conducted a similar analysis with a large group of people from Finland, Estonia and Sweden looking for a connection between gene mutations and school dropout rates. Both teams have published their results in the journal Nature Neuroscience. In the first study, the researchers looked at protein encoding sequences of DNA, focusing on rare mutations that did not appear in people who had never been diagnosed with a psychiatric illness. In so doing, they were able to see that the mutations were more common in those people that had been diagnosed with schizophrenia. They also found that the mutations were involved in the expression of proteins in the synapses of brain cells. These finding, the researchers suggest, indicate that such mutations play at least some role in the development of schizophrenia. In the other study, the researchers looked at similar rare mutations, but compared them to the amount of time that people stayed in school. They found that one such mutation could be linked with three fewer months of school attendance by those that had it than by students in the general population. For other people who had the rare mutations—specifically in parts of their brains—the researchers found a difference of six months less school attendance. Both teams note that they do not believe a single factor such as a person having a rare mutation is solely responsible for the development of brain disorders such as schizophrenia or for the amount of time a student remains in school—rather, both are suggesting that rare gene mutations may be one of the factors involved, along with other influences such as the environment in which people live. <|im_end|>

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1766, 304, 279, 506, 20969, 315, 220, 19, 11, 23873, 7931, 11754, 449, 58533, 13, 19575, 220, 16, 25, 35514, 53, 8141, 323, 15360, 449, 58533, 13, 320, 264, 1174, 293, 883, 86759, 4028, 11058, 7962, 4474, 323, 89390, 29654, 9024, 27103, 44397, 1908, 555, 9099, 70510, 1797, 4028, 506, 638, 12, 6741, 11627, 828, 505, 220, 717, 11, 17079, 7931, 19392, 1268, 1690, 27103, 1051, 13468, 304, 279, 1398, 1741, 41944, 320, 264, 883, 323, 1268, 1690, 27103, 1051, 21771, 439, 62642, 11, 34446, 11, 3194, 1137, 2536, 1773, 309, 4210, 323, 69593, 320, 293, 7609, 320, 272, 883, 51541, 2841, 70272, 304, 58533, 5157, 7863, 449, 11835, 369, 11058, 7962, 4474, 323, 89390, 29654, 35514, 52837, 4028, 279, 1925, 3116, 21917, 4595, 13, 2998, 14172, 479, 323, 393, 2819, 1051, 25157, 1701, 264, 13790, 31649, 1646, 320, 2414, 8, 323, 264, 72810, 31649, 1646, 320, 1315, 570, 41009, 16283, 13519, 220, 2721, 4, 12410, 28090, 13, 8797, 1404, 2217, 18591, 1398, 638, 25480, 70272, 315, 35514, 52837, 1226, 30239, 279, 13128, 1824, 3785, 24630, 320, 1820, 506, 20969, 8, 315, 220, 717, 11, 17079, 46305, 31209, 7931, 11, 2737, 220, 19, 11, 26491, 11754, 7931, 449, 58533, 320, 17, 11, 24989, 25000, 323, 220, 16, 11, 22101, 28585, 705, 220, 21, 11, 12754, 78622, 11835, 320, 18, 11, 10828, 25000, 323, 220, 18, 11, 15101, 28585, 8, 323, 220, 16, 11, 8929, 7931, 11754, 449, 1023, 24673, 320, 17147, 25000, 323, 220, 19597, 28585, 11, 1511, 369, 7187, 19465, 29060, 11, 719, 539, 439, 5157, 477, 11835, 570, 4740, 18054, 220, 9079, 7931, 369, 4367, 2585, 8125, 320, 63995, 1606, 315, 37441, 16149, 66004, 11, 8267, 19331, 7026, 584, 11054, 220, 13719, 11, 14205, 11058, 7962, 4474, 323, 89390, 29654, 35514, 52837, 320, 77405, 220, 19, 11, 23873, 58533, 5157, 323, 220, 21, 11, 9639, 11835, 8, 430, 1051, 3118, 304, 1193, 220, 16, 315, 279, 220, 717, 11, 17079, 46305, 31209, 506, 20969, 30239, 323, 2646, 3970, 304, 279, 1398, 638, 4701, 35542, 73547, 320, 849, 1741, 8, 41944, 320, 8370, 49926, 220, 1774, 11, 18322, 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74285, 29060, 315, 17436, 4791, 12, 17324, 3194, 1137, 27103, 11, 439, 584, 7664, 3770, 13, 1226, 21771, 11058, 7962, 4474, 323, 89390, 29654, 27103, 1139, 3116, 5315, 320, 23966, 13, 220, 16, 65, 16919, 69593, 11, 902, 1051, 506, 14338, 27103, 539, 19698, 311, 2349, 279, 21136, 13128, 320, 5495, 11, 9870, 35514, 52837, 1237, 3194, 1137, 2536, 1773, 309, 4210, 11, 902, 1051, 3194, 1137, 27103, 539, 19698, 311, 5674, 13128, 734, 320, 1729, 279, 13186, 3770, 8, 320, 9565, 11, 1041, 35514, 52837, 1237, 34446, 11, 902, 1051, 3194, 1137, 27103, 19698, 320, 1729, 459, 12384, 8, 311, 30485, 13128, 734, 320, 20171, 19331, 7026, 304, 47867, 1280, 2053, 477, 27103, 28987, 13128, 10039, 39340, 54096, 31576, 320, 1544, 11, 15515, 35514, 52837, 1237, 323, 62642, 11, 902, 1051, 27103, 430, 60856, 477, 671, 12184, 660, 279, 21136, 13128, 304, 264, 1648, 430, 574, 31368, 21771, 439, 4814, 315, 734, 220, 605, 477, 439, 52605, 41902, 82076, 31815, 320, 45, 6204, 8, 220, 806, 1174, 2737, 41902, 11, 4124, 6541, 11, 89390, 29654, 323, 11, 1633, 19029, 11, 1373, 43847, 27103, 13, 320, 777, 11, 22593, 35514, 52837, 570, 578, 3878, 13128, 1773, 309, 4210, 323, 15207, 10694, 6722, 535, 8464, 311, 19698, 6372, 389, 3927, 15207, 11236, 323, 279, 21136, 28896, 11, 4856, 1109, 311, 6372, 389, 14345, 22583, 26, 6372, 389, 14345, 22583, 649, 387, 68695, 128257, 198, 128256, 78191, 198, 3269, 291, 950, 1630, 1911, 68850, 11874, 7411, 315, 12074, 3411, 311, 2731, 3619, 1148, 8741, 311, 1274, 9405, 449, 3738, 9024, 19465, 34684, 617, 1766, 264, 2723, 1990, 459, 7319, 5326, 315, 58533, 323, 1268, 1317, 1778, 1274, 7293, 304, 2978, 13, 763, 832, 315, 279, 7978, 11, 264, 2128, 1903, 709, 315, 12074, 505, 3892, 14673, 304, 279, 549, 815, 13, 323, 24067, 13375, 264, 4007, 315, 15207, 34684, 304, 264, 3544, 1912, 315, 31209, 1274, 11, 1063, 315, 8884, 1047, 1027, 29704, 449, 58533, 323, 7863, 1124, 449, 58533, 7969, 13, 578, 1023, 1912, 13375, 264, 4528, 6492, 449, 264, 3544, 1912, 315, 1274, 505, 37355, 11, 69462, 323, 24067, 3411, 369, 264, 3717, 1990, 15207, 34684, 323, 2978, 44381, 7969, 13, 11995, 7411, 617, 4756, 872, 3135, 304, 279, 8486, 22037, 85879, 13, 763, 279, 1176, 4007, 11, 279, 12074, 7111, 520, 13128, 11418, 24630, 315, 15922, 11, 21760, 389, 9024, 34684, 430, 1550, 539, 5101, 304, 1274, 889, 1047, 2646, 1027, 29704, 449, 264, 47657, 17563, 13, 763, 779, 3815, 11, 814, 1051, 3025, 311, 1518, 430, 279, 34684, 1051, 810, 4279, 304, 1884, 1274, 430, 1047, 1027, 29704, 449, 58533, 13, 2435, 1101, 1766, 430, 279, 34684, 1051, 6532, 304, 279, 7645, 315, 28896, 304, 279, 6925, 79390, 315, 8271, 7917, 13, 4314, 9455, 11, 279, 12074, 4284, 11, 13519, 430, 1778, 34684, 1514, 520, 3325, 1063, 3560, 304, 279, 4500, 315, 58533, 13, 763, 279, 1023, 4007, 11, 279, 12074, 7111, 520, 4528, 9024, 34684, 11, 719, 7863, 1124, 311, 279, 3392, 315, 892, 430, 1274, 20186, 304, 2978, 13, 2435, 1766, 430, 832, 1778, 27472, 1436, 387, 10815, 449, 2380, 17162, 4038, 315, 2978, 28116, 555, 1884, 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1,855

[ { "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 hexose transporter, GLUT2 (SLC2A2), which is expressed by mouse embryos, is important for survival before embryonic day 10.5, but its function in embryos is unknown. GLUT2 can transport the amino sugar glucosamine (GlcN), which could increase substrate for the hexosamine biosynthetic pathway (HBSP) that produces UDP-N-acetylglucosamine for O -linked N-acetylglucosamine modification ( O -GlcNAcylation) of proteins. To understand this, we employed a novel murine embryonic stem cell (ESC) line that, like mouse embryos, expresses functional GLUT2 transporters. GlcN stimulated ESC proliferation in a GLUT2-dependent fashion but did not regulate pluripotency. Stimulation of proliferation was not due to increased O -GlcNAcylation. Instead, GlcN decreased dependence of the HBSP on fructose-6-PO 4 and glutamine. Consequently, glycolytic- and glutamine-derived intermediates that are needed for anabolic metabolism were increased. Thus, maternally obtained GlcN may increase substrates for biomass accumulation by embryos, as exogenous GlcN does for GLUT2-expressing ESC and may explain the need for GLUT2 expression by embryos. Introduction Glut2 , also called Slc2a2 (solute carrier family 2 (facilitated glucose transporter), member 2), mRNA is expressed by mouse embryos during pre- and early postimplantation development 1 . GLUT2 is classically known as a high K M (~16 mM) glucose transporter that is expressed by pancreatic β cells and liver 2 . However, a biological function to explain why embryos express GLUT2 is not obvious. GLUT2 is not likely to function as a glucose transporter because its K M for glucose is much higher than glucose concentrations in the oviduct (3.4 mM) or in maternal circulation (5.5 mM) 2 , 3 . Furthermore, embryos also express GLUT1 (SLC2A1) and GLUT3 (SLC2A3) 1 , 4 , 5 , transporters with K M s for glucose (~5 mM) that are equivalent to normal maternal blood glucose concentrations and so, would transport glucose more efficiently than GLUT2. However, we found that GLUT2 +/− and GLUT2 −/− embryos were not recovered on embryonic (E) 10.5 from heterozygous crosses at the expected Mendelian frequencies (ratios of GLUT2 +/+ : GLUT2 +/− : GLUT2 −/− were 52%: 30%: 18% instead of the expected 25%: 50%: 25%) 6 . This demonstrated that GLUT2 performs an, as yet, undetermined function that is important for embryo survival prior to E 10.5. The amino sugar, GlcN, can be transported by GLUT2 when expressed by microinjected Xenopus oocytes, transfected HEK293T cells, or hepatocytes, with a K M of 0.8 mM 7 . GlcN can also be transported by GLUT1, but with a higher K M (2 mM). However, it is not known if GLUT2 functions as a physiological GlcN transporter for any tissue. Exogenously transported GlcN can serve as substrate for the HBSP, but GlcN-6-PO 4 , the first metabolite in the HBSP, can also be synthesized from the glycolytic intermediate, fructose-6-PO 4 , plus the amino acid, glutamine by the rate-limiting enzyme, glutamine-fructose-6-PO 4 amidotransferase (GFAT) 8 , 9 . The HBSP generates UDP-N-Acetyl-GlcN for N - and O -linked glycosylation reactions. Many signaling proteins and transcription factors are modified by O -GlcNAcylation, having opposite effects on their activities from phosphorylation 10 , 11 . There are reports that O -GlcNAcylation of the pluripotency transcription factors, OCT4 and SOX2, is required to inhibit differentiation 12 and that GLUT1-transported supplemental GlcN stimulates ESC proliferation utilizing signaling pathways dependent on O -GlcNAcylation 13 , 14 . Knockout of Ogt , which encodes O -GlcNAc transferase, the enzyme that catalyzes O -GlcNAcylation, is embryonic lethal 15 . Thus, transport of exogenous GlcN could increase substrate for O -GlcNAcylation may be important to promote embryo and ESC pluripotency and self-renewal. Study of the function of GLUT2-mediated GlcN transport on embryo cell physiology in vivo is constrained by the inability to reduce or eliminate GlcN from maternal circulation, but could be circumvented, in theory, by use of embryo-derived ESC to study these processes in vitro . However, a shortcoming of existing ESC lines is that they (like most mammalian cell lines) are conventionally isolated and propagated in media containing a high glucose concentration (25 mM) which causes high rates of glucose influx by GLUT2-expressing pre- or postimplantation embryos, which can induce oxidative stress and cell death as shown by us and others 6 , 16 , 17 , 18 , 19 , 20 . We recently showed that D3 ESC, a long-established ESC line that was isolated and maintained in high glucose media 21 , express barely detectable levels of GLUT2 and transport glucose only with low K M kinetics 22 , suggesting that ESC lines that survive isolation in high glucose media stably adapt to the adverse high glucose environment by losing expression or function of GLUT2. However, an ESC line that we established in media containing a physiological glucose concentration (5.5 mM), which we named, LG-ESC ( L ow G lucose-isolated ESC), expresses GLUT2 and transports glucose with the same kinetics as does the embryo 12 , 13 , 14 . Thus, LG-ESC can be used to test for a physiological role of GLUT2 as a GlcN transporter to favorably affect ESC and by extension, embryo physiology. Results Exogenous GlcN Stimulates ESC Proliferation in a GLUT2-Dependent Manner Because of previous reports that increased O -GlcNAcylation stimulates ESC proliferation or pluripotency 12 , 13 , 14 , we hypothesized that the normal function of GLUT2 for embryos and GLUT2-expressing ESC is to transport GlcN, which would increase substrate for O -GlcNAcylation and stimulate proliferation and/or pluripotency. To test this, we stained LG-ESC colonies for alkaline phosphatase, a marker of pluripotency 23 , after culture with or without GlcN added at 0.8 mM, the K M of GLUT2 for GlcN. All colonies were alkaline phosphatase-positive (AP+) and GlcN increased numbers of AP+ LG-ESC colonies 1.6-fold ( Fig. 1a ). GlcN increased numbers of AP+ colonies of two additional independently-derived LG-ESC lines, LG-ESC-2 and LG-ESC-3, that also express Glut2 22 by 1.8- and 2-fold, respectively. In contrast, the conventional D3 ESC, which are normally cultured in high glucose media 21 and lack functional GLUT2 transporters 22 were AP+ regardless", "role": "user" }, { "content": "Most pregnant women with well-controlled diabetes give birth to healthy children. But their babies run much higher risks of birth defects than babies born to women without diabetes, because very early in embryonic development, the babies are exposed to higher levels of glucose in maternal blood. In research done in mice, Harvard Medical School researchers at Joslin Diabetes Center have uncovered new clues about the role that glucosamine, another sugar that circulates in blood, can play in early embryonic development. If glucosamine performs similarly in humans, understanding its role eventually may aid in avoiding birth defects, said Mary Loeken, HMS associate professor of medicine (physiology) and an investigator in the Section on Islet and Regenerative Cell Biology at Joslin. Moreover, her work suggests an approach to developing stem cells that might help to strengthen future regenerative therapies for many diseases. \"The implications of this research go beyond the diabetic population,\" said Loeken, senior author on a paper published in Scientific Reports. Loeken, who studies how diabetes drives changes in the early embryo that lead to birth defects, began looking at a gene called GLUT2 after other researchers showed that it is activated in mouse embryos. GLUT2 can transport glucose from blood into cells, but it doesn't perform this efficiently unless the levels of glucose are very high. So what was its role in embryonic development? Studying mouse models of diabetes, Loeken and her team first showed that modifying the mice genetically to lack GLUT2 protected the mice from producing embryos suffering from malformations when the mothers were diabetic. However, the Joslin scientists also found evidence suggesting that fewer of these embryos were surviving even when the mothers were not diabetic. This indicated that GLUT2 performs some function that is important for early embryonic survival. Other researchers had shown that GLUT2 also can transport glucosamine, but whether GLUT2 functions as a glucosamine transporter under normal conditions has not been demonstrated. Loeken thought that embryo cells may need to obtain glucosamine from the mother's circulation. To examine the role of glucosamine, which can't be effectively adjusted in live animals, the Loeken lab created a line of mouse embryonic stem cells with activated GLUT2 that was grown in a culture with levels of glucose that are normal in mouse blood—unlike most stem cells, which are grown in very high levels of glucose. In their latest paper, the investigators showed that GLUT2 can move glucosamine into these stem cells, and giving the cells this sugar greatly increased their rates of proliferation, while not having much effect on the ways they differentiated into other forms of more specialized cells. Boosting proliferation could help embryos develop normally. Early embryos are \"rapidly proliferating sets of cells,\" Loeken said. \"They need to make more of themselves and they need to grow in size.\" Among its functions in the cell, glucosamine is needed to assist in protein processing and the creation of signaling proteins. Cells can make glucosamine from glucose, but that takes away critical resources from energy production and building blocks for cell growth. \"If a cell can't take up glucosamine, it will sort of starve,\" she said, so GLUT2 is critical. Additionally, she said, her research suggests that glucosamine, under some conditions, may be considered an essential nutrient for embryonic cells. However, the GLUT2 protein also can play a destructive role if the maternal blood has high levels of glucose. \"GLUT2 is not a very good glucose transporter under normal conditions, but when glucose levels are high it transports glucose very efficiently,\" Loeken points out. \"So if the mother has diabetes, it could allow the embryo to act like a glucose sponge.\" Her earlier research in mice embryos revealed that exposure to high blood glucose levels for a little as one day can produce a high rate of defects in the neural tube, the predecessor to the brain and spinal cord. \"Additionally, at high glucose concentrations, transport of glucosamine is significantly inhibited,\" Loeken adds. \"This suggests that the adverse effects of high glucose on embryos are not just that more glucose is getting into cells, but also that less glucosamine is being taken up. Therefore, the beneficial effects of glucosamine on growth may be compromised.\" Loeken cautions that no one has yet shown whether GLUT2 is expressed in human embryos, although research by other investigators has shown a correlation between mutations of GLUT2 in humans and risk of neural tube defects. Her work also suggests that the high proliferation ability of mouse embryonic stem cells created in normal levels of glucose with activated GLUT2 may help to point the way for generating stem cells for future regenerative medicine treatments. Most researchers now engineering embryonic stem cells or embryonic-like \"induced pluripotent stem cells\", with either mouse or human cells, grow them in glucose levels that are much higher than is normal in the body. That means that the metabolism of these new cells doesn't match the conditions the cells may find at the organ they are meant to repair Today, glucosamine tablets are sold for joint pain, but they are not recommended for pregnant women, a point that Loeken stresses. Glucosamine mechanisms in humans are not fully understood, and there are unfavorable effects when glucosamine levels get too high. Even if adding small amounts of glucosamine eventually might be proven to be helpful, achieving the right levels in a pregnant woman's blood \"would be a delicate balance,\" she said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The hexose transporter, GLUT2 (SLC2A2), which is expressed by mouse embryos, is important for survival before embryonic day 10.5, but its function in embryos is unknown. GLUT2 can transport the amino sugar glucosamine (GlcN), which could increase substrate for the hexosamine biosynthetic pathway (HBSP) that produces UDP-N-acetylglucosamine for O -linked N-acetylglucosamine modification ( O -GlcNAcylation) of proteins. To understand this, we employed a novel murine embryonic stem cell (ESC) line that, like mouse embryos, expresses functional GLUT2 transporters. GlcN stimulated ESC proliferation in a GLUT2-dependent fashion but did not regulate pluripotency. Stimulation of proliferation was not due to increased O -GlcNAcylation. Instead, GlcN decreased dependence of the HBSP on fructose-6-PO 4 and glutamine. Consequently, glycolytic- and glutamine-derived intermediates that are needed for anabolic metabolism were increased. Thus, maternally obtained GlcN may increase substrates for biomass accumulation by embryos, as exogenous GlcN does for GLUT2-expressing ESC and may explain the need for GLUT2 expression by embryos. Introduction Glut2 , also called Slc2a2 (solute carrier family 2 (facilitated glucose transporter), member 2), mRNA is expressed by mouse embryos during pre- and early postimplantation development 1 . GLUT2 is classically known as a high K M (~16 mM) glucose transporter that is expressed by pancreatic β cells and liver 2 . However, a biological function to explain why embryos express GLUT2 is not obvious. GLUT2 is not likely to function as a glucose transporter because its K M for glucose is much higher than glucose concentrations in the oviduct (3.4 mM) or in maternal circulation (5.5 mM) 2 , 3 . Furthermore, embryos also express GLUT1 (SLC2A1) and GLUT3 (SLC2A3) 1 , 4 , 5 , transporters with K M s for glucose (~5 mM) that are equivalent to normal maternal blood glucose concentrations and so, would transport glucose more efficiently than GLUT2. However, we found that GLUT2 +/− and GLUT2 −/− embryos were not recovered on embryonic (E) 10.5 from heterozygous crosses at the expected Mendelian frequencies (ratios of GLUT2 +/+ : GLUT2 +/− : GLUT2 −/− were 52%: 30%: 18% instead of the expected 25%: 50%: 25%) 6 . This demonstrated that GLUT2 performs an, as yet, undetermined function that is important for embryo survival prior to E 10.5. The amino sugar, GlcN, can be transported by GLUT2 when expressed by microinjected Xenopus oocytes, transfected HEK293T cells, or hepatocytes, with a K M of 0.8 mM 7 . GlcN can also be transported by GLUT1, but with a higher K M (2 mM). However, it is not known if GLUT2 functions as a physiological GlcN transporter for any tissue. Exogenously transported GlcN can serve as substrate for the HBSP, but GlcN-6-PO 4 , the first metabolite in the HBSP, can also be synthesized from the glycolytic intermediate, fructose-6-PO 4 , plus the amino acid, glutamine by the rate-limiting enzyme, glutamine-fructose-6-PO 4 amidotransferase (GFAT) 8 , 9 . The HBSP generates UDP-N-Acetyl-GlcN for N - and O -linked glycosylation reactions. Many signaling proteins and transcription factors are modified by O -GlcNAcylation, having opposite effects on their activities from phosphorylation 10 , 11 . There are reports that O -GlcNAcylation of the pluripotency transcription factors, OCT4 and SOX2, is required to inhibit differentiation 12 and that GLUT1-transported supplemental GlcN stimulates ESC proliferation utilizing signaling pathways dependent on O -GlcNAcylation 13 , 14 . Knockout of Ogt , which encodes O -GlcNAc transferase, the enzyme that catalyzes O -GlcNAcylation, is embryonic lethal 15 . Thus, transport of exogenous GlcN could increase substrate for O -GlcNAcylation may be important to promote embryo and ESC pluripotency and self-renewal. Study of the function of GLUT2-mediated GlcN transport on embryo cell physiology in vivo is constrained by the inability to reduce or eliminate GlcN from maternal circulation, but could be circumvented, in theory, by use of embryo-derived ESC to study these processes in vitro . However, a shortcoming of existing ESC lines is that they (like most mammalian cell lines) are conventionally isolated and propagated in media containing a high glucose concentration (25 mM) which causes high rates of glucose influx by GLUT2-expressing pre- or postimplantation embryos, which can induce oxidative stress and cell death as shown by us and others 6 , 16 , 17 , 18 , 19 , 20 . We recently showed that D3 ESC, a long-established ESC line that was isolated and maintained in high glucose media 21 , express barely detectable levels of GLUT2 and transport glucose only with low K M kinetics 22 , suggesting that ESC lines that survive isolation in high glucose media stably adapt to the adverse high glucose environment by losing expression or function of GLUT2. However, an ESC line that we established in media containing a physiological glucose concentration (5.5 mM), which we named, LG-ESC ( L ow G lucose-isolated ESC), expresses GLUT2 and transports glucose with the same kinetics as does the embryo 12 , 13 , 14 . Thus, LG-ESC can be used to test for a physiological role of GLUT2 as a GlcN transporter to favorably affect ESC and by extension, embryo physiology. Results Exogenous GlcN Stimulates ESC Proliferation in a GLUT2-Dependent Manner Because of previous reports that increased O -GlcNAcylation stimulates ESC proliferation or pluripotency 12 , 13 , 14 , we hypothesized that the normal function of GLUT2 for embryos and GLUT2-expressing ESC is to transport GlcN, which would increase substrate for O -GlcNAcylation and stimulate proliferation and/or pluripotency. To test this, we stained LG-ESC colonies for alkaline phosphatase, a marker of pluripotency 23 , after culture with or without GlcN added at 0.8 mM, the K M of GLUT2 for GlcN. All colonies were alkaline phosphatase-positive (AP+) and GlcN increased numbers of AP+ LG-ESC colonies 1.6-fold ( Fig. 1a ). GlcN increased numbers of AP+ colonies of two additional independently-derived LG-ESC lines, LG-ESC-2 and LG-ESC-3, that also express Glut2 22 by 1.8- and 2-fold, respectively. In contrast, the conventional D3 ESC, which are normally cultured in high glucose media 21 and lack functional GLUT2 transporters 22 were AP+ regardless<|im_end|> <|im_start|>assistant Most pregnant women with well-controlled diabetes give birth to healthy children. But their babies run much higher risks of birth defects than babies born to women without diabetes, because very early in embryonic development, the babies are exposed to higher levels of glucose in maternal blood. In research done in mice, Harvard Medical School researchers at Joslin Diabetes Center have uncovered new clues about the role that glucosamine, another sugar that circulates in blood, can play in early embryonic development. If glucosamine performs similarly in humans, understanding its role eventually may aid in avoiding birth defects, said Mary Loeken, HMS associate professor of medicine (physiology) and an investigator in the Section on Islet and Regenerative Cell Biology at Joslin. Moreover, her work suggests an approach to developing stem cells that might help to strengthen future regenerative therapies for many diseases. "The implications of this research go beyond the diabetic population," said Loeken, senior author on a paper published in Scientific Reports. Loeken, who studies how diabetes drives changes in the early embryo that lead to birth defects, began looking at a gene called GLUT2 after other researchers showed that it is activated in mouse embryos. GLUT2 can transport glucose from blood into cells, but it doesn't perform this efficiently unless the levels of glucose are very high. So what was its role in embryonic development? Studying mouse models of diabetes, Loeken and her team first showed that modifying the mice genetically to lack GLUT2 protected the mice from producing embryos suffering from malformations when the mothers were diabetic. However, the Joslin scientists also found evidence suggesting that fewer of these embryos were surviving even when the mothers were not diabetic. This indicated that GLUT2 performs some function that is important for early embryonic survival. Other researchers had shown that GLUT2 also can transport glucosamine, but whether GLUT2 functions as a glucosamine transporter under normal conditions has not been demonstrated. Loeken thought that embryo cells may need to obtain glucosamine from the mother's circulation. To examine the role of glucosamine, which can't be effectively adjusted in live animals, the Loeken lab created a line of mouse embryonic stem cells with activated GLUT2 that was grown in a culture with levels of glucose that are normal in mouse blood—unlike most stem cells, which are grown in very high levels of glucose. In their latest paper, the investigators showed that GLUT2 can move glucosamine into these stem cells, and giving the cells this sugar greatly increased their rates of proliferation, while not having much effect on the ways they differentiated into other forms of more specialized cells. Boosting proliferation could help embryos develop normally. Early embryos are "rapidly proliferating sets of cells," Loeken said. "They need to make more of themselves and they need to grow in size." Among its functions in the cell, glucosamine is needed to assist in protein processing and the creation of signaling proteins. Cells can make glucosamine from glucose, but that takes away critical resources from energy production and building blocks for cell growth. "If a cell can't take up glucosamine, it will sort of starve," she said, so GLUT2 is critical. Additionally, she said, her research suggests that glucosamine, under some conditions, may be considered an essential nutrient for embryonic cells. However, the GLUT2 protein also can play a destructive role if the maternal blood has high levels of glucose. "GLUT2 is not a very good glucose transporter under normal conditions, but when glucose levels are high it transports glucose very efficiently," Loeken points out. "So if the mother has diabetes, it could allow the embryo to act like a glucose sponge." Her earlier research in mice embryos revealed that exposure to high blood glucose levels for a little as one day can produce a high rate of defects in the neural tube, the predecessor to the brain and spinal cord. "Additionally, at high glucose concentrations, transport of glucosamine is significantly inhibited," Loeken adds. "This suggests that the adverse effects of high glucose on embryos are not just that more glucose is getting into cells, but also that less glucosamine is being taken up. Therefore, the beneficial effects of glucosamine on growth may be compromised." Loeken cautions that no one has yet shown whether GLUT2 is expressed in human embryos, although research by other investigators has shown a correlation between mutations of GLUT2 in humans and risk of neural tube defects. Her work also suggests that the high proliferation ability of mouse embryonic stem cells created in normal levels of glucose with activated GLUT2 may help to point the way for generating stem cells for future regenerative medicine treatments. Most researchers now engineering embryonic stem cells or embryonic-like "induced pluripotent stem cells", with either mouse or human cells, grow them in glucose levels that are much higher than is normal in the body. That means that the metabolism of these new cells doesn't match the conditions the cells may find at the organ they are meant to repair Today, glucosamine tablets are sold for joint pain, but they are not recommended for pregnant women, a point that Loeken stresses. Glucosamine mechanisms in humans are not fully understood, and there are unfavorable effects when glucosamine levels get too high. Even if adding small amounts of glucosamine eventually might be proven to be helpful, achieving the right levels in a pregnant woman's blood "would be a delicate balance," she said. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered for the prevention and treatment of certain solid tumor types. However, whether and how dietary restriction affects hematopoietic malignancies is unknown. Here we report that fasting alone robustly inhibits the initiation and reverses the leukemic progression of both B cell and T cell acute lymphoblastic leukemia (B-ALL and T-ALL, respectively), but not acute myeloid leukemia (AML), in mouse models of these tumors. Mechanistically, we found that attenuated leptin-receptor (LEPR) expression is essential for the development and maintenance of ALL, and that fasting inhibits ALL development by upregulation of LEPR and its downstream signaling through the protein PR/SET domain 1 (PRDM1). The expression of LEPR signaling-related genes correlated with the prognosis of pediatric patients with pre-B-ALL, and fasting effectively inhibited B-ALL growth in a human xenograft model. Our results indicate that the effects of fasting on tumor growth are cancer-type dependent, and they suggest new avenues for the development of treatment strategies for leukemia. Main Dietary restriction, including fasting, delays aging and has pro-longevity effects in a wide range of organisms, and so has been considered for cancer prevention and the treatment of certain solid tumor types 1 , 2 , 3 , 4 , 5 , 6 . Fasting can promote hematopoietic stem cell–based regeneration and reverse immunosuppression 7 , 8 , 9 , and has been reported to promote the anti-cancer effects of chemotherapy 5 , 10 . However, the responsiveness of hematopoietic malignancies to dietary restriction, including fasting, remains unknown. AML is the most common form of adult acute leukemia, whereas ALL is the most common form of cancer in children; ALL also occurs in adults 11 , 12 , 13 . Although treatment of pediatric ALL is highly effective, a sizeable number of patients are nonresponders who succumb to this disease. The outcome of ALL in adults is substantially worse than for pediatric ALL, with a 5-year survival rate of approximately 40% 12 . Additionally, some types of ALL have a much poorer prognosis than others 12 . New therapeutic targets and approaches need to be identified to treat these leukemias more effectively. Here we investigated whether and how fasting regulates the development of B-ALL, T-ALL and AML. Results Fasting selectively inhibits the development of ALL but not AML To extend our previous work on the extrinsic and metabolic regulation of hematopoietic stem cells and cancer development 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , we studied the effects of fasting on leukemia development. Mice from several retrovirus transplantation acute leukemia models, including the N-Myc B-ALL model 23 , the activated Notch1 T-ALL model 24 and the MLL-AF9 AML model 25 , 26 , were placed on various dietary regimens. Strikingly, a regimen consisting of six cycles of 1 d of fasting, followed by 1 d of feeding, implemented 2 d after transplantation ( Fig. 1a ) completely inhibited B-ALL development. The fasted mice had 32.85 ± 5.16, 11.31 ± 5.42 and 0.48 ± 0.12% of leukemic GFP + cells in peripheral blood (PB) at 3, 5 and 7 weeks post-transplantation, respectively, as compared to 49.52 ± 5.75, 56.27 ± 9.36 and 67.68 ± 8.39% of GFP + cells of the control mice ( Fig. 1b,c ). Concordantly, the percentages of leukemic cells in the bone marrow (BM) and spleen (SP) and the numbers of white blood cells (WBCs) in PB were also dramatically lower in the fasted mice at 7 weeks post-transplantation ( Fig. 1c,d ). Figure 1: Fasting selectively inhibits ALL development. ( a ) Leukemia induction and fasting scheme. Lin − cells were infected with N-Myc-IRES-GFP (B-ALL), Notch1-IRES-GFP (T-ALL), or MLL-AF9-IRES-YFP (AML) expressing retrovirus and transplanted into irradiated mice. Mice were fed normally or fasted with six cycles of 1-d fasting/1-d feeding at day 2 after transplantation. ( b – i ) N-Myc-infected Lin − cells were transplanted into lethally irradiated recipient mice to induce B-ALL. Mice were either placed on a standard diet or fasted (six cycles of 1-d fast/1-d fed), initiated at day 2 after transplantation. PB was analyzed at 3, 5 and 7 weeks after transplantation; BM and SP were collected at 7 weeks. ( b ) Representative flow cytometry plot of GFP + leukemic BM cells in fed and fasted mice. ( c ) Percentage of cells expressing GFP in PB at the indicated time points and in BM and SP ( n = 5 mice per group). ( d ) WBC numbers in the PB at week 7 ( n = 5 per group). ( e ) Representative flow cytometry plot of Mac-1 and B220 staining in GFP + BM cells in fed and fasted mice. ( f ) Percentages of B220 and Mac-1 cells in GFP + cells from PB, BM and SP ( n = 5 per group). ( g ) Analysis of B-ALL surface markers B220 (pan B cell marker), CD19 (B cell marker) and IgM (B cell maturation marker) in GFP + cells from PB, BM and SP ( n = 5 per group). ( h ) Photographs of representative spleens and lymph nodes (left; scale bars, 1 cm) and quantitation of spleen weight (right) from fed and fasted mice with B-ALL and nonleukemic (healthy) mice ( n = 3 per group). ( i ) Combined survival analysis of fed and fasted mice with N-Myc-driven B-ALL from four independent experiments ( n = 20 per group). ( j – m ) Notch1-infected fetal liver Lin − cells were transplanted into lethally irradiated recipient mice to induce T-ALL. Mice were placed on a standard diet or a six-cycle fasting regimen initiated at 2 d after transplantation. ( j ) Percentage of GFP + cells in PB at 3, 5 and 7 weeks and in BM and SP at 7 weeks post-transplantation ( n = 5 per group). ( k ) WBC numbers in the PB at 7 weeks", "role": "user" }, { "content": "UT Southwestern Medical Center researchers have found that intermittent fasting inhibits the development and progression of the most common type of childhood leukemia. This strategy was not effective, however, in another type of blood cancer that commonly strikes adults. \"This study using mouse models indicates that the effects of fasting on blood cancers are type-dependent and provides a platform for identifying new targets for leukemia treatments,\" said Dr. Chengcheng \"Alec\" Zhang, Associate Professor of Physiology at UT Southwestern and senior author of the study, published online today by Nature Medicine. \"We also identified a mechanism responsible for the differing response to the fasting treatment,\" he added. The researchers found that fasting both inhibits the initiation and reverses the progression of two subtypes of acute lymphoblastic leukemia, or ALL - B-cell ALL and T-cell ALL. The same method did not work with acute myeloid leukemia (AML), the type that is more common in adults. ALL, the most common type of leukemia found in children, can occur at any age. Current ALL treatments are effective about 90 percent of the time in children, but far less often in adults, said Dr. Zhang, who also holds the Hortense L. and Morton H. Sanger Professorship in Oncology and is a Michael L. Rosenberg Scholar in Medical Research. The two types of leukemia arise from different bone marrow-derived blood cells, he explained. ALL affects B cells and T cells, two types of the immune system's disease-fighting white blood cells. AML targets other types of white blood cells such as macrophages and granulocytes, among other cells. In both ALL and AML, the cancerous cells remain immature yet proliferate uncontrollably. Those cells fail to work well and displace healthy blood cells, leading to anemia and infection. They may also infiltrate into tissues and thus cause problems. The researchers created several mouse models of acute leukemia and tried various dietary restriction plans. They used green or yellow florescent proteins to mark the cancer cells so they could trace them and determine if their levels rose or fell in response to the fasting treatment, Dr. Zhang explained. \"Strikingly, we found that in models of ALL, a regimen consisting of six cycles of one day of fasting followed by one day of feeding completely inhibited cancer development,\" he said. At the end of seven weeks, the fasted mice had virtually no detectible cancerous cells compared to an average of nearly 68 percent of cells found to be cancerous in the test areas of the non-fasted mice. Compared to mice that ate normally, the rodents on alternate-day fasting had dramatic reductions in the percentage of cancerous cells in the bone marrow and the spleen as well as reduced numbers of white blood cells, he said. The spleen filters blood. \"In addition, following the fasting treatment, the spleens and lymph nodes in the fasted ALL model mice were similar in size to those in normal mice. Although initially cancerous, the few fluorescent cells that remained in the fasted mice after seven weeks appeared to behave like normal cells,\" he said. \"Mice in the ALL model group that ate normally died within 59 days, while 75 percent of the fasted mice survived more than 120 days without signs of leukemia.\" Fasting is known to reduce the level of leptin, a cell signaling molecule created by fat tissue. In addition, previous studies have shown weakened activity by leptin receptors in human patients with ALL. For those reasons, the researchers studied both leptin levels and leptin receptors in the mouse models. They found that mice with ALL showed reduced leptin receptor activity that then increased with intermittent fasting, he said. \"We found that fasting decreased the levels of leptin circulating in the bloodstream as well as decreased the leptin levels in the bone marrow. These effects became more pronounced with repeated cycles of fasting. After fasting, the rate at which the leptin levels recovered seemed to correspond to the rate at which the cancerous ALL cells were cleared from the blood,\" he added. Interestingly, AML was associated with higher levels of leptin receptors that were unaffected by fasting, which could help explain why the fasting treatment was ineffective against that form of leukemia. It also suggests a mechanism - the leptin receptor pathway - by which fasting exerts its effects in ALL, he said. \"It will be important to determine whether ALL cells can become resistant to the effects of fasting,\" he said. \"It also will be interesting to investigate whether we can find alternative ways that mimic fasting to block ALL development.\" Given that the study did not involve drug treatments, just fasting, researchers are discussing with clinicians whether the tested regimen might be able to move forward quickly to human clinical trials ", "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 New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered for the prevention and treatment of certain solid tumor types. However, whether and how dietary restriction affects hematopoietic malignancies is unknown. Here we report that fasting alone robustly inhibits the initiation and reverses the leukemic progression of both B cell and T cell acute lymphoblastic leukemia (B-ALL and T-ALL, respectively), but not acute myeloid leukemia (AML), in mouse models of these tumors. Mechanistically, we found that attenuated leptin-receptor (LEPR) expression is essential for the development and maintenance of ALL, and that fasting inhibits ALL development by upregulation of LEPR and its downstream signaling through the protein PR/SET domain 1 (PRDM1). The expression of LEPR signaling-related genes correlated with the prognosis of pediatric patients with pre-B-ALL, and fasting effectively inhibited B-ALL growth in a human xenograft model. Our results indicate that the effects of fasting on tumor growth are cancer-type dependent, and they suggest new avenues for the development of treatment strategies for leukemia. Main Dietary restriction, including fasting, delays aging and has pro-longevity effects in a wide range of organisms, and so has been considered for cancer prevention and the treatment of certain solid tumor types 1 , 2 , 3 , 4 , 5 , 6 . Fasting can promote hematopoietic stem cell–based regeneration and reverse immunosuppression 7 , 8 , 9 , and has been reported to promote the anti-cancer effects of chemotherapy 5 , 10 . However, the responsiveness of hematopoietic malignancies to dietary restriction, including fasting, remains unknown. AML is the most common form of adult acute leukemia, whereas ALL is the most common form of cancer in children; ALL also occurs in adults 11 , 12 , 13 . Although treatment of pediatric ALL is highly effective, a sizeable number of patients are nonresponders who succumb to this disease. The outcome of ALL in adults is substantially worse than for pediatric ALL, with a 5-year survival rate of approximately 40% 12 . Additionally, some types of ALL have a much poorer prognosis than others 12 . New therapeutic targets and approaches need to be identified to treat these leukemias more effectively. Here we investigated whether and how fasting regulates the development of B-ALL, T-ALL and AML. Results Fasting selectively inhibits the development of ALL but not AML To extend our previous work on the extrinsic and metabolic regulation of hematopoietic stem cells and cancer development 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , we studied the effects of fasting on leukemia development. Mice from several retrovirus transplantation acute leukemia models, including the N-Myc B-ALL model 23 , the activated Notch1 T-ALL model 24 and the MLL-AF9 AML model 25 , 26 , were placed on various dietary regimens. Strikingly, a regimen consisting of six cycles of 1 d of fasting, followed by 1 d of feeding, implemented 2 d after transplantation ( Fig. 1a ) completely inhibited B-ALL development. The fasted mice had 32.85 ± 5.16, 11.31 ± 5.42 and 0.48 ± 0.12% of leukemic GFP + cells in peripheral blood (PB) at 3, 5 and 7 weeks post-transplantation, respectively, as compared to 49.52 ± 5.75, 56.27 ± 9.36 and 67.68 ± 8.39% of GFP + cells of the control mice ( Fig. 1b,c ). Concordantly, the percentages of leukemic cells in the bone marrow (BM) and spleen (SP) and the numbers of white blood cells (WBCs) in PB were also dramatically lower in the fasted mice at 7 weeks post-transplantation ( Fig. 1c,d ). Figure 1: Fasting selectively inhibits ALL development. ( a ) Leukemia induction and fasting scheme. Lin − cells were infected with N-Myc-IRES-GFP (B-ALL), Notch1-IRES-GFP (T-ALL), or MLL-AF9-IRES-YFP (AML) expressing retrovirus and transplanted into irradiated mice. Mice were fed normally or fasted with six cycles of 1-d fasting/1-d feeding at day 2 after transplantation. ( b – i ) N-Myc-infected Lin − cells were transplanted into lethally irradiated recipient mice to induce B-ALL. Mice were either placed on a standard diet or fasted (six cycles of 1-d fast/1-d fed), initiated at day 2 after transplantation. PB was analyzed at 3, 5 and 7 weeks after transplantation; BM and SP were collected at 7 weeks. ( b ) Representative flow cytometry plot of GFP + leukemic BM cells in fed and fasted mice. ( c ) Percentage of cells expressing GFP in PB at the indicated time points and in BM and SP ( n = 5 mice per group). ( d ) WBC numbers in the PB at week 7 ( n = 5 per group). ( e ) Representative flow cytometry plot of Mac-1 and B220 staining in GFP + BM cells in fed and fasted mice. ( f ) Percentages of B220 and Mac-1 cells in GFP + cells from PB, BM and SP ( n = 5 per group). ( g ) Analysis of B-ALL surface markers B220 (pan B cell marker), CD19 (B cell marker) and IgM (B cell maturation marker) in GFP + cells from PB, BM and SP ( n = 5 per group). ( h ) Photographs of representative spleens and lymph nodes (left; scale bars, 1 cm) and quantitation of spleen weight (right) from fed and fasted mice with B-ALL and nonleukemic (healthy) mice ( n = 3 per group). ( i ) Combined survival analysis of fed and fasted mice with N-Myc-driven B-ALL from four independent experiments ( n = 20 per group). ( j – m ) Notch1-infected fetal liver Lin − cells were transplanted into lethally irradiated recipient mice to induce T-ALL. Mice were placed on a standard diet or a six-cycle fasting regimen initiated at 2 d after transplantation. ( j ) Percentage of GFP + cells in PB at 3, 5 and 7 weeks and in BM and SP at 7 weeks post-transplantation ( n = 5 per group). ( k ) WBC numbers in the PB at 7 weeks<|im_end|> <|im_start|>assistant UT Southwestern Medical Center researchers have found that intermittent fasting inhibits the development and progression of the most common type of childhood leukemia. This strategy was not effective, however, in another type of blood cancer that commonly strikes adults. "This study using mouse models indicates that the effects of fasting on blood cancers are type-dependent and provides a platform for identifying new targets for leukemia treatments," said Dr. Chengcheng "Alec" Zhang, Associate Professor of Physiology at UT Southwestern and senior author of the study, published online today by Nature Medicine. "We also identified a mechanism responsible for the differing response to the fasting treatment," he added. The researchers found that fasting both inhibits the initiation and reverses the progression of two subtypes of acute lymphoblastic leukemia, or ALL - B-cell ALL and T-cell ALL. The same method did not work with acute myeloid leukemia (AML), the type that is more common in adults. ALL, the most common type of leukemia found in children, can occur at any age. Current ALL treatments are effective about 90 percent of the time in children, but far less often in adults, said Dr. Zhang, who also holds the Hortense L. and Morton H. Sanger Professorship in Oncology and is a Michael L. Rosenberg Scholar in Medical Research. The two types of leukemia arise from different bone marrow-derived blood cells, he explained. ALL affects B cells and T cells, two types of the immune system's disease-fighting white blood cells. AML targets other types of white blood cells such as macrophages and granulocytes, among other cells. In both ALL and AML, the cancerous cells remain immature yet proliferate uncontrollably. Those cells fail to work well and displace healthy blood cells, leading to anemia and infection. They may also infiltrate into tissues and thus cause problems. The researchers created several mouse models of acute leukemia and tried various dietary restriction plans. They used green or yellow florescent proteins to mark the cancer cells so they could trace them and determine if their levels rose or fell in response to the fasting treatment, Dr. Zhang explained. "Strikingly, we found that in models of ALL, a regimen consisting of six cycles of one day of fasting followed by one day of feeding completely inhibited cancer development," he said. At the end of seven weeks, the fasted mice had virtually no detectible cancerous cells compared to an average of nearly 68 percent of cells found to be cancerous in the test areas of the non-fasted mice. Compared to mice that ate normally, the rodents on alternate-day fasting had dramatic reductions in the percentage of cancerous cells in the bone marrow and the spleen as well as reduced numbers of white blood cells, he said. The spleen filters blood. "In addition, following the fasting treatment, the spleens and lymph nodes in the fasted ALL model mice were similar in size to those in normal mice. Although initially cancerous, the few fluorescent cells that remained in the fasted mice after seven weeks appeared to behave like normal cells," he said. "Mice in the ALL model group that ate normally died within 59 days, while 75 percent of the fasted mice survived more than 120 days without signs of leukemia." Fasting is known to reduce the level of leptin, a cell signaling molecule created by fat tissue. In addition, previous studies have shown weakened activity by leptin receptors in human patients with ALL. For those reasons, the researchers studied both leptin levels and leptin receptors in the mouse models. They found that mice with ALL showed reduced leptin receptor activity that then increased with intermittent fasting, he said. "We found that fasting decreased the levels of leptin circulating in the bloodstream as well as decreased the leptin levels in the bone marrow. These effects became more pronounced with repeated cycles of fasting. After fasting, the rate at which the leptin levels recovered seemed to correspond to the rate at which the cancerous ALL cells were cleared from the blood," he added. Interestingly, AML was associated with higher levels of leptin receptors that were unaffected by fasting, which could help explain why the fasting treatment was ineffective against that form of leukemia. It also suggests a mechanism - the leptin receptor pathway - by which fasting exerts its effects in ALL, he said. "It will be important to determine whether ALL cells can become resistant to the effects of fasting," he said. "It also will be interesting to investigate whether we can find alternative ways that mimic fasting to block ALL development." Given that the study did not involve drug treatments, just fasting, researchers are discussing with clinicians whether the tested regimen might be able to move forward quickly to human clinical trials <|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 Reduction of seed dormancy mechanisms, allowing for rapid germination after planting, is a recurrent trait in domesticated plants, and can often be linked to changes in seed coat structure, in particular thinning. We report evidence for seed coat thinning between 2,000 BC and 1,200 BC, in southern Indian archaeological horsegram ( Macrotyloma uniflorum ), which it has been possible to document with high precision and non-destructively, through high resolution x-ray computed tomography using a synchrotron. We find that this trait underwent stepped change, from thick to semi-thin to thin seed coats, and that the rate of change was gradual. This is the first time that the rate of evolution of seed coat thinning in a legume crop has been directly documented from archaeological remains, and it contradicts previous predictions that legume domestication occurred through selection of pre-adapted low dormancy phenotypes from the wild. Introduction Crop domestication is a co-evolutionary process which adapted plants to cultivation and facilitated the growth of larger sedentary human populations 1 , 2 . The documentation of domestication in the archaeological record is often hampered by limited preservation of diagnostic morphology in archaeological plant specimens, with seed dispersal traits preserved in some cereals and grain size information in a wider range of taxa 3 , 4 . Reduction of seed dormancy mechanisms, allowing for rapid germination after planting, is a recurrent trait in domesticated plants, and can often be linked to changes in seed coat structure, in particular thinning 5 , but this has been documented previously in sub-fossil material of only a few taxa, such as New World Chenopodium spp. 4 , 6 , 7 . In pulses (domesticated Fabaceae seed crops) reduction of seed dormancy is regarded as central to domestication as wild legumes have conspicuous dormancy related to thick, hard seed coats 8 , 9 , 10 , 11 . In some legumes, such as pea ( Pisum sativum ) the reduction in dormancy is linked to a conspicuous reduction in seed coat sculpturing 9 , but this is by no means universal across pulses. It has been inferred that only rare, wild plants that had reduced dormancy would have been suitable for early cultivators to select from the wild for cultivation 8 , 12 , 13 . However, archaeobotanical evidence documenting the presence of thin-seed coated, low dormancy phenotypes prior to or at the beginnings of cultivation has never been reported, nor have archaeobotanists previously documented evidence for the evolution, whether rapid or gradual, of pulse testa morphology. While this has been discussed largely in relation to Southwest Asian domesticates such a lentil ( Lens culinaris ) and pea 8 , 9 , 10 , 12 , 13 , it should apply equally across all pulses. Using a novel methodology to non-destructively document seed coat thickness around entire archaeological pulse seeds, we report data from the South Asia pulse crop horsegram ( Macrotyloma uniflorum ). Horsegram is an annual native to South Asia 14 , where it has been an important crop since the beginnings of agriculture in many parts of South Asia. It is the most widely recovered pulse crop on prehistoric or early historic sites in India 15 . Today it is the fifth most widely cultivated grain legume in India, and arguably the most hardy, as well as a key vegetable protein source for hundreds of millions of rural inhabitants on the subcontinent 16 , 17 . Evidence from the wild progenitor ( Macrotyloma uniflorum var. stenocarpum ) has been poorly studied and has never been described in the floristic studies of India. Thus, the regional origins of Horsegram still remain largely obscure 18 . Recent archaeobotanical sampling in the Deccan plateau of South India, a large, arid region featuring rich Neolithic period remains 5 , 18 , 19 , 20 , 21 has shown that a number of the earliest Southern Neolithic crop domesticates, including horsegram, appear to have been locally domesticated. Thus, based upon this evidence and limited assessment of herbarium specimens from the Botanical Survey of India, Pune an inferred possible South Indian origin has been postulated 15 , suggesting that wild horsegram was native to the semi-arid scrub savannah environments ranging from the Acacia thickets from the Aravalli hills in Rajasthan, the savannahs of the Southern Peninsula 22 , while the lower slopes of the western Himalayas are all also plausible foci of early cultivation or domestication (Fig. 1 ) 23 , 24 . Previously, it had been simply assumed that all archaeological examples were domesticated crops, lending speculation to the question of where and when the domestication process took place 25 . In contrast, here we report findings for morphological change dating to this domestication process. Figure 1 Map showing the distribution of early archaeological horsegram, indicating those sites included in the present study (Pa = Paithan, Pi = Piklihal, H = Hallur, S = Sanganakallu). Additional sites with horsegram recorded (1) Arikamedu (2) Veerapuram (3) Vikrampura Bangladesh (4) Ter (5) Saunphari (6) Perur (7) Noh (8) Nevasa (9) Ahirua Rajarampur (10) Brahmagiri (11) Ostapur (12) Inamgaon (13) Watgal (14) Tuljapur Garhi (15) Tokwa (16) Tekkalakota (17) Singanapalle (18) Sanghol (19) Rojdi (20) Rohira (21) Peddamudiyam (22) Paiyampalli (23) Paithan (24) Ojiyana (25) Narhan (26) Mithathal (27) Malhar (28) Ludwala (29) Kurugodu (30) Kunal (31) Kaothe (32) Kadebakele (33) Kayatha (34) Iinjedu (35) Hulas (36) Hiregudda (37) Hattibelagallu (38) Harirajpur (39) Bhagimohari (41) Banawali (42) Golbai Sassan (43) Apegaon (44) Adam (45) Daimabad (46) Kanmer (47) Lotehswar. Also shown the predicted original wild range. Map created using QGIS Development Team, QGIS 2.12.3- Lyon 2015. QGIS Geographic Information System. Open Source Geospatial Foundation Project. . Full size image It may be that wild horsegram populations were more widespread during the mid-Holocene climatic wet phase, and the subsequent reduction of their availability, during the aridification that began in the later Fourth Millennium BC, may be connected to their domestication and the emergence of the Southern Neolithic (which coincide largely with the territory of the modern", "role": "user" }, { "content": "Scientists from UCL have used the UK's synchrotron facility, Diamond Light Source, to document for the first time the rate of evolution of seed coat thinning, a major marker of crop domestication, from archaeological remains. Writing in the journal Scientific Reports, the authors present evidence for seed coat thinning between 2,000 BC and 1,200 BC in the legume horsegram (Macrotyloma uniflorum), a bean commonly eaten in southern India. By using the high-resolution X-ray computed tomography (HRXCT) technique on Diamond's I13-2 beamline, the researchers were able to measure for the first time the coat thickness throughout the entire seed. \"Seed coat thickness is a great indicator of domestication, as thinner coats will mean faster germination of a seed when it is watered,\" explains Dorian Fuller, co-author on the paper. \"But conventional methods of looking at the seed coat require breaking and destroying archaeological specimens.\" \"Being able to look at the seed coat thickness without breaking the sample is possible by other methods, but you can only look at a spot on the seed,\" adds Charlene Murphy, co-author on the paper. \"The beamline at Diamond has allowed us to look at the entire seed, and has shown considerable variation within individual specimen's seed coat thickness.\" This is the first time that HRXCT has been applied to entire archaeological seeds, with results suggesting that previous spot measurement thickness tests could be misleading. Of the twelve samples analysed, the seeds could be categorised into two distinct groups, thicker (wild type) seed coats, with averages thicknesses above 17 micrometres, and thinner (more domesticated) seed coats between 10 and 15 micrometres. The results indicated that domestication of horsegram took place during the second millennium BC, with seed coats fair fixed in thickness by the early centuries AD. The findings also show the potential for HRXCT to be used to look at a variety of domesticated grains and pulses, such as peas. Christoph Rau, Principal Beamline Scientist on I13, where the work was carried out, says \"The beamline is a unique tool and is involved in a wide range of applications from high resolution imaging of biological tissues to palaeontological research. In this case, the beamline has enabled the team to produce 3D images of the seeds with incredible micrometer scale resolution, without damaging their precious samples\" \"We're continuing to work with Diamond to look at other interesting archaeological seeds, and how they've become domesticated,\" concludes Fuller. \"Peas are a great example of this - wild peas are ejected from their pods naturally, but domesticated peas only leave the pod when the cultivator removes them - a quite symbiotic relationship.\" ", "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 Reduction of seed dormancy mechanisms, allowing for rapid germination after planting, is a recurrent trait in domesticated plants, and can often be linked to changes in seed coat structure, in particular thinning. We report evidence for seed coat thinning between 2,000 BC and 1,200 BC, in southern Indian archaeological horsegram ( Macrotyloma uniflorum ), which it has been possible to document with high precision and non-destructively, through high resolution x-ray computed tomography using a synchrotron. We find that this trait underwent stepped change, from thick to semi-thin to thin seed coats, and that the rate of change was gradual. This is the first time that the rate of evolution of seed coat thinning in a legume crop has been directly documented from archaeological remains, and it contradicts previous predictions that legume domestication occurred through selection of pre-adapted low dormancy phenotypes from the wild. Introduction Crop domestication is a co-evolutionary process which adapted plants to cultivation and facilitated the growth of larger sedentary human populations 1 , 2 . The documentation of domestication in the archaeological record is often hampered by limited preservation of diagnostic morphology in archaeological plant specimens, with seed dispersal traits preserved in some cereals and grain size information in a wider range of taxa 3 , 4 . Reduction of seed dormancy mechanisms, allowing for rapid germination after planting, is a recurrent trait in domesticated plants, and can often be linked to changes in seed coat structure, in particular thinning 5 , but this has been documented previously in sub-fossil material of only a few taxa, such as New World Chenopodium spp. 4 , 6 , 7 . In pulses (domesticated Fabaceae seed crops) reduction of seed dormancy is regarded as central to domestication as wild legumes have conspicuous dormancy related to thick, hard seed coats 8 , 9 , 10 , 11 . In some legumes, such as pea ( Pisum sativum ) the reduction in dormancy is linked to a conspicuous reduction in seed coat sculpturing 9 , but this is by no means universal across pulses. It has been inferred that only rare, wild plants that had reduced dormancy would have been suitable for early cultivators to select from the wild for cultivation 8 , 12 , 13 . However, archaeobotanical evidence documenting the presence of thin-seed coated, low dormancy phenotypes prior to or at the beginnings of cultivation has never been reported, nor have archaeobotanists previously documented evidence for the evolution, whether rapid or gradual, of pulse testa morphology. While this has been discussed largely in relation to Southwest Asian domesticates such a lentil ( Lens culinaris ) and pea 8 , 9 , 10 , 12 , 13 , it should apply equally across all pulses. Using a novel methodology to non-destructively document seed coat thickness around entire archaeological pulse seeds, we report data from the South Asia pulse crop horsegram ( Macrotyloma uniflorum ). Horsegram is an annual native to South Asia 14 , where it has been an important crop since the beginnings of agriculture in many parts of South Asia. It is the most widely recovered pulse crop on prehistoric or early historic sites in India 15 . Today it is the fifth most widely cultivated grain legume in India, and arguably the most hardy, as well as a key vegetable protein source for hundreds of millions of rural inhabitants on the subcontinent 16 , 17 . Evidence from the wild progenitor ( Macrotyloma uniflorum var. stenocarpum ) has been poorly studied and has never been described in the floristic studies of India. Thus, the regional origins of Horsegram still remain largely obscure 18 . Recent archaeobotanical sampling in the Deccan plateau of South India, a large, arid region featuring rich Neolithic period remains 5 , 18 , 19 , 20 , 21 has shown that a number of the earliest Southern Neolithic crop domesticates, including horsegram, appear to have been locally domesticated. Thus, based upon this evidence and limited assessment of herbarium specimens from the Botanical Survey of India, Pune an inferred possible South Indian origin has been postulated 15 , suggesting that wild horsegram was native to the semi-arid scrub savannah environments ranging from the Acacia thickets from the Aravalli hills in Rajasthan, the savannahs of the Southern Peninsula 22 , while the lower slopes of the western Himalayas are all also plausible foci of early cultivation or domestication (Fig. 1 ) 23 , 24 . Previously, it had been simply assumed that all archaeological examples were domesticated crops, lending speculation to the question of where and when the domestication process took place 25 . In contrast, here we report findings for morphological change dating to this domestication process. Figure 1 Map showing the distribution of early archaeological horsegram, indicating those sites included in the present study (Pa = Paithan, Pi = Piklihal, H = Hallur, S = Sanganakallu). Additional sites with horsegram recorded (1) Arikamedu (2) Veerapuram (3) Vikrampura Bangladesh (4) Ter (5) Saunphari (6) Perur (7) Noh (8) Nevasa (9) Ahirua Rajarampur (10) Brahmagiri (11) Ostapur (12) Inamgaon (13) Watgal (14) Tuljapur Garhi (15) Tokwa (16) Tekkalakota (17) Singanapalle (18) Sanghol (19) Rojdi (20) Rohira (21) Peddamudiyam (22) Paiyampalli (23) Paithan (24) Ojiyana (25) Narhan (26) Mithathal (27) Malhar (28) Ludwala (29) Kurugodu (30) Kunal (31) Kaothe (32) Kadebakele (33) Kayatha (34) Iinjedu (35) Hulas (36) Hiregudda (37) Hattibelagallu (38) Harirajpur (39) Bhagimohari (41) Banawali (42) Golbai Sassan (43) Apegaon (44) Adam (45) Daimabad (46) Kanmer (47) Lotehswar. Also shown the predicted original wild range. Map created using QGIS Development Team, QGIS 2.12.3- Lyon 2015. QGIS Geographic Information System. Open Source Geospatial Foundation Project. . Full size image It may be that wild horsegram populations were more widespread during the mid-Holocene climatic wet phase, and the subsequent reduction of their availability, during the aridification that began in the later Fourth Millennium BC, may be connected to their domestication and the emergence of the Southern Neolithic (which coincide largely with the territory of the modern<|im_end|> <|im_start|>assistant Scientists from UCL have used the UK's synchrotron facility, Diamond Light Source, to document for the first time the rate of evolution of seed coat thinning, a major marker of crop domestication, from archaeological remains. Writing in the journal Scientific Reports, the authors present evidence for seed coat thinning between 2,000 BC and 1,200 BC in the legume horsegram (Macrotyloma uniflorum), a bean commonly eaten in southern India. By using the high-resolution X-ray computed tomography (HRXCT) technique on Diamond's I13-2 beamline, the researchers were able to measure for the first time the coat thickness throughout the entire seed. "Seed coat thickness is a great indicator of domestication, as thinner coats will mean faster germination of a seed when it is watered," explains Dorian Fuller, co-author on the paper. "But conventional methods of looking at the seed coat require breaking and destroying archaeological specimens." "Being able to look at the seed coat thickness without breaking the sample is possible by other methods, but you can only look at a spot on the seed," adds Charlene Murphy, co-author on the paper. "The beamline at Diamond has allowed us to look at the entire seed, and has shown considerable variation within individual specimen's seed coat thickness." This is the first time that HRXCT has been applied to entire archaeological seeds, with results suggesting that previous spot measurement thickness tests could be misleading. Of the twelve samples analysed, the seeds could be categorised into two distinct groups, thicker (wild type) seed coats, with averages thicknesses above 17 micrometres, and thinner (more domesticated) seed coats between 10 and 15 micrometres. The results indicated that domestication of horsegram took place during the second millennium BC, with seed coats fair fixed in thickness by the early centuries AD. The findings also show the potential for HRXCT to be used to look at a variety of domesticated grains and pulses, such as peas. Christoph Rau, Principal Beamline Scientist on I13, where the work was carried out, says "The beamline is a unique tool and is involved in a wide range of applications from high resolution imaging of biological tissues to palaeontological research. In this case, the beamline has enabled the team to produce 3D images of the seeds with incredible micrometer scale resolution, without damaging their precious samples" "We're continuing to work with Diamond to look at other interesting archaeological seeds, and how they've become domesticated," concludes Fuller. "Peas are a great example of this - wild peas are ejected from their pods naturally, but domesticated peas only leave the pod when the cultivator removes them - a quite symbiotic relationship." <|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 pollination in large-scale agriculture is dependent on managed colonies of a single species, the honey bee Apis mellifera . More than 1 million hives are transported to California each year just to pollinate the almonds and bees are trucked across the country for various cropping systems. Concerns have been raised about whether such “migratory management” causes bees undue stress; however to date there have been no longer-term studies rigorously addressing whether migratory management is detrimental to bee health. To address this issue, we conducted field experiments comparing bees from commercial and experimental migratory beekeeping operations to those from stationary colonies to quantify effects on lifespan, colony health and productivity and levels of oxidative damage for individual bees. We detected a significant decrease in lifespan of migratory adult bees relative to stationary bees. We also found that migration affected oxidative stress levels in honey bees, but that food scarcity had an even larger impact; some detrimental effects of migration may be alleviated by a greater abundance of forage. In addition, rearing conditions affect levels of oxidative damage incurred as adults. This is the first comprehensive study on impacts of migratory management on the health and oxidative stress of honey bees. Introduction Honey bees ( Apis mellifera ) are the most economically important pollinators in North America and are crucial for sustaining production in many agroecosystems 1 . Honey bee colonies are composed of tens of thousands of individuals, which allows them to pollinate crops effectively over a large geographic area, particularly with the assistance of beekeepers who transport colonies for pollination services. The major economic driver of the beekeeping industry in the U.S. is fulfilling pollination contracts for various growers, including almonds, berries, apples and cucurbits 2 . Therefore, commercial beekeepers transport bee colonies on trucks both regionally and nationally for many months of the year 3 , 4 , 5 . Given this paradigm, many colonies are repeatedly moved over several months to a series of large monocultures, which potentially increases a colony’s exposure to pesticides 3 , 6 and pathogens 7 , limits access to diversified pollen sources 8 and forces the foraging bees to re-learn and re-assess their environmental surroundings. The assumption, therefore, is that factors associated with migratory beekeeping operations overwhelm bees and induce a stress response, ultimately contributing to increased colony losses and susceptibility to disease, parasites and syndrome-like effects such as Colony Collapse Disorder (CCD) 9 . However, the impact of transporting colonies for pollination services has currently received minimal investigation 7 , 10 . Furthermore, no study has empirically examined the cellular consequences of stress to honey bee workers under this paradigm. On a physiological level, the immediate effect of transportation (i.e., 24-hours after a 3-day trip) has been shown to lead to a reduction in the size of the glands that are essential for brood food production in nurse bees 10 . However, the long-term implications of this finding are unclear. Thus, the goal of this study was to better resolve the question regarding whether migratory beekeeping practices cause changes in measurable levels of oxidative stress and possible impacts of the cells throughout a season. Our ability to understand and quantify stress is critical for evaluating the impacts of abiotic and biotic factors influencing honey bee health and colony productivity. Oxidative stress is important in eukaryotic organisms and can have severe negative effects. Reactive oxygen species (ROS) are the causative agents of oxidative stress and they are produced as a by-product of normal metabolic processes (or otherwise suffer from diminished redox homeostasis). Cells that lose their ability to remove excess ROS undergo oxidative stress, which leads to DNA mutation 11 , irreparable damage of proteins 12 and membrane instability 13 . Oxidative stress can lead to apoptosis and cellular damage, which are intimately linked to aging 14 , 15 . Acute exposure to mild stress can extend lifespan because stress-resistance mechanisms, like the production of antioxidants, can be activated 16 . However, severe or chronic stressors, like prolonged sublethal pesticide exposure 17 , usually shorten lifespan 18 . In particular, some theories argue that aging is simply a result of the accumulation of oxidative damage 19 , 20 . Furthermore, ROS may be induced by exogenous sources (i.e. pesticides and environment). We hypothesized that migratory honey bees experience oxidative stress and may have shorter life spans. The biomarker malondialdehyde (MDA) is a common measure of oxidative stress in honey bees, other insects and vertebrate systems 21 , 22 , 23 , 24 . MDA is the main organic compound produced from lipid peroxidation of polyunsaturated fatty acids in cellular membranes 25 . MDA levels reflect the combined effects of exposure to oxidative stress and the ability or lack thereof to resist oxidative damage through various repair mechanisms 26 . We determined how the movement of managed honey bee colonies across different agricultural landscapes influenced colony health and productivity, adult lifespan and levels of oxidative stress, measured as MDA. Our study is the first to examine the long-term effects of migratory colony management on stress accumulation in honey bees. This study was conducted in three parts where we: 1) determined the effect of migratory management on honey bee lifespan; 2) investigated the effects of migratory management on colony health, productivity, lifespan and oxidative stress on either stationary or migratory bees; and 3) investigated the effects of intensive, short-term migratory movement on levels of oxidative stress in honey bees. Methods A scheme of the general experimental designs for Experiments 1, 2 and 3 is shown in Fig. 1 . Figure 1 The experimental schemes of Experiment 1, 2 and 3. The first panel depicts where the bees were transported for the different experiments, the second shows the procedures used (lifespan analysis in incubator cages or oxidative stress analyses) and the third depicts the paired design aspect where colonies were matched and newly emerged bees were paint-marked and swapped across these pairs. This figure was created in Microsoft Powerpoint. Pictures were taken by and", "role": "user" }, { "content": "In the first large-scale and comprehensive study on the impacts of transporting honey bees to pollinate various crops, research from North Carolina State University shows that travel can adversely affect bee health and lifespan. Some of these negative impacts may be reduced by moving bee colonies into patches with readily available food or by providing supplemental nutrition when there are few flowers for honey bees to visit, the researchers say. Honey bees (Apis mellifera) are among the country's most important agricultural pollinators. They are frequently trucked around the United States - in short and long distances—to pollinate crops like apples, almonds and berries. But the impact of that travel remains unclear and ripe for study, says Hongmei Li-Byarlay, a National Research Council senior research associate in NC State's Department of Entomology and Plant Pathology and co-first author of a paper describing the research, which aimed to be the first to directly measure stress in these types of colonies. Combining the results of three different experiments, the research shows that traveling bees generally have shorter lives than stationary bees. Traveling bees also have greater oxidative stress levels—which ages them more quickly and may lessen their capacity to fight off disease and parasites. \"We found that migratory beekeeping influences the lifespan of bees, but how this impacts health and honey bee aging is more complicated and often more influenced by the environment these colonies are in,\" said Michael Simone-Finstrom, an NC State postdoctoral researcher during this research and co-first author of the study who currently works at the USDA honey bee research lab in Baton Rouge, La. In one experiment, bees from commercial colonies that had traveled to pollinate almonds in California and then in Maine were compared to bees from colonies that remained stationary in the NC State apiary. Traveling colony bees lived about one day less than the stationary bees. \"One day may seem trivial, but when a normal forager bee lifespan is only around 20 days, one day is significant,\" Simone-Finstrom said. In the second experiment, researchers compared lifespan and colony health of migratory bees that traveled relatively short distances in North Carolina—35 to 60 miles in a handful of trips—to stationary bees; both types of colonies were controlled by the researchers. \"We saw the same lifespan differences as in the first experiment, plus we saw more oxidative stress in traveling bees when compared to stationary bees,\" Li-Byarlay said. However, this increase in stress levels was only apparent early in the season—May and June—when the stationary bees had plenty of access to food. As the flowers dried up in the North Carolina summer heat, stationary bees had to work harder to find food while the traveling bees were moved into fields of blooming plants and therefore did better. In the third experiment, researchers compared oxidative stress levels of stationary bees with bees that were transported across North Carolina for three hours each day for six consecutive days—a more intensive bee travel regimen than the second experiment. The results shed light on how the bee-rearing environment—where bees were raised as larvae—can impact the oxidative stress levels when bees become adults. In this experiment, foraging bees raised in migratory bee colonies had higher oxidative stress levels than foraging bees raised in stationary hives. Li-Byarlay says she'd like to look at longer-term effects of bee migration and the interaction with nutrition, as this study examined bees over the course of roughly four months in late spring and summer. As honey bee colonies nationwide currently experience higher annual mortality, understanding effects through overwintering and mitigation of these effects would be particularly insightful. ", "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 pollination in large-scale agriculture is dependent on managed colonies of a single species, the honey bee Apis mellifera . More than 1 million hives are transported to California each year just to pollinate the almonds and bees are trucked across the country for various cropping systems. Concerns have been raised about whether such “migratory management” causes bees undue stress; however to date there have been no longer-term studies rigorously addressing whether migratory management is detrimental to bee health. To address this issue, we conducted field experiments comparing bees from commercial and experimental migratory beekeeping operations to those from stationary colonies to quantify effects on lifespan, colony health and productivity and levels of oxidative damage for individual bees. We detected a significant decrease in lifespan of migratory adult bees relative to stationary bees. We also found that migration affected oxidative stress levels in honey bees, but that food scarcity had an even larger impact; some detrimental effects of migration may be alleviated by a greater abundance of forage. In addition, rearing conditions affect levels of oxidative damage incurred as adults. This is the first comprehensive study on impacts of migratory management on the health and oxidative stress of honey bees. Introduction Honey bees ( Apis mellifera ) are the most economically important pollinators in North America and are crucial for sustaining production in many agroecosystems 1 . Honey bee colonies are composed of tens of thousands of individuals, which allows them to pollinate crops effectively over a large geographic area, particularly with the assistance of beekeepers who transport colonies for pollination services. The major economic driver of the beekeeping industry in the U.S. is fulfilling pollination contracts for various growers, including almonds, berries, apples and cucurbits 2 . Therefore, commercial beekeepers transport bee colonies on trucks both regionally and nationally for many months of the year 3 , 4 , 5 . Given this paradigm, many colonies are repeatedly moved over several months to a series of large monocultures, which potentially increases a colony’s exposure to pesticides 3 , 6 and pathogens 7 , limits access to diversified pollen sources 8 and forces the foraging bees to re-learn and re-assess their environmental surroundings. The assumption, therefore, is that factors associated with migratory beekeeping operations overwhelm bees and induce a stress response, ultimately contributing to increased colony losses and susceptibility to disease, parasites and syndrome-like effects such as Colony Collapse Disorder (CCD) 9 . However, the impact of transporting colonies for pollination services has currently received minimal investigation 7 , 10 . Furthermore, no study has empirically examined the cellular consequences of stress to honey bee workers under this paradigm. On a physiological level, the immediate effect of transportation (i.e., 24-hours after a 3-day trip) has been shown to lead to a reduction in the size of the glands that are essential for brood food production in nurse bees 10 . However, the long-term implications of this finding are unclear. Thus, the goal of this study was to better resolve the question regarding whether migratory beekeeping practices cause changes in measurable levels of oxidative stress and possible impacts of the cells throughout a season. Our ability to understand and quantify stress is critical for evaluating the impacts of abiotic and biotic factors influencing honey bee health and colony productivity. Oxidative stress is important in eukaryotic organisms and can have severe negative effects. Reactive oxygen species (ROS) are the causative agents of oxidative stress and they are produced as a by-product of normal metabolic processes (or otherwise suffer from diminished redox homeostasis). Cells that lose their ability to remove excess ROS undergo oxidative stress, which leads to DNA mutation 11 , irreparable damage of proteins 12 and membrane instability 13 . Oxidative stress can lead to apoptosis and cellular damage, which are intimately linked to aging 14 , 15 . Acute exposure to mild stress can extend lifespan because stress-resistance mechanisms, like the production of antioxidants, can be activated 16 . However, severe or chronic stressors, like prolonged sublethal pesticide exposure 17 , usually shorten lifespan 18 . In particular, some theories argue that aging is simply a result of the accumulation of oxidative damage 19 , 20 . Furthermore, ROS may be induced by exogenous sources (i.e. pesticides and environment). We hypothesized that migratory honey bees experience oxidative stress and may have shorter life spans. The biomarker malondialdehyde (MDA) is a common measure of oxidative stress in honey bees, other insects and vertebrate systems 21 , 22 , 23 , 24 . MDA is the main organic compound produced from lipid peroxidation of polyunsaturated fatty acids in cellular membranes 25 . MDA levels reflect the combined effects of exposure to oxidative stress and the ability or lack thereof to resist oxidative damage through various repair mechanisms 26 . We determined how the movement of managed honey bee colonies across different agricultural landscapes influenced colony health and productivity, adult lifespan and levels of oxidative stress, measured as MDA. Our study is the first to examine the long-term effects of migratory colony management on stress accumulation in honey bees. This study was conducted in three parts where we: 1) determined the effect of migratory management on honey bee lifespan; 2) investigated the effects of migratory management on colony health, productivity, lifespan and oxidative stress on either stationary or migratory bees; and 3) investigated the effects of intensive, short-term migratory movement on levels of oxidative stress in honey bees. Methods A scheme of the general experimental designs for Experiments 1, 2 and 3 is shown in Fig. 1 . Figure 1 The experimental schemes of Experiment 1, 2 and 3. The first panel depicts where the bees were transported for the different experiments, the second shows the procedures used (lifespan analysis in incubator cages or oxidative stress analyses) and the third depicts the paired design aspect where colonies were matched and newly emerged bees were paint-marked and swapped across these pairs. This figure was created in Microsoft Powerpoint. Pictures were taken by and<|im_end|> <|im_start|>assistant In the first large-scale and comprehensive study on the impacts of transporting honey bees to pollinate various crops, research from North Carolina State University shows that travel can adversely affect bee health and lifespan. Some of these negative impacts may be reduced by moving bee colonies into patches with readily available food or by providing supplemental nutrition when there are few flowers for honey bees to visit, the researchers say. Honey bees (Apis mellifera) are among the country's most important agricultural pollinators. They are frequently trucked around the United States - in short and long distances—to pollinate crops like apples, almonds and berries. But the impact of that travel remains unclear and ripe for study, says Hongmei Li-Byarlay, a National Research Council senior research associate in NC State's Department of Entomology and Plant Pathology and co-first author of a paper describing the research, which aimed to be the first to directly measure stress in these types of colonies. Combining the results of three different experiments, the research shows that traveling bees generally have shorter lives than stationary bees. Traveling bees also have greater oxidative stress levels—which ages them more quickly and may lessen their capacity to fight off disease and parasites. "We found that migratory beekeeping influences the lifespan of bees, but how this impacts health and honey bee aging is more complicated and often more influenced by the environment these colonies are in," said Michael Simone-Finstrom, an NC State postdoctoral researcher during this research and co-first author of the study who currently works at the USDA honey bee research lab in Baton Rouge, La. In one experiment, bees from commercial colonies that had traveled to pollinate almonds in California and then in Maine were compared to bees from colonies that remained stationary in the NC State apiary. Traveling colony bees lived about one day less than the stationary bees. "One day may seem trivial, but when a normal forager bee lifespan is only around 20 days, one day is significant," Simone-Finstrom said. In the second experiment, researchers compared lifespan and colony health of migratory bees that traveled relatively short distances in North Carolina—35 to 60 miles in a handful of trips—to stationary bees; both types of colonies were controlled by the researchers. "We saw the same lifespan differences as in the first experiment, plus we saw more oxidative stress in traveling bees when compared to stationary bees," Li-Byarlay said. However, this increase in stress levels was only apparent early in the season—May and June—when the stationary bees had plenty of access to food. As the flowers dried up in the North Carolina summer heat, stationary bees had to work harder to find food while the traveling bees were moved into fields of blooming plants and therefore did better. In the third experiment, researchers compared oxidative stress levels of stationary bees with bees that were transported across North Carolina for three hours each day for six consecutive days—a more intensive bee travel regimen than the second experiment. The results shed light on how the bee-rearing environment—where bees were raised as larvae—can impact the oxidative stress levels when bees become adults. In this experiment, foraging bees raised in migratory bee colonies had higher oxidative stress levels than foraging bees raised in stationary hives. Li-Byarlay says she'd like to look at longer-term effects of bee migration and the interaction with nutrition, as this study examined bees over the course of roughly four months in late spring and summer. As honey bee colonies nationwide currently experience higher annual mortality, understanding effects through overwintering and mitigation of these effects would be particularly insightful. <|im_end|>

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2,007

[ { "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 Molecular phylogenetic studies that have included sirenians from the genera Trichechus , Dugong , and Hydrodamalis have resolved their interrelationships but have yielded divergence age estimates that are problematically discordant. The ages of these lineage splits have profound implications for how to interpret the sirenian fossil record—including clade membership, biogeographic patterns, and correlations with Earth history events. In an effort to address these issues, here we present a total evidence phylogenetic analysis of Sirenia that includes living and fossil species and applies Bayesian tip-dating methods to estimate their interrelationships and divergence times. In addition to extant sirenians, our dataset includes 56 fossil species from 106 dated localities and numerous afrotherian outgroup taxa. Genetic, morphological, temporal, and biogeographic data are assessed simultaneously to bring all available evidence to bear on sirenian phylogeny. The resulting time-tree is then used for Bayesian geocoordinates reconstruction analysis, which models ancestral geographic areas at splits throughout the phylogeny, thereby allowing us to infer the direction and timing of dispersals. Our results suggest that Pan-Sirenia arose in North Africa during the latest Paleocene and that the Eocene evolution of stem sirenians was primarily situated in the Tethyan realm. In the late Eocene, some lineages moved into more northern European latitudes, an area that became the source region for a key trans-Atlantic dispersal towards the Caribbean and northern-adjacent west Atlantic. This event led to the phylogenetic and biogeographic founding of crown Sirenia with the Dugongidae-Trichechidae split occurring at the Eocene-Oligocene boundary (~33.9 Ma), temporally coincident with the onset of dropping global sea levels and temperatures. This region became the nexus of sirenian diversification and supported taxonomically-rich dugongid communities until the earliest Pliocene. The Dugonginae-Hydrodamalinae split occurred near Florida during the early Miocene (~21.2 Ma) and was followed by a west-bound dispersal that gave rise to the Pacific hydrodamalines. The late middle Miocene (~12.2 Ma) split of Dugong from all other dugongines also occurred near Florida and our analyses suggest that the Indo-Pacific distribution of modern dugongs is the result of a trans-Pacific dispersal. From at least the early Miocene, trichechid evolution was based entirely in South America, presumably within the Pebas Wetlands System. We infer that the eventual establishment of Amazon drainage into the South Atlantic allowed the dispersal of Trichechus out of South America no earlier than the mid-Pliocene. Our analyses provide a new temporal and biogeographic framework for understanding major events in sirenian evolution and their possible relationships to oceanographic and climatic changes. These hypotheses can be further tested with the recovery and integration of new fossil evidence. Cite this as Heritage S, Seiffert ER. 2022 . Total evidence time-scaled phylogenetic and biogeographic models for the evolution of sea cows (Sirenia, Afrotheria) PeerJ 10 : e13886 Main article text Introduction The mammalian order Sirenia, commonly called the sea cows, includes only four living species—the dugong (genus Dugong , family Dugongidae) and three manatees (genus Trichechus , family Trichechidae). Sirenians are unique in being the only fully aquatic mammals that are also obligate herbivores, and their habitats are predominantly warm, near-shore, and relatively shallow waters that accommodate the vegetative growth that comprises their diets ( Marsh, 2014 ; O’Shea, 2014 ). The fossil record of sea cows begins near the onset of the middle Eocene, about 48 million years ago, and since that time their evolving diversity and biogeography has ensued to leave fossil occurrences on every continent except Antarctica ( Marsh, O’Shea & Reynolds, 2012 ). While the extant species of sea cows lack hindlimbs and are equipped with several anatomical adaptations that suit them to wholly aquatic lifeways, some of the earliest fossil sirenians were, by contrast, quadrupedal and amphibious ( Domning, 2001a ; Domning, 2009 ). The geographic distributions of the living sirenian species are mapped in Fig. 1 . The West Indian manatee ( Trichechus manatus ) occurs throughout the Caribbean, in parts of the Gulf of Mexico, and along the Atlantic coasts of North and South America—while the Amazonian manatee ( Trichechus inunguis ) inhabits the river systems of the Amazon Basin. The West African manatee ( Trichechus senegalensis ) occurs along the Atlantic coasts of West and Central Africa and in several lake and river systems of that region which ultimately drain into the east Atlantic and Gulf of Guinea ( O’Shea, 2014 ). Compared to the other living sea cow species, the dugong ( Dugong dugon ) has the broadest distribution—inhabiting tropical and subtropical waters of the Eastern Hemisphere from the coasts of East Africa and Madagascar to the Red Sea and Persian Gulf, along the western coast of India, and throughout the near-shore waters of Southeast Asia and Australasia all the way to New Caledonia ( Marsh, 2014 ; Plön et al., 2019 ). The Recent species Steller’s sea cow ( Hydrodamalis gigas , family Dugongidae; Fig. 1 ) was last reported alive in the middle of the 18 th century but has since been hunted to extinction ( Turvey & Risley, 2006 ). Steller’s sea cow was much larger than the living sirenian species, was apparently adapted to colder waters, and is documented by Pacific Rim occurrences from Japan, to the Aleutian Islands, to Northern California ( Domning, 1978 ; Furusawa, 2004 ). Substantial genomic data derived from relatively young specimens (<300 years old) have enabled robust phylogenetic placement of Steller’s sea cow among the extant sirenian genera ( Springer et al., 2015 ). These five species, living and Recent, are only a narrow temporal sample from the order’s long history. Therefore, the evolutionary events that have led to this small group’s relatively widespread geographic range might be better understood through a deep-time lens and in a richer taxonomic context (see below). Figure 1: The four extant sirenian species and Steller’s sea cow (recently extinct). All five taxa are represented by DNA sequences. Cladogram of molecular phylogenetic relationships is a composite from Springer et al. (2015) and de Souza et al. (2021) . Species distribution maps are adapted from the IUCN (2021) Red List of Threatened Species", "role": "user" }, { "content": "Zoologists refer to manatees and dugongs as \"sea cows\" but a simple internet search might return the more playful moniker \"floaty potatoes.\" Now, imagine a 24,000-pound version, twice the size of an elephant, swimming in the Bering Sea. While only four species of the round, slow-moving aquatic herbivores of the order Sirenia remain on Earth—and all are considered vulnerable to extinction—fossil evidence suggests that many different kinds of sea cows lived in the past, and at times numerous species coexisted. Over their long history sea cows have lived along the coasts of every continent but Antarctica. A new paper appearing today in the journal PeerJ has assembled the most complete story yet of these unique creatures' ancestry. \"The earliest known fossil sea cows are about 47 million years old, and those animals lived along the coasts of northern Africa in the proto-Mediterranean Sea,\" said co-author Steven Heritage of the Duke Lemur Center's Museum of Natural History. \"Our analysis found that this first appearance was about 11 million years after the sea cow lineage diverged from their closest living relatives, the elephants.\" The earliest fossil ancestors of elephants are also from northern Africa and lived during the early Cenozoic, the era that followed the extinction of the dinosaurs. While modern manatees and dugongs have no hind limbs and are strictly aquatic, the oldest known fossil sea cows had four limbs and could walk on land. Steven Heritage, a researcher at the Duke Lemur Center’s Museum of Natural History, holds the 33-million-year-old fossil mandible of an extinct sea cow which is related to modern manatees. Credit: Catherine Riddle The study assembled the largest-yet dataset of living and fossil species, combining genetics, anatomy, geography, and geologic ages. The team's analyses included time-scaled statistical models for the ancestry of sea cows and models of historical biogeography that identify the ages and directions of their migrations across Earth's oceans. \"Our models suggest that the direct ancestors of manatees evolved within continental South America and the migration of manatees into the Caribbean and towards the coasts of North America was a relatively recent event,\" said Erik Seiffert of the Keck School of Medicine at USC, who is also a research affiliate of the Duke Lemur Center and coauthor of the paper. \"In a sense, manatees are newcomers to these West Atlantic ecosystems,\" Seiffert said. For much of the past 20 million years, a large portion of northern South America was covered by fresh water wetlands—these eventually gave rise to the Amazon River system with drainage into the South Atlantic Ocean beginning only a few million years ago. Manatees from that vast marshland seem to have made their way out of South America after that time. Around 34 million years ago, a key trans-Atlantic migration from the Eastern Hemisphere towards southern North America and the Caribbean gave rise to the common ancestor of the living sea cow species. The 43 million-year-old fossil skeleton of Pezosiren, an amphibious quadruped of the sea cow family tree. Credit: Thesupermat via Creative Commons The age of that migration corresponds to the Eocene-Oligocene boundary, which was a time of plummeting global sea levels, a rapidly cooling climate, and widespread and severe extinctions of numerous animal species both on land and in the sea. After that time, the ancestral sea cows of the Eastern Hemisphere faced a steep decline and eventually disappeared. But the Western Hemisphere lineage that was established near the beginning of the Oligocene gave rise to many species of sea cows that flourished and persisted for tens of millions of years, sometimes living in communities of multiple species. The analysis also found that at least three Caribbean sea cow lineages migrated into the Pacific Ocean during the Miocene epoch, between 23 and 5 million years ago, before Central and South America were connected. One descendant of those Pacific migrations was the gigantic Steller's Sea Cow, a cold-adapted species that measured up to 33 feet. European naturalists who explored the islands of the Bering Sea during the mid-1700s observed living Steller's Sea Cows, but the species was hunted to extinction shortly thereafter. The researchers say the highest diversity of sea cow lineages occurred around 22 and 16 million years ago. But over the past 9 million years, the number of lineages has dropped precipitously resulting in the few species that remain today. ", "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 Molecular phylogenetic studies that have included sirenians from the genera Trichechus , Dugong , and Hydrodamalis have resolved their interrelationships but have yielded divergence age estimates that are problematically discordant. The ages of these lineage splits have profound implications for how to interpret the sirenian fossil record—including clade membership, biogeographic patterns, and correlations with Earth history events. In an effort to address these issues, here we present a total evidence phylogenetic analysis of Sirenia that includes living and fossil species and applies Bayesian tip-dating methods to estimate their interrelationships and divergence times. In addition to extant sirenians, our dataset includes 56 fossil species from 106 dated localities and numerous afrotherian outgroup taxa. Genetic, morphological, temporal, and biogeographic data are assessed simultaneously to bring all available evidence to bear on sirenian phylogeny. The resulting time-tree is then used for Bayesian geocoordinates reconstruction analysis, which models ancestral geographic areas at splits throughout the phylogeny, thereby allowing us to infer the direction and timing of dispersals. Our results suggest that Pan-Sirenia arose in North Africa during the latest Paleocene and that the Eocene evolution of stem sirenians was primarily situated in the Tethyan realm. In the late Eocene, some lineages moved into more northern European latitudes, an area that became the source region for a key trans-Atlantic dispersal towards the Caribbean and northern-adjacent west Atlantic. This event led to the phylogenetic and biogeographic founding of crown Sirenia with the Dugongidae-Trichechidae split occurring at the Eocene-Oligocene boundary (~33.9 Ma), temporally coincident with the onset of dropping global sea levels and temperatures. This region became the nexus of sirenian diversification and supported taxonomically-rich dugongid communities until the earliest Pliocene. The Dugonginae-Hydrodamalinae split occurred near Florida during the early Miocene (~21.2 Ma) and was followed by a west-bound dispersal that gave rise to the Pacific hydrodamalines. The late middle Miocene (~12.2 Ma) split of Dugong from all other dugongines also occurred near Florida and our analyses suggest that the Indo-Pacific distribution of modern dugongs is the result of a trans-Pacific dispersal. From at least the early Miocene, trichechid evolution was based entirely in South America, presumably within the Pebas Wetlands System. We infer that the eventual establishment of Amazon drainage into the South Atlantic allowed the dispersal of Trichechus out of South America no earlier than the mid-Pliocene. Our analyses provide a new temporal and biogeographic framework for understanding major events in sirenian evolution and their possible relationships to oceanographic and climatic changes. These hypotheses can be further tested with the recovery and integration of new fossil evidence. Cite this as Heritage S, Seiffert ER. 2022 . Total evidence time-scaled phylogenetic and biogeographic models for the evolution of sea cows (Sirenia, Afrotheria) PeerJ 10 : e13886 Main article text Introduction The mammalian order Sirenia, commonly called the sea cows, includes only four living species—the dugong (genus Dugong , family Dugongidae) and three manatees (genus Trichechus , family Trichechidae). Sirenians are unique in being the only fully aquatic mammals that are also obligate herbivores, and their habitats are predominantly warm, near-shore, and relatively shallow waters that accommodate the vegetative growth that comprises their diets ( Marsh, 2014 ; O’Shea, 2014 ). The fossil record of sea cows begins near the onset of the middle Eocene, about 48 million years ago, and since that time their evolving diversity and biogeography has ensued to leave fossil occurrences on every continent except Antarctica ( Marsh, O’Shea & Reynolds, 2012 ). While the extant species of sea cows lack hindlimbs and are equipped with several anatomical adaptations that suit them to wholly aquatic lifeways, some of the earliest fossil sirenians were, by contrast, quadrupedal and amphibious ( Domning, 2001a ; Domning, 2009 ). The geographic distributions of the living sirenian species are mapped in Fig. 1 . The West Indian manatee ( Trichechus manatus ) occurs throughout the Caribbean, in parts of the Gulf of Mexico, and along the Atlantic coasts of North and South America—while the Amazonian manatee ( Trichechus inunguis ) inhabits the river systems of the Amazon Basin. The West African manatee ( Trichechus senegalensis ) occurs along the Atlantic coasts of West and Central Africa and in several lake and river systems of that region which ultimately drain into the east Atlantic and Gulf of Guinea ( O’Shea, 2014 ). Compared to the other living sea cow species, the dugong ( Dugong dugon ) has the broadest distribution—inhabiting tropical and subtropical waters of the Eastern Hemisphere from the coasts of East Africa and Madagascar to the Red Sea and Persian Gulf, along the western coast of India, and throughout the near-shore waters of Southeast Asia and Australasia all the way to New Caledonia ( Marsh, 2014 ; Plön et al., 2019 ). The Recent species Steller’s sea cow ( Hydrodamalis gigas , family Dugongidae; Fig. 1 ) was last reported alive in the middle of the 18 th century but has since been hunted to extinction ( Turvey & Risley, 2006 ). Steller’s sea cow was much larger than the living sirenian species, was apparently adapted to colder waters, and is documented by Pacific Rim occurrences from Japan, to the Aleutian Islands, to Northern California ( Domning, 1978 ; Furusawa, 2004 ). Substantial genomic data derived from relatively young specimens (<300 years old) have enabled robust phylogenetic placement of Steller’s sea cow among the extant sirenian genera ( Springer et al., 2015 ). These five species, living and Recent, are only a narrow temporal sample from the order’s long history. Therefore, the evolutionary events that have led to this small group’s relatively widespread geographic range might be better understood through a deep-time lens and in a richer taxonomic context (see below). Figure 1: The four extant sirenian species and Steller’s sea cow (recently extinct). All five taxa are represented by DNA sequences. Cladogram of molecular phylogenetic relationships is a composite from Springer et al. (2015) and de Souza et al. (2021) . Species distribution maps are adapted from the IUCN (2021) Red List of Threatened Species<|im_end|> <|im_start|>assistant Zoologists refer to manatees and dugongs as "sea cows" but a simple internet search might return the more playful moniker "floaty potatoes." Now, imagine a 24,000-pound version, twice the size of an elephant, swimming in the Bering Sea. While only four species of the round, slow-moving aquatic herbivores of the order Sirenia remain on Earth—and all are considered vulnerable to extinction—fossil evidence suggests that many different kinds of sea cows lived in the past, and at times numerous species coexisted. Over their long history sea cows have lived along the coasts of every continent but Antarctica. A new paper appearing today in the journal PeerJ has assembled the most complete story yet of these unique creatures' ancestry. "The earliest known fossil sea cows are about 47 million years old, and those animals lived along the coasts of northern Africa in the proto-Mediterranean Sea," said co-author Steven Heritage of the Duke Lemur Center's Museum of Natural History. "Our analysis found that this first appearance was about 11 million years after the sea cow lineage diverged from their closest living relatives, the elephants." The earliest fossil ancestors of elephants are also from northern Africa and lived during the early Cenozoic, the era that followed the extinction of the dinosaurs. While modern manatees and dugongs have no hind limbs and are strictly aquatic, the oldest known fossil sea cows had four limbs and could walk on land. Steven Heritage, a researcher at the Duke Lemur Center’s Museum of Natural History, holds the 33-million-year-old fossil mandible of an extinct sea cow which is related to modern manatees. Credit: Catherine Riddle The study assembled the largest-yet dataset of living and fossil species, combining genetics, anatomy, geography, and geologic ages. The team's analyses included time-scaled statistical models for the ancestry of sea cows and models of historical biogeography that identify the ages and directions of their migrations across Earth's oceans. "Our models suggest that the direct ancestors of manatees evolved within continental South America and the migration of manatees into the Caribbean and towards the coasts of North America was a relatively recent event," said Erik Seiffert of the Keck School of Medicine at USC, who is also a research affiliate of the Duke Lemur Center and coauthor of the paper. "In a sense, manatees are newcomers to these West Atlantic ecosystems," Seiffert said. For much of the past 20 million years, a large portion of northern South America was covered by fresh water wetlands—these eventually gave rise to the Amazon River system with drainage into the South Atlantic Ocean beginning only a few million years ago. Manatees from that vast marshland seem to have made their way out of South America after that time. Around 34 million years ago, a key trans-Atlantic migration from the Eastern Hemisphere towards southern North America and the Caribbean gave rise to the common ancestor of the living sea cow species. The 43 million-year-old fossil skeleton of Pezosiren, an amphibious quadruped of the sea cow family tree. Credit: Thesupermat via Creative Commons The age of that migration corresponds to the Eocene-Oligocene boundary, which was a time of plummeting global sea levels, a rapidly cooling climate, and widespread and severe extinctions of numerous animal species both on land and in the sea. After that time, the ancestral sea cows of the Eastern Hemisphere faced a steep decline and eventually disappeared. But the Western Hemisphere lineage that was established near the beginning of the Oligocene gave rise to many species of sea cows that flourished and persisted for tens of millions of years, sometimes living in communities of multiple species. The analysis also found that at least three Caribbean sea cow lineages migrated into the Pacific Ocean during the Miocene epoch, between 23 and 5 million years ago, before Central and South America were connected. One descendant of those Pacific migrations was the gigantic Steller's Sea Cow, a cold-adapted species that measured up to 33 feet. European naturalists who explored the islands of the Bering Sea during the mid-1700s observed living Steller's Sea Cows, but the species was hunted to extinction shortly thereafter. The researchers say the highest diversity of sea cow lineages occurred around 22 and 16 million years ago. But over the past 9 million years, the number of lineages has dropped precipitously resulting in the few species that remain today. <|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 Newly formed black holes of stellar mass launch collimated outflows (jets) of ionized matter that approach the speed of light. These outflows power prompt, brief and intense flashes of γ-rays known as γ-ray bursts (GRBs), followed by longer-lived afterglow radiation that is detected across the electromagnetic spectrum. Measuring the polarization of the observed GRB radiation provides a direct probe of the magnetic fields in the collimated jets. Rapid-response polarimetric observations of newly discovered bursts have probed the initial afterglow phase 1 , 2 , 3 , and show that, minutes after the prompt emission has ended, the degree of linear polarization can be as high as 30 per cent—consistent with the idea that a stable, globally ordered magnetic field permeates the jet at large distances from the central source 3 . By contrast, optical 4 , 5 , 6 and γ-ray 7 , 8 , 9 observations during the prompt phase have led to discordant and often controversial 10 , 11 , 12 results, and no definitive conclusions have been reached regarding the origin of the prompt radiation or the configuration of the magnetic field. Here we report the detection of substantial (8.3 ± 0.8 per cent from our most conservative simulation), variable linear polarization of a prompt optical flash that accompanied the extremely energetic and long-lived prompt γ-ray emission from GRB 160625B. Our measurements probe the structure of the magnetic field at an early stage of the jet, closer to its central black hole, and show that the prompt phase is produced via fast-cooling synchrotron radiation in a large-scale magnetic field that is advected from the black hole and distorted by dissipation processes within the jet. Main On 25 June 2016 at 22:40:16.28 Universal Time ( ut ), the γ-ray burst monitor (GBM) aboard NASA’s Fermi Gamma-ray Space Telescope discovered GRB 160625B as a short-lived pulse (lasting about 1 second) of γ-ray radiation (G1 in Fig. 1 ). An automatic localization was published rapidly by the spacecraft, allowing wide-field optical facilities to start follow-up observations. Three minutes after the first alert, at 22:43:24.82 ut (hereafter T 0 ), the Large Area Telescope (LAT) aboard Fermi was triggered by another bright but longer-lasting pulse (of about 30 seconds; G2 in Fig. 1 ), visible up to gigaelectronvolt (GeV) energies 13 . A rapid increase in brightness was observed simultaneously at optical wavelengths ( Fig. 1 ): the optical brightness rose by a factor of 100 in a few seconds, reaching its peak at T 0 + 5.9 seconds, with an observed visual magnitude of 7.9. After a second, fainter peak at T 0 + 15.9 seconds, the optical light declined steadily. During this phase, the MASTER 14 -IAC telescope on Tenerife, Spain, observed the optical counterpart in two orthogonal polaroids simultaneously, starting at T 0 + 95 seconds and ending at T 0 + 360 seconds. The detection of a polarized signal with this instrumental configuration provides a lower bound ( Π L,min ) to the true degree of linear polarization, thus Π L,min = ( I 2 − I 1 )/( I 1 + I 2 ), where I 1 and I 2 refer to the source intensity in each polaroid. Substantial levels of linear polarization, up to Π L,min = 8.0 ± 0.5%, were thereby detected ( Fig. 2 ; by comparison, values of less than 2% have been detected for other nearby objects of similar brightness). Over this time interval a weak tail of γ-ray emission was visible, until the onset of a third, longer-lived episode of prompt γ-ray radiation (G3), starting at T 0 + 337 seconds and ending at T 0 + 630 seconds. Figure 1: Prompt γ-ray and optical light curves of GRB 160625B. The γ-ray light curve (black; 10–250 keV) consists of three main episodes: a short precursor (G1), a bright main burst (G2), and a fainter and longer-lasting tail (G3). Optical data from the MASTER Net telescopes and other ground-based facilities 19 are overlaid for comparison. Error bars represent 1 σ ; upper limits are 3 σ . The red box marks the time interval over which polarimetric measurements were taken. Within the sample of nearly 2,000 bursts detected by the GBM, only six other events have a comparable duration ( ). Most GRBs end before the start of polarimetric observations. PowerPoint slide Source data Full size image Figure 2: Temporal evolution of the optical polarization measured for GRB 160625B. The minimum polarization ( Π L,min ), measured in four different temporal bins (red squares), remains fairly constant over the first three exposures, then increases by 60% during the fourth (and last) observation. At the same time, an evident increase in the γ-ray count rates (grey shaded area; 5-second time bins) marks the onset of the third episode of prompt emission (G3 in Fig. 1 ). The spectral shape and fast temporal variability observed during G3 are typical of a GRB’s prompt emission. For comparison, we also show simultaneous polarimetric measurements of the three brightest stars in the MASTER-IAC field of view. Error bars represent 1 σ . PowerPoint slide Full size image In the standard GRB model 15 , 16 , after a jet is launched, dissipation processes within the ultra-relativistic flow produce a prompt flash of radiation, mostly visible as γ-rays. Later, the jet’s outermost layers interact with the surrounding medium and two shocks develop, one propagating outwards into the external medium (the forward shock) and the other one travelling backwards into the jet (the reverse shock). These shocks heat up the ambient electrons, which emit, via synchrotron emission, a broadband afterglow radiation. At an early time (around T 0 + 10 seconds), the observed optical flux from GRB 160625B is orders of magnitude brighter than the extrapolated prompt emission component ( Fig. 3 ), suggesting that optical and γ-ray emissions originate from different physical locations in the flow. A plausible interpretation is that the early (around T 0 + 10 seconds) optical emission arises from a strong reverse", "role": "user" }, { "content": "A study which is published in Nature magazine with observations from the robotic telescope MASTER-IAC at the Teide Observatory will help to clear up some unknown factors in the initial phase and the evolution of the huge jets of matter and energy which form as a consequence of these explosions, which are the most powerful in the universe. Gamma ray bursts are among the most energetic and explosive events in the universe. They are so fleeting, lasting from a few milliseconds to about a minute that to observe them accurately has been, until now, a difficult task. Using several ground-based and satellite telescopes, among them the robotic telescope MASTER-IAC, of Moscow State University, situated in the Teide Observatory (Tenerife) an international team led by the University of Maryland (USA) and in which researchers from the Instituto de Astrofísica de Canarias (IAC) have taken part, has observed one of these explosions with unprecedented detail. The event, named GRB160625B, revealed key details about the initial phase of the gamma ray explosion and the evolution of the huge jets of matter and energy which form as a result of it. \"Gamma Ray bursts are catastrophic events, related to the explosion of massive stars, some 50 times bigger than our sun\" explains Eleonora Troja, a researcher at UMD and the first author on the paper. \"If we classify all the explosions in the universe by their energy, gamma ray bursts would be just less than the Big Bang. In a matter of seconds the process can emit as much energy as the sun during its whole lifetime. For that reason we are very interested to know how these phenomena occur. The observations revealed some of the unknown details about the process in which a gamma ray explosion evolves while a dying star collapses and turns into a black hole. In the first place the data suggest that the black hole produces a strong magnetic field, which at the beginning controls the jets in which energy is emitted. Then when the magnetic field decays the matter takes control and starts to dominate the jets. The majority of specialists in gamma ray bursts thought that the jets were dominated by the matter or by the magnetic field, but not by both. Now the results of this research, to be published tomorrow in Nature magazine suggest that both factors play a basic role. Formation of black holes \"A few seconds after the detection of a gamma ray burst by NASA's Fermi satellite the robotic telescope MASTER-IAC began to observe this highly energetic phenomenon at visible wavelengths, which lasted only a few seconds. This allowed us to measure the polarization of the emitted radiation and in this way learn about the nature of the physical processes involved\" explains Rafael Rebolo, director of the IAC and one of the authors of the article. \"In the future\" he adds \"with the telescopes of the CTA (Cherenkov Telescope Array) to be installed on La Palma, it will be possible to observe this kind of phenomena, related to the formation of black holes, in detail at much higher energy\". The data suggest that the synchrotron radiation-produced when electrons are accelerated along a curved or spiral trajectory- activates the initial extremely bright phase of the outburst known as the \"rapid\" phase. For a long time two other candidates were considered possible: black body radiation emitted by an object at high temperature, or inverse Compton radiation, which is produced when an accelerated particle transfers energy to a photon. \"Synchrotron radiation is the only mechanism which can create the degree of polarization and the spectrum which we observed at the beginning of the explosion\" notes Eleonora Troja. \"Our study gives convincing proof that the sudden emission of gamma rays is driven by synchrotron radiation. This is an important achievement because in spite of decades of research the physical mechanism which drives gamma ray bursts had not been precisely identified\". Fermi, NASA's Gamma Ray Space telescope was the first to detect the gamma ray emission from GRB160625B. Shortly afterwards MASTER-IAC, one of the network of MASTER robotic telescopes whose Principal Investigator is Vladimir Lipunov, of Moscow State University (Russia) followed up with observations in the visible while the alert phase was still active. MASTER-IAC took data on the quantity of polarized visible light compared to the total light produced during the rapid outburst. Given that synchrotron radiation is one of the phenomena which can produce polarized light the data have yielded a crucial link between the synchrotron radiation and the initial phase of the gamma ray explosion. A magnetic field can also influence the fraction of polarized light emitted as time proceeds, and the burst evolves. As they were able to analyze the polarization data during almost the complete burst, they could make out the presence of a magnetic field and observed how it varied while GRB160625B continued to throw out jets of matter. ", "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 Newly formed black holes of stellar mass launch collimated outflows (jets) of ionized matter that approach the speed of light. These outflows power prompt, brief and intense flashes of γ-rays known as γ-ray bursts (GRBs), followed by longer-lived afterglow radiation that is detected across the electromagnetic spectrum. Measuring the polarization of the observed GRB radiation provides a direct probe of the magnetic fields in the collimated jets. Rapid-response polarimetric observations of newly discovered bursts have probed the initial afterglow phase 1 , 2 , 3 , and show that, minutes after the prompt emission has ended, the degree of linear polarization can be as high as 30 per cent—consistent with the idea that a stable, globally ordered magnetic field permeates the jet at large distances from the central source 3 . By contrast, optical 4 , 5 , 6 and γ-ray 7 , 8 , 9 observations during the prompt phase have led to discordant and often controversial 10 , 11 , 12 results, and no definitive conclusions have been reached regarding the origin of the prompt radiation or the configuration of the magnetic field. Here we report the detection of substantial (8.3 ± 0.8 per cent from our most conservative simulation), variable linear polarization of a prompt optical flash that accompanied the extremely energetic and long-lived prompt γ-ray emission from GRB 160625B. Our measurements probe the structure of the magnetic field at an early stage of the jet, closer to its central black hole, and show that the prompt phase is produced via fast-cooling synchrotron radiation in a large-scale magnetic field that is advected from the black hole and distorted by dissipation processes within the jet. Main On 25 June 2016 at 22:40:16.28 Universal Time ( ut ), the γ-ray burst monitor (GBM) aboard NASA’s Fermi Gamma-ray Space Telescope discovered GRB 160625B as a short-lived pulse (lasting about 1 second) of γ-ray radiation (G1 in Fig. 1 ). An automatic localization was published rapidly by the spacecraft, allowing wide-field optical facilities to start follow-up observations. Three minutes after the first alert, at 22:43:24.82 ut (hereafter T 0 ), the Large Area Telescope (LAT) aboard Fermi was triggered by another bright but longer-lasting pulse (of about 30 seconds; G2 in Fig. 1 ), visible up to gigaelectronvolt (GeV) energies 13 . A rapid increase in brightness was observed simultaneously at optical wavelengths ( Fig. 1 ): the optical brightness rose by a factor of 100 in a few seconds, reaching its peak at T 0 + 5.9 seconds, with an observed visual magnitude of 7.9. After a second, fainter peak at T 0 + 15.9 seconds, the optical light declined steadily. During this phase, the MASTER 14 -IAC telescope on Tenerife, Spain, observed the optical counterpart in two orthogonal polaroids simultaneously, starting at T 0 + 95 seconds and ending at T 0 + 360 seconds. The detection of a polarized signal with this instrumental configuration provides a lower bound ( Π L,min ) to the true degree of linear polarization, thus Π L,min = ( I 2 − I 1 )/( I 1 + I 2 ), where I 1 and I 2 refer to the source intensity in each polaroid. Substantial levels of linear polarization, up to Π L,min = 8.0 ± 0.5%, were thereby detected ( Fig. 2 ; by comparison, values of less than 2% have been detected for other nearby objects of similar brightness). Over this time interval a weak tail of γ-ray emission was visible, until the onset of a third, longer-lived episode of prompt γ-ray radiation (G3), starting at T 0 + 337 seconds and ending at T 0 + 630 seconds. Figure 1: Prompt γ-ray and optical light curves of GRB 160625B. The γ-ray light curve (black; 10–250 keV) consists of three main episodes: a short precursor (G1), a bright main burst (G2), and a fainter and longer-lasting tail (G3). Optical data from the MASTER Net telescopes and other ground-based facilities 19 are overlaid for comparison. Error bars represent 1 σ ; upper limits are 3 σ . The red box marks the time interval over which polarimetric measurements were taken. Within the sample of nearly 2,000 bursts detected by the GBM, only six other events have a comparable duration ( ). Most GRBs end before the start of polarimetric observations. PowerPoint slide Source data Full size image Figure 2: Temporal evolution of the optical polarization measured for GRB 160625B. The minimum polarization ( Π L,min ), measured in four different temporal bins (red squares), remains fairly constant over the first three exposures, then increases by 60% during the fourth (and last) observation. At the same time, an evident increase in the γ-ray count rates (grey shaded area; 5-second time bins) marks the onset of the third episode of prompt emission (G3 in Fig. 1 ). The spectral shape and fast temporal variability observed during G3 are typical of a GRB’s prompt emission. For comparison, we also show simultaneous polarimetric measurements of the three brightest stars in the MASTER-IAC field of view. Error bars represent 1 σ . PowerPoint slide Full size image In the standard GRB model 15 , 16 , after a jet is launched, dissipation processes within the ultra-relativistic flow produce a prompt flash of radiation, mostly visible as γ-rays. Later, the jet’s outermost layers interact with the surrounding medium and two shocks develop, one propagating outwards into the external medium (the forward shock) and the other one travelling backwards into the jet (the reverse shock). These shocks heat up the ambient electrons, which emit, via synchrotron emission, a broadband afterglow radiation. At an early time (around T 0 + 10 seconds), the observed optical flux from GRB 160625B is orders of magnitude brighter than the extrapolated prompt emission component ( Fig. 3 ), suggesting that optical and γ-ray emissions originate from different physical locations in the flow. A plausible interpretation is that the early (around T 0 + 10 seconds) optical emission arises from a strong reverse<|im_end|> <|im_start|>assistant A study which is published in Nature magazine with observations from the robotic telescope MASTER-IAC at the Teide Observatory will help to clear up some unknown factors in the initial phase and the evolution of the huge jets of matter and energy which form as a consequence of these explosions, which are the most powerful in the universe. Gamma ray bursts are among the most energetic and explosive events in the universe. They are so fleeting, lasting from a few milliseconds to about a minute that to observe them accurately has been, until now, a difficult task. Using several ground-based and satellite telescopes, among them the robotic telescope MASTER-IAC, of Moscow State University, situated in the Teide Observatory (Tenerife) an international team led by the University of Maryland (USA) and in which researchers from the Instituto de Astrofísica de Canarias (IAC) have taken part, has observed one of these explosions with unprecedented detail. The event, named GRB160625B, revealed key details about the initial phase of the gamma ray explosion and the evolution of the huge jets of matter and energy which form as a result of it. "Gamma Ray bursts are catastrophic events, related to the explosion of massive stars, some 50 times bigger than our sun" explains Eleonora Troja, a researcher at UMD and the first author on the paper. "If we classify all the explosions in the universe by their energy, gamma ray bursts would be just less than the Big Bang. In a matter of seconds the process can emit as much energy as the sun during its whole lifetime. For that reason we are very interested to know how these phenomena occur. The observations revealed some of the unknown details about the process in which a gamma ray explosion evolves while a dying star collapses and turns into a black hole. In the first place the data suggest that the black hole produces a strong magnetic field, which at the beginning controls the jets in which energy is emitted. Then when the magnetic field decays the matter takes control and starts to dominate the jets. The majority of specialists in gamma ray bursts thought that the jets were dominated by the matter or by the magnetic field, but not by both. Now the results of this research, to be published tomorrow in Nature magazine suggest that both factors play a basic role. Formation of black holes "A few seconds after the detection of a gamma ray burst by NASA's Fermi satellite the robotic telescope MASTER-IAC began to observe this highly energetic phenomenon at visible wavelengths, which lasted only a few seconds. This allowed us to measure the polarization of the emitted radiation and in this way learn about the nature of the physical processes involved" explains Rafael Rebolo, director of the IAC and one of the authors of the article. "In the future" he adds "with the telescopes of the CTA (Cherenkov Telescope Array) to be installed on La Palma, it will be possible to observe this kind of phenomena, related to the formation of black holes, in detail at much higher energy". The data suggest that the synchrotron radiation-produced when electrons are accelerated along a curved or spiral trajectory- activates the initial extremely bright phase of the outburst known as the "rapid" phase. For a long time two other candidates were considered possible: black body radiation emitted by an object at high temperature, or inverse Compton radiation, which is produced when an accelerated particle transfers energy to a photon. "Synchrotron radiation is the only mechanism which can create the degree of polarization and the spectrum which we observed at the beginning of the explosion" notes Eleonora Troja. "Our study gives convincing proof that the sudden emission of gamma rays is driven by synchrotron radiation. This is an important achievement because in spite of decades of research the physical mechanism which drives gamma ray bursts had not been precisely identified". Fermi, NASA's Gamma Ray Space telescope was the first to detect the gamma ray emission from GRB160625B. Shortly afterwards MASTER-IAC, one of the network of MASTER robotic telescopes whose Principal Investigator is Vladimir Lipunov, of Moscow State University (Russia) followed up with observations in the visible while the alert phase was still active. MASTER-IAC took data on the quantity of polarized visible light compared to the total light produced during the rapid outburst. Given that synchrotron radiation is one of the phenomena which can produce polarized light the data have yielded a crucial link between the synchrotron radiation and the initial phase of the gamma ray explosion. A magnetic field can also influence the fraction of polarized light emitted as time proceeds, and the burst evolves. As they were able to analyze the polarization data during almost the complete burst, they could make out the presence of a magnetic field and observed how it varied while GRB160625B continued to throw out jets of matter. <|im_end|>

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2,369

[ { "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 Originally intended as a replication study, this study discusses differences in problem solving performance among different domains caused by the same instructional intervention. The learning sciences acknowledges similarities in the learners’ cognitive architecture that allow interventions to apply across domains, but it also argues that each domain has characteristics that might affect how interventions impact learning. The present study uses an instructional design technique that had previously improved learners’ problem solving performance in programming: subgoal labeled expository text and subgoal labeled worked examples. It intended to replicate this effect for solving problems in statistics and chemistry. However, each of the experiments in the three domains had a different pattern of results for problem solving performance. While the subgoal labeled worked example consistently improved performance, the subgoal labeled expository text, which interacted with subgoal labeled worked examples in programming, had an additive effect with subgoal labeled worked examples in chemistry and no effect in statistics. Differences in patterns of results are believed to be due to complexity of the content to be learned, especially in terms of mapping problem solving procedures to solving problems, and the familiarity of tools used to solve problems in the domain. Subgoal labeled expository text was effective only when students learned more complex content and used unfamiliar problem solving tools. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes The learning sciences, and discipline based educational research in particular, has started to identify similarities and differences in teaching and learning practices in science, technology, engineering, and mathematics (STEM) domains. This community argues, correctly, that some aspects of STEM domains overlap (e.g., Kirschner et al. 2017 ), but each has features that make it unique, which matter when teaching in that domain (e.g., Mishra and Koehler 2006 ). For example, many STEM disciplines are similar in that they use formulas to solve problems and need to train learners to match parts of a problem to part of a formula, making formula-matching a general problem solving skill (Singer et al. 2012 ). In contrast, STEM disciplines are different in that some are more rooted in the physical world, such as biology, some, such as algebra and computer science, focus on processes that are fundamentally abstract but can be exemplified through concrete examples, while others such as physics involve real objects that experience processes that are not directly observable even though the results might be. This difference matters because students in disciplines that have obvious connections to items that we interact with regularly are more prone to having misconceptions about how those objects operate (Chi 2005 ) whereas students in more abstract disciplines can have more difficulty grasping concepts with which they have little experience (Booth 1988 ; Küchemann 1981 ). In light of differences like these, interventions that improve learning across different disciplines are valuable. Interventions that are effective across disciplines can provide insight into similarities among domains and how people learn them. They also have practical pedagogical value in providing approaches of wide utility. Similarly, finding interventions that are not effective across disciplines can provide insight into differences among domains and how those differences affect learning. Both types of results can contribute meaningfully to the learning sciences, making cross-disciplinary research beneficial to our community. The present study attempted to replicate the effect of a new intervention, subgoal labeled expository text, that was successful in improving learning in one domain, computer programming, but has yet to be tested in other domains. Subgoal learning and subgoal labeled instructional material Subgoal labeled expository text is an extension of the subgoal learning framework, which focuses on teaching learners the subgoals of problem solving procedures to improve their retention and transfer (Catramboe 1998 ). A subgoal is a functional component of a problem’s solution. For example, consider the procedure described in Fig. 1 . To find the solution, which is your goal, you would divide 243 by 104 to calculate the average frequency of an event. The subgoal label, in this case “calculate average frequency,” points out the function of this step to the learner. This explicit explanation of the function is necessary because novices tend to organize and encode procedural information based on surface features of the problem, such as frequency of a video being rented, rather than structural features of the problem, such as calculating the average frequency of an event (Bransford et al. 2000 ; Chi et al. 1981 ). Fig. 1 Expository text (a, b) and worked examples (c, d), either subgoal labeled (a, c) or unlabeled (b, d), describing and demonstrating the procedure used to solve problems with the Poisson distribution. The only difference is the presence of subgoal labels Full size image Subgoals repeat within a class of problems within a discipline, and learning to identify and complete subgoals helps learners solve novel problems better (Catrambone and Holyoak 1990 ). For this reason, subgoal labels have been used extensively to help students learn from worked examples. Worked examples are example problems presented with their step-by-step solution. Subgoal labeled worked examples improve learning by highlighting the procedure used in examples (Atkinson and Derry 2000 ; Atkinson et al. 2003 ; Margulieux et al. 2016 ), providing organization for new information (Morrison et al. 2015 ), and inducing self-explanation (Catrambone 1998 ; Renkl and Atkinson 2002 ; Morrison et al. 2016 ). In most domains, students receive both worked examples and expository text. Expository text is text that introduces and defines terminology and also describes problem solving procedures conceptually (Trafton and Reiser 1993 ). For instance, the expository text in Fig. 1 describes the procedure conceptually, whereas the worked example gives an exemplar of the procedure being used to solve a concrete problem. Expository text is valuable because learners who master the problem solving procedure conceptually can solve novel problems better than learners who are given more specific instructions (Eiriksdottir and Catrambone 2011 ). Because expository text is abstract, however, it can be difficult for students to grasp, especially when they", "role": "user" }, { "content": "Easy as 1, 2, 3! Such claims have touted the ease of use of a new gadget, although a closer look would reveal that it would take dozens of steps to make it work. Just ask School of Psychology Professor Richard Catrambone. In his research, Catrambone often undertakes a task analysis. It involves recording in excruciating detail the steps to accomplish a procedural task, such as executing a pirouette, solving an algebra problem, or programming a Lego toy tank to pivot from any of its two wheels. For the experts explaining the detailed procedure to Catrambone, the analysis can be overwhelming. They've solved these problems so many times before that the solutions have become second nature. Going over each step in detail is like moving in plodding motion. For Catrambone, task analysis yields copious notes. The process, he says, is necessary in creating effective materials and tools for education and training, because they enable identification of the subgoals embedded in a procedure of multiple steps. Catrambone and his award-winning former Ph.D. student Lauren Margulieux, now an assistant professor at Georgia State University, have shown in various studies that when problem-solving procedures are taught through subgoals, learners can apply them to a wider variety of problems. \"Imagine you're in an algebra class and the teacher solves a problem on the board. Then the teacher erases the problem and gives you another that is just like it,\" Catrambone says. \"Most students can rip out the old numbers, shove in the new numbers, and get an answer. They've memorized what the teacher did.\" When students get a conceptually similar problem but is not solved in the exact set of steps, they fail. Margulieux offers an example. Solving equation A, 2x – 4 = 4x + 8, is conceptually similar to solving equation B, 6x – 15 = 3x/4 + 2x. Solving either equation involves two subgoals: isolate the variable and simplify it. The specific subgoal steps, however, are different for equations A and B. Students who only memorize the solution to equation A will unlikely solve equation B. At Play, At Home, At Work Subgoal-based learning is good for learning procedures and solving problems with knowable correct answers, Margulieux says. Applications are everywhere. Catrambone says he often creates wacky poker games that annoy his friends by varying the steps within each subgoal of the game. The subgoals include dealing a certain number of cards, designating a common pool of cards, and assigning certain cards as wild. \"Whether the number of cards dealt is 5 or 4 or 3 is irrelevant,\" he says. \"All I do is create new games that meet the subgoals.\" Meanwhile, Margulieux sees the principle in cooking. To cook vegetables, a subgoal cook would \"pick a vegetable, pick a way to cook it, and pick the flavors to go with it,\" Margulieux says. A by-the-recipe cook would get a cup of broccoli, get a tablespoon of olive oil, roast the broccoli in the oven, and garnish it with salt and pepper, all the while checking the recipe again and again in between steps. If the menu calls for Brussel sprouts, the cook would need another recipe. An important application is in education. Catrambone observes that many learning tools often do not work as intended. \"Especially at Georgia Tech, we can get caught up in creating widgets and learning environments and multimedia simulations for education and training,\" he says. \"But you need to do the task analysis first to identify what the learner needs to know – the subgoals and associated steps – and then use that knowledge to guide the creation of learning materials and tools. Otherwise, those materials and tools will be much less effective.\" Margulieux aims to apply these findings to online learning. In a real classroom, she says, struggling students have the advantage of the teacher seeing the difficulty they are having – even if they are not asking the exact right questions – and doing something about it. Online, where the student and instructor are not in the same space, the barrier to asking a question is high, Margulieux says. \"The cost of asking follow-up questions is even higher because if students don't get an answer that makes sense, they probably won't ask another question. They will just try to figure it out themselves, and if they don't have the knowledge to do this, it could be detrimental for learning.\" \"My interest is to make instructions very explicit in what students need to know to understand procedural problem solving so that they can perform well even if they don't have anyone online to help them,\" Margulieux says. How else can learning be made more effective? Catrambone and Margulieux have established that subgoal-labeled worked examples improve learning outcomes. For equation A, that would look like this: Original problem: 2x – 4 = 4x + 8Isolate variable: 2x – 4 – 2x – 8 = 4x + 8 – 2x – 8Isolate variable: –12 = 2xSimplify variable: –12/2 = 2x/2Answer: –6 = x Furthermore, they have shown that in some fields, computer programming for example, combining the subgoal-labeled worked example with subgoal-labeled expository text improves learning even more. Their latest work, with Ph.D. student Laura Schaeffer, shows, however, that the improvement does not play out the same way in other fields. \"While subgoal-oriented examples help learning in all domains tested so far, subgoal-oriented expository text seems to help in some domains but not others,\" Margulieux says. \"Why this might be the case is a focus of ongoing 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 Originally intended as a replication study, this study discusses differences in problem solving performance among different domains caused by the same instructional intervention. The learning sciences acknowledges similarities in the learners’ cognitive architecture that allow interventions to apply across domains, but it also argues that each domain has characteristics that might affect how interventions impact learning. The present study uses an instructional design technique that had previously improved learners’ problem solving performance in programming: subgoal labeled expository text and subgoal labeled worked examples. It intended to replicate this effect for solving problems in statistics and chemistry. However, each of the experiments in the three domains had a different pattern of results for problem solving performance. While the subgoal labeled worked example consistently improved performance, the subgoal labeled expository text, which interacted with subgoal labeled worked examples in programming, had an additive effect with subgoal labeled worked examples in chemistry and no effect in statistics. Differences in patterns of results are believed to be due to complexity of the content to be learned, especially in terms of mapping problem solving procedures to solving problems, and the familiarity of tools used to solve problems in the domain. Subgoal labeled expository text was effective only when students learned more complex content and used unfamiliar problem solving tools. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes The learning sciences, and discipline based educational research in particular, has started to identify similarities and differences in teaching and learning practices in science, technology, engineering, and mathematics (STEM) domains. This community argues, correctly, that some aspects of STEM domains overlap (e.g., Kirschner et al. 2017 ), but each has features that make it unique, which matter when teaching in that domain (e.g., Mishra and Koehler 2006 ). For example, many STEM disciplines are similar in that they use formulas to solve problems and need to train learners to match parts of a problem to part of a formula, making formula-matching a general problem solving skill (Singer et al. 2012 ). In contrast, STEM disciplines are different in that some are more rooted in the physical world, such as biology, some, such as algebra and computer science, focus on processes that are fundamentally abstract but can be exemplified through concrete examples, while others such as physics involve real objects that experience processes that are not directly observable even though the results might be. This difference matters because students in disciplines that have obvious connections to items that we interact with regularly are more prone to having misconceptions about how those objects operate (Chi 2005 ) whereas students in more abstract disciplines can have more difficulty grasping concepts with which they have little experience (Booth 1988 ; Küchemann 1981 ). In light of differences like these, interventions that improve learning across different disciplines are valuable. Interventions that are effective across disciplines can provide insight into similarities among domains and how people learn them. They also have practical pedagogical value in providing approaches of wide utility. Similarly, finding interventions that are not effective across disciplines can provide insight into differences among domains and how those differences affect learning. Both types of results can contribute meaningfully to the learning sciences, making cross-disciplinary research beneficial to our community. The present study attempted to replicate the effect of a new intervention, subgoal labeled expository text, that was successful in improving learning in one domain, computer programming, but has yet to be tested in other domains. Subgoal learning and subgoal labeled instructional material Subgoal labeled expository text is an extension of the subgoal learning framework, which focuses on teaching learners the subgoals of problem solving procedures to improve their retention and transfer (Catramboe 1998 ). A subgoal is a functional component of a problem’s solution. For example, consider the procedure described in Fig. 1 . To find the solution, which is your goal, you would divide 243 by 104 to calculate the average frequency of an event. The subgoal label, in this case “calculate average frequency,” points out the function of this step to the learner. This explicit explanation of the function is necessary because novices tend to organize and encode procedural information based on surface features of the problem, such as frequency of a video being rented, rather than structural features of the problem, such as calculating the average frequency of an event (Bransford et al. 2000 ; Chi et al. 1981 ). Fig. 1 Expository text (a, b) and worked examples (c, d), either subgoal labeled (a, c) or unlabeled (b, d), describing and demonstrating the procedure used to solve problems with the Poisson distribution. The only difference is the presence of subgoal labels Full size image Subgoals repeat within a class of problems within a discipline, and learning to identify and complete subgoals helps learners solve novel problems better (Catrambone and Holyoak 1990 ). For this reason, subgoal labels have been used extensively to help students learn from worked examples. Worked examples are example problems presented with their step-by-step solution. Subgoal labeled worked examples improve learning by highlighting the procedure used in examples (Atkinson and Derry 2000 ; Atkinson et al. 2003 ; Margulieux et al. 2016 ), providing organization for new information (Morrison et al. 2015 ), and inducing self-explanation (Catrambone 1998 ; Renkl and Atkinson 2002 ; Morrison et al. 2016 ). In most domains, students receive both worked examples and expository text. Expository text is text that introduces and defines terminology and also describes problem solving procedures conceptually (Trafton and Reiser 1993 ). For instance, the expository text in Fig. 1 describes the procedure conceptually, whereas the worked example gives an exemplar of the procedure being used to solve a concrete problem. Expository text is valuable because learners who master the problem solving procedure conceptually can solve novel problems better than learners who are given more specific instructions (Eiriksdottir and Catrambone 2011 ). Because expository text is abstract, however, it can be difficult for students to grasp, especially when they<|im_end|> <|im_start|>assistant Easy as 1, 2, 3! Such claims have touted the ease of use of a new gadget, although a closer look would reveal that it would take dozens of steps to make it work. Just ask School of Psychology Professor Richard Catrambone. In his research, Catrambone often undertakes a task analysis. It involves recording in excruciating detail the steps to accomplish a procedural task, such as executing a pirouette, solving an algebra problem, or programming a Lego toy tank to pivot from any of its two wheels. For the experts explaining the detailed procedure to Catrambone, the analysis can be overwhelming. They've solved these problems so many times before that the solutions have become second nature. Going over each step in detail is like moving in plodding motion. For Catrambone, task analysis yields copious notes. The process, he says, is necessary in creating effective materials and tools for education and training, because they enable identification of the subgoals embedded in a procedure of multiple steps. Catrambone and his award-winning former Ph.D. student Lauren Margulieux, now an assistant professor at Georgia State University, have shown in various studies that when problem-solving procedures are taught through subgoals, learners can apply them to a wider variety of problems. "Imagine you're in an algebra class and the teacher solves a problem on the board. Then the teacher erases the problem and gives you another that is just like it," Catrambone says. "Most students can rip out the old numbers, shove in the new numbers, and get an answer. They've memorized what the teacher did." When students get a conceptually similar problem but is not solved in the exact set of steps, they fail. Margulieux offers an example. Solving equation A, 2x – 4 = 4x + 8, is conceptually similar to solving equation B, 6x – 15 = 3x/4 + 2x. Solving either equation involves two subgoals: isolate the variable and simplify it. The specific subgoal steps, however, are different for equations A and B. Students who only memorize the solution to equation A will unlikely solve equation B. At Play, At Home, At Work Subgoal-based learning is good for learning procedures and solving problems with knowable correct answers, Margulieux says. Applications are everywhere. Catrambone says he often creates wacky poker games that annoy his friends by varying the steps within each subgoal of the game. The subgoals include dealing a certain number of cards, designating a common pool of cards, and assigning certain cards as wild. "Whether the number of cards dealt is 5 or 4 or 3 is irrelevant," he says. "All I do is create new games that meet the subgoals." Meanwhile, Margulieux sees the principle in cooking. To cook vegetables, a subgoal cook would "pick a vegetable, pick a way to cook it, and pick the flavors to go with it," Margulieux says. A by-the-recipe cook would get a cup of broccoli, get a tablespoon of olive oil, roast the broccoli in the oven, and garnish it with salt and pepper, all the while checking the recipe again and again in between steps. If the menu calls for Brussel sprouts, the cook would need another recipe. An important application is in education. Catrambone observes that many learning tools often do not work as intended. "Especially at Georgia Tech, we can get caught up in creating widgets and learning environments and multimedia simulations for education and training," he says. "But you need to do the task analysis first to identify what the learner needs to know – the subgoals and associated steps – and then use that knowledge to guide the creation of learning materials and tools. Otherwise, those materials and tools will be much less effective." Margulieux aims to apply these findings to online learning. In a real classroom, she says, struggling students have the advantage of the teacher seeing the difficulty they are having – even if they are not asking the exact right questions – and doing something about it. Online, where the student and instructor are not in the same space, the barrier to asking a question is high, Margulieux says. "The cost of asking follow-up questions is even higher because if students don't get an answer that makes sense, they probably won't ask another question. They will just try to figure it out themselves, and if they don't have the knowledge to do this, it could be detrimental for learning." "My interest is to make instructions very explicit in what students need to know to understand procedural problem solving so that they can perform well even if they don't have anyone online to help them," Margulieux says. How else can learning be made more effective? Catrambone and Margulieux have established that subgoal-labeled worked examples improve learning outcomes. For equation A, that would look like this: Original problem: 2x – 4 = 4x + 8Isolate variable: 2x – 4 – 2x – 8 = 4x + 8 – 2x – 8Isolate variable: –12 = 2xSimplify variable: –12/2 = 2x/2Answer: –6 = x Furthermore, they have shown that in some fields, computer programming for example, combining the subgoal-labeled worked example with subgoal-labeled expository text improves learning even more. Their latest work, with Ph.D. student Laura Schaeffer, shows, however, that the improvement does not play out the same way in other fields. "While subgoal-oriented examples help learning in all domains tested so far, subgoal-oriented expository text seems to help in some domains but not others," Margulieux says. "Why this might be the case is a focus of ongoing research." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Owing to its unique penetrating power and high-resolution capability, X-ray imaging has been an irreplaceable tool since its discovery. Despite the significance, the resolution of X-ray imaging has largely been limited by the technical difficulties on X-ray lens making. Various lensless imaging methods have been proposed, but are yet relying on multiple measurements or additional constraints on measurements or samples. Here we present coherent speckle-correlation imaging (CSI) using a designed X-ray diffuser. CSI has no prerequisites for samples or measurements. Instead, from a single shot measurement, the complex sample field is retrieved based on the pseudorandomness of the speckle intensity pattern, ensured through a diffuser. We achieve a spatial resolution of 13.9 nm at 5.46 keV, beating the feature size of the diffuser used (300 nm). The high-resolution imaging capability is theoretically explained based on fundamental and practical limits. We expect the CSI to be a versatile tool for navigating the unexplored world of nanometer. Introduction Making an X-ray imaging lens has been a challenging quest. Because of the near-unity refractive indexes of materials in X-ray, collecting scattered rays through refractive optics is difficult 1 . Although Fresnel zone plates have been used, their low coupling efficiency and technical difficulties in high-resolution zone plate fabrication have been problematic, particularly for hard X-rays 2 , 3 . Lensless X-ray imaging methods have therefore been investigated 4 . The main concept of these methods is applying a numerical, instead of physical, lens by measuring the sample diffraction field. However, the complex-valued sample field is not a measurable quantity. Although an image sensor can measure the intensity of a diffracted sample field, its phase information is lost during acquisition; reconstruction of the lost phase has been a major challenge in lens-free X-ray imaging 5 . Additional constraints should be introduced a priori to determine the correct phase values 6 , 7 . A successful example is coherent diffractive imaging (CDI), which utilizes the sample support as a constraint 8 , 9 . With CDI, the sample field is reconstructed from a far-field diffraction pattern using iterative algorithms 10 , 11 . High-resolution phase imaging and a simple setup are the advantages of CDI in materials 12 , 13 and biological studies 14 , 15 , 16 , 17 , 18 . Nevertheless, sample support constraints often limit the utility and feasibility of CDI. Because small support deviations may induce severe artifacts, defining proper support is critical in CDI 19 , 20 . Such strict support criteria hinder the application of CDI for more general samples with ambiguous boundaries or extended structures. Although the support criteria can be effectively mitigated by inserting an additional modulator after the sample 21 , 22 or introducing a known probe instead of sample support, the convergence and reliability of the results still depend on sample properties such as support looseness, resolution, size, or phase variation. Ptychography is another lensless imaging technique; it utilizes multiple acquisitions instead of a sample support constraint. In ptychography, a sample is laterally scanned using an X-ray probe, and position-dependent far-field diffraction patterns are obtained 23 , 24 . With sufficient overlap between adjacent probe beams, the correct phase solution can be determined without additional constraints 25 . Owing to the sample generality, ptychography is a promising solution for extended or confluent samples. Various samples have been investigated for two- 26 , 27 , 28 , 29 and three-dimensions 30 , 31 . However, the requirement of multiple acquisitions results in limitations in applicability; dynamic or degradable samples may not be applicable. Sample radiation damage can be severe, particularly for biological samples and X-ray free-electron laser (XFEL) applications 32 , 33 . Although reducing the X-ray dose and portions of overlap may prevent radiation damage, it may limit the signal-to-noise ratio and image resolution 34 , 35 . Thus, we present coherent speckle-correlation imaging (CSI) in X-ray. In CSI, we transform the sample field into a random speckle before the measurement using an X-ray diffuser 36 . Although the phase of the speckle is immeasurable either, the complex-valued sample field can be uniquely reconstructed from the magnitude image through the pseudorandomness of speckle 37 , 38 , 39 , 40 . Our CSI exploits a designed X-ray diffuser after the sample instead of a zone plate (Fig. 1 ), achieving a 13.9-nm image resolution at 5.46 keV; this is far below the feature size of the diffuser used (300 nm). The oversampling ratio and setup requirements are discussed in relation to the image resolution and sample field of view (FOV) acquired. Fig. 1: Designed diffuser as X-ray imaging lens. a Schematic of full-field transmission X-ray microscopy. The attenuation (amplitude) map of a sample is measured. The system resolution is defined by the outermost zone width of the zone plate (δ x ≈ Δ). b Schematic of the proposed CSI method. The zone plate is replaced with a designed diffuser. The complex-valued sample field is measured. The system resolution is finer than the hole size of the diffuser (δ x « Δ) Full size image Results Experimental setup The experimental setup of the CSI is shown in Fig. 2a (see Methods). A coherent X-ray beam (5.46 keV) was used at the 9C beamline of the Pohang Light Source II (PLS-II). A field stop (<3.0 μm) is placed before a sample to maintain the spatial coherence and eliminate ambient signals outside the sampling domain. The diffuser is a sputtered tungsten layer on a silicon nitride membrane with 300-nm etched holes in unordered but known locations (Fig. 2b ). The tungsten thickness and hole density are designed to minimize the unmodulated term ( q = 0) of the diffuser and generate well-developed speckle patterns for a given photon energy (see Methods). The diameter of the diffuser is defined by the aperture stop (100 μm). Because the locations of the holes are predefined, the transmission function of the diffuser is known (Fig. 2c ), and the output field for a given incident field can be calculated. An", "role": "user" }, { "content": "X-ray microscopes have the advantage of penetrating most substances, so internal organs and skeletons can be observed non-invasively through chest X-rays or CT scans. Recently, studies to increase the resolution of X-ray imaging technology are being actively conducted in order to precisely observe the internal structure of semiconductors and batteries at the nanoscale. A joint research team led by Professor YongKeun Park of the KAIST Department of Physics and Dr. Jun Lim of the Pohang Accelerator Laboratory has succeeded in developing a core technology that can overcome the resolution limitations of existing X-ray microscopes. This study, in which Dr. KyeoReh Lee participated as the first author, was published on April 6 in Light: Science and Applications. It is titled \"Direct high-resolution X-ray imaging exploiting pseudorandomness.\" X-ray nanomicroscopes do not have refractive lenses. In an X-ray microscope, a circular grating called a concentric zone plate is used instead of a lens. The resolution of an image obtained using the zone plate is determined by the quality of the nanostructure that constitutes the plate. There are several difficulties in fabricating and maintaining these nanostructures, which set the limit to the level of resolution for X-ray microscopy. Fig. 2. The left panel is a surface electron microscopy (SEM) image of the X-ray diffuser used in the experiment. The middle panel shows the design of the X-ray diffuser, and there is an inset in the middle of the panel that shows a corresponding part of the SEM image. The right panel shows an experimental random X-ray diffraction pattern, also known as a speckle pattern, obtained from the X-ray diffuser. Credit: The Korea Advanced Institute of Science and Technology (KAIST) The research team developed a new X-ray nanomicroscopy technology to overcome this problem. The X-ray lens proposed by the research team is in the form of numerous holes punched in a thin tungsten film, and generates random diffraction patterns by diffracting incident X-rays. The research team mathematically identified that, paradoxically, the high-resolution information of the sample was fully contained in these random diffraction patterns, and actually succeeded in extracting the information and imaging the internal states of the samples. The imaging method using the mathematical properties of random diffraction was proposed and implemented in the visible light band for the first time by Dr. KyeoReh Lee and Professor YongKeun Park in 2016. This study uses the results of previous studies to solve the difficult, lingering problem in the field of the X-ray imaging. The resolution of the image of the constructed sample has no direct correlation with the size of the pattern etched on the random lens used. Based on this idea, the research team succeeded in acquiring images with 14 nm resolution (approximately 1/7 the size of the coronavirus) by using random lenses made in a circular pattern with a diameter of 300 nm. Fig. 3. Images taken from the proposed randomness-based X-ray imaging (bottom) and the corresponding surface electron microscope (SEM) images (top). Credit: The Korea Advanced Institute of Science and Technology (KAIST) The imaging technology developed by this research team is a key fundamental technology that can enhance the resolution of X-ray nanomicroscopy, which has been blocked by limitations of the production of existing zone plates. The first author and one of the co-corresponding author, Dr. KyeoReh Lee of KAIST Department of Physics, said, \"In this study, the resolution was limited to 14 nm, but if the next-generation X-ray light source and high-performance X-ray detector are used, the resolution would exceed that of the conventional X-ray nano-imaging and approach the resolution of an electron microscope.\" \"Unlike an electron microscope, X-rays can observe the internal structure without damaging the sample, so it will be able to present a new standard for non-invasive nanostructure observation processes such as quality inspections for semiconductors.\" The co-corresponding author, Dr. Jun Lim of the Pohang Accelerator Laboratory, said, \"In the same context, the developed image technology is expected to greatly increase the performance in the 4th generation multipurpose radiation accelerator which is set to be established in Ochang of the Northern Chungcheong Province.\" ", "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 its unique penetrating power and high-resolution capability, X-ray imaging has been an irreplaceable tool since its discovery. Despite the significance, the resolution of X-ray imaging has largely been limited by the technical difficulties on X-ray lens making. Various lensless imaging methods have been proposed, but are yet relying on multiple measurements or additional constraints on measurements or samples. Here we present coherent speckle-correlation imaging (CSI) using a designed X-ray diffuser. CSI has no prerequisites for samples or measurements. Instead, from a single shot measurement, the complex sample field is retrieved based on the pseudorandomness of the speckle intensity pattern, ensured through a diffuser. We achieve a spatial resolution of 13.9 nm at 5.46 keV, beating the feature size of the diffuser used (300 nm). The high-resolution imaging capability is theoretically explained based on fundamental and practical limits. We expect the CSI to be a versatile tool for navigating the unexplored world of nanometer. Introduction Making an X-ray imaging lens has been a challenging quest. Because of the near-unity refractive indexes of materials in X-ray, collecting scattered rays through refractive optics is difficult 1 . Although Fresnel zone plates have been used, their low coupling efficiency and technical difficulties in high-resolution zone plate fabrication have been problematic, particularly for hard X-rays 2 , 3 . Lensless X-ray imaging methods have therefore been investigated 4 . The main concept of these methods is applying a numerical, instead of physical, lens by measuring the sample diffraction field. However, the complex-valued sample field is not a measurable quantity. Although an image sensor can measure the intensity of a diffracted sample field, its phase information is lost during acquisition; reconstruction of the lost phase has been a major challenge in lens-free X-ray imaging 5 . Additional constraints should be introduced a priori to determine the correct phase values 6 , 7 . A successful example is coherent diffractive imaging (CDI), which utilizes the sample support as a constraint 8 , 9 . With CDI, the sample field is reconstructed from a far-field diffraction pattern using iterative algorithms 10 , 11 . High-resolution phase imaging and a simple setup are the advantages of CDI in materials 12 , 13 and biological studies 14 , 15 , 16 , 17 , 18 . Nevertheless, sample support constraints often limit the utility and feasibility of CDI. Because small support deviations may induce severe artifacts, defining proper support is critical in CDI 19 , 20 . Such strict support criteria hinder the application of CDI for more general samples with ambiguous boundaries or extended structures. Although the support criteria can be effectively mitigated by inserting an additional modulator after the sample 21 , 22 or introducing a known probe instead of sample support, the convergence and reliability of the results still depend on sample properties such as support looseness, resolution, size, or phase variation. Ptychography is another lensless imaging technique; it utilizes multiple acquisitions instead of a sample support constraint. In ptychography, a sample is laterally scanned using an X-ray probe, and position-dependent far-field diffraction patterns are obtained 23 , 24 . With sufficient overlap between adjacent probe beams, the correct phase solution can be determined without additional constraints 25 . Owing to the sample generality, ptychography is a promising solution for extended or confluent samples. Various samples have been investigated for two- 26 , 27 , 28 , 29 and three-dimensions 30 , 31 . However, the requirement of multiple acquisitions results in limitations in applicability; dynamic or degradable samples may not be applicable. Sample radiation damage can be severe, particularly for biological samples and X-ray free-electron laser (XFEL) applications 32 , 33 . Although reducing the X-ray dose and portions of overlap may prevent radiation damage, it may limit the signal-to-noise ratio and image resolution 34 , 35 . Thus, we present coherent speckle-correlation imaging (CSI) in X-ray. In CSI, we transform the sample field into a random speckle before the measurement using an X-ray diffuser 36 . Although the phase of the speckle is immeasurable either, the complex-valued sample field can be uniquely reconstructed from the magnitude image through the pseudorandomness of speckle 37 , 38 , 39 , 40 . Our CSI exploits a designed X-ray diffuser after the sample instead of a zone plate (Fig. 1 ), achieving a 13.9-nm image resolution at 5.46 keV; this is far below the feature size of the diffuser used (300 nm). The oversampling ratio and setup requirements are discussed in relation to the image resolution and sample field of view (FOV) acquired. Fig. 1: Designed diffuser as X-ray imaging lens. a Schematic of full-field transmission X-ray microscopy. The attenuation (amplitude) map of a sample is measured. The system resolution is defined by the outermost zone width of the zone plate (δ x ≈ Δ). b Schematic of the proposed CSI method. The zone plate is replaced with a designed diffuser. The complex-valued sample field is measured. The system resolution is finer than the hole size of the diffuser (δ x « Δ) Full size image Results Experimental setup The experimental setup of the CSI is shown in Fig. 2a (see Methods). A coherent X-ray beam (5.46 keV) was used at the 9C beamline of the Pohang Light Source II (PLS-II). A field stop (<3.0 μm) is placed before a sample to maintain the spatial coherence and eliminate ambient signals outside the sampling domain. The diffuser is a sputtered tungsten layer on a silicon nitride membrane with 300-nm etched holes in unordered but known locations (Fig. 2b ). The tungsten thickness and hole density are designed to minimize the unmodulated term ( q = 0) of the diffuser and generate well-developed speckle patterns for a given photon energy (see Methods). The diameter of the diffuser is defined by the aperture stop (100 μm). Because the locations of the holes are predefined, the transmission function of the diffuser is known (Fig. 2c ), and the output field for a given incident field can be calculated. An<|im_end|> <|im_start|>assistant X-ray microscopes have the advantage of penetrating most substances, so internal organs and skeletons can be observed non-invasively through chest X-rays or CT scans. Recently, studies to increase the resolution of X-ray imaging technology are being actively conducted in order to precisely observe the internal structure of semiconductors and batteries at the nanoscale. A joint research team led by Professor YongKeun Park of the KAIST Department of Physics and Dr. Jun Lim of the Pohang Accelerator Laboratory has succeeded in developing a core technology that can overcome the resolution limitations of existing X-ray microscopes. This study, in which Dr. KyeoReh Lee participated as the first author, was published on April 6 in Light: Science and Applications. It is titled "Direct high-resolution X-ray imaging exploiting pseudorandomness." X-ray nanomicroscopes do not have refractive lenses. In an X-ray microscope, a circular grating called a concentric zone plate is used instead of a lens. The resolution of an image obtained using the zone plate is determined by the quality of the nanostructure that constitutes the plate. There are several difficulties in fabricating and maintaining these nanostructures, which set the limit to the level of resolution for X-ray microscopy. Fig. 2. The left panel is a surface electron microscopy (SEM) image of the X-ray diffuser used in the experiment. The middle panel shows the design of the X-ray diffuser, and there is an inset in the middle of the panel that shows a corresponding part of the SEM image. The right panel shows an experimental random X-ray diffraction pattern, also known as a speckle pattern, obtained from the X-ray diffuser. Credit: The Korea Advanced Institute of Science and Technology (KAIST) The research team developed a new X-ray nanomicroscopy technology to overcome this problem. The X-ray lens proposed by the research team is in the form of numerous holes punched in a thin tungsten film, and generates random diffraction patterns by diffracting incident X-rays. The research team mathematically identified that, paradoxically, the high-resolution information of the sample was fully contained in these random diffraction patterns, and actually succeeded in extracting the information and imaging the internal states of the samples. The imaging method using the mathematical properties of random diffraction was proposed and implemented in the visible light band for the first time by Dr. KyeoReh Lee and Professor YongKeun Park in 2016. This study uses the results of previous studies to solve the difficult, lingering problem in the field of the X-ray imaging. The resolution of the image of the constructed sample has no direct correlation with the size of the pattern etched on the random lens used. Based on this idea, the research team succeeded in acquiring images with 14 nm resolution (approximately 1/7 the size of the coronavirus) by using random lenses made in a circular pattern with a diameter of 300 nm. Fig. 3. Images taken from the proposed randomness-based X-ray imaging (bottom) and the corresponding surface electron microscope (SEM) images (top). Credit: The Korea Advanced Institute of Science and Technology (KAIST) The imaging technology developed by this research team is a key fundamental technology that can enhance the resolution of X-ray nanomicroscopy, which has been blocked by limitations of the production of existing zone plates. The first author and one of the co-corresponding author, Dr. KyeoReh Lee of KAIST Department of Physics, said, "In this study, the resolution was limited to 14 nm, but if the next-generation X-ray light source and high-performance X-ray detector are used, the resolution would exceed that of the conventional X-ray nano-imaging and approach the resolution of an electron microscope." "Unlike an electron microscope, X-rays can observe the internal structure without damaging the sample, so it will be able to present a new standard for non-invasive nanostructure observation processes such as quality inspections for semiconductors." The co-corresponding author, Dr. Jun Lim of the Pohang Accelerator Laboratory, said, "In the same context, the developed image technology is expected to greatly increase the performance in the 4th generation multipurpose radiation accelerator which is set to be established in Ochang of the Northern Chungcheong Province." <|im_end|>

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2,252

[ { "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 infection, Salmonella senses and responds to harsh environments within the host. Persistence in a bile-rich environment is important for Salmonella to infect the small intestine or gallbladder and the multidrug efflux system AcrAB-TolC is required for bile resistance. The genes encoding this system are mainly regulated by the ramRA locus, which is composed of the divergently transcribed ramA and ramR genes. The acrAB and tolC genes are transcriptionally activated by RamA, whose encoding gene is itself transcriptionally repressed by RamR. RamR recognizes multiple drugs; however, the identity of the environmental signals to which it responds is unclear. Here, we describe the crystal structures of RamR in complexes with bile components, including cholic acid and chenodeoxycholic acid, determined at resolutions of 2.0 and 1.8 Å, respectively. Both cholic and chenodeoxycholic acids form four hydrogen bonds with Tyr59, Thr85, Ser137 and Asp152 of RamR, instead of π–π interactions with Phe155, a residue that is important for the recognition of multiple compounds including berberine, crystal violet, dequalinium, ethidium bromide and rhodamine 6 G. Binding of these compounds to RamR reduces its DNA-binding affinity, resulting in the increased transcription of ramA and acrAB-tolC . Our results reveal that Salmonella senses bile acid components through RamR and then upregulates the expression of RamA, which can lead to induction of acrAB-tolC expression with resulting tolerance to bile-rich environments. Introduction Salmonella is a bacterial pathogen that causes a variety of foodborne illnesses in humans. During the course of its infection of the intestinal tract and gallbladder, Salmonella is exposed to bile acids. These are detergent-like biological substances that are synthesized in the liver from cholesterol and stored in the gallbladder. These bile acids possess strong antimicrobial activity, disrupt cell membranes, denature proteins and trigger DNA damage 1 , 2 . Enteric bacteria such as Salmonella must tolerate the presence of bile acids in order to survive in the gastrointestinal transit and gallbladder 3 , 4 . Enteric bacteria have developed an intrinsic resistance to the toxic effects of bile acids, due to the low permeability of their outer membranes to lipophilic solutes and the presence of active efflux mechanisms 5 , 6 . Salmonella enterica serovar Typhimurium ( S . Typhimurium) contains at least nine multidrug efflux systems 7 . Among these, the AcrAB-TolC system, whose AcrB transporter belongs to the resistance–nodulation–cell division family, is particularly effective in generating bile acid resistance 7 , 8 . Bile induces the expression of acrAB 8 , and this induction is mediated by the transcriptional regulators RamA and RamR 9 , 10 . The global transcriptional activator RamA, which belongs to the AraC/XylS family of regulatory proteins, activates the expression of acrAB and tolC genes 9 . The local transcriptional repressor RamR, which is located directly upstream of ramA , belongs to the TetR family of regulatory proteins and represses the expression of both ramA and ramR (Fig. 1a ) 10 , 11 . Additionally, it has recently been found that bile inhibits the binding of RamR to the ramA promoter region and activates ramA gene expression, resulting in the increased expression of acrAB and tolC 10 . Figure 1 Chenodeoxycholic and cholic acids activate the ramA gene in a RamR-dependent manner. ( a ) Model for gene regulation pathway by RamR. RamR represses the ramA gene encoding the activator protein for the acrAB drug efflux pump genes. RamR binds to the region between the ramR and ramA genes, while RamA binds to the upstream region to acrAB . ( b ) The chemical structures of chenodeoxycholic, cholic and deoxycholic acids. ( c ) Effect of bile and chenodeoxycholic, cholic and deoxycholic acids on the expression of ramA in wild-type and ∆ ramR Salmonella strains, as assessed by qRT-PCR. Cells were grown in LB broth supplemented with 25.6 mg/ml bile, or 5 mM of chenodeoxycholic, cholic or deoxycholic acids. Values above the bars indicate the fold difference in ramA mRNA levels relative to the control in the same strain (wild-type or ∆ ramR) . In the right panel (expression in ∆ ramR) , the horizontal broken lines represents ramA mRNA levels in the wild-type control. The error bars indicate the standard deviation from three independent replicates. A.U., arbitrary units. ( d ) Binding of chenodeoxycholic and cholic acids to RamR detected by SPR analysis. RamR was immobilized onto a sensor chip and then the chenodeoxycholic or cholic acid was passed over the sensor surface at the various concentrations indicated. A representative result from one of three experiments that produced similar data is shown. SPR, surface plasmon resonance. Full size image Our previous biochemical and structural studies found that RamR can recognize multiple compounds, including berberine, crystal violet, dequalinium, ethidium bromide and rhodamine 6 G 12 . Binding of these compounds to RamR results in the increased expression of ramA ; all the compounds recognized by RamR are also known substrates of AcrAB. However, these five drug compounds are not usually present in environments inhabited by Salmonella , such as the intestine, and so, because bile induces ramA expression, we hypothesized that RamR also recognizes some components of bile acids 10 . There are several derivatives of bile acids. Two primary compounds, cholic (3α, 7α, 12α-trihydroxy-5β-cholan-24-oic acid; Fig. 1b ) and chenodeoxycholic acids (3α, 7α-dihydroxy-5β-cholan-24-oic acid; Fig. 1b ) belong to the C24 group, whose members have steroidal backbones and are metabolized from cholesterol in hepatocytes. Primary bile acids are metabolized in the liver, via conjugation to glycine or taurine 13 . In the intestine, a broad range of intestinal anaerobic bacteria modify primary bile acids through hydrolysis and hydroxyl group dehydrogenation to produce secondary bile acids, such as deoxycholic acid (3α, 12αdihydroxy-5β-cholan-24-oic acid; Fig. 1b ) and lithocholic acid (3α-hydroxy-5β-cholan-24-oic acid). Here, we report the crystal structure of RamR in complex with cholic and chenodeoxycholic acids. Both cholic and chenodeoxycholic acids decreased the DNA-binding affinity of RamR, resulting in increased transcription of ramA . Results Cholic and chenodeoxycholic acids induce ramA expression in a RamR-dependent manner It has", "role": "user" }, { "content": "When bacteria enter the digestive tracts of their hosts, including humans, they encounter a highly acidic environment. Bacteria have evolved elegant mechanisms to survive and colonize this habitat, such as highly resistant and impermeable outer membranes and systems to pump out any toxins that make it beyond that barrier. However, the molecular mechanisms behind many of these processes have remained unclear. As part of an international effort, a research team centered at Osaka University has revealed how Salmonella bacteria use a protein called RamR to sense the presence of bile acids in their surroundings. This induces a cascade of events that help the bacteria to adapt to the difficult conditions in the gut. In this work, reported in the journal Scientific Reports, the team first analyzed a regular strain of Salmonella and one in which RamR had been deleted. As it was already known that RamR represses the expression of the gene RamA, which is linked to the export of substances from bacterial cells (Figure 1), they compared RamA expression in the two sets of bacteria upon exposure to different types of bile acid. The results showed that two particular bile acids common in the gut caused dramatic increases of RamA expression in the regular Salmonella, but not in the RamR mutant. \"We already knew that Salmonella starts to express many genes when reaching the gut, but these findings clearly showed that RamR is a key part of its adaptation,\" corresponding author Kunihiko Nishino says. \"We then used surface plasmon resonance analysis to show that RamR binds directly to the primary bile acids cholic acid and chenodeoxycholic acid.\" Figure 2: Full structure of the RamR dimer with two molecules of cholic or chenodeoxycholic acid. Both compounds were completely enclosed in the binding pocket of RamR. Both cholic and chenodeoxycholic acids form four hydrogen bounds with RamR. Credit: Osaka University To obtain more details about this binding and its downstream effects, the team then determined the crystal structures of RamR when bound to each of these acids. In these complexes, they identified the formation of hydrogen bonds and the associated uncoiling of an alpha-helix domain in RamR, both of which are novel binding mechanisms for this protein (Figure 2). \"When RamR is bound in this way, it loses some DNA binding affinity and can no longer repress its RamA target,\" lead author Suguru Yamasaki says. \"This leaves the RamA protein free to activate the AcrAB-TolC efflux system, which pumps damaging substances out of bacterial cells and helps them to survive in the small intestine and gallbladder.\" These findings about RamR suggest that it could be a good target for developing new treatments against infections of gut bacteria or for rebalancing the bacterial population in the gut to ensure better intestinal function. The article \"Crystal structure of the multidrug resistance regulator RamR complexed with bile acids\" is published 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 During infection, Salmonella senses and responds to harsh environments within the host. Persistence in a bile-rich environment is important for Salmonella to infect the small intestine or gallbladder and the multidrug efflux system AcrAB-TolC is required for bile resistance. The genes encoding this system are mainly regulated by the ramRA locus, which is composed of the divergently transcribed ramA and ramR genes. The acrAB and tolC genes are transcriptionally activated by RamA, whose encoding gene is itself transcriptionally repressed by RamR. RamR recognizes multiple drugs; however, the identity of the environmental signals to which it responds is unclear. Here, we describe the crystal structures of RamR in complexes with bile components, including cholic acid and chenodeoxycholic acid, determined at resolutions of 2.0 and 1.8 Å, respectively. Both cholic and chenodeoxycholic acids form four hydrogen bonds with Tyr59, Thr85, Ser137 and Asp152 of RamR, instead of π–π interactions with Phe155, a residue that is important for the recognition of multiple compounds including berberine, crystal violet, dequalinium, ethidium bromide and rhodamine 6 G. Binding of these compounds to RamR reduces its DNA-binding affinity, resulting in the increased transcription of ramA and acrAB-tolC . Our results reveal that Salmonella senses bile acid components through RamR and then upregulates the expression of RamA, which can lead to induction of acrAB-tolC expression with resulting tolerance to bile-rich environments. Introduction Salmonella is a bacterial pathogen that causes a variety of foodborne illnesses in humans. During the course of its infection of the intestinal tract and gallbladder, Salmonella is exposed to bile acids. These are detergent-like biological substances that are synthesized in the liver from cholesterol and stored in the gallbladder. These bile acids possess strong antimicrobial activity, disrupt cell membranes, denature proteins and trigger DNA damage 1 , 2 . Enteric bacteria such as Salmonella must tolerate the presence of bile acids in order to survive in the gastrointestinal transit and gallbladder 3 , 4 . Enteric bacteria have developed an intrinsic resistance to the toxic effects of bile acids, due to the low permeability of their outer membranes to lipophilic solutes and the presence of active efflux mechanisms 5 , 6 . Salmonella enterica serovar Typhimurium ( S . Typhimurium) contains at least nine multidrug efflux systems 7 . Among these, the AcrAB-TolC system, whose AcrB transporter belongs to the resistance–nodulation–cell division family, is particularly effective in generating bile acid resistance 7 , 8 . Bile induces the expression of acrAB 8 , and this induction is mediated by the transcriptional regulators RamA and RamR 9 , 10 . The global transcriptional activator RamA, which belongs to the AraC/XylS family of regulatory proteins, activates the expression of acrAB and tolC genes 9 . The local transcriptional repressor RamR, which is located directly upstream of ramA , belongs to the TetR family of regulatory proteins and represses the expression of both ramA and ramR (Fig. 1a ) 10 , 11 . Additionally, it has recently been found that bile inhibits the binding of RamR to the ramA promoter region and activates ramA gene expression, resulting in the increased expression of acrAB and tolC 10 . Figure 1 Chenodeoxycholic and cholic acids activate the ramA gene in a RamR-dependent manner. ( a ) Model for gene regulation pathway by RamR. RamR represses the ramA gene encoding the activator protein for the acrAB drug efflux pump genes. RamR binds to the region between the ramR and ramA genes, while RamA binds to the upstream region to acrAB . ( b ) The chemical structures of chenodeoxycholic, cholic and deoxycholic acids. ( c ) Effect of bile and chenodeoxycholic, cholic and deoxycholic acids on the expression of ramA in wild-type and ∆ ramR Salmonella strains, as assessed by qRT-PCR. Cells were grown in LB broth supplemented with 25.6 mg/ml bile, or 5 mM of chenodeoxycholic, cholic or deoxycholic acids. Values above the bars indicate the fold difference in ramA mRNA levels relative to the control in the same strain (wild-type or ∆ ramR) . In the right panel (expression in ∆ ramR) , the horizontal broken lines represents ramA mRNA levels in the wild-type control. The error bars indicate the standard deviation from three independent replicates. A.U., arbitrary units. ( d ) Binding of chenodeoxycholic and cholic acids to RamR detected by SPR analysis. RamR was immobilized onto a sensor chip and then the chenodeoxycholic or cholic acid was passed over the sensor surface at the various concentrations indicated. A representative result from one of three experiments that produced similar data is shown. SPR, surface plasmon resonance. Full size image Our previous biochemical and structural studies found that RamR can recognize multiple compounds, including berberine, crystal violet, dequalinium, ethidium bromide and rhodamine 6 G 12 . Binding of these compounds to RamR results in the increased expression of ramA ; all the compounds recognized by RamR are also known substrates of AcrAB. However, these five drug compounds are not usually present in environments inhabited by Salmonella , such as the intestine, and so, because bile induces ramA expression, we hypothesized that RamR also recognizes some components of bile acids 10 . There are several derivatives of bile acids. Two primary compounds, cholic (3α, 7α, 12α-trihydroxy-5β-cholan-24-oic acid; Fig. 1b ) and chenodeoxycholic acids (3α, 7α-dihydroxy-5β-cholan-24-oic acid; Fig. 1b ) belong to the C24 group, whose members have steroidal backbones and are metabolized from cholesterol in hepatocytes. Primary bile acids are metabolized in the liver, via conjugation to glycine or taurine 13 . In the intestine, a broad range of intestinal anaerobic bacteria modify primary bile acids through hydrolysis and hydroxyl group dehydrogenation to produce secondary bile acids, such as deoxycholic acid (3α, 12αdihydroxy-5β-cholan-24-oic acid; Fig. 1b ) and lithocholic acid (3α-hydroxy-5β-cholan-24-oic acid). Here, we report the crystal structure of RamR in complex with cholic and chenodeoxycholic acids. Both cholic and chenodeoxycholic acids decreased the DNA-binding affinity of RamR, resulting in increased transcription of ramA . Results Cholic and chenodeoxycholic acids induce ramA expression in a RamR-dependent manner It has<|im_end|> <|im_start|>assistant When bacteria enter the digestive tracts of their hosts, including humans, they encounter a highly acidic environment. Bacteria have evolved elegant mechanisms to survive and colonize this habitat, such as highly resistant and impermeable outer membranes and systems to pump out any toxins that make it beyond that barrier. However, the molecular mechanisms behind many of these processes have remained unclear. As part of an international effort, a research team centered at Osaka University has revealed how Salmonella bacteria use a protein called RamR to sense the presence of bile acids in their surroundings. This induces a cascade of events that help the bacteria to adapt to the difficult conditions in the gut. In this work, reported in the journal Scientific Reports, the team first analyzed a regular strain of Salmonella and one in which RamR had been deleted. As it was already known that RamR represses the expression of the gene RamA, which is linked to the export of substances from bacterial cells (Figure 1), they compared RamA expression in the two sets of bacteria upon exposure to different types of bile acid. The results showed that two particular bile acids common in the gut caused dramatic increases of RamA expression in the regular Salmonella, but not in the RamR mutant. "We already knew that Salmonella starts to express many genes when reaching the gut, but these findings clearly showed that RamR is a key part of its adaptation," corresponding author Kunihiko Nishino says. "We then used surface plasmon resonance analysis to show that RamR binds directly to the primary bile acids cholic acid and chenodeoxycholic acid." Figure 2: Full structure of the RamR dimer with two molecules of cholic or chenodeoxycholic acid. Both compounds were completely enclosed in the binding pocket of RamR. Both cholic and chenodeoxycholic acids form four hydrogen bounds with RamR. Credit: Osaka University To obtain more details about this binding and its downstream effects, the team then determined the crystal structures of RamR when bound to each of these acids. In these complexes, they identified the formation of hydrogen bonds and the associated uncoiling of an alpha-helix domain in RamR, both of which are novel binding mechanisms for this protein (Figure 2). "When RamR is bound in this way, it loses some DNA binding affinity and can no longer repress its RamA target," lead author Suguru Yamasaki says. "This leaves the RamA protein free to activate the AcrAB-TolC efflux system, which pumps damaging substances out of bacterial cells and helps them to survive in the small intestine and gallbladder." These findings about RamR suggest that it could be a good target for developing new treatments against infections of gut bacteria or for rebalancing the bacterial population in the gut to ensure better intestinal function. The article "Crystal structure of the multidrug resistance regulator RamR complexed with bile acids" is published in Scientific Reports. <|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 Myocardial tracking and strain estimation can non-invasively assess cardiac functioning using subject-specific MRI. As the left-ventricle does not have a uniform shape and functioning from base to apex, the development of 3D MRI has provided opportunities for simultaneous 3D tracking, and 3D strain estimation. We have extended a Local Weighted Mean (LWM) transformation function for 3D, and incorporated in a Hierarchical Template Matching model to solve 3D myocardial tracking and strain estimation problem. The LWM does not need to solve a large system of equations, provides smooth displacement of myocardial points, and adapt local geometric differences in images. Hence, 3D myocardial tracking can be performed with 1.49 mm median error, and without large error outliers. The maximum error of tracking is up to 24% reduced compared to benchmark methods. Moreover, the estimated strain can be insightful to improve 3D imaging protocols, and the computer code of LWM could also be useful for geo-spatial and manufacturing image analysis researchers. Introduction Cardiovascular Disease (CVD) is an important burden on the global population. It accounts for almost 31% of the mortality 1 . CVD covers a spectrum of diseases but mainly dysfunction of the heart muscles, from various aetiologies, and heart rhythm. The heart can be investigated and assessed using invasive and increasingly more non-invasive techniques 2 . Magnetic resonance imaging (MRI) with 3D imaging capabilities is gaining more support and applications 2 , 3 . The assessment of myocardium (heart wall muscles) provides clinical experts with the details of CVD diagnosis, prognosis and therapeutic interventions 2 , 4 , 5 . The details such as left ventricular (LV) myocardial tracking and strain (shortening or lengthening of the myocardium muscles) could objectively quantify myocardial health, providing a better understanding of cardiac diseases such as cardiomyopathy, myocardial infarction, arrhythmia, and valvular diseases 2 , 6 . Heart muscles shrink, expand, rotate and create torsion simultaneously during a cardiac cycle and a common complication that arises in left ventricular (LV) myocardial tracking is the consideration of longitudinal heart movement. As a conventional or common practice, multiple 2D short-axis and 2D long-axis images are used to construct 3D myocardial motion and strain 7 , 8 , 9 . However, the approach is prone to 2D slice misregistration, patient cooperation, and dependent on radiographer (subjective) 10 , because the acquisition of 2D long-axis and 2D short-axis images happen at a different time while scanning a patient. As a result, 3D tagging is emerged as a promising method to allow reconstruction of 3D myocardial strain from single image volume rather than multiple different 2D images 10 , 11 , 12 . However, methods such as HARmonic Phase (HARP), Strain Encoding (SENC) are natively 1D or 2D, and merged with other methods or multiple 2D long- and short-axis images to calculate 3D myocardial strain 11 , 13 , 14 . However, a limited number of long-axis images could affect the accuracy of such tracking 11 . This fact motivates the use of 3D MRI instead of 2D short- and long-axis images, making it crucial to perform accurate 3D myocardial tracking. Medical image analysis researchers have contributed algorithms using direct detection-based methods 15 , Fourier-based methods 13 , 14 , 16 , tracking-based methods 17 , 18 , 19 , 20 , 21 , 22 , and block-matching-based methods 17 , 23 , 24 , 25 . Direct detection-based methods detect and track tag intersection points which could avoid image artefacts but too sparse tag points could limit the accuracy of myocardial tracking 12 , 26 . Fourier-based methods (for example HARP 14 ) exploit the correspondence property of a local shift in the spatial domain and a phase shift in the Fourier domain but the method is limited to use tagged MRI 12 . Tracking-based methods optimize similarity between frame intensities and estimates transformation model, however, they can be dependent on a spatial regularization which could limit the accuracy 12 . The block-matching approach has provided promising results using 3D ultrasound images 17 , and 2D MRI 25 . The standard myocardial tracking technique uses 3D speckle tracking through ultrasound images 2 , 17 . The method tracks an inherent pattern (speckle) of ultrasound imaging using a matching kernel (block or volume-of-interest), and the sum of absolute difference as a block-matching criterion. However, the accuracy of such a method is highly dependent on the size of the kernel, as too large or too small kernels could lead to incorrect tracking 17 . Such technical limitation could be overcome by using a hierarchy of matchings, which can provide a promising correlation up to the smallest level of the matching 25 , 27 . The hierarchical matching using 2D MRI is reported with promising accuracy in the literature 25 , however, 3D myocardial tracking using 3D MRI has received less attention in the literature 12 . Therefore, in this article, we have extended the standard block-matching technique by incorporating a hierarchical matching for 3D myocardial tracking. Myocardial tracking algorithms use a transformation function to establish a point-to-point correspondence between two images 28 . Spline-based functions are commonly used as they can efficiently handle image deformations 11 , 20 , 29 , 30 . However, researchers have reported that the spline functions can generate large errors when the spacing between points is irregular 28 . It is also reported that the Cartesian coordinate B-spline model can generate errors due to ill-conditioned and ill-posed polynomials 30 . To address this issue, other approaches are suggested such as cylindrical coordinate B-spline model 30 (as LV is roughly cylindrical), explicit regularization 29 and local weighted-mean transformation function 25 , 28 , 31 , 32 . The cylindrical coordinate system and regularisation function with B-spline function could lead to detailed and complicated design and planning of myocardial tracking, whereas, Local Weighted Mean (LWM) function is proposed in the literature to overcome the elaborated procedure of spline interpolation 33 . The function is reported advantageous over the thin-plate spline and multi quadratics as the LWM function", "role": "user" }, { "content": "3-D MRI computing can measure strain in the heart using image registration method. Traditional method involves giving the patient a dose of gadolinium which can affect the kidney, researchers at WMG, University of Warwick have found. MRIs are used to diagnose cardiac disease such as cardiomyopathy, heart attacks, irregular heartbeats and other heart disease. Traditionally when a patient goes for an MRI scan they are given a dose of gadolinium, which reacts the magnetic field of the scanner to produce an image of the protons in the metal realigning with the magnetic field. The faster the protons realign, the brighter the image features and can show where the dead muscles are in the heart and what the diagnosis is. The dose of gadolinium can have detrimental effects to other parts of the body, particularly the risk of kidney failure. A new 3-D MRI computing technique developed by scientists in WMG at the University of Warwick, published today, 28th August, in the journal Scientific Reports titled 'Hierarchical Template Matching for 3-D Myocardial Tracking and Cardiac Strain Estimation' focuses on Hierarchical Template Matching (HTM) technique. Which involves: A numerically stable technique of LV myocardial tracking A 3-D extension of local weighted mean function to transform MRI pixelsA 3-D extension of Hierarchical Template Matching model for myocardial tracking problems Therefore meaning there is no need for gadolinium reducing the risk of damage to other organs. The 3DTag MRI volume, and segmented LV mesh. Credit: WMG University of Warwick Professor Mark Williams, from WMG at the University of Warwick comments: \"Using 3-D MRI computing technique we can see in more depth what is happening to the heart, more precisely to each heart muscles, and diagnose any issues such as remodelling of heart that causes heart failure. The new method avoids the risk of damaging the kidney opposite to what traditional methods do by using gadolinium.\" Jayendra Bhalodiya, who conducted the research from WMG, University of Warwick adds: \"This new MRI technique also takes away stress from the patient, as during an MRI the patient must be very still in a very enclosed environment meaning some people suffer from claustrophobia and have to stop the scan, often when they do this they have to administer another dose of the damaging gadolinium and start again. This technique doesn't require a dosage of anything, as it tracks the heart naturally.\" ", "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 Myocardial tracking and strain estimation can non-invasively assess cardiac functioning using subject-specific MRI. As the left-ventricle does not have a uniform shape and functioning from base to apex, the development of 3D MRI has provided opportunities for simultaneous 3D tracking, and 3D strain estimation. We have extended a Local Weighted Mean (LWM) transformation function for 3D, and incorporated in a Hierarchical Template Matching model to solve 3D myocardial tracking and strain estimation problem. The LWM does not need to solve a large system of equations, provides smooth displacement of myocardial points, and adapt local geometric differences in images. Hence, 3D myocardial tracking can be performed with 1.49 mm median error, and without large error outliers. The maximum error of tracking is up to 24% reduced compared to benchmark methods. Moreover, the estimated strain can be insightful to improve 3D imaging protocols, and the computer code of LWM could also be useful for geo-spatial and manufacturing image analysis researchers. Introduction Cardiovascular Disease (CVD) is an important burden on the global population. It accounts for almost 31% of the mortality 1 . CVD covers a spectrum of diseases but mainly dysfunction of the heart muscles, from various aetiologies, and heart rhythm. The heart can be investigated and assessed using invasive and increasingly more non-invasive techniques 2 . Magnetic resonance imaging (MRI) with 3D imaging capabilities is gaining more support and applications 2 , 3 . The assessment of myocardium (heart wall muscles) provides clinical experts with the details of CVD diagnosis, prognosis and therapeutic interventions 2 , 4 , 5 . The details such as left ventricular (LV) myocardial tracking and strain (shortening or lengthening of the myocardium muscles) could objectively quantify myocardial health, providing a better understanding of cardiac diseases such as cardiomyopathy, myocardial infarction, arrhythmia, and valvular diseases 2 , 6 . Heart muscles shrink, expand, rotate and create torsion simultaneously during a cardiac cycle and a common complication that arises in left ventricular (LV) myocardial tracking is the consideration of longitudinal heart movement. As a conventional or common practice, multiple 2D short-axis and 2D long-axis images are used to construct 3D myocardial motion and strain 7 , 8 , 9 . However, the approach is prone to 2D slice misregistration, patient cooperation, and dependent on radiographer (subjective) 10 , because the acquisition of 2D long-axis and 2D short-axis images happen at a different time while scanning a patient. As a result, 3D tagging is emerged as a promising method to allow reconstruction of 3D myocardial strain from single image volume rather than multiple different 2D images 10 , 11 , 12 . However, methods such as HARmonic Phase (HARP), Strain Encoding (SENC) are natively 1D or 2D, and merged with other methods or multiple 2D long- and short-axis images to calculate 3D myocardial strain 11 , 13 , 14 . However, a limited number of long-axis images could affect the accuracy of such tracking 11 . This fact motivates the use of 3D MRI instead of 2D short- and long-axis images, making it crucial to perform accurate 3D myocardial tracking. Medical image analysis researchers have contributed algorithms using direct detection-based methods 15 , Fourier-based methods 13 , 14 , 16 , tracking-based methods 17 , 18 , 19 , 20 , 21 , 22 , and block-matching-based methods 17 , 23 , 24 , 25 . Direct detection-based methods detect and track tag intersection points which could avoid image artefacts but too sparse tag points could limit the accuracy of myocardial tracking 12 , 26 . Fourier-based methods (for example HARP 14 ) exploit the correspondence property of a local shift in the spatial domain and a phase shift in the Fourier domain but the method is limited to use tagged MRI 12 . Tracking-based methods optimize similarity between frame intensities and estimates transformation model, however, they can be dependent on a spatial regularization which could limit the accuracy 12 . The block-matching approach has provided promising results using 3D ultrasound images 17 , and 2D MRI 25 . The standard myocardial tracking technique uses 3D speckle tracking through ultrasound images 2 , 17 . The method tracks an inherent pattern (speckle) of ultrasound imaging using a matching kernel (block or volume-of-interest), and the sum of absolute difference as a block-matching criterion. However, the accuracy of such a method is highly dependent on the size of the kernel, as too large or too small kernels could lead to incorrect tracking 17 . Such technical limitation could be overcome by using a hierarchy of matchings, which can provide a promising correlation up to the smallest level of the matching 25 , 27 . The hierarchical matching using 2D MRI is reported with promising accuracy in the literature 25 , however, 3D myocardial tracking using 3D MRI has received less attention in the literature 12 . Therefore, in this article, we have extended the standard block-matching technique by incorporating a hierarchical matching for 3D myocardial tracking. Myocardial tracking algorithms use a transformation function to establish a point-to-point correspondence between two images 28 . Spline-based functions are commonly used as they can efficiently handle image deformations 11 , 20 , 29 , 30 . However, researchers have reported that the spline functions can generate large errors when the spacing between points is irregular 28 . It is also reported that the Cartesian coordinate B-spline model can generate errors due to ill-conditioned and ill-posed polynomials 30 . To address this issue, other approaches are suggested such as cylindrical coordinate B-spline model 30 (as LV is roughly cylindrical), explicit regularization 29 and local weighted-mean transformation function 25 , 28 , 31 , 32 . The cylindrical coordinate system and regularisation function with B-spline function could lead to detailed and complicated design and planning of myocardial tracking, whereas, Local Weighted Mean (LWM) function is proposed in the literature to overcome the elaborated procedure of spline interpolation 33 . The function is reported advantageous over the thin-plate spline and multi quadratics as the LWM function<|im_end|> <|im_start|>assistant 3-D MRI computing can measure strain in the heart using image registration method. Traditional method involves giving the patient a dose of gadolinium which can affect the kidney, researchers at WMG, University of Warwick have found. MRIs are used to diagnose cardiac disease such as cardiomyopathy, heart attacks, irregular heartbeats and other heart disease. Traditionally when a patient goes for an MRI scan they are given a dose of gadolinium, which reacts the magnetic field of the scanner to produce an image of the protons in the metal realigning with the magnetic field. The faster the protons realign, the brighter the image features and can show where the dead muscles are in the heart and what the diagnosis is. The dose of gadolinium can have detrimental effects to other parts of the body, particularly the risk of kidney failure. A new 3-D MRI computing technique developed by scientists in WMG at the University of Warwick, published today, 28th August, in the journal Scientific Reports titled 'Hierarchical Template Matching for 3-D Myocardial Tracking and Cardiac Strain Estimation' focuses on Hierarchical Template Matching (HTM) technique. Which involves: A numerically stable technique of LV myocardial tracking A 3-D extension of local weighted mean function to transform MRI pixelsA 3-D extension of Hierarchical Template Matching model for myocardial tracking problems Therefore meaning there is no need for gadolinium reducing the risk of damage to other organs. The 3DTag MRI volume, and segmented LV mesh. Credit: WMG University of Warwick Professor Mark Williams, from WMG at the University of Warwick comments: "Using 3-D MRI computing technique we can see in more depth what is happening to the heart, more precisely to each heart muscles, and diagnose any issues such as remodelling of heart that causes heart failure. The new method avoids the risk of damaging the kidney opposite to what traditional methods do by using gadolinium." Jayendra Bhalodiya, who conducted the research from WMG, University of Warwick adds: "This new MRI technique also takes away stress from the patient, as during an MRI the patient must be very still in a very enclosed environment meaning some people suffer from claustrophobia and have to stop the scan, often when they do this they have to administer another dose of the damaging gadolinium and start again. This technique doesn't require a dosage of anything, as it tracks the heart naturally." <|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 The genome-wide hyperacetylation of chromatin caused by histone deacetylase inhibitors (HDACi) is surprisingly well tolerated by most eukaryotic cells. The homeostatic mechanisms that underlie this tolerance are unknown. Here we identify the transcriptional and epigenomic changes that constitute the earliest response of human lymphoblastoid cells to two HDACi, valproic acid and suberoylanilide hydroxamic acid (Vorinostat), both in widespread clinical use. Results Dynamic changes in transcript levels over the first 2 h of exposure to HDACi were assayed on High Density microarrays. There was a consistent response to the two different inhibitors at several concentrations. Strikingly, components of all known lysine acetyltransferase (KAT) complexes were down-regulated, as were genes required for growth and maintenance of the lymphoid phenotype. Up-regulated gene clusters were enriched in regulators of transcription, development and phenotypic change. In untreated cells, HDACi-responsive genes, whether up- or down-regulated, were packaged in highly acetylated chromatin. This was essentially unaffected by HDACi. In contrast, HDACi induced a strong increase in H3K27me3 at transcription start sites, irrespective of their transcriptional response. Inhibition of the H3K27 methylating enzymes, EZH1/2, altered the transcriptional response to HDACi, confirming the functional significance of H3K27 methylation for specific genes. Conclusions We propose that the observed transcriptional changes constitute an inbuilt adaptive response to HDACi that promotes cell survival by minimising protein hyperacetylation, slowing growth and re-balancing patterns of gene expression. The transcriptional response to HDACi is mediated by a precisely timed increase in H3K27me3 at transcription start sites. In contrast, histone acetylation, at least at the three lysine residues tested, seems to play no direct role. Instead, it may provide a stable chromatin environment that allows transcriptional change to be induced by other factors, possibly acetylated non-histone proteins. Background Levels of histone acetylation across the genome reflect a dynamic equilibrium between the activities of two enzyme families, lysine acetyltransferases (KATs) and histone deacetylases (HDACs) [ 1 , 2 ]. HDAC activity can be suppressed by a variety of naturally occurring and synthetic compounds, resulting in a detectable increase in global histone acetylation after 10 min or less, and hyperacetylation of over 90 % of H4 molecules after just a few hours, indicating that most of the genome is acted on by KATs and HDACs ([ 3 , 4 ] and references therein). This conclusion is consistent with studies on the genomic distribution of these enzymes [ 5 – 9 ]. Like other post-translational histone modifications, acetylation rarely acts in isolation, but as part of a combination of different modifications, usually along the histone N-terminal tails, that collectively regulate chromatin function [ 10 – 12 ]. They do this either by directly influencing chromatin structure, or by serving as docking sites for non-histone proteins which, in turn, exert functional change [ 13 – 15 ]. In view of this, generalisations about the functional roles of particular modifications are rarely appropriate or useful. However, there is a long-standing connection between relatively high levels of overall histone acetylation and transcriptional activity [ 16 – 18 ]. This association is supported by more recent epigenomic studies [ 19 – 24 ], and by experiments on the functional consequences of acetylation of specific histone lysines. For example, enhanced acetylation of H4 specifically at lysine 16 is a marker of the transcriptionally hyperactive male X chromosome in D. melanogaster [ 25 , 26 ] and has recently been linked more generally to transcriptionally active genes [ 27 ]. H3K9 acetylation is consistently enhanced at gene promoter regions [ 28 , 29 ], while H3K27 acetylation protects this residue from methylation by the Polycomb silencing Complex PRC2 and consequent long-term suppression of transcription [ 30 , 31 ]. In view of this, it is puzzling that cells can tolerate so well the massive hyperacetylation of core histones, and other proteins, caused by histone deacetylase inhibitors (HDACi). Many cultured cell types, including non-transformed lines such as mouse embryonic stem cells, continue to grow, albeit slowly, in the presence of HDACi [ 32 , 33 ] and whole organisms continue to function [ 34 , 35 ]. Indeed, various HDACi have been in clinical use for many years. Valproic acid (VPA), a short-chain fatty acid, is an effective anti-epileptic and mood stabiliser [ 36 ], while VPA and chemically more complex HDACi such as hydroxamic acid derivatives and depsipeptide, have been tested against a variety of cancers [ 37 – 40 ]. It has been known for some time that cultured cells treated with HDACi do not undergo a global up-regulation of transcription. In fact, only a small proportion of genes significantly change expression, and up to half of these are down-regulated [ 41 – 45 ]. These findings raise fundamental questions regarding the relationship between histone acetylation and transcription, and about the mechanisms by which cells might protect their transcriptional programmes from the potentially disruptive effects of induced epigenetic change. Attempts to define the processes through which HDACi influence cell function, are complicated by the fact that they usually inhibit several different members of the 18-strong HDAC family. The most commonly used HDACi, including short-chain fatty acids and hydroxamic acid derivatives, inhibit the class I and IIa enzymes, HDACs 1, 2, 3, 6 and 8, of which HDACs 1–3 are consistently chromatin associated and likely to be key players in regulation of gene expression [ 5 ]. These enzymes are catalytically active only when physically associated with specific partner proteins and four complexes have been isolated and characterised, namely CoRest, NuRD, Sin3 and NCoR/SMRT [ 46 – 48 ]. Class IIb and IV enzymes have little or no catalytic activity, while the NAD-dependent Class III enzymes (the Sirtuins, SIRT1-7) have a different catalytic mechanism and are unaffected by HDACi [ 49 , 50 ]. Finally, each of the class I/IIa HDACs has multiple substrates, both histones and non-histone proteins, including various acetyltransferases and deacetylases [ 51 – 53 ]. Most previous work to explore cellular responses to HDACi has used treatment times of at least 4 h and often 24 h or longer,", "role": "user" }, { "content": "Cancer Research UK scientists have found how cells adapt to overcome cancer drugs designed to interfere with their genetic controls, according to a study published today in Epigenetics and Chromatin. Normally molecular 'tags' are attached to DNA which send signals to the cell, telling it how to package its DNA and switch genes on or off. Drugs called HDAC inhibitors cause a build-up of certain types of tags, leading to potentially damaging changes in gene activity that can kill cancer cells. But while HDAC inhibitors can successfully treat certain types of cancer, such as lymphoma, other types survive this disruption. Scientists from the University of Birmingham, suggest that they do this by activating an in-built 'survival' response to HDAC inhibitors which rebalances the tags, maintaining normal gene activity and keeping the cells alive. These findings could help identify which patients are suitable for treatment with these drugs. And could help develop future therapies that override the survival mechanism in tumour types that don't respond. Lead author Dr John Halsall, Cancer Research UK scientist from the University of Birmingham, said: \"Our work has shown that some cancer cells can survive the gene damage caused by HDAC inhibitor drugs, so we've unveiled a new layer of the cancer cell's defence that we need to target to destroy tumours. \"If we work out exactly which types of cancer are vulnerable to these drugs we can use them in a smarter way to treat patients more effectively.\" Dr Kat Arney, Cancer Research UK's science information manager, said: \"Working out how genes are switched on and off in cancer is vital if we're to truly understand and beat the disease. This study could help us tailor how we use HDAC inhibitors so that more patients could benefit from them, and we'll continue to work towards finding more effective ways to target cancer's control mechanisms in the future.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background The genome-wide hyperacetylation of chromatin caused by histone deacetylase inhibitors (HDACi) is surprisingly well tolerated by most eukaryotic cells. The homeostatic mechanisms that underlie this tolerance are unknown. Here we identify the transcriptional and epigenomic changes that constitute the earliest response of human lymphoblastoid cells to two HDACi, valproic acid and suberoylanilide hydroxamic acid (Vorinostat), both in widespread clinical use. Results Dynamic changes in transcript levels over the first 2 h of exposure to HDACi were assayed on High Density microarrays. There was a consistent response to the two different inhibitors at several concentrations. Strikingly, components of all known lysine acetyltransferase (KAT) complexes were down-regulated, as were genes required for growth and maintenance of the lymphoid phenotype. Up-regulated gene clusters were enriched in regulators of transcription, development and phenotypic change. In untreated cells, HDACi-responsive genes, whether up- or down-regulated, were packaged in highly acetylated chromatin. This was essentially unaffected by HDACi. In contrast, HDACi induced a strong increase in H3K27me3 at transcription start sites, irrespective of their transcriptional response. Inhibition of the H3K27 methylating enzymes, EZH1/2, altered the transcriptional response to HDACi, confirming the functional significance of H3K27 methylation for specific genes. Conclusions We propose that the observed transcriptional changes constitute an inbuilt adaptive response to HDACi that promotes cell survival by minimising protein hyperacetylation, slowing growth and re-balancing patterns of gene expression. The transcriptional response to HDACi is mediated by a precisely timed increase in H3K27me3 at transcription start sites. In contrast, histone acetylation, at least at the three lysine residues tested, seems to play no direct role. Instead, it may provide a stable chromatin environment that allows transcriptional change to be induced by other factors, possibly acetylated non-histone proteins. Background Levels of histone acetylation across the genome reflect a dynamic equilibrium between the activities of two enzyme families, lysine acetyltransferases (KATs) and histone deacetylases (HDACs) [ 1 , 2 ]. HDAC activity can be suppressed by a variety of naturally occurring and synthetic compounds, resulting in a detectable increase in global histone acetylation after 10 min or less, and hyperacetylation of over 90 % of H4 molecules after just a few hours, indicating that most of the genome is acted on by KATs and HDACs ([ 3 , 4 ] and references therein). This conclusion is consistent with studies on the genomic distribution of these enzymes [ 5 – 9 ]. Like other post-translational histone modifications, acetylation rarely acts in isolation, but as part of a combination of different modifications, usually along the histone N-terminal tails, that collectively regulate chromatin function [ 10 – 12 ]. They do this either by directly influencing chromatin structure, or by serving as docking sites for non-histone proteins which, in turn, exert functional change [ 13 – 15 ]. In view of this, generalisations about the functional roles of particular modifications are rarely appropriate or useful. However, there is a long-standing connection between relatively high levels of overall histone acetylation and transcriptional activity [ 16 – 18 ]. This association is supported by more recent epigenomic studies [ 19 – 24 ], and by experiments on the functional consequences of acetylation of specific histone lysines. For example, enhanced acetylation of H4 specifically at lysine 16 is a marker of the transcriptionally hyperactive male X chromosome in D. melanogaster [ 25 , 26 ] and has recently been linked more generally to transcriptionally active genes [ 27 ]. H3K9 acetylation is consistently enhanced at gene promoter regions [ 28 , 29 ], while H3K27 acetylation protects this residue from methylation by the Polycomb silencing Complex PRC2 and consequent long-term suppression of transcription [ 30 , 31 ]. In view of this, it is puzzling that cells can tolerate so well the massive hyperacetylation of core histones, and other proteins, caused by histone deacetylase inhibitors (HDACi). Many cultured cell types, including non-transformed lines such as mouse embryonic stem cells, continue to grow, albeit slowly, in the presence of HDACi [ 32 , 33 ] and whole organisms continue to function [ 34 , 35 ]. Indeed, various HDACi have been in clinical use for many years. Valproic acid (VPA), a short-chain fatty acid, is an effective anti-epileptic and mood stabiliser [ 36 ], while VPA and chemically more complex HDACi such as hydroxamic acid derivatives and depsipeptide, have been tested against a variety of cancers [ 37 – 40 ]. It has been known for some time that cultured cells treated with HDACi do not undergo a global up-regulation of transcription. In fact, only a small proportion of genes significantly change expression, and up to half of these are down-regulated [ 41 – 45 ]. These findings raise fundamental questions regarding the relationship between histone acetylation and transcription, and about the mechanisms by which cells might protect their transcriptional programmes from the potentially disruptive effects of induced epigenetic change. Attempts to define the processes through which HDACi influence cell function, are complicated by the fact that they usually inhibit several different members of the 18-strong HDAC family. The most commonly used HDACi, including short-chain fatty acids and hydroxamic acid derivatives, inhibit the class I and IIa enzymes, HDACs 1, 2, 3, 6 and 8, of which HDACs 1–3 are consistently chromatin associated and likely to be key players in regulation of gene expression [ 5 ]. These enzymes are catalytically active only when physically associated with specific partner proteins and four complexes have been isolated and characterised, namely CoRest, NuRD, Sin3 and NCoR/SMRT [ 46 – 48 ]. Class IIb and IV enzymes have little or no catalytic activity, while the NAD-dependent Class III enzymes (the Sirtuins, SIRT1-7) have a different catalytic mechanism and are unaffected by HDACi [ 49 , 50 ]. Finally, each of the class I/IIa HDACs has multiple substrates, both histones and non-histone proteins, including various acetyltransferases and deacetylases [ 51 – 53 ]. Most previous work to explore cellular responses to HDACi has used treatment times of at least 4 h and often 24 h or longer,<|im_end|> <|im_start|>assistant Cancer Research UK scientists have found how cells adapt to overcome cancer drugs designed to interfere with their genetic controls, according to a study published today in Epigenetics and Chromatin. Normally molecular 'tags' are attached to DNA which send signals to the cell, telling it how to package its DNA and switch genes on or off. Drugs called HDAC inhibitors cause a build-up of certain types of tags, leading to potentially damaging changes in gene activity that can kill cancer cells. But while HDAC inhibitors can successfully treat certain types of cancer, such as lymphoma, other types survive this disruption. Scientists from the University of Birmingham, suggest that they do this by activating an in-built 'survival' response to HDAC inhibitors which rebalances the tags, maintaining normal gene activity and keeping the cells alive. These findings could help identify which patients are suitable for treatment with these drugs. And could help develop future therapies that override the survival mechanism in tumour types that don't respond. Lead author Dr John Halsall, Cancer Research UK scientist from the University of Birmingham, said: "Our work has shown that some cancer cells can survive the gene damage caused by HDAC inhibitor drugs, so we've unveiled a new layer of the cancer cell's defence that we need to target to destroy tumours. "If we work out exactly which types of cancer are vulnerable to these drugs we can use them in a smarter way to treat patients more effectively." Dr Kat Arney, Cancer Research UK's science information manager, said: "Working out how genes are switched on and off in cancer is vital if we're to truly understand and beat the disease. This study could help us tailor how we use HDAC inhibitors so that more patients could benefit from them, and we'll continue to work towards finding more effective ways to target cancer's control mechanisms in the future." <|im_end|>

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Photovoltaics Advanced Porous Ceramics and Its Applications Advanced Porous Materials for Gas Adsorption and Environmental Catalysis Advanced Research on Electrical, Optical, and Magnetic Nanoparticles, Nanowires, and Thin Films Advanced Temperature Sensitive Materials, Devices and Systems Advanced/Alternative Transparent Conducting Oxides Advancement of Photocatalytic Materials 2016 Advances in Biointerfaces Advances in Bulk Metallic Glasses Advances in Catalytic Materials Advances in Cellulosic Materials Advances in Cellulosic Materials 2014 Advances in Colorants Advances in Colorants 2014 Advances in Computational Materials Micro-Mechanics Advances in Cosmetics Advances in Dyes and Pigments Advances in Fracture Mechanics and Fatigue of Engineering Materials and Structures Advances in Functional Hybrid Materials Advances in Geopolymers and Alkali-Activated Materials Advances in Hard-to-Cut Materials: Manufacturing, Properties, Process Mechanics and Evaluation of Surface Integrity Advances in Lightweight Aggregate Concrete Advances in Magnetic Materials Advances in Materials Science Advances in Mechanical Problems of Functionally Graded Materials and Structures Advances in Metal Foams Advances in Microelectromechanical Systems (MEMS) Materials Advances in Molecular Magnets and related Phenomena Advances in Multifunctional Materials Advances in Nanolime and Other Nanomaterials for Built Heritage Conservation Advances in Natural and Renewable Materials for Biotechnological Applications Advances in Novel Materials for Aerospace Engineering Advances in Optical Materials Advances in Photocatalysis: Photocatalytic Materials and Applications Advances in Physical and Wet-Chemical Methods for Inorganic Nanoparticles Synthesis Advances in Pillared Clays and Similar Materials: Synthesis, Characterization and Applications Advances in Porous Inorganic Materials Advances in Renewable Energy Conversion Materials Advances in Research on Elastomers Advances in Sol-gel Derived Materials Advances in Solid Oxide Cell Materials Advances in Structural Health Monitoring for Aerospace Structures Advances in Structural Metallic Systems for Gas Turbines Advances in Superconductive and Magnetic Nanomaterials Advances in Testing and Predictive Modelling of Failure in Heat Resistant Steels Advances in the Dynamics of Granular Materials Advances in Transparent Conducting Oxides Advances in Zintl Phases Aerogels and Their Functionalization for Practical Applications Aerogels: Synthesis, Characterization and Application Aerospace Materials Alloys and Composites for High Temperature Applications Amorphous Alloys Amorphous and Nanocrystalline Materials for Electrochemical Energy Storage Analytical Characterization of Functionalized Surfaces Anodized Nanoporous Materials: Porous Silicon, Nanoporous Alumina, and Titania Nanotube Arrays Antimicrobial Materials: Application in Food Processing and Storage Antimicrobial Textile Application of Photocatalytic Technology in Environmental Sustainability Applied Mathematics and Computer Methods in Materials, Mechanics and Engineering Auxetic Materials Auxetic Materials 2017-2018 Behavior of Metallic and Composite Structures Bio- and Natural-Fiber Composites Bio-devices and Materials Bioactive Glasses Bioactive Glasses 2017 Bioapplications of Graphene Composites Biobased Polymers for Packaging Applications Biochemical/Inorganic Hybrid Materials Biocompatibility of Materials Biocompatibility of Materials 2011 Biocompatibility of Materials 2013 Biocompatible Metals for Skeletal Fixation and Joint Replacement Devices Biocompatible Surface Functionalization of Nanomaterials Biodegradability of Materials in Biomedical Applications 2011 Biodegradable and Bio-Based Polymers Biodegradable Polymeric Composites: Development and Industrial Applications Biofilm and Materials Science Bioinspired and Biomimetic Materials Bioinspired Materials: From Living System to New Concepts in Materials Chemistry Biological and Synthetic Organic–Inorganic Composite Materials Biological Applications and Synthesis of Organic Synthetic Dyes Biomass Fuels Biomaterials and Tissue Biomechanics Biomaterials for Cancer Therapy Biomaterials for Controlling Inflammation and Wound Healing Biomaterials Synthesized via Sol–Gel Methods Biomedical Applications of Biodegradable Composites BioPlastics–Emerging Materials for a Circular Economy Biorheology at Micro- and Macro-Scales Biosensors Based on Carbon Nanotube Brittle Materials in Mechanical Extremes CAD-CAM Materials for Biomedical Applications Calcium Phosphate in Biomedical Applications Carbohydrate Polymers Carbon Dots: Properties and Applications Carbon Fibers Carbon Fibers and Their Composite Materials Carbon Nanotube Nanocomposites: Modeling and Applications Carbon Nanotubes 2018 Carbon-Refractory Metals Nanostructures: Synthesis, Characterization and Applications Catalytic Materials for Sustainable Development Catalytic Performance of Zeolites and Nanostructured Materials in Bio-Refinery Applications Characterization of Amorphous Materials Chiral Materials Chitins Collagens, Collagen-Based and Collagen-Mimetic Biomaterials: Preparation, Characterization and Applications Collection of Papers in Material Science from Romania Collection of Papers in Materials Science from Croatia Collection of Papers in Materials Science from Estonia Collection of Scientific Papers by Polish Scientists in the Field of Materials Research Colloidal Quantum Dots Composites for Wind Energy Applications Compound Semiconductor Materials Compound Semiconductor Materials 2014 Computational Design of Complex Structural Alloys Computational Design of Nanoporous Materials: New Structures, Applications,", "role": "user" }, { "content": "Researchers at the Toyohashi University of Technology have successfully fabricated a lithium trivanadate (LVO) cathode thick film on a garnet-type oxide solid electrolyte using the aerosol deposition method. The LVO cathode thick-film fabricated on the solid electrolyte showed a large reversible charge and discharge capacity as high as 300 mAh/g and a good cycling stability at 100 ºC. This finding may contribute to the realization of highly safe and chemically stable oxide-based all-solid-state lithium batteries. The research results were reported in Materials on September 1st, 2018. Rechargeable lithium-ion batteries (LiBs) have been widely utilized globally as a power source for mobile electronic devices such as smart phones, tablets, and laptop computers because of their high-energy density and good cycling performance. Recently, the development of middle- and large-scale LiBs has been accelerated for use in automotive propulsion and stationary load-leveling for intermittent power generation from solar or wind energy. However, a larger battery size causes more serious safety issues in LIBs; one of the main reasons is the increased amount of flammable organic liquid electrolytes. All-solid-state LiBs with nonflammable inorganic Li-ion (Li+) conductors as solid electrolytes (SE) are expected to be the next generation of energy storage devices because of their high energy density, safety, and reliability. The SE materials must have not only high lithium-ion conductivity at room temperature, but also deformability and chemical stability. Oxide-based SE materials have a relatively low conductivity and poor deformability compared to sulfide-based ones; however, they have other advantages such as chemical stability and ease of handling. Comparison of the galvanostatic charge and discharge curves for the LVO/LLZTO/Li solid-state cell at 50 and 100 ºC. The measurements at each temperature are repeated for five cycles. Credit: Toyohashi University of Technology The garnet-type fast Li+ conducting oxide, Li7-xLa3Zr2-xTaxO12 (x = 0.4-0.5, LLZTO), is considered as a good candidate for SE because of its good ionic conducting property and high electrochemical stability. However, high-temperature sintering at 1000-1200 ºC is generally needed for densification, and this temperature is too high to suppress the undesired side reaction at the interface between SE and the majority of electrode materials. Therefore, there are currently limited electrode materials that can be used for solid-state batteries with garnet-type SEs developed by the co-sintering process. Ryoji Inada and his colleagues at the Department of Electrical and Electronic Information Engineering, Toyohashi University of Technology, succeeded in fabricating a lithium trivanadate (LiV3O8, LVO) thick-film cathode on garnet-type LLZTO by using the aerosol deposition (AD) method. All-solid-state cell samples were prepared and tested using the fabricated composite. The AD method is known to be a room-temperature film-fabrication process, which uses the impact-consolidation of ceramic particles onto a substrate. By controlling the particle size and morphology, dense ceramic thick films can be fabricated on various substrates without thermal treatment. This feature is attractive in the fabrication of oxide-based solid-state batteries because various electrode active materials can be selected and formed on SE with no thermal treatment. Cycling performance for the LVO/LLZTO/Li solid-state cell at 100 ºC and different current densities from 0.015 to 0.240 mA/cm2. Credit: Toyohashi University of Technology LVO has been studied at length as a cathode material for Li-based batteries because of its large Li+ storage capacity of approximately 300 mAh/g. However, the feasibility of LVO as a cathode for solid-state batteries has not yet been investigated. The reaction of LVO initiates at the discharging (i.e., Li+ insertion) process, which differs from that of other conventional cathode materials of LiBs such as LiCoO2, LiMn2O4, and LiFePO4. Therefore, graphite anodes, which are widely used in current LiBs, are difficult to use in batteries with LVO cathodes. In solid-state batteries with garnet-type SEs, Li metal electrodes may potentially be used as anodes; thus, LVO would become an attractive candidate for high-capacity cathodes. To fabricate a dense LVO film on an LLZTO pellet, the size of the LVO particles was controlled by ball-milling. As a result, an LVO thick film with a thickness of 5-6 μm was successfully fabricated on LLZTO at room temperature. The relative density of the LVO thick film was approximately 85 percent. For the electrochemical characterization of the LVO thick film as a cathode, Li metal foil was attached on the opposite end face of the LLZTO pellet as an anode to form an LVO/LLZTO/Li structured solid-state cell. The galvanostatic charge (Li+ extraction from LVO) and discharge (Li+ insertion into LVO) properties in an LVO/LLZTO/Li all-solid-state cell were measured at 50 and 100 ºC. Although the polarization was considerably large at 50 ºC, a reversible capacity of approximately 100 mAh/g was confirmed. With an increase in temperature to 100 ºC, the polarization reduced and the capacity increased significantly to 300 mAh/g at an averaged cell voltage of approximately 2.5 V; this is a typical behavior of an LVO electrode observed in an organic liquid electrolyte. In addition, we confirm that the charge and discharge reactions in the solid-state cell are stably cycled at various current densities. This can be attributed to the strong adhesion between the LVO film fabricated via impact consolidation and the LLZTO and LVO particles in the film. These results indicate that LVO can potentially be used as a high-capacity cathode in an oxide-based solid-state battery with high safety and chemical stability, even though additional investigation is needed to enhance the performance. Researchers have carried out further studies to realize oxide-based solid-state batteries at lower operating temperatures. ", "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 Guidelines Hypothesis Interesting Images Letter New Book Received Obituary Opinion Perspective Proceeding Paper Project Report Protocol Registered Report Reply Retraction Short Note Study Protocol Systematic Review Technical Note Tutorial Viewpoint All Article Types Advanced Search Section All Sections Advanced and Functional Ceramics and Glasses Advanced Composites Advanced Materials Characterization Advanced Nanomaterials and Nanotechnology Biomaterials Carbon Materials Catalytic Materials Construction and Building Materials Corrosion Electronic Materials Energy Materials Green Materials Manufacturing Processes and Systems Materials Chemistry Materials Physics Materials Simulation and Design Mechanics of Materials Metals and Alloys Optical and Photonic Materials Polymeric Materials Porous Materials Quantum Materials Smart Materials Soft Matter Thin 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Advances in Lightweight Aggregate Concrete Advances in Magnetic Materials Advances in Materials Science Advances in Mechanical Problems of Functionally Graded Materials and Structures Advances in Metal Foams Advances in Microelectromechanical Systems (MEMS) Materials Advances in Molecular Magnets and related Phenomena Advances in Multifunctional Materials Advances in Nanolime and Other Nanomaterials for Built Heritage Conservation Advances in Natural and Renewable Materials for Biotechnological Applications Advances in Novel Materials for Aerospace Engineering Advances in Optical Materials Advances in Photocatalysis: Photocatalytic Materials and Applications Advances in Physical and Wet-Chemical Methods for Inorganic Nanoparticles Synthesis Advances in Pillared Clays and Similar Materials: Synthesis, Characterization and Applications Advances in Porous Inorganic Materials Advances in Renewable Energy Conversion Materials Advances in Research on Elastomers Advances in Sol-gel Derived Materials Advances in Solid Oxide Cell Materials Advances in Structural Health Monitoring for Aerospace Structures Advances in Structural Metallic Systems for Gas Turbines Advances in Superconductive and Magnetic Nanomaterials Advances in Testing and Predictive Modelling of Failure in Heat Resistant Steels Advances in the Dynamics of Granular Materials Advances in Transparent Conducting Oxides Advances in Zintl Phases Aerogels and Their Functionalization for Practical Applications Aerogels: Synthesis, Characterization and Application Aerospace Materials Alloys and Composites for High Temperature Applications Amorphous Alloys Amorphous and Nanocrystalline Materials for Electrochemical Energy Storage Analytical Characterization of Functionalized Surfaces Anodized Nanoporous Materials: Porous Silicon, Nanoporous Alumina, and Titania Nanotube Arrays Antimicrobial Materials: Application in Food Processing and Storage Antimicrobial Textile Application of Photocatalytic Technology in Environmental Sustainability Applied Mathematics and Computer Methods in Materials, Mechanics and Engineering Auxetic Materials Auxetic Materials 2017-2018 Behavior of Metallic and Composite Structures Bio- and Natural-Fiber Composites Bio-devices and Materials Bioactive Glasses Bioactive Glasses 2017 Bioapplications of Graphene Composites Biobased Polymers for Packaging Applications Biochemical/Inorganic Hybrid Materials Biocompatibility of Materials Biocompatibility of Materials 2011 Biocompatibility of Materials 2013 Biocompatible Metals for Skeletal Fixation and Joint Replacement Devices Biocompatible Surface Functionalization of Nanomaterials Biodegradability of Materials in Biomedical Applications 2011 Biodegradable and Bio-Based Polymers Biodegradable Polymeric Composites: Development and Industrial Applications Biofilm and Materials Science Bioinspired and Biomimetic Materials Bioinspired Materials: From Living System to New Concepts in Materials Chemistry Biological and Synthetic Organic–Inorganic Composite Materials Biological Applications and Synthesis of Organic Synthetic Dyes Biomass Fuels Biomaterials and Tissue Biomechanics Biomaterials for Cancer Therapy Biomaterials for Controlling Inflammation and Wound Healing Biomaterials Synthesized via Sol–Gel Methods Biomedical Applications of Biodegradable Composites BioPlastics–Emerging Materials for a Circular Economy Biorheology at Micro- and Macro-Scales Biosensors Based on Carbon Nanotube Brittle Materials in Mechanical Extremes CAD-CAM Materials for Biomedical Applications Calcium Phosphate in Biomedical Applications Carbohydrate Polymers Carbon Dots: Properties and Applications Carbon Fibers Carbon Fibers and Their Composite Materials Carbon Nanotube Nanocomposites: Modeling and Applications Carbon Nanotubes 2018 Carbon-Refractory Metals Nanostructures: Synthesis, Characterization and Applications Catalytic Materials for Sustainable Development Catalytic Performance of Zeolites and Nanostructured Materials in Bio-Refinery Applications Characterization of Amorphous Materials Chiral Materials Chitins Collagens, Collagen-Based and Collagen-Mimetic Biomaterials: Preparation, Characterization and Applications Collection of Papers in Material Science from Romania Collection of Papers in Materials Science from Croatia Collection of Papers in Materials Science from Estonia Collection of Scientific Papers by Polish Scientists in the Field of Materials Research Colloidal Quantum Dots Composites for Wind Energy Applications Compound Semiconductor Materials Compound Semiconductor Materials 2014 Computational Design of Complex Structural Alloys Computational Design of Nanoporous Materials: New Structures, Applications,<|im_end|> <|im_start|>assistant Researchers at the Toyohashi University of Technology have successfully fabricated a lithium trivanadate (LVO) cathode thick film on a garnet-type oxide solid electrolyte using the aerosol deposition method. The LVO cathode thick-film fabricated on the solid electrolyte showed a large reversible charge and discharge capacity as high as 300 mAh/g and a good cycling stability at 100 ºC. This finding may contribute to the realization of highly safe and chemically stable oxide-based all-solid-state lithium batteries. The research results were reported in Materials on September 1st, 2018. Rechargeable lithium-ion batteries (LiBs) have been widely utilized globally as a power source for mobile electronic devices such as smart phones, tablets, and laptop computers because of their high-energy density and good cycling performance. Recently, the development of middle- and large-scale LiBs has been accelerated for use in automotive propulsion and stationary load-leveling for intermittent power generation from solar or wind energy. However, a larger battery size causes more serious safety issues in LIBs; one of the main reasons is the increased amount of flammable organic liquid electrolytes. All-solid-state LiBs with nonflammable inorganic Li-ion (Li+) conductors as solid electrolytes (SE) are expected to be the next generation of energy storage devices because of their high energy density, safety, and reliability. The SE materials must have not only high lithium-ion conductivity at room temperature, but also deformability and chemical stability. Oxide-based SE materials have a relatively low conductivity and poor deformability compared to sulfide-based ones; however, they have other advantages such as chemical stability and ease of handling. Comparison of the galvanostatic charge and discharge curves for the LVO/LLZTO/Li solid-state cell at 50 and 100 ºC. The measurements at each temperature are repeated for five cycles. Credit: Toyohashi University of Technology The garnet-type fast Li+ conducting oxide, Li7-xLa3Zr2-xTaxO12 (x = 0.4-0.5, LLZTO), is considered as a good candidate for SE because of its good ionic conducting property and high electrochemical stability. However, high-temperature sintering at 1000-1200 ºC is generally needed for densification, and this temperature is too high to suppress the undesired side reaction at the interface between SE and the majority of electrode materials. Therefore, there are currently limited electrode materials that can be used for solid-state batteries with garnet-type SEs developed by the co-sintering process. Ryoji Inada and his colleagues at the Department of Electrical and Electronic Information Engineering, Toyohashi University of Technology, succeeded in fabricating a lithium trivanadate (LiV3O8, LVO) thick-film cathode on garnet-type LLZTO by using the aerosol deposition (AD) method. All-solid-state cell samples were prepared and tested using the fabricated composite. The AD method is known to be a room-temperature film-fabrication process, which uses the impact-consolidation of ceramic particles onto a substrate. By controlling the particle size and morphology, dense ceramic thick films can be fabricated on various substrates without thermal treatment. This feature is attractive in the fabrication of oxide-based solid-state batteries because various electrode active materials can be selected and formed on SE with no thermal treatment. Cycling performance for the LVO/LLZTO/Li solid-state cell at 100 ºC and different current densities from 0.015 to 0.240 mA/cm2. Credit: Toyohashi University of Technology LVO has been studied at length as a cathode material for Li-based batteries because of its large Li+ storage capacity of approximately 300 mAh/g. However, the feasibility of LVO as a cathode for solid-state batteries has not yet been investigated. The reaction of LVO initiates at the discharging (i.e., Li+ insertion) process, which differs from that of other conventional cathode materials of LiBs such as LiCoO2, LiMn2O4, and LiFePO4. Therefore, graphite anodes, which are widely used in current LiBs, are difficult to use in batteries with LVO cathodes. In solid-state batteries with garnet-type SEs, Li metal electrodes may potentially be used as anodes; thus, LVO would become an attractive candidate for high-capacity cathodes. To fabricate a dense LVO film on an LLZTO pellet, the size of the LVO particles was controlled by ball-milling. As a result, an LVO thick film with a thickness of 5-6 μm was successfully fabricated on LLZTO at room temperature. The relative density of the LVO thick film was approximately 85 percent. For the electrochemical characterization of the LVO thick film as a cathode, Li metal foil was attached on the opposite end face of the LLZTO pellet as an anode to form an LVO/LLZTO/Li structured solid-state cell. The galvanostatic charge (Li+ extraction from LVO) and discharge (Li+ insertion into LVO) properties in an LVO/LLZTO/Li all-solid-state cell were measured at 50 and 100 ºC. Although the polarization was considerably large at 50 ºC, a reversible capacity of approximately 100 mAh/g was confirmed. With an increase in temperature to 100 ºC, the polarization reduced and the capacity increased significantly to 300 mAh/g at an averaged cell voltage of approximately 2.5 V; this is a typical behavior of an LVO electrode observed in an organic liquid electrolyte. In addition, we confirm that the charge and discharge reactions in the solid-state cell are stably cycled at various current densities. This can be attributed to the strong adhesion between the LVO film fabricated via impact consolidation and the LLZTO and LVO particles in the film. These results indicate that LVO can potentially be used as a high-capacity cathode in an oxide-based solid-state battery with high safety and chemical stability, even though additional investigation is needed to enhance the performance. Researchers have carried out further studies to realize oxide-based solid-state batteries at lower operating temperatures. <|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 Integrins are conformationally flexible cell surface receptors that survey the extracellular environment for their cognate ligands. Interactions with ligands are thought to be linked to global structural rearrangements involving transitions between bent, extended-closed and extended-open forms. Thus far, structural details are lacking for integrins in the extended conformations due to extensive flexibility between the headpiece and legs in this conformation. Here we present single-particle electron cryomicroscopy structures of human αvβ8 integrin in the extended-closed conformation, which has been considered to be a low-affinity intermediate. Our structures show the headpiece rotating about a flexible αv knee, suggesting a ligand surveillance mechanism for integrins in their extended-closed form. Our model predicts that the extended conformation is mainly stabilized by an interface formed between flexible loops in the upper and lower domains of the αv leg. Confirming these findings with the αvβ3 integrin suggests that our model of stabilizing the extended-closed conformation is generalizable to other integrins. Main Integrins are a family of heterodimeric type I transmembrane receptors that are sentinel sensors of the extracellular environment through their mediation of cell adhesive events involved in homeostasis, immunity, tissue repair and neoplasia 1 . Integrin ectodomains are composed of an α and β subunit stably joined at the α- and β-head domain, each connected to a flexible leg, which continues to a single transmembrane helix followed by a short cytoplasmic domain (Supplementary Fig. 1a ). Integrins utilize the flexibility of their ectodomains to bidirectionally transduce conformational signals to and from the cell interior 2 . In current models of integrin function, regulation of ligand affinity and signaling is thought to be mediated by a series of coupled motions of the ligand-binding headpiece with leg domains, changing the overall shape from a bent to an extended conformation: the so called ‘switchblade’ model (Supplementary Fig. 1b ) 3 . Despite extensive studies, the mechanistic structural details of integrin extension remain elusive. The opposing model proposes that integrins can regulate ligand affinity and transduce signaling entirely in a bent conformation (Supplementary Fig. 1c ) 4 . Furthermore, it is not known how integrins probe the extracellular milieu to find target-binding motifs in extracellular matrix proteins, cytokines and growth factors, a function not elucidated by either model. Three main conformational states are currently proposed: bent integrins with a closed headpiece and extended integrins with either a closed or open headpiece (Supplementary Fig. 1 ). Crystal structures of integrin ectodomains reveal exclusively bent conformations (Supplementary Table 1 ). Negative-stain electron microscopy (ns-EM) images of numerous integrin heterodimers exhibit all three conformational states, with ligand occupancy favoring the extended-open conformation (Supplementary Table 1 ). These studies mainly support the prevailing hypothesis that the high-affinity state has an extended-open conformation 5 . For the αvβ8 integrin, only the extended-closed form has been observed by ns-EM, either alone or in association with ligand 6 , 7 . Those findings are inconsistent with both the bent and the switchblade models and suggest that the αvβ8 integrin functions entirely in the extended-closed form (Supplementary Fig. 1d ). The relative conformational homogeneity of αvβ8 makes it an ideal target for structural studies of an integrin in the extended conformation. Here we present single-particle electron cryomicroscopy (cryo-EM) structures of the αvβ8 integrin in complex with two immunoglobulin antigen-binding fragments (Fab) to reveal an integrin in a range of extended conformations with unprecedented clarity. We achieve an overall resolution of 6.4 Å, with a resolution of 4.8 Å in the headpiece. The motion between the headpiece and the leg suggests a mechanism by which integrin headpieces survey extracellular surfaces for ligands. Our structures predict the interactions between αv thigh and calf-1 domains in this extended conformation, which is confirmed with rationally designed αvβ3 mutants. Results Cryo-EM structures of the αvβ8 integrin Integrins in an extended conformation have not been crystallized. Current single-particle EM structures do not have sufficient detail to provide insights into integrin extension or surveillance mechanisms (Supplementary Table 1 ). Even with the recent advances in single particle cryo-EM 8 , determining high-resolution integrin structures remains challenging. The main technical barriers are the low mass density, asymmetry and extreme conformational flexibility, all of which conspire to hinder accurate image alignment and conformational classification 9 . To mitigate these challenges, we use two different monoclonal Fabs (8B8 and 68) directed at the headpiece of the αvβ8 integrin to increase the molecular mass and facilitate more accurate image alignment 10 . Neither Fab alters αvβ8 function, with 8B8 directed at the αv head and 68 at the β8 βI-domain 6 . With this combination of Fabs, we determined the structure of the αvβ8-8B8-68 complex, in which the integrin is in the extended-closed conformation, to an overall resolution of 6.4 Å (Fig. 1a , Table 1 and Supplementary Fig. 2 ). An atomic model of the αvβ8 integrin in the extended conformation was obtained by fitting homology models of individual domains (based on available crystal structures of integrin αvβ3) into the cryo-EM density map. Subsequently, the model was iteratively rebuilt and refined into the density using Phenix 11 and Rosetta 12 (Fig. 1b ). At this resolution, the boundaries for all the individual domains in the αv leg and β8 headpiece are clearly defined, with well-resolved secondary structural features including all α-helices and many β-sheets (Fig. 1a,b ). Fig. 1: Structure of the αvβ8 integrin in extended-closed conformation. a , Cryo-EM structure of αvβ8-8B8-68 complex at a global 6.4 Å resolution. Axial and head-domain dimensions are shown. b , The atomic model shown in ribbon format, fitted into the cryo-EM density. The headpiece consists of the αv head, thigh, β8 βI, hybrid and PSI-EGF1 domains. Names of individual domains are indicated. c , Close-up of the headpiece, which is resolved to 4.8 Å through focused alignment. d , Close-up of the β8 headpiece, showing the glycan attached to N191 as well as the two bulky side chains H200 and F195. e , Close-up of the αv headpiece, showing the glycan attached to N44 and the bulky side", "role": "user" }, { "content": "A collaboration between three labs at UC San Francisco has resulted in an unprecedented look at a member of a vital and ubiquitous class of proteins called integrins (pronounced \"INT-uh-grins\"). Integrins are associated with fibrosis, scarring and stiffening of tissues that is associated with nearly half of all deaths in developed countries, and yet researchers had no high-resolution structural model of the proteins in their active state. Now, a combination of perseverance, technological achievement and insight has pinned down an elusive moving target. Older techniques like X-ray crystallography require researchers to undergo laborious processes to pack proteins into crystals before they can make images to determine a protein's structure. This method works best on stationary, rigid, and symmetrical proteins: the opposite of integrins, which are quite flexible in their active form, said Stephen Nishimura, MD, one of the paper's senior authors and a professor of pathology at UCSF. Integrins are embedded on the surfaces of all animal cells, connecting each cell to its surroundings and allowing it to communicate and respond to external forces. In order to encounter its targets, the new work suggests for the first time that an active integrin bends and sways at a flexible midpoint \"like a sunflower seeking the sun,\" said Nishimura. To explore an integrin's structure, the team used cryo-electron microscopy, a technique that has recently benefited from major advancements in hardware and software at UCSF. Melody Campbell, Ph.D., worked to visualize one type of integrin protein down to near-atomic precision. She imaged and analyzed the purified and frozen proteins in the lab of Yifan Cheng, Ph.D., a professor of biochemistry and biophysics at UCSF and the other senior author of the study. But visualizing the protein was only part of the effort. The team's new paper in Nature Structural and Molecular Biology includes Campbell's work, genetic manipulation from Saburo Ito, Ph.D., and protein engineering, purification and expertise from Anthony Cormier, Ph.D. Once the protein was visualized, the researchers validated their structural model by genetically engineering a related integrin that responded to biochemical cues exactly as the team's model predicted, suggesting that their findings extended to many, if not all, integrins. With antibody engineering pioneers Jim Marks, MD, Ph.D., and Jianlong Lou, Ph.D., both in the Department of Anesthesia at UCSF, the authors have already developed several promising therapeutic antibodies, using the new structure as a template. Some companies are already working with those antibodies to develop treatments for conditions like cancer and fibrosis. But for Nishimura, who has been working with integrins for more than two decades, the detailed model is also personally satisfying: \"It's like seeking an old archnemesis, and finally freezing him in his tracks.\" ", "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 Integrins are conformationally flexible cell surface receptors that survey the extracellular environment for their cognate ligands. Interactions with ligands are thought to be linked to global structural rearrangements involving transitions between bent, extended-closed and extended-open forms. Thus far, structural details are lacking for integrins in the extended conformations due to extensive flexibility between the headpiece and legs in this conformation. Here we present single-particle electron cryomicroscopy structures of human αvβ8 integrin in the extended-closed conformation, which has been considered to be a low-affinity intermediate. Our structures show the headpiece rotating about a flexible αv knee, suggesting a ligand surveillance mechanism for integrins in their extended-closed form. Our model predicts that the extended conformation is mainly stabilized by an interface formed between flexible loops in the upper and lower domains of the αv leg. Confirming these findings with the αvβ3 integrin suggests that our model of stabilizing the extended-closed conformation is generalizable to other integrins. Main Integrins are a family of heterodimeric type I transmembrane receptors that are sentinel sensors of the extracellular environment through their mediation of cell adhesive events involved in homeostasis, immunity, tissue repair and neoplasia 1 . Integrin ectodomains are composed of an α and β subunit stably joined at the α- and β-head domain, each connected to a flexible leg, which continues to a single transmembrane helix followed by a short cytoplasmic domain (Supplementary Fig. 1a ). Integrins utilize the flexibility of their ectodomains to bidirectionally transduce conformational signals to and from the cell interior 2 . In current models of integrin function, regulation of ligand affinity and signaling is thought to be mediated by a series of coupled motions of the ligand-binding headpiece with leg domains, changing the overall shape from a bent to an extended conformation: the so called ‘switchblade’ model (Supplementary Fig. 1b ) 3 . Despite extensive studies, the mechanistic structural details of integrin extension remain elusive. The opposing model proposes that integrins can regulate ligand affinity and transduce signaling entirely in a bent conformation (Supplementary Fig. 1c ) 4 . Furthermore, it is not known how integrins probe the extracellular milieu to find target-binding motifs in extracellular matrix proteins, cytokines and growth factors, a function not elucidated by either model. Three main conformational states are currently proposed: bent integrins with a closed headpiece and extended integrins with either a closed or open headpiece (Supplementary Fig. 1 ). Crystal structures of integrin ectodomains reveal exclusively bent conformations (Supplementary Table 1 ). Negative-stain electron microscopy (ns-EM) images of numerous integrin heterodimers exhibit all three conformational states, with ligand occupancy favoring the extended-open conformation (Supplementary Table 1 ). These studies mainly support the prevailing hypothesis that the high-affinity state has an extended-open conformation 5 . For the αvβ8 integrin, only the extended-closed form has been observed by ns-EM, either alone or in association with ligand 6 , 7 . Those findings are inconsistent with both the bent and the switchblade models and suggest that the αvβ8 integrin functions entirely in the extended-closed form (Supplementary Fig. 1d ). The relative conformational homogeneity of αvβ8 makes it an ideal target for structural studies of an integrin in the extended conformation. Here we present single-particle electron cryomicroscopy (cryo-EM) structures of the αvβ8 integrin in complex with two immunoglobulin antigen-binding fragments (Fab) to reveal an integrin in a range of extended conformations with unprecedented clarity. We achieve an overall resolution of 6.4 Å, with a resolution of 4.8 Å in the headpiece. The motion between the headpiece and the leg suggests a mechanism by which integrin headpieces survey extracellular surfaces for ligands. Our structures predict the interactions between αv thigh and calf-1 domains in this extended conformation, which is confirmed with rationally designed αvβ3 mutants. Results Cryo-EM structures of the αvβ8 integrin Integrins in an extended conformation have not been crystallized. Current single-particle EM structures do not have sufficient detail to provide insights into integrin extension or surveillance mechanisms (Supplementary Table 1 ). Even with the recent advances in single particle cryo-EM 8 , determining high-resolution integrin structures remains challenging. The main technical barriers are the low mass density, asymmetry and extreme conformational flexibility, all of which conspire to hinder accurate image alignment and conformational classification 9 . To mitigate these challenges, we use two different monoclonal Fabs (8B8 and 68) directed at the headpiece of the αvβ8 integrin to increase the molecular mass and facilitate more accurate image alignment 10 . Neither Fab alters αvβ8 function, with 8B8 directed at the αv head and 68 at the β8 βI-domain 6 . With this combination of Fabs, we determined the structure of the αvβ8-8B8-68 complex, in which the integrin is in the extended-closed conformation, to an overall resolution of 6.4 Å (Fig. 1a , Table 1 and Supplementary Fig. 2 ). An atomic model of the αvβ8 integrin in the extended conformation was obtained by fitting homology models of individual domains (based on available crystal structures of integrin αvβ3) into the cryo-EM density map. Subsequently, the model was iteratively rebuilt and refined into the density using Phenix 11 and Rosetta 12 (Fig. 1b ). At this resolution, the boundaries for all the individual domains in the αv leg and β8 headpiece are clearly defined, with well-resolved secondary structural features including all α-helices and many β-sheets (Fig. 1a,b ). Fig. 1: Structure of the αvβ8 integrin in extended-closed conformation. a , Cryo-EM structure of αvβ8-8B8-68 complex at a global 6.4 Å resolution. Axial and head-domain dimensions are shown. b , The atomic model shown in ribbon format, fitted into the cryo-EM density. The headpiece consists of the αv head, thigh, β8 βI, hybrid and PSI-EGF1 domains. Names of individual domains are indicated. c , Close-up of the headpiece, which is resolved to 4.8 Å through focused alignment. d , Close-up of the β8 headpiece, showing the glycan attached to N191 as well as the two bulky side chains H200 and F195. e , Close-up of the αv headpiece, showing the glycan attached to N44 and the bulky side<|im_end|> <|im_start|>assistant A collaboration between three labs at UC San Francisco has resulted in an unprecedented look at a member of a vital and ubiquitous class of proteins called integrins (pronounced "INT-uh-grins"). Integrins are associated with fibrosis, scarring and stiffening of tissues that is associated with nearly half of all deaths in developed countries, and yet researchers had no high-resolution structural model of the proteins in their active state. Now, a combination of perseverance, technological achievement and insight has pinned down an elusive moving target. Older techniques like X-ray crystallography require researchers to undergo laborious processes to pack proteins into crystals before they can make images to determine a protein's structure. This method works best on stationary, rigid, and symmetrical proteins: the opposite of integrins, which are quite flexible in their active form, said Stephen Nishimura, MD, one of the paper's senior authors and a professor of pathology at UCSF. Integrins are embedded on the surfaces of all animal cells, connecting each cell to its surroundings and allowing it to communicate and respond to external forces. In order to encounter its targets, the new work suggests for the first time that an active integrin bends and sways at a flexible midpoint "like a sunflower seeking the sun," said Nishimura. To explore an integrin's structure, the team used cryo-electron microscopy, a technique that has recently benefited from major advancements in hardware and software at UCSF. Melody Campbell, Ph.D., worked to visualize one type of integrin protein down to near-atomic precision. She imaged and analyzed the purified and frozen proteins in the lab of Yifan Cheng, Ph.D., a professor of biochemistry and biophysics at UCSF and the other senior author of the study. But visualizing the protein was only part of the effort. The team's new paper in Nature Structural and Molecular Biology includes Campbell's work, genetic manipulation from Saburo Ito, Ph.D., and protein engineering, purification and expertise from Anthony Cormier, Ph.D. Once the protein was visualized, the researchers validated their structural model by genetically engineering a related integrin that responded to biochemical cues exactly as the team's model predicted, suggesting that their findings extended to many, if not all, integrins. With antibody engineering pioneers Jim Marks, MD, Ph.D., and Jianlong Lou, Ph.D., both in the Department of Anesthesia at UCSF, the authors have already developed several promising therapeutic antibodies, using the new structure as a template. Some companies are already working with those antibodies to develop treatments for conditions like cancer and fibrosis. But for Nishimura, who has been working with integrins for more than two decades, the detailed model is also personally satisfying: "It's like seeking an old archnemesis, and finally freezing him in his tracks." <|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 Growing interest in quantum computing for practical applications has led to a surge in the availability of programmable machines for executing quantum algorithms 1 , 2 . Present-day photonic quantum computers 3 , 4 , 5 , 6 , 7 have been limited either to non-deterministic operation, low photon numbers and rates, or fixed random gate sequences. Here we introduce a full-stack hardware−software system for executing many-photon quantum circuit operations using integrated nanophotonics: a programmable chip, operating at room temperature and interfaced with a fully automated control system. The system enables remote users to execute quantum algorithms that require up to eight modes of strongly squeezed vacuum initialized as two-mode squeezed states in single temporal modes, a fully general and programmable four-mode interferometer, and photon number-resolving readout on all outputs. Detection of multi-photon events with photon numbers and rates exceeding any previous programmable quantum optical demonstration is made possible by strong squeezing and high sampling rates. We verify the non-classicality of the device output, and use the platform to carry out proof-of-principle demonstrations of three quantum algorithms: Gaussian boson sampling, molecular vibronic spectra and graph similarity 8 . These demonstrations validate the platform as a launchpad for scaling photonic technologies for quantum information processing. Main The past decade has seen remarkable progress in quantum computation and simulation. Breakthroughs across a range of platforms have enabled the construction of programmable machines delivering the automation, stability and repeatability demanded by increasingly sophisticated quantum algorithms. Rigorous benchmarks have been carried out on an 11-qubit trapped ion system 1 , 9 , and a 53-qubit superconducting system has been used to generate random samples from a probability distribution at a rate exceeding what is reasonably achievable using classical hardware 2 , 10 . Similar machines can now be remotely accessed and loaded with algorithms written in high-level programming languages by users having little knowledge of the low-level quantum hardware details of the apparatus. These capabilities have accelerated application development for near-term quantum computers 11 , 12 , 13 . Such hardware has primarily been designed to access problems in the qubit model, where computation is carried out by initializing a quantum state in a space spanned by a product of binary-valued basis states, followed by a sequence of gates selected from a typically discrete set of operations 14 . Present-day machines are limited to dozens of noisy qubits, restricting their applicability to quantum algorithms compatible with this scale 15 . Other algorithms are more efficiently expressed in a model where each independent quantum system is described by a state in an infinite-dimensional Hilbert space. Examples include those implementing bosonic error correction codes 16 , 17 , a wide class of Gaussian boson sampling (GBS) applications 8 , 18 , 19 , 20 , 21 , 22 , 23 , and bespoke algorithms exploiting the structure of infinite-dimensional Hilbert spaces 24 , 25 . A promising platform for the large-scale implementation of bosonic quantum algorithms is offered by photonic hardware. A number of groundbreaking demonstrations of photonic quantum information processing have recently been completed. Two-dimensional cluster states with tens of thousands of entangled nodes have been deterministically generated using bulk-optical components 3 , 4 , and photonic experiments have been constructed to sample from the photon number distribution of multi-mode Gaussian states 6 , 7 . Combined with advances in photonic chip fabrication 26 , such demonstrations coincide with new optimism towards photonics as a platform for quantum computation 27 . Despite these advances, much work remains in developing photonic systems for practical use in quantum computation. Photonic cluster state demonstrations 3 , 4 were limited to all-Gaussian states, gates and measurements, rendering them efficiently simulatable at any scale by classical computers. Single-photon-based experiments on integrated platforms 5 suffer from non-deterministic state preparation and gate implementation, hindering their scalability. This deficit can be evaded in photonic experiments by using deterministically prepared squeezed states and linear optics, with non-Gaussian operations provided by photon-counting detectors. In such experiments, and in the machine we present, squeezed state inputs have the role of qubits as the basic independently accessible quantum systems. But demonstrations of such squeezing-based photonic machines 6 , 7 lacked programmability, with each accessing only a fixed, randomized quantum state. Furthermore, these demonstrations were limited to small numbers of detected photons. To date, no photonic machine has been demonstrated that is simultaneously (1) dynamically programmable, (2) readily scalable to hundreds of modes and photons, and (3) able to access a class of quantum circuits that could not, when the system size is scaled, be efficiently simulated by classical hardware. Here we report results from a device based on a programmable nanophotonic chip that includes all of these capabilities in a single scalable and unified machine. We describe the performance of the components designed for initial state preparation, gate sequence implementation, and readout, and verify the non-classicality of the device output. We then use the machine to carry out proof-of-principle demonstrations of the execution of three types of quantum algorithms: GBS 28 , molecular vibronic spectra 18 and graph similarity 22 . Although our device, at its current scale, can readily be simulated by a classical computer, the architecture and platform developed can potentially enable future generations of such machines to exit this regime and perform tasks that are not practically simulatable by classical systems. The core of our device is a 10 mm × 4 mm photonic chip. It generates squeezed light 29 in up to eight optical modes, with a fixed initialization into four independent two-mode squeezed vacuum states. The squeezing is generated between bichromatic mode pairs, with each such pair populating one of four spatially separated waveguide modes. An interferometer, based on a network of beam splitters and phase shifters, implements a user-programmable gate sequence corresponding to an SU(4) transformation (with SU( n ) the special unitary group of degree n ) applied to the spatial modes. The resulting eight-mode Gaussian state synthesized by the chip is then measured in the Fock basis using", "role": "user" }, { "content": "A team of researchers and engineers at Canadian company Xanadu Quantum Technologies Inc., working with the National Institute of Standards and Technology in the U.S., has developed a programmable, scalable photonic quantum chip that can execute multiple algorithms. In their paper published in the journal Nature, the group describes how they made their chip, its characteristics and how it can be used. Ulrik Andersen with the Technical University of Denmark has published a News & Views piece in the same journal issue outlining current research on quantum computers and the work by the team in Canada. Scientists around the world are working to build a truly useful quantum computer that can perform calculations that would take traditional computers millions of years to carry out. To date, most such efforts have been focused on two main architectures—those based on superconducting electrical circuits and those based on trapped-ion technology. Both have their advantages and disadvantages, and both must operate in a supercooled environment, making them difficult to scale up. Receiving less attention is work using a photonics-based approach to building a quantum computer. Such an approach has been seen as less feasible because of the problems inherent in generating quantum states and also of transforming such states on demand. One big advantage photonics-based systems would have over the other two architectures is that they would not have to be chilled—they could work at room temperature. In this new effort, the group at Xanadu has overcome some of the problems associated with photonics-based systems and created a working programmable photonic quantum chip that can execute multiple algorithms and can also be scaled up. They have named it the X8 photonic quantum processing unit. During operation, the chip is connected to what the team at Xanadu describe as a \"squeezed light\" source—infrared laser pulses working with microscopic resonators. This is because the new system performs continuous variable quantum computing rather than using single-photon generators. As part of its announcement, Xanadu reps noted that their new system is the first photonic quantum computing platform to be made available to the public. Those wishing to run applications on it can opt for systems running 8 or 12 qubits over Xanadu's quantum cloud. ", "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 Growing interest in quantum computing for practical applications has led to a surge in the availability of programmable machines for executing quantum algorithms 1 , 2 . Present-day photonic quantum computers 3 , 4 , 5 , 6 , 7 have been limited either to non-deterministic operation, low photon numbers and rates, or fixed random gate sequences. Here we introduce a full-stack hardware−software system for executing many-photon quantum circuit operations using integrated nanophotonics: a programmable chip, operating at room temperature and interfaced with a fully automated control system. The system enables remote users to execute quantum algorithms that require up to eight modes of strongly squeezed vacuum initialized as two-mode squeezed states in single temporal modes, a fully general and programmable four-mode interferometer, and photon number-resolving readout on all outputs. Detection of multi-photon events with photon numbers and rates exceeding any previous programmable quantum optical demonstration is made possible by strong squeezing and high sampling rates. We verify the non-classicality of the device output, and use the platform to carry out proof-of-principle demonstrations of three quantum algorithms: Gaussian boson sampling, molecular vibronic spectra and graph similarity 8 . These demonstrations validate the platform as a launchpad for scaling photonic technologies for quantum information processing. Main The past decade has seen remarkable progress in quantum computation and simulation. Breakthroughs across a range of platforms have enabled the construction of programmable machines delivering the automation, stability and repeatability demanded by increasingly sophisticated quantum algorithms. Rigorous benchmarks have been carried out on an 11-qubit trapped ion system 1 , 9 , and a 53-qubit superconducting system has been used to generate random samples from a probability distribution at a rate exceeding what is reasonably achievable using classical hardware 2 , 10 . Similar machines can now be remotely accessed and loaded with algorithms written in high-level programming languages by users having little knowledge of the low-level quantum hardware details of the apparatus. These capabilities have accelerated application development for near-term quantum computers 11 , 12 , 13 . Such hardware has primarily been designed to access problems in the qubit model, where computation is carried out by initializing a quantum state in a space spanned by a product of binary-valued basis states, followed by a sequence of gates selected from a typically discrete set of operations 14 . Present-day machines are limited to dozens of noisy qubits, restricting their applicability to quantum algorithms compatible with this scale 15 . Other algorithms are more efficiently expressed in a model where each independent quantum system is described by a state in an infinite-dimensional Hilbert space. Examples include those implementing bosonic error correction codes 16 , 17 , a wide class of Gaussian boson sampling (GBS) applications 8 , 18 , 19 , 20 , 21 , 22 , 23 , and bespoke algorithms exploiting the structure of infinite-dimensional Hilbert spaces 24 , 25 . A promising platform for the large-scale implementation of bosonic quantum algorithms is offered by photonic hardware. A number of groundbreaking demonstrations of photonic quantum information processing have recently been completed. Two-dimensional cluster states with tens of thousands of entangled nodes have been deterministically generated using bulk-optical components 3 , 4 , and photonic experiments have been constructed to sample from the photon number distribution of multi-mode Gaussian states 6 , 7 . Combined with advances in photonic chip fabrication 26 , such demonstrations coincide with new optimism towards photonics as a platform for quantum computation 27 . Despite these advances, much work remains in developing photonic systems for practical use in quantum computation. Photonic cluster state demonstrations 3 , 4 were limited to all-Gaussian states, gates and measurements, rendering them efficiently simulatable at any scale by classical computers. Single-photon-based experiments on integrated platforms 5 suffer from non-deterministic state preparation and gate implementation, hindering their scalability. This deficit can be evaded in photonic experiments by using deterministically prepared squeezed states and linear optics, with non-Gaussian operations provided by photon-counting detectors. In such experiments, and in the machine we present, squeezed state inputs have the role of qubits as the basic independently accessible quantum systems. But demonstrations of such squeezing-based photonic machines 6 , 7 lacked programmability, with each accessing only a fixed, randomized quantum state. Furthermore, these demonstrations were limited to small numbers of detected photons. To date, no photonic machine has been demonstrated that is simultaneously (1) dynamically programmable, (2) readily scalable to hundreds of modes and photons, and (3) able to access a class of quantum circuits that could not, when the system size is scaled, be efficiently simulated by classical hardware. Here we report results from a device based on a programmable nanophotonic chip that includes all of these capabilities in a single scalable and unified machine. We describe the performance of the components designed for initial state preparation, gate sequence implementation, and readout, and verify the non-classicality of the device output. We then use the machine to carry out proof-of-principle demonstrations of the execution of three types of quantum algorithms: GBS 28 , molecular vibronic spectra 18 and graph similarity 22 . Although our device, at its current scale, can readily be simulated by a classical computer, the architecture and platform developed can potentially enable future generations of such machines to exit this regime and perform tasks that are not practically simulatable by classical systems. The core of our device is a 10 mm × 4 mm photonic chip. It generates squeezed light 29 in up to eight optical modes, with a fixed initialization into four independent two-mode squeezed vacuum states. The squeezing is generated between bichromatic mode pairs, with each such pair populating one of four spatially separated waveguide modes. An interferometer, based on a network of beam splitters and phase shifters, implements a user-programmable gate sequence corresponding to an SU(4) transformation (with SU( n ) the special unitary group of degree n ) applied to the spatial modes. The resulting eight-mode Gaussian state synthesized by the chip is then measured in the Fock basis using<|im_end|> <|im_start|>assistant A team of researchers and engineers at Canadian company Xanadu Quantum Technologies Inc., working with the National Institute of Standards and Technology in the U.S., has developed a programmable, scalable photonic quantum chip that can execute multiple algorithms. In their paper published in the journal Nature, the group describes how they made their chip, its characteristics and how it can be used. Ulrik Andersen with the Technical University of Denmark has published a News & Views piece in the same journal issue outlining current research on quantum computers and the work by the team in Canada. Scientists around the world are working to build a truly useful quantum computer that can perform calculations that would take traditional computers millions of years to carry out. To date, most such efforts have been focused on two main architectures—those based on superconducting electrical circuits and those based on trapped-ion technology. Both have their advantages and disadvantages, and both must operate in a supercooled environment, making them difficult to scale up. Receiving less attention is work using a photonics-based approach to building a quantum computer. Such an approach has been seen as less feasible because of the problems inherent in generating quantum states and also of transforming such states on demand. One big advantage photonics-based systems would have over the other two architectures is that they would not have to be chilled—they could work at room temperature. In this new effort, the group at Xanadu has overcome some of the problems associated with photonics-based systems and created a working programmable photonic quantum chip that can execute multiple algorithms and can also be scaled up. They have named it the X8 photonic quantum processing unit. During operation, the chip is connected to what the team at Xanadu describe as a "squeezed light" source—infrared laser pulses working with microscopic resonators. This is because the new system performs continuous variable quantum computing rather than using single-photon generators. As part of its announcement, Xanadu reps noted that their new system is the first photonic quantum computing platform to be made available to the public. Those wishing to run applications on it can opt for systems running 8 or 12 qubits over Xanadu's quantum cloud. <|im_end|>

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1,739

[ { "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 Objective To compare the effectiveness of sotrovimab (a neutralising monoclonal antibody) with molnupiravir (an antiviral) in preventing severe outcomes of covid-19 in adult patients infected with SARS-CoV-2 in the community and at high risk of severe outcomes from covid-19. Design Observational cohort study with the OpenSAFELY platform. Setting With the approval of NHS England, a real world cohort study was conducted with the OpenSAFELY-TPP platform (a secure, transparent, open source software platform for analysis of NHS electronic health records), and patient level electronic health record data were obtained from 24 million people registered with a general practice in England that uses TPP software. The primary care data were securely linked with data on SARS-CoV-2 infection and treatments, hospital admission, and death, over a period when both drug treatments were frequently prescribed in community settings. Participants Adult patients with covid-19 in the community at high risk of severe outcomes from covid-19, treated with sotrovimab or molnupiravir from 16 December 2021. Interventions Sotrovimab or molnupiravir given in the community by covid-19 medicine delivery units. Main outcome measures Admission to hospital with covid-19 (ie, with covid-19 as the primary diagnosis) or death from covid-19 (ie, with covid-19 as the underlying or contributing cause of death) within 28 days of the start of treatment. Results Between 16 December 2021 and 10 February 2022, 3331 and 2689 patients were treated with sotrovimab and molnupiravir, respectively, with no substantial differences in baseline characteristics. Mean age of all 6020 patients was 52 (standard deviation 16) years; 59% were women, 89% were white, and 88% had received three or more covid-19 vaccinations. Within 28 days of the start of treatment, 87 (1.4%) patients were admitted to hospital or died of infection from SARS-CoV-2 (32 treated with sotrovimab and 55 with molnupiravir). Cox proportional hazards models stratified by area showed that after adjusting for demographic information, high risk cohort categories, vaccination status, calendar time, body mass index, and other comorbidities, treatment with sotrovimab was associated with a substantially lower risk than treatment with molnupiravir (hazard ratio 0.54, 95% confidence interval 0.33 to 0.88, P=0.01). Consistent results were found from propensity score weighted Cox models (0.50, 0.31 to 0.81, P=0.005) and when restricted to people who were fully vaccinated (0.53, 0.31 to 0.90, P=0.02). No substantial effect modifications by other characteristics were detected (all P values for interaction >0.10). The findings were similar in an exploratory analysis of patients treated between 16 February and 1 May 2022 when omicron BA.2 was the predominant variant in England. Conclusions In routine care of adult patients in England with covid-19 in the community, at high risk of severe outcomes from covid-19, those who received sotrovimab were at lower risk of severe outcomes of covid-19 than those treated with molnupiravir. Introduction Neutralising monoclonal antibodies and antiviral medicines were approved by the UK Medicines and Healthcare products Regulatory Agency for use in patients with covid-19 not requiring admission to hospital to prevent progression of disease. On 16 December 2021, covid-19 medicine delivery units were launched across England to provide neutralising monoclonal antibodies and antivirals in community settings to treat patients with symptoms of covid-19 who were at high risk of severe outcomes. Among the first available treatment options were sotrovimab (an intravenous neutralising monoclonal antibody) and molnupiravir (an oral antiviral). 1 2 3 The approval and early clinical use of these drug treatments were mainly based on data from two phase 3 randomised controlled trials. 4 5 The findings of these trials could be limited, however, by the relatively small sample size, lack of population generalisability, given the strict inclusion and exclusion criteria, and the predominant circulating variants when the trials were conducted. In particular, little evidence is available on their effectiveness in patients with covid-19 who had received covid-19 vaccinations, in patients infected with omicron variants of the virus, or in those with severe renal or liver impairment. Uncertainty exists about the efficacy of molnupiravir in patients previously infected with SARS-CoV-2, in those with diabetes, and in non-white ethnic groups, 5 and the appropriateness of early regulatory authorisation for this drug has been debated given the modest effect magnitude found in the randomised controlled trial. 6 Also, both lower compliance with courses of oral drug treatment and longer time to administration of treatments after the onset of symptoms in routine care compared with clinical trials might affect potential benefit. Therefore, validating the effectiveness of sotrovimab and molnupiravir in preventing adverse outcomes in real world settings with varied populations is crucial in supporting their widescale clinical use in patients with covid-19. In the first two months after the launch of covid-19 medicine delivery units, sotrovimab and molnupiravir were the most frequently prescribed drug treatments, 2 with anecdotal reports that choice of drug was in part determined by the availability of facilities to deliver intravenous infusions and relative clinical equipoise for the choice of drug. 3 This situation provided the opportunity for observational comparison of the effectiveness of the two drug treatments, possibly with limited bias according to patient characteristics. A comparative effectiveness study would also provide real world evidence for the clinical practice guideline on the prioritised treatment. 7 Therefore, we sought to compare the effectiveness of sotrovimab versus molnupiravir in preventing severe outcomes from SARS-CoV-2 infection in adult patients in England with covid-19, who were at high risk of severe outcomes from infection but who did not require admission to hospital, during the first two months of the national rollout of covid-19 medicine delivery units, by using near real time electronic health record data in the OpenSAFELY-TPP platform. The OpenSAFELY-TPP platform is a secure, transparent, open source software platform for analysis of NHS electronic health records. We also explored the potential modifying effects of different demographic and clinical factors on the effectiveness of the drugs. We then conducted an exploratory analysis of patients treated in the next three months when omicron BA.2 had replaced BA.1 as the predominant variant of the SARS-CoV-2 virus in England. 8 Methods Study design and population In this", "role": "user" }, { "content": "Two studies published by The BMJ today provide up to date evidence on the effectiveness of both currently licensed and possible COVID-19 treatments under everyday (\"real world\") conditions, helping to shed more light on whether these drugs can prevent people from becoming seriously ill. The first is an observational study carried out in England between December 2021 and February 2022. Researchers used hospital records and death certificates for high-risk adults with COVID-19 (average age 52) to compare the effectiveness of the antibody treatment sotrovimab with the antiviral drug molnupiravir. The researchers found that those who received sotrovimab were at a substantially lower (46%) risk of severe COVID-19 outcomes than those receiving molnupiravir, within 28 days of treatment. Results were consistent when restricted to fully vaccinated people and also after further analysis of patients treated between February and May 2022 when the BA.2 omicron variant of COVID-19 was dominant in England, suggesting that they are relevant to current clinical care. There is currently ongoing discussion about the effectiveness of different antibody and antiviral treatments for COVID-19 with recent World Health Organization guidance recommending against use of sotrovimab. However, both drugs are currently available for use in England. The researchers say that their \"real-world findings within a time period when both drugs were frequently prescribed and when new variants of COVID-19 were circulating provide evidence of current effectiveness of sotrovimab over molnupiravir.\" Their analysis also \"supports the conclusion that sotrovimab remains beneficial in fully vaccinated patients, which now represent the majority of the COVID-19 patient population in many settings,\" they add. The second is a randomized controlled trial involving 787 patients (778 from India and nine from Australia) with an average age of 49 years, admitted to hospital from May 2020 to November 2021. Included patients had predominantly mild disease, although the researchers aimed to recruit patients at risk of severe COVID. Half received angiotensin receptor blockers or ARBs (drugs widely used to treat high blood pressure and heart disease) and the other half (controls) received a placebo for 28 days. A standard dose of the ARB drug telmisartan (starting dose 40 mg/d) was used only in India while the type and dose of ARB was at the discretion of the treating physicians in Australia. These particular drugs were chosen because they work by regulating the same angiotensin protein as coronavirus uses to enter the body, and in the laboratory have shown potential protectivity against severe effects of coronaviruses. However, after 14 days of treatment, the researchers found no meaningful difference in illness severity between the two groups. These findings should help to inform clinical practice. The lack of effect provides reassurance that it is safe to use these protective agents in people indicated, with or without COVID-19. Both studies have some important limitations. For instance, in the observational study, some misclassification about cause of death or hospital admission may have occurred, and the researchers can't rule out the possibility that differences in initial severity of COVID-19 or other unmeasured factors between treatment groups may have influenced their results. And in the randomized controlled trial, the researchers were unable to source placebo in Australia, meaning participants and treating clinicians knew they were taking an active drug. Participants were also treated with a relatively low drug dose, so the effect of higher doses remains unknown. Nevertheless, key strengths included the scale, level of detail and completeness of the underlying data in the observational study, and good adherence to study treatment and an adaptive design that allowed the study question to be answered most quickly in the randomized trial. ", "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 Objective To compare the effectiveness of sotrovimab (a neutralising monoclonal antibody) with molnupiravir (an antiviral) in preventing severe outcomes of covid-19 in adult patients infected with SARS-CoV-2 in the community and at high risk of severe outcomes from covid-19. Design Observational cohort study with the OpenSAFELY platform. Setting With the approval of NHS England, a real world cohort study was conducted with the OpenSAFELY-TPP platform (a secure, transparent, open source software platform for analysis of NHS electronic health records), and patient level electronic health record data were obtained from 24 million people registered with a general practice in England that uses TPP software. The primary care data were securely linked with data on SARS-CoV-2 infection and treatments, hospital admission, and death, over a period when both drug treatments were frequently prescribed in community settings. Participants Adult patients with covid-19 in the community at high risk of severe outcomes from covid-19, treated with sotrovimab or molnupiravir from 16 December 2021. Interventions Sotrovimab or molnupiravir given in the community by covid-19 medicine delivery units. Main outcome measures Admission to hospital with covid-19 (ie, with covid-19 as the primary diagnosis) or death from covid-19 (ie, with covid-19 as the underlying or contributing cause of death) within 28 days of the start of treatment. Results Between 16 December 2021 and 10 February 2022, 3331 and 2689 patients were treated with sotrovimab and molnupiravir, respectively, with no substantial differences in baseline characteristics. Mean age of all 6020 patients was 52 (standard deviation 16) years; 59% were women, 89% were white, and 88% had received three or more covid-19 vaccinations. Within 28 days of the start of treatment, 87 (1.4%) patients were admitted to hospital or died of infection from SARS-CoV-2 (32 treated with sotrovimab and 55 with molnupiravir). Cox proportional hazards models stratified by area showed that after adjusting for demographic information, high risk cohort categories, vaccination status, calendar time, body mass index, and other comorbidities, treatment with sotrovimab was associated with a substantially lower risk than treatment with molnupiravir (hazard ratio 0.54, 95% confidence interval 0.33 to 0.88, P=0.01). Consistent results were found from propensity score weighted Cox models (0.50, 0.31 to 0.81, P=0.005) and when restricted to people who were fully vaccinated (0.53, 0.31 to 0.90, P=0.02). No substantial effect modifications by other characteristics were detected (all P values for interaction >0.10). The findings were similar in an exploratory analysis of patients treated between 16 February and 1 May 2022 when omicron BA.2 was the predominant variant in England. Conclusions In routine care of adult patients in England with covid-19 in the community, at high risk of severe outcomes from covid-19, those who received sotrovimab were at lower risk of severe outcomes of covid-19 than those treated with molnupiravir. Introduction Neutralising monoclonal antibodies and antiviral medicines were approved by the UK Medicines and Healthcare products Regulatory Agency for use in patients with covid-19 not requiring admission to hospital to prevent progression of disease. On 16 December 2021, covid-19 medicine delivery units were launched across England to provide neutralising monoclonal antibodies and antivirals in community settings to treat patients with symptoms of covid-19 who were at high risk of severe outcomes. Among the first available treatment options were sotrovimab (an intravenous neutralising monoclonal antibody) and molnupiravir (an oral antiviral). 1 2 3 The approval and early clinical use of these drug treatments were mainly based on data from two phase 3 randomised controlled trials. 4 5 The findings of these trials could be limited, however, by the relatively small sample size, lack of population generalisability, given the strict inclusion and exclusion criteria, and the predominant circulating variants when the trials were conducted. In particular, little evidence is available on their effectiveness in patients with covid-19 who had received covid-19 vaccinations, in patients infected with omicron variants of the virus, or in those with severe renal or liver impairment. Uncertainty exists about the efficacy of molnupiravir in patients previously infected with SARS-CoV-2, in those with diabetes, and in non-white ethnic groups, 5 and the appropriateness of early regulatory authorisation for this drug has been debated given the modest effect magnitude found in the randomised controlled trial. 6 Also, both lower compliance with courses of oral drug treatment and longer time to administration of treatments after the onset of symptoms in routine care compared with clinical trials might affect potential benefit. Therefore, validating the effectiveness of sotrovimab and molnupiravir in preventing adverse outcomes in real world settings with varied populations is crucial in supporting their widescale clinical use in patients with covid-19. In the first two months after the launch of covid-19 medicine delivery units, sotrovimab and molnupiravir were the most frequently prescribed drug treatments, 2 with anecdotal reports that choice of drug was in part determined by the availability of facilities to deliver intravenous infusions and relative clinical equipoise for the choice of drug. 3 This situation provided the opportunity for observational comparison of the effectiveness of the two drug treatments, possibly with limited bias according to patient characteristics. A comparative effectiveness study would also provide real world evidence for the clinical practice guideline on the prioritised treatment. 7 Therefore, we sought to compare the effectiveness of sotrovimab versus molnupiravir in preventing severe outcomes from SARS-CoV-2 infection in adult patients in England with covid-19, who were at high risk of severe outcomes from infection but who did not require admission to hospital, during the first two months of the national rollout of covid-19 medicine delivery units, by using near real time electronic health record data in the OpenSAFELY-TPP platform. The OpenSAFELY-TPP platform is a secure, transparent, open source software platform for analysis of NHS electronic health records. We also explored the potential modifying effects of different demographic and clinical factors on the effectiveness of the drugs. We then conducted an exploratory analysis of patients treated in the next three months when omicron BA.2 had replaced BA.1 as the predominant variant of the SARS-CoV-2 virus in England. 8 Methods Study design and population In this<|im_end|> <|im_start|>assistant Two studies published by The BMJ today provide up to date evidence on the effectiveness of both currently licensed and possible COVID-19 treatments under everyday ("real world") conditions, helping to shed more light on whether these drugs can prevent people from becoming seriously ill. The first is an observational study carried out in England between December 2021 and February 2022. Researchers used hospital records and death certificates for high-risk adults with COVID-19 (average age 52) to compare the effectiveness of the antibody treatment sotrovimab with the antiviral drug molnupiravir. The researchers found that those who received sotrovimab were at a substantially lower (46%) risk of severe COVID-19 outcomes than those receiving molnupiravir, within 28 days of treatment. Results were consistent when restricted to fully vaccinated people and also after further analysis of patients treated between February and May 2022 when the BA.2 omicron variant of COVID-19 was dominant in England, suggesting that they are relevant to current clinical care. There is currently ongoing discussion about the effectiveness of different antibody and antiviral treatments for COVID-19 with recent World Health Organization guidance recommending against use of sotrovimab. However, both drugs are currently available for use in England. The researchers say that their "real-world findings within a time period when both drugs were frequently prescribed and when new variants of COVID-19 were circulating provide evidence of current effectiveness of sotrovimab over molnupiravir." Their analysis also "supports the conclusion that sotrovimab remains beneficial in fully vaccinated patients, which now represent the majority of the COVID-19 patient population in many settings," they add. The second is a randomized controlled trial involving 787 patients (778 from India and nine from Australia) with an average age of 49 years, admitted to hospital from May 2020 to November 2021. Included patients had predominantly mild disease, although the researchers aimed to recruit patients at risk of severe COVID. Half received angiotensin receptor blockers or ARBs (drugs widely used to treat high blood pressure and heart disease) and the other half (controls) received a placebo for 28 days. A standard dose of the ARB drug telmisartan (starting dose 40 mg/d) was used only in India while the type and dose of ARB was at the discretion of the treating physicians in Australia. These particular drugs were chosen because they work by regulating the same angiotensin protein as coronavirus uses to enter the body, and in the laboratory have shown potential protectivity against severe effects of coronaviruses. However, after 14 days of treatment, the researchers found no meaningful difference in illness severity between the two groups. These findings should help to inform clinical practice. The lack of effect provides reassurance that it is safe to use these protective agents in people indicated, with or without COVID-19. Both studies have some important limitations. For instance, in the observational study, some misclassification about cause of death or hospital admission may have occurred, and the researchers can't rule out the possibility that differences in initial severity of COVID-19 or other unmeasured factors between treatment groups may have influenced their results. And in the randomized controlled trial, the researchers were unable to source placebo in Australia, meaning participants and treating clinicians knew they were taking an active drug. Participants were also treated with a relatively low drug dose, so the effect of higher doses remains unknown. Nevertheless, key strengths included the scale, level of detail and completeness of the underlying data in the observational study, and good adherence to study treatment and an adaptive design that allowed the study question to be answered most quickly in the randomized trial. <|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 Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells for the induction of immune tolerance 1 , 2 . Tumour cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), facilitating their escape from the immune system 3 , 4 . Monoclonal antibodies that block the interaction between PD-1 and PD-L1, by binding to either the ligand or receptor, have shown notable clinical efficacy in patients with a variety of cancers, including melanoma, colorectal cancer, non-small-cell lung cancer and Hodgkin’s lymphoma 5 , 6 , 7 , 8 , 9 . Although it is well established that PD-1–PD-L1 blockade activates T cells, little is known about the role that this pathway may have in tumour-associated macrophages (TAMs). Here we show that both mouse and human TAMs express PD-1. TAM PD-1 expression increases over time in mouse models of cancer and with increasing disease stage in primary human cancers. TAM PD-1 expression correlates negatively with phagocytic potency against tumour cells, and blockade of PD-1–PD-L1 in vivo increases macrophage phagocytosis, reduces tumour growth and lengthens the survival of mice in mouse models of cancer in a macrophage-dependent fashion. This suggests that PD-1–PD-L1 therapies may also function through a direct effect on macrophages, with substantial implications for the treatment of cancer with these agents. Main The presence of TAMs correlates with poor prognosis in human cancers 10 . However, recent work has demonstrated that macrophages can be induced to phagocytose tumour cells through the blockade of the interaction between SIRPα and CD47 (ref. 11 ) and this therapeutic strategy is currently the subject of multiple clinical trials in cancer 12 , 13 . Although SIRPα–CD47 may serve as a primary regulatory ‘checkpoint’ on macrophages, other immune-regulatory receptors could serve a complementary or redundant role. The PD-1 receptor is one of the best-studied and most clinically successful immune-checkpoint drug targets, but its primary function is widely understood to be the regulation of T cells. However, given that macrophages have previously been reported to express PD-1 in the context of pathogen infection 14 , 15 , 16 , 17 , we wondered whether macrophages might also express PD-1 in the tumour microenvironment, and if so, what consequences PD-1 expression might have on anti-tumour immunity. To assess the expression of PD-1 on TAMs in an immunocompetent syngeneic setting, we used the colon cancer mouse cell line CT26. Fluorescence-activated cell sorting (FACS) of dissociated tumours three weeks after engraftment into mice showed that a high percentage of macrophages in the tumour expressed surface PD-1 (around 50%), whereas no circulating monocytes or splenic macrophages expressed detectable levels of PD-1 ( Fig. 1a and Extended Data Fig. 1 (gating strategy)). Immunofluorescence microscopy revealed a clear and abundant population of cells that expressed both the macrophage marker CD68 and PD-1 ( Fig. 1b and Extended Data Fig. 2a (no primary control)), further confirming the expression of PD-1 on TAMs. Figure 1: Mouse and human TAMs express high levels of PD-1. a , Representative flow cytometry plots (top) and analysis (bottom) of CT26 tumours 3 weeks after engraftment showing tissue-specific expression of PD-1 by TAMs. n = 5 mice, three experimental repeats. Paired one-way ANOVA with multiple-comparisons correction. b , Immunofluorescence images of FACS-sorted CT26 TAMs showing PD-1 and CD68 double-positive cells. n = 2, two experimental repeats. Representative images are shown; 20× magnification; scale bar, 20 μm. Red, PD-1; green, CD68; blue, Hoechst. c , Mouse PD-1 + TAMs from CT26 tumours are predominantly M2 (CD206 + MHC II low or negative ) rather than M1 (CD206 − MHC II high ) macrophages. n = 5, experiment conducted once. Paired one-tailed t -test. d , Left, representative flow cytometry plots of the TAM population in CT26 tumours over time. Right, analysis comparing time after engraftment (day) and the percentage of PD-1 + TAMs, showing a correlation between time and PD-1 expression. n = 20, two experimental repeats. An exponential growth equation is shown. e , Human TAMs from patient colorectal cancer samples express PD-1, and PD-1 + TAMs are predominantly M2 (CD206 + CD64 − ) and not M1 (CD206 − CD64 + ) macrophages. n = 10, two experimental repeats. Paired one-tailed t -test. f , Patient disease stage compared to the percentage of PD-1 + M1 TAMs. n = 10. An exponential growth equation is shown. g , Patient disease stage compared to the percentage of PD-1 + M2 TAMs. n = 10. An exponential growth equation is shown. Data are mean ± s.e.m.; * P < 0.05; ** P < 0.01; **** P < 0.0001; NS, not significant. PowerPoint slide Source data Full size image TAMs are often thought to polarize towards an inflammatory ‘M1’ or pro-tumour ‘M2’ state, depending on their environmental stimuli 18 . Flow cytometry analysis showed that almost all PD-1 + TAMs expressed an M2-like surface profile ( Fig. 1c ), whereas PD-1 − TAMs showed a trend towards the expression of an M1-like profile ( Extended Data Fig. 2b ). Further analysis of mouse CT26 tumours in syngeneic hosts revealed that this PD-1 + TAM population is not static; it begins to emerge circa 2 weeks after engraftment, and increases over time ( Fig. 1d , left). We found that PD-1 expression correlated strongly with time after engraftment ( Fig. 1d , right), as well as with tumour volume ( Extended Data Fig. 2d ). Given these observations in mice, we wondered whether human macrophages similarly express PD-1 in the primary tumour setting. Upon profiling the TAMs in human colorectal cancer samples, we found high but variable PD-1 expression on human TAMs. Notably, we also found that, similar to what was observed in mice, the M2 population expressed significantly more PD-1 than the M1 population ( Fig. 1e ), and the PD-1 − population had a predominantly M1 phenotype ( Extended Data Fig. 2c ). Furthermore, the frequency of PD-1 + TAMs increased with disease stage, but only within", "role": "user" }, { "content": "Antibodies to the proteins PD-1 and PD-L1 have been shown to fight cancer by unleashing the body's T cells, a type of immune cell. Now, researchers at the Stanford University School of Medicine have shown that the therapy also fights cancer in a completely different way, by prompting immune cells called macrophages to engulf and devour cancer cells. The finding may have important implications for improving and expanding the use of this cancer treatment, the researchers said. A study describing the work, which was done in mice, was published online May 17 in Nature. The senior author is Irving Weissman, MD, professor of pathology and of developmental biology. The lead author is graduate student Sydney Gordon. PD-1 is a cell receptor that plays an important role in protecting the body from an overactive immune system. T cells, which are immune cells that learn to detect and destroy damaged or diseased cells, can at times mistakenly attack healthy cells, producing autoimmune disorders like lupus or multiple sclerosis. PD-1 is what's called an \"immune checkpoint,\" a protein receptor that tamps down highly active T cells so that they are less likely to attack healthy tissue. How cancer hijacks PD-1 About 10 years ago, researchers discovered that cancer cells learn to use this immune safeguard for their own purposes. Tumor cells crank up the production of PD-L1 proteins, which are detected by the PD-1 receptor, inhibiting T cells from attacking the tumors. In effect, the proteins are a \"don't kill me\" signal to the immune system, the Stanford researchers said. Cancer patients are now being treated with antibodies that block the PD-1 receptor or latch onto its binding partner, PD-L1, to turn off this \"don't kill me\" signal and enable the T cells' attack. \"Using antibodies to PD-1 or PD-L1 is one of the major advances in cancer immunotherapy,\" said Weissman, who is also the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine and director of the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford. \"While most investigators accept the idea that anti-PD-1 and PD-L1 antibodies work by taking the brakes off of the T-cell attack on cancer cells, we have shown that there is a second mechanism that is also involved.\" What Weissman and his colleagues discovered is that PD-1 activation also inhibits the anti-cancer activity of other immune cells called macrophages. \"Macrophages that infiltrate tumors are induced to create the PD-1 receptor on their surface, and when PD-1 or PD-L1 is blocked with antibodies, it prompts those macrophage cells to attack the cancer,\" Gordon said. Similar to anti-CD47 antibody This mechanism is similar to that of another antibody studied in the Weissman lab: the antibody that blocks the protein CD47. Weissman and his colleagues showed that using anti-CD47 antibodies prompted macrophages to destroy cancer cells. The approach is now the subject of a small clinical trial in human patients. As it stands, it's unclear to what degree macrophages are responsible for the therapeutic success of the anti-PD-1 and anti-PD-L1 antibodies. The practical implications of the discovery could be important, the researchers said. \"This could lead to novel therapies that are aimed at promoting either the T-cell component of the attack on cancer or promoting the macrophage component,\" Gordon said. Another implication is that antibodies to PD-1 or PD-L1 may be more potent and broadly effective than previously thought. \"In order for T cells to attack cancer when you take the brakes off with antibodies, you need to start with a population of T cells that have learned to recognize specific cancer cells in the first place,\" Weissman said. \"Macrophage cells are part of the innate immune system, which means they should be able to recognize every kind of cancer in every patient.\" ", "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 Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells for the induction of immune tolerance 1 , 2 . Tumour cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), facilitating their escape from the immune system 3 , 4 . Monoclonal antibodies that block the interaction between PD-1 and PD-L1, by binding to either the ligand or receptor, have shown notable clinical efficacy in patients with a variety of cancers, including melanoma, colorectal cancer, non-small-cell lung cancer and Hodgkin’s lymphoma 5 , 6 , 7 , 8 , 9 . Although it is well established that PD-1–PD-L1 blockade activates T cells, little is known about the role that this pathway may have in tumour-associated macrophages (TAMs). Here we show that both mouse and human TAMs express PD-1. TAM PD-1 expression increases over time in mouse models of cancer and with increasing disease stage in primary human cancers. TAM PD-1 expression correlates negatively with phagocytic potency against tumour cells, and blockade of PD-1–PD-L1 in vivo increases macrophage phagocytosis, reduces tumour growth and lengthens the survival of mice in mouse models of cancer in a macrophage-dependent fashion. This suggests that PD-1–PD-L1 therapies may also function through a direct effect on macrophages, with substantial implications for the treatment of cancer with these agents. Main The presence of TAMs correlates with poor prognosis in human cancers 10 . However, recent work has demonstrated that macrophages can be induced to phagocytose tumour cells through the blockade of the interaction between SIRPα and CD47 (ref. 11 ) and this therapeutic strategy is currently the subject of multiple clinical trials in cancer 12 , 13 . Although SIRPα–CD47 may serve as a primary regulatory ‘checkpoint’ on macrophages, other immune-regulatory receptors could serve a complementary or redundant role. The PD-1 receptor is one of the best-studied and most clinically successful immune-checkpoint drug targets, but its primary function is widely understood to be the regulation of T cells. However, given that macrophages have previously been reported to express PD-1 in the context of pathogen infection 14 , 15 , 16 , 17 , we wondered whether macrophages might also express PD-1 in the tumour microenvironment, and if so, what consequences PD-1 expression might have on anti-tumour immunity. To assess the expression of PD-1 on TAMs in an immunocompetent syngeneic setting, we used the colon cancer mouse cell line CT26. Fluorescence-activated cell sorting (FACS) of dissociated tumours three weeks after engraftment into mice showed that a high percentage of macrophages in the tumour expressed surface PD-1 (around 50%), whereas no circulating monocytes or splenic macrophages expressed detectable levels of PD-1 ( Fig. 1a and Extended Data Fig. 1 (gating strategy)). Immunofluorescence microscopy revealed a clear and abundant population of cells that expressed both the macrophage marker CD68 and PD-1 ( Fig. 1b and Extended Data Fig. 2a (no primary control)), further confirming the expression of PD-1 on TAMs. Figure 1: Mouse and human TAMs express high levels of PD-1. a , Representative flow cytometry plots (top) and analysis (bottom) of CT26 tumours 3 weeks after engraftment showing tissue-specific expression of PD-1 by TAMs. n = 5 mice, three experimental repeats. Paired one-way ANOVA with multiple-comparisons correction. b , Immunofluorescence images of FACS-sorted CT26 TAMs showing PD-1 and CD68 double-positive cells. n = 2, two experimental repeats. Representative images are shown; 20× magnification; scale bar, 20 μm. Red, PD-1; green, CD68; blue, Hoechst. c , Mouse PD-1 + TAMs from CT26 tumours are predominantly M2 (CD206 + MHC II low or negative ) rather than M1 (CD206 − MHC II high ) macrophages. n = 5, experiment conducted once. Paired one-tailed t -test. d , Left, representative flow cytometry plots of the TAM population in CT26 tumours over time. Right, analysis comparing time after engraftment (day) and the percentage of PD-1 + TAMs, showing a correlation between time and PD-1 expression. n = 20, two experimental repeats. An exponential growth equation is shown. e , Human TAMs from patient colorectal cancer samples express PD-1, and PD-1 + TAMs are predominantly M2 (CD206 + CD64 − ) and not M1 (CD206 − CD64 + ) macrophages. n = 10, two experimental repeats. Paired one-tailed t -test. f , Patient disease stage compared to the percentage of PD-1 + M1 TAMs. n = 10. An exponential growth equation is shown. g , Patient disease stage compared to the percentage of PD-1 + M2 TAMs. n = 10. An exponential growth equation is shown. Data are mean ± s.e.m.; * P < 0.05; ** P < 0.01; **** P < 0.0001; NS, not significant. PowerPoint slide Source data Full size image TAMs are often thought to polarize towards an inflammatory ‘M1’ or pro-tumour ‘M2’ state, depending on their environmental stimuli 18 . Flow cytometry analysis showed that almost all PD-1 + TAMs expressed an M2-like surface profile ( Fig. 1c ), whereas PD-1 − TAMs showed a trend towards the expression of an M1-like profile ( Extended Data Fig. 2b ). Further analysis of mouse CT26 tumours in syngeneic hosts revealed that this PD-1 + TAM population is not static; it begins to emerge circa 2 weeks after engraftment, and increases over time ( Fig. 1d , left). We found that PD-1 expression correlated strongly with time after engraftment ( Fig. 1d , right), as well as with tumour volume ( Extended Data Fig. 2d ). Given these observations in mice, we wondered whether human macrophages similarly express PD-1 in the primary tumour setting. Upon profiling the TAMs in human colorectal cancer samples, we found high but variable PD-1 expression on human TAMs. Notably, we also found that, similar to what was observed in mice, the M2 population expressed significantly more PD-1 than the M1 population ( Fig. 1e ), and the PD-1 − population had a predominantly M1 phenotype ( Extended Data Fig. 2c ). Furthermore, the frequency of PD-1 + TAMs increased with disease stage, but only within<|im_end|> <|im_start|>assistant Antibodies to the proteins PD-1 and PD-L1 have been shown to fight cancer by unleashing the body's T cells, a type of immune cell. Now, researchers at the Stanford University School of Medicine have shown that the therapy also fights cancer in a completely different way, by prompting immune cells called macrophages to engulf and devour cancer cells. The finding may have important implications for improving and expanding the use of this cancer treatment, the researchers said. A study describing the work, which was done in mice, was published online May 17 in Nature. The senior author is Irving Weissman, MD, professor of pathology and of developmental biology. The lead author is graduate student Sydney Gordon. PD-1 is a cell receptor that plays an important role in protecting the body from an overactive immune system. T cells, which are immune cells that learn to detect and destroy damaged or diseased cells, can at times mistakenly attack healthy cells, producing autoimmune disorders like lupus or multiple sclerosis. PD-1 is what's called an "immune checkpoint," a protein receptor that tamps down highly active T cells so that they are less likely to attack healthy tissue. How cancer hijacks PD-1 About 10 years ago, researchers discovered that cancer cells learn to use this immune safeguard for their own purposes. Tumor cells crank up the production of PD-L1 proteins, which are detected by the PD-1 receptor, inhibiting T cells from attacking the tumors. In effect, the proteins are a "don't kill me" signal to the immune system, the Stanford researchers said. Cancer patients are now being treated with antibodies that block the PD-1 receptor or latch onto its binding partner, PD-L1, to turn off this "don't kill me" signal and enable the T cells' attack. "Using antibodies to PD-1 or PD-L1 is one of the major advances in cancer immunotherapy," said Weissman, who is also the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine and director of the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford. "While most investigators accept the idea that anti-PD-1 and PD-L1 antibodies work by taking the brakes off of the T-cell attack on cancer cells, we have shown that there is a second mechanism that is also involved." What Weissman and his colleagues discovered is that PD-1 activation also inhibits the anti-cancer activity of other immune cells called macrophages. "Macrophages that infiltrate tumors are induced to create the PD-1 receptor on their surface, and when PD-1 or PD-L1 is blocked with antibodies, it prompts those macrophage cells to attack the cancer," Gordon said. Similar to anti-CD47 antibody This mechanism is similar to that of another antibody studied in the Weissman lab: the antibody that blocks the protein CD47. Weissman and his colleagues showed that using anti-CD47 antibodies prompted macrophages to destroy cancer cells. The approach is now the subject of a small clinical trial in human patients. As it stands, it's unclear to what degree macrophages are responsible for the therapeutic success of the anti-PD-1 and anti-PD-L1 antibodies. The practical implications of the discovery could be important, the researchers said. "This could lead to novel therapies that are aimed at promoting either the T-cell component of the attack on cancer or promoting the macrophage component," Gordon said. Another implication is that antibodies to PD-1 or PD-L1 may be more potent and broadly effective than previously thought. "In order for T cells to attack cancer when you take the brakes off with antibodies, you need to start with a population of T cells that have learned to recognize specific cancer cells in the first place," Weissman said. "Macrophage cells are part of the innate immune system, which means they should be able to recognize every kind of cancer in every patient." <|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 performance of modern chips is strongly related to the multi-layer interconnect structure that interfaces the semiconductor layer with the outside world. The resulting demand to continuously reduce the k-value of the dielectric in these interconnects creates multiple integration challenges and encourages the search for novel materials. Here we report a strategy for the integration of metal-organic frameworks (MOFs) as gap-filling low-k dielectrics in advanced on-chip interconnects. The method relies on the selective conversion of purpose-grown or native metal-oxide films on the metal interconnect lines into MOFs by exposure to organic linker vapor. The proposed strategy is validated for thin films of the zeolitic imidazolate frameworks ZIF-8 and ZIF-67, formed in 2-methylimidazole vapor from ALD ZnO and native CoO x , respectively. Both materials show a Young’s modulus and dielectric constant comparable to state-of-the-art porous organosilica dielectrics. Moreover, the fast nucleation and volume expansion accompanying the oxide-to-MOF conversion enable uniform growth and gap-filling of narrow trenches, as demonstrated for 45 nm half-pitch fork-fork capacitors. Introduction Since the invention of integrated circuits (ICs) 60 years ago, there has been a persistent incentive toward the miniaturization of IC components. An indispensable part of every contemporary IC is a multilevel wiring system fabricated on top of the semiconductor device layer. As transistors get smaller and more densely packed, the complexity and the impact on performance of the on-chip interconnects rises. Modern chips can incorporate several billion transistors and require multilayered interconnects that have wire dimensions below 30 nm in diameter near the silicon surface 1 , 2 . The nonzero resistance ( R ) and capacitance ( C ) associated with the metal wires and the insulating medium between them induce cross-talk noise, limit the speed of signal propagation, and contribute to the power consumption of a chip 3 . Both R and C tend to increase with further interconnect miniaturization, an effect particularly noticeable at wire diameters and spacings below 50 nm. To address this challenge, the materials used for on-chip interconnects have been significantly diversified in last two decades 4 . Two major changes concerned (i) the replacement of traditional dielectrics such as silicon oxide with “low-k” materials featuring a dielectric constant (or “ k -value”) <4.3 and (ii) the introduction of low-resistivity metals instead of aluminum. Currently, copper is the metal of choice due to its high conductivity and good resistance to electromigration, while state-of-the-art low-k dielectrics are typically porous organosilica glasses (OSGs) deposited from plasma or solution 5 , 6 , 7 , 8 . Due to difficulties associated with direct plasma etching of copper films 9 , copper interconnect wires are formed via a “damascene” process 10 . This metallization route relies on first patterning the dielectric layer via anisotropic plasma etching before Cu electroplating and planarization. Plasma-induced damage of new potential low-k materials, especially porous ones, during this patterning step is a major roadblock to achieve k -values < 2.4 11 , 12 . An alternative metallization approach is to first pattern a sacrificial layer that can be removed after the formation of metal interconnect wires, leaving the latter as a patterned top layer 13 . In such an integration scheme, the low-k dielectric is subsequently deposited and needs to fill the gaps between the metal wires. Driven by the steep increase in copper resistivity at wire dimensions below 50 nm 14 , this and other alternative metallization strategies relying on initial formation of metal pattern are quickly gaining attention 15 , 16 , 17 , 18 , together with a shift to beyond-Cu metals that perform better at these dimensions (e.g., Co and Ru) 19 , 20 , 21 , 22 . The common challenge shared between these alternative metallization approaches is gap filling the narrow trenches (width < 50 nm, height/width ratio >2) between metal interconnect lines with the low-k dielectric 23 , 24 . For the current state-of-the-art OSG dielectrics deposited by plasma-enhanced chemical vapor deposition or spin-on methods, this task is not straightforward because of local deposition nonuniformity and postdeposition material shrinkage upon porogen removal. While current ultra-low-k dielectrics thus seem unsuitable for novel, plasma-damage free integration, the alleviated plasma stability requirement allows to significantly widen the range of potential low-k dielectrics. One promising class of dielectric materials are metal-organic frameworks (MOFs) 25 , which possess many properties sought for in interconnects: (i) uniformly distributed pores with diameters < 2 nm that significantly reduce possible infiltration during subsequent processing 26 , 27 and makes the porous dielectric applicable in sub-10 nm intermetal spacings 28 , 29 ; (ii) a low dielectric constant; and (iii) a suitable mechanical stability 6 , 7 . The potential of MOFs as advanced low-k dielectrics was first recognized by Zagorodniy et al., who used a simple Clausius–Mossotti model to estimate the dielectric constants of various MOFs 30 . Eslava et al. provided the first experimental validation of the k -value of solution-deposited films of ZIF-8 ( k = 2.33) 31 , a well-studied thermally and chemically stable MOF consisting of Zn(II) nodes and 2-methylimidazolate linkers 32 . Since then, other MOFs have been studied as potential low-k dielectrics 33 , 34 , 35 , 36 . Despite these encouraging results, no integration of MOFs in interconnects has been shown to date, mainly because typical MOF thin film growth methods are solution based, and therefore hard to scale and mostly incompatible with microelectronics fabrication infrastructure 37 . Nevertheless, recent advances in vapor-phase deposition of MOF films 38 , 39 , 40 bridge this gap and make integration in on-chip interconnects possible. In this work, we adapted the method of chemical vapor-phase deposition of zeolitic imidazolate frameworks (ZIFs) proposed by Stassen et al. (MOF-CVD) 37 to achieve gap filling of narrow spacings between metal interconnect lines (90 nm pitch, 45 nm trench width, and 90 nm trench height). In MOF-CVD, a metal oxide precursor film is consumed through a vapor-solid reaction with the organic linker and converted to a porous MOF film. In the case of ZIF-8 MOF-CVD, a", "role": "user" }, { "content": "Researchers at KU Leuven and imec have successfully developed a new technique to insulate microchips. The technique uses metal-organic frameworks, a new type of materials consisting of structured nanopores. In the long term, this method can be used for the development of even smaller and more powerful chips that consume less energy. The team has received an ERC Proof of Concept grant to further their research. Computer chips are getting increasingly smaller. That's not new: Gordon Moore, one of the founders of chip manufacturer Intel, already predicted it in 1965. Moore's law states that the number of transistors in a chip, or integrated circuit, doubles about every two years. This prognosis was later adjusted to 18 months, but the theory still stands. Chips are getting smaller and their processing power is increasing. Nowadays, a chip can have over a billion transistors. But this continued reduction in size also brings with it a number of obstacles. The switches and wires are packed together so tightly that they generate more resistance. This, in turn, causes the chip to consume more energy to send signals. To have a well-functioning chip, you need an insulating substance that separates the wires from each other, and ensures that the electrical signals are not disrupted. However, that's not an easy thing to achieve at the nanoscale level. Nanoporous crystals A study led by KU Leuven professor Rob Ameloot (Department of Microbial and Molecular systems) shows that a new technique might provide the solution. \"We're using metal-organic frameworks (MOFs) as the insulating substance. These are materials that consist of metal ions and organic molecules. Together, they form a crystal that is porous yet sturdy.\" For the first time, a research team at KU Leuven and imec managed to apply the MOF insulation to electronic material. An industrial method called chemical vapor deposition was used for this, says postdoctoral researcher Mikhail Krishtab (Department of Microbial and Molecular systems). \"First, we place an oxide film on the surface. Then, we let it react with vapour of the organic material. This reaction causes the material to expand, forming the nanoporous crystals.\" \"The main advantage of this method is that it's bottom-up,\" says Krishtab. \"We first deposit an oxide film, which then swells up to a very porous MOF material. You can compare it to a soufflé that puffs up in the oven and becomes very light. The MOF material forms a porous structure that fills all the gaps between the conductors. That's how we know the insulation is complete and homogeneous. With other, top-down methods, there's always still the risk of small gaps in the insulation.\" Powerful and energy efficient Professor Ameloot's research group has received an ERC Proof of Concept grant to further develop the technique, in collaboration with Silvia Armini from imec's team working on advanced dielectric materials for nanochips. \"At imec, we have the expertise to develop wafer-based solutions, scaling technologies from lab to fab and paving the way to realizing a manufacturable solution for the microelectronics industry.\" \"We've shown that the MOF material has the right properties,\" Ameloot continues. \"Now, we just have to refine the finishing. The surface of the crystals is still irregular at the moment. We have to smoothen this to integrate the material in a chip.\" Once the technique has been perfected, it can be used to create powerful, small chips that consume less energy. Ameloot: \"Various AI applications require a lot of processing power. Think of self-driving cars and smart cities. Technology companies are constantly looking for new solutions that are both quick and energy efficient. Our research can be a valuable contribution to a new generation of chips.\" ", "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 performance of modern chips is strongly related to the multi-layer interconnect structure that interfaces the semiconductor layer with the outside world. The resulting demand to continuously reduce the k-value of the dielectric in these interconnects creates multiple integration challenges and encourages the search for novel materials. Here we report a strategy for the integration of metal-organic frameworks (MOFs) as gap-filling low-k dielectrics in advanced on-chip interconnects. The method relies on the selective conversion of purpose-grown or native metal-oxide films on the metal interconnect lines into MOFs by exposure to organic linker vapor. The proposed strategy is validated for thin films of the zeolitic imidazolate frameworks ZIF-8 and ZIF-67, formed in 2-methylimidazole vapor from ALD ZnO and native CoO x , respectively. Both materials show a Young’s modulus and dielectric constant comparable to state-of-the-art porous organosilica dielectrics. Moreover, the fast nucleation and volume expansion accompanying the oxide-to-MOF conversion enable uniform growth and gap-filling of narrow trenches, as demonstrated for 45 nm half-pitch fork-fork capacitors. Introduction Since the invention of integrated circuits (ICs) 60 years ago, there has been a persistent incentive toward the miniaturization of IC components. An indispensable part of every contemporary IC is a multilevel wiring system fabricated on top of the semiconductor device layer. As transistors get smaller and more densely packed, the complexity and the impact on performance of the on-chip interconnects rises. Modern chips can incorporate several billion transistors and require multilayered interconnects that have wire dimensions below 30 nm in diameter near the silicon surface 1 , 2 . The nonzero resistance ( R ) and capacitance ( C ) associated with the metal wires and the insulating medium between them induce cross-talk noise, limit the speed of signal propagation, and contribute to the power consumption of a chip 3 . Both R and C tend to increase with further interconnect miniaturization, an effect particularly noticeable at wire diameters and spacings below 50 nm. To address this challenge, the materials used for on-chip interconnects have been significantly diversified in last two decades 4 . Two major changes concerned (i) the replacement of traditional dielectrics such as silicon oxide with “low-k” materials featuring a dielectric constant (or “ k -value”) <4.3 and (ii) the introduction of low-resistivity metals instead of aluminum. Currently, copper is the metal of choice due to its high conductivity and good resistance to electromigration, while state-of-the-art low-k dielectrics are typically porous organosilica glasses (OSGs) deposited from plasma or solution 5 , 6 , 7 , 8 . Due to difficulties associated with direct plasma etching of copper films 9 , copper interconnect wires are formed via a “damascene” process 10 . This metallization route relies on first patterning the dielectric layer via anisotropic plasma etching before Cu electroplating and planarization. Plasma-induced damage of new potential low-k materials, especially porous ones, during this patterning step is a major roadblock to achieve k -values < 2.4 11 , 12 . An alternative metallization approach is to first pattern a sacrificial layer that can be removed after the formation of metal interconnect wires, leaving the latter as a patterned top layer 13 . In such an integration scheme, the low-k dielectric is subsequently deposited and needs to fill the gaps between the metal wires. Driven by the steep increase in copper resistivity at wire dimensions below 50 nm 14 , this and other alternative metallization strategies relying on initial formation of metal pattern are quickly gaining attention 15 , 16 , 17 , 18 , together with a shift to beyond-Cu metals that perform better at these dimensions (e.g., Co and Ru) 19 , 20 , 21 , 22 . The common challenge shared between these alternative metallization approaches is gap filling the narrow trenches (width < 50 nm, height/width ratio >2) between metal interconnect lines with the low-k dielectric 23 , 24 . For the current state-of-the-art OSG dielectrics deposited by plasma-enhanced chemical vapor deposition or spin-on methods, this task is not straightforward because of local deposition nonuniformity and postdeposition material shrinkage upon porogen removal. While current ultra-low-k dielectrics thus seem unsuitable for novel, plasma-damage free integration, the alleviated plasma stability requirement allows to significantly widen the range of potential low-k dielectrics. One promising class of dielectric materials are metal-organic frameworks (MOFs) 25 , which possess many properties sought for in interconnects: (i) uniformly distributed pores with diameters < 2 nm that significantly reduce possible infiltration during subsequent processing 26 , 27 and makes the porous dielectric applicable in sub-10 nm intermetal spacings 28 , 29 ; (ii) a low dielectric constant; and (iii) a suitable mechanical stability 6 , 7 . The potential of MOFs as advanced low-k dielectrics was first recognized by Zagorodniy et al., who used a simple Clausius–Mossotti model to estimate the dielectric constants of various MOFs 30 . Eslava et al. provided the first experimental validation of the k -value of solution-deposited films of ZIF-8 ( k = 2.33) 31 , a well-studied thermally and chemically stable MOF consisting of Zn(II) nodes and 2-methylimidazolate linkers 32 . Since then, other MOFs have been studied as potential low-k dielectrics 33 , 34 , 35 , 36 . Despite these encouraging results, no integration of MOFs in interconnects has been shown to date, mainly because typical MOF thin film growth methods are solution based, and therefore hard to scale and mostly incompatible with microelectronics fabrication infrastructure 37 . Nevertheless, recent advances in vapor-phase deposition of MOF films 38 , 39 , 40 bridge this gap and make integration in on-chip interconnects possible. In this work, we adapted the method of chemical vapor-phase deposition of zeolitic imidazolate frameworks (ZIFs) proposed by Stassen et al. (MOF-CVD) 37 to achieve gap filling of narrow spacings between metal interconnect lines (90 nm pitch, 45 nm trench width, and 90 nm trench height). In MOF-CVD, a metal oxide precursor film is consumed through a vapor-solid reaction with the organic linker and converted to a porous MOF film. In the case of ZIF-8 MOF-CVD, a<|im_end|> <|im_start|>assistant Researchers at KU Leuven and imec have successfully developed a new technique to insulate microchips. The technique uses metal-organic frameworks, a new type of materials consisting of structured nanopores. In the long term, this method can be used for the development of even smaller and more powerful chips that consume less energy. The team has received an ERC Proof of Concept grant to further their research. Computer chips are getting increasingly smaller. That's not new: Gordon Moore, one of the founders of chip manufacturer Intel, already predicted it in 1965. Moore's law states that the number of transistors in a chip, or integrated circuit, doubles about every two years. This prognosis was later adjusted to 18 months, but the theory still stands. Chips are getting smaller and their processing power is increasing. Nowadays, a chip can have over a billion transistors. But this continued reduction in size also brings with it a number of obstacles. The switches and wires are packed together so tightly that they generate more resistance. This, in turn, causes the chip to consume more energy to send signals. To have a well-functioning chip, you need an insulating substance that separates the wires from each other, and ensures that the electrical signals are not disrupted. However, that's not an easy thing to achieve at the nanoscale level. Nanoporous crystals A study led by KU Leuven professor Rob Ameloot (Department of Microbial and Molecular systems) shows that a new technique might provide the solution. "We're using metal-organic frameworks (MOFs) as the insulating substance. These are materials that consist of metal ions and organic molecules. Together, they form a crystal that is porous yet sturdy." For the first time, a research team at KU Leuven and imec managed to apply the MOF insulation to electronic material. An industrial method called chemical vapor deposition was used for this, says postdoctoral researcher Mikhail Krishtab (Department of Microbial and Molecular systems). "First, we place an oxide film on the surface. Then, we let it react with vapour of the organic material. This reaction causes the material to expand, forming the nanoporous crystals." "The main advantage of this method is that it's bottom-up," says Krishtab. "We first deposit an oxide film, which then swells up to a very porous MOF material. You can compare it to a soufflé that puffs up in the oven and becomes very light. The MOF material forms a porous structure that fills all the gaps between the conductors. That's how we know the insulation is complete and homogeneous. With other, top-down methods, there's always still the risk of small gaps in the insulation." Powerful and energy efficient Professor Ameloot's research group has received an ERC Proof of Concept grant to further develop the technique, in collaboration with Silvia Armini from imec's team working on advanced dielectric materials for nanochips. "At imec, we have the expertise to develop wafer-based solutions, scaling technologies from lab to fab and paving the way to realizing a manufacturable solution for the microelectronics industry." "We've shown that the MOF material has the right properties," Ameloot continues. "Now, we just have to refine the finishing. The surface of the crystals is still irregular at the moment. We have to smoothen this to integrate the material in a chip." Once the technique has been perfected, it can be used to create powerful, small chips that consume less energy. Ameloot: "Various AI applications require a lot of processing power. Think of self-driving cars and smart cities. Technology companies are constantly looking for new solutions that are both quick and energy efficient. Our research can be a valuable contribution to a new generation of chips." <|im_end|>

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2,241

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Coral reefs harbor diverse assemblages of organisms yet the majority of this diversity is hidden within the three dimensional structure of the reef and neglected using standard visual surveys. This study uses Autonomous Reef Monitoring Structures (ARMS) and amplicon sequencing methodologies, targeting mitochondrial cytochrome oxidase I and 18S rRNA genes, to investigate changes in the cryptic reef biodiversity. ARMS, deployed at 11 sites across a near- to off-shore gradient in the Red Sea were dominated by Porifera (sessile fraction), Arthropoda and Annelida (mobile fractions). The two primer sets detected different taxa lists, but patterns in community composition and structure were similar. While the microhabitat of the ARMS deployment affected the community structure, a clear cross-shelf gradient was observed for all fractions investigated. The partitioning of beta-diversity revealed that replacement (i.e. the substitution of species) made the highest contribution with richness playing a smaller role. Hence, different reef habitats across the shelf are relevant to regional diversity, as they harbor different communities, a result with clear implications for the design of Marine Protected Areas. ARMS can be vital tools to assess biodiversity patterns in the generally neglected but species-rich cryptic benthos, providing invaluable information for the management and conservation of hard-bottomed habitats over local and global scales. Introduction Understanding how diversity is partitioned along natural and anthropogenic gradients within ecosystems is a central topic in ecology and a key goal for conservation 1 , 2 . Cross-shelf habitats present some of the sharpest gradients in physical and chemical conditions (e.g. salinity, temperature and nutrients) in marine systems 3 , 4 , 5 . Near-shore areas are under the influence of terrestrial systems while outer regions are more exposed to oceanic currents and wave action 3 , 4 , 5 , 6 . These environmental differences, in turn, affect the distribution of marine organisms as a function of taxon-specific physiological requirements and life history traits 7 . For example, Ellis and co-authors 8 indicated that nutrient availability across the shelf gradient in the southern Red Sea was associated with patterns of macro-algal cover (higher in nutrient enriched near-shore sites) and scleractinian coral diversity (higher at off-shore sites with lower levels of nutrients). Further in the central Red Sea distinct gradients across the shelf have been detected in physio-chemical parameters (e.g. chlorophyll and sedimentation) 9 as well as differences in the coral community with Acriporoa and Pocillopora being comparatively rare in near-shore reefs 10 . On coral reefs, various studies have reported cross-shelf differences in population size, biomass, recruitment rates and species composition among fish 11 , 12 , 13 , corals 10 , 14 , sponges 15 , 16 , molluscs 17 , crustaceans 18 and siphonophores 19 . However, studies assessing multiple taxonomic groups have received less attention and have predominantly focused on more conspicuous taxa 5 , 7 , 8 , 20 , 21 , 22 , 23 , 24 . As a result, there is still a poor understanding of community-wide changes both in terms of the composition and structure across inshore-offshore gradients, especially in highly diverse tropical ecosystems such as coral reefs. This is particularly true for the small and highly diverse cryptic invertebrates that exist within the reef matrix 7 , 25 , 26 , 27 , 28 , 29 . This neglect is due to the fact that many of these species are either undescribed or very difficult to identify. Despite being overlooked in most of the coral reef research, benthic cryptic fauna include a variety of sessile and mobile taxa 30 , 31 , 32 , 33 , 34 , 35 inhabiting hidden spaces that can account for up to two thirds of the reef’s volume 36 . Little is understood about the life histories and habitat preferences of these organisms beyond size-related generalizations 37 . Some studies have investigated the community composition patterns at very small spatial scales and found that crevices within reefs are often dominated by coralline algae near sunlit entrances and by filter feeders in posterior sections 38 , 39 . Species inhabiting these cryptic spaces, especially Porifera, act as a sink for dissolved organic matter, thus preventing energy and nutrient losses into the open ocean 40 . Therefore, a better understanding of the distributional patterns of the crypto-benthic fauna may reveal insights into biogeochemical cycles within the reef system. In recent decades, standardized sampling units have been proposed as a means to quantify the diversity and composition of benthic assemblages in a consistent manner across space and time. In this study, we use Autonomous Reef Monitoring Structures (ARMS) which are designed to partially mimic the 3D structure of a reef 41 , 42 . The structures enable the study of both the sessile components growing on the plates as well as the mobile organisms that settle on or move into the spaces. The communities collected in ARMS are typically analyzed using some form of genetic barcoding (of individual organisms) (e.g.) 43 or high-throughput amplicon sequencing (i.e. metabarcoding of communities) (e.g.) 42 . Studies utilizing ARMS have revealed much about the hidden diversity of the Indo-Pacific and Caribbean 43 , as well as using high throughput amplicon sequencing (i.e. metabarcoding) to assess the sessile and mobile fractions on the US Atlantic coast 42 and the Red Sea 44 , 45 . Cryptic organisms include a diverse selection of ecologically important groups such as suspension feeders 46 , 47 , predators 48 , herbivores 49 and detritivores 50 . Because of their smaller sizes, they also have larger population sizes and faster generation times 51 . Their response to environmental changes may therefore differ from those of the better-studied fish and corals. The cryptic fauna represents a large proportion of the reef diversity, and thus to best conserve biodiversity of the reefs across spatial scales, an understanding of how the cryptic fauna responds to environmental changes is vital 33 . To achieve this, an assessment of not only the local species assemblages (alpha diversity) but also the inter-site differences (beta diversity)", "role": "user" }, { "content": "Cryptic fauna—small organisms that inhabit the hidden spaces within a reef structure—represent a substantial proportion of the diversity within coral reefs but are typically neglected in traditional visual surveys, which tend to focus on large and conspicuous species, such as fish and corals. An international collaboration comprised of marine scientists from KAUST, the United States and Taiwan investigated the diversity patterns of the cryptic fauna in eight reefs in the central region of the Red Sea. The distribution patterns of these small creatures was unraveled using autonomous reef monitoring structures (ARMS), which consist of stacks of plates creating an artificial three-dimensional habitat for colonization, in conjunction with amplicon sequencing methodologies. \"Cryptic fauna have previously been revealed to show different responses to those organisms normally assessed in reef monitoring,\" says lead author, John Pearman, from KAUST. \"Therefore to effectively manage the biodiversity of coral reefs it is important to understand how cryptic fauna vary across spatial scales and how these organisms may respond to environmental changes.\" Depending on distance from the coast, organisms experience changes in conditions, such as salinity, temperature, nutrients and sedimentation: all of which can have impacts on the distribution of those organisms and therefore in the composition of the ecological communities. \"Our study shows that different reef habitats across the shelf are inhabited by different sets of species and are therefore relevant to the regional diversity. These results have clear implications for the design of marine protected areas,\" explains Pearman. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Coral reefs harbor diverse assemblages of organisms yet the majority of this diversity is hidden within the three dimensional structure of the reef and neglected using standard visual surveys. This study uses Autonomous Reef Monitoring Structures (ARMS) and amplicon sequencing methodologies, targeting mitochondrial cytochrome oxidase I and 18S rRNA genes, to investigate changes in the cryptic reef biodiversity. ARMS, deployed at 11 sites across a near- to off-shore gradient in the Red Sea were dominated by Porifera (sessile fraction), Arthropoda and Annelida (mobile fractions). The two primer sets detected different taxa lists, but patterns in community composition and structure were similar. While the microhabitat of the ARMS deployment affected the community structure, a clear cross-shelf gradient was observed for all fractions investigated. The partitioning of beta-diversity revealed that replacement (i.e. the substitution of species) made the highest contribution with richness playing a smaller role. Hence, different reef habitats across the shelf are relevant to regional diversity, as they harbor different communities, a result with clear implications for the design of Marine Protected Areas. ARMS can be vital tools to assess biodiversity patterns in the generally neglected but species-rich cryptic benthos, providing invaluable information for the management and conservation of hard-bottomed habitats over local and global scales. Introduction Understanding how diversity is partitioned along natural and anthropogenic gradients within ecosystems is a central topic in ecology and a key goal for conservation 1 , 2 . Cross-shelf habitats present some of the sharpest gradients in physical and chemical conditions (e.g. salinity, temperature and nutrients) in marine systems 3 , 4 , 5 . Near-shore areas are under the influence of terrestrial systems while outer regions are more exposed to oceanic currents and wave action 3 , 4 , 5 , 6 . These environmental differences, in turn, affect the distribution of marine organisms as a function of taxon-specific physiological requirements and life history traits 7 . For example, Ellis and co-authors 8 indicated that nutrient availability across the shelf gradient in the southern Red Sea was associated with patterns of macro-algal cover (higher in nutrient enriched near-shore sites) and scleractinian coral diversity (higher at off-shore sites with lower levels of nutrients). Further in the central Red Sea distinct gradients across the shelf have been detected in physio-chemical parameters (e.g. chlorophyll and sedimentation) 9 as well as differences in the coral community with Acriporoa and Pocillopora being comparatively rare in near-shore reefs 10 . On coral reefs, various studies have reported cross-shelf differences in population size, biomass, recruitment rates and species composition among fish 11 , 12 , 13 , corals 10 , 14 , sponges 15 , 16 , molluscs 17 , crustaceans 18 and siphonophores 19 . However, studies assessing multiple taxonomic groups have received less attention and have predominantly focused on more conspicuous taxa 5 , 7 , 8 , 20 , 21 , 22 , 23 , 24 . As a result, there is still a poor understanding of community-wide changes both in terms of the composition and structure across inshore-offshore gradients, especially in highly diverse tropical ecosystems such as coral reefs. This is particularly true for the small and highly diverse cryptic invertebrates that exist within the reef matrix 7 , 25 , 26 , 27 , 28 , 29 . This neglect is due to the fact that many of these species are either undescribed or very difficult to identify. Despite being overlooked in most of the coral reef research, benthic cryptic fauna include a variety of sessile and mobile taxa 30 , 31 , 32 , 33 , 34 , 35 inhabiting hidden spaces that can account for up to two thirds of the reef’s volume 36 . Little is understood about the life histories and habitat preferences of these organisms beyond size-related generalizations 37 . Some studies have investigated the community composition patterns at very small spatial scales and found that crevices within reefs are often dominated by coralline algae near sunlit entrances and by filter feeders in posterior sections 38 , 39 . Species inhabiting these cryptic spaces, especially Porifera, act as a sink for dissolved organic matter, thus preventing energy and nutrient losses into the open ocean 40 . Therefore, a better understanding of the distributional patterns of the crypto-benthic fauna may reveal insights into biogeochemical cycles within the reef system. In recent decades, standardized sampling units have been proposed as a means to quantify the diversity and composition of benthic assemblages in a consistent manner across space and time. In this study, we use Autonomous Reef Monitoring Structures (ARMS) which are designed to partially mimic the 3D structure of a reef 41 , 42 . The structures enable the study of both the sessile components growing on the plates as well as the mobile organisms that settle on or move into the spaces. The communities collected in ARMS are typically analyzed using some form of genetic barcoding (of individual organisms) (e.g.) 43 or high-throughput amplicon sequencing (i.e. metabarcoding of communities) (e.g.) 42 . Studies utilizing ARMS have revealed much about the hidden diversity of the Indo-Pacific and Caribbean 43 , as well as using high throughput amplicon sequencing (i.e. metabarcoding) to assess the sessile and mobile fractions on the US Atlantic coast 42 and the Red Sea 44 , 45 . Cryptic organisms include a diverse selection of ecologically important groups such as suspension feeders 46 , 47 , predators 48 , herbivores 49 and detritivores 50 . Because of their smaller sizes, they also have larger population sizes and faster generation times 51 . Their response to environmental changes may therefore differ from those of the better-studied fish and corals. The cryptic fauna represents a large proportion of the reef diversity, and thus to best conserve biodiversity of the reefs across spatial scales, an understanding of how the cryptic fauna responds to environmental changes is vital 33 . To achieve this, an assessment of not only the local species assemblages (alpha diversity) but also the inter-site differences (beta diversity)<|im_end|> <|im_start|>assistant Cryptic fauna—small organisms that inhabit the hidden spaces within a reef structure—represent a substantial proportion of the diversity within coral reefs but are typically neglected in traditional visual surveys, which tend to focus on large and conspicuous species, such as fish and corals. An international collaboration comprised of marine scientists from KAUST, the United States and Taiwan investigated the diversity patterns of the cryptic fauna in eight reefs in the central region of the Red Sea. The distribution patterns of these small creatures was unraveled using autonomous reef monitoring structures (ARMS), which consist of stacks of plates creating an artificial three-dimensional habitat for colonization, in conjunction with amplicon sequencing methodologies. "Cryptic fauna have previously been revealed to show different responses to those organisms normally assessed in reef monitoring," says lead author, John Pearman, from KAUST. "Therefore to effectively manage the biodiversity of coral reefs it is important to understand how cryptic fauna vary across spatial scales and how these organisms may respond to environmental changes." Depending on distance from the coast, organisms experience changes in conditions, such as salinity, temperature, nutrients and sedimentation: all of which can have impacts on the distribution of those organisms and therefore in the composition of the ecological communities. "Our study shows that different reef habitats across the shelf are inhabited by different sets of species and are therefore relevant to the regional diversity. These results have clear implications for the design of marine protected areas," explains Pearman. <|im_end|>

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1,642

[ { "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 better-than-classical quantum information processing (QIP) models which consume very little or no entanglement suggests that separable or weakly entangled states could be extremely useful tools for information processing as they are much easier to prepare and control even in dissipative environments. It has been proposed that a resource of advantage is the generation of quantum discord, a measure of non-classical correlations that includes entanglement as a subset. Here we show that quantum discord is the necessary resource for quantum remote state preparation. We explicitly show that the geometric measure of quantum discord is related to the fidelity of this task, which provides its operational meaning. Our results are experimentally demonstrated using photonic quantum systems. Moreover, we demonstrate that separable states with non-zero quantum discord can outperform entangled states. Therefore, the role of quantum discord might provide fundamental insights for resource-efficient QIP. Main Quantum computation and quantum communication are believed to allow for information processing with an efficiency that cannot be achieved by any classical device. It is usually assumed that a key resource for this enhanced performance is quantum entanglement 1 . Quantum entanglement is widely recognized as one of the key resources for the advantages of QIP, including universal quantum computation 2 , reduction of communication complexity 3 , 4 or secret key distribution 5 . The creation and manipulation of entanglement, however, is a very demanding task, as it requires extremely precise quantum control and isolation from the environment. Thus, current experimental achievements are limited to rather small-scale entangled systems 6 , 7 , 8 . Whereas quantum computing with pure states requires the presence of quantum entanglement for exponential enhancements 9 , there is no proof that entanglement is needed for providing computational speed-up for mixed state quantum computing or enhanced QIP in general. The investigation of QIP protocols that allow for significant enhancements in the efficiency of data processing by using only separable states is of high interest. Obviously, such states have the benefit of being easier to prepare and more robust against losses and experimental imperfections. In fact, there are quantum computational models based on mixed, separable states, most notably the so-called deterministic quantum computation with one qubit 10 , that are believed to be classically intractable 10 , 11 . Recently, they have been demonstrated experimentally 12 , 13 , 14 . The quantum advantage of these models has been associated with the generation of so-called quantum discord 15 , 16 , 17 , a measure of ‘non-classicality’ that captures quantum entanglement as a subset. The role of quantum discord in QIP has been studied in the past 18 , 19 , 20 , 21 , 22 , 23 . Quantum discord has been proposed as the resource that can provide the enhancement for the computation in the deterministic quantum computation with a one qubit model 24 , 25 , but its relation to the computational speed-up remains ambiguous 26 , 27 . A relation to quantum communication was studied and has been shown to exist, for example in local broadcasting 22 and quantum state merging 19 , 20 . A more general approach has been adopted by Madhok and Datta 21 showing the relation to all bipartite, unidirectional, memoryless quantum communication protocols, called the mother of all protocols. Here we identify quantum discord as the necessary resource for quantum remote (pure) state preparation 28 , 29 (RSP). This protocol is a variant of quantum state teleportation 30 in which the sender (Alice) knows the quantum state to be communicated to the receiver (Bob). We explicitly show that a quantum state retrieving non-trivial RSP fidelity is necessarily discordant. Our result is generic and holds for any two-qubit state, and does not rely on a particular measure of quantum discord. The experimental implementation was performed on a quantum optical platform using polarization-correlated single photons. We find that for a broad class of states the fidelity of RSP is directly given by the geometric measure of quantum discord. This provides an operational meaning to this measure of ‘quantumness’ of correlations in quantum information. Remarkably, states with no entanglement, yet non-zero geometric quantum discord, can outperform entangled states in accomplishing RSP. Theory Two systems are correlated if together they contain more information than taken separately. This intuitive definition is formally captured by (quantum) mutual information 31 I ( A : B ) = H ( A )+ H ( B )− H ( A , B ), where A and B are random variables. In classical probability theory H (·) stands for the Shannon entropy , where p = ( p 1 , p 2 ,…) is the probability distribution vector, whereas in the quantum case it denotes the von Neumann entropy H ( ρ ) = −Tr ρ log ρ of a density matrix ρ . Classically, we can use the Bayes rule and find an equivalent expression for the mutual information I ( A : B ) = H ( A )− H ( A | B ), where H ( A | B ) is the Shannon entropy of A conditioned on the measurement outcome of B . For quantum systems, these two expressions are inequivalent and their difference defines a non-negative quantity, the so-called quantum discord 15 , 17 . Whenever quantum discord vanishes the systems are classically correlated. A very simple expression for zero-discord states was proposed 32 , which will be illustrated in the following example. Consider the case of a two-qubit state shared by Alice and Bob, where the Hilbert space of each qubit is spanned by the orthogonal states |0〉 and |1〉. A general zero-discord state χ can be written as where p 1 + p 2 = 1 and ρ 1,2 are arbitrary states of the second qubit. Intuitively, this can be understood as a joint system containing one classical bit (cbit) and one quantum bit (qubit), 1 cbit×1 qubit. One of the systems can be identified as a cbit, because it is always", "role": "user" }, { "content": "An international collaboration led by physicists of the University of Vienna shines new light on the question of the resources required for achieving quantum information processing. The scientists demonstrate that less demanding resources, which are easier to prepare and to control, can be used for quantum-enhanced technologies. In the experiment, which is published in Nature Physics, the researchers achieve remote quantum state preparation without requiring entanglement as a resource. A fundamental characteristic of quantum physics is the fact that two or more particles can exhibit correlations stronger than classically allowed. This unique characteristic applies particularly to quantum entanglement: as soon as the quantum state of a particle is measured the state of its entangled partner changes accordingly, regardless of how far apart the two entangled particles might be. This feature allows for the remote quantum state preparation, which is an essential ingredient for applications in quantum communication, quantum cryptography, and quantum computation. The degree of entanglement is often used as a figure of merit for determining its usefulness for quantum technologies. Strongly entangled systems, however, are very sensitive to extrinsic influence and difficult to prepare and to control. A team of researchers headed by the physicists Caslav Brukner (theory) and Philip Walther (experiment) at the University of Vienna have been able to show that in order to achieve successful remote state preparation entanglement is not the only way forward. Under certain circumstances, non-entangled states can outperform their entangled counterparts for such tasks - as long as they have a significant amount of so-called \"quantum discord\". This novel and not yet fully understood measure of quantum correlations quantifies the disturbance of correlated particles when being measured. In their experiments, the researchers used a variety of two-photon states with different polarization correlations. \"By measuring the polarization state of a certain photon we prepare the state of the respective partner photon remotely\", explains Philip Walther. \"In the experiment we observe how the quality of our remotely prepared quantum state is affected by changes in the quantum discord.\" This work provides an important and significant step towards future quantum information processing schemes that would rely on less demanding resources. ", "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 better-than-classical quantum information processing (QIP) models which consume very little or no entanglement suggests that separable or weakly entangled states could be extremely useful tools for information processing as they are much easier to prepare and control even in dissipative environments. It has been proposed that a resource of advantage is the generation of quantum discord, a measure of non-classical correlations that includes entanglement as a subset. Here we show that quantum discord is the necessary resource for quantum remote state preparation. We explicitly show that the geometric measure of quantum discord is related to the fidelity of this task, which provides its operational meaning. Our results are experimentally demonstrated using photonic quantum systems. Moreover, we demonstrate that separable states with non-zero quantum discord can outperform entangled states. Therefore, the role of quantum discord might provide fundamental insights for resource-efficient QIP. Main Quantum computation and quantum communication are believed to allow for information processing with an efficiency that cannot be achieved by any classical device. It is usually assumed that a key resource for this enhanced performance is quantum entanglement 1 . Quantum entanglement is widely recognized as one of the key resources for the advantages of QIP, including universal quantum computation 2 , reduction of communication complexity 3 , 4 or secret key distribution 5 . The creation and manipulation of entanglement, however, is a very demanding task, as it requires extremely precise quantum control and isolation from the environment. Thus, current experimental achievements are limited to rather small-scale entangled systems 6 , 7 , 8 . Whereas quantum computing with pure states requires the presence of quantum entanglement for exponential enhancements 9 , there is no proof that entanglement is needed for providing computational speed-up for mixed state quantum computing or enhanced QIP in general. The investigation of QIP protocols that allow for significant enhancements in the efficiency of data processing by using only separable states is of high interest. Obviously, such states have the benefit of being easier to prepare and more robust against losses and experimental imperfections. In fact, there are quantum computational models based on mixed, separable states, most notably the so-called deterministic quantum computation with one qubit 10 , that are believed to be classically intractable 10 , 11 . Recently, they have been demonstrated experimentally 12 , 13 , 14 . The quantum advantage of these models has been associated with the generation of so-called quantum discord 15 , 16 , 17 , a measure of ‘non-classicality’ that captures quantum entanglement as a subset. The role of quantum discord in QIP has been studied in the past 18 , 19 , 20 , 21 , 22 , 23 . Quantum discord has been proposed as the resource that can provide the enhancement for the computation in the deterministic quantum computation with a one qubit model 24 , 25 , but its relation to the computational speed-up remains ambiguous 26 , 27 . A relation to quantum communication was studied and has been shown to exist, for example in local broadcasting 22 and quantum state merging 19 , 20 . A more general approach has been adopted by Madhok and Datta 21 showing the relation to all bipartite, unidirectional, memoryless quantum communication protocols, called the mother of all protocols. Here we identify quantum discord as the necessary resource for quantum remote (pure) state preparation 28 , 29 (RSP). This protocol is a variant of quantum state teleportation 30 in which the sender (Alice) knows the quantum state to be communicated to the receiver (Bob). We explicitly show that a quantum state retrieving non-trivial RSP fidelity is necessarily discordant. Our result is generic and holds for any two-qubit state, and does not rely on a particular measure of quantum discord. The experimental implementation was performed on a quantum optical platform using polarization-correlated single photons. We find that for a broad class of states the fidelity of RSP is directly given by the geometric measure of quantum discord. This provides an operational meaning to this measure of ‘quantumness’ of correlations in quantum information. Remarkably, states with no entanglement, yet non-zero geometric quantum discord, can outperform entangled states in accomplishing RSP. Theory Two systems are correlated if together they contain more information than taken separately. This intuitive definition is formally captured by (quantum) mutual information 31 I ( A : B ) = H ( A )+ H ( B )− H ( A , B ), where A and B are random variables. In classical probability theory H (·) stands for the Shannon entropy , where p = ( p 1 , p 2 ,…) is the probability distribution vector, whereas in the quantum case it denotes the von Neumann entropy H ( ρ ) = −Tr ρ log ρ of a density matrix ρ . Classically, we can use the Bayes rule and find an equivalent expression for the mutual information I ( A : B ) = H ( A )− H ( A | B ), where H ( A | B ) is the Shannon entropy of A conditioned on the measurement outcome of B . For quantum systems, these two expressions are inequivalent and their difference defines a non-negative quantity, the so-called quantum discord 15 , 17 . Whenever quantum discord vanishes the systems are classically correlated. A very simple expression for zero-discord states was proposed 32 , which will be illustrated in the following example. Consider the case of a two-qubit state shared by Alice and Bob, where the Hilbert space of each qubit is spanned by the orthogonal states |0〉 and |1〉. A general zero-discord state χ can be written as where p 1 + p 2 = 1 and ρ 1,2 are arbitrary states of the second qubit. Intuitively, this can be understood as a joint system containing one classical bit (cbit) and one quantum bit (qubit), 1 cbit×1 qubit. One of the systems can be identified as a cbit, because it is always<|im_end|> <|im_start|>assistant An international collaboration led by physicists of the University of Vienna shines new light on the question of the resources required for achieving quantum information processing. The scientists demonstrate that less demanding resources, which are easier to prepare and to control, can be used for quantum-enhanced technologies. In the experiment, which is published in Nature Physics, the researchers achieve remote quantum state preparation without requiring entanglement as a resource. A fundamental characteristic of quantum physics is the fact that two or more particles can exhibit correlations stronger than classically allowed. This unique characteristic applies particularly to quantum entanglement: as soon as the quantum state of a particle is measured the state of its entangled partner changes accordingly, regardless of how far apart the two entangled particles might be. This feature allows for the remote quantum state preparation, which is an essential ingredient for applications in quantum communication, quantum cryptography, and quantum computation. The degree of entanglement is often used as a figure of merit for determining its usefulness for quantum technologies. Strongly entangled systems, however, are very sensitive to extrinsic influence and difficult to prepare and to control. A team of researchers headed by the physicists Caslav Brukner (theory) and Philip Walther (experiment) at the University of Vienna have been able to show that in order to achieve successful remote state preparation entanglement is not the only way forward. Under certain circumstances, non-entangled states can outperform their entangled counterparts for such tasks - as long as they have a significant amount of so-called "quantum discord". This novel and not yet fully understood measure of quantum correlations quantifies the disturbance of correlated particles when being measured. In their experiments, the researchers used a variety of two-photon states with different polarization correlations. "By measuring the polarization state of a certain photon we prepare the state of the respective partner photon remotely", explains Philip Walther. "In the experiment we observe how the quality of our remotely prepared quantum state is affected by changes in the quantum discord." This work provides an important and significant step towards future quantum information processing schemes that would rely on less demanding resources. <|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 Single-cell RNA sequencing methods can profile the transcriptomes of single cells but cannot preserve spatial information. Conversely, spatial transcriptomics assays can profile spatial regions in tissue sections, but do not have single-cell resolution. Here, we developed a computational method called CellTrek that combines these two datasets to achieve single-cell spatial mapping through coembedding and metric learning approaches. We benchmarked CellTrek using simulation and in situ hybridization datasets, which demonstrated its accuracy and robustness. We then applied CellTrek to existing mouse brain and kidney datasets and showed that CellTrek can detect topological patterns of different cell types and cell states. We performed single-cell RNA sequencing and spatial transcriptomics experiments on two ductal carcinoma in situ tissues and applied CellTrek to identify tumor subclones that were restricted to different ducts, and specific T cell states adjacent to the tumor areas. Our data show that CellTrek can accurately map single cells in diverse tissue types to resolve their spatial organization. Main Single-cell RNA sequencing (scRNA-seq) methods have greatly expanded our understanding of the gene expression programs of diverse cell types and their role in development and disease 1 , 2 , 3 , 4 , 5 . However, scRNA-seq loses cellular spatial information during the tissue dissociation step, which is critical for understanding cellular microenvironment and cell–cell interactions 6 , 7 , 8 . While spatial sequencing methods, including spatial transcriptomics (ST) 9 and Slide-seq 10 , can profile gene expression spatially across tissue sections, they are limited to measuring small regions with mixtures of cells and cannot easily provide single-cell information. To address this issue, computational approaches (for example, cell2location, RCTD (robust cell type decomposition)) have been designed to deconvolute ST spots into proportions of different cell types 6 , 11 , 12 , 13 , 14 , 15 , 16 . However, spatial deconvolution methods are limited to inferring only cell type proportions for each spot, and cannot achieve single-cell resolution. Additionally, deconvolution methods have limited ability to further resolve cell types into more granular ‘cell states’ (expression programs) that reflect different biological functions. Finally, most deconvolution methods can only predict categorical labels and cannot infer continuous cell information (for example, lineage trajectories, gene signatures) at a spatial resolution. Here, we introduce CellTrek—a computational toolkit that can directly map single cells back to their spatial coordinates in tissue sections based on scRNA-seq and ST data. This method is distinct from ST deconvolution, enabling a more flexible and direct investigation of single-cell data with spatial topography. The CellTrek toolkit also provides two downstream analysis modules, including SColoc for spatial colocalization analysis and SCoexp for spatial coexpression analysis. We benchmarked CellTrek using simulations and in situ datasets. We then applied CellTrek to existing datasets from normal mouse brain 17 and kidney 18 tissues as well as to data that we generated from two human ductal carcinoma in situ (DCIS) samples to study the spatial organization of cell types/states at a single-cell resolution. Results Overview of CellTrek toolkit CellTrek first integrates and coembeds ST and scRNA-seq data into a shared feature space (Fig. 1 ; Methods ). Using the ST data, CellTrek trains a multivariate random forests (RF) model 19 to predict the spatial coordinates using shared dimension reduction features. A spatial nonlinear interpolation on ST data is introduced to augment the spatial resolution. The trained model is then applied to the coembedded data to derive an RF distance matrix that measures the expression similarities between ST spots and single cells supervised by spatial coordinates. Based on the RF distance matrix, CellTrek produces a sparse spot-cell graph using mutual nearest neighbors (MNN) after thresholding. Finally, CellTrek transfers spatial coordinates for cells from their neighbor spots. To improve the compatibility, CellTrek can accept any cell-location probability/distance matrix calculated from other methods (for example, novoSpaRc 20 ) as an input for cell spatial charting. Additionally, we provide a graphical user interface (GUI) for interactive visualization of the resulting CellTrek map. Fig. 1: Overview of the CellTrek workflow. CellTrek first coembeds scRNA-seq and ST datasets into a shared latent space. Using the ST data, CellTrek trains a multivariate RF model with spatial coordinates as the outcome and latent features as the predictors. A 2D spatial interpolation on the ST data is introduced to augment the ST spots. The trained RF model is then applied to the coembedded data (ST interpolated) to derive an RF distance matrix, which will be converted into a sparse graph using MNN. Based on the sparse graph, CellTrek transfers the coordinates to single cells from their neighboring ST spots. Full size image To recapitulate spatial relationships between different cell types, we developed a downstream computational module, SColoc, which summarizes the CellTrek result into a graph abstraction (Supplementary Fig. 1a ; Methods ). Three approaches, Kullback-Leibler divergence (KL), Delaunay triangulation (DT) and K-nearest neighbor distance (KD), are provided to calculate spatial dissimilarity between cell types. Based on the dissimilarity matrix, SColoc can construct a minimum spanning tree (MST) that represents a simplified spatial cellular proximity. The above steps will be executed iteratively on bootstrapping samples to generate consensus matrices. Thereafter, a graph will be rendered through a GUI with tunable edge thresholding and color mapping functions. Additionally, SColoc provides a K-distance metric for measuring the spatial distance of cells to a selected reference group. To investigate whether different expression programs are distributed across different topographic areas, we developed SCoexp, which uses the CellTrek coordinates to detect coexpression gene modules within the cells of interest (Supplementary Fig. 1b ; Methods ). First, SCoexp calculates a spatial kernel weight matrix. Using this weight matrix, SCoexp calculates spatial-weighted gene coexpression matrix. Thereafter, SCoexp utilizes consensus clustering 21 (CC) or weighted correlation network analysis 22 (WGCNA) to identify gene modules. For the identified modules, we can calculate module scores and investigate their spatial organizations. Benchmarking and simulations To benchmark the performance of CellTrek, we exploited three spatial datasets: (1) a simulated scRNA-seq dataset with customized spatial patterns (Supplementary Fig. 2a,b ), (2) a fluorescence in situ hybridization", "role": "user" }, { "content": "A new computational approach developed by researchers at The University of Texas MD Anderson Cancer Center successfully combines data from parallel gene-expression profiling methods to create spatial maps of a given tissue at single-cell resolution. The resulting maps can provide unique biological insights into the cancer microenvironment and many other tissue types. The study was published today in Nature Biotechnology and will be presented at the upcoming American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract 2129). The tool, called CellTrek, uses data from single-cell RNA sequencing (scRNA-seq) together with that of spatial transcriptomics (ST) assays—which measure spatial gene expression in many small groups of cells—to accurately pinpoint the location of individual cell types within a tissue. The researchers presented findings from analysis of kidney and brain tissues as well as samples of ductal carcincoma in situ (DCIS) breast cancer. \"Single-cell RNA sequencing provides tremendous information about the cells within a tissue, but, ultimately, you want to know where these cells are distributed, particularly in tumor samples,\" said senior author Nicholas Navin, Ph.D., professor of Genetics and Bioinformatics & Computational Biology. \"This tool allows us to answer that question with an unbiased approach that improves upon currently available spatial mapping techniques.\" Single-cell RNA sequencing is an established method to analyze the gene expression of many individual cells from a sample, but it cannot provide information on the location of cells within a tissue. On the other hand, ST assays can measure spatial gene expression by analyzing many small groups of cells across a tissue but are not capable of providing single-cell resolution. Current computational approaches, known as deconvolution techniques, can identify different cell types present from ST data, but they are not capable of providing detailed information at the single-cell level, Navin explained. Therefore, co-first authors Runmin Wei, Ph.D., and Siyuan He of the Navin Laboratory led the efforts to develop CellTrek as a tool to combine the unique advantages of scRNA-seq and ST assays and create accurate spatial maps of tissue samples. Using publicly available scRNA-seq and ST data from brain and kidney tissues, the researchers demonstrated that CellTrek achieved the most accurate and detailed spatial resolution of the methods evaluated. The CellTrek approach also was able to distinguish subtle gene expression differences within the same cell type to gain information on their heterogeneity within a sample. The researchers also collaborated with Savitri Krishnamurthy, M.D., professor of Pathology, to apply CellTrek to study DCIS breast cancer tissues. In an analysis of 6,800 single cells and 1,500 ST regions from a single DCIS sample, the team learned that different subgroups of tumor cells were evolving in unique patterns within specific regions of the tumor. Analysis of a second DCIS sample demonstrated the ability of CellTrek to reconstruct the spatial tumor-immune microenvironment within a tumor tissue. \"While this approach is not restricted to analyzing tumor tissues, there are obvious applications for better understanding cancer,\" Navin said. \"Pathology really drives cancer diagnoses and, with this tool, we're able to map molecular data on top of pathological data to allow even deeper classifications of tumors and to better guide treatment approaches.\" Collaborating MD Anderson authors include Shanshan Bai, Emi Sei, Ph.D., and Min Hu, all of Genetics; and Ken Chen, Ph.D., of Bioinformatics. Additional authors include Alastair Thompson, M.D., of Baylor College of Medicine, Houston. The authors have no conflicts of interest. ", "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 Single-cell RNA sequencing methods can profile the transcriptomes of single cells but cannot preserve spatial information. Conversely, spatial transcriptomics assays can profile spatial regions in tissue sections, but do not have single-cell resolution. Here, we developed a computational method called CellTrek that combines these two datasets to achieve single-cell spatial mapping through coembedding and metric learning approaches. We benchmarked CellTrek using simulation and in situ hybridization datasets, which demonstrated its accuracy and robustness. We then applied CellTrek to existing mouse brain and kidney datasets and showed that CellTrek can detect topological patterns of different cell types and cell states. We performed single-cell RNA sequencing and spatial transcriptomics experiments on two ductal carcinoma in situ tissues and applied CellTrek to identify tumor subclones that were restricted to different ducts, and specific T cell states adjacent to the tumor areas. Our data show that CellTrek can accurately map single cells in diverse tissue types to resolve their spatial organization. Main Single-cell RNA sequencing (scRNA-seq) methods have greatly expanded our understanding of the gene expression programs of diverse cell types and their role in development and disease 1 , 2 , 3 , 4 , 5 . However, scRNA-seq loses cellular spatial information during the tissue dissociation step, which is critical for understanding cellular microenvironment and cell–cell interactions 6 , 7 , 8 . While spatial sequencing methods, including spatial transcriptomics (ST) 9 and Slide-seq 10 , can profile gene expression spatially across tissue sections, they are limited to measuring small regions with mixtures of cells and cannot easily provide single-cell information. To address this issue, computational approaches (for example, cell2location, RCTD (robust cell type decomposition)) have been designed to deconvolute ST spots into proportions of different cell types 6 , 11 , 12 , 13 , 14 , 15 , 16 . However, spatial deconvolution methods are limited to inferring only cell type proportions for each spot, and cannot achieve single-cell resolution. Additionally, deconvolution methods have limited ability to further resolve cell types into more granular ‘cell states’ (expression programs) that reflect different biological functions. Finally, most deconvolution methods can only predict categorical labels and cannot infer continuous cell information (for example, lineage trajectories, gene signatures) at a spatial resolution. Here, we introduce CellTrek—a computational toolkit that can directly map single cells back to their spatial coordinates in tissue sections based on scRNA-seq and ST data. This method is distinct from ST deconvolution, enabling a more flexible and direct investigation of single-cell data with spatial topography. The CellTrek toolkit also provides two downstream analysis modules, including SColoc for spatial colocalization analysis and SCoexp for spatial coexpression analysis. We benchmarked CellTrek using simulations and in situ datasets. We then applied CellTrek to existing datasets from normal mouse brain 17 and kidney 18 tissues as well as to data that we generated from two human ductal carcinoma in situ (DCIS) samples to study the spatial organization of cell types/states at a single-cell resolution. Results Overview of CellTrek toolkit CellTrek first integrates and coembeds ST and scRNA-seq data into a shared feature space (Fig. 1 ; Methods ). Using the ST data, CellTrek trains a multivariate random forests (RF) model 19 to predict the spatial coordinates using shared dimension reduction features. A spatial nonlinear interpolation on ST data is introduced to augment the spatial resolution. The trained model is then applied to the coembedded data to derive an RF distance matrix that measures the expression similarities between ST spots and single cells supervised by spatial coordinates. Based on the RF distance matrix, CellTrek produces a sparse spot-cell graph using mutual nearest neighbors (MNN) after thresholding. Finally, CellTrek transfers spatial coordinates for cells from their neighbor spots. To improve the compatibility, CellTrek can accept any cell-location probability/distance matrix calculated from other methods (for example, novoSpaRc 20 ) as an input for cell spatial charting. Additionally, we provide a graphical user interface (GUI) for interactive visualization of the resulting CellTrek map. Fig. 1: Overview of the CellTrek workflow. CellTrek first coembeds scRNA-seq and ST datasets into a shared latent space. Using the ST data, CellTrek trains a multivariate RF model with spatial coordinates as the outcome and latent features as the predictors. A 2D spatial interpolation on the ST data is introduced to augment the ST spots. The trained RF model is then applied to the coembedded data (ST interpolated) to derive an RF distance matrix, which will be converted into a sparse graph using MNN. Based on the sparse graph, CellTrek transfers the coordinates to single cells from their neighboring ST spots. Full size image To recapitulate spatial relationships between different cell types, we developed a downstream computational module, SColoc, which summarizes the CellTrek result into a graph abstraction (Supplementary Fig. 1a ; Methods ). Three approaches, Kullback-Leibler divergence (KL), Delaunay triangulation (DT) and K-nearest neighbor distance (KD), are provided to calculate spatial dissimilarity between cell types. Based on the dissimilarity matrix, SColoc can construct a minimum spanning tree (MST) that represents a simplified spatial cellular proximity. The above steps will be executed iteratively on bootstrapping samples to generate consensus matrices. Thereafter, a graph will be rendered through a GUI with tunable edge thresholding and color mapping functions. Additionally, SColoc provides a K-distance metric for measuring the spatial distance of cells to a selected reference group. To investigate whether different expression programs are distributed across different topographic areas, we developed SCoexp, which uses the CellTrek coordinates to detect coexpression gene modules within the cells of interest (Supplementary Fig. 1b ; Methods ). First, SCoexp calculates a spatial kernel weight matrix. Using this weight matrix, SCoexp calculates spatial-weighted gene coexpression matrix. Thereafter, SCoexp utilizes consensus clustering 21 (CC) or weighted correlation network analysis 22 (WGCNA) to identify gene modules. For the identified modules, we can calculate module scores and investigate their spatial organizations. Benchmarking and simulations To benchmark the performance of CellTrek, we exploited three spatial datasets: (1) a simulated scRNA-seq dataset with customized spatial patterns (Supplementary Fig. 2a,b ), (2) a fluorescence in situ hybridization<|im_end|> <|im_start|>assistant A new computational approach developed by researchers at The University of Texas MD Anderson Cancer Center successfully combines data from parallel gene-expression profiling methods to create spatial maps of a given tissue at single-cell resolution. The resulting maps can provide unique biological insights into the cancer microenvironment and many other tissue types. The study was published today in Nature Biotechnology and will be presented at the upcoming American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract 2129). The tool, called CellTrek, uses data from single-cell RNA sequencing (scRNA-seq) together with that of spatial transcriptomics (ST) assays—which measure spatial gene expression in many small groups of cells—to accurately pinpoint the location of individual cell types within a tissue. The researchers presented findings from analysis of kidney and brain tissues as well as samples of ductal carcincoma in situ (DCIS) breast cancer. "Single-cell RNA sequencing provides tremendous information about the cells within a tissue, but, ultimately, you want to know where these cells are distributed, particularly in tumor samples," said senior author Nicholas Navin, Ph.D., professor of Genetics and Bioinformatics & Computational Biology. "This tool allows us to answer that question with an unbiased approach that improves upon currently available spatial mapping techniques." Single-cell RNA sequencing is an established method to analyze the gene expression of many individual cells from a sample, but it cannot provide information on the location of cells within a tissue. On the other hand, ST assays can measure spatial gene expression by analyzing many small groups of cells across a tissue but are not capable of providing single-cell resolution. Current computational approaches, known as deconvolution techniques, can identify different cell types present from ST data, but they are not capable of providing detailed information at the single-cell level, Navin explained. Therefore, co-first authors Runmin Wei, Ph.D., and Siyuan He of the Navin Laboratory led the efforts to develop CellTrek as a tool to combine the unique advantages of scRNA-seq and ST assays and create accurate spatial maps of tissue samples. Using publicly available scRNA-seq and ST data from brain and kidney tissues, the researchers demonstrated that CellTrek achieved the most accurate and detailed spatial resolution of the methods evaluated. The CellTrek approach also was able to distinguish subtle gene expression differences within the same cell type to gain information on their heterogeneity within a sample. The researchers also collaborated with Savitri Krishnamurthy, M.D., professor of Pathology, to apply CellTrek to study DCIS breast cancer tissues. In an analysis of 6,800 single cells and 1,500 ST regions from a single DCIS sample, the team learned that different subgroups of tumor cells were evolving in unique patterns within specific regions of the tumor. Analysis of a second DCIS sample demonstrated the ability of CellTrek to reconstruct the spatial tumor-immune microenvironment within a tumor tissue. "While this approach is not restricted to analyzing tumor tissues, there are obvious applications for better understanding cancer," Navin said. "Pathology really drives cancer diagnoses and, with this tool, we're able to map molecular data on top of pathological data to allow even deeper classifications of tumors and to better guide treatment approaches." Collaborating MD Anderson authors include Shanshan Bai, Emi Sei, Ph.D., and Min Hu, all of Genetics; and Ken Chen, Ph.D., of Bioinformatics. Additional authors include Alastair Thompson, M.D., of Baylor College of Medicine, Houston. The authors have no conflicts of interest. <|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 Although calcareous anatomical structures have evolved in diverse animal groups, such structures have been unknown in insects. Here, we report the discovery of high-magnesium calcite [CaMg(CO 3 ) 2 ] armor overlaying the exoskeletons of major workers of the leaf-cutter ant Acromyrmex echinatior . Live-rearing and in vitro synthesis experiments indicate that the biomineral layer accumulates rapidly as ant workers mature, that the layer is continuously distributed, covering nearly the entire integument, and that the ant epicuticle catalyzes biomineral nucleation and growth. In situ nanoindentation demonstrates that the biomineral layer significantly hardens the exoskeleton. Increased survival of ant workers with biomineralized exoskeletons during aggressive encounters with other ants and reduced infection by entomopathogenic fungi demonstrate the protective role of the biomineral layer. The discovery of biogenic high-magnesium calcite in the relatively well-studied leaf-cutting ants suggests that calcareous biominerals enriched in magnesium may be more common in metazoans than previously recognized. Introduction Biomineral skeletons first appeared more than 550 million years ago 1 , 2 , 3 , 4 , 5 , and by the early Cambrian biomineral-based defensive structures had evolved in most extant metazoan phyla, apparently in response to increasing predation pressure 6 . The minerals involved, as well as the biogenic structures they form, are diverse. Calcium carbonate biomineralization is particularly widespread among metazoans 1 , 7 : the hard parts of corals 8 , mollusk shells 9 , stomatopod dactyl club 10 , and sea urchin spines 11 contain calcium carbonate, as do the light-focusing eye lenses of chitons and brittlestars 12 , 13 . Magnesium-enriched calcite (CaCO 3 ) has been discovered in the central part of the sea urchin tooth, where the increased hardness imparted by magnesium is thought to aid in the grinding of limestone 14 , 15 , 16 . Given the importance of calcareous anatomical structures across metazoan phyla and given that magnesium significantly strengthens such structures 17 , it is surprising that high-magnesium calcite appears to be rare in animals 18 . It is also surprising that despite the near ubiquity of biogenic mineralization across metazoan phyla and the widespread presence of calcium carbonate in the Crustacea, biomineralized calcium carbonate has so far remained unknown in the most diverse group of animals, the insects, which arose from within the Crustacea 19 . Here we report the discovery of a dense layer of biogenic high-magnesium calcite in the leaf-cutter ant Acromyrmex echinatior . Fungus-growing attine ants (tribe Attini, subtribe Attina) engage in an ancient and obligate mutualism with coevolved fungi (order Agaricales), which they cultivate for food. Fungus farming, which has been described as a major transition in evolution 20 , evolved only once in ants around 60 million years ago 20 . Leaf-cutting ants (genera Acromyrmex and Atta ), a phylogenetically derived lineage that arose within the fungus-growing ants around 20 million years ago, harvest fresh vegetation as the substrate on which they grow their fungal mutualists. They are ecologically dominant herbivores in the New World tropics 20 , 21 and serve important roles in carbon and nitrogen cycling 22 . A mature Atta leaf-cutter ant colony comprises a superorganism with >5 million workers, a single queen, and complex society with a highly refined division of labor based both on worker size and age. Acromyrmex leaf-cutter colonies vary in size, generally within the range of 15,000–100,000 workers 23 , 24 , and in some species may have more than one queen. Acromyrmex echinatior , the focus of the present study, has a mean colony size of 137,500 workers and is facultatively polygynous 25 , 26 . In addition to the leaf-cutters, 17 other genera of ants occur within the Attina, all of which grow fungus gardens, form colonies of hundreds to a few thousand workers, and use dead vegetative matter or caterpillar frass rather than fresh leaves and grasses as substrates for their gardens. In addition to the symbiotic association with their fungal cultivars, many fungus-growing ants engage in a second mutualism with Actinobacteria (genus Pseudonocardia ), which produce antibiotics that help defend the garden from fungal pathogens 27 , 28 , 29 . Fungus-growing ant colonies, containing both fungal crops and immature ant brood, represent a rich nutritional resource for a wide variety of marauding ant species, including army ants and other known agro-predatory raiders of ant agriculture 30 . Smaller fungus-growing ant colonies, including those of Acromyrmex , are also occasionally subject to attack by the large-sized soldier castes of Atta leaf-cutter ants, which use their powerful zinc-enriched mandibles to defend their colonies’ territories against other, encroaching ant species 31 , 32 , 33 . Many species of fungus-growing ants are variably covered with a whitish granular coating, uniformly distributed on their otherwise dark brown cuticles 34 , including, in addition to Acromyrmex echinatior (Fig. 1a ), some species of Trachymyrmex and Sericomyrmex . Fig. 1: Morphological and structural characterization of minerals on the cuticle of Ac. echinatior . a Ac. echinatior ant with a whitish cuticular coating (Photo T.R.S.). b SEM image of ant cuticle with crystalline coating. c Backscattered electron (BSE) image of a polished cuticular cross-section of an ant. This layer is brighter than the cuticle in backscattered electron (BSE) mode scanning electron microscopy (SEM), indicating that it consists of heavier elements and is continuous, covering nearly the entire surface. d BSE image close-up of a polished cuticular cross-section of an ant. Full size image Based on combined data from in situ X-ray diffraction (XRD), electron microscopy, electron backscatter diffraction (EBSD), quantitative electron probe micro-analysis (EPMA), and Raman and attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy, we report here that this coating is in fact a mineral layer covering the ant exoskeleton. The layer is composed of euhedral rhombohedral crystals with curved faces, 3–5 μm in size (Fig. 1b ). To examine the mechanism of crystal growth, we conducted synchrotron X-ray PhotoEmission electron spectro-microscopy (X-PEEM), in vitro synthesis, and in vivo observation of crystallization and growth in an ant-rearing experiment. We measure the cuticle hardness", "role": "user" }, { "content": "A well-known leaf-cutting ant grows its own body armour using biominerals, a protective power previously unknown in the insect world, scientists have discovered in research published Tuesday showing this makes the ants almost unbeatable in battle. Biomineral armour is seen in the natural world in crustaceans like lobsters as well as in other marine animals—sea urchin spines contain calcium carbonate for example—but it has not previously been found in insects. Researchers stumbled across the discovery while investigating the relationship between the fungus-growing ant species Acromyrmex echinatior and antibiotic-producing bacteria that helps them protect their crops. They noticed that the larger worker ants, known as majors, have a \"whitish, granular coating\" over the surface of their bodies, according to co-author Cameron Currie, professor of Bacteriology at the University of Wisconsin-Madison. He said Hongjie Li, the lead author of the report published in Nature Communications, \"became fascinated with the crystals\" and discovered it was a biomineral layer that develops as the ants mature, increasing the hardness of their exoskeleton and covering nearly the entire body. While researchers do not know for certain why the ants have this unusual armour, Currie told AFP they suspect it has a lot to do with the soldier ants of another species of fungus-growing ants, Atta cephalotes. The two species will often engage in territorial \"ant wars\", which the researchers simulated in lab-based battles. \"When the Acro majors are without their armour the Atta soldiers quickly cut them into pieces, literally,\" Currie said. \"When they have their armour, they actually go from almost always losing the battles to almost always winning.\" The authors found that the benefits of a biomineralised exoskeleton go beyond giving the workers an edge in ant wars. Their studies suggest it also helps protect them against infection from the disease-causing fungus Metarhizium anisopliae, which might otherwise spread quickly through their dense colonies. Rare as sea urchin teeth Ants are believed to have started fungus subsistence farming about 60 million years ago in South America. Some 20 million years ago the practice became more \"industrialised\", with the emergence of leaf-cutting ant species like Acromyrmex echinatior and Atta cephalotes living in large, complex colonies and harvesting fresh vegetation that they use to grow their fungus. Acromyrmex echinatior colonies can be formed with hundreds of thousands of large and small worker ants. \"The large ones do the cutting and carrying of leaves, as well as engaging in wars and battles with other ants,\" said Currie. \"The small ones do the gardening.\" Atta colonies are bigger, composed of perhaps millions of ants, with up to seven different sizes of workers, including soldiers for \"defence and ant wars\", Currie said. The Acromyrmex echinatior armour is made from a high-magnesium calcite, researchers found. This is a rarer form of biomineralisation where the increased hardness from the magnesium is thought to help them grind up limestone. Given that the armour has only just been found on a relatively well-studied ant species, the researchers said this type of biomineral protection could be more widespread in the insect world. But Currie said this was likely to be the calcite biominerals found more commonly in marine animals like lobsters, rather than the high-magnesium calcite of the ants' armour and sea urchin teeth. \"These ants are pretty special in many regards,\" he added. ", "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 calcareous anatomical structures have evolved in diverse animal groups, such structures have been unknown in insects. Here, we report the discovery of high-magnesium calcite [CaMg(CO 3 ) 2 ] armor overlaying the exoskeletons of major workers of the leaf-cutter ant Acromyrmex echinatior . Live-rearing and in vitro synthesis experiments indicate that the biomineral layer accumulates rapidly as ant workers mature, that the layer is continuously distributed, covering nearly the entire integument, and that the ant epicuticle catalyzes biomineral nucleation and growth. In situ nanoindentation demonstrates that the biomineral layer significantly hardens the exoskeleton. Increased survival of ant workers with biomineralized exoskeletons during aggressive encounters with other ants and reduced infection by entomopathogenic fungi demonstrate the protective role of the biomineral layer. The discovery of biogenic high-magnesium calcite in the relatively well-studied leaf-cutting ants suggests that calcareous biominerals enriched in magnesium may be more common in metazoans than previously recognized. Introduction Biomineral skeletons first appeared more than 550 million years ago 1 , 2 , 3 , 4 , 5 , and by the early Cambrian biomineral-based defensive structures had evolved in most extant metazoan phyla, apparently in response to increasing predation pressure 6 . The minerals involved, as well as the biogenic structures they form, are diverse. Calcium carbonate biomineralization is particularly widespread among metazoans 1 , 7 : the hard parts of corals 8 , mollusk shells 9 , stomatopod dactyl club 10 , and sea urchin spines 11 contain calcium carbonate, as do the light-focusing eye lenses of chitons and brittlestars 12 , 13 . Magnesium-enriched calcite (CaCO 3 ) has been discovered in the central part of the sea urchin tooth, where the increased hardness imparted by magnesium is thought to aid in the grinding of limestone 14 , 15 , 16 . Given the importance of calcareous anatomical structures across metazoan phyla and given that magnesium significantly strengthens such structures 17 , it is surprising that high-magnesium calcite appears to be rare in animals 18 . It is also surprising that despite the near ubiquity of biogenic mineralization across metazoan phyla and the widespread presence of calcium carbonate in the Crustacea, biomineralized calcium carbonate has so far remained unknown in the most diverse group of animals, the insects, which arose from within the Crustacea 19 . Here we report the discovery of a dense layer of biogenic high-magnesium calcite in the leaf-cutter ant Acromyrmex echinatior . Fungus-growing attine ants (tribe Attini, subtribe Attina) engage in an ancient and obligate mutualism with coevolved fungi (order Agaricales), which they cultivate for food. Fungus farming, which has been described as a major transition in evolution 20 , evolved only once in ants around 60 million years ago 20 . Leaf-cutting ants (genera Acromyrmex and Atta ), a phylogenetically derived lineage that arose within the fungus-growing ants around 20 million years ago, harvest fresh vegetation as the substrate on which they grow their fungal mutualists. They are ecologically dominant herbivores in the New World tropics 20 , 21 and serve important roles in carbon and nitrogen cycling 22 . A mature Atta leaf-cutter ant colony comprises a superorganism with >5 million workers, a single queen, and complex society with a highly refined division of labor based both on worker size and age. Acromyrmex leaf-cutter colonies vary in size, generally within the range of 15,000–100,000 workers 23 , 24 , and in some species may have more than one queen. Acromyrmex echinatior , the focus of the present study, has a mean colony size of 137,500 workers and is facultatively polygynous 25 , 26 . In addition to the leaf-cutters, 17 other genera of ants occur within the Attina, all of which grow fungus gardens, form colonies of hundreds to a few thousand workers, and use dead vegetative matter or caterpillar frass rather than fresh leaves and grasses as substrates for their gardens. In addition to the symbiotic association with their fungal cultivars, many fungus-growing ants engage in a second mutualism with Actinobacteria (genus Pseudonocardia ), which produce antibiotics that help defend the garden from fungal pathogens 27 , 28 , 29 . Fungus-growing ant colonies, containing both fungal crops and immature ant brood, represent a rich nutritional resource for a wide variety of marauding ant species, including army ants and other known agro-predatory raiders of ant agriculture 30 . Smaller fungus-growing ant colonies, including those of Acromyrmex , are also occasionally subject to attack by the large-sized soldier castes of Atta leaf-cutter ants, which use their powerful zinc-enriched mandibles to defend their colonies’ territories against other, encroaching ant species 31 , 32 , 33 . Many species of fungus-growing ants are variably covered with a whitish granular coating, uniformly distributed on their otherwise dark brown cuticles 34 , including, in addition to Acromyrmex echinatior (Fig. 1a ), some species of Trachymyrmex and Sericomyrmex . Fig. 1: Morphological and structural characterization of minerals on the cuticle of Ac. echinatior . a Ac. echinatior ant with a whitish cuticular coating (Photo T.R.S.). b SEM image of ant cuticle with crystalline coating. c Backscattered electron (BSE) image of a polished cuticular cross-section of an ant. This layer is brighter than the cuticle in backscattered electron (BSE) mode scanning electron microscopy (SEM), indicating that it consists of heavier elements and is continuous, covering nearly the entire surface. d BSE image close-up of a polished cuticular cross-section of an ant. Full size image Based on combined data from in situ X-ray diffraction (XRD), electron microscopy, electron backscatter diffraction (EBSD), quantitative electron probe micro-analysis (EPMA), and Raman and attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy, we report here that this coating is in fact a mineral layer covering the ant exoskeleton. The layer is composed of euhedral rhombohedral crystals with curved faces, 3–5 μm in size (Fig. 1b ). To examine the mechanism of crystal growth, we conducted synchrotron X-ray PhotoEmission electron spectro-microscopy (X-PEEM), in vitro synthesis, and in vivo observation of crystallization and growth in an ant-rearing experiment. We measure the cuticle hardness<|im_end|> <|im_start|>assistant A well-known leaf-cutting ant grows its own body armour using biominerals, a protective power previously unknown in the insect world, scientists have discovered in research published Tuesday showing this makes the ants almost unbeatable in battle. Biomineral armour is seen in the natural world in crustaceans like lobsters as well as in other marine animals—sea urchin spines contain calcium carbonate for example—but it has not previously been found in insects. Researchers stumbled across the discovery while investigating the relationship between the fungus-growing ant species Acromyrmex echinatior and antibiotic-producing bacteria that helps them protect their crops. They noticed that the larger worker ants, known as majors, have a "whitish, granular coating" over the surface of their bodies, according to co-author Cameron Currie, professor of Bacteriology at the University of Wisconsin-Madison. He said Hongjie Li, the lead author of the report published in Nature Communications, "became fascinated with the crystals" and discovered it was a biomineral layer that develops as the ants mature, increasing the hardness of their exoskeleton and covering nearly the entire body. While researchers do not know for certain why the ants have this unusual armour, Currie told AFP they suspect it has a lot to do with the soldier ants of another species of fungus-growing ants, Atta cephalotes. The two species will often engage in territorial "ant wars", which the researchers simulated in lab-based battles. "When the Acro majors are without their armour the Atta soldiers quickly cut them into pieces, literally," Currie said. "When they have their armour, they actually go from almost always losing the battles to almost always winning." The authors found that the benefits of a biomineralised exoskeleton go beyond giving the workers an edge in ant wars. Their studies suggest it also helps protect them against infection from the disease-causing fungus Metarhizium anisopliae, which might otherwise spread quickly through their dense colonies. Rare as sea urchin teeth Ants are believed to have started fungus subsistence farming about 60 million years ago in South America. Some 20 million years ago the practice became more "industrialised", with the emergence of leaf-cutting ant species like Acromyrmex echinatior and Atta cephalotes living in large, complex colonies and harvesting fresh vegetation that they use to grow their fungus. Acromyrmex echinatior colonies can be formed with hundreds of thousands of large and small worker ants. "The large ones do the cutting and carrying of leaves, as well as engaging in wars and battles with other ants," said Currie. "The small ones do the gardening." Atta colonies are bigger, composed of perhaps millions of ants, with up to seven different sizes of workers, including soldiers for "defence and ant wars", Currie said. The Acromyrmex echinatior armour is made from a high-magnesium calcite, researchers found. This is a rarer form of biomineralisation where the increased hardness from the magnesium is thought to help them grind up limestone. Given that the armour has only just been found on a relatively well-studied ant species, the researchers said this type of biomineral protection could be more widespread in the insect world. But Currie said this was likely to be the calcite biominerals found more commonly in marine animals like lobsters, rather than the high-magnesium calcite of the ants' armour and sea urchin teeth. "These ants are pretty special in many regards," he added. <|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 Oxidation can deteriorate the properties of copper that are critical for its use, particularly in the semiconductor industry and electro-optics applications 1 , 2 , 3 , 4 , 5 , 6 , 7 . This has prompted numerous studies exploring copper oxidation and possible passivation strategies 8 . In situ observations have, for example, shown that oxidation involves stepped surfaces: Cu 2 O growth occurs on flat surfaces as a result of Cu adatoms detaching from steps and diffusing across terraces 9 , 10 , 11 . But even though this mechanism explains why single-crystalline copper is more resistant to oxidation than polycrystalline copper, the fact that flat copper surfaces can be free of oxidation has not been explored further. Here we report the fabrication of copper thin films that are semi-permanently oxidation resistant because they consist of flat surfaces with only occasional mono-atomic steps. First-principles calculations confirm that mono-atomic step edges are as impervious to oxygen as flat surfaces and that surface adsorption of O atoms is suppressed once an oxygen face-centred cubic (fcc) surface site coverage of 50% has been reached. These combined effects explain the exceptional oxidation resistance of ultraflat Cu surfaces. Main Given that the step edge is vulnerable to oxidation because surface steps act as the dominant source of Cu adatoms for oxide growth on surface terraces 2 , 11 , oxidation resistance requires that surface step edges are avoided 6 , 12 , 13 . In this regard, the close-packed Cu(111) surface is superior to other Cu surfaces 14 , 15 and our experimental demonstration thus used a single-crystal Cu(111) film (SCCF) grown by atomic sputtering epitaxy (ASE) 16 to show that a tightly coordinated flat surface can remain semi-permanently stable against oxidation. Theoretical calculations show the atomic-scale oxidation-resistant mechanism of the flat copper surface from the perspective of the likely pathways for oxygen atoms into the viable structures of the copper surface with a discovery of the self-regulated protection layer at elevated oxygen coverages. The implication is that the atomically flat surface of the SCCF shows oxidation-resistant properties owing to the high energy barrier for oxygen infiltration and self-regulation owing to high oxygen coverages. Flatness of Cu(111) surface The surface and structural characteristics of a 110-nm-thick SCCF with an ultraflat surface (see Extended Data Fig. 1 for a large-scale characterization) are examined using high-resolution (scanning) transmission electron microscopy (HR(S)TEM) combined with geometrical phase analysis (GPA) 17 , 18 (Fig. 1 ). The cross-sectional (S)TEM images (Fig. 1a, e ) show that the copper film grew along the [111] direction, thus creating an exposed surface (111) plane with mono-atomic step-edge structures. Typical multi-atomic step edges and intrinsic defects such as grain boundaries and stacking faults are rarely detected. It is remarkable that the outermost copper surface layer has the same atomic configuration as the interior copper without evidence of surface relaxation or structural changes by surface oxidation, even at the step-edge positions. To examine the local strain behaviour near the surface region, lattice distortions along the in-plane ( x ) and out-of-plane ( y ) directions relative to the inside of the SCCF were measured by the GPA technique (Fig. 1b, c ). The resulting strain field maps ( E xx and E yy ) clearly show that no noticeable changein lattice strain is observed throughout the entire surface region. This means that the SCCF has a nearly perfect atomic structure up to its outermost surface layer without any structural defects, such as vacancies or dislocations. The simulated HRTEM image using an amorphous carbon/flat copper surface model matches well with the experimental HRTEM image (Fig. 1a ). By comparing the layer spacings of the (111) stacking planes ( d (111) = 0.21 nm) between the simulated and experimental images (Fig. 1d ), it is evident that the Cu surface is undistorted and ultraflat, and has the same structure as bulk Cu. Annular dark-field (ADF) and annular bright-field (ABF) STEM images of the SCCF surface are complementary to the HRTEM observation results (Fig. 1e ). We can discriminate this remarkable ultraflat surface structure of the SCCF from that of the conventional polycrystalline Cu thin film (PCCF) and the Cu(111) surface of a bulk Cu single crystal with a notable oxidized copper layer on top of them (Extended Data Fig. 2 and Fig. 3 ). Notably, we found that the SCCF sample maintained its ultraflat and pristine surface even after more than a year of air exposure (Fig. 2a–d ), suggesting that our SCCF has exceptional oxidation-resistant properties (also see Extended Data Fig. 4 for a large-scale scanning tunnelling microscope (STM) topography). Fig. 1: Surface of a single-crystal copper thin film grown by ASE. a , Cross-sectional HRTEM image of the surface region of the copper thin film observed in the \$[1\\overline{1}0]\$ orientation. The simulated HRTEM image and the corresponding model of the carbon–copper supercell are presented alongside the experimental HRTEM image. Scale bar is 2 nm. b , c , In-plane ( E xx ) and out-of-plane ( E yy ) strain field maps obtained by GPA for the experimental HRTEM image. The reference area of Cu chosen for GPA is marked by the white square boxes in each map. Note that complex patterns for parts of the carbon film are shaded by a grey colour for clarity, as those are not relevant for the strain behaviour of the SCCF. Scale bars are 2 nm. d , Comparison of the experimental and simulated intensity profiles obtained along the out-of-plane direction for (111) layer spacings ( d (111) = 0.21 nm). e , Simultaneously acquired ADF-STEM and ABF-STEM images for the surface region of the copper thin film. Scale bars are 2 nm. Source data Full size image Fig. 2: Long-term oxidation resistance and structural stability of the SCCF surface. a , Low-magnification BF-TEM image of the SCCF sample exposed to ambient air at room temperature for about 1 year (top). The result shows that the atomically flat surface morphology over the entire SCCF", "role": "user" }, { "content": "Copper (Cu) is of fundamental importance to our daily lives due to its excellent electrical conductivity, as well as other valuable physical properties, such as the ability to draw copper into thin wires. Cu is the metal that is at the heart of the electronics, semiconductor and electro-optics industry. But oxidation and unwanted corrosion on its surface can limit the lifespan and increase the electrical resistance of Cu. Now, a team of researchers led by Prof. Se-Young Jeong from Pusan National University have developed a way to fabricate oxidation-resistant thin films of copper. \"Oxidation-resistant Cu could potentially replace gold in semiconductor devices, which would help bring down their costs. Oxidation-resistant Cu could also reduce electrical consumption, as well as increase the lifespan of devices with nanocircuitry,\" says Prof. Jeong. The study has been published in Nature. Previous studies have shown that Cu oxidation occurs due to microscopic \"multi-steps\" on the surface of copper. These steps provide a source of Cu adatoms (adsorbed atoms), which interact with oxygen and provide a place for oxides to grow. This is why single-crystalline Cu is resistant to oxidation. \"We used a method called atomic sputtering epitaxy to grow tightly coordinated flat single-crystal copper films. By using noise reduction systems to reduce electrical and mechanical noises, we were able to keep the Cu surfaces nearly defect-free and fabricate atomically flat films,\" explains Prof. Jeong. The research team then used high-resolution transmission electron microscopy (HR-TEM) to study the Cu films. They found that the film grew in the [111] direction and had an almost flat surface with occasional mono-atomic steps. They then compared the single-crystal Cu (111) films (SCCFs) with other Cu films which had higher surface roughness and found that unlike with the other films, the SCCFs were oxidation-resistant, i.e., it is very difficult for oxygen to penetrate the mono-atomic step edge. The researchers then used a microscopic model of Cu oxidation based on \"density functional theory\" to investigate how the SCCF interacts with oxygen. They found that the surface of the SCCF was protected by oxygen itself, once 50% of its surface was covered with oxygen atoms. Additional absorption of oxygen atoms on the SCCF was suppressed by the high energy barrier they, themselves, created. \"The novelty of our research lies in the realization of atomically flat surfaces, i.e., surfaces that are flat on the atomic level, as well as an elucidation of the oxidation-resistance mechanism of ultraflat metals,\" concludes Prof. Jeong. The findings of this study make major contributions not only to the electronics and semiconductor industry, but also go a long way towards helping protect priceless bronze sculptures from damage. ", "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 Oxidation can deteriorate the properties of copper that are critical for its use, particularly in the semiconductor industry and electro-optics applications 1 , 2 , 3 , 4 , 5 , 6 , 7 . This has prompted numerous studies exploring copper oxidation and possible passivation strategies 8 . In situ observations have, for example, shown that oxidation involves stepped surfaces: Cu 2 O growth occurs on flat surfaces as a result of Cu adatoms detaching from steps and diffusing across terraces 9 , 10 , 11 . But even though this mechanism explains why single-crystalline copper is more resistant to oxidation than polycrystalline copper, the fact that flat copper surfaces can be free of oxidation has not been explored further. Here we report the fabrication of copper thin films that are semi-permanently oxidation resistant because they consist of flat surfaces with only occasional mono-atomic steps. First-principles calculations confirm that mono-atomic step edges are as impervious to oxygen as flat surfaces and that surface adsorption of O atoms is suppressed once an oxygen face-centred cubic (fcc) surface site coverage of 50% has been reached. These combined effects explain the exceptional oxidation resistance of ultraflat Cu surfaces. Main Given that the step edge is vulnerable to oxidation because surface steps act as the dominant source of Cu adatoms for oxide growth on surface terraces 2 , 11 , oxidation resistance requires that surface step edges are avoided 6 , 12 , 13 . In this regard, the close-packed Cu(111) surface is superior to other Cu surfaces 14 , 15 and our experimental demonstration thus used a single-crystal Cu(111) film (SCCF) grown by atomic sputtering epitaxy (ASE) 16 to show that a tightly coordinated flat surface can remain semi-permanently stable against oxidation. Theoretical calculations show the atomic-scale oxidation-resistant mechanism of the flat copper surface from the perspective of the likely pathways for oxygen atoms into the viable structures of the copper surface with a discovery of the self-regulated protection layer at elevated oxygen coverages. The implication is that the atomically flat surface of the SCCF shows oxidation-resistant properties owing to the high energy barrier for oxygen infiltration and self-regulation owing to high oxygen coverages. Flatness of Cu(111) surface The surface and structural characteristics of a 110-nm-thick SCCF with an ultraflat surface (see Extended Data Fig. 1 for a large-scale characterization) are examined using high-resolution (scanning) transmission electron microscopy (HR(S)TEM) combined with geometrical phase analysis (GPA) 17 , 18 (Fig. 1 ). The cross-sectional (S)TEM images (Fig. 1a, e ) show that the copper film grew along the [111] direction, thus creating an exposed surface (111) plane with mono-atomic step-edge structures. Typical multi-atomic step edges and intrinsic defects such as grain boundaries and stacking faults are rarely detected. It is remarkable that the outermost copper surface layer has the same atomic configuration as the interior copper without evidence of surface relaxation or structural changes by surface oxidation, even at the step-edge positions. To examine the local strain behaviour near the surface region, lattice distortions along the in-plane ( x ) and out-of-plane ( y ) directions relative to the inside of the SCCF were measured by the GPA technique (Fig. 1b, c ). The resulting strain field maps ( E xx and E yy ) clearly show that no noticeable changein lattice strain is observed throughout the entire surface region. This means that the SCCF has a nearly perfect atomic structure up to its outermost surface layer without any structural defects, such as vacancies or dislocations. The simulated HRTEM image using an amorphous carbon/flat copper surface model matches well with the experimental HRTEM image (Fig. 1a ). By comparing the layer spacings of the (111) stacking planes ( d (111) = 0.21 nm) between the simulated and experimental images (Fig. 1d ), it is evident that the Cu surface is undistorted and ultraflat, and has the same structure as bulk Cu. Annular dark-field (ADF) and annular bright-field (ABF) STEM images of the SCCF surface are complementary to the HRTEM observation results (Fig. 1e ). We can discriminate this remarkable ultraflat surface structure of the SCCF from that of the conventional polycrystalline Cu thin film (PCCF) and the Cu(111) surface of a bulk Cu single crystal with a notable oxidized copper layer on top of them (Extended Data Fig. 2 and Fig. 3 ). Notably, we found that the SCCF sample maintained its ultraflat and pristine surface even after more than a year of air exposure (Fig. 2a–d ), suggesting that our SCCF has exceptional oxidation-resistant properties (also see Extended Data Fig. 4 for a large-scale scanning tunnelling microscope (STM) topography). Fig. 1: Surface of a single-crystal copper thin film grown by ASE. a , Cross-sectional HRTEM image of the surface region of the copper thin film observed in the $[1\overline{1}0]$ orientation. The simulated HRTEM image and the corresponding model of the carbon–copper supercell are presented alongside the experimental HRTEM image. Scale bar is 2 nm. b , c , In-plane ( E xx ) and out-of-plane ( E yy ) strain field maps obtained by GPA for the experimental HRTEM image. The reference area of Cu chosen for GPA is marked by the white square boxes in each map. Note that complex patterns for parts of the carbon film are shaded by a grey colour for clarity, as those are not relevant for the strain behaviour of the SCCF. Scale bars are 2 nm. d , Comparison of the experimental and simulated intensity profiles obtained along the out-of-plane direction for (111) layer spacings ( d (111) = 0.21 nm). e , Simultaneously acquired ADF-STEM and ABF-STEM images for the surface region of the copper thin film. Scale bars are 2 nm. Source data Full size image Fig. 2: Long-term oxidation resistance and structural stability of the SCCF surface. a , Low-magnification BF-TEM image of the SCCF sample exposed to ambient air at room temperature for about 1 year (top). The result shows that the atomically flat surface morphology over the entire SCCF<|im_end|> <|im_start|>assistant Copper (Cu) is of fundamental importance to our daily lives due to its excellent electrical conductivity, as well as other valuable physical properties, such as the ability to draw copper into thin wires. Cu is the metal that is at the heart of the electronics, semiconductor and electro-optics industry. But oxidation and unwanted corrosion on its surface can limit the lifespan and increase the electrical resistance of Cu. Now, a team of researchers led by Prof. Se-Young Jeong from Pusan National University have developed a way to fabricate oxidation-resistant thin films of copper. "Oxidation-resistant Cu could potentially replace gold in semiconductor devices, which would help bring down their costs. Oxidation-resistant Cu could also reduce electrical consumption, as well as increase the lifespan of devices with nanocircuitry," says Prof. Jeong. The study has been published in Nature. Previous studies have shown that Cu oxidation occurs due to microscopic "multi-steps" on the surface of copper. These steps provide a source of Cu adatoms (adsorbed atoms), which interact with oxygen and provide a place for oxides to grow. This is why single-crystalline Cu is resistant to oxidation. "We used a method called atomic sputtering epitaxy to grow tightly coordinated flat single-crystal copper films. By using noise reduction systems to reduce electrical and mechanical noises, we were able to keep the Cu surfaces nearly defect-free and fabricate atomically flat films," explains Prof. Jeong. The research team then used high-resolution transmission electron microscopy (HR-TEM) to study the Cu films. They found that the film grew in the [111] direction and had an almost flat surface with occasional mono-atomic steps. They then compared the single-crystal Cu (111) films (SCCFs) with other Cu films which had higher surface roughness and found that unlike with the other films, the SCCFs were oxidation-resistant, i.e., it is very difficult for oxygen to penetrate the mono-atomic step edge. The researchers then used a microscopic model of Cu oxidation based on "density functional theory" to investigate how the SCCF interacts with oxygen. They found that the surface of the SCCF was protected by oxygen itself, once 50% of its surface was covered with oxygen atoms. Additional absorption of oxygen atoms on the SCCF was suppressed by the high energy barrier they, themselves, created. "The novelty of our research lies in the realization of atomically flat surfaces, i.e., surfaces that are flat on the atomic level, as well as an elucidation of the oxidation-resistance mechanism of ultraflat metals," concludes Prof. Jeong. The findings of this study make major contributions not only to the electronics and semiconductor industry, but also go a long way towards helping protect priceless bronze sculptures from damage. <|im_end|>

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30576, 430, 279, 27560, 7479, 374, 2073, 380, 13909, 323, 24955, 27323, 11, 323, 706, 279, 1890, 6070, 439, 20155, 27560, 13, 9489, 1299, 6453, 19677, 320, 92363, 8, 323, 3008, 1299, 10107, 19677, 320, 1905, 37, 8, 64182, 5448, 315, 279, 80399, 37, 7479, 527, 58535, 311, 279, 23096, 21695, 22695, 3135, 320, 30035, 13, 220, 16, 68, 7609, 1226, 649, 60541, 420, 23649, 24955, 27323, 7479, 6070, 315, 279, 80399, 37, 505, 430, 315, 279, 21349, 1499, 3418, 81, 599, 543, 483, 27560, 15792, 4632, 320, 47, 3791, 37, 8, 323, 279, 27560, 7, 5037, 8, 7479, 315, 264, 20155, 27560, 3254, 26110, 449, 264, 28289, 36172, 1534, 24166, 6324, 389, 1948, 315, 1124, 320, 54290, 2956, 23966, 13, 220, 17, 323, 23966, 13, 220, 18, 7609, 2876, 2915, 11, 584, 1766, 430, 279, 80399, 37, 6205, 18908, 1202, 24955, 27323, 323, 66085, 7479, 1524, 1306, 810, 1109, 264, 1060, 315, 3805, 14675, 320, 30035, 13, 220, 17, 64, 4235, 67, 7026, 23377, 430, 1057, 80399, 37, 706, 25363, 71162, 47056, 6012, 320, 19171, 1518, 41665, 2956, 23966, 13, 220, 19, 369, 264, 3544, 13230, 36201, 11716, 77, 6427, 73757, 320, 36949, 8, 1948, 5814, 570, 23966, 13, 220, 16, 25, 28061, 315, 264, 3254, 48689, 14272, 24166, 15792, 4632, 15042, 555, 99967, 13, 264, 1174, 11511, 97319, 23096, 21695, 2217, 315, 279, 7479, 5654, 315, 279, 24166, 15792, 4632, 13468, 304, 279, 1144, 2625, 16, 59, 2017, 1074, 90, 16, 92, 15, 18444, 8, 17140, 13, 578, 46836, 23096, 21695, 2217, 323, 279, 12435, 1646, 315, 279, 12782, 4235, 66, 18994, 2307, 5997, 527, 10666, 16662, 279, 22772, 23096, 21695, 2217, 13, 25635, 3703, 374, 220, 17, 26807, 13, 293, 1174, 272, 1174, 763, 90649, 320, 469, 21578, 883, 323, 704, 8838, 90649, 320, 469, 13499, 883, 26800, 2115, 14370, 12457, 555, 71155, 369, 279, 22772, 23096, 21695, 2217, 13, 578, 5905, 3158, 315, 27560, 12146, 369, 71155, 374, 13160, 555, 279, 4251, 9518, 15039, 304, 1855, 2472, 13, 7181, 430, 6485, 12912, 369, 5596, 315, 279, 12782, 4632, 527, 92866, 555, 264, 20366, 12745, 369, 32373, 11, 439, 1884, 527, 539, 9959, 369, 279, 26800, 17432, 315, 279, 80399, 37, 13, 25635, 16283, 527, 220, 17, 26807, 13, 294, 1174, 43551, 315, 279, 22772, 323, 46836, 21261, 21542, 12457, 3235, 279, 704, 8838, 90649, 5216, 369, 320, 5037, 8, 6324, 100108, 826, 320, 294, 320, 5037, 8, 284, 220, 15, 13, 1691, 26807, 570, 384, 1174, 4567, 495, 20933, 19426, 362, 5375, 12, 15642, 323, 14469, 37, 12, 15642, 5448, 369, 279, 7479, 5654, 315, 279, 24166, 15792, 4632, 13, 25635, 16283, 527, 220, 17, 26807, 13, 8922, 828, 8797, 1404, 2217, 23966, 13, 220, 17, 25, 5843, 9860, 71162, 13957, 323, 24693, 20334, 315, 279, 80399, 37, 7479, 13, 264, 1174, 12310, 1474, 3326, 2461, 51604, 12, 21695, 2217, 315, 279, 80399, 37, 6205, 15246, 311, 35288, 3805, 520, 3130, 9499, 369, 922, 220, 16, 1060, 320, 3565, 570, 578, 1121, 5039, 430, 279, 19670, 2740, 10269, 7479, 79612, 927, 279, 4553, 80399, 37, 128257, 198, 128256, 78191, 198, 34, 18994, 320, 45919, 8, 374, 315, 16188, 12939, 311, 1057, 7446, 6439, 4245, 311, 1202, 9250, 20314, 98971, 11, 439, 1664, 439, 1023, 15525, 7106, 6012, 11, 1778, 439, 279, 5845, 311, 4128, 24166, 1139, 15792, 36108, 13, 27560, 374, 279, 9501, 430, 374, 520, 279, 4851, 315, 279, 31591, 11, 87836, 323, 25396, 57212, 1233, 5064, 13, 2030, 71162, 323, 36021, 56488, 389, 1202, 7479, 649, 4017, 279, 61961, 323, 5376, 279, 20314, 13957, 315, 27560, 13, 4800, 11, 264, 2128, 315, 12074, 6197, 555, 8626, 13, 1369, 12, 41672, 14465, 647, 505, 393, 41312, 5165, 3907, 617, 8040, 264, 1648, 311, 13354, 349, 71162, 47056, 15792, 12631, 315, 24166, 13, 330, 46, 87, 307, 367, 47056, 27560, 1436, 13893, 8454, 6761, 304, 87836, 7766, 11, 902, 1053, 1520, 4546, 1523, 872, 7194, 13, 51715, 307, 367, 47056, 27560, 1436, 1101, 8108, 20314, 15652, 11, 439, 1664, 439, 5376, 279, 61961, 315, 7766, 449, 20622, 511, 38368, 894, 1359, 2795, 8626, 13, 14465, 647, 13, 578, 4007, 706, 1027, 4756, 304, 22037, 13, 30013, 7978, 617, 6982, 430, 27560, 71162, 13980, 4245, 311, 90090, 330, 27364, 5594, 7270, 1, 389, 279, 7479, 315, 24166, 13, 4314, 7504, 3493, 264, 2592, 315, 27560, 1008, 66650, 320, 7819, 269, 2788, 33299, 705, 902, 16681, 449, 24463, 323, 3493, 264, 2035, 369, 19488, 3422, 311, 3139, 13, 1115, 374, 3249, 3254, 48689, 599, 543, 483, 27560, 374, 31785, 311, 71162, 13, 330, 1687, 1511, 264, 1749, 2663, 25524, 274, 631, 60485, 67422, 14092, 311, 3139, 40069, 47672, 10269, 3254, 48689, 14272, 24166, 12631, 13, 3296, 1701, 12248, 14278, 6067, 311, 8108, 20314, 323, 22936, 58448, 11, 584, 1051, 3025, 311, 2567, 279, 27560, 27529, 7154, 23011, 12862, 323, 13354, 349, 19670, 2740, 10269, 12631, 1359, 15100, 8626, 13, 14465, 647, 13, 578, 3495, 2128, 1243, 1511, 1579, 64036, 18874, 17130, 92914, 320, 17526, 12, 21695, 8, 311, 4007, 279, 27560, 12631, 13, 2435, 1766, 430, 279, 4632, 14264, 304, 279, 510, 5037, 60, 5216, 323, 1047, 459, 4661, 10269, 7479, 449, 28961, 40774, 12, 6756, 7504, 13, 2435, 1243, 7863, 279, 3254, 48689, 14272, 27560, 320, 5037, 8, 12631, 320, 3624, 9847, 82, 8, 449, 1023, 27560, 12631, 902, 1047, 5190, 7479, 11413, 2136, 323, 1766, 430, 20426, 449, 279, 1023, 12631, 11, 279, 80399, 49400, 1051, 71162, 47056, 11, 602, 1770, 2637, 433, 374, 1633, 5107, 369, 24463, 311, 64855, 279, 40774, 12, 6756, 3094, 6964, 13, 578, 12074, 1243, 1511, 264, 90090, 1646, 315, 27560, 71162, 3196, 389, 330, 70918, 16003, 10334, 1, 311, 19874, 1268, 279, 80399, 37, 84261, 449, 24463, 13, 2435, 1766, 430, 279, 7479, 315, 279, 80399, 37, 574, 2682, 555, 24463, 5196, 11, 3131, 220, 1135, 4, 315, 1202, 7479, 574, 9960, 449, 24463, 33299, 13, 24086, 44225, 315, 24463, 33299, 389, 279, 80399, 37, 574, 56089, 555, 279, 1579, 4907, 22881, 814, 11, 5694, 11, 3549, 13, 330, 791, 67409, 315, 1057, 3495, 15812, 304, 279, 49803, 315, 19670, 2740, 10269, 27529, 11, 602, 1770, 2637, 27529, 430, 527, 10269, 389, 279, 25524, 2237, 11, 439, 1664, 439, 459, 97298, 367, 315, 279, 71162, 11849, 4011, 17383, 315, 24955, 27323, 37182, 1359, 45537, 8626, 13, 14465, 647, 13, 578, 14955, 315, 420, 4007, 1304, 3682, 19564, 539, 1193, 311, 279, 31591, 323, 87836, 5064, 11, 719, 1101, 733, 264, 1317, 1648, 7119, 10695, 6144, 92044, 40907, 75973, 505, 5674, 13, 220, 128257, 198 ]

1,955

[ { "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 Early-life trauma (ELT) is a risk factor for binge eating and obesity later in life, yet the neural circuits that underlie this association have not been addressed. Here, we show in mice that downregulation of the leptin receptor (Lepr) in the lateral hypothalamus (LH) and its effect on neural activity is crucial in causing ELT-induced binge-like eating and obesity upon high-fat diet exposure. We also found that the increased activity of Lepr-expressing LH (LH Lepr ) neurons encodes sustained binge-like eating in ELT mice. Inhibition of LH Lepr neurons projecting to the ventrolateral periaqueductal gray normalizes these behavioral features of ELT mice. Furthermore, activation of proenkephalin-expressing ventrolateral periaqueductal gray neurons, which receive inhibitory inputs from LH Lepr neurons, rescues ELT-induced maladaptive eating habits. Our results identify a circuit pathway that mediates ELT-induced maladaptive eating and may lead to the identification of novel therapeutic targets for binge eating and obesity. Main Stress has a powerful effect on food consumption, dietary preferences and food responsiveness 1 . In particular, exposure to traumatic events early in life, including child maltreatment or physical abuse, is a major risk factor for the development of maladaptive eating habits like emotional overeating and binge eating in adulthood 2 , 3 , 4 . Binge eating is characterized by the emotionally triggered consumption of large amounts of foods in a short period. Binge eating disorder (BED), the most common type of eating disorder, is defined by recurrent episodes of binge eating accompanied by feelings of loss of control even in the absence of hunger 5 , and it is often associated with being overweight 6 . Importantly, clinical studies suggest adults with BED frequently report histories of certain forms of ELT (for example, family conflict, loss of family members or economic distress), highlighting the importance of ELT in the development of binge eating habits later in life 7 , 8 . Thus, identifying the specific neural mechanisms underlying ELT-induced binge eating may aid the development of more effective therapies for BED and obesity. Because ELT is associated with long-lasting changes in the activity of the hypothalamic–pituitary–adrenal (HPA) axis, which influences the hormones that regulate appetite such as leptin 9 , 10 , studies have examined the mechanisms by which ELT alters the feeding-related hormonal system to induce maladaptive eating behaviors 11 , 12 . Leptin acts as a trophic factor during early development 13 , and a surge in circulating leptin levels regulates gene expression and synaptic connectivity crucial for the development of hypothalamic circuits 14 . Given that the hypothalamus is central in the regulation of feeding behaviors 15 , it is plausible that ELT may disturb the leptin system and impair hypothalamic function, with long-term consequences for appetite control and weight gain. However, leptin-responsive neural mechanisms or hypothalamic pathways that may drive ELT-induced binge eating habits have not been explored. Leptin exerts its anorexic effects by acting on its receptors (Lepr) in the hypothalamus. Lepr activation stimulates multiple signal transduction pathways and regulates neuronal activity to suppress food intake and body weight gain 16 , 17 . The arcuate nucleus (Arc) is one of the hypothalamic subregions in which considerable effort has been made to elucidate the central role of Lepr 18 ; however, the functions of Lepr beyond the Arc in the pathophysiology of BED are unknown. Indeed, Lepr is widely expressed in several hypothalamic subregions, including the LH, dorsomedial hypothalamus (DMH) and ventromedial hypothalamus (VMH) 19 . This wide hypothalamic distribution indicates that Lepr signaling may be involved in various functions, including regulation of stress responses, reward processing and emotional states 20 . However, apart from the homeostatic control of feeding, how leptin-responsive hypothalamic pathways may underlie emotional overeating and adapt to ELT has not been addressed. The LH is a heterogeneous structure that contains genetically and functionally distinct cell populations 21 , 22 . Early work with electrolytic lesions and electrical stimulation identified the LH as a crucial area for regulating food intake and motivated behaviors 23 . The LH also modulates the HPA axis to coordinate behavioral and physiological responses to stressful events 24 . However, the specific cell types or the precise LH circuit mechanisms that transduce ELT into a maladaptive circuit state that leads to binge eating and obesity later in life have not been explored. Here, we show in mice that ELT impairs Lepr signaling in the LH and that impaired LH Lepr signaling is sufficient to replicate the binge-like eating habits and accelerated weight gain of ELT mice. Moreover, LH Lepr neurons of ELT mice show consistent activation in response to repetitive high-fat diet (HFD) reexposures, which was associated with sustained binge-like eating patterns. In addition, acute and chronic silencing of the ventrolateral periaqueductal gray (vlPAG)-projecting LH Lepr neurons attenuates the maladaptive eating habits and excessive body weight gain in ELT mice. Finally, we show that vlPAG neurons expressing the opioid peptide proenkephalin (Penk) are important downstream targets of LH Lepr neurons that mediate the effect of ELT on binge-like eating habits. Together, our findings identify a discrete leptin-responsive LH–vlPAG pathway that is an important mediator of ELT-induced binge-like HFD overconsumption and weight gain. Results Early-life trauma augments binge-like eating in adulthood To investigate the effects of ELT on binge eating habits in adults, we adopted a modified version of the ELT paradigm in which mouse pups at postnatal day 3 (P3) were subjected to 23 h of separation from their dam and littermates, thus exposing pups to conditions with deficits in emotional and physical care 25 ( Methods and Fig. 1a ). To examine the impact of ELT on the modulation of peripheral hormones associated with feeding and stress, we measured serum leptin and corticosterone levels at the end of the ELT session. ELT pups had lower leptin and higher corticosterone levels than control pups at P4 (Extended Data Fig. 1a,b ). Altered levels of these hormones in early life are known to have long-lasting effects on body weight or behavioral stress responses 26 , 27", "role": "user" }, { "content": "Nearly 3 percent of Americans suffer from binge-eating disorder at some point their lifetimes, and of them, more than eight in 10 survived childhood abuse, neglect, or other trauma. Now, a Virginia Tech scientist has identified how early life trauma may change the brain to increase the risk of binge eating later in life. Research led by principal investigator Sora Shin, an assistant professor with the Fralin Biomedical Research Institute at VTC, revealed how a pathway in the brain that typically provides signals to stop eating may be altered by early life trauma. The discovery, obtained from studies in mice, in Nature Neuroscience on Dec. 12 adds new perspective to behaviors such as binge eating and obesity. \"We wanted to know the mechanism underlying how early life trauma induces these eating disorders,\" said Shin, who is also an assistant professor in the Department of Human Nutrition, Foods and Exercise in the College of Agriculture and Life Sciences. \"What we found is a specific brain circuit that is vulnerable to stress, causing it to become dysfunctional.\" \"This finding speaks to a set of broader health questions, which is how life's health course is set based on certain early experiences,\" said Michael Friedlander, executive director of the Fralin Biomedical Research Institute at VTC and Virginia Tech's vice president for Health Sciences and Technology. \"We are increasingly aware that early experiences and exposures ranging from those that occur even pre-conception in future parents through those that the fetus experiences in utero and to those that the child experiences throughout postnatal life can have dramatic impact on our health course throughout life. Dr. Shin's latest discovery in this one particular case shines an important new mechanistic light on this process. Like all innovative research, the study also raises additional important questions such as whether and how these effects can be changed. Dr. Shin's research can empower such lines of inquiry since a neural substrate and mechanism have been identified.\" Credit: Virginia Tech Stress symptoms can affect our body, thoughts and feelings, and behavior. In Shin's finding, the stress on mice who were separated from their litter mates may trigger life-long eating behavior changes. Binge-eating disorder is marked by recurring episodes of eating more rapidly than normal to beyond a feeling of fullness, and feelings of distress and loss of control, according to the Diagnostic and Statistical Manual of Mental Disorders. To identify the connection between the disorder and early life trauma, Shin and her lab team studied the impact of a hormone in the brain called leptin. Leptin has long been known suppress appetite and weight gain by signaling the brain that it's time to stop eating. The team found that in mice that experienced early life stress and exhibited behavior similar to binge-eating, leptin is less effective in a part of the brain called the lateral hypothalamus, where many behaviors are regulated. Without these signals from the brain, the overeating continues. Digging deeper, the researchers identified neurons in another part of the brain called the ventrolateral periaqueductal gray that respond to the message from leptin and lateral hypothalamus, thereby regulating binge eating. \"There is much more research to do,\" Shin said, \"but by knowing the specific molecule and receptors in the brain to target, we can now provide insight and the foundation for developing therapeutic strategies for the disorder.\" The discovery's potential is significant. \"This paper extends and brings considerable hope that the progress in the neuroscience of binge-eating disorder. Advanced imaging, and brain circuitry may allow experts to find risk factors, triggers, and causes,\" said Mark S. Gold, professor in the department of psychiatry at Washington University in St. Louis and formerly a University of Florida Distinguished Professor, Eminent Scholar, and chairman of the department of psychiatry, who was not involved in the research. \"Studying the role of traumatic and early life experiences of this pathway may help us fine-tune prevention and early intervention efforts to prevent binge-eating disorder.\" The paper's authors also include In-Jee You, a research associate in the Shin lab; Yeeun Bae, graduate student in Virginia Tech's Department of Human Nutrition, Foods, and Exercise; Mikel Cawley, former research assistant; and Abraham Han, former undergraduate volunteer; and from the University of California, San Diego, postdoctoral scholar Minju Jeong, postdoctoral scholar, Xiao-yun Wang, lab assistant, and Byungkook Lim, an associate professor of neurobiology. Shin is an iTHRIV Scholar, part of the integrated Translational Research Institute of Virginia (iTHRIV). ", "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 Early-life trauma (ELT) is a risk factor for binge eating and obesity later in life, yet the neural circuits that underlie this association have not been addressed. Here, we show in mice that downregulation of the leptin receptor (Lepr) in the lateral hypothalamus (LH) and its effect on neural activity is crucial in causing ELT-induced binge-like eating and obesity upon high-fat diet exposure. We also found that the increased activity of Lepr-expressing LH (LH Lepr ) neurons encodes sustained binge-like eating in ELT mice. Inhibition of LH Lepr neurons projecting to the ventrolateral periaqueductal gray normalizes these behavioral features of ELT mice. Furthermore, activation of proenkephalin-expressing ventrolateral periaqueductal gray neurons, which receive inhibitory inputs from LH Lepr neurons, rescues ELT-induced maladaptive eating habits. Our results identify a circuit pathway that mediates ELT-induced maladaptive eating and may lead to the identification of novel therapeutic targets for binge eating and obesity. Main Stress has a powerful effect on food consumption, dietary preferences and food responsiveness 1 . In particular, exposure to traumatic events early in life, including child maltreatment or physical abuse, is a major risk factor for the development of maladaptive eating habits like emotional overeating and binge eating in adulthood 2 , 3 , 4 . Binge eating is characterized by the emotionally triggered consumption of large amounts of foods in a short period. Binge eating disorder (BED), the most common type of eating disorder, is defined by recurrent episodes of binge eating accompanied by feelings of loss of control even in the absence of hunger 5 , and it is often associated with being overweight 6 . Importantly, clinical studies suggest adults with BED frequently report histories of certain forms of ELT (for example, family conflict, loss of family members or economic distress), highlighting the importance of ELT in the development of binge eating habits later in life 7 , 8 . Thus, identifying the specific neural mechanisms underlying ELT-induced binge eating may aid the development of more effective therapies for BED and obesity. Because ELT is associated with long-lasting changes in the activity of the hypothalamic–pituitary–adrenal (HPA) axis, which influences the hormones that regulate appetite such as leptin 9 , 10 , studies have examined the mechanisms by which ELT alters the feeding-related hormonal system to induce maladaptive eating behaviors 11 , 12 . Leptin acts as a trophic factor during early development 13 , and a surge in circulating leptin levels regulates gene expression and synaptic connectivity crucial for the development of hypothalamic circuits 14 . Given that the hypothalamus is central in the regulation of feeding behaviors 15 , it is plausible that ELT may disturb the leptin system and impair hypothalamic function, with long-term consequences for appetite control and weight gain. However, leptin-responsive neural mechanisms or hypothalamic pathways that may drive ELT-induced binge eating habits have not been explored. Leptin exerts its anorexic effects by acting on its receptors (Lepr) in the hypothalamus. Lepr activation stimulates multiple signal transduction pathways and regulates neuronal activity to suppress food intake and body weight gain 16 , 17 . The arcuate nucleus (Arc) is one of the hypothalamic subregions in which considerable effort has been made to elucidate the central role of Lepr 18 ; however, the functions of Lepr beyond the Arc in the pathophysiology of BED are unknown. Indeed, Lepr is widely expressed in several hypothalamic subregions, including the LH, dorsomedial hypothalamus (DMH) and ventromedial hypothalamus (VMH) 19 . This wide hypothalamic distribution indicates that Lepr signaling may be involved in various functions, including regulation of stress responses, reward processing and emotional states 20 . However, apart from the homeostatic control of feeding, how leptin-responsive hypothalamic pathways may underlie emotional overeating and adapt to ELT has not been addressed. The LH is a heterogeneous structure that contains genetically and functionally distinct cell populations 21 , 22 . Early work with electrolytic lesions and electrical stimulation identified the LH as a crucial area for regulating food intake and motivated behaviors 23 . The LH also modulates the HPA axis to coordinate behavioral and physiological responses to stressful events 24 . However, the specific cell types or the precise LH circuit mechanisms that transduce ELT into a maladaptive circuit state that leads to binge eating and obesity later in life have not been explored. Here, we show in mice that ELT impairs Lepr signaling in the LH and that impaired LH Lepr signaling is sufficient to replicate the binge-like eating habits and accelerated weight gain of ELT mice. Moreover, LH Lepr neurons of ELT mice show consistent activation in response to repetitive high-fat diet (HFD) reexposures, which was associated with sustained binge-like eating patterns. In addition, acute and chronic silencing of the ventrolateral periaqueductal gray (vlPAG)-projecting LH Lepr neurons attenuates the maladaptive eating habits and excessive body weight gain in ELT mice. Finally, we show that vlPAG neurons expressing the opioid peptide proenkephalin (Penk) are important downstream targets of LH Lepr neurons that mediate the effect of ELT on binge-like eating habits. Together, our findings identify a discrete leptin-responsive LH–vlPAG pathway that is an important mediator of ELT-induced binge-like HFD overconsumption and weight gain. Results Early-life trauma augments binge-like eating in adulthood To investigate the effects of ELT on binge eating habits in adults, we adopted a modified version of the ELT paradigm in which mouse pups at postnatal day 3 (P3) were subjected to 23 h of separation from their dam and littermates, thus exposing pups to conditions with deficits in emotional and physical care 25 ( Methods and Fig. 1a ). To examine the impact of ELT on the modulation of peripheral hormones associated with feeding and stress, we measured serum leptin and corticosterone levels at the end of the ELT session. ELT pups had lower leptin and higher corticosterone levels than control pups at P4 (Extended Data Fig. 1a,b ). Altered levels of these hormones in early life are known to have long-lasting effects on body weight or behavioral stress responses 26 , 27<|im_end|> <|im_start|>assistant Nearly 3 percent of Americans suffer from binge-eating disorder at some point their lifetimes, and of them, more than eight in 10 survived childhood abuse, neglect, or other trauma. Now, a Virginia Tech scientist has identified how early life trauma may change the brain to increase the risk of binge eating later in life. Research led by principal investigator Sora Shin, an assistant professor with the Fralin Biomedical Research Institute at VTC, revealed how a pathway in the brain that typically provides signals to stop eating may be altered by early life trauma. The discovery, obtained from studies in mice, in Nature Neuroscience on Dec. 12 adds new perspective to behaviors such as binge eating and obesity. "We wanted to know the mechanism underlying how early life trauma induces these eating disorders," said Shin, who is also an assistant professor in the Department of Human Nutrition, Foods and Exercise in the College of Agriculture and Life Sciences. "What we found is a specific brain circuit that is vulnerable to stress, causing it to become dysfunctional." "This finding speaks to a set of broader health questions, which is how life's health course is set based on certain early experiences," said Michael Friedlander, executive director of the Fralin Biomedical Research Institute at VTC and Virginia Tech's vice president for Health Sciences and Technology. "We are increasingly aware that early experiences and exposures ranging from those that occur even pre-conception in future parents through those that the fetus experiences in utero and to those that the child experiences throughout postnatal life can have dramatic impact on our health course throughout life. Dr. Shin's latest discovery in this one particular case shines an important new mechanistic light on this process. Like all innovative research, the study also raises additional important questions such as whether and how these effects can be changed. Dr. Shin's research can empower such lines of inquiry since a neural substrate and mechanism have been identified." Credit: Virginia Tech Stress symptoms can affect our body, thoughts and feelings, and behavior. In Shin's finding, the stress on mice who were separated from their litter mates may trigger life-long eating behavior changes. Binge-eating disorder is marked by recurring episodes of eating more rapidly than normal to beyond a feeling of fullness, and feelings of distress and loss of control, according to the Diagnostic and Statistical Manual of Mental Disorders. To identify the connection between the disorder and early life trauma, Shin and her lab team studied the impact of a hormone in the brain called leptin. Leptin has long been known suppress appetite and weight gain by signaling the brain that it's time to stop eating. The team found that in mice that experienced early life stress and exhibited behavior similar to binge-eating, leptin is less effective in a part of the brain called the lateral hypothalamus, where many behaviors are regulated. Without these signals from the brain, the overeating continues. Digging deeper, the researchers identified neurons in another part of the brain called the ventrolateral periaqueductal gray that respond to the message from leptin and lateral hypothalamus, thereby regulating binge eating. "There is much more research to do," Shin said, "but by knowing the specific molecule and receptors in the brain to target, we can now provide insight and the foundation for developing therapeutic strategies for the disorder." The discovery's potential is significant. "This paper extends and brings considerable hope that the progress in the neuroscience of binge-eating disorder. Advanced imaging, and brain circuitry may allow experts to find risk factors, triggers, and causes," said Mark S. Gold, professor in the department of psychiatry at Washington University in St. Louis and formerly a University of Florida Distinguished Professor, Eminent Scholar, and chairman of the department of psychiatry, who was not involved in the research. "Studying the role of traumatic and early life experiences of this pathway may help us fine-tune prevention and early intervention efforts to prevent binge-eating disorder." The paper's authors also include In-Jee You, a research associate in the Shin lab; Yeeun Bae, graduate student in Virginia Tech's Department of Human Nutrition, Foods, and Exercise; Mikel Cawley, former research assistant; and Abraham Han, former undergraduate volunteer; and from the University of California, San Diego, postdoctoral scholar Minju Jeong, postdoctoral scholar, Xiao-yun Wang, lab assistant, and Byungkook Lim, an associate professor of neurobiology. Shin is an iTHRIV Scholar, part of the integrated Translational Research Institute of Virginia (iTHRIV). <|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 Biological responses to climate change have been widely documented across taxa and regions, but it remains unclear whether species are maintaining a good match between phenotype and environment, i.e. whether observed trait changes are adaptive. Here we reviewed 10,090 abstracts and extracted data from 71 studies reported in 58 relevant publications, to assess quantitatively whether phenotypic trait changes associated with climate change are adaptive in animals. A meta-analysis focussing on birds, the taxon best represented in our dataset, suggests that global warming has not systematically affected morphological traits, but has advanced phenological traits. We demonstrate that these advances are adaptive for some species, but imperfect as evidenced by the observed consistent selection for earlier timing. Application of a theoretical model indicates that the evolutionary load imposed by incomplete adaptive responses to ongoing climate change may already be threatening the persistence of species. Introduction Climate change can reduce the viability of species and associated biodiversity loss can impact ecosystem functions and services 1 , 2 , 3 . Fitness losses (i.e. reductions in survival or reproductive rates) can be mitigated, however, if populations respond adaptively by undergoing morphological, physiological or behavioural changes that maintain an adequate match—or at least reduce the extent of mismatch—between phenotype and environment. Such adaptive phenotypic changes—which we call ‘adaptive response’ (to climate change)—come about via phenotypic plasticity, microevolution or a combination of both, and can occur in tandem with geographic range shifts 4 , 5 , 6 . Quantifying adaptive responses, or demonstrating their absence despite directional selection, is important in a biodiversity conservation context for predicting species’ abundances or distributions 4 , 5 and for mitigating the effects of climate change on biodiversity by developing strategies tailored to species’ ecologies 4 , 5 , 6 . Longitudinal studies of wild populations provide the opportunity to determine whether phenotypic changes are adaptive (e.g. refs. 7 , 8 , 9 ). A phenotypic change qualifies as an adaptive response to climate change if three conditions are met: (1) a climatic factor changes over time, (2) this climatic factor affects a phenotypic trait of a species and (3) the corresponding trait change confers fitness benefits (Fig. 1 ) 10 , 11 . These conditions are usually assessed in isolation 11 , 12 , 13 , 14 (but see, for example, refs. 7 , 8 ) and hence most studies can only speculate on whether adaptive responses have occurred. Here, we extracted data from many published studies to assess these three conditions in free-living animals and thus determine whether the observed phenotypic changes are adaptive. Fig. 1 A framework for inferring phenotypic adaptive responses using three conditions. a General framework. Arrows indicate hypothesized causal relationships, with dashed arrow indicating that we accounted for the effects associated with years when assessing the effect of climate on traits. b – f demonstrate steps of the framework using as an example one study from our dataset—Wilson et al. 69 . b Condition 1 is assessed by β Clim , the slope of a climatic variable on years, c Condition 2 is assessed by β Trait , the slope of the mean population trait values on climate. d Interim step: assessing the linear selection differentials ( β ). Note that each dot here represents an individual measurement in the respective year and not a population mean; analyses of selection were not performed here but in original publications, except for a few studies, thus inset d is a conceptual depiction and not based on real data. e To assess condition 3, first the weighted mean annual selection differential (WMSD) is estimated. f Condition 3 is then assessed by checking whether selection occurs in the same direction as the trait change over time, calculated as the product of the slopes from conditions 1 and 2. Red lines and font in b – f illustrate the predictions from model fits. Grey lines and font illustrate the lack of effect in each condition. As an example, if temperature increased over years (as shown by the red line in b ), phenology advanced (depicted by the red line in c ) and WMSD was negative (as depicted by the red line in e ), then fitness benefits are associated with phenological advancement, reflecting an adaptive response (point falls in quadrant 3 in f ). Source data are provided as a Source Data file Full size image Multiple studies report data satisfying the first two conditions. In particular, increases in temperatures across multiple locations during recent decades are well documented (i.e. global warming 15 ). Similarly, the effects of climate change on several traits are well characterized. For example, the timing of biological events, such as reproduction or migration (hereafter ‘phenological traits’), has generally advanced across multiple taxa and locations 13 , 16 , 17 , 18 . ‘Morphological traits’, such as body size or mass, have also responded to climate change, but show no general systematic pattern 8 , 14 , 19 , 20 . A substantial challenge to test the third condition is that the data must be collected over multiple generations in single populations. Existing datasets assembling data on either trait variation 21 , 22 , 23 or selection 24 , 25 , 26 across taxa, although valuable, are not well suited for testing whether phenotypic trait changes are adaptive, because these two types of datasets rarely overlap in terms of species, traits, study location and study period. Recently, Siepielski et al. 27 assembled a global dataset combining climatic factors and selection in species and showed that precipitation, rather than temperature, explained most of the variation in selection. However, neither their analysis nor a follow-up study 28 assessed whether phenotypic responses to climate (PRC) were adaptive because the assembled dataset does not contain data on trait changes. We conducted a systematic literature search to assemble the necessary data to assess whether trait changes in response to climate change are adaptive across animal species worldwide. We mainly investigated the phenotypic responses of birds, because complete data", "role": "user" }, { "content": "Climate change can threaten species, and extinctions can impact ecosystem health. It is therefore of vital importance to assess to which degree animals can respond to changing environmental conditions, for example, by shifting the timing of breeding, and whether these shifts enable the persistence of populations in the long run. To answer these questions, an international team of 64 researchers led by Viktoriia Radchuk, Alexandre Courtiol and Stephanie Kramer-Schadt from the Leibniz Institute for Zoo and Wildlife Research (Leibniz-IZW) evaluated more than 10,000 published scientific studies. The results of their analysis are worrisome: Although animals do commonly respond to climate change, such responses are in general insufficient to cope with the rapid pace of rising temperatures, and sometimes go in wrong directions. The results are published in the scientific journal Nature Communications. In wildlife, the most commonly observed response to climate change is an alteration in the timing of biological events such as hibernation, reproduction or migration (phenological traits). Changes in body size, body mass or other morphological traits have also been associated with climate change, but show no systematic pattern, as confirmed by this study. The researchers extracted relevant information from the scientific literature to relate changes in climate over the years to possible changes in phenological and morphological traits. Next, they evaluated whether observed trait changes were associated with higher survival or an increased number of offspring. \"Our research focused on birds because complete data on other groups were scarce,\" says lead author Viktoriia Radchuk (Leibniz-IZW). She adds, \"We demonstrate that in temperate regions, the rising temperatures are associated with the shift of the timing of biological events to earlier dates.\" Co-author Steven Beissinger, professor at the University of California-Berkeley, says, \"This suggests that species could stay in their warming habitat as long as they change fast enough to cope with climate change.\" However, senior author Alexandre Courtiol (Leibniz-IZW) says, \"This is unlikely to be the case, because even populations undergoing adaptive change do so at a pace that does not guarantee their persistence.\" Co-author Thomas Reed, senior lecturer at University College Cork, Ireland, says, \"These results were obtained by comparing the observed response to climate change with the one expected if a population would be able to adjust their traits so to track the climate change perfectly.\" Even more worrisome is the fact that the data included predominantly common and abundant species such as the great tit (Parus major), the European pied flycatcher (Ficedula hypoleuca) or the common magpie (Pica pica), which are known to cope with climate change relatively well. \"Adaptive responses among rare or endangered species remain to be analyzed. We fear that the forecasts of population persistence for such species of conservation concern will be even more pessimistic,\" concludes Stephanie Kramer-Schadt, head of the Department of Ecological Dynamics, Leibniz-IZW. The scientists hope that their analysis and the assembled datasets will stimulate research on the resilience of animal populations in the face of global change and contribute to a better predictive framework to assist future conservation management actions. ", "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 Biological responses to climate change have been widely documented across taxa and regions, but it remains unclear whether species are maintaining a good match between phenotype and environment, i.e. whether observed trait changes are adaptive. Here we reviewed 10,090 abstracts and extracted data from 71 studies reported in 58 relevant publications, to assess quantitatively whether phenotypic trait changes associated with climate change are adaptive in animals. A meta-analysis focussing on birds, the taxon best represented in our dataset, suggests that global warming has not systematically affected morphological traits, but has advanced phenological traits. We demonstrate that these advances are adaptive for some species, but imperfect as evidenced by the observed consistent selection for earlier timing. Application of a theoretical model indicates that the evolutionary load imposed by incomplete adaptive responses to ongoing climate change may already be threatening the persistence of species. Introduction Climate change can reduce the viability of species and associated biodiversity loss can impact ecosystem functions and services 1 , 2 , 3 . Fitness losses (i.e. reductions in survival or reproductive rates) can be mitigated, however, if populations respond adaptively by undergoing morphological, physiological or behavioural changes that maintain an adequate match—or at least reduce the extent of mismatch—between phenotype and environment. Such adaptive phenotypic changes—which we call ‘adaptive response’ (to climate change)—come about via phenotypic plasticity, microevolution or a combination of both, and can occur in tandem with geographic range shifts 4 , 5 , 6 . Quantifying adaptive responses, or demonstrating their absence despite directional selection, is important in a biodiversity conservation context for predicting species’ abundances or distributions 4 , 5 and for mitigating the effects of climate change on biodiversity by developing strategies tailored to species’ ecologies 4 , 5 , 6 . Longitudinal studies of wild populations provide the opportunity to determine whether phenotypic changes are adaptive (e.g. refs. 7 , 8 , 9 ). A phenotypic change qualifies as an adaptive response to climate change if three conditions are met: (1) a climatic factor changes over time, (2) this climatic factor affects a phenotypic trait of a species and (3) the corresponding trait change confers fitness benefits (Fig. 1 ) 10 , 11 . These conditions are usually assessed in isolation 11 , 12 , 13 , 14 (but see, for example, refs. 7 , 8 ) and hence most studies can only speculate on whether adaptive responses have occurred. Here, we extracted data from many published studies to assess these three conditions in free-living animals and thus determine whether the observed phenotypic changes are adaptive. Fig. 1 A framework for inferring phenotypic adaptive responses using three conditions. a General framework. Arrows indicate hypothesized causal relationships, with dashed arrow indicating that we accounted for the effects associated with years when assessing the effect of climate on traits. b – f demonstrate steps of the framework using as an example one study from our dataset—Wilson et al. 69 . b Condition 1 is assessed by β Clim , the slope of a climatic variable on years, c Condition 2 is assessed by β Trait , the slope of the mean population trait values on climate. d Interim step: assessing the linear selection differentials ( β ). Note that each dot here represents an individual measurement in the respective year and not a population mean; analyses of selection were not performed here but in original publications, except for a few studies, thus inset d is a conceptual depiction and not based on real data. e To assess condition 3, first the weighted mean annual selection differential (WMSD) is estimated. f Condition 3 is then assessed by checking whether selection occurs in the same direction as the trait change over time, calculated as the product of the slopes from conditions 1 and 2. Red lines and font in b – f illustrate the predictions from model fits. Grey lines and font illustrate the lack of effect in each condition. As an example, if temperature increased over years (as shown by the red line in b ), phenology advanced (depicted by the red line in c ) and WMSD was negative (as depicted by the red line in e ), then fitness benefits are associated with phenological advancement, reflecting an adaptive response (point falls in quadrant 3 in f ). Source data are provided as a Source Data file Full size image Multiple studies report data satisfying the first two conditions. In particular, increases in temperatures across multiple locations during recent decades are well documented (i.e. global warming 15 ). Similarly, the effects of climate change on several traits are well characterized. For example, the timing of biological events, such as reproduction or migration (hereafter ‘phenological traits’), has generally advanced across multiple taxa and locations 13 , 16 , 17 , 18 . ‘Morphological traits’, such as body size or mass, have also responded to climate change, but show no general systematic pattern 8 , 14 , 19 , 20 . A substantial challenge to test the third condition is that the data must be collected over multiple generations in single populations. Existing datasets assembling data on either trait variation 21 , 22 , 23 or selection 24 , 25 , 26 across taxa, although valuable, are not well suited for testing whether phenotypic trait changes are adaptive, because these two types of datasets rarely overlap in terms of species, traits, study location and study period. Recently, Siepielski et al. 27 assembled a global dataset combining climatic factors and selection in species and showed that precipitation, rather than temperature, explained most of the variation in selection. However, neither their analysis nor a follow-up study 28 assessed whether phenotypic responses to climate (PRC) were adaptive because the assembled dataset does not contain data on trait changes. We conducted a systematic literature search to assemble the necessary data to assess whether trait changes in response to climate change are adaptive across animal species worldwide. We mainly investigated the phenotypic responses of birds, because complete data<|im_end|> <|im_start|>assistant Climate change can threaten species, and extinctions can impact ecosystem health. It is therefore of vital importance to assess to which degree animals can respond to changing environmental conditions, for example, by shifting the timing of breeding, and whether these shifts enable the persistence of populations in the long run. To answer these questions, an international team of 64 researchers led by Viktoriia Radchuk, Alexandre Courtiol and Stephanie Kramer-Schadt from the Leibniz Institute for Zoo and Wildlife Research (Leibniz-IZW) evaluated more than 10,000 published scientific studies. The results of their analysis are worrisome: Although animals do commonly respond to climate change, such responses are in general insufficient to cope with the rapid pace of rising temperatures, and sometimes go in wrong directions. The results are published in the scientific journal Nature Communications. In wildlife, the most commonly observed response to climate change is an alteration in the timing of biological events such as hibernation, reproduction or migration (phenological traits). Changes in body size, body mass or other morphological traits have also been associated with climate change, but show no systematic pattern, as confirmed by this study. The researchers extracted relevant information from the scientific literature to relate changes in climate over the years to possible changes in phenological and morphological traits. Next, they evaluated whether observed trait changes were associated with higher survival or an increased number of offspring. "Our research focused on birds because complete data on other groups were scarce," says lead author Viktoriia Radchuk (Leibniz-IZW). She adds, "We demonstrate that in temperate regions, the rising temperatures are associated with the shift of the timing of biological events to earlier dates." Co-author Steven Beissinger, professor at the University of California-Berkeley, says, "This suggests that species could stay in their warming habitat as long as they change fast enough to cope with climate change." However, senior author Alexandre Courtiol (Leibniz-IZW) says, "This is unlikely to be the case, because even populations undergoing adaptive change do so at a pace that does not guarantee their persistence." Co-author Thomas Reed, senior lecturer at University College Cork, Ireland, says, "These results were obtained by comparing the observed response to climate change with the one expected if a population would be able to adjust their traits so to track the climate change perfectly." Even more worrisome is the fact that the data included predominantly common and abundant species such as the great tit (Parus major), the European pied flycatcher (Ficedula hypoleuca) or the common magpie (Pica pica), which are known to cope with climate change relatively well. "Adaptive responses among rare or endangered species remain to be analyzed. We fear that the forecasts of population persistence for such species of conservation concern will be even more pessimistic," concludes Stephanie Kramer-Schadt, head of the Department of Ecological Dynamics, Leibniz-IZW. The scientists hope that their analysis and the assembled datasets will stimulate research on the resilience of animal populations in the face of global change and contribute to a better predictive framework to assist future conservation management actions. <|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 Rationale Lung transplantation is the ultimate treatment option for patients with end-stage respiratory diseases but bears the highest mortality rate among all solid organ transplantations due to chronic lung allograft dysfunction (CLAD). The mechanisms leading to CLAD remain elusive due to an insufficient understanding of the complex post-transplant adaptation processes. Objectives To better understand these lung adaptation processes after transplantation and to investigate their association with future changes in allograft function. Methods We performed an exploratory cohort study of bronchoalveolar lavage samples from 78 lung recipients and donors. We analysed the alveolar microbiome using 16S rRNA sequencing, the cellular composition using flow cytometry, as well as metabolome and lipidome profiling. Measurements and main results We established distinct temporal dynamics for each of the analysed data sets. Comparing matched donor and recipient samples, we revealed that recipient-specific as well as environmental factors, rather than the donor microbiome, shape the long-term lung microbiome. We further discovered that the abundance of certain bacterial strains correlated with underlying lung diseases even after transplantation. A decline in forced expiratory volume during the first second (FEV 1 ) is a major characteristic of lung allograft dysfunction in transplant recipients. By using a machine learning approach, we could accurately predict future changes in FEV 1 from our multi-omics data, whereby microbial profiles showed a particularly high predictive power. Conclusion Bronchoalveolar microbiome, cellular composition, metabolome and lipidome show specific temporal dynamics after lung transplantation. The lung microbiome can predict future changes in lung function with high precision. Tweetable abstract @ERSpublications click to tweet Broncho-alveolar microbiome, cellular composition, metabolome and lipidome show specific temporal dynamics after lung transplantation. The post-transplantation lung microbiome can predict future changes in lung function with high precision. Introduction Lung transplantation is the ultimate, life-saving treatment for patients with end-stage respiratory failure. Despite substantial medical advances, the 5-year survival rate remains at only 54%, which is the lowest among all solid organ recipients [ 1 ]. This grim prognosis is a consequence of a range of pathologies that prevent the transplanted lung from maintaining normal function, which are summarised under the umbrella term chronic lung allograft dysfunction (CLAD). The most frequent manifestation of CLAD is bronchiolitis obliterans syndrome (BOS), which is characterised by the development of airflow limitation caused by bronchiolitis obliterans [ 2 ]. The underlying disease mechanism has been linked to allo- and auto-immunity as well as microbial triggers [ 3 ], but the precise pathophysiology is not known and no specific treatment is available. Once considered a sterile body site, the lungs are now known to harbour a unique microbiome that is critical for respiratory health and immune homeostasis [ 4 ]. Recent studies indicate that community-level activities can modulate microbiome pathogenicity [ 5 ], myeloid cell responses [ 6 ], pulmonary remodelling [ 7 , 8 ] and CLAD development [ 9 , 10 ] after lung transplantation. However, host–microbe interplay in the transplanted lung is insufficiently understood and it is unclear to what degree the donor lung microbiome contributes to the post-transplant microbiome and whether this bears relevance for CLAD development. Innate immune responses are an emerging concept in understanding the events leading to chronic inflammation and CLAD [ 11 ]. As such, resident alveolar macrophages (AMs) seem to be instrumental in CLAD development [ 12 ], and the higher abundance of neutrophils in transplants is considered detrimental in graft acceptance and survival [ 11 , 13 ]. These findings clearly suggest a role for myeloid cells in transplant adaptation and function, yet studies investigating the simultaneous coordination of cellular and pulmonary microbial changes are lacking. Metabolites reflect local metabolic states and can mediate the crosstalk between immune responses and microbiota. In lung transplant recipients, the metabolome composition of bronchoalveolar lavage (BAL) fluid was used to reliably classify the degree of BOS severity [ 14 ] and metabolomics/lipidomics of donor lung ex vivo lung perfusion fluids were shown to predict primary graft dysfunction [ 15 ]. Considering these findings, we hypothesised that the pulmonary metabolome and lipidome might provide important clues to understanding multi-level adaptation after lung transplantation. A better understanding of the contribution of the pulmonary microbiome, metabolome, lipidome and cellular profiles to the development of CLAD requires a holistic assessment of post-transplant dynamics. In this explorative cohort study, we characterised the reshaping of the pulmonary environment after transplantation with the primary objective to identify time-dependent factors of the process and the secondary objective to describe drivers of lung function decline. Variation of cell composition, microbial diversity, lipid and metabolite profiles, as well as the spirometry parameter FEV 1 (forced expiratory volume during the first second) served as statistical endpoints. We discovered that the microbial composition after lung transplantation was primarily driven by environmental and recipient-specific factors, independent of the donor microbiome, and identified selected microbial species that correlated with transplant indication. Using a computational model enabled us to predict lung function trajectories from multi-omics data sets. The explorative study design entails a descriptive interpretation of p-values and limits conclusions on negative results due to lack of power for small effects. Ultimately, a more comprehensive knowledge of graft adaptation will enable us to identify novel therapeutic angles to prevent lung allograft dysfunction in the future. Materials and methods Detailed descriptions of materials and methods are provided as a supplement . Patient collective and recruitment We included all 78 patients who underwent lung transplantation at the Medical University of Vienna between February 2017 and November 2018. The cohort consisted of 76 double lung and two single lung recipients. Donor lung derived BAL samples of sufficiently high quality were available for 23 matched transplant recipients. To obtain a reliable number of donor samples for cross-sectional analyses we included 24 additional high-quality donor BALs without matching recipients. Detailed inclusion and exclusion criteria are stated in the supplementary information . All BAL samples were collected under sterile conditions during routine bronchoscopy, except for one sample that was collected due to acute respiratory symptoms. Routine bronchoscopy was performed before extubation, at four, eight,", "role": "user" }, { "content": "Lung transplantation is a life-saving intervention in cases of severe respiratory failure. A feared and common complication following a lung transplant is chronic deterioration in lung function (CLAD/Chronic Lung Allograft Dysfunction). Early diagnosis of any threatened deterioration in lung function is therefore important, so that therapeutic measures can be taken to prevent it. MedUni Vienna scientists from the Department of Medicine I and from the Department of Thoracic Surgery have now discovered that a detailed analysis of the lung microbiome can be used to predict future changes in lung function. The working groups of Sylvia Knapp and Konrad Hötzenecker successfully used Machine Learning to show that certain microbiome profiles of the lung following lung transplantation can provide prognostic information. \"This method therefore enables us to predict future changes in lung function—and so could help to identify at-risk patients early on,\" emphasizes Knapp. CLAD affects up to 50% of lung transplant patient within the first five years following the procedure. Previous illnesses also determine the post-transplantation lung microbiome. \"We looked closely at how the environment of the lower airways changes over time in the allografts of a total of 78 patients following lung transplantation and adapts to the new host. For example, we investigated which bacteria, which immune cells and which metabolites are present and how these change in their new host,\" explains Knapp. The researchers were able to show that the lung microbiome changes continuously until ultimately recipient-specific factors—such as age, gender, underlying disease—define the microbiome in the long term. Moreover, the scientists discovered that certain bacteria, which are prevalent in some lung diseases prior to transplantation (e.g. in cystic fibrosis), can also move into the otherwise healthy lung following transplantation and become established. The conclusion: \"That means that pre-existing conditions of the allograft recipient also determine the lung microbiome after transplantation.\" Using artificial intelligence in the form of machine learning and based on the analysis of the multiomics data—including not only the microbiome, but also the lipidome (lipid composition), the metabolome (metabolic building blocks of the cells) and clinical parameters—enabled them to predict changes in lung function. \"Our calculations therefore show that certain microbiome profiles provide prognostic information,\" say Knapp and Hötzenecker in summary. ", "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 Rationale Lung transplantation is the ultimate treatment option for patients with end-stage respiratory diseases but bears the highest mortality rate among all solid organ transplantations due to chronic lung allograft dysfunction (CLAD). The mechanisms leading to CLAD remain elusive due to an insufficient understanding of the complex post-transplant adaptation processes. Objectives To better understand these lung adaptation processes after transplantation and to investigate their association with future changes in allograft function. Methods We performed an exploratory cohort study of bronchoalveolar lavage samples from 78 lung recipients and donors. We analysed the alveolar microbiome using 16S rRNA sequencing, the cellular composition using flow cytometry, as well as metabolome and lipidome profiling. Measurements and main results We established distinct temporal dynamics for each of the analysed data sets. Comparing matched donor and recipient samples, we revealed that recipient-specific as well as environmental factors, rather than the donor microbiome, shape the long-term lung microbiome. We further discovered that the abundance of certain bacterial strains correlated with underlying lung diseases even after transplantation. A decline in forced expiratory volume during the first second (FEV 1 ) is a major characteristic of lung allograft dysfunction in transplant recipients. By using a machine learning approach, we could accurately predict future changes in FEV 1 from our multi-omics data, whereby microbial profiles showed a particularly high predictive power. Conclusion Bronchoalveolar microbiome, cellular composition, metabolome and lipidome show specific temporal dynamics after lung transplantation. The lung microbiome can predict future changes in lung function with high precision. Tweetable abstract @ERSpublications click to tweet Broncho-alveolar microbiome, cellular composition, metabolome and lipidome show specific temporal dynamics after lung transplantation. The post-transplantation lung microbiome can predict future changes in lung function with high precision. Introduction Lung transplantation is the ultimate, life-saving treatment for patients with end-stage respiratory failure. Despite substantial medical advances, the 5-year survival rate remains at only 54%, which is the lowest among all solid organ recipients [ 1 ]. This grim prognosis is a consequence of a range of pathologies that prevent the transplanted lung from maintaining normal function, which are summarised under the umbrella term chronic lung allograft dysfunction (CLAD). The most frequent manifestation of CLAD is bronchiolitis obliterans syndrome (BOS), which is characterised by the development of airflow limitation caused by bronchiolitis obliterans [ 2 ]. The underlying disease mechanism has been linked to allo- and auto-immunity as well as microbial triggers [ 3 ], but the precise pathophysiology is not known and no specific treatment is available. Once considered a sterile body site, the lungs are now known to harbour a unique microbiome that is critical for respiratory health and immune homeostasis [ 4 ]. Recent studies indicate that community-level activities can modulate microbiome pathogenicity [ 5 ], myeloid cell responses [ 6 ], pulmonary remodelling [ 7 , 8 ] and CLAD development [ 9 , 10 ] after lung transplantation. However, host–microbe interplay in the transplanted lung is insufficiently understood and it is unclear to what degree the donor lung microbiome contributes to the post-transplant microbiome and whether this bears relevance for CLAD development. Innate immune responses are an emerging concept in understanding the events leading to chronic inflammation and CLAD [ 11 ]. As such, resident alveolar macrophages (AMs) seem to be instrumental in CLAD development [ 12 ], and the higher abundance of neutrophils in transplants is considered detrimental in graft acceptance and survival [ 11 , 13 ]. These findings clearly suggest a role for myeloid cells in transplant adaptation and function, yet studies investigating the simultaneous coordination of cellular and pulmonary microbial changes are lacking. Metabolites reflect local metabolic states and can mediate the crosstalk between immune responses and microbiota. In lung transplant recipients, the metabolome composition of bronchoalveolar lavage (BAL) fluid was used to reliably classify the degree of BOS severity [ 14 ] and metabolomics/lipidomics of donor lung ex vivo lung perfusion fluids were shown to predict primary graft dysfunction [ 15 ]. Considering these findings, we hypothesised that the pulmonary metabolome and lipidome might provide important clues to understanding multi-level adaptation after lung transplantation. A better understanding of the contribution of the pulmonary microbiome, metabolome, lipidome and cellular profiles to the development of CLAD requires a holistic assessment of post-transplant dynamics. In this explorative cohort study, we characterised the reshaping of the pulmonary environment after transplantation with the primary objective to identify time-dependent factors of the process and the secondary objective to describe drivers of lung function decline. Variation of cell composition, microbial diversity, lipid and metabolite profiles, as well as the spirometry parameter FEV 1 (forced expiratory volume during the first second) served as statistical endpoints. We discovered that the microbial composition after lung transplantation was primarily driven by environmental and recipient-specific factors, independent of the donor microbiome, and identified selected microbial species that correlated with transplant indication. Using a computational model enabled us to predict lung function trajectories from multi-omics data sets. The explorative study design entails a descriptive interpretation of p-values and limits conclusions on negative results due to lack of power for small effects. Ultimately, a more comprehensive knowledge of graft adaptation will enable us to identify novel therapeutic angles to prevent lung allograft dysfunction in the future. Materials and methods Detailed descriptions of materials and methods are provided as a supplement . Patient collective and recruitment We included all 78 patients who underwent lung transplantation at the Medical University of Vienna between February 2017 and November 2018. The cohort consisted of 76 double lung and two single lung recipients. Donor lung derived BAL samples of sufficiently high quality were available for 23 matched transplant recipients. To obtain a reliable number of donor samples for cross-sectional analyses we included 24 additional high-quality donor BALs without matching recipients. Detailed inclusion and exclusion criteria are stated in the supplementary information . All BAL samples were collected under sterile conditions during routine bronchoscopy, except for one sample that was collected due to acute respiratory symptoms. Routine bronchoscopy was performed before extubation, at four, eight,<|im_end|> <|im_start|>assistant Lung transplantation is a life-saving intervention in cases of severe respiratory failure. A feared and common complication following a lung transplant is chronic deterioration in lung function (CLAD/Chronic Lung Allograft Dysfunction). Early diagnosis of any threatened deterioration in lung function is therefore important, so that therapeutic measures can be taken to prevent it. MedUni Vienna scientists from the Department of Medicine I and from the Department of Thoracic Surgery have now discovered that a detailed analysis of the lung microbiome can be used to predict future changes in lung function. The working groups of Sylvia Knapp and Konrad Hötzenecker successfully used Machine Learning to show that certain microbiome profiles of the lung following lung transplantation can provide prognostic information. "This method therefore enables us to predict future changes in lung function—and so could help to identify at-risk patients early on," emphasizes Knapp. CLAD affects up to 50% of lung transplant patient within the first five years following the procedure. Previous illnesses also determine the post-transplantation lung microbiome. "We looked closely at how the environment of the lower airways changes over time in the allografts of a total of 78 patients following lung transplantation and adapts to the new host. For example, we investigated which bacteria, which immune cells and which metabolites are present and how these change in their new host," explains Knapp. The researchers were able to show that the lung microbiome changes continuously until ultimately recipient-specific factors—such as age, gender, underlying disease—define the microbiome in the long term. Moreover, the scientists discovered that certain bacteria, which are prevalent in some lung diseases prior to transplantation (e.g. in cystic fibrosis), can also move into the otherwise healthy lung following transplantation and become established. The conclusion: "That means that pre-existing conditions of the allograft recipient also determine the lung microbiome after transplantation." Using artificial intelligence in the form of machine learning and based on the analysis of the multiomics data—including not only the microbiome, but also the lipidome (lipid composition), the metabolome (metabolic building blocks of the cells) and clinical parameters—enabled them to predict changes in lung function. "Our calculations therefore show that certain microbiome profiles provide prognostic information," say Knapp and Hötzenecker in summary. <|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 Despite knowing a familiar individual (such as a daughter) well, anecdotal evidence suggests that naming errors can occur among very familiar individuals. Here, we investigate the conditions surrounding these types of errors, or misnamings , in which a person (the misnamer ) incorrectly calls a familiar individual (the misnamed ) by someone else’s name (the named ). Across 5 studies including over 1,700 participants, we investigated the prevalence of the phenomenon of misnaming, identified factors underlying why it may occur, and tested potential mechanisms. We included undergraduates and MTurk workers and asked questions of both the misnamed and the misnamer. We find that familiar individuals are often misnamed with the name of another member of the same semantic category; family members are misnamed with another family member’s name and friends are misnamed with another friend’s name. Phonetic similarity between names also leads to misnamings; however, the size of this effect was smaller than that of the semantic category effect. Overall, the misnaming of familiar individuals is driven by the relationship between the misnamer, misnamed, and named; phonetic similarity between the incorrect name used by the misnamer and the correct name also plays a role in misnaming. Working on a manuscript? Avoid the common mistakes “Becky . . . Jesse . . . Molly . . . no, Samantha! Help me with the groceries,” your mother yells, looking at you. Each of the authors, though different in gender, age, and background, have been called a sibling’s name by an older family member who actually knew who we were; for three of us who owned a dog, we were even called the dog’s name. The last author, having experienced this seeming insult by loving parents as a child, now does it to his graduate students, and he only has two. This could not be simply part of the aging process; a young adult calling a romantic partner by another real or imagined partner's name (e. g., “I, Ross, take thee, Rachel...”) is a common plot line in popular culture. Instead of leaving this as a laboratory joke, we decided to study it because, despite the prevalence of research into the retrieval of proper names that are low in familiarity (e.g., Burke, MacKay, Worthley, & Wade, 1991 ; Cohen, 1990 ; McKenna & Warrington, 1980 ), very few studies have looked at how the names of highly familiar (noncelebrity) people are retrieved, or more interestingly, incorrectly retrieved. More formally, we investigate the conditions surrounding these types of errors, or misnamings , in which a person (the misnamer ) incorrectly calls a familiar individual (the misnamed ) by the name of someone else (the named ). In spite of the anecdotal data suggesting that misnamings are a common phenomenon, we could find only two diary studies that examine the phenomenon of individuals misnaming those whom they know personally. Young, Hay, and Ellis ( 1985 ) had participants record errors in person recognition, including not recognizing a familiar person and difficulty retrieving a person’s name. Of interest here, roughly one-third of the reports were for the misidentification of a familiar person. The authors suggest that these misnamings occurred because of both semantic (within the same category) and physical similarity between the misnamed and the named. Cohen and Faulkner ( 1986 ; also see Burke et al., 1991 ) also questioned people about naming blocks (the inability to recall a name), although their focus was on age differences. No naming blocks for relatives were reported, but the majority of naming difficulties reported did occur for friends and acquaintances. When trying to retrieve the correct name, people reported recalling the names of those semantically similar to the individual in question, suggesting that proper names are linked with other semantic information about a person that in turn connects them to similar individuals. Other studies have examined difficulty in remembering the correct names of moderately well-known individuals rather than the problem of easily remembering a wrong name for a personally known individual. For example, research on the naming of celebrities has shown that naming blocks or misnaming of celebrities can occur (Brédart, 1993 ; Griffin, 2010 ; Young, Ellis, & Flude, 1988 ), but these misnamings may be qualitatively different from misnaming a personally and well-known individual. However, given the paucity of data on the phenomenon of interest, these studies also provide useful sources of information and hypotheses. In one misnaming study by Griffin ( 2010 ), college students were asked to recognize the faces of well-known celebrities. When subjects failed at recognizing the celebrities, they did not make random errors. Instead, celebrities that were misrecognized were mistaken for individuals with similar characteristics. These characteristics were occasionally physical, but errors also occurred because of similarities in nationality and profession. For instance, President Kennedy was mistaken for President Regan, and Elizabeth I was mistaken for Mary, Queen of Scots. This observed semantic relatedness between misnamed individuals and named individuals is consistent with a possible mechanism by which misnaming occurs: semantic information activated by seeing or thinking of a person can cause the incorrect activation of another person’s name because those people are within the same group or semantic category (here, family, friends, or other). Results of these studies are consistent with the interactive activations and competition model of person recognition (Brédart, Valentine, Calder, & Gassi, 1995 ; Burton, Bruce, & Hancock, 1999 ; Burton, Bruce, & Johnston, 1990 ), which posits that information about a person is coded as a shared semantic unit or category (e.g., relative, friend); activation of a semantic unit can spread to facilitate retrieval of other individuals within the same unit. This shared semantic information can lead to associative and categorical priming when naming closely related individuals (Carson & Burton, 2001 ; Darling & Valentine, 2005 ; Vladeanu, Lewis, & Ellis, 2006 ; see Stone, 2008 , for a more nuanced examination of the associative vs. categorical priming debate). Names of people within a given category can even cause proactive interference for the name of", "role": "user" }, { "content": "It's happened to many of us: While looking right at someone you know very well, you open your mouth and blurt out the wrong name. The name you blurt is not just any old name, though, says new research from Duke University that finds \"misnaming\" follows predictable patterns. Among people who know each other well, the wrong name is usually plucked from the same relationship category, the study finds. Friends call each other by other friends' names, and family members by other family members' names. And that includes the family dog. \"It's a cognitive mistake we make, which reveals something about who we consider to be in our group,\" said Duke psychology and neuroscience professor David Rubin, one of the study authors. \"It's not just random.\" The new paper, based on five separate surveys of more than 1,700 respondents, appears online this week in the journal Memory & Cognition. Many of the patterns didn't surprise lead author Samantha Deffler, a Ph.D. student at Duke. One did, though. In addition to mixing up sibling for sibling and daughter for son, study participants frequently called other family members by the name of the family pet—but only when the pet was a dog. Owners of cats or other pets didn't commit such slips of the tongue. Deffler says she was surprised how consistent that finding was, and how often it happened. \"I'll preface this by saying I have cats and I love them,\" Deffler says. \"But our study does seem to add to evidence about the special relationship between people and dogs. \"Also, dogs will respond to their names much more than cats, so those names are used more often. Perhaps because of that, the dog's name seems to become more integrated with people's conceptions of their families.\" Phonetic similarity between names helps fuel mix-ups too, the authors found. Names with the same beginning or ending sounds, such as Michael and Mitchell or Joey and Mikey, were more likely to be swapped. So were names that shared phonemes, or sounds, such as John and Bob, which share the same vowel sound. Physical similarities between people, on the other hand, played little to no role. For instance, parents were inclined to swap their children's names even when the children looked nothing alike and were different genders. It's not a question of aging, either: The authors found plenty of instances of misnaming among college undergraduates. Although misnaming is a common theme in popular culture, Deffler said the new study is one of few describing how the phenomenon works. Deffler is no stranger to the experience in her own life. Her graduate supervisor frequently swaps the names of his two graduate assistants. And growing up, she said, her mom often called her Rebecca, Jesse or Molly—the names of her sister, brother and the family pit bull. \"I'm graduating in two weeks and my siblings will all be there,\" Deffler said. \"I know my mom will make mistakes.\" Now she knows why. In addition to Deffler and Rubin, the authors included Duke postdoctoral researcher Christin Ogle and Cassidy Fox, a 2013 Duke graduate. Fox helped lead the research project while studying at Duke as an undergraduate and devoted her senior thesis to the topic. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Despite knowing a familiar individual (such as a daughter) well, anecdotal evidence suggests that naming errors can occur among very familiar individuals. Here, we investigate the conditions surrounding these types of errors, or misnamings , in which a person (the misnamer ) incorrectly calls a familiar individual (the misnamed ) by someone else’s name (the named ). Across 5 studies including over 1,700 participants, we investigated the prevalence of the phenomenon of misnaming, identified factors underlying why it may occur, and tested potential mechanisms. We included undergraduates and MTurk workers and asked questions of both the misnamed and the misnamer. We find that familiar individuals are often misnamed with the name of another member of the same semantic category; family members are misnamed with another family member’s name and friends are misnamed with another friend’s name. Phonetic similarity between names also leads to misnamings; however, the size of this effect was smaller than that of the semantic category effect. Overall, the misnaming of familiar individuals is driven by the relationship between the misnamer, misnamed, and named; phonetic similarity between the incorrect name used by the misnamer and the correct name also plays a role in misnaming. Working on a manuscript? Avoid the common mistakes “Becky . . . Jesse . . . Molly . . . no, Samantha! Help me with the groceries,” your mother yells, looking at you. Each of the authors, though different in gender, age, and background, have been called a sibling’s name by an older family member who actually knew who we were; for three of us who owned a dog, we were even called the dog’s name. The last author, having experienced this seeming insult by loving parents as a child, now does it to his graduate students, and he only has two. This could not be simply part of the aging process; a young adult calling a romantic partner by another real or imagined partner's name (e. g., “I, Ross, take thee, Rachel...”) is a common plot line in popular culture. Instead of leaving this as a laboratory joke, we decided to study it because, despite the prevalence of research into the retrieval of proper names that are low in familiarity (e.g., Burke, MacKay, Worthley, & Wade, 1991 ; Cohen, 1990 ; McKenna & Warrington, 1980 ), very few studies have looked at how the names of highly familiar (noncelebrity) people are retrieved, or more interestingly, incorrectly retrieved. More formally, we investigate the conditions surrounding these types of errors, or misnamings , in which a person (the misnamer ) incorrectly calls a familiar individual (the misnamed ) by the name of someone else (the named ). In spite of the anecdotal data suggesting that misnamings are a common phenomenon, we could find only two diary studies that examine the phenomenon of individuals misnaming those whom they know personally. Young, Hay, and Ellis ( 1985 ) had participants record errors in person recognition, including not recognizing a familiar person and difficulty retrieving a person’s name. Of interest here, roughly one-third of the reports were for the misidentification of a familiar person. The authors suggest that these misnamings occurred because of both semantic (within the same category) and physical similarity between the misnamed and the named. Cohen and Faulkner ( 1986 ; also see Burke et al., 1991 ) also questioned people about naming blocks (the inability to recall a name), although their focus was on age differences. No naming blocks for relatives were reported, but the majority of naming difficulties reported did occur for friends and acquaintances. When trying to retrieve the correct name, people reported recalling the names of those semantically similar to the individual in question, suggesting that proper names are linked with other semantic information about a person that in turn connects them to similar individuals. Other studies have examined difficulty in remembering the correct names of moderately well-known individuals rather than the problem of easily remembering a wrong name for a personally known individual. For example, research on the naming of celebrities has shown that naming blocks or misnaming of celebrities can occur (Brédart, 1993 ; Griffin, 2010 ; Young, Ellis, & Flude, 1988 ), but these misnamings may be qualitatively different from misnaming a personally and well-known individual. However, given the paucity of data on the phenomenon of interest, these studies also provide useful sources of information and hypotheses. In one misnaming study by Griffin ( 2010 ), college students were asked to recognize the faces of well-known celebrities. When subjects failed at recognizing the celebrities, they did not make random errors. Instead, celebrities that were misrecognized were mistaken for individuals with similar characteristics. These characteristics were occasionally physical, but errors also occurred because of similarities in nationality and profession. For instance, President Kennedy was mistaken for President Regan, and Elizabeth I was mistaken for Mary, Queen of Scots. This observed semantic relatedness between misnamed individuals and named individuals is consistent with a possible mechanism by which misnaming occurs: semantic information activated by seeing or thinking of a person can cause the incorrect activation of another person’s name because those people are within the same group or semantic category (here, family, friends, or other). Results of these studies are consistent with the interactive activations and competition model of person recognition (Brédart, Valentine, Calder, & Gassi, 1995 ; Burton, Bruce, & Hancock, 1999 ; Burton, Bruce, & Johnston, 1990 ), which posits that information about a person is coded as a shared semantic unit or category (e.g., relative, friend); activation of a semantic unit can spread to facilitate retrieval of other individuals within the same unit. This shared semantic information can lead to associative and categorical priming when naming closely related individuals (Carson & Burton, 2001 ; Darling & Valentine, 2005 ; Vladeanu, Lewis, & Ellis, 2006 ; see Stone, 2008 , for a more nuanced examination of the associative vs. categorical priming debate). Names of people within a given category can even cause proactive interference for the name of<|im_end|> <|im_start|>assistant It's happened to many of us: While looking right at someone you know very well, you open your mouth and blurt out the wrong name. The name you blurt is not just any old name, though, says new research from Duke University that finds "misnaming" follows predictable patterns. Among people who know each other well, the wrong name is usually plucked from the same relationship category, the study finds. Friends call each other by other friends' names, and family members by other family members' names. And that includes the family dog. "It's a cognitive mistake we make, which reveals something about who we consider to be in our group," said Duke psychology and neuroscience professor David Rubin, one of the study authors. "It's not just random." The new paper, based on five separate surveys of more than 1,700 respondents, appears online this week in the journal Memory & Cognition. Many of the patterns didn't surprise lead author Samantha Deffler, a Ph.D. student at Duke. One did, though. In addition to mixing up sibling for sibling and daughter for son, study participants frequently called other family members by the name of the family pet—but only when the pet was a dog. Owners of cats or other pets didn't commit such slips of the tongue. Deffler says she was surprised how consistent that finding was, and how often it happened. "I'll preface this by saying I have cats and I love them," Deffler says. "But our study does seem to add to evidence about the special relationship between people and dogs. "Also, dogs will respond to their names much more than cats, so those names are used more often. Perhaps because of that, the dog's name seems to become more integrated with people's conceptions of their families." Phonetic similarity between names helps fuel mix-ups too, the authors found. Names with the same beginning or ending sounds, such as Michael and Mitchell or Joey and Mikey, were more likely to be swapped. So were names that shared phonemes, or sounds, such as John and Bob, which share the same vowel sound. Physical similarities between people, on the other hand, played little to no role. For instance, parents were inclined to swap their children's names even when the children looked nothing alike and were different genders. It's not a question of aging, either: The authors found plenty of instances of misnaming among college undergraduates. Although misnaming is a common theme in popular culture, Deffler said the new study is one of few describing how the phenomenon works. Deffler is no stranger to the experience in her own life. Her graduate supervisor frequently swaps the names of his two graduate assistants. And growing up, she said, her mom often called her Rebecca, Jesse or Molly—the names of her sister, brother and the family pit bull. "I'm graduating in two weeks and my siblings will all be there," Deffler said. "I know my mom will make mistakes." Now she knows why. In addition to Deffler and Rubin, the authors included Duke postdoctoral researcher Christin Ogle and Cassidy Fox, a 2013 Duke graduate. Fox helped lead the research project while studying at Duke as an undergraduate and devoted her senior thesis to the topic. <|im_end|>

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2,003

[ { "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 Until now, organic semiconductors have failed to achieve high performance in highly integrated, sub-100 nm transistors. Consequently, single-crystalline materials such as single-walled carbon nanotubes, MoS 2 or inorganic semiconductors are the materials of choice at the nanoscale. Here we show, using a vertical field-effect transistor design with a channel length of only 40 nm and a footprint of 2 × 80 × 80 nm 2 , that high electrical performance with organic polymers can be realized when using electrolyte gating. Our organic transistors combine high on-state current densities of above 3 MA cm −2 , on/off current modulation ratios of up to 10 8 and large transconductances of up to 5,000 S m −1 . Given the high on-state currents at such large on/off ratios, our novel structures also show promise for use in artificial neural networks, where they could operate as memristive devices with sub-100 fJ energy usage. Main Organic semiconductors are promising components for novel flexible electronics such as displays and sensors. Large-scale processability via printing and the inherent flexibility of organic materials are two key advantages in this context. Attributes that do not usually come to mind when discussing organic materials are high current densities in the MA cm −2 range, large transconductances in the 10–100 S m −1 regime, low-power operation or low supply voltages in the sub-volt regime, as are common in highly integrated nanoscale transistors 1 . More specifically, while, for example, state-of-the-art single-walled carbon nanotube (SWCNT) or MoS 2 field-effect transistors (FETs) are able to sustain current densities in the range of MA cm −2 (refs. 1 , 2 , 3 ), organic transistors are currently only able to operate at tens of kA cm −2 (refs. 4 , 5 ). Although such high current densities in the MA cm −2 range are crucial for realizing highly integrated, high-performance electronics 1 , low-power operation is critical for operation in handheld devices or in neuronal networks. In the latter, the energy per switching event is required to be in the sub-pJ regime, implying the need for high on-state conductance, large current modulation ratios and low voltage operation. Here, we discuss a nanoscopic device design based on a vertical transistor structure that enables electrolyte-gated organic semiconductors to drive MA cm −2 currents combined with on/off ratios of 10 8 . The small channel length of less than 50 nm and nanoscopic device footprint of 2 × 80 × 80 nm 2 in principle allows the use of such devices in highly integrated circuits. Additionally, we show that our device design makes organic semiconductors prime candidates for use in low-power neuromorphic computing. The established approach to the realization of nanosopic channels is a planar transistor geometry, which we also used in our initial investigations (Fig. 1a ). We used a diketopyrrolopyrrole–terthiophene donor–acceptor polymer (PDPP, Fig. 1a inset) as the prototype semiconductor for our device structures 6 . A PDPP solution was deposited via doctor blading, yielding a sub-monolayer thin film. After deposition of the ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMIM][TFSI]) 7 the transistors were electrically characterized in vacuum or ambient atmosphere. Electrolyte gating has been established in the past as a reliable method to enable large gate coupling 8 , 9 , 10 , 11 . Consequently, the short channel effects in laterally sub-micrometre devices have been drastically reduced 12 . Typical transfer curves of transistors with 220 nm and 40 nm channel lengths as well as corresponding scanning electron microscopy (SEM) images are shown in Fig. 1a–d . As is common for electrolyte-gated transistors, due to the large capacitance of the electrolyte 7 the transistors can be operated at a gate–source voltage V GS below 2 V. The respective output characteristics are provided in Supplementary Fig. 1 . We note that the maximum on-state currents of the transistors shown in Fig. 1a,b are different because the threshold voltages of the transistors differ. Transistors with similar threshold voltage exhibit an increased on-state current for shorter channel lengths (Supplementary Fig. 2 ). An important figure of merit of short-channel transistors is the contact resistance 13 . Our transistors show exceptionally low contact resistances of below 3 Ω cm (estimated from transmission line measurements; Supplementary Fig. 3 ), which are similar to values previously observed in electrolyte-gated transistors and can be explained by electrochemical doping of the contacts 14 , and which are a prerequisite to the operation of transistors at high frequencies. Furthermore, high on/off current ratios of 10 5 are observed, and our devices show large transconductances of up to 6 S m −1 . Even though these values are lower than what has been shown before, for example in P3HT transistors 15 , the electrical characteristics are encouraging, especially given the fact that the semiconducting film is only 2 nm thick (Fig. 1d ). Finally, our on-state resistance of ρ on,PDPP = 5.4 × 10 –4 Ω m compares favourably to P(NDI2OD-T2) transistors ( ρ on,P(NDI2OD-T2) = 0.12 Ω m) 16 , the only other monolayer polymer transistors of which we are aware. Fig. 1: Planar, electrolyte-gated nanoscopic PDPP OFETs. a – d , Transfer characteristics of two transistors with L c of 220 nm ( a ) (inset, molecular structure of the PDPP used) and 40 nm ( b ), and corresponding SEM images ( c , d ) (measured at 32 mV s –1 under vacuum). e , Atomic force microscopy topography image of a SiO 2 substrate with sub-monolayer PDPP coverage, allowing the height of individual polymer nanofibres to be measured (inset). In a and b , the solid lines represent the trace and the dashed lines the re-trace. Full size image Although the electrical characteristics of these lateral transistors are very encouraging, for highly integrated applications a smaller-footprint channel is needed. We thus realized transistors with vertical contact separation that can be gated with an electrolyte. Vertical organic field-effect transistors (VOFETs) have been established as a promising approach to achieve nanoscopic source–drain contact separation without the need for high-resolution patterning 17", "role": "user" }, { "content": "In mobiles, fridges, planes – transistors are everywhere. But they often operate only within a restricted current range. LMU physicists have now developed an organic transistor that functions perfectly under both low and high currents. Transistors are semiconductor devices that control voltage and currents in electrical circuits. To reduce economic and environmental costs, electronic devices must become smaller and more effective. This applies above all to transistors. In the field of inorganic semiconductors, dimensions below 100 nanometers are already standard. In this respect, organic semiconductors have not been able to keep up. In addition, their performance with regard to charge-carrier transport is considerably worse. But organic structures offer other advantages. They can easily be printed on an industrial scale, the material costs are lower, and they can be transparently applied to flexible surfaces. Thomas Weitz, a professor in LMU's Faculty of Physics and a member of the Nanosystems Initiative Munich, and his team are working intensively on the optimization of organic transistors. In their latest publication in Nature Nanotechnology, they describe the fabrication of transistors with an unusual structure, which are tiny, powerful and above all versatile. By carefully tailoring a small set of parameters during the production process, they have been able to design nanoscale devices for high or low current densities. The primary innovation lies in the use of an atypical geometry, which also facilitates assembly of the nanoscopic transistors. \"Our aim was to develop a transistor design which combines the ability to drive high currents that is typical of classical transistors with the low-voltage operation required for use as artificial synapses,\" says Weitz. With the successful assembly and characterization of vertical organic field-effect transistors with exactly selectable dimensions and an ionic gating, this goal has now been achieved. Potential areas of application for the new devices include OLEDs and sensors where low voltages, high ON-state current densities or large transconductances are required. Of special interest is their possible use in so-called memristive elements. \"Memristors can be thought of as artificial neurons, as they can be used to model the behavior of neurons when processing electrical signals,\" explains Weitz. \"By fine-tuning the geometry of a memristive device, it could be applied in a variety of contexts, such as learning processes in artificial synapses.\" The researchers have already submitted a patent application for the device to enable them to develop the new transistor architecture for industrial use. ", "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 Until now, organic semiconductors have failed to achieve high performance in highly integrated, sub-100 nm transistors. Consequently, single-crystalline materials such as single-walled carbon nanotubes, MoS 2 or inorganic semiconductors are the materials of choice at the nanoscale. Here we show, using a vertical field-effect transistor design with a channel length of only 40 nm and a footprint of 2 × 80 × 80 nm 2 , that high electrical performance with organic polymers can be realized when using electrolyte gating. Our organic transistors combine high on-state current densities of above 3 MA cm −2 , on/off current modulation ratios of up to 10 8 and large transconductances of up to 5,000 S m −1 . Given the high on-state currents at such large on/off ratios, our novel structures also show promise for use in artificial neural networks, where they could operate as memristive devices with sub-100 fJ energy usage. Main Organic semiconductors are promising components for novel flexible electronics such as displays and sensors. Large-scale processability via printing and the inherent flexibility of organic materials are two key advantages in this context. Attributes that do not usually come to mind when discussing organic materials are high current densities in the MA cm −2 range, large transconductances in the 10–100 S m −1 regime, low-power operation or low supply voltages in the sub-volt regime, as are common in highly integrated nanoscale transistors 1 . More specifically, while, for example, state-of-the-art single-walled carbon nanotube (SWCNT) or MoS 2 field-effect transistors (FETs) are able to sustain current densities in the range of MA cm −2 (refs. 1 , 2 , 3 ), organic transistors are currently only able to operate at tens of kA cm −2 (refs. 4 , 5 ). Although such high current densities in the MA cm −2 range are crucial for realizing highly integrated, high-performance electronics 1 , low-power operation is critical for operation in handheld devices or in neuronal networks. In the latter, the energy per switching event is required to be in the sub-pJ regime, implying the need for high on-state conductance, large current modulation ratios and low voltage operation. Here, we discuss a nanoscopic device design based on a vertical transistor structure that enables electrolyte-gated organic semiconductors to drive MA cm −2 currents combined with on/off ratios of 10 8 . The small channel length of less than 50 nm and nanoscopic device footprint of 2 × 80 × 80 nm 2 in principle allows the use of such devices in highly integrated circuits. Additionally, we show that our device design makes organic semiconductors prime candidates for use in low-power neuromorphic computing. The established approach to the realization of nanosopic channels is a planar transistor geometry, which we also used in our initial investigations (Fig. 1a ). We used a diketopyrrolopyrrole–terthiophene donor–acceptor polymer (PDPP, Fig. 1a inset) as the prototype semiconductor for our device structures 6 . A PDPP solution was deposited via doctor blading, yielding a sub-monolayer thin film. After deposition of the ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMIM][TFSI]) 7 the transistors were electrically characterized in vacuum or ambient atmosphere. Electrolyte gating has been established in the past as a reliable method to enable large gate coupling 8 , 9 , 10 , 11 . Consequently, the short channel effects in laterally sub-micrometre devices have been drastically reduced 12 . Typical transfer curves of transistors with 220 nm and 40 nm channel lengths as well as corresponding scanning electron microscopy (SEM) images are shown in Fig. 1a–d . As is common for electrolyte-gated transistors, due to the large capacitance of the electrolyte 7 the transistors can be operated at a gate–source voltage V GS below 2 V. The respective output characteristics are provided in Supplementary Fig. 1 . We note that the maximum on-state currents of the transistors shown in Fig. 1a,b are different because the threshold voltages of the transistors differ. Transistors with similar threshold voltage exhibit an increased on-state current for shorter channel lengths (Supplementary Fig. 2 ). An important figure of merit of short-channel transistors is the contact resistance 13 . Our transistors show exceptionally low contact resistances of below 3 Ω cm (estimated from transmission line measurements; Supplementary Fig. 3 ), which are similar to values previously observed in electrolyte-gated transistors and can be explained by electrochemical doping of the contacts 14 , and which are a prerequisite to the operation of transistors at high frequencies. Furthermore, high on/off current ratios of 10 5 are observed, and our devices show large transconductances of up to 6 S m −1 . Even though these values are lower than what has been shown before, for example in P3HT transistors 15 , the electrical characteristics are encouraging, especially given the fact that the semiconducting film is only 2 nm thick (Fig. 1d ). Finally, our on-state resistance of ρ on,PDPP = 5.4 × 10 –4 Ω m compares favourably to P(NDI2OD-T2) transistors ( ρ on,P(NDI2OD-T2) = 0.12 Ω m) 16 , the only other monolayer polymer transistors of which we are aware. Fig. 1: Planar, electrolyte-gated nanoscopic PDPP OFETs. a – d , Transfer characteristics of two transistors with L c of 220 nm ( a ) (inset, molecular structure of the PDPP used) and 40 nm ( b ), and corresponding SEM images ( c , d ) (measured at 32 mV s –1 under vacuum). e , Atomic force microscopy topography image of a SiO 2 substrate with sub-monolayer PDPP coverage, allowing the height of individual polymer nanofibres to be measured (inset). In a and b , the solid lines represent the trace and the dashed lines the re-trace. Full size image Although the electrical characteristics of these lateral transistors are very encouraging, for highly integrated applications a smaller-footprint channel is needed. We thus realized transistors with vertical contact separation that can be gated with an electrolyte. Vertical organic field-effect transistors (VOFETs) have been established as a promising approach to achieve nanoscopic source–drain contact separation without the need for high-resolution patterning 17<|im_end|> <|im_start|>assistant In mobiles, fridges, planes – transistors are everywhere. But they often operate only within a restricted current range. LMU physicists have now developed an organic transistor that functions perfectly under both low and high currents. Transistors are semiconductor devices that control voltage and currents in electrical circuits. To reduce economic and environmental costs, electronic devices must become smaller and more effective. This applies above all to transistors. In the field of inorganic semiconductors, dimensions below 100 nanometers are already standard. In this respect, organic semiconductors have not been able to keep up. In addition, their performance with regard to charge-carrier transport is considerably worse. But organic structures offer other advantages. They can easily be printed on an industrial scale, the material costs are lower, and they can be transparently applied to flexible surfaces. Thomas Weitz, a professor in LMU's Faculty of Physics and a member of the Nanosystems Initiative Munich, and his team are working intensively on the optimization of organic transistors. In their latest publication in Nature Nanotechnology, they describe the fabrication of transistors with an unusual structure, which are tiny, powerful and above all versatile. By carefully tailoring a small set of parameters during the production process, they have been able to design nanoscale devices for high or low current densities. The primary innovation lies in the use of an atypical geometry, which also facilitates assembly of the nanoscopic transistors. "Our aim was to develop a transistor design which combines the ability to drive high currents that is typical of classical transistors with the low-voltage operation required for use as artificial synapses," says Weitz. With the successful assembly and characterization of vertical organic field-effect transistors with exactly selectable dimensions and an ionic gating, this goal has now been achieved. Potential areas of application for the new devices include OLEDs and sensors where low voltages, high ON-state current densities or large transconductances are required. Of special interest is their possible use in so-called memristive elements. "Memristors can be thought of as artificial neurons, as they can be used to model the behavior of neurons when processing electrical signals," explains Weitz. "By fine-tuning the geometry of a memristive device, it could be applied in a variety of contexts, such as learning processes in artificial synapses." The researchers have already submitted a patent application for the device to enable them to develop the new transistor architecture for industrial use. <|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 (PD) is a debilitating neurodegenerative disorder in which nonmotor symptoms, such as constipation and hyposmia, precede the onset of motor symptoms by 20 years. The aim of this study was to identify biomarkers at the premotor stage of PD. We assessed the differences in longitudinal changes in anthropometric and serological indices obtained from health check-up data before and after the onset of motor symptoms between male and female PD patients and healthy subjects. We enrolled 22 male and 23 female PD patients and 60 male and 60 female healthy controls. A mixed-effects model was used to estimate the trajectory of each clinical marker over the years before and after motor symptoms onset in the PD subjects, which were then compared with the trajectories of the healthy controls. The results showed a premotor blood pressure increase in female PD patients and premotor decreases in haematocrit, total cholesterol and low-density lipoprotein cholesterol in the male patients. Our results indicated that blood pressure, haematocrit and serum cholesterol levels are potential premotor markers of PD. Additionally, the changes in anthropometric and serological indices before PD motor symptoms onset were sex specific. Introduction Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. The frequency of the disorder is relatively high at 1.3 cases per 10,0000 people < 45 years old, 3100 per 10,0000 in those 75–85 years old and 4300 per 10,0000 in those > 85 years old 1 , 2 . PD is characterised by motor signs of bradykinesia, rigidity and resting tremor, and by nonmotor symptoms, including cognitive, neuropsychiatric, sleep, autonomic and sensory disturbances 3 , 4 . Some nonmotor symptoms, such as constipation, rapid eye movement sleep behaviour disorder (RBD), hyposmia and depression, are known as premotor/prodromal symptoms 5 , 6 . Because these symptoms manifest decades before motor symptoms, the pathogenesis of PD is thought to emerge long before the onset of motor symptoms. This view is supported by the histopathological observation that > 50% of dopaminergic neurons are lost at the onset of motor symptoms 7 . In neurodegenerative diseases, including PD, attempts to identify biological markers for the preclinical stages have received increased attention because several studies have identified potential preclinical biomarkers. For instance, serum neurofilament light-chain levels are elevated in the preclinical stage of Alzheimer’s disease (AD) and amyotrophic lateral sclerosis/frontotemporal lobar degeneration 8 , 9 , 10 . The cerebrospinal fluid levels of amyloid beta and tau are established preclinical biomarkers for AD 11 . Dipeptide repeat protein is another potential preclinical marker for C9ORF72 -associated amyotrophic lateral sclerosis 12 . Neuroimaging and neurophysiological alteration have also been detected in the preclinical phase of spinocerebellar ataxias and Huntington’s disease 13 , 14 . The mean height of young adults is significantly lower in those affected by PD than in controls 15 . Weight loss in PD patients has appeared to be a continuous process that starts several years before the diagnosis of PD 16 . Anaemia is associated with PD and may precede the onset of motor symptoms by ≥ 20 years 17 . Higher serum levels of total and low-density lipoprotein (LDL) cholesterol (T-Cho and LDL-Cho, respectively) have been shown to be associated with a decreased risk of PD 18 , 19 , and higher serum levels of urate were also associated with a decreased risk of developing PD 20 , 21 . However, little is known about the longitudinal changes in biomarkers at a premotor stage of PD. Recently, by analysing patients’ health check-up longitudinal data, we found that serum creatinine (Cr) levels started to decrease before the onset of neurological symptoms in spinal and bulbar muscular atrophy, a hereditary neuromuscular disease 22 . The aim of the present study was to examine longitudinal changes in biochemical and anthropometric indices at the premotor stage of PD. To this end, we investigated changes before and after motor symptoms onset in PD patients by analysing health check-up longitudinal data. Results Participant characteristics We recruited a total of 133 patients with PD and 187 age- and sex-matched healthy controls between October 2016 and January 2019 (Fig. 1 ). We excluded 88 PD patients for whom health check-up data before the onset of motor symptoms were not available; accordingly, we analysed 45 PD patients (22 males and 23 females). All included patients submitted their health checkup data > 4 years from their last evaluation and provided written informed consent. Among the potential healthy controls, we excluded six subjects who had a family history of PD, seven subjects who had serious complications (active cancer, severe anaemia, pancreatitis, epicarditis, inflammatory bowel disease, gastric ulcer or stroke) and 54 individuals who had prodromal symptoms of PD (any of hyposmia, RBD and constipation). Finally, we analysed 120 healthy controls, 60 males and 60 females. There were no significant differences in the mean ages at PD onset between the males and females (Supplemental Fig. 1 ). The evaluation period in all patients with PD included their premotor period. The profiles of medication history were similar between the PD subjects and healthy controls for males and females (Table 1 ). Figure 1 Flowchart of the study population. PD = Parkinson’s disease, MIBG = metaiodobenzylguanidine. Full size image Table 1 Clinical backgrounds of the subjects. Full size table Comparison of baseline data First, we compared the baseline values of each item between the PD and healthy subjects for each sex separately. We defined the baseline as the onset of motor symptoms for PD groups and as the last evaluation for the healthy subjects. In males, there were significant differences between the PD patients and healthy controls in weight, body mass index (BMI), haematocrit (Ht), T-Cho, LDL-Cho and creatinine (Cr), and all the values of all these indices were lower in male PD patients than in the male healthy controls. In females, significant differences were found in height, systolic blood pressure (BP), diastolic BP, aspartate aminotransferase (AST) and T-Cho between the groups. The values of AST, systolic BP and diastolic", "role": "user" }, { "content": "A research team led by Nagoya University in Japan has found that blood pressure, the hematocrit (the percentage of red blood cells in blood), and serum cholesterol levels change in patients with Parkinson's disease long before the onset of motor symptoms. This finding, which was recently published online in Scientific Reports, may pave the way for early diagnosis and treatment of the disease. Parkinson's disease, the second most common disease affecting the nervous system after Alzheimer's disease, is caused by a deficiency in a neurotransmitter called dopamine. It is known that more than half of all dopaminergic neurons are already lost in patients with Parkinson's disease in the stage wherein they experience motor symptoms such as tremors, stiffness, and slowness of movement. In addition, previous studies have shown that non-motor symptoms, such as constipation, rapid eye movement sleep behavior disorder, impairment of the sense of smell, and depression, emerge in patients with Parkinson's disease10 to 20 years before the onset of motor symptoms. These results suggest that Parkinson's disease develops decades before the onset of motor symptoms. \"If we can detect biological changes in the patients' bodies well before the onset of the motor symptoms, we can start medical treatments in an early stage,\" says Professor Masahisa Katsuno of the Graduate School of Medicine at Nagoya University. From this perspective, the research team led by Prof. Katsuno and Katsunori Yokoi, the lead author and graduate student at Nagoya University, focused on the results of general health checkups, which are carried out among individuals yearly in Japan. The team analyzed multiple years of data from the checkups of 22 male and 23 female patients with Parkinson's disease whose checkup results before the onset of motor symptoms were available. For comparison, the team also used data from the checkups of 60 male and 60 female healthy individuals who underwent checkups for at least four years. The researchers first compared the baseline values of each checkup item between patients with Parkinson's disease and healthy individuals separately by sex. In male patients, the weight, body mass index, hematocrit, total and low-density cholesterol levels, and serum creatinine levels were lower than those in healthy male individuals. In female patients, the levels of blood pressure and an enzyme called aspartate aminotransferase were higher, while other items' values were lower compared to those in healthy female individuals. Next, the researchers examined longitudinal changes in the checkup items in patients with Parkinson's disease before the onset of motor symptoms. As a result, they found that in the premotor stage, blood pressure levels are increased in female patients, whereas total and low-density cholesterol levels and the hematocrit are decreased in male patients. Regarding other checkup items, no significant changes were observed. \"In this study, we found that blood pressure, hematocrit, and serum cholesterol levels are potential biomarkers of Parkinson's disease before the onset of its motor symptoms,\" says Prof. Katsuno. \"This finding indicates that general health checkups can help detect early signs of developing Parkinson's disease.\" In this context, his team is now pursuing studies to identify individuals who are at high risk for the disease based on checkup examinees. \"We are also conducting clinical trials of medication in the individuals who are considered, based on their checkup data, to be at high risk for Parkinson's, in an attempt to prevent the development of the disease in 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 Parkinson’s disease (PD) is a debilitating neurodegenerative disorder in which nonmotor symptoms, such as constipation and hyposmia, precede the onset of motor symptoms by 20 years. The aim of this study was to identify biomarkers at the premotor stage of PD. We assessed the differences in longitudinal changes in anthropometric and serological indices obtained from health check-up data before and after the onset of motor symptoms between male and female PD patients and healthy subjects. We enrolled 22 male and 23 female PD patients and 60 male and 60 female healthy controls. A mixed-effects model was used to estimate the trajectory of each clinical marker over the years before and after motor symptoms onset in the PD subjects, which were then compared with the trajectories of the healthy controls. The results showed a premotor blood pressure increase in female PD patients and premotor decreases in haematocrit, total cholesterol and low-density lipoprotein cholesterol in the male patients. Our results indicated that blood pressure, haematocrit and serum cholesterol levels are potential premotor markers of PD. Additionally, the changes in anthropometric and serological indices before PD motor symptoms onset were sex specific. Introduction Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. The frequency of the disorder is relatively high at 1.3 cases per 10,0000 people < 45 years old, 3100 per 10,0000 in those 75–85 years old and 4300 per 10,0000 in those > 85 years old 1 , 2 . PD is characterised by motor signs of bradykinesia, rigidity and resting tremor, and by nonmotor symptoms, including cognitive, neuropsychiatric, sleep, autonomic and sensory disturbances 3 , 4 . Some nonmotor symptoms, such as constipation, rapid eye movement sleep behaviour disorder (RBD), hyposmia and depression, are known as premotor/prodromal symptoms 5 , 6 . Because these symptoms manifest decades before motor symptoms, the pathogenesis of PD is thought to emerge long before the onset of motor symptoms. This view is supported by the histopathological observation that > 50% of dopaminergic neurons are lost at the onset of motor symptoms 7 . In neurodegenerative diseases, including PD, attempts to identify biological markers for the preclinical stages have received increased attention because several studies have identified potential preclinical biomarkers. For instance, serum neurofilament light-chain levels are elevated in the preclinical stage of Alzheimer’s disease (AD) and amyotrophic lateral sclerosis/frontotemporal lobar degeneration 8 , 9 , 10 . The cerebrospinal fluid levels of amyloid beta and tau are established preclinical biomarkers for AD 11 . Dipeptide repeat protein is another potential preclinical marker for C9ORF72 -associated amyotrophic lateral sclerosis 12 . Neuroimaging and neurophysiological alteration have also been detected in the preclinical phase of spinocerebellar ataxias and Huntington’s disease 13 , 14 . The mean height of young adults is significantly lower in those affected by PD than in controls 15 . Weight loss in PD patients has appeared to be a continuous process that starts several years before the diagnosis of PD 16 . Anaemia is associated with PD and may precede the onset of motor symptoms by ≥ 20 years 17 . Higher serum levels of total and low-density lipoprotein (LDL) cholesterol (T-Cho and LDL-Cho, respectively) have been shown to be associated with a decreased risk of PD 18 , 19 , and higher serum levels of urate were also associated with a decreased risk of developing PD 20 , 21 . However, little is known about the longitudinal changes in biomarkers at a premotor stage of PD. Recently, by analysing patients’ health check-up longitudinal data, we found that serum creatinine (Cr) levels started to decrease before the onset of neurological symptoms in spinal and bulbar muscular atrophy, a hereditary neuromuscular disease 22 . The aim of the present study was to examine longitudinal changes in biochemical and anthropometric indices at the premotor stage of PD. To this end, we investigated changes before and after motor symptoms onset in PD patients by analysing health check-up longitudinal data. Results Participant characteristics We recruited a total of 133 patients with PD and 187 age- and sex-matched healthy controls between October 2016 and January 2019 (Fig. 1 ). We excluded 88 PD patients for whom health check-up data before the onset of motor symptoms were not available; accordingly, we analysed 45 PD patients (22 males and 23 females). All included patients submitted their health checkup data > 4 years from their last evaluation and provided written informed consent. Among the potential healthy controls, we excluded six subjects who had a family history of PD, seven subjects who had serious complications (active cancer, severe anaemia, pancreatitis, epicarditis, inflammatory bowel disease, gastric ulcer or stroke) and 54 individuals who had prodromal symptoms of PD (any of hyposmia, RBD and constipation). Finally, we analysed 120 healthy controls, 60 males and 60 females. There were no significant differences in the mean ages at PD onset between the males and females (Supplemental Fig. 1 ). The evaluation period in all patients with PD included their premotor period. The profiles of medication history were similar between the PD subjects and healthy controls for males and females (Table 1 ). Figure 1 Flowchart of the study population. PD = Parkinson’s disease, MIBG = metaiodobenzylguanidine. Full size image Table 1 Clinical backgrounds of the subjects. Full size table Comparison of baseline data First, we compared the baseline values of each item between the PD and healthy subjects for each sex separately. We defined the baseline as the onset of motor symptoms for PD groups and as the last evaluation for the healthy subjects. In males, there were significant differences between the PD patients and healthy controls in weight, body mass index (BMI), haematocrit (Ht), T-Cho, LDL-Cho and creatinine (Cr), and all the values of all these indices were lower in male PD patients than in the male healthy controls. In females, significant differences were found in height, systolic blood pressure (BP), diastolic BP, aspartate aminotransferase (AST) and T-Cho between the groups. The values of AST, systolic BP and diastolic<|im_end|> <|im_start|>assistant A research team led by Nagoya University in Japan has found that blood pressure, the hematocrit (the percentage of red blood cells in blood), and serum cholesterol levels change in patients with Parkinson's disease long before the onset of motor symptoms. This finding, which was recently published online in Scientific Reports, may pave the way for early diagnosis and treatment of the disease. Parkinson's disease, the second most common disease affecting the nervous system after Alzheimer's disease, is caused by a deficiency in a neurotransmitter called dopamine. It is known that more than half of all dopaminergic neurons are already lost in patients with Parkinson's disease in the stage wherein they experience motor symptoms such as tremors, stiffness, and slowness of movement. In addition, previous studies have shown that non-motor symptoms, such as constipation, rapid eye movement sleep behavior disorder, impairment of the sense of smell, and depression, emerge in patients with Parkinson's disease10 to 20 years before the onset of motor symptoms. These results suggest that Parkinson's disease develops decades before the onset of motor symptoms. "If we can detect biological changes in the patients' bodies well before the onset of the motor symptoms, we can start medical treatments in an early stage," says Professor Masahisa Katsuno of the Graduate School of Medicine at Nagoya University. From this perspective, the research team led by Prof. Katsuno and Katsunori Yokoi, the lead author and graduate student at Nagoya University, focused on the results of general health checkups, which are carried out among individuals yearly in Japan. The team analyzed multiple years of data from the checkups of 22 male and 23 female patients with Parkinson's disease whose checkup results before the onset of motor symptoms were available. For comparison, the team also used data from the checkups of 60 male and 60 female healthy individuals who underwent checkups for at least four years. The researchers first compared the baseline values of each checkup item between patients with Parkinson's disease and healthy individuals separately by sex. In male patients, the weight, body mass index, hematocrit, total and low-density cholesterol levels, and serum creatinine levels were lower than those in healthy male individuals. In female patients, the levels of blood pressure and an enzyme called aspartate aminotransferase were higher, while other items' values were lower compared to those in healthy female individuals. Next, the researchers examined longitudinal changes in the checkup items in patients with Parkinson's disease before the onset of motor symptoms. As a result, they found that in the premotor stage, blood pressure levels are increased in female patients, whereas total and low-density cholesterol levels and the hematocrit are decreased in male patients. Regarding other checkup items, no significant changes were observed. "In this study, we found that blood pressure, hematocrit, and serum cholesterol levels are potential biomarkers of Parkinson's disease before the onset of its motor symptoms," says Prof. Katsuno. "This finding indicates that general health checkups can help detect early signs of developing Parkinson's disease." In this context, his team is now pursuing studies to identify individuals who are at high risk for the disease based on checkup examinees. "We are also conducting clinical trials of medication in the individuals who are considered, based on their checkup data, to be at high risk for Parkinson's, in an attempt to prevent the development of the disease in 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 For decades, scientists have pursued the goal of performing automated reactions in a compact fluid processor with minimal human intervention. Most advanced fluidic handling technologies (e.g., microfluidic chips and micro-well plates) lack fluid rewritability, and the associated benefits of multi-path routing and re-programmability, due to surface-adsorption-induced contamination on contacting structures. This limits their processing speed and the complexity of reaction test matrices. We present a contactless droplet transport and processing technique called digital acoustofluidics which dynamically manipulates droplets with volumes from 1 nL to 100 µL along any planar axis via acoustic-streaming-induced hydrodynamic traps, all in a contamination-free (lower than 10 −10 % diffusion into the fluorinated carrier oil layer) and biocompatible (99.2% cell viability) manner. Hence, digital acoustofluidics can execute reactions on overlapping, non-contaminated, fluidic paths and can scale to perform massive interaction matrices within a single device. Introduction Handling of liquids is essential in a majority of applications associated with chemical, biological, and biomedical protocols. Current automated fluid processing technologies 1 , 2 , 3 , 4 have brought unprecedented accuracy, speed, and repeatability to biomedical research and the pharmaceutical industry, such as the preparation of sequencing libraries, clinical diagnostics, and large-scale compound screening. A myriad of different liquid handling mechanisms, including robotics 4 , micro-droplets 5 , 6 , 7 , pneumatic valves 8 , 9 , 10 , electrical 11 , 12 , 13 , 14 , 15 , 16 , 17 , acoustics 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , hydrodynamics 27 , 28 , 29 , 30 , 31 , magnetics 32 , and liquid marbles 33 , have been applied to numerous fluid processing scenarios. Among all these mechanisms, the robotic pipetting system (e.g., Cloud Lab 4 ) is, by far, the most widely adopted solution for automation, yet it requires considerable expense, space, and maintenance. Lab-on-a-chip solutions miniaturize the bulky wet lab onto a compact chip 2 , but are generally optimized for specific reaction protocols and hence lack programmability and dynamic re-configurability since all channel designs are fixed after fabrication. Digital microfluidics offers an appealing solution for efficient automation by programmable manipulation of nano- to pico-liter droplets on a miniaturized device using electro-wetting forces 11 , 12 , 13 , 14 , 15 , 16 . It has demonstrated remarkable programmability in terms of reaction automation, particularly for reaction protocols that require serial addition of reagents or precise temporal control. Despite these strengths, most current methods suffer from a fundamental constraint. They generally rely on physical contact with a solid structure in order to contain, transport, or manipulate liquid reagents. Therefore, traces of a reagent inevitably adsorb onto the contact surface and can possibly later dissolve into another liquid sample. Thus, the risk of cross-contamination due to this undesirable “fouling of the surface” 34 intrinsically limits the transport surfaces to a single type of working liquid plus reagent combination, and restricts the repetitive actuation of liquids with sticky biomolecules (e.g., undiluted blood). So a matrix of successive cascading interaction experiments requires an exponential number of available channel paths, as well as a complex, multi-layered array of independently-actuated switches, to avoid cross contamination. Contactless liquid-handling methods, in contrast, eliminate surface adsorption by employing long-range forces to isolate liquid reagents from solid structures, allowing for massively scalable, dynamic, multi-path fluidic processing due to the custom programmable and rewritable nature of the fluidic channels. The rewritability (i.e., the ability to reuse the same fluidic path without cross contamination) enables the use of multi-path routing and test optimization with respect to time and space when applied to the testing of large matrices of experimental variables. We label this advantage as “droplet rewritability” since there can be many different possible reagent combinations within a droplet which is enabled by reusable paths for transportation or mixing, even with a small array of acoustic transducers. Recently, there has been renewed interest in acoustics as a straightforward and promising solution for liquid handling owing to its contactless operation, label-free selectivity, and high biocompatibility 35 , 36 , 37 , 38 , 39 . An embodiment of contactless, acoustic-based liquid handling was in the form of ultrasonic levitation 19 . This method used a standing bulk acoustic wave to suspend liquid drops at pressure nodes in open air. These acoustic mechanisms have evolved to either holographic 40 , 41 , 42 or digital 43 manipulation of levitated objects or droplets. However, with its limited resolution, low controllability, and bulky transducer size, ultrasonic levitation is not suitable for manipulation in small scales. Not only does ultrasonic levitation have difficulties in accurately manipulating small objects (e.g., microparticles or nanoliter droplets), it also presents significant challenges when trying to load or collect these objects from the device. Herein we present digital acoustofluidics, an acoustic-based, programmable, contactless liquid-handling technology, which allows one to digitally transport, merge, mix, and split reagents within aqueous droplets in a contamination-free, biocompatible manner. In digital acoustofluidics, the droplets are floating on an inert, immiscible layer of oil that effectively isolates the droplet above a solid surface. We demonstrate fluidic manipulation between potential wells, characterize the acoustic streaming within and around the droplets, integrate the on-demand traps into a digital fluidic processor, evaluate the risk of cross-contamination, and finally apply digital acoustofluidics using six droplets to perform an optimized cascading sequence of enzymatic reactions. In comparison to existing fluidic processing approaches, the digital acoustofluidics platform has four advantages as rewritability (i.e., reusable fluid-paths), biocompatibility (e.g., 99.2% Hela cell viability), versatility (i.e., suitable for handling a wide range of liquids and solids, such as organic solvents, blood, sputum, reactive fluids, and fecal samples), and uniformity (i.e., minimizing internal polarization in aqueous droplets). Thus digital acoustofluidics offers unique pathways for addressing the obstacles in existing liquid-handling systems associated with surface adsorption, surface degradation, and internal polarization. It provides a compelling platform for the development of robust, rewritable, and digitally programmable fluidic processors. Results Three-dimensional acoustic streaming induces hydrodynamic traps As", "role": "user" }, { "content": "Engineers at Duke University have developed a way to manipulate, split and mix droplets of biological fluids by having them surf on acoustic waves in oil. The technology could form the basis of a small-scale, programmable, rewritable biomedical chip that is completely reusable for disparate purposes from on-site diagnostics to laboratory-based research. The study appears on July 26 in the journal Nature Communications. Automated fluid handling has driven the development of many scientific fields. Robotic pipetting systems have, for example, revolutionized the preparation of sequencing libraries, clinical diagnostics and large-scale compound screening. While ubiquitous in the modern biomedical research and pharmaceutical industries, these systems are bulky, expensive and do not handle small volumes of liquids well. Lab-on-a-chip systems have been able to fill this space to some extent, but most are hindered by one major drawback—surface absorption. Because these devices rely on solid surfaces, the samples being transported inevitably leave traces of themselves that can lead to contamination. \"There are a lot of protein-laden fluids and certain reagents that tend to stick to the chips that are handling them,\" said Tony Jun Huang, the William Bevan Professor of Mechanical Engineering and Materials Science at Duke. \"This is especially true of biological samples like undiluted blood, sputum and fecal samples. Our technology is well-suited for processing these difficult samples.\" Researchers have developed a way to manipulate, split and mix droplets of biological fluids without leaving any trace of contamination by having them surf on acoustic waves. Credit: Duke University The new lab-on-a-chip platform uses a thin layer of inert, immiscible oil to stop droplets from leaving behind any trace of themselves. Just below the oil, a series of piezoelectric transducers vibrate when electricity is passed through them. Just like the surface of a subwoofer, these vibrations create sound waves in the thin layer of oil above them. By carefully controlling the sound waves, the researchers create vertical vortexes that form small dimples in the oil to either side of the active transducer. These dimples can hold droplets with volumes ranging from one nanoliter to 100 microliters and pass them along the surface of the oil as the sound waves are modulated and different transducers are activated. The droplets are effectively surfing on tiny soundwaves. \"Our contactless liquid-handling mechanism inherently eliminates cross-contamination associated with surface adsorption and the need for surface modification,\" Huang said. \"It enables reusable paths for the droplets to be dynamically processed on arbitrary routes without cross-talk between each other, exponentially increasing the allowable number of combinations of reagent inputs on the same device.\" Huang next wants to take this proof-of-concept demonstration and create a fully automated lab-on-a-chip platform that can handle complex operations with dozens of droplets simultaneously. He's planning to collaborate with peers at Duke for various applications in biology and 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 For decades, scientists have pursued the goal of performing automated reactions in a compact fluid processor with minimal human intervention. Most advanced fluidic handling technologies (e.g., microfluidic chips and micro-well plates) lack fluid rewritability, and the associated benefits of multi-path routing and re-programmability, due to surface-adsorption-induced contamination on contacting structures. This limits their processing speed and the complexity of reaction test matrices. We present a contactless droplet transport and processing technique called digital acoustofluidics which dynamically manipulates droplets with volumes from 1 nL to 100 µL along any planar axis via acoustic-streaming-induced hydrodynamic traps, all in a contamination-free (lower than 10 −10 % diffusion into the fluorinated carrier oil layer) and biocompatible (99.2% cell viability) manner. Hence, digital acoustofluidics can execute reactions on overlapping, non-contaminated, fluidic paths and can scale to perform massive interaction matrices within a single device. Introduction Handling of liquids is essential in a majority of applications associated with chemical, biological, and biomedical protocols. Current automated fluid processing technologies 1 , 2 , 3 , 4 have brought unprecedented accuracy, speed, and repeatability to biomedical research and the pharmaceutical industry, such as the preparation of sequencing libraries, clinical diagnostics, and large-scale compound screening. A myriad of different liquid handling mechanisms, including robotics 4 , micro-droplets 5 , 6 , 7 , pneumatic valves 8 , 9 , 10 , electrical 11 , 12 , 13 , 14 , 15 , 16 , 17 , acoustics 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , hydrodynamics 27 , 28 , 29 , 30 , 31 , magnetics 32 , and liquid marbles 33 , have been applied to numerous fluid processing scenarios. Among all these mechanisms, the robotic pipetting system (e.g., Cloud Lab 4 ) is, by far, the most widely adopted solution for automation, yet it requires considerable expense, space, and maintenance. Lab-on-a-chip solutions miniaturize the bulky wet lab onto a compact chip 2 , but are generally optimized for specific reaction protocols and hence lack programmability and dynamic re-configurability since all channel designs are fixed after fabrication. Digital microfluidics offers an appealing solution for efficient automation by programmable manipulation of nano- to pico-liter droplets on a miniaturized device using electro-wetting forces 11 , 12 , 13 , 14 , 15 , 16 . It has demonstrated remarkable programmability in terms of reaction automation, particularly for reaction protocols that require serial addition of reagents or precise temporal control. Despite these strengths, most current methods suffer from a fundamental constraint. They generally rely on physical contact with a solid structure in order to contain, transport, or manipulate liquid reagents. Therefore, traces of a reagent inevitably adsorb onto the contact surface and can possibly later dissolve into another liquid sample. Thus, the risk of cross-contamination due to this undesirable “fouling of the surface” 34 intrinsically limits the transport surfaces to a single type of working liquid plus reagent combination, and restricts the repetitive actuation of liquids with sticky biomolecules (e.g., undiluted blood). So a matrix of successive cascading interaction experiments requires an exponential number of available channel paths, as well as a complex, multi-layered array of independently-actuated switches, to avoid cross contamination. Contactless liquid-handling methods, in contrast, eliminate surface adsorption by employing long-range forces to isolate liquid reagents from solid structures, allowing for massively scalable, dynamic, multi-path fluidic processing due to the custom programmable and rewritable nature of the fluidic channels. The rewritability (i.e., the ability to reuse the same fluidic path without cross contamination) enables the use of multi-path routing and test optimization with respect to time and space when applied to the testing of large matrices of experimental variables. We label this advantage as “droplet rewritability” since there can be many different possible reagent combinations within a droplet which is enabled by reusable paths for transportation or mixing, even with a small array of acoustic transducers. Recently, there has been renewed interest in acoustics as a straightforward and promising solution for liquid handling owing to its contactless operation, label-free selectivity, and high biocompatibility 35 , 36 , 37 , 38 , 39 . An embodiment of contactless, acoustic-based liquid handling was in the form of ultrasonic levitation 19 . This method used a standing bulk acoustic wave to suspend liquid drops at pressure nodes in open air. These acoustic mechanisms have evolved to either holographic 40 , 41 , 42 or digital 43 manipulation of levitated objects or droplets. However, with its limited resolution, low controllability, and bulky transducer size, ultrasonic levitation is not suitable for manipulation in small scales. Not only does ultrasonic levitation have difficulties in accurately manipulating small objects (e.g., microparticles or nanoliter droplets), it also presents significant challenges when trying to load or collect these objects from the device. Herein we present digital acoustofluidics, an acoustic-based, programmable, contactless liquid-handling technology, which allows one to digitally transport, merge, mix, and split reagents within aqueous droplets in a contamination-free, biocompatible manner. In digital acoustofluidics, the droplets are floating on an inert, immiscible layer of oil that effectively isolates the droplet above a solid surface. We demonstrate fluidic manipulation between potential wells, characterize the acoustic streaming within and around the droplets, integrate the on-demand traps into a digital fluidic processor, evaluate the risk of cross-contamination, and finally apply digital acoustofluidics using six droplets to perform an optimized cascading sequence of enzymatic reactions. In comparison to existing fluidic processing approaches, the digital acoustofluidics platform has four advantages as rewritability (i.e., reusable fluid-paths), biocompatibility (e.g., 99.2% Hela cell viability), versatility (i.e., suitable for handling a wide range of liquids and solids, such as organic solvents, blood, sputum, reactive fluids, and fecal samples), and uniformity (i.e., minimizing internal polarization in aqueous droplets). Thus digital acoustofluidics offers unique pathways for addressing the obstacles in existing liquid-handling systems associated with surface adsorption, surface degradation, and internal polarization. It provides a compelling platform for the development of robust, rewritable, and digitally programmable fluidic processors. Results Three-dimensional acoustic streaming induces hydrodynamic traps As<|im_end|> <|im_start|>assistant Engineers at Duke University have developed a way to manipulate, split and mix droplets of biological fluids by having them surf on acoustic waves in oil. The technology could form the basis of a small-scale, programmable, rewritable biomedical chip that is completely reusable for disparate purposes from on-site diagnostics to laboratory-based research. The study appears on July 26 in the journal Nature Communications. Automated fluid handling has driven the development of many scientific fields. Robotic pipetting systems have, for example, revolutionized the preparation of sequencing libraries, clinical diagnostics and large-scale compound screening. While ubiquitous in the modern biomedical research and pharmaceutical industries, these systems are bulky, expensive and do not handle small volumes of liquids well. Lab-on-a-chip systems have been able to fill this space to some extent, but most are hindered by one major drawback—surface absorption. Because these devices rely on solid surfaces, the samples being transported inevitably leave traces of themselves that can lead to contamination. "There are a lot of protein-laden fluids and certain reagents that tend to stick to the chips that are handling them," said Tony Jun Huang, the William Bevan Professor of Mechanical Engineering and Materials Science at Duke. "This is especially true of biological samples like undiluted blood, sputum and fecal samples. Our technology is well-suited for processing these difficult samples." Researchers have developed a way to manipulate, split and mix droplets of biological fluids without leaving any trace of contamination by having them surf on acoustic waves. Credit: Duke University The new lab-on-a-chip platform uses a thin layer of inert, immiscible oil to stop droplets from leaving behind any trace of themselves. Just below the oil, a series of piezoelectric transducers vibrate when electricity is passed through them. Just like the surface of a subwoofer, these vibrations create sound waves in the thin layer of oil above them. By carefully controlling the sound waves, the researchers create vertical vortexes that form small dimples in the oil to either side of the active transducer. These dimples can hold droplets with volumes ranging from one nanoliter to 100 microliters and pass them along the surface of the oil as the sound waves are modulated and different transducers are activated. The droplets are effectively surfing on tiny soundwaves. "Our contactless liquid-handling mechanism inherently eliminates cross-contamination associated with surface adsorption and the need for surface modification," Huang said. "It enables reusable paths for the droplets to be dynamically processed on arbitrary routes without cross-talk between each other, exponentially increasing the allowable number of combinations of reagent inputs on the same device." Huang next wants to take this proof-of-concept demonstration and create a fully automated lab-on-a-chip platform that can handle complex operations with dozens of droplets simultaneously. He's planning to collaborate with peers at Duke for various applications in biology and medicine. <|im_end|>

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2,057

[ { "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 the evolution of SARS-CoV-2 in humans, a D614G substitution in the spike glycoprotein (S) has emerged; virus containing this substitution has become the predominant circulating variant in the COVID-19 pandemic 1 . However, whether the increasing prevalence of this variant reflects a fitness advantage that improves replication and/or transmission in humans or is merely due to founder effects remains unknown. Here we use isogenic SARS-CoV-2 variants to demonstrate that the variant that contains S(D614G) has enhanced binding to the human cell-surface receptor angiotensin-converting enzyme 2 (ACE2), increased replication in primary human bronchial and nasal airway epithelial cultures as well as in a human ACE2 knock-in mouse model, and markedly increased replication and transmissibility in hamster and ferret models of SARS-CoV-2 infection. Our data show that the D614G substitution in S results in subtle increases in binding and replication in vitro, and provides a real competitive advantage in vivo—particularly during the transmission bottleneck. Our data therefore provide an explanation for the global predominance of the variant that contains S(D614G) among the SARS-CoV-2 viruses that are currently circulating. Main In late 2019, SARS-CoV-2 was detected in Wuhan (Hubei province, China) 2 , 3 and rapidly led to the COVID-19 pandemic; by December 2020, 70 million cases and 1.5 million deaths attributable to this disease had been confirmed 4 . SARS-CoV-2 causes a life-threatening pneumonia in vulnerable groups of people 5 . The entry of SARS-CoV-2 into cells is dependent on the interaction of S and ACE2 3 , 6 . S is a homotrimeric class-I fusion protein that comprises two subunits (S1 and S2) that are separated by a protease cleavage site. S1 forms a globular head and is essential for receptor binding, and S2 mediates fusion of the viral envelope with host cell membranes. During entry, the receptor-binding domain within the S1 subunit binds ACE2, which generates conformational changes in the S2 subunit and facilitates internalization of the virus 7 , 8 . S(D614G) is a variant of S that contains a substitution outside of the receptor-binding domain that is thought to cause a conformational change in the protein, which improves ACE2 binding and increases the probability of infection 1 , 9 . As the pandemic has progressed, the SARS-CoV-2 variant that contains S(D614G) (hereafter, SARS-CoV-2 G614 )) has rapidly superseded the parental variant (with D in amino acid position 614 of S; hereafter, SARS-CoV-2 D614 ) in frequency to become globally dominant. Such a shift in genotype frequency might be caused by a founder effect following introduction into a highly interconnected population; alternatively, SARS-CoV-2 G614 may have a fitness advantage over SARS-CoV-2 D614 . Some studies have suggested the D614G substitution in S may confer a fitness advantage on the virus by improving cell entry 8 , 9 . To address the role of D614G substitution in S in the dissemination and predominance of SARS-CoV-2 G614 during the COVID-19 pandemic, we characterized S binding to human ACE2 (hACE2) and replication kinetics in vitro, and evaluated infection and transmission dynamics in vivo using three animal models. Our data show that the D614G substitution in S confers increased binding to the hACE2 receptor and increased replication in primary human airway epithelial cultures. Moreover, comparison of recombinant isogenic SARS-CoV-2 variants demonstrates that the D614G substitution in S provides competitive advantage in a hACE2 knock-in mouse model, and markedly increases replication and transmission in Syrian hamster and ferret models of SARS-CoV-2 infection. D614G substitution in S enhances hACE2 binding To measure the effects of the D614G substitution in S, we first quantified the binding of S1 domain monomers to hACE2 using biolayer interferometry. Both S1 and S1(D614G) bind efficiently to hACE2; however, S1(D614G) showed an affinity about twofold higher than that of S1 (Fig. 1a , Supplementary Table 2 ). Similarly, S(D614G) had a higher affinity to hACE2 than that of S when full-length monomeric forms were used (Extended Data Fig. 1a , Supplementary Table 2 ). The D614G substitution in S also resulted in enhanced S1 binding to hACE2 exogenously expressed in baby hamster kidney cells (hereafter, BHK–hACE2 cells) (Fig. 1b , Extended Data Fig. 1b ). The binding of polyhistidine-tagged S1 or S1(D614G) to BHK–hACE2 cells showed that more S1(D614G) bound to BHK–hACE2 cells than did S1, by flow cytometry (Fig. 1b , Extended Data Fig. 1b ). When using homodimeric recombinant constructs comprising S1 attached to an IgG C terminus, we observed a more notable effect in the increased binding of the S1(D614G) protein to the BHK–hACE2 cell (Fig. 1b , Extended Data Fig. 1b ). Fig. 1: In vitro characterization of S1 and of recombinant SARS-CoV-2 D614 and SARS-CoV-2 G614 . a , Affinity between S1 and hACE2 determined by biolayer interferometry. Fc-tagged ACE2 protein was loaded onto surface of anti-human Fc capture biosensors. Association was conducted using S1 (left) or S1(D614G) (right), followed by dissociation. Data represent three biological replicates. b , Binding of polyhistidine-tagged or Fc-tagged S1 to BHK–hACE2 cells is shown as peaks of fluorescence, detected by flow cytometry. c , Replication kinetics of recombinant viruses in Vero E6 cells at 37 °C (left) and human nasal epithelial cells at 33 °C (right). Supernatant was collected at the indicated time points and titrated by plaque assay. D614, SARS-CoV-2 D614 ; G614, SARS-CoV-2 G614 . d , Replication kinetics of recombinant viruses in human NBE cells at 33 °C (left), 37 °C (middle) and 39 °C (right). Supernatant was collected daily and titrated by TCID 50 assay. In c , d , data are mean ± s.d. of three biological replicates (Vero E6 cells) or four technical replicates (human nasal epithelial and human NBE cells). Statistical significance was determined by two-sided, unpaired Student’s t -test without adjustments for multiple comparisons. e , f , Competition assay of recombinant viruses in human nasal epithelial cells at 33 °C ( e ) and human NBE cells at 33 °C ( f , left), 37 °C ( f , middle) and 39 °C ( f , right). The inoculum", "role": "user" }, { "content": "Prior to the emergence of new mutants of the coronavirus, such as the British variant B.1.1.7, the SARS-CoV-2 variant named D614G had already mutated from the original SARS-CoV-2 pathogen that triggered the pandemic. D614G has rapidly spread to become the most abundant variant worldwide and this D614G mutation remains in all the new emerging variants. An international team including researchers from Bern has now been able to demonstrate in both the laboratory and in animal models why the D614G variant was able to gain the upper hand over the original SARS-CoV-2 virus. \"Our approach also allows us to characterize emerging mutations such as the British variant B.1.1.7 better and quicker,\" says Volker Thiel of the Institute of Virology and Immunology (IVI), one of the four lead authors of the study. The findings are extremely important for assessing the risk of new mutants running rampant, as they show how a fitness advantage of virus variants can lead to higher transmission. First results were released earlier allowing for scientific discussion on what is known as a preprint server. The results of the study have now been published in full in Nature. The D614G variant carries a mutation in the spike protein that makes it easier for the virus to dock onto human cells. The researchers at IVI and in David E. Wentworth's laboratory at the Centers for Disease Control and Prevention in Atlanta (USA) first demonstrated in human cell cultures from the upper respiratory tract, as well as from the nose, that the D614G variant binds more strongly and also replicates faster than the original virus. The increased replication of the D614G variant was also confirmed in vivo, in a new mouse model first described in this study. These experiments were also carried out at the IVI in Charaf Benarafa's group. The new mutation clearly prevails The spread of SARS-CoV-2 viruses can be studied better in other animals rather than mice. Hamsters and ferrets are well established in infection research and are especially suitable animal models. To compare the two variants, a mixture of equal parts of the original version of the SARS-CoV-2 virus and the D614G variant was applied into the nose of each animal under light anesthesia. After one day, experimentally infected animals were rehoused with another healthy sentinel animal of the same species, to evaluate the transmission of the two variants in direct competition with each other. The experiment was repeated with six pairs of animals in total. In virtually all sentinel animals, the proportion of transmitted SARS-CoV-2 viruses was massively dominated by the D614G variant early on. The differentiation of the variants was carried out using the latest sequencing technology and PCR techniques by Martin Beer's team at the Friedrich Loeffler Institute, Federal Research Institute for Animal Health, in Greifswald-Insel Riems (D). \"Our study stands out because we were able to clearly discern the more efficient transmission of the mutated variant in direct comparison with the original variant,\" says Volker Thiel. A fitness test for further mutations This approach can even be used to test any single mutation or a specific combination of mutations that are present in a number of currently circulating viral variants. The IVI relies on a cloning technique developed in Bern a year ago, in which SARS-CoV-2 viruses can be exactly reproduced in the laboratory. The British virus, for example, is known to have not just one but often more than 14 mutations, eight of which occur in the spike protein. Thus, with the help of the cloning technique, any number of mutations of variants can be reproduced and used to compete against each other in the established cell cultures and animal models. The results show how single mutations affect the fitness and transmissibility of new variants. \"Our testing strategy allows us to rapidly examine why other, newly emerging virus variants have become established,\" says Volker Thiel. Similar research projects on infectious pathogens could also be carried out in the future at the newly established Multidisciplinary Center for Infectious Diseases and Immunity (MCIDI) at the University of Bern. ", "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 the evolution of SARS-CoV-2 in humans, a D614G substitution in the spike glycoprotein (S) has emerged; virus containing this substitution has become the predominant circulating variant in the COVID-19 pandemic 1 . However, whether the increasing prevalence of this variant reflects a fitness advantage that improves replication and/or transmission in humans or is merely due to founder effects remains unknown. Here we use isogenic SARS-CoV-2 variants to demonstrate that the variant that contains S(D614G) has enhanced binding to the human cell-surface receptor angiotensin-converting enzyme 2 (ACE2), increased replication in primary human bronchial and nasal airway epithelial cultures as well as in a human ACE2 knock-in mouse model, and markedly increased replication and transmissibility in hamster and ferret models of SARS-CoV-2 infection. Our data show that the D614G substitution in S results in subtle increases in binding and replication in vitro, and provides a real competitive advantage in vivo—particularly during the transmission bottleneck. Our data therefore provide an explanation for the global predominance of the variant that contains S(D614G) among the SARS-CoV-2 viruses that are currently circulating. Main In late 2019, SARS-CoV-2 was detected in Wuhan (Hubei province, China) 2 , 3 and rapidly led to the COVID-19 pandemic; by December 2020, 70 million cases and 1.5 million deaths attributable to this disease had been confirmed 4 . SARS-CoV-2 causes a life-threatening pneumonia in vulnerable groups of people 5 . The entry of SARS-CoV-2 into cells is dependent on the interaction of S and ACE2 3 , 6 . S is a homotrimeric class-I fusion protein that comprises two subunits (S1 and S2) that are separated by a protease cleavage site. S1 forms a globular head and is essential for receptor binding, and S2 mediates fusion of the viral envelope with host cell membranes. During entry, the receptor-binding domain within the S1 subunit binds ACE2, which generates conformational changes in the S2 subunit and facilitates internalization of the virus 7 , 8 . S(D614G) is a variant of S that contains a substitution outside of the receptor-binding domain that is thought to cause a conformational change in the protein, which improves ACE2 binding and increases the probability of infection 1 , 9 . As the pandemic has progressed, the SARS-CoV-2 variant that contains S(D614G) (hereafter, SARS-CoV-2 G614 )) has rapidly superseded the parental variant (with D in amino acid position 614 of S; hereafter, SARS-CoV-2 D614 ) in frequency to become globally dominant. Such a shift in genotype frequency might be caused by a founder effect following introduction into a highly interconnected population; alternatively, SARS-CoV-2 G614 may have a fitness advantage over SARS-CoV-2 D614 . Some studies have suggested the D614G substitution in S may confer a fitness advantage on the virus by improving cell entry 8 , 9 . To address the role of D614G substitution in S in the dissemination and predominance of SARS-CoV-2 G614 during the COVID-19 pandemic, we characterized S binding to human ACE2 (hACE2) and replication kinetics in vitro, and evaluated infection and transmission dynamics in vivo using three animal models. Our data show that the D614G substitution in S confers increased binding to the hACE2 receptor and increased replication in primary human airway epithelial cultures. Moreover, comparison of recombinant isogenic SARS-CoV-2 variants demonstrates that the D614G substitution in S provides competitive advantage in a hACE2 knock-in mouse model, and markedly increases replication and transmission in Syrian hamster and ferret models of SARS-CoV-2 infection. D614G substitution in S enhances hACE2 binding To measure the effects of the D614G substitution in S, we first quantified the binding of S1 domain monomers to hACE2 using biolayer interferometry. Both S1 and S1(D614G) bind efficiently to hACE2; however, S1(D614G) showed an affinity about twofold higher than that of S1 (Fig. 1a , Supplementary Table 2 ). Similarly, S(D614G) had a higher affinity to hACE2 than that of S when full-length monomeric forms were used (Extended Data Fig. 1a , Supplementary Table 2 ). The D614G substitution in S also resulted in enhanced S1 binding to hACE2 exogenously expressed in baby hamster kidney cells (hereafter, BHK–hACE2 cells) (Fig. 1b , Extended Data Fig. 1b ). The binding of polyhistidine-tagged S1 or S1(D614G) to BHK–hACE2 cells showed that more S1(D614G) bound to BHK–hACE2 cells than did S1, by flow cytometry (Fig. 1b , Extended Data Fig. 1b ). When using homodimeric recombinant constructs comprising S1 attached to an IgG C terminus, we observed a more notable effect in the increased binding of the S1(D614G) protein to the BHK–hACE2 cell (Fig. 1b , Extended Data Fig. 1b ). Fig. 1: In vitro characterization of S1 and of recombinant SARS-CoV-2 D614 and SARS-CoV-2 G614 . a , Affinity between S1 and hACE2 determined by biolayer interferometry. Fc-tagged ACE2 protein was loaded onto surface of anti-human Fc capture biosensors. Association was conducted using S1 (left) or S1(D614G) (right), followed by dissociation. Data represent three biological replicates. b , Binding of polyhistidine-tagged or Fc-tagged S1 to BHK–hACE2 cells is shown as peaks of fluorescence, detected by flow cytometry. c , Replication kinetics of recombinant viruses in Vero E6 cells at 37 °C (left) and human nasal epithelial cells at 33 °C (right). Supernatant was collected at the indicated time points and titrated by plaque assay. D614, SARS-CoV-2 D614 ; G614, SARS-CoV-2 G614 . d , Replication kinetics of recombinant viruses in human NBE cells at 33 °C (left), 37 °C (middle) and 39 °C (right). Supernatant was collected daily and titrated by TCID 50 assay. In c , d , data are mean ± s.d. of three biological replicates (Vero E6 cells) or four technical replicates (human nasal epithelial and human NBE cells). Statistical significance was determined by two-sided, unpaired Student’s t -test without adjustments for multiple comparisons. e , f , Competition assay of recombinant viruses in human nasal epithelial cells at 33 °C ( e ) and human NBE cells at 33 °C ( f , left), 37 °C ( f , middle) and 39 °C ( f , right). The inoculum<|im_end|> <|im_start|>assistant Prior to the emergence of new mutants of the coronavirus, such as the British variant B.1.1.7, the SARS-CoV-2 variant named D614G had already mutated from the original SARS-CoV-2 pathogen that triggered the pandemic. D614G has rapidly spread to become the most abundant variant worldwide and this D614G mutation remains in all the new emerging variants. An international team including researchers from Bern has now been able to demonstrate in both the laboratory and in animal models why the D614G variant was able to gain the upper hand over the original SARS-CoV-2 virus. "Our approach also allows us to characterize emerging mutations such as the British variant B.1.1.7 better and quicker," says Volker Thiel of the Institute of Virology and Immunology (IVI), one of the four lead authors of the study. The findings are extremely important for assessing the risk of new mutants running rampant, as they show how a fitness advantage of virus variants can lead to higher transmission. First results were released earlier allowing for scientific discussion on what is known as a preprint server. The results of the study have now been published in full in Nature. The D614G variant carries a mutation in the spike protein that makes it easier for the virus to dock onto human cells. The researchers at IVI and in David E. Wentworth's laboratory at the Centers for Disease Control and Prevention in Atlanta (USA) first demonstrated in human cell cultures from the upper respiratory tract, as well as from the nose, that the D614G variant binds more strongly and also replicates faster than the original virus. The increased replication of the D614G variant was also confirmed in vivo, in a new mouse model first described in this study. These experiments were also carried out at the IVI in Charaf Benarafa's group. The new mutation clearly prevails The spread of SARS-CoV-2 viruses can be studied better in other animals rather than mice. Hamsters and ferrets are well established in infection research and are especially suitable animal models. To compare the two variants, a mixture of equal parts of the original version of the SARS-CoV-2 virus and the D614G variant was applied into the nose of each animal under light anesthesia. After one day, experimentally infected animals were rehoused with another healthy sentinel animal of the same species, to evaluate the transmission of the two variants in direct competition with each other. The experiment was repeated with six pairs of animals in total. In virtually all sentinel animals, the proportion of transmitted SARS-CoV-2 viruses was massively dominated by the D614G variant early on. The differentiation of the variants was carried out using the latest sequencing technology and PCR techniques by Martin Beer's team at the Friedrich Loeffler Institute, Federal Research Institute for Animal Health, in Greifswald-Insel Riems (D). "Our study stands out because we were able to clearly discern the more efficient transmission of the mutated variant in direct comparison with the original variant," says Volker Thiel. A fitness test for further mutations This approach can even be used to test any single mutation or a specific combination of mutations that are present in a number of currently circulating viral variants. The IVI relies on a cloning technique developed in Bern a year ago, in which SARS-CoV-2 viruses can be exactly reproduced in the laboratory. The British virus, for example, is known to have not just one but often more than 14 mutations, eight of which occur in the spike protein. Thus, with the help of the cloning technique, any number of mutations of variants can be reproduced and used to compete against each other in the established cell cultures and animal models. The results show how single mutations affect the fitness and transmissibility of new variants. "Our testing strategy allows us to rapidly examine why other, newly emerging virus variants have become established," says Volker Thiel. Similar research projects on infectious pathogens could also be carried out in the future at the newly established Multidisciplinary Center for Infectious Diseases and Immunity (MCIDI) at the University of Bern. <|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 Macromolecular complexes are essential to conserved biological processes, but their prevalence across animals is unclear. By combining extensive biochemical fractionation with quantitative mass spectrometry, here we directly examined the composition of soluble multiprotein complexes among diverse metazoan models. Using an integrative approach, we generated a draft conservation map consisting of more than one million putative high-confidence co-complex interactions for species with fully sequenced genomes that encompasses functional modules present broadly across all extant animals. Clustering reveals a spectrum of conservation, ranging from ancient eukaryotic assemblies that have probably served cellular housekeeping roles for at least one billion years, ancestral complexes that have accrued contemporary components, and rarer metazoan innovations linked to multicellularity. We validated these projections by independent co-fractionation experiments in evolutionarily distant species, affinity purification and functional analyses. The comprehensiveness, centrality and modularity of these reconstructed interactomes reflect their fundamental mechanistic importance and adaptive value to animal cell systems. Introduction Elucidating the components, conservation and functions of multiprotein complexes is essential to understand cellular processes 1 , 2 , but mapping physical association networks on a proteome-wide scale is challenging. The development of high-throughput methods for systematically determining protein–protein interactions (PPIs) has led to global molecular interaction maps for model organisms including E. coli , yeast, worm, fly and human 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 . In turn, comparative analyses have shown that PPI networks tend to be conserved 11 , 12 , evolve more slowly than regulatory networks 13 , and closely mirror function retention across orthologous groups 11 , 14 , 15 . Yet fundamental questions arise 16 , 17 . Here we define: (i) the extent to which physical interactions are preserved between phyla; (ii) the identity of protein complexes that are evolutionarily stable across animals; and (iii) the unique attributes of macromolecule composition, phylogenetic distribution and phenotypic significance. Generating a high-quality conserved interaction dataset As previous cross-species interactome comparisons, based on experimental data from different sources and methods, show limited overlap 12 , 18 , we sought to produce a more comprehensive and accurate map of protein complexes common to metazoa by applying a standardized approach to multiple species. We employed biochemical fractionation of native macromolecular assemblies followed by tandem mass spectrometry to elucidate protein complex membership ( Fig. 1 ; see Supplementary Methods ). Previous application of this co-fractionation strategy to human cell lines preferentially identified vertebrate-specific protein complexes 6 , so we selected eight additional species for study on the basis of their relevance as model organisms, spanning roughly a billion years of evolutionary divergence ( Fig. 1a ). The resulting co-fractionation data ( Fig. 1b ) acquired for Caenorhabditis elegans (worm), Drosophila melanogaster (fly), Mus musculus (mouse), Strongylocentrotus purpuratus (sea urchin), and human were used to discover conserved interactions ( Fig. 1c ), while the data obtained for Xenopus laevis (frog), Nematostella vectensis (sea anemone), Dictyostelium discoideum (amoeba) and Saccharomyces cerevisiae (yeast) were used for independent validation. Details on the cell types, developmental stages and fractionation procedures used are provided in Supplementary Table 1 . Figure 1: Workflow. a , Phylogenetic relationships of organisms analysed in this study. We fractionated soluble protein complexes from worm ( C. elegans ) larvae, fly ( D. melanogaster ) S2 cells, mouse ( M. musculus ) embryonic stem cells, sea urchin ( S. purpuratus ) eggs and human (HEK293/HeLa) cell lines. Holdout species (‘T’, for test) likewise analysed were frog ( X. laevis ), an amphibian; sea anemone ( N. vectensis ), a cnidarian with primitive eumetazoan tissue organization; slime mould ( D. discoideum ), an amoeba; and yeast ( S. cerevisiae ), a unicellular eukaryote. b , Protein fractions were digested and analysed by high-performance liquid chromatography tandem mass spectrometry (LC–MS/MS), measuring peptide spectral counts and precursor ion intensities. c , Integrative computational analysis. After orthologue mapping to human, correlation scores of co-eluting protein pairs detected in each ‘input’ species were subjected to machine learning together with additional external association evidence, using the CORUM complex database as a reference standard for training. High-confidence interactions were clustered to define co-complex membership. PowerPoint slide Full size image We identified and quantified (see Supplementary Methods ) 13,386 protein orthologues across 6,387 fractions obtained from 69 different experiments ( Fig. 2a ), an order of magnitude expansion in data coverage relative to our original ( H. sapiens only) study 6 . Individual pair-wise protein associations were scored based on the fractionation profile similarity measured in each species. Next, we used an integrative computational scoring procedure ( Fig. 1c ; see Supplementary Methods ) to derive conserved interactions for human proteins and their orthologues in worm, fly, mouse and sea urchin, defined as high pair-wise protein co-fractionation in at least two of the five input species. The support vector machine learning classifier used was trained (using fivefold cross-validation) on correlation scores obtained for conserved reference annotated protein complexes (see Supplementary Methods ), and combined all of the input species co-fractionation data together with previously published human 6 , 19 and fly interactions 5 and additional supporting functional association evidence 20 (HumanNet). Measurements of overall performance showed high precision with reasonable recall by the co-fractionation data alone ( Fig. 2b ), with external data sets serving only to increase precision and recall as we required all derived interactions to have extensive biochemical support (see Supplementary Methods ). Co-fractionation data of each input species affected overall performance, in each case increasing precision and recall ( Extended Data Fig. 1a ). The final filtered interaction network consists of 16,655 high-confidence co-complex interactions in human ( Supplementary Table 2 ). All of the interactions were supported by direct biochemical evidence in at least two input species, with half (8,121) detected in three or more ( Extended Data Fig. 1b ), enabling cross-species modelling and functional inference. Figure 2: Derivation and projection of protein co-complex associations across taxa. a , Expanded coverage via experimental scale-up relative to our previous human study 6 . Chart", "role": "user" }, { "content": "A multinational team of scientists have sifted through cells of vastly different organisms, from amoebae to worms to mice to humans, to reveal how proteins fit together to build different cells and bodies. This tour de force of protein science, a result of a collaboration between seven research groups from three countries, led by Professor Andrew Emili from the University of Toronto's Donnelly Centre and Professor Edward Marcotte from the University of Texas at Austin, uncovered tens of thousands of new protein interactions, accounting for about a quarter of all estimated protein contacts in a cell. When even a single one of these interactions is lost it can lead to disease, and the map is already helping scientists spot individual proteins that could be at the root of complex human disorders. The data will be available to researchers across the world through open access databases. The study comes out in Nature on September 7. While the sequencing of the human genome more than a decade ago was undoubtedly one of the greatest discoveries in biology, it was only the beginning of our in-depth understanding of how cells work. Genes are just blueprints and it is the genes' products, the proteins, that do much of the work in a cell. Proteins work in teams by sticking to each other to carry out their jobs. Many proteins come together to form so called molecular machines that play key roles, such a building new proteins or recycling those no longer needed by literally grinding them into reusable parts. But for the vast majority of proteins, and there are tens of thousands of them in human cells, we still don't know what they do. This is where Emili and Marcotte's map comes in. Using a state-of-the-art method developed by the groups, the researchers were able to fish thousands of protein machineries out of cells and count individual proteins they are made of. They then built a network that, similar to social networks, offers clues into protein function based on which other proteins they hang out with. For example, a new and unstudied protein, whose role we don't yet know, is likely to be involved in fixing damage in a cell if it sticks to cell's known \"handymen\" proteins. Today's landmark study gathered information on protein machineries from nine species that represent the tree of life: baker's yeast, amoeba, sea anemones, flies, worms, sea urchins, frogs, mice and humans. The new map expands the number of known protein associations over 10 fold, and gives insights into how they evolved over time. \"For me the highlight of the study is its sheer scale. We have tripled the number of protein interactions for every species. So across all the animals, we can now predict, with high confidence, more than 1 million protein interactions - a fundamentally 'big step' moving the goal posts forward in terms of protein interactions networks,\" says Emili, who is also Ontario Research Chair in Biomarkers in Disease Management and a professor in the Department of Molecular Genetics. The researchers discovered that tens of thousands of protein associations remained unchanged since the first ancestral cell appeared, one billion years ago (!), preceding all of animal life on Earth. \"Protein assemblies in humans were often identical to those in other species. This not only reinforces what we already know about our common evolutionary ancestry, it also has practical implications, providing the ability to study the genetic basis for a wide variety of diseases and how they present in different species,\" says Marcotte. The map is already proving useful in pinpointing possible causes of human disease. One example is a newly discovered molecular machine, dubbed Commander, which consists of about a dozen individual proteins. Genes that encode some of Commander's components had previously been found to be mutated in people with intellectual disabilities but it was not clear how these proteins worked. Because Commander is present in all animal cells, graduate student Fan Tu went on to disrupt its components in tadpoles, revealing abnormalities in the way brain cells are positioned during embryo development and providing a possible origin for a complex human condition. \"With tens of thousands of other new protein interactions, our map promises to open many more lines of research into links between proteins and disease, which we are keen to explore in depth over the coming years,\" concludes Dr. Emili. ", "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 Macromolecular complexes are essential to conserved biological processes, but their prevalence across animals is unclear. By combining extensive biochemical fractionation with quantitative mass spectrometry, here we directly examined the composition of soluble multiprotein complexes among diverse metazoan models. Using an integrative approach, we generated a draft conservation map consisting of more than one million putative high-confidence co-complex interactions for species with fully sequenced genomes that encompasses functional modules present broadly across all extant animals. Clustering reveals a spectrum of conservation, ranging from ancient eukaryotic assemblies that have probably served cellular housekeeping roles for at least one billion years, ancestral complexes that have accrued contemporary components, and rarer metazoan innovations linked to multicellularity. We validated these projections by independent co-fractionation experiments in evolutionarily distant species, affinity purification and functional analyses. The comprehensiveness, centrality and modularity of these reconstructed interactomes reflect their fundamental mechanistic importance and adaptive value to animal cell systems. Introduction Elucidating the components, conservation and functions of multiprotein complexes is essential to understand cellular processes 1 , 2 , but mapping physical association networks on a proteome-wide scale is challenging. The development of high-throughput methods for systematically determining protein–protein interactions (PPIs) has led to global molecular interaction maps for model organisms including E. coli , yeast, worm, fly and human 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 . In turn, comparative analyses have shown that PPI networks tend to be conserved 11 , 12 , evolve more slowly than regulatory networks 13 , and closely mirror function retention across orthologous groups 11 , 14 , 15 . Yet fundamental questions arise 16 , 17 . Here we define: (i) the extent to which physical interactions are preserved between phyla; (ii) the identity of protein complexes that are evolutionarily stable across animals; and (iii) the unique attributes of macromolecule composition, phylogenetic distribution and phenotypic significance. Generating a high-quality conserved interaction dataset As previous cross-species interactome comparisons, based on experimental data from different sources and methods, show limited overlap 12 , 18 , we sought to produce a more comprehensive and accurate map of protein complexes common to metazoa by applying a standardized approach to multiple species. We employed biochemical fractionation of native macromolecular assemblies followed by tandem mass spectrometry to elucidate protein complex membership ( Fig. 1 ; see Supplementary Methods ). Previous application of this co-fractionation strategy to human cell lines preferentially identified vertebrate-specific protein complexes 6 , so we selected eight additional species for study on the basis of their relevance as model organisms, spanning roughly a billion years of evolutionary divergence ( Fig. 1a ). The resulting co-fractionation data ( Fig. 1b ) acquired for Caenorhabditis elegans (worm), Drosophila melanogaster (fly), Mus musculus (mouse), Strongylocentrotus purpuratus (sea urchin), and human were used to discover conserved interactions ( Fig. 1c ), while the data obtained for Xenopus laevis (frog), Nematostella vectensis (sea anemone), Dictyostelium discoideum (amoeba) and Saccharomyces cerevisiae (yeast) were used for independent validation. Details on the cell types, developmental stages and fractionation procedures used are provided in Supplementary Table 1 . Figure 1: Workflow. a , Phylogenetic relationships of organisms analysed in this study. We fractionated soluble protein complexes from worm ( C. elegans ) larvae, fly ( D. melanogaster ) S2 cells, mouse ( M. musculus ) embryonic stem cells, sea urchin ( S. purpuratus ) eggs and human (HEK293/HeLa) cell lines. Holdout species (‘T’, for test) likewise analysed were frog ( X. laevis ), an amphibian; sea anemone ( N. vectensis ), a cnidarian with primitive eumetazoan tissue organization; slime mould ( D. discoideum ), an amoeba; and yeast ( S. cerevisiae ), a unicellular eukaryote. b , Protein fractions were digested and analysed by high-performance liquid chromatography tandem mass spectrometry (LC–MS/MS), measuring peptide spectral counts and precursor ion intensities. c , Integrative computational analysis. After orthologue mapping to human, correlation scores of co-eluting protein pairs detected in each ‘input’ species were subjected to machine learning together with additional external association evidence, using the CORUM complex database as a reference standard for training. High-confidence interactions were clustered to define co-complex membership. PowerPoint slide Full size image We identified and quantified (see Supplementary Methods ) 13,386 protein orthologues across 6,387 fractions obtained from 69 different experiments ( Fig. 2a ), an order of magnitude expansion in data coverage relative to our original ( H. sapiens only) study 6 . Individual pair-wise protein associations were scored based on the fractionation profile similarity measured in each species. Next, we used an integrative computational scoring procedure ( Fig. 1c ; see Supplementary Methods ) to derive conserved interactions for human proteins and their orthologues in worm, fly, mouse and sea urchin, defined as high pair-wise protein co-fractionation in at least two of the five input species. The support vector machine learning classifier used was trained (using fivefold cross-validation) on correlation scores obtained for conserved reference annotated protein complexes (see Supplementary Methods ), and combined all of the input species co-fractionation data together with previously published human 6 , 19 and fly interactions 5 and additional supporting functional association evidence 20 (HumanNet). Measurements of overall performance showed high precision with reasonable recall by the co-fractionation data alone ( Fig. 2b ), with external data sets serving only to increase precision and recall as we required all derived interactions to have extensive biochemical support (see Supplementary Methods ). Co-fractionation data of each input species affected overall performance, in each case increasing precision and recall ( Extended Data Fig. 1a ). The final filtered interaction network consists of 16,655 high-confidence co-complex interactions in human ( Supplementary Table 2 ). All of the interactions were supported by direct biochemical evidence in at least two input species, with half (8,121) detected in three or more ( Extended Data Fig. 1b ), enabling cross-species modelling and functional inference. Figure 2: Derivation and projection of protein co-complex associations across taxa. a , Expanded coverage via experimental scale-up relative to our previous human study 6 . Chart<|im_end|> <|im_start|>assistant A multinational team of scientists have sifted through cells of vastly different organisms, from amoebae to worms to mice to humans, to reveal how proteins fit together to build different cells and bodies. This tour de force of protein science, a result of a collaboration between seven research groups from three countries, led by Professor Andrew Emili from the University of Toronto's Donnelly Centre and Professor Edward Marcotte from the University of Texas at Austin, uncovered tens of thousands of new protein interactions, accounting for about a quarter of all estimated protein contacts in a cell. When even a single one of these interactions is lost it can lead to disease, and the map is already helping scientists spot individual proteins that could be at the root of complex human disorders. The data will be available to researchers across the world through open access databases. The study comes out in Nature on September 7. While the sequencing of the human genome more than a decade ago was undoubtedly one of the greatest discoveries in biology, it was only the beginning of our in-depth understanding of how cells work. Genes are just blueprints and it is the genes' products, the proteins, that do much of the work in a cell. Proteins work in teams by sticking to each other to carry out their jobs. Many proteins come together to form so called molecular machines that play key roles, such a building new proteins or recycling those no longer needed by literally grinding them into reusable parts. But for the vast majority of proteins, and there are tens of thousands of them in human cells, we still don't know what they do. This is where Emili and Marcotte's map comes in. Using a state-of-the-art method developed by the groups, the researchers were able to fish thousands of protein machineries out of cells and count individual proteins they are made of. They then built a network that, similar to social networks, offers clues into protein function based on which other proteins they hang out with. For example, a new and unstudied protein, whose role we don't yet know, is likely to be involved in fixing damage in a cell if it sticks to cell's known "handymen" proteins. Today's landmark study gathered information on protein machineries from nine species that represent the tree of life: baker's yeast, amoeba, sea anemones, flies, worms, sea urchins, frogs, mice and humans. The new map expands the number of known protein associations over 10 fold, and gives insights into how they evolved over time. "For me the highlight of the study is its sheer scale. We have tripled the number of protein interactions for every species. So across all the animals, we can now predict, with high confidence, more than 1 million protein interactions - a fundamentally 'big step' moving the goal posts forward in terms of protein interactions networks," says Emili, who is also Ontario Research Chair in Biomarkers in Disease Management and a professor in the Department of Molecular Genetics. The researchers discovered that tens of thousands of protein associations remained unchanged since the first ancestral cell appeared, one billion years ago (!), preceding all of animal life on Earth. "Protein assemblies in humans were often identical to those in other species. This not only reinforces what we already know about our common evolutionary ancestry, it also has practical implications, providing the ability to study the genetic basis for a wide variety of diseases and how they present in different species," says Marcotte. The map is already proving useful in pinpointing possible causes of human disease. One example is a newly discovered molecular machine, dubbed Commander, which consists of about a dozen individual proteins. Genes that encode some of Commander's components had previously been found to be mutated in people with intellectual disabilities but it was not clear how these proteins worked. Because Commander is present in all animal cells, graduate student Fan Tu went on to disrupt its components in tadpoles, revealing abnormalities in the way brain cells are positioned during embryo development and providing a possible origin for a complex human condition. "With tens of thousands of other new protein interactions, our map promises to open many more lines of research into links between proteins and disease, which we are keen to explore in depth over the coming years," concludes Dr. Emili. <|im_end|>

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2,300

[ { "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 Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development 1 , 2 , 3 , 4 , 5 . This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling. 1938 allosterically activates PI3Kα through a distinct mechanism by enhancing multiple steps of the PI3Kα catalytic cycle and causes both local and global conformational changes in the PI3Kα structure. This compound is selective for PI3Kα over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia–reperfusion injury and, after local administration, enhances nerve regeneration following nerve crush. This study identifies a chemical tool to directly probe the PI3Kα signalling pathway and a new approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development. Main Protein and lipid kinases have been the subject of extensive kinase inhibitor development programmes. This contrasts with the limited efforts that have been undertaken to generate pharmacological kinase activators to harness the beneficial activities of some of these enzymes, such as in tissue regeneration and protection, wound healing, immune stimulation and metabolic sensitization 1 , 2 , 3 , 4 , 5 . Class IA PI3Ks signal downstream of tyrosine kinases, G protein-coupled receptors and small GTPases to regulate cell metabolism, growth, proliferation and migration. They consist of a p110α, p110β or p110δ catalytic subunit and a p85 regulatory subunit (referred to as PI3Kα, PI3Kβ and PI3Kδ, respectively, hereon). p110α and p110β have broad tissue distribution, whereas p110δ is enriched in leukocytes 6 , 7 . Overactivation of class IA PI3Ks and their effectors AKT and mTORC1 in cancer and the immune system has driven extensive development of PI3K pathway inhibitors 6 . PI3K pathway activation could also be of therapeutic benefit in tissue protection and regeneration. PI3K inhibition dampens the protective effect of growth factors and other agents in models of cell and tissue damage 8 , 9 , 10 , 11 . This includes protection from ischaemia–reperfusion injury (IRI) (such as in neurons following a stroke 12 , 13 and in cardiomyocytes following myocardial infarction 14 ), protection from ionizing radiation 15 , enhancement of tissue and wound repair 8 , 16 and neuroprotection or regeneration 17 , 18 , 19 , 20 . Genetic strategies that have been tested to activate the PI3K pathway in this context include expression of activated alleles of genes encoding PI3Kα 21 or AKT 22 , or deletion or knockdown of PTEN , a lipid phosphatase that downregulates PI3K signalling 8 , 23 . Non-genetic PI3K pathway activators include p85-binding phosphopeptides 17 , 24 , the AKT-activating small-molecule SC79 (refs. 25 , 26 ) and PTEN inhibitors 8 , 27 . These agents have poor drug-like properties, obscure mechanisms of PI3K pathway activation and poor selectivity for their target proteins. A screen for PI3Kα activators We conducted an unbiased high-throughput screen for small-molecule activators of recombinant human p110α/p85α with liposomes mimicking the plasma membrane composition. The liposomes were enriched with 5% phosphatidylinositol(4,5)bisphosphate (PtdIns(4,5)P 2 ), the natural PI3Kα substrate. Confirmed hits were screened using a fluorescence polarization assay (an orthogonal assay for lipid kinase activity) and microscale thermophoresis (to test for direct PI3Kα binding). Validated hits were investigated for the generation of phospho-S473-AKT (pAKT(S473)) in the human A549 cells. Subsequent medicinal chemistry to improve cellular potency (as assessed by measuring pAKT(S473) levels in A549 cells) led to the generation of 1938 (Fig. 1a ). Fig. 1: Biochemical mechanism of PI3Kα activation by 1938. a , Structure of compound 1938. b , Effect of the PI3Kα-selective inhibitor BYL719 (500 nM) on 1938-activated PI3K. Enzyme activity in the presence of 1938 alone was considered 100%. c , Selectivity of 1938 for PI3Kα compared with PI3Kβ and PI3Kδ. d , Enzyme kinetics (calculated using the k cat function in Prism 8) following ATP titration on PI3Kα with or without 1938 and pY. e , Membrane binding of PI3Kα shown as FRET signal ( I – I 0 ). I , fluorescence intensity at 520 nm; I 0 , fluorescence intensity at 520 nm in the absence of enzyme. f , Effect of 1938 on PI3Kα catalytic activity in the presence of a saturating dose of pY. g , Effect of 1938 on the catalytic activity of oncogenic mutants of PI3Kα. Data shown as n = 2 independent experiments ( b , e ). Data shown as the mean ± s.e.m., n = 6 ( c , top), n = 4 ( c , bottom), n = 3 ( d , f , g ) experiments. Kinetic values in d shown as the mean ± s.d. Statistical analysis performed using two-way analysis of variance (ANOVA), Tukey’s multiple comparisons test ( c ), Dunnett’s multiple comparisons test ( g ) or one-way ANOVA, Dunnett’s multiple comparisons test ( f ). **** P < 0.0001. Full size image 1938 is an allosteric activator of PI3Kα 1938 is a drug-like compound ( M r < 500 and calculated logarithm of partition coefficient (clog P ) < 5), with a half-maximum effective concentration (EC 50 ) of around 60 μM for PI3Kα (based on in vitro lipid kinase activity). The measured dissociation constant ( K d ) values for PI3Kα were 36 ± 5 µM and 16 ± 2 µM as determined by surface plasmon resonance and by differential scanning fluorimetry, respectively (Extended Data Fig. 1a,b ). 1938-stimulated PI3Kα", "role": "user" }, { "content": "Research led by UCL, in partnership with the MRC Laboratory of Molecular Biology (MRC LMB) and AstraZeneca, has identified a new compound that can stimulate nerve regeneration after injury, as well as protect cardiac tissue from the sort of damage seen following a heart attack. The study, published in Nature, identified a chemical compound, named \"1938,\" that activates the PI3K signaling pathway, and is involved in cell growth. Results from this early research showed the compound increased neuron growth in nerve cells, and in animal models, it reduced heart tissue damage after major trauma and regenerated lost motor function in a model of nerve injury. Though further research is needed to translate these findings into the clinic, 1938 is one of just a few compounds in development that can promote nerve regeneration, for which there are currently no approved medicines. Phosphoinositide 3-kinase (PI3K) is a type of enzyme that helps to control cell growth. It is active in various situations, such as initiating wound healing, but its functions can also be hijacked by cancer cells to allow them to proliferate. As a result, cancer drugs have been developed that inhibit PI3K to restrict tumor growth. But the clinical potential of activating the PI3K pathway remains underexplored. Dr. Roger Williams, a senior author of the study from the MRC Laboratory of Molecular Biology, said, \"Kinases are molecular machines that are key to controlling the activities of our cells, and they are targets for a wide range of drugs. Our aim was to find activators of one of these molecular machines, with the goal of making the machine work better. We found that we can directly activate a kinase with a small molecule to achieve therapeutic benefits in protecting hearts from injury and stimulating neural regeneration in animal studies.\" In this study, researchers from UCL and MRC LMB worked with researchers from AstraZeneca to screen thousands of molecules from its chemical compound library to create one that could activate the PI3K signaling pathway. They found that the compound named 1938 was able to activate PI3K reliably and its biological effect were assessed through experiments on cardiac tissue and nerve cells. Researchers at UCL's Hatter Cardiovascular Institute found that administering 1938 during the first 15 minutes of blood flow restoration following a heart attack provided substantial tissue protection in a preclinical model. Ordinarily, areas of dead tissue form when blood flow is restored that can lead to heart problems later in life. When 1938 was added to lab-grown nerve cells, neuron growth was significantly increased. A rat model with a sciatic nerve injury was also tested, with delivery of 1938 to the injured nerve resulting in increased recovery in the hind leg muscle, indicative of nerve regeneration. Professor James Phillips (UCL School of Pharmacy), a senior author of the study, said, \"There are currently no approved medicines to regenerate nerves, which can be damaged as a result of injury or disease, so there's a huge unmet need. Our results show that there's potential for drugs that activate PI3K to accelerate nerve regeneration and, crucially, localized delivery methods could avoid issues with off-target effects that have seen other compounds fail.\" Given the positive findings, the group is now working to develop new therapies for peripheral nerve damage, such as those sustained in serious hand and arm injuries. They are also exploring whether PI3K activators could be used to help treat damage in the central nervous system, for example due to spinal cord injury, stroke or neurodegenerative disease. Professor Bart Vanhaesebroeck (UCL Cancer Institute), a senior author of the study, said, \"This is a prime example of interdisciplinary research, in which people with expertise ranging from basic science, drug development and clinical studies join forces around an innovative idea, while also crossing boundaries between academia and industry.\" \"Blue sky research of this kind is difficult to get funding for in a world of increasing specialization, but hopefully this project can provide something of a model for future ambitious 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 Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development 1 , 2 , 3 , 4 , 5 . This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling. 1938 allosterically activates PI3Kα through a distinct mechanism by enhancing multiple steps of the PI3Kα catalytic cycle and causes both local and global conformational changes in the PI3Kα structure. This compound is selective for PI3Kα over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia–reperfusion injury and, after local administration, enhances nerve regeneration following nerve crush. This study identifies a chemical tool to directly probe the PI3Kα signalling pathway and a new approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development. Main Protein and lipid kinases have been the subject of extensive kinase inhibitor development programmes. This contrasts with the limited efforts that have been undertaken to generate pharmacological kinase activators to harness the beneficial activities of some of these enzymes, such as in tissue regeneration and protection, wound healing, immune stimulation and metabolic sensitization 1 , 2 , 3 , 4 , 5 . Class IA PI3Ks signal downstream of tyrosine kinases, G protein-coupled receptors and small GTPases to regulate cell metabolism, growth, proliferation and migration. They consist of a p110α, p110β or p110δ catalytic subunit and a p85 regulatory subunit (referred to as PI3Kα, PI3Kβ and PI3Kδ, respectively, hereon). p110α and p110β have broad tissue distribution, whereas p110δ is enriched in leukocytes 6 , 7 . Overactivation of class IA PI3Ks and their effectors AKT and mTORC1 in cancer and the immune system has driven extensive development of PI3K pathway inhibitors 6 . PI3K pathway activation could also be of therapeutic benefit in tissue protection and regeneration. PI3K inhibition dampens the protective effect of growth factors and other agents in models of cell and tissue damage 8 , 9 , 10 , 11 . This includes protection from ischaemia–reperfusion injury (IRI) (such as in neurons following a stroke 12 , 13 and in cardiomyocytes following myocardial infarction 14 ), protection from ionizing radiation 15 , enhancement of tissue and wound repair 8 , 16 and neuroprotection or regeneration 17 , 18 , 19 , 20 . Genetic strategies that have been tested to activate the PI3K pathway in this context include expression of activated alleles of genes encoding PI3Kα 21 or AKT 22 , or deletion or knockdown of PTEN , a lipid phosphatase that downregulates PI3K signalling 8 , 23 . Non-genetic PI3K pathway activators include p85-binding phosphopeptides 17 , 24 , the AKT-activating small-molecule SC79 (refs. 25 , 26 ) and PTEN inhibitors 8 , 27 . These agents have poor drug-like properties, obscure mechanisms of PI3K pathway activation and poor selectivity for their target proteins. A screen for PI3Kα activators We conducted an unbiased high-throughput screen for small-molecule activators of recombinant human p110α/p85α with liposomes mimicking the plasma membrane composition. The liposomes were enriched with 5% phosphatidylinositol(4,5)bisphosphate (PtdIns(4,5)P 2 ), the natural PI3Kα substrate. Confirmed hits were screened using a fluorescence polarization assay (an orthogonal assay for lipid kinase activity) and microscale thermophoresis (to test for direct PI3Kα binding). Validated hits were investigated for the generation of phospho-S473-AKT (pAKT(S473)) in the human A549 cells. Subsequent medicinal chemistry to improve cellular potency (as assessed by measuring pAKT(S473) levels in A549 cells) led to the generation of 1938 (Fig. 1a ). Fig. 1: Biochemical mechanism of PI3Kα activation by 1938. a , Structure of compound 1938. b , Effect of the PI3Kα-selective inhibitor BYL719 (500 nM) on 1938-activated PI3K. Enzyme activity in the presence of 1938 alone was considered 100%. c , Selectivity of 1938 for PI3Kα compared with PI3Kβ and PI3Kδ. d , Enzyme kinetics (calculated using the k cat function in Prism 8) following ATP titration on PI3Kα with or without 1938 and pY. e , Membrane binding of PI3Kα shown as FRET signal ( I – I 0 ). I , fluorescence intensity at 520 nm; I 0 , fluorescence intensity at 520 nm in the absence of enzyme. f , Effect of 1938 on PI3Kα catalytic activity in the presence of a saturating dose of pY. g , Effect of 1938 on the catalytic activity of oncogenic mutants of PI3Kα. Data shown as n = 2 independent experiments ( b , e ). Data shown as the mean ± s.e.m., n = 6 ( c , top), n = 4 ( c , bottom), n = 3 ( d , f , g ) experiments. Kinetic values in d shown as the mean ± s.d. Statistical analysis performed using two-way analysis of variance (ANOVA), Tukey’s multiple comparisons test ( c ), Dunnett’s multiple comparisons test ( g ) or one-way ANOVA, Dunnett’s multiple comparisons test ( f ). **** P < 0.0001. Full size image 1938 is an allosteric activator of PI3Kα 1938 is a drug-like compound ( M r < 500 and calculated logarithm of partition coefficient (clog P ) < 5), with a half-maximum effective concentration (EC 50 ) of around 60 μM for PI3Kα (based on in vitro lipid kinase activity). The measured dissociation constant ( K d ) values for PI3Kα were 36 ± 5 µM and 16 ± 2 µM as determined by surface plasmon resonance and by differential scanning fluorimetry, respectively (Extended Data Fig. 1a,b ). 1938-stimulated PI3Kα<|im_end|> <|im_start|>assistant Research led by UCL, in partnership with the MRC Laboratory of Molecular Biology (MRC LMB) and AstraZeneca, has identified a new compound that can stimulate nerve regeneration after injury, as well as protect cardiac tissue from the sort of damage seen following a heart attack. The study, published in Nature, identified a chemical compound, named "1938," that activates the PI3K signaling pathway, and is involved in cell growth. Results from this early research showed the compound increased neuron growth in nerve cells, and in animal models, it reduced heart tissue damage after major trauma and regenerated lost motor function in a model of nerve injury. Though further research is needed to translate these findings into the clinic, 1938 is one of just a few compounds in development that can promote nerve regeneration, for which there are currently no approved medicines. Phosphoinositide 3-kinase (PI3K) is a type of enzyme that helps to control cell growth. It is active in various situations, such as initiating wound healing, but its functions can also be hijacked by cancer cells to allow them to proliferate. As a result, cancer drugs have been developed that inhibit PI3K to restrict tumor growth. But the clinical potential of activating the PI3K pathway remains underexplored. Dr. Roger Williams, a senior author of the study from the MRC Laboratory of Molecular Biology, said, "Kinases are molecular machines that are key to controlling the activities of our cells, and they are targets for a wide range of drugs. Our aim was to find activators of one of these molecular machines, with the goal of making the machine work better. We found that we can directly activate a kinase with a small molecule to achieve therapeutic benefits in protecting hearts from injury and stimulating neural regeneration in animal studies." In this study, researchers from UCL and MRC LMB worked with researchers from AstraZeneca to screen thousands of molecules from its chemical compound library to create one that could activate the PI3K signaling pathway. They found that the compound named 1938 was able to activate PI3K reliably and its biological effect were assessed through experiments on cardiac tissue and nerve cells. Researchers at UCL's Hatter Cardiovascular Institute found that administering 1938 during the first 15 minutes of blood flow restoration following a heart attack provided substantial tissue protection in a preclinical model. Ordinarily, areas of dead tissue form when blood flow is restored that can lead to heart problems later in life. When 1938 was added to lab-grown nerve cells, neuron growth was significantly increased. A rat model with a sciatic nerve injury was also tested, with delivery of 1938 to the injured nerve resulting in increased recovery in the hind leg muscle, indicative of nerve regeneration. Professor James Phillips (UCL School of Pharmacy), a senior author of the study, said, "There are currently no approved medicines to regenerate nerves, which can be damaged as a result of injury or disease, so there's a huge unmet need. Our results show that there's potential for drugs that activate PI3K to accelerate nerve regeneration and, crucially, localized delivery methods could avoid issues with off-target effects that have seen other compounds fail." Given the positive findings, the group is now working to develop new therapies for peripheral nerve damage, such as those sustained in serious hand and arm injuries. They are also exploring whether PI3K activators could be used to help treat damage in the central nervous system, for example due to spinal cord injury, stroke or neurodegenerative disease. Professor Bart Vanhaesebroeck (UCL Cancer Institute), a senior author of the study, said, "This is a prime example of interdisciplinary research, in which people with expertise ranging from basic science, drug development and clinical studies join forces around an innovative idea, while also crossing boundaries between academia and industry." "Blue sky research of this kind is difficult to get funding for in a world of increasing specialization, but hopefully this project can provide something of a model for future ambitious research." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Gastric diseases, including peptic ulcer disease and gastric cancer, affect 10% of the world’s population and are largely due to chronic Helicobacter pylori infection 1 , 2 , 3 . Species differences in embryonic development and architecture of the adult stomach make animal models suboptimal for studying human stomach organogenesis and pathogenesis 4 , and there is no experimental model of normal human gastric mucosa. Here we report the de novo generation of three-dimensional human gastric tissue in vitro through the directed differentiation of human pluripotent stem cells. We show that temporal manipulation of the FGF, WNT, BMP, retinoic acid and EGF signalling pathways and three-dimensional growth are sufficient to generate human gastric organoids (hGOs). Developing hGOs progressed through molecular and morphogenetic stages that were nearly identical to the developing antrum of the mouse stomach. Organoids formed primitive gastric gland- and pit-like domains, proliferative zones containing LGR5-expressing cells, surface and antral mucous cells, and a diversity of gastric endocrine cells. We used hGO cultures to identify novel signalling mechanisms that regulate early endoderm patterning and gastric endocrine cell differentiation upstream of the transcription factor NEUROG3. Using hGOs to model pathogenesis of human disease, we found that H. pylori infection resulted in rapid association of the virulence factor CagA with the c-Met receptor, activation of signalling and induction of epithelial proliferation. Together, these studies describe a new and robust in vitro system for elucidating the mechanisms underlying human stomach development and disease. Main The human stomach contains a complex, three-dimensional glandular epithelium that is organized into two distinct functional domains 5 : the fundus (corpus), which is the major source of peptidases and acid, and the antrum (pylorus) that comprises a concentration of mucus-secreting cells and hormone-producing endocrine cells. Unlike other endoderm organs, little is known about signalling pathways regulating gastric development and, to our knowledge, no one has yet generated gastric tissues from human pluripotent stem cells 6 , 7 , 8 . Therefore, to direct differentiation of stem cells into complex, three-dimensional gastric tissue, we needed to identify the signalling pathways that regulate several critical stages of early stomach development including: (1) posterior foregut specification and formation of the anterior gut tube; (2) gastric specification and patterning into the fundus or antrum; and (3) epithelial growth, morphogenesis, and differentiation into gastric cell lineages. We first differentiated pluripotent stem cells into definitive endoderm 9 , which in vivo is then patterned along the anterior-to-posterior axis and transformed into a gut tube consisting of Sox2 + foregut in the anterior and Cdx2 + mid-hindgut in the posterior as shown in control mouse embryos ( Fig. 1a ). We previously demonstrated that WNT3A and FGF4 synergize to induce the morphogenesis of gut tube-like structures expressing the posterior marker CDX2 (refs 6 , 10 ). To generate foregut, from which the stomach derives, we aimed to stimulate gut tube morphogenesis with WNT and FGF while inhibiting their ability to promote posterior fate. We found that WNT/FGF require BMP activity to initiate posterior gene expression, consistent with the known role of BMP as a posterior-defining factor 11 , 12 , 13 . Specifically, inhibiting BMP signalling with the antagonist noggin (NOG) resulted in repression of the posterior marker CDX2, activation of the foregut marker SOX2 and assembly of three-dimensional foregut spheroids ( Fig. 1b–d and Extended Data Fig. 1 ). Foregut spheroid morphogenesis was a robust process using both human embryonic stem (ES) cell and human induced pluripotent stem (iPS) cell lines ( Fig. 1c, d and Extended Data Fig. 2 ). Thus, we identified a new epistatic relationship between WNT, FGF and BMP in which all three pathways cooperate to promote a mid-hindgut fate, but WNT and FGF act separately from BMP to drive morphogenesis of gut tube structures. Figure 1: Generation of three-dimensional posterior foregut spheroids. a , Sox2 marks foregut endoderm and Cdx2 marks mid/hindgut endoderm in E8.5 (14-somite stage) mouse embryo. b , c , Quantitative PCR (qPCR) analysis ( b ) and wholemount immunostaining ( c ) for patterning markers at day 6 in human pluripotent stem-cell definitive endoderm cultures exposed to 3 days in media alone (control) or with the indicated growth factors/antagonists. WNT3A (WNT) and FGF4 (FGF) induced CDX2 expression whereas the BMP antagonist NOG repressed CDX2 and induced high levels of the foregut marker SOX2. Results are normalized to expression in control endoderm (stage-matched, no-growth-factor-treated). * P < 0.05 compared to control; ** P < 0.005 compared to WNT/FGF; two-tailed Student’s t -test; n = 3 biological replicates per condition, data representative of 6 independent experiments. d , Quantitation of SOX2- and CDX2-expressing cells in day 6 spheroids generated in hindgut (WNT/FGF4) and foregut (WNT/FGF4/NOG) patterning conditions. Data are expressed as the percentage of cells expressing indicated markers, normalized to the total number of cells in the spheroids. * P < 1.0 × 10 −6 ; two-tailed Student’s t -test; n = 5 biological replicates per condition, data representative of 3 independent experiments. e , The posterior foregut in the E8.5 mouse embryo expressed both Sox2 and Hnf1β. f , g , Exposing cultures to retinoic acid (RA) on the final day (day 5–6) of the spheroid generation step induced expression of HNF1β in SOX2-expressing epithelium, measured by both qPCR ( f ) and wholemount immunofluorescent staining ( g ) at day 6, indicating the formation of posterior foregut spheroids. * P < 0.005; two-tailed Student’s t -test; n = 3 biological replicates per condition, data representative of 3 independent experiments. Scale bars, 100 μm ( a and e ) and 50 µm ( c and g ). Error bars represent s.d. PowerPoint slide Full size image The subsequent events of stomach development in vivo are posterior patterning of the foregut and specification of the fundic and antral domains of the stomach. To direct spheroids into a posterior foregut fate (indicated in mouse embryos by co-expression of Sox2 and Hnf1β; Fig. 1e ), we focused on retinoic acid signalling given its role in development of", "role": "user" }, { "content": "Scientists used pluripotent stem cells to generate functional, three-dimensional human stomach tissue in a laboratory – creating an unprecedented tool for researching the development and diseases of an organ central to several public health crises, ranging from cancer to diabetes. Scientists at Cincinnati Children's Hospital Medical Center report Oct. 29 in Nature they used human pluripotent stem cells – which can become any cell type in the body – to grow a miniature version of the stomach. In collaboration with researchers at the University of Cincinnati College of Medicine, they used laboratory generated mini-stomachs (called gastric organoids) to study infection by H. pylori bacteria, a major cause of peptic ulcer disease and stomach cancer. This first-time molecular generation of 3D human gastric organoids (hGOs) presents new opportunities for drug discovery, modeling early stages of stomach cancer and studying some of the underpinnings of obesity related diabetes, according to Jim Wells, PhD, principal investigator and a scientist in the divisions of Developmental Biology and Endocrinology at Cincinnati Children's. It also is the first time researchers have produced 3D human embryonic foregut – a promising starting point for generating other foregut organ tissues like the lungs and pancreas, he said. Jim Wells, Ph.D., divisions of Developmental Biology and Endocrinology at Cincinnati Children's Hospital Medical Center, explains how the first-time molecular generation of 3-D human gastric organoids (hGOs) presents new opportunities for drug discovery, modeling early stages of stomach cancer and studying some of the underpinnings of obesity related diabetes. The study was published online Oct. 29 in Nature. Credit: Cincinnati Children's Hospital Medical Center \"Until this study, no one had generated gastric cells from human pluripotent stem cells (hPSCs),\" Wells said. \"In addition, we discovered how to promote formation of three-dimensional gastric tissue with complex architecture and cellular composition.\" This is important because differences between species in the embryonic development and architecture of the adult stomach make mouse models less than optimal for studying human stomach development and disease, Wells added. Researchers can use human gastric organoids as a new discovery tool to help unlock other secrets of the stomach, such as identifying biochemical processes in the gut that allow gastric-bypass patients to become diabetes-free soon after surgery before losing significant weight. Obesity fueled diabetes and metabolic syndrome are an exploding public health epidemic. Until now, a major challenge to addressing these and other medical conditions involving the stomach has been a relative lack of reliable laboratory modeling systems to accurately simulate human biology, Wells explained. The key to growing human gastric organoids was to identify the steps involved in normal stomach formation during embryonic development. By manipulating these normal processes in a petri dish, the scientists were able to coax pluripotent stem cells toward becoming stomach. Over the course of a month, these steps resulted in the formation of 3D human gastric organoids that were about 3mm (1/10th of an inch) in diameter. Wells and his colleagues also used this approach to identify what drives normal stomach formation in humans with the goal of understanding what goes wrong when the stomach does not form correctly. Immunofluorecent image of human gastric organoid derived stained with Pdx1(green), H. pylori (red) and E-cadherin (blue). Credit: Kyle McCracken Along with study first author Kyle McCracken, an MD/PhD graduate student working in Wells' laboratory, and Yana Zavros, PhD, a researcher at UC's Department of Molecular and Cellular Physiology, the authors report they were impressed by how rapidly H. pylori bacteria infected stomach epithelial tissues. Within 24 hours, the bacteria had triggered biochemical changes to the organ, according to McCracken. The human gastric organoids faithfully mimicked the early stages of gastric disease caused by the bacteria, including the activation of a cancer gene called c-Met and the rapid spread of infection in epithelial tissues. Immunofluorecent image of human gastric organoid derived stained with E-cadherin (green), MUC5AC (red) and DAPI (blue). Credit: Kyle McCracken Another significant part of the team's challenge has been the relative lack of previous research literature on how the human stomach develops, the authors said. Wells said the scientists had to use a combination of published work, as well as studies from his own lab, to answer a number of basic developmental questions about how the stomach forms. Over the course of two years, this approach of experimenting with different factors to drive the formation of the stomach eventually resulted in the formation of 3D human gastric tissues in the petri dish. Wells emphasized importance of basic research for the eventual success of this project, adding, \"This milestone would not have been possible if it hadn't been for previous studies from many other basic researchers on understanding embryonic organ development.\" ", "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 Gastric diseases, including peptic ulcer disease and gastric cancer, affect 10% of the world’s population and are largely due to chronic Helicobacter pylori infection 1 , 2 , 3 . Species differences in embryonic development and architecture of the adult stomach make animal models suboptimal for studying human stomach organogenesis and pathogenesis 4 , and there is no experimental model of normal human gastric mucosa. Here we report the de novo generation of three-dimensional human gastric tissue in vitro through the directed differentiation of human pluripotent stem cells. We show that temporal manipulation of the FGF, WNT, BMP, retinoic acid and EGF signalling pathways and three-dimensional growth are sufficient to generate human gastric organoids (hGOs). Developing hGOs progressed through molecular and morphogenetic stages that were nearly identical to the developing antrum of the mouse stomach. Organoids formed primitive gastric gland- and pit-like domains, proliferative zones containing LGR5-expressing cells, surface and antral mucous cells, and a diversity of gastric endocrine cells. We used hGO cultures to identify novel signalling mechanisms that regulate early endoderm patterning and gastric endocrine cell differentiation upstream of the transcription factor NEUROG3. Using hGOs to model pathogenesis of human disease, we found that H. pylori infection resulted in rapid association of the virulence factor CagA with the c-Met receptor, activation of signalling and induction of epithelial proliferation. Together, these studies describe a new and robust in vitro system for elucidating the mechanisms underlying human stomach development and disease. Main The human stomach contains a complex, three-dimensional glandular epithelium that is organized into two distinct functional domains 5 : the fundus (corpus), which is the major source of peptidases and acid, and the antrum (pylorus) that comprises a concentration of mucus-secreting cells and hormone-producing endocrine cells. Unlike other endoderm organs, little is known about signalling pathways regulating gastric development and, to our knowledge, no one has yet generated gastric tissues from human pluripotent stem cells 6 , 7 , 8 . Therefore, to direct differentiation of stem cells into complex, three-dimensional gastric tissue, we needed to identify the signalling pathways that regulate several critical stages of early stomach development including: (1) posterior foregut specification and formation of the anterior gut tube; (2) gastric specification and patterning into the fundus or antrum; and (3) epithelial growth, morphogenesis, and differentiation into gastric cell lineages. We first differentiated pluripotent stem cells into definitive endoderm 9 , which in vivo is then patterned along the anterior-to-posterior axis and transformed into a gut tube consisting of Sox2 + foregut in the anterior and Cdx2 + mid-hindgut in the posterior as shown in control mouse embryos ( Fig. 1a ). We previously demonstrated that WNT3A and FGF4 synergize to induce the morphogenesis of gut tube-like structures expressing the posterior marker CDX2 (refs 6 , 10 ). To generate foregut, from which the stomach derives, we aimed to stimulate gut tube morphogenesis with WNT and FGF while inhibiting their ability to promote posterior fate. We found that WNT/FGF require BMP activity to initiate posterior gene expression, consistent with the known role of BMP as a posterior-defining factor 11 , 12 , 13 . Specifically, inhibiting BMP signalling with the antagonist noggin (NOG) resulted in repression of the posterior marker CDX2, activation of the foregut marker SOX2 and assembly of three-dimensional foregut spheroids ( Fig. 1b–d and Extended Data Fig. 1 ). Foregut spheroid morphogenesis was a robust process using both human embryonic stem (ES) cell and human induced pluripotent stem (iPS) cell lines ( Fig. 1c, d and Extended Data Fig. 2 ). Thus, we identified a new epistatic relationship between WNT, FGF and BMP in which all three pathways cooperate to promote a mid-hindgut fate, but WNT and FGF act separately from BMP to drive morphogenesis of gut tube structures. Figure 1: Generation of three-dimensional posterior foregut spheroids. a , Sox2 marks foregut endoderm and Cdx2 marks mid/hindgut endoderm in E8.5 (14-somite stage) mouse embryo. b , c , Quantitative PCR (qPCR) analysis ( b ) and wholemount immunostaining ( c ) for patterning markers at day 6 in human pluripotent stem-cell definitive endoderm cultures exposed to 3 days in media alone (control) or with the indicated growth factors/antagonists. WNT3A (WNT) and FGF4 (FGF) induced CDX2 expression whereas the BMP antagonist NOG repressed CDX2 and induced high levels of the foregut marker SOX2. Results are normalized to expression in control endoderm (stage-matched, no-growth-factor-treated). * P < 0.05 compared to control; ** P < 0.005 compared to WNT/FGF; two-tailed Student’s t -test; n = 3 biological replicates per condition, data representative of 6 independent experiments. d , Quantitation of SOX2- and CDX2-expressing cells in day 6 spheroids generated in hindgut (WNT/FGF4) and foregut (WNT/FGF4/NOG) patterning conditions. Data are expressed as the percentage of cells expressing indicated markers, normalized to the total number of cells in the spheroids. * P < 1.0 × 10 −6 ; two-tailed Student’s t -test; n = 5 biological replicates per condition, data representative of 3 independent experiments. e , The posterior foregut in the E8.5 mouse embryo expressed both Sox2 and Hnf1β. f , g , Exposing cultures to retinoic acid (RA) on the final day (day 5–6) of the spheroid generation step induced expression of HNF1β in SOX2-expressing epithelium, measured by both qPCR ( f ) and wholemount immunofluorescent staining ( g ) at day 6, indicating the formation of posterior foregut spheroids. * P < 0.005; two-tailed Student’s t -test; n = 3 biological replicates per condition, data representative of 3 independent experiments. Scale bars, 100 μm ( a and e ) and 50 µm ( c and g ). Error bars represent s.d. PowerPoint slide Full size image The subsequent events of stomach development in vivo are posterior patterning of the foregut and specification of the fundic and antral domains of the stomach. To direct spheroids into a posterior foregut fate (indicated in mouse embryos by co-expression of Sox2 and Hnf1β; Fig. 1e ), we focused on retinoic acid signalling given its role in development of<|im_end|> <|im_start|>assistant Scientists used pluripotent stem cells to generate functional, three-dimensional human stomach tissue in a laboratory – creating an unprecedented tool for researching the development and diseases of an organ central to several public health crises, ranging from cancer to diabetes. Scientists at Cincinnati Children's Hospital Medical Center report Oct. 29 in Nature they used human pluripotent stem cells – which can become any cell type in the body – to grow a miniature version of the stomach. In collaboration with researchers at the University of Cincinnati College of Medicine, they used laboratory generated mini-stomachs (called gastric organoids) to study infection by H. pylori bacteria, a major cause of peptic ulcer disease and stomach cancer. This first-time molecular generation of 3D human gastric organoids (hGOs) presents new opportunities for drug discovery, modeling early stages of stomach cancer and studying some of the underpinnings of obesity related diabetes, according to Jim Wells, PhD, principal investigator and a scientist in the divisions of Developmental Biology and Endocrinology at Cincinnati Children's. It also is the first time researchers have produced 3D human embryonic foregut – a promising starting point for generating other foregut organ tissues like the lungs and pancreas, he said. Jim Wells, Ph.D., divisions of Developmental Biology and Endocrinology at Cincinnati Children's Hospital Medical Center, explains how the first-time molecular generation of 3-D human gastric organoids (hGOs) presents new opportunities for drug discovery, modeling early stages of stomach cancer and studying some of the underpinnings of obesity related diabetes. The study was published online Oct. 29 in Nature. Credit: Cincinnati Children's Hospital Medical Center "Until this study, no one had generated gastric cells from human pluripotent stem cells (hPSCs)," Wells said. "In addition, we discovered how to promote formation of three-dimensional gastric tissue with complex architecture and cellular composition." This is important because differences between species in the embryonic development and architecture of the adult stomach make mouse models less than optimal for studying human stomach development and disease, Wells added. Researchers can use human gastric organoids as a new discovery tool to help unlock other secrets of the stomach, such as identifying biochemical processes in the gut that allow gastric-bypass patients to become diabetes-free soon after surgery before losing significant weight. Obesity fueled diabetes and metabolic syndrome are an exploding public health epidemic. Until now, a major challenge to addressing these and other medical conditions involving the stomach has been a relative lack of reliable laboratory modeling systems to accurately simulate human biology, Wells explained. The key to growing human gastric organoids was to identify the steps involved in normal stomach formation during embryonic development. By manipulating these normal processes in a petri dish, the scientists were able to coax pluripotent stem cells toward becoming stomach. Over the course of a month, these steps resulted in the formation of 3D human gastric organoids that were about 3mm (1/10th of an inch) in diameter. Wells and his colleagues also used this approach to identify what drives normal stomach formation in humans with the goal of understanding what goes wrong when the stomach does not form correctly. Immunofluorecent image of human gastric organoid derived stained with Pdx1(green), H. pylori (red) and E-cadherin (blue). Credit: Kyle McCracken Along with study first author Kyle McCracken, an MD/PhD graduate student working in Wells' laboratory, and Yana Zavros, PhD, a researcher at UC's Department of Molecular and Cellular Physiology, the authors report they were impressed by how rapidly H. pylori bacteria infected stomach epithelial tissues. Within 24 hours, the bacteria had triggered biochemical changes to the organ, according to McCracken. The human gastric organoids faithfully mimicked the early stages of gastric disease caused by the bacteria, including the activation of a cancer gene called c-Met and the rapid spread of infection in epithelial tissues. Immunofluorecent image of human gastric organoid derived stained with E-cadherin (green), MUC5AC (red) and DAPI (blue). Credit: Kyle McCracken Another significant part of the team's challenge has been the relative lack of previous research literature on how the human stomach develops, the authors said. Wells said the scientists had to use a combination of published work, as well as studies from his own lab, to answer a number of basic developmental questions about how the stomach forms. Over the course of two years, this approach of experimenting with different factors to drive the formation of the stomach eventually resulted in the formation of 3D human gastric tissues in the petri dish. Wells emphasized importance of basic research for the eventual success of this project, adding, "This milestone would not have been possible if it hadn't been for previous studies from many other basic researchers on understanding embryonic organ development." <|im_end|>

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2,558

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Understanding the origin of organic material on Mars is a major issue in modern planetary science. Recent robotic exploration of Martian sedimentary rocks and laboratory analyses of Martian meteorites have both reported plausible indigenous organic components. However, little is known about their origin, evolution, and preservation. Here we report that 4-billion-year-old (Ga) carbonates in Martian meteorite, Allan Hills 84001, preserve indigenous nitrogen(N)-bearing organics by developing a new technique for high-spatial resolution in situ N-chemical speciation. The organic materials were synthesized locally and/or delivered meteoritically on Mars during Noachian age. The carbonates, alteration minerals from the Martian near-surface aqueous fluid, trapped and kept the organic materials intact over long geological times. This presence of N-bearing compounds requires abiotic or possibly biotic N-fixation and ammonia storage, suggesting that early Mars had a less oxidizing environment than today. Introduction Questions concerning life on Mars have driven intensive studies of the Red Planet for decades, including focused investigation of possible organic molecules in recent Mars exploration. NASA’s Mars Science Laboratory, Curiosity, reported various organic materials including sulfur and/or chlorine-bearing hydrocarbons from ~3.5 Ga mudstones in Gale crater 1 , 2 , 3 , 4 , 5 . Cl-bearing methane was also found from an earlier exploration by the Viking landers, which was considered to be of Martian origin 6 . These previous investigations suggested the existence of organic matter in the near-surface system on Mars. However, little is known about the origin, distribution, preservation, and evolution of such organics, as well as their possible relationship with Martian biological activity. Along with robotic exploration, complementary knowledge has been obtained from detailed geochemical investigations of Martian meteorites 7 . Allan Hills (ALH) 84001, a unique early/middle Noachian igneous rock 8 , 9 , 10 , contains fine-grained assemblages of secondary carbonate minerals 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 (Fig. 1 ; hereafter referred to as ALH carbonates). Previous studies reported the presence of organic carbon components in ALH carbonates, which are either Martian or terrestrial contaminants 21 , 22 , 23 , 24 , 25 , 26 , 27 . Because ALH carbonates are considered to have precipitated via a low-temperature aqueous alteration at 4.04–3.90 Ga at Martian near-surface 18 , 19 , their organic records, if any, should reflect the geochemical conditions at Noachian Mars. In situ study of their chemical speciation, including N, H, O, and S, will help further understanding. Fig. 1: Optical and secondary electron images of ALH carbonates. a Rock fragment of ALH 84001, 248. The whole size is ~1.5 cm. White squares (Crb-1,2 and Crb-3,4) indicate the locations of orange-colored carbonate patches used for our XANES measurements. A silicate grain was collected from the visibly carbonate-free area, shown by a white arrow in this image (Opx-1). Enlarged images of the carbonate patches ( b ) and the carbonate-free silicates ( c ). d The carbonate grains on a silver double-sided sticky tape. Secondary electron images of the ALH carbonate ( e ) and silicate ( f ) grains. These images were taken after the SEM-FIB processing to remove surface contaminants (see “Methods”). Full size image Nitrogen (N) is an essential element for all life on Earth, as it is necessary for protein, DNA, RNA, and other vital materials. Nitrogen is also a useful geochemical tracer to reveal the co-evolution of the planetary atmospheres, hydrospheres, lithospheres, and biospheres. Previous studies of Martian N-chemical and isotopic signatures were done by bulk-rock destructive analyses 23 , 28 , 29 , 30 . However, in situ analysis of nitrogen chemical speciation has not been achieved due to technical difficulties. In this study we demonstrated for the first time the presence of trapped N-bearing organic compounds from micrometer-scale in situ analysis of N K-edge micro X-ray absorption near-edge structure (μ-XANES) on the 4 Ga ALH carbonates. Several carbonate grains were peeled off from a rock fragment of ALH 84001, 248 (allocated from NASA JSC in Texas, US), using silver double-sided sticky tape (Fig. 1b, d, e ), which allowed us to investigate the interiors of the individual carbonate grains. Similarly, a silicate grain in the same rock fragment was collected to serve as a background control (Fig. 1c, f ). Nitrogen µ-XANES measurements were conducted along with various N-bearing reference compounds at the SPring-8 synchrotron facility at Hyogo, Japan. The XANES spectra indicate the presence of indigenous N-bearing organics, which may have been trapped in ALH carbonates on Noachian Mars and preserved since then. Results and discussion Detection of nitrogen-bearing organics in ALH carbonates Nitrogen XANES spectra of ALH carbonates present two prominent absorption peaks at 398.9 and 399.9 eV with a broader absorption peak around 408 eV (Fig. 2 ). Their detailed analytical conditions are described in the “Method” section and Supplementary Table 1 . There are additional smaller peak(s) between 400.7 and 402 eV. Such spectral shapes do not match the XANES spectra of molecular nitrogen (N 2 ), sodium nitrate (NaNO 3 ), or ammonium chloride (NH 4 Cl) 31 , 32 , suggesting that contributions from the inorganic N-bearing species are insignificant. On the other hand, the first two peaks at 398.9 and 399.9 eV are consistent with the absorptions of organic imino and nitrile groups, respectively (Supplementary Table 2 ). Pyridinic N-heterocyclic groups also have a similar energy range 31 , 32 , 33 . The third peak(s) between 400.7 and 402 eV may correspond to pyrrolic N-heterocyclic, amide, and/or amino groups 31 , 33 . The all XANES spectra are provided in the Supplementary Notes and Supplementary Figs. 1 – 3 . Their original data are available in Supplementary Table 3 . It is uncertain whether all of these organic groups are intrinsic to ALH carbonates or if some of them are due to X-ray beam damage during the XANES measurements. Considering that the imino and/or nitrile signatures were also observed in our amino acid references, some of the imino and/or nitrile features may come", "role": "user" }, { "content": "A research team including research scientist Atsuko Kobayashi from the Earth-Life Science Institute (ELSI) at Tokyo Institute of Technology, Japan, and research scientist Mizuho Koike from the Institute of Space and Astronautical Science at Japan Aerospace Exploration Agency, have found nitrogen-bearing organic material in carbonate minerals in a Martian meteorite. This organic material has most likely been preserved for 4 billion years since Mars' Noachian age. Because carbonate minerals typically precipitate from the groundwater, this finding suggests a wet and organic-rich early Mars, which could have been habitable and favorable for life to start. For decades, scientists have tried to understand whether there are organic compounds on Mars and if so, what their source is. Although recent studies from rover-based Mars exploration have detected strong evidence for Martian organics, little is known about where they came from, how old they are, how widely distributed and preserved they may be, or what their possible relationship with biochemical activity could be. Martian meteorites are pieces of Mars' surface that were themselves blasted into space by meteor impacts, and which ultimately landed on Earth. They provide important insights into Martian history. One meteorite in particular, named Allan Hills (ALH) 84001, named for the region in Antarctica it was found in 1984, is especially important. It contains orange-coloured carbonate minerals, which precipitated from salty liquid water on Mars' near-surface 4 billion years ago. As these minerals record Mars' early aqueous environment, many studies have tried to understand their unique chemistry and whether they might provide evidence for ancient life on Mars. However, previous analyses suffered from contamination with terrestrial material from Antarctic snow and ice, making it difficult to say how much of the organic material in the meteorite were truly Martian. In addition to carbon, nitrogen (N) is an essential element for terrestrial life and a useful tracer for planetary system evolution. However, due to previous technical limitations, nitrogen had not yet been measured in ALH84001. Carbonates plucked from ALH 84001 on the silver tape (left) and their nitrogen XANES spectra with reference compounds (right). Blue colour bar indicates the absorption energy of N-bearing organics. Credit: Koike et al. (2020) Nature Communications This new research conducted by the joint ELSI-JAXA team used state-of-the-art analytical techniques to study the nitrogen content of the ALH84001 carbonates, and the team is now confident they have found the first solid evidence for 4-billion-year-old Martian organics containing nitrogen. Terrestrial contamination is a serious problem for studies of extraterrestrial materials. To avoid such contamination, the team developed new techniques to prepare the samples with. For example, they used silver tape in an ELSI clean lab to pluck off the tiny carbonate grains, which are about the width of a human hair, from the host meteorite. The team then prepared these grains further to remove possible surface contaminants with a scanning electron microscope-focused ion beam instrument at JAXA. They also used a technique called Nitrogen K-edge micro X-ray Absorption Near Edge Structure (μ-XANES) spectroscopy, which allowed them to detect nitrogen present in very small amounts and to determine what chemical form that nitrogen was in. Control samples from nearby igneous minerals gave no detectable nitrogen, showing the organic molecules were only in the carbonate. After the careful contamination checks, the team determined the detected organics were most likely truly Martian. They also determined the contribution of nitrogen in the form of nitrate, one of the strong oxidants on current Mars, was insignificant, suggesting the early Mars probably did not contain strong oxidants, and as scientists have suspected, it was less-oxidizing than it is today. Schematic images of early (4 billion years ago) and present Mars. The ancient N-bearing organics were trapped and preserved in the carbonates over a long period of time. Credit: Koike et al. (2020) Nature Communications Mars' present surface is too harsh for most organics to survive. However, scientists predict that organic compounds could be preserved in near-surface settings for billions of years. This seems to be the case for the nitrogen-bearing organic compounds the team found in the ALH84001 carbonates, which appear to have been trapped in the minerals 4 billion years ago and preserved for long periods before finally being delivered to Earth. The team agrees that there are many important open questions, such as where did these nitrogen-containing organics come from? Kobayashi explains, \"There are two main possibilities: either they came from outside Mars, or they formed on Mars. Early in the Solar System's history, Mars was likely showered with significant amounts of organic matter, for example from carbon-rich meteorites, comets and dust particles. Some of them may have dissolved in the brine and been trapped inside the carbonates.\" The research team lead, Koike adds that alternatively, chemical reactions on early Mars may have produced the N-bearing organics on-site. Either way, they say, these findings show there was organic nitrogen on Mars before it became the red planet we know today; early Mars may have been more \"Earth-like,\" less oxidising, wetter, and organic-rich. Perhaps it was 'blue.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Understanding the origin of organic material on Mars is a major issue in modern planetary science. Recent robotic exploration of Martian sedimentary rocks and laboratory analyses of Martian meteorites have both reported plausible indigenous organic components. However, little is known about their origin, evolution, and preservation. Here we report that 4-billion-year-old (Ga) carbonates in Martian meteorite, Allan Hills 84001, preserve indigenous nitrogen(N)-bearing organics by developing a new technique for high-spatial resolution in situ N-chemical speciation. The organic materials were synthesized locally and/or delivered meteoritically on Mars during Noachian age. The carbonates, alteration minerals from the Martian near-surface aqueous fluid, trapped and kept the organic materials intact over long geological times. This presence of N-bearing compounds requires abiotic or possibly biotic N-fixation and ammonia storage, suggesting that early Mars had a less oxidizing environment than today. Introduction Questions concerning life on Mars have driven intensive studies of the Red Planet for decades, including focused investigation of possible organic molecules in recent Mars exploration. NASA’s Mars Science Laboratory, Curiosity, reported various organic materials including sulfur and/or chlorine-bearing hydrocarbons from ~3.5 Ga mudstones in Gale crater 1 , 2 , 3 , 4 , 5 . Cl-bearing methane was also found from an earlier exploration by the Viking landers, which was considered to be of Martian origin 6 . These previous investigations suggested the existence of organic matter in the near-surface system on Mars. However, little is known about the origin, distribution, preservation, and evolution of such organics, as well as their possible relationship with Martian biological activity. Along with robotic exploration, complementary knowledge has been obtained from detailed geochemical investigations of Martian meteorites 7 . Allan Hills (ALH) 84001, a unique early/middle Noachian igneous rock 8 , 9 , 10 , contains fine-grained assemblages of secondary carbonate minerals 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 (Fig. 1 ; hereafter referred to as ALH carbonates). Previous studies reported the presence of organic carbon components in ALH carbonates, which are either Martian or terrestrial contaminants 21 , 22 , 23 , 24 , 25 , 26 , 27 . Because ALH carbonates are considered to have precipitated via a low-temperature aqueous alteration at 4.04–3.90 Ga at Martian near-surface 18 , 19 , their organic records, if any, should reflect the geochemical conditions at Noachian Mars. In situ study of their chemical speciation, including N, H, O, and S, will help further understanding. Fig. 1: Optical and secondary electron images of ALH carbonates. a Rock fragment of ALH 84001, 248. The whole size is ~1.5 cm. White squares (Crb-1,2 and Crb-3,4) indicate the locations of orange-colored carbonate patches used for our XANES measurements. A silicate grain was collected from the visibly carbonate-free area, shown by a white arrow in this image (Opx-1). Enlarged images of the carbonate patches ( b ) and the carbonate-free silicates ( c ). d The carbonate grains on a silver double-sided sticky tape. Secondary electron images of the ALH carbonate ( e ) and silicate ( f ) grains. These images were taken after the SEM-FIB processing to remove surface contaminants (see “Methods”). Full size image Nitrogen (N) is an essential element for all life on Earth, as it is necessary for protein, DNA, RNA, and other vital materials. Nitrogen is also a useful geochemical tracer to reveal the co-evolution of the planetary atmospheres, hydrospheres, lithospheres, and biospheres. Previous studies of Martian N-chemical and isotopic signatures were done by bulk-rock destructive analyses 23 , 28 , 29 , 30 . However, in situ analysis of nitrogen chemical speciation has not been achieved due to technical difficulties. In this study we demonstrated for the first time the presence of trapped N-bearing organic compounds from micrometer-scale in situ analysis of N K-edge micro X-ray absorption near-edge structure (μ-XANES) on the 4 Ga ALH carbonates. Several carbonate grains were peeled off from a rock fragment of ALH 84001, 248 (allocated from NASA JSC in Texas, US), using silver double-sided sticky tape (Fig. 1b, d, e ), which allowed us to investigate the interiors of the individual carbonate grains. Similarly, a silicate grain in the same rock fragment was collected to serve as a background control (Fig. 1c, f ). Nitrogen µ-XANES measurements were conducted along with various N-bearing reference compounds at the SPring-8 synchrotron facility at Hyogo, Japan. The XANES spectra indicate the presence of indigenous N-bearing organics, which may have been trapped in ALH carbonates on Noachian Mars and preserved since then. Results and discussion Detection of nitrogen-bearing organics in ALH carbonates Nitrogen XANES spectra of ALH carbonates present two prominent absorption peaks at 398.9 and 399.9 eV with a broader absorption peak around 408 eV (Fig. 2 ). Their detailed analytical conditions are described in the “Method” section and Supplementary Table 1 . There are additional smaller peak(s) between 400.7 and 402 eV. Such spectral shapes do not match the XANES spectra of molecular nitrogen (N 2 ), sodium nitrate (NaNO 3 ), or ammonium chloride (NH 4 Cl) 31 , 32 , suggesting that contributions from the inorganic N-bearing species are insignificant. On the other hand, the first two peaks at 398.9 and 399.9 eV are consistent with the absorptions of organic imino and nitrile groups, respectively (Supplementary Table 2 ). Pyridinic N-heterocyclic groups also have a similar energy range 31 , 32 , 33 . The third peak(s) between 400.7 and 402 eV may correspond to pyrrolic N-heterocyclic, amide, and/or amino groups 31 , 33 . The all XANES spectra are provided in the Supplementary Notes and Supplementary Figs. 1 – 3 . Their original data are available in Supplementary Table 3 . It is uncertain whether all of these organic groups are intrinsic to ALH carbonates or if some of them are due to X-ray beam damage during the XANES measurements. Considering that the imino and/or nitrile signatures were also observed in our amino acid references, some of the imino and/or nitrile features may come<|im_end|> <|im_start|>assistant A research team including research scientist Atsuko Kobayashi from the Earth-Life Science Institute (ELSI) at Tokyo Institute of Technology, Japan, and research scientist Mizuho Koike from the Institute of Space and Astronautical Science at Japan Aerospace Exploration Agency, have found nitrogen-bearing organic material in carbonate minerals in a Martian meteorite. This organic material has most likely been preserved for 4 billion years since Mars' Noachian age. Because carbonate minerals typically precipitate from the groundwater, this finding suggests a wet and organic-rich early Mars, which could have been habitable and favorable for life to start. For decades, scientists have tried to understand whether there are organic compounds on Mars and if so, what their source is. Although recent studies from rover-based Mars exploration have detected strong evidence for Martian organics, little is known about where they came from, how old they are, how widely distributed and preserved they may be, or what their possible relationship with biochemical activity could be. Martian meteorites are pieces of Mars' surface that were themselves blasted into space by meteor impacts, and which ultimately landed on Earth. They provide important insights into Martian history. One meteorite in particular, named Allan Hills (ALH) 84001, named for the region in Antarctica it was found in 1984, is especially important. It contains orange-coloured carbonate minerals, which precipitated from salty liquid water on Mars' near-surface 4 billion years ago. As these minerals record Mars' early aqueous environment, many studies have tried to understand their unique chemistry and whether they might provide evidence for ancient life on Mars. However, previous analyses suffered from contamination with terrestrial material from Antarctic snow and ice, making it difficult to say how much of the organic material in the meteorite were truly Martian. In addition to carbon, nitrogen (N) is an essential element for terrestrial life and a useful tracer for planetary system evolution. However, due to previous technical limitations, nitrogen had not yet been measured in ALH84001. Carbonates plucked from ALH 84001 on the silver tape (left) and their nitrogen XANES spectra with reference compounds (right). Blue colour bar indicates the absorption energy of N-bearing organics. Credit: Koike et al. (2020) Nature Communications This new research conducted by the joint ELSI-JAXA team used state-of-the-art analytical techniques to study the nitrogen content of the ALH84001 carbonates, and the team is now confident they have found the first solid evidence for 4-billion-year-old Martian organics containing nitrogen. Terrestrial contamination is a serious problem for studies of extraterrestrial materials. To avoid such contamination, the team developed new techniques to prepare the samples with. For example, they used silver tape in an ELSI clean lab to pluck off the tiny carbonate grains, which are about the width of a human hair, from the host meteorite. The team then prepared these grains further to remove possible surface contaminants with a scanning electron microscope-focused ion beam instrument at JAXA. They also used a technique called Nitrogen K-edge micro X-ray Absorption Near Edge Structure (μ-XANES) spectroscopy, which allowed them to detect nitrogen present in very small amounts and to determine what chemical form that nitrogen was in. Control samples from nearby igneous minerals gave no detectable nitrogen, showing the organic molecules were only in the carbonate. After the careful contamination checks, the team determined the detected organics were most likely truly Martian. They also determined the contribution of nitrogen in the form of nitrate, one of the strong oxidants on current Mars, was insignificant, suggesting the early Mars probably did not contain strong oxidants, and as scientists have suspected, it was less-oxidizing than it is today. Schematic images of early (4 billion years ago) and present Mars. The ancient N-bearing organics were trapped and preserved in the carbonates over a long period of time. Credit: Koike et al. (2020) Nature Communications Mars' present surface is too harsh for most organics to survive. However, scientists predict that organic compounds could be preserved in near-surface settings for billions of years. This seems to be the case for the nitrogen-bearing organic compounds the team found in the ALH84001 carbonates, which appear to have been trapped in the minerals 4 billion years ago and preserved for long periods before finally being delivered to Earth. The team agrees that there are many important open questions, such as where did these nitrogen-containing organics come from? Kobayashi explains, "There are two main possibilities: either they came from outside Mars, or they formed on Mars. Early in the Solar System's history, Mars was likely showered with significant amounts of organic matter, for example from carbon-rich meteorites, comets and dust particles. Some of them may have dissolved in the brine and been trapped inside the carbonates." The research team lead, Koike adds that alternatively, chemical reactions on early Mars may have produced the N-bearing organics on-site. Either way, they say, these findings show there was organic nitrogen on Mars before it became the red planet we know today; early Mars may have been more "Earth-like," less oxidising, wetter, and organic-rich. Perhaps it was 'blue." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract How turbulent energy is dissipated in weakly collisional space and astrophysical plasmas is a major open question. Here, we present the application of a field-particle correlation technique to directly measure the transfer of energy between the turbulent electromagnetic field and electrons in the Earth’s magnetosheath, the region of solar wind downstream of the Earth’s bow shock. The measurement of the secular energy transfer from the parallel electric field as a function of electron velocity shows a signature consistent with Landau damping. This signature is coherent over time, close to the predicted resonant velocity, similar to that seen in kinetic Alfven turbulence simulations, and disappears under phase randomisation. This suggests that electron Landau damping could play a significant role in turbulent plasma heating, and that the technique is a valuable tool for determining the particle energisation processes operating in space and astrophysical plasmas Introduction It is well-established that turbulence pervades space and astrophysical plasmas, transferring energy from the large scales at which it is injected down to the plasma microscales where it can be dissipated. The resulting plasma heating is thought to be dynamically important in a number of systems, e.g., the solar corona and solar wind 1 , the interstellar medium 2 , and galaxy clusters 3 , although it is not yet known which physical dissipation mechanisms are responsible. It is therefore a major open question as to how turbulent plasma heating occurs, although due to the weakly collisional nature of these plasmas, it is inevitably through a series of different microphysical plasma processes. In this paper, we apply a field-particle correlation technique to in situ spacecraft data to investigate the first step in the thermalisation process: the mechanism by which energy is transferred from the turbulent electromagnetic field to the plasma particles. The solar wind provides an ideal opportunity to study turbulent heating, due to the high-resolution in situ measurements available, and several different mechanisms have been proposed. Early suggestions 4 invoked cyclotron damping to enable perpendicular ion energisation 5 , 6 , 7 . The realisation that the turbulence could have a substantial k ⊥ component led also to suggestions of Landau damping 8 , 9 and later work predicted that this would be dominant over cyclotron damping 10 , 11 , 12 due to the anisotropic nature of the turbulent cascade 13 , 14 , 15 . Many models now incorporate the effect of both ion and electron Landau damping 16 , 17 , 18 , 19 , 20 , although recent work has raised interesting questions about how effective this is in turbulent systems 21 , 22 , 23 , 24 . Non-resonant mechanisms have also been proposed, most notably stochastic heating 25 , 26 , 27 , which leads to the broadening of particle distributions in a stochastic field. It has also been suggested that dissipation is localised at structures, such as reconnecting current sheets 28 , 29 , vortices 30 , 31 , and double layers 32 , although the question remains which dissipation processes would occur within such structures 33 , 34 , 35 , 36 , 37 , 38 . Various observational evidence has been presented for the above mechanisms, although to date this has been somewhat indirect. For example, evidence for cyclotron damping has been based on the wavenumber of the ion-scale break in the turbulence spectrum 4 , 39 , 40 , 41 , 42 , 43 , the shape of contours in the ion distributions 44 , 45 , or correlations between species temperatures and drifts 46 , 47 , 48 . Similarly, evidence for stochastic heating has been based on relationships between measured temperatures and turbulence amplitudes 49 , 50 , 51 . Localised enhancements in temperature 28 , 52 , 53 and work done on the particles 28 , 29 , 53 have also been cited as evidence for dissipation at structures. In this paper, we present a direct measurement of the secular transfer of energy from the turbulent electromagnetic field at kinetic scales to the electrons as a function of the electron velocity. This velocity-space signature allows the different heating mechanisms to be identified, and here is found to be consistent with electron Landau damping. Results Data set Data from the Magnetospheric Multiscale (MMS) mission 54 were used, when the spacecraft were in the Earth’s magnetosheath on 16 October 2015 09:24:11–09:25:21. The mean plasma parameters at this time were: magnetic field strength B ≈ 39 nT, number density n i ≈ n e ≈ 14 cm −3 , bulk velocity u i ≈ u e ≈ 180 km s −1 , and temperatures \$T_{||{\\mathrm{i}}} \\approx 150\\,{\\mathrm{eV}}\$ , T ⊥ i ≈ 240 eV, \$T_{||{\\mathrm{e}}} \\approx 22\\,{\\mathrm{eV}}\$ , T ⊥ e ≈ 23 eV. These correspond to average plasma betas β i ≈ 0.80 and β e ≈ 0.088 (where β s = 2 μ 0 n s k B T s / B 2 ). Magnetic field data were measured by FGM 55 and SCM 56 , electric field data by SDP 57 and ADP 58 , and particle data by FPI 59 . All data in this paper are from MMS3 and the turbulence measured during this time period was previously characterised 60 . Here, we focus on the energy transfer to the electrons, which were measured at 30 ms resolution, resulting in a total of 2333 three-dimensional velocity distributions. The average of these, f 0e = 〈 f e 〉, is shown in Fig. 1a , in the frame in which the mean electron bulk flow is zero and in a coordinate system in which v || is parallel to the global mean field B 0 = 〈 B 〉, \$v_ \\bot = \\sqrt {v_{ \\bot 1}^2 + v_{ \\bot 2}^2}\$ , and \$v_{{\\mathrm{th,e}}} = \\sqrt {2k_{\\mathrm{B}}T_{\\mathrm{e}}/m_{\\mathrm{e}}}\$ is the isotropic electron thermal speed. In the conversion from measured energy bin to particle velocity, the mean spacecraft potential (relative to the plasma) of +4.2 V was subtracted to compensate for the energy gain", "role": "user" }, { "content": "Queen Mary University of London has led a study which describes the first direct measurement of how energy is transferred from the chaotic electromagnetic fields in space to the particles that make up the solar wind, leading to the heating of interplanetary space. The study, published in Nature Communications and carried out with University of Arizona and the University of Iowa, shows that a process known as Landau damping is responsible for transferring energy from the electromagnetic plasma turbulence in space to electrons in the solar wind, causing their energisation. This process, named after the Nobel-prize winning physicist Lev Landau (1908-1968), occurs when a wave travels through a plasma and the plasma particles that are travelling at a similar speed absorb this energy, leading to a reduction of energy (damping) of the wave. Although this process had been measured in some simple situations previously, it was not known whether it would still operate in the highly turbulent and complex plasmas occurring naturally in space, or whether there would be a different process entirely. All across the universe, matter is in an energised plasma state at far higher temperatures than expected. For example, the solar corona is hundreds of times hotter than the surface of the Sun, a mystery which scientists are still trying to understand. It is also vital to understand the heating of many other astrophysical plasmas, such as the interstellar medium and the disks of plasma surrounding black holes, in order to explain some of the extreme behaviour displayed in these environments. Being able to make direct measurements of the plasma energisation mechanisms in action in the solar wind (as shown in this paper for the first time) will help scientists to understand numerous open questions, such as these, about the universe. The researchers discovered this using new high-resolution measurements from NASA's Magnetospheric Multi-Scale (MMS) spacecraft (recently launched in 2015), together with a newly-developed data analysis technique (the field-particle correlation technique). The solar wind is the stream of charged particles (i.e., plasma) that comes from the Sun and fills our entire solar system, and the MMS spacecraft are located in the solar wind measuring the fields and particles within it as it streams past. Lead author Dr. Christopher Chen, from Queen Mary University of London, said: \"Plasma is by far the most abundant form of visible matter in the universe, and is often in a highly dynamic and apparently chaotic state known as turbulence. This turbulence transfers energy to the particles in the plasma leading to heating and energisation, making turbulence and the associated heating very widespread phenomena in nature. \"In this study, we made the first direct measurement of the processes involved in turbulent heating in a naturally occurring astrophysical plasma. We also verified the new analysis technique as a tool that can be used to probe plasma energisation and that can be used in a range of follow-up studies on different aspects of plasma behaviour.\" University of Iowa's Professor Greg Howes, who co-devised this new analysis technique, said: \"In the process of Landau damping, the electric field associated with waves moving through the plasma can accelerate electrons moving with just the right speed along with the wave, analogous to a surfer catching a wave. This first successful observational application of the field-particle correlation technique demonstrates its promise to answer long-standing, fundamental questions about the behavior and evolution of space plasmas, such as the heating of the solar corona.\" This paper also paves the way for the technique to be used on future missions to other areas of the solar system, such as the NASA Parker Solar Probe (launched in 2018) which is beginning to explore the solar corona and plasma environment near the Sun for the first 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 How turbulent energy is dissipated in weakly collisional space and astrophysical plasmas is a major open question. Here, we present the application of a field-particle correlation technique to directly measure the transfer of energy between the turbulent electromagnetic field and electrons in the Earth’s magnetosheath, the region of solar wind downstream of the Earth’s bow shock. The measurement of the secular energy transfer from the parallel electric field as a function of electron velocity shows a signature consistent with Landau damping. This signature is coherent over time, close to the predicted resonant velocity, similar to that seen in kinetic Alfven turbulence simulations, and disappears under phase randomisation. This suggests that electron Landau damping could play a significant role in turbulent plasma heating, and that the technique is a valuable tool for determining the particle energisation processes operating in space and astrophysical plasmas Introduction It is well-established that turbulence pervades space and astrophysical plasmas, transferring energy from the large scales at which it is injected down to the plasma microscales where it can be dissipated. The resulting plasma heating is thought to be dynamically important in a number of systems, e.g., the solar corona and solar wind 1 , the interstellar medium 2 , and galaxy clusters 3 , although it is not yet known which physical dissipation mechanisms are responsible. It is therefore a major open question as to how turbulent plasma heating occurs, although due to the weakly collisional nature of these plasmas, it is inevitably through a series of different microphysical plasma processes. In this paper, we apply a field-particle correlation technique to in situ spacecraft data to investigate the first step in the thermalisation process: the mechanism by which energy is transferred from the turbulent electromagnetic field to the plasma particles. The solar wind provides an ideal opportunity to study turbulent heating, due to the high-resolution in situ measurements available, and several different mechanisms have been proposed. Early suggestions 4 invoked cyclotron damping to enable perpendicular ion energisation 5 , 6 , 7 . The realisation that the turbulence could have a substantial k ⊥ component led also to suggestions of Landau damping 8 , 9 and later work predicted that this would be dominant over cyclotron damping 10 , 11 , 12 due to the anisotropic nature of the turbulent cascade 13 , 14 , 15 . Many models now incorporate the effect of both ion and electron Landau damping 16 , 17 , 18 , 19 , 20 , although recent work has raised interesting questions about how effective this is in turbulent systems 21 , 22 , 23 , 24 . Non-resonant mechanisms have also been proposed, most notably stochastic heating 25 , 26 , 27 , which leads to the broadening of particle distributions in a stochastic field. It has also been suggested that dissipation is localised at structures, such as reconnecting current sheets 28 , 29 , vortices 30 , 31 , and double layers 32 , although the question remains which dissipation processes would occur within such structures 33 , 34 , 35 , 36 , 37 , 38 . Various observational evidence has been presented for the above mechanisms, although to date this has been somewhat indirect. For example, evidence for cyclotron damping has been based on the wavenumber of the ion-scale break in the turbulence spectrum 4 , 39 , 40 , 41 , 42 , 43 , the shape of contours in the ion distributions 44 , 45 , or correlations between species temperatures and drifts 46 , 47 , 48 . Similarly, evidence for stochastic heating has been based on relationships between measured temperatures and turbulence amplitudes 49 , 50 , 51 . Localised enhancements in temperature 28 , 52 , 53 and work done on the particles 28 , 29 , 53 have also been cited as evidence for dissipation at structures. In this paper, we present a direct measurement of the secular transfer of energy from the turbulent electromagnetic field at kinetic scales to the electrons as a function of the electron velocity. This velocity-space signature allows the different heating mechanisms to be identified, and here is found to be consistent with electron Landau damping. Results Data set Data from the Magnetospheric Multiscale (MMS) mission 54 were used, when the spacecraft were in the Earth’s magnetosheath on 16 October 2015 09:24:11–09:25:21. The mean plasma parameters at this time were: magnetic field strength B ≈ 39 nT, number density n i ≈ n e ≈ 14 cm −3 , bulk velocity u i ≈ u e ≈ 180 km s −1 , and temperatures $T_{||{\mathrm{i}}} \approx 150\,{\mathrm{eV}}$ , T ⊥ i ≈ 240 eV, $T_{||{\mathrm{e}}} \approx 22\,{\mathrm{eV}}$ , T ⊥ e ≈ 23 eV. These correspond to average plasma betas β i ≈ 0.80 and β e ≈ 0.088 (where β s = 2 μ 0 n s k B T s / B 2 ). Magnetic field data were measured by FGM 55 and SCM 56 , electric field data by SDP 57 and ADP 58 , and particle data by FPI 59 . All data in this paper are from MMS3 and the turbulence measured during this time period was previously characterised 60 . Here, we focus on the energy transfer to the electrons, which were measured at 30 ms resolution, resulting in a total of 2333 three-dimensional velocity distributions. The average of these, f 0e = 〈 f e 〉, is shown in Fig. 1a , in the frame in which the mean electron bulk flow is zero and in a coordinate system in which v || is parallel to the global mean field B 0 = 〈 B 〉, $v_ \bot = \sqrt {v_{ \bot 1}^2 + v_{ \bot 2}^2}$ , and $v_{{\mathrm{th,e}}} = \sqrt {2k_{\mathrm{B}}T_{\mathrm{e}}/m_{\mathrm{e}}}$ is the isotropic electron thermal speed. In the conversion from measured energy bin to particle velocity, the mean spacecraft potential (relative to the plasma) of +4.2 V was subtracted to compensate for the energy gain<|im_end|> <|im_start|>assistant Queen Mary University of London has led a study which describes the first direct measurement of how energy is transferred from the chaotic electromagnetic fields in space to the particles that make up the solar wind, leading to the heating of interplanetary space. The study, published in Nature Communications and carried out with University of Arizona and the University of Iowa, shows that a process known as Landau damping is responsible for transferring energy from the electromagnetic plasma turbulence in space to electrons in the solar wind, causing their energisation. This process, named after the Nobel-prize winning physicist Lev Landau (1908-1968), occurs when a wave travels through a plasma and the plasma particles that are travelling at a similar speed absorb this energy, leading to a reduction of energy (damping) of the wave. Although this process had been measured in some simple situations previously, it was not known whether it would still operate in the highly turbulent and complex plasmas occurring naturally in space, or whether there would be a different process entirely. All across the universe, matter is in an energised plasma state at far higher temperatures than expected. For example, the solar corona is hundreds of times hotter than the surface of the Sun, a mystery which scientists are still trying to understand. It is also vital to understand the heating of many other astrophysical plasmas, such as the interstellar medium and the disks of plasma surrounding black holes, in order to explain some of the extreme behaviour displayed in these environments. Being able to make direct measurements of the plasma energisation mechanisms in action in the solar wind (as shown in this paper for the first time) will help scientists to understand numerous open questions, such as these, about the universe. The researchers discovered this using new high-resolution measurements from NASA's Magnetospheric Multi-Scale (MMS) spacecraft (recently launched in 2015), together with a newly-developed data analysis technique (the field-particle correlation technique). The solar wind is the stream of charged particles (i.e., plasma) that comes from the Sun and fills our entire solar system, and the MMS spacecraft are located in the solar wind measuring the fields and particles within it as it streams past. Lead author Dr. Christopher Chen, from Queen Mary University of London, said: "Plasma is by far the most abundant form of visible matter in the universe, and is often in a highly dynamic and apparently chaotic state known as turbulence. This turbulence transfers energy to the particles in the plasma leading to heating and energisation, making turbulence and the associated heating very widespread phenomena in nature. "In this study, we made the first direct measurement of the processes involved in turbulent heating in a naturally occurring astrophysical plasma. We also verified the new analysis technique as a tool that can be used to probe plasma energisation and that can be used in a range of follow-up studies on different aspects of plasma behaviour." University of Iowa's Professor Greg Howes, who co-devised this new analysis technique, said: "In the process of Landau damping, the electric field associated with waves moving through the plasma can accelerate electrons moving with just the right speed along with the wave, analogous to a surfer catching a wave. This first successful observational application of the field-particle correlation technique demonstrates its promise to answer long-standing, fundamental questions about the behavior and evolution of space plasmas, such as the heating of the solar corona." This paper also paves the way for the technique to be used on future missions to other areas of the solar system, such as the NASA Parker Solar Probe (launched in 2018) which is beginning to explore the solar corona and plasma environment near the Sun for the first time. <|im_end|>

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2,146

[ { "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 search for extraterrestrial intelligence (SETI) is to quantify the prevalence of technological life beyond Earth via their ‘technosignatures’. One theorized technosignature is narrowband Doppler drifting radio signals. The principal challenge in conducting SETI in the radio domain is developing a generalized technique to reject human radiofrequency interference. Here we present a comprehensive deep-learning-based technosignature search on 820 stellar targets from the Hipparcos catalogue, totalling over 480 h of on-sky data taken with the Robert C. Byrd Green Bank Telescope as part of the Breakthrough Listen initiative. We implement a novel β- convolutional variational autoencoder to identify technosignature candidates in a semi-unsupervised manner while keeping the false-positive rate manageably low, reducing the number of candidate signals by approximately two orders of magnitude compared with previous analyses on the same dataset. Our work also returned eight promising extraterrestrial intelligence signals of interest not previously identified. Re-observations on these targets have so far not resulted in re-detections of signals with similar morphology. This machine-learning approach presents itself as a leading solution in accelerating SETI and other transient research into the age of data-driven astronomy. Main ‘Are we alone?’ is one of the most profound scientific questions that humans have asked. The search for extraterrestrial intelligence (SETI) aims to answer this question by looking for evidence of intelligent life elsewhere in the galaxy via the ‘technosignatures’ created by their technology. The majority of technosignature searches so far have been conducted at radiofrequencies, given the ease of propagation of radio signals through interstellar space 1 , as well as the relative efficiency of the construction of powerful radio transmitters and receivers. One type of technosignature that is most readily distinguishable from natural astrophysical radio emissions is narrowband (on the order of 1 Hz) and/or Doppler drifting signals due to the relative motions of transmitter and receiver 2 . The detection of an unambiguous technosignature would demonstrate the existence of extraterrestrial intelligence (ETI) and is thus of acute interest to both scientists and the general public. At present, one of the main driving forces of SETI research is the Breakthrough Listen (BL) initiative ( ). Since 2016, BL has been using the Robert C. Byrd Green Bank Telescope (GBT) in the United States and the Parkes ‘Murriyang’ Telescope in Australia to search thousands of stars and hundreds of galaxies across multiple bands for technosignatures 3 , 4 , 5 , 6 . Despite the fact that these radio telescopes are located in radio-quiet zones, radiofrequency interference (RFI) due to human technology still poses a major challenge for SETI research. To reject RFI, one of the techniques employed is spatial filtering using cadence observations, also known as position switching. The key idea is that an ETI signal observed on-axis in the primary beam should appear in only the ON-source scans, whereas RFI being near-field in nature would appear in multiple adjacent (OFF-source) observations within a cadence irrespective of whether it is on- or off-source. However, the presence of RFI in observational data can often still result in a high false-positive rate: previous searches on a related GBT dataset as used in this work, where 29 million hits were reported by ref. 3 and 37 million hits were reported by ref. 5 . In addition, one can imagine a nearly infinite range of possible ETI signals that might not be captured by the conventional de-Doppler SETI algorithm turboSETI 3 , 7 . Recently, machine learning (ML) has seen increasing application in the field of astronomy, owing to its ability to generalize relationships in large datasets. In the context of SETI, some examples include a generic signal classifier for observations obtained at the Allen Telescope Array 8 and at the Five-hundred-meter Aperture Spherical Radio Telescope (FAST) 9 , convolutional neural network (CNN)-based RFI identifiers 10 , 11 , and anomaly detection algorithms 12 , 13 . None of this work has yet constructed a purely ML-based SETI analysis pipeline. Here we apply recent advances in disentangled deep learning, especially regarding the β -variational autoencoder ( β -VAE, where β is the hyperparameter that adjust the weighting of the Kulback–Leibler (KL) divergence loss in a traditional VAE) 14 framework, in combination with a random forest decision tree to conduct a comprehensive ML SETI. β -VAE defines a neural network that implicitly learns and identifies uncorrelated features within a dataset. This design attempts to tackle the black-box problem with neural networks by forcing the network to learn human-interpretable features from training data 15 . More concretely, this design of autoencoders allows the model to implicitly learn the features of cadence filtering and narrowband Doppler drifting signals, meaning that a wider range of potential ETI signals can be searched. Furthermore, autoencoders can also implicitly learn how RFI appears in observational data, without having to be programmed for the nearly infinite possible morphologies an RFI signal can take. We apply our ML model on the BL GBT 1.1–1.9 GHz dataset of 820 nearby stars from 1,004 cadences. We analyse the observational data in small snippets of 4,096 frequency bins × 16 time bins, which provides sensitivity to a maximum drift rate of about ±10 Hz s −1 (refer to Methods ). We devise an overlapping search (Supplementary Fig. 1 ) that covers snippets offset by half the size of a snippet window. Our search includes a total of 57 million unique snippets, excluding the regions of the band affected by instrumental effects. Results From the 115 million snippet windows searched, our ML model returns a total of 2,917,789 signals of interest. A small drift rate signal can potentially be seen by two adjacent overlapped snippets. Currently, each snippet is searched independently and we have not attempted to associate detections across them. Hence this 3 million signals of interest is probably an over count. We note that nearly 10% of these events came from a handful (~1%) of cadences. These observations are heavily contaminated by RFI and skew the false-positive rate of our analysis. We visualize the distribution of", "role": "user" }, { "content": "Some 540 million years ago, diverse life forms suddenly began to emerge from the muddy ocean floors of planet Earth. This period is known as the Cambrian Explosion, and these aquatic critters are our ancient ancestors. All complex life on Earth evolved from these underwater creatures. Scientists believe all it took was an ever-so-slight increase in ocean oxygen levels above a certain threshold. We may now be in the midst of a Cambrian Explosion for artificial intelligence (AI). In the past few years, a burst of incredibly capable AI programs like Midjourney, DALL-E 2 and ChatGPT have showcased the rapid progress we've made in machine learning. AI is now used in virtually all areas of science to help researchers with routine classification tasks. It's also helping our team of radio astronomers broaden the search for extraterrestrial life, and results so far have been promising. Discovering alien signals with AI As scientists searching for evidence of intelligent life beyond Earth, we have built an AI system that beats classical algorithms in signal detection tasks. Our AI was trained to search through data from radio telescopes for signals that couldn't be generated by natural astrophysical processes. When we fed our AI a previously studied dataset, it discovered eight signals of interest the classic algorithm missed. To be clear, these signals are probably not from extraterrestrial intelligence, and are more likely rare cases of radio interference. Nonetheless, our findings—published today in Nature Astronomy— highlight how AI techniques are sure to play a continued role in the search for extraterrestrial intelligence. Not so intelligent AI algorithms do not \"understand\" or \"think\". They do excel at pattern recognition, and have proven exceedingly useful for tasks such as classification—but they don't have the ability to problem solve. They only do the specific tasks they were trained to do. So although the idea of an AI detecting extraterrestrial intelligence sounds like the plot of an exciting science fiction novel, both terms are flawed: AI programs are not intelligent, and searches for extraterrestrial intelligence can't find direct evidence of intelligence. Instead, radio astronomers look for radio \"technosignatures\". These hypothesized signals would indicate the presence of technology and, by proxy, the existence of a society with the capability to harness technology for communication. For our research, we created an algorithm that uses AI methods to classify signals as being either radio interference, or a genuine technosignature candidate. And our algorithm is performing better than we'd hoped. What our AI algorithm does Technosignature searches have been likened to looking for a needle in a cosmic haystack. Radio telescopes produce huge volumes of data, and in it are huge amounts of interference from sources such as phones, WiFi and satellites. Search algorithms need to be able to sift out real technosignatures from \"false positives\", and do so quickly. Our AI classifier delivers on these requirements. It was devised by Peter Ma, a University of Toronto student and the lead author on our paper. To create a set of training data, Peter inserted simulated signals into real data, and then used this dataset to train an AI algorithm called an autoencoder. As the autoencoder processed the data, it \"learned\" to identify salient features in the data. In a second step, these features were fed to an algorithm called a random forest classifier. This classifier creates decision trees to decide if a signal is noteworthy, or just radio interference—essentially separating the technosignature \"needles\" from the haystack. After training our AI algorithm, we fed it more than 150 terabytes of data (480 observing hours) from the Green Bank Telescope in West Virginia. It identified 20,515 signals of interest, which we then had to manually inspect. Of these, eight signals had the characteristics of technosignatures, and couldn't be attributed to radio interference. Eight signals, no re-detections To try and verify these signals, we went back to the telescope to re-observe all eight signals of interest. Unfortunately, we were not able to re-detect any of them in our follow-up observations. We've been in similar situations before. In 2020 we detected a signal that turned out to be pernicious radio interference. While we will monitor these eight new candidates, the most likely explanation is they were unusual manifestations of radio interference: not aliens. Sadly the issue of radio interference isn't going anywhere. But we will be better equipped to deal with it as new technologies emerge. Narrowing the search Our team recently deployed a powerful signal processor on the MeerKAT telescope in South Africa. MeerKAT uses a technique called interferometry to combine its 64 dishes to act as a single telescope. This technique is better able to pinpoint where in the sky a signal comes from, which will drastically reduce false positives from radio interference. If astronomers do manage to detect a technosignature that can't be explained away as interference, it would strongly suggest humans aren't the sole creators of technology within the Galaxy. This would be one of the most profound discoveries imaginable. At the same time, if we detect nothing, that doesn't necessarily mean we're the only technologically-capable \"intelligent\" species around. A non-detection could also mean we haven't looked for the right type of signals, or our telescopes aren't yet sensitive enough to detect faint transmissions from distant exoplanets. We may need to cross a sensitivity threshold before a Cambrian Explosion of discoveries can be made. Alternatively, if we really are alone, we should reflect on the unique beauty and fragility of life here on Earth. ", "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 search for extraterrestrial intelligence (SETI) is to quantify the prevalence of technological life beyond Earth via their ‘technosignatures’. One theorized technosignature is narrowband Doppler drifting radio signals. The principal challenge in conducting SETI in the radio domain is developing a generalized technique to reject human radiofrequency interference. Here we present a comprehensive deep-learning-based technosignature search on 820 stellar targets from the Hipparcos catalogue, totalling over 480 h of on-sky data taken with the Robert C. Byrd Green Bank Telescope as part of the Breakthrough Listen initiative. We implement a novel β- convolutional variational autoencoder to identify technosignature candidates in a semi-unsupervised manner while keeping the false-positive rate manageably low, reducing the number of candidate signals by approximately two orders of magnitude compared with previous analyses on the same dataset. Our work also returned eight promising extraterrestrial intelligence signals of interest not previously identified. Re-observations on these targets have so far not resulted in re-detections of signals with similar morphology. This machine-learning approach presents itself as a leading solution in accelerating SETI and other transient research into the age of data-driven astronomy. Main ‘Are we alone?’ is one of the most profound scientific questions that humans have asked. The search for extraterrestrial intelligence (SETI) aims to answer this question by looking for evidence of intelligent life elsewhere in the galaxy via the ‘technosignatures’ created by their technology. The majority of technosignature searches so far have been conducted at radiofrequencies, given the ease of propagation of radio signals through interstellar space 1 , as well as the relative efficiency of the construction of powerful radio transmitters and receivers. One type of technosignature that is most readily distinguishable from natural astrophysical radio emissions is narrowband (on the order of 1 Hz) and/or Doppler drifting signals due to the relative motions of transmitter and receiver 2 . The detection of an unambiguous technosignature would demonstrate the existence of extraterrestrial intelligence (ETI) and is thus of acute interest to both scientists and the general public. At present, one of the main driving forces of SETI research is the Breakthrough Listen (BL) initiative ( ). Since 2016, BL has been using the Robert C. Byrd Green Bank Telescope (GBT) in the United States and the Parkes ‘Murriyang’ Telescope in Australia to search thousands of stars and hundreds of galaxies across multiple bands for technosignatures 3 , 4 , 5 , 6 . Despite the fact that these radio telescopes are located in radio-quiet zones, radiofrequency interference (RFI) due to human technology still poses a major challenge for SETI research. To reject RFI, one of the techniques employed is spatial filtering using cadence observations, also known as position switching. The key idea is that an ETI signal observed on-axis in the primary beam should appear in only the ON-source scans, whereas RFI being near-field in nature would appear in multiple adjacent (OFF-source) observations within a cadence irrespective of whether it is on- or off-source. However, the presence of RFI in observational data can often still result in a high false-positive rate: previous searches on a related GBT dataset as used in this work, where 29 million hits were reported by ref. 3 and 37 million hits were reported by ref. 5 . In addition, one can imagine a nearly infinite range of possible ETI signals that might not be captured by the conventional de-Doppler SETI algorithm turboSETI 3 , 7 . Recently, machine learning (ML) has seen increasing application in the field of astronomy, owing to its ability to generalize relationships in large datasets. In the context of SETI, some examples include a generic signal classifier for observations obtained at the Allen Telescope Array 8 and at the Five-hundred-meter Aperture Spherical Radio Telescope (FAST) 9 , convolutional neural network (CNN)-based RFI identifiers 10 , 11 , and anomaly detection algorithms 12 , 13 . None of this work has yet constructed a purely ML-based SETI analysis pipeline. Here we apply recent advances in disentangled deep learning, especially regarding the β -variational autoencoder ( β -VAE, where β is the hyperparameter that adjust the weighting of the Kulback–Leibler (KL) divergence loss in a traditional VAE) 14 framework, in combination with a random forest decision tree to conduct a comprehensive ML SETI. β -VAE defines a neural network that implicitly learns and identifies uncorrelated features within a dataset. This design attempts to tackle the black-box problem with neural networks by forcing the network to learn human-interpretable features from training data 15 . More concretely, this design of autoencoders allows the model to implicitly learn the features of cadence filtering and narrowband Doppler drifting signals, meaning that a wider range of potential ETI signals can be searched. Furthermore, autoencoders can also implicitly learn how RFI appears in observational data, without having to be programmed for the nearly infinite possible morphologies an RFI signal can take. We apply our ML model on the BL GBT 1.1–1.9 GHz dataset of 820 nearby stars from 1,004 cadences. We analyse the observational data in small snippets of 4,096 frequency bins × 16 time bins, which provides sensitivity to a maximum drift rate of about ±10 Hz s −1 (refer to Methods ). We devise an overlapping search (Supplementary Fig. 1 ) that covers snippets offset by half the size of a snippet window. Our search includes a total of 57 million unique snippets, excluding the regions of the band affected by instrumental effects. Results From the 115 million snippet windows searched, our ML model returns a total of 2,917,789 signals of interest. A small drift rate signal can potentially be seen by two adjacent overlapped snippets. Currently, each snippet is searched independently and we have not attempted to associate detections across them. Hence this 3 million signals of interest is probably an over count. We note that nearly 10% of these events came from a handful (~1%) of cadences. These observations are heavily contaminated by RFI and skew the false-positive rate of our analysis. We visualize the distribution of<|im_end|> <|im_start|>assistant Some 540 million years ago, diverse life forms suddenly began to emerge from the muddy ocean floors of planet Earth. This period is known as the Cambrian Explosion, and these aquatic critters are our ancient ancestors. All complex life on Earth evolved from these underwater creatures. Scientists believe all it took was an ever-so-slight increase in ocean oxygen levels above a certain threshold. We may now be in the midst of a Cambrian Explosion for artificial intelligence (AI). In the past few years, a burst of incredibly capable AI programs like Midjourney, DALL-E 2 and ChatGPT have showcased the rapid progress we've made in machine learning. AI is now used in virtually all areas of science to help researchers with routine classification tasks. It's also helping our team of radio astronomers broaden the search for extraterrestrial life, and results so far have been promising. Discovering alien signals with AI As scientists searching for evidence of intelligent life beyond Earth, we have built an AI system that beats classical algorithms in signal detection tasks. Our AI was trained to search through data from radio telescopes for signals that couldn't be generated by natural astrophysical processes. When we fed our AI a previously studied dataset, it discovered eight signals of interest the classic algorithm missed. To be clear, these signals are probably not from extraterrestrial intelligence, and are more likely rare cases of radio interference. Nonetheless, our findings—published today in Nature Astronomy— highlight how AI techniques are sure to play a continued role in the search for extraterrestrial intelligence. Not so intelligent AI algorithms do not "understand" or "think". They do excel at pattern recognition, and have proven exceedingly useful for tasks such as classification—but they don't have the ability to problem solve. They only do the specific tasks they were trained to do. So although the idea of an AI detecting extraterrestrial intelligence sounds like the plot of an exciting science fiction novel, both terms are flawed: AI programs are not intelligent, and searches for extraterrestrial intelligence can't find direct evidence of intelligence. Instead, radio astronomers look for radio "technosignatures". These hypothesized signals would indicate the presence of technology and, by proxy, the existence of a society with the capability to harness technology for communication. For our research, we created an algorithm that uses AI methods to classify signals as being either radio interference, or a genuine technosignature candidate. And our algorithm is performing better than we'd hoped. What our AI algorithm does Technosignature searches have been likened to looking for a needle in a cosmic haystack. Radio telescopes produce huge volumes of data, and in it are huge amounts of interference from sources such as phones, WiFi and satellites. Search algorithms need to be able to sift out real technosignatures from "false positives", and do so quickly. Our AI classifier delivers on these requirements. It was devised by Peter Ma, a University of Toronto student and the lead author on our paper. To create a set of training data, Peter inserted simulated signals into real data, and then used this dataset to train an AI algorithm called an autoencoder. As the autoencoder processed the data, it "learned" to identify salient features in the data. In a second step, these features were fed to an algorithm called a random forest classifier. This classifier creates decision trees to decide if a signal is noteworthy, or just radio interference—essentially separating the technosignature "needles" from the haystack. After training our AI algorithm, we fed it more than 150 terabytes of data (480 observing hours) from the Green Bank Telescope in West Virginia. It identified 20,515 signals of interest, which we then had to manually inspect. Of these, eight signals had the characteristics of technosignatures, and couldn't be attributed to radio interference. Eight signals, no re-detections To try and verify these signals, we went back to the telescope to re-observe all eight signals of interest. Unfortunately, we were not able to re-detect any of them in our follow-up observations. We've been in similar situations before. In 2020 we detected a signal that turned out to be pernicious radio interference. While we will monitor these eight new candidates, the most likely explanation is they were unusual manifestations of radio interference: not aliens. Sadly the issue of radio interference isn't going anywhere. But we will be better equipped to deal with it as new technologies emerge. Narrowing the search Our team recently deployed a powerful signal processor on the MeerKAT telescope in South Africa. MeerKAT uses a technique called interferometry to combine its 64 dishes to act as a single telescope. This technique is better able to pinpoint where in the sky a signal comes from, which will drastically reduce false positives from radio interference. If astronomers do manage to detect a technosignature that can't be explained away as interference, it would strongly suggest humans aren't the sole creators of technology within the Galaxy. This would be one of the most profound discoveries imaginable. At the same time, if we detect nothing, that doesn't necessarily mean we're the only technologically-capable "intelligent" species around. A non-detection could also mean we haven't looked for the right type of signals, or our telescopes aren't yet sensitive enough to detect faint transmissions from distant exoplanets. We may need to cross a sensitivity threshold before a Cambrian Explosion of discoveries can be made. Alternatively, if we really are alone, we should reflect on the unique beauty and fragility of life here on Earth. <|im_end|>

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27167, 264, 8147, 8450, 18121, 389, 279, 95816, 42, 835, 56925, 304, 4987, 10384, 13, 95816, 42, 835, 5829, 264, 15105, 2663, 41305, 7133, 311, 16343, 1202, 220, 1227, 26863, 311, 1180, 439, 264, 3254, 56925, 13, 1115, 15105, 374, 2731, 3025, 311, 67638, 1405, 304, 279, 13180, 264, 8450, 4131, 505, 11, 902, 690, 48863, 8108, 905, 64756, 505, 9063, 32317, 13, 1442, 87887, 656, 10299, 311, 11388, 264, 2869, 437, 625, 1598, 430, 649, 956, 387, 11497, 3201, 439, 32317, 11, 433, 1053, 16917, 4284, 12966, 7784, 956, 279, 13612, 34899, 315, 5557, 2949, 279, 20238, 13, 1115, 1053, 387, 832, 315, 279, 1455, 28254, 54098, 90267, 13, 2468, 279, 1890, 892, 11, 422, 584, 11388, 4400, 11, 430, 3250, 956, 14647, 3152, 584, 2351, 279, 1193, 2869, 30450, 37789, 481, 330, 396, 21149, 1, 9606, 2212, 13, 362, 2536, 1773, 23076, 1436, 1101, 3152, 584, 9167, 956, 7111, 369, 279, 1314, 955, 315, 17738, 11, 477, 1057, 78513, 19031, 7784, 956, 3686, 16614, 3403, 311, 11388, 38678, 92096, 505, 29827, 506, 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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 Exposure to natural environments is thought to be beneficial for human health, but the evidence is inconsistent. Objective To examine whether exposure to green and blue spaces in urban environments is associated with mental and physical health in Finland. Methods The Helsinki Capital Region Environmental Health Survey was conducted in 2015−2016 in Helsinki, Espoo and Vantaa in Finland (n=7321). Cross-sectional associations of the amounts of residential green and blue spaces within 1 km radius around the respondent’s home (based on the Urban Atlas 2012), green and blue views from home and green space visits with self-reported use of psychotropic (anxiolytics, hypnotics and antidepressants), antihypertensive and asthma medication were examined using logistic regression models. Indicators of health behaviour, traffic-related outdoor air pollution and noise and socioeconomic status (SES) were used as covariates, the last of these also as a potential effect modifier. Results Amounts of residential green and blue spaces or green and blue views from home were not associated with medications. However, the frequency of green space visits was associated with lower odds of using psychotropic medication (OR=0.67, 95% CI 0.55 to 0.82 for 3–4 times/week; 0.78, 0.63 to 0.96 for ≥5 times/week) and antihypertensive (0.64, 0.52 to 0.78; 0.59, 0.48 to 0.74, respectively) and asthma (0.74, 0.58 to 0.94; 0.76, 0.59 to 0.99, respectively) medication use. The observed associations were attenuated by body mass index, but no consistent interactions with SES indicators were observed. Conclusions Frequent green space visits, but not the amounts of residential green or blue spaces, or green and blue views from home, were associated with less frequent use of psychotropic, antihypertensive and asthma medication in urban environments. Epidemiology Public health Environment Cross-Sectional Studies Data availability statement No data available based on General Data Protection Regulation. 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 167 news outlets Blogged by 9 Tweeted by 102 On 3 Facebook pages Reddited by 2 25 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 Epidemiology Public health Environment Cross-Sectional Studies WHAT IS ALREADY KNOWN ON THIS TOPIC Exposure to natural environments is thought to be beneficial for human health, but the evidence is inconsistent. WHAT THIS STUDY ADDS In this cross-sectional study, higher frequency of green space visits was associated with lower frequency of psychotropic, antihypertensive and asthma medication use, and the association was not dependent on socioeconomic status. Amounts of residential green and blue spaces or green and blue views from home were not associated with psychotropic, antihypertensive and asthma medication use. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY Mounting scientific evidence supporting the health benefits of nature exposure is likely to increase the supply of high-quality green spaces in urban environments and promote their active use. This might be one way to improve health and welfare in cities. Introduction Nature exposure (ie, exposure to green and blue spaces) is thought to be beneficial, especially for mental, cardiovascular and respiratory health. 1–4 For example, many reviews have reported an association between green space exposure and mental 1 5 and cardiovascular 1 6–8 health, mainly based on cross-sectional studies. However, reviews of longitudinal and experimental studies have evaluated the evidence as inconsistent or suggestive. 9–12 In particular, findings for asthma have been inconsistent. 11 In addition to some protective associations, exposure to different types of green spaces has been linked to adverse asthma outcomes in some, 13 but not all, 14 studies. Regarding blue space exposure, a review of mainly cross-sectional studies suggests an association between exposure to blue space and mental well-being, while evidence regarding cardiovascular health is more limited. 2 Inconsistent evidence may stem from differences, for example, in study designs; characteristics of green space exposure, such as definitions, quality and accessibility 15 ; cultural and individual characteristics, such as environmental preferences 4 16 and intrinsic motivation to nature visits. 17 Therefore, it is possible that such associations do not exist in some populations. A majority of evidence on the association between green space and health is derived from objectively measured residential green space, and information on the actual active or passive use of green space is often lacking. 5 18 However, tentative evidence suggests that visiting green spaces or even having views over green spaces may be more strongly associated with health and well-being than the mere amount of green space in the residential area. 19 Despite inconsistent evidence, there are plausible pathways that can explain potential beneficial effects of nature exposure on physical and mental health and well-being, such as increased physical activity, reduced stress, social cohesion and beneficial immunological reactions, 4 11 18 20–22 but these mechanisms and the interlinkages between them are not yet fully understood. Medication use indicates an illness that is serious enough to require the use of a prescribed drug. However, medications have rarely been used as indicators of health status in studies on the health effects of nature exposure. This study aimed to investigate whether the amounts of residential green and blue space, frequency of green space visits and green or blue views from home are separately associated with self-reported use of psychotropic (anxiolytics, hypnotics and antidepressants), antihypertensive and asthma medication in Finland. These medicine groups were chosen because mental health problems, insomnia, hypertension and asthma are major disease groups from a public health perspective, and information on", "role": "user" }, { "content": "Frequent visits to urban green spaces, such as parks and community gardens in Finland, rather than the amount, or views of them from home, may be linked to lower use of certain prescription meds, suggests research published online in Occupational & Environmental Medicine. The observed associations between frequent green space visits and lower use of drugs for depression, anxiety, insomnia, high blood pressure, and asthma were not dependent on socio-economic position. Exposure to natural environments is thought to be good for health, but the evidence is inconsistent, say the researchers. They wanted to find out if the amount of residential green and blue space (bodies of water), frequency of green space visits, and views of green and blue spaces from home might be separately associated with the use of certain prescription meds. They chose prescription meds as a proxy for ill health, and those for anxiety and insomnia, depression, high blood pressure, and asthma, in particular, because they are used to treat common and potentially serious health issues. They drew on the responses of 16,000 randomly selected residents of Helsinki, Espoo, and Vantaa, to the Helsinki Capital Region Environmental Health Survey in 2015-16. These three cities make up the largest urban area in Finland. The survey gathered information on how city dwellers, aged at least 25, experience residential green and blue spaces within a 1 km radius of home. Respondents were also asked to report their use of prescribed meds—drugs for anxiety, insomnia, and depression, collectively known as psychotropic drugs; high blood pressure and asthma drugs—if applicable, for periods ranging from within the past week up to more than a year ago or never. They were also asked how often they spent time, or exercised outdoors, in green spaces, during May and September, with options ranging from never to 5 or more times a week. And they were asked whether they could see green or blue spaces from any of their windows at home, and if so, how often they took in these views, with options ranging from seldom to often. Green areas were defined as forests, gardens, parks, castle parks, cemeteries, zoos, herbaceous vegetation associations such as natural grassland and moors, and wetlands. Blue areas were defined as sea, lakes, and rivers. Potentially influential factors, including health behaviors, outdoor air pollution and noise, and household income and educational attainment were also considered. The final analysis included approximately 6000 participants who provided complete information. This showed that the amount of residential green and blue spaces, or views of them from home, weren't associated with the use of prescription meds for mental health, insomnia, high blood pressure or asthma. But the frequency of green space visits was. Compared with less than one weekly visit, visiting 3-4 times weekly was associated with 33% lower odds of using mental health meds, 36% lower odds of using blood pressure meds, and 26% lower odds of using asthma meds. The equivalent figures for visiting at least 5 times a week were, respectively, 22%, 41%, and 24% lower. These observed associations were weakened when weight (BMI) was factored in, particularly for asthma meds, as obesity is a known risk factor for asthma, point out the researchers. The effects of visiting green spaces were also stronger among those reporting the lowest annual household income ( below €30, 000). But overall, the associations found didn't depend on household income and educational attainment. This is an observational study, and so can't establish cause and effect. No information was available on illness severity, and better health may enable a person to spend more time outdoors. Finland has high forest cover, while Finnish cities are relatively green, making it easy for those willing to use green spaces to access them with minimal effort, they add. But they conclude: \"Mounting scientific evidence supporting the health benefits of nature exposure is likely to increase the supply of high quality green spaces in urban environments and promote their active use. This might be one way to improve health and welfare in cities.\" ", "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 Exposure to natural environments is thought to be beneficial for human health, but the evidence is inconsistent. Objective To examine whether exposure to green and blue spaces in urban environments is associated with mental and physical health in Finland. Methods The Helsinki Capital Region Environmental Health Survey was conducted in 2015−2016 in Helsinki, Espoo and Vantaa in Finland (n=7321). Cross-sectional associations of the amounts of residential green and blue spaces within 1 km radius around the respondent’s home (based on the Urban Atlas 2012), green and blue views from home and green space visits with self-reported use of psychotropic (anxiolytics, hypnotics and antidepressants), antihypertensive and asthma medication were examined using logistic regression models. Indicators of health behaviour, traffic-related outdoor air pollution and noise and socioeconomic status (SES) were used as covariates, the last of these also as a potential effect modifier. Results Amounts of residential green and blue spaces or green and blue views from home were not associated with medications. However, the frequency of green space visits was associated with lower odds of using psychotropic medication (OR=0.67, 95% CI 0.55 to 0.82 for 3–4 times/week; 0.78, 0.63 to 0.96 for ≥5 times/week) and antihypertensive (0.64, 0.52 to 0.78; 0.59, 0.48 to 0.74, respectively) and asthma (0.74, 0.58 to 0.94; 0.76, 0.59 to 0.99, respectively) medication use. The observed associations were attenuated by body mass index, but no consistent interactions with SES indicators were observed. Conclusions Frequent green space visits, but not the amounts of residential green or blue spaces, or green and blue views from home, were associated with less frequent use of psychotropic, antihypertensive and asthma medication in urban environments. Epidemiology Public health Environment Cross-Sectional Studies Data availability statement No data available based on General Data Protection Regulation. 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 167 news outlets Blogged by 9 Tweeted by 102 On 3 Facebook pages Reddited by 2 25 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 Epidemiology Public health Environment Cross-Sectional Studies WHAT IS ALREADY KNOWN ON THIS TOPIC Exposure to natural environments is thought to be beneficial for human health, but the evidence is inconsistent. WHAT THIS STUDY ADDS In this cross-sectional study, higher frequency of green space visits was associated with lower frequency of psychotropic, antihypertensive and asthma medication use, and the association was not dependent on socioeconomic status. Amounts of residential green and blue spaces or green and blue views from home were not associated with psychotropic, antihypertensive and asthma medication use. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY Mounting scientific evidence supporting the health benefits of nature exposure is likely to increase the supply of high-quality green spaces in urban environments and promote their active use. This might be one way to improve health and welfare in cities. Introduction Nature exposure (ie, exposure to green and blue spaces) is thought to be beneficial, especially for mental, cardiovascular and respiratory health. 1–4 For example, many reviews have reported an association between green space exposure and mental 1 5 and cardiovascular 1 6–8 health, mainly based on cross-sectional studies. However, reviews of longitudinal and experimental studies have evaluated the evidence as inconsistent or suggestive. 9–12 In particular, findings for asthma have been inconsistent. 11 In addition to some protective associations, exposure to different types of green spaces has been linked to adverse asthma outcomes in some, 13 but not all, 14 studies. Regarding blue space exposure, a review of mainly cross-sectional studies suggests an association between exposure to blue space and mental well-being, while evidence regarding cardiovascular health is more limited. 2 Inconsistent evidence may stem from differences, for example, in study designs; characteristics of green space exposure, such as definitions, quality and accessibility 15 ; cultural and individual characteristics, such as environmental preferences 4 16 and intrinsic motivation to nature visits. 17 Therefore, it is possible that such associations do not exist in some populations. A majority of evidence on the association between green space and health is derived from objectively measured residential green space, and information on the actual active or passive use of green space is often lacking. 5 18 However, tentative evidence suggests that visiting green spaces or even having views over green spaces may be more strongly associated with health and well-being than the mere amount of green space in the residential area. 19 Despite inconsistent evidence, there are plausible pathways that can explain potential beneficial effects of nature exposure on physical and mental health and well-being, such as increased physical activity, reduced stress, social cohesion and beneficial immunological reactions, 4 11 18 20–22 but these mechanisms and the interlinkages between them are not yet fully understood. Medication use indicates an illness that is serious enough to require the use of a prescribed drug. However, medications have rarely been used as indicators of health status in studies on the health effects of nature exposure. This study aimed to investigate whether the amounts of residential green and blue space, frequency of green space visits and green or blue views from home are separately associated with self-reported use of psychotropic (anxiolytics, hypnotics and antidepressants), antihypertensive and asthma medication in Finland. These medicine groups were chosen because mental health problems, insomnia, hypertension and asthma are major disease groups from a public health perspective, and information on<|im_end|> <|im_start|>assistant Frequent visits to urban green spaces, such as parks and community gardens in Finland, rather than the amount, or views of them from home, may be linked to lower use of certain prescription meds, suggests research published online in Occupational & Environmental Medicine. The observed associations between frequent green space visits and lower use of drugs for depression, anxiety, insomnia, high blood pressure, and asthma were not dependent on socio-economic position. Exposure to natural environments is thought to be good for health, but the evidence is inconsistent, say the researchers. They wanted to find out if the amount of residential green and blue space (bodies of water), frequency of green space visits, and views of green and blue spaces from home might be separately associated with the use of certain prescription meds. They chose prescription meds as a proxy for ill health, and those for anxiety and insomnia, depression, high blood pressure, and asthma, in particular, because they are used to treat common and potentially serious health issues. They drew on the responses of 16,000 randomly selected residents of Helsinki, Espoo, and Vantaa, to the Helsinki Capital Region Environmental Health Survey in 2015-16. These three cities make up the largest urban area in Finland. The survey gathered information on how city dwellers, aged at least 25, experience residential green and blue spaces within a 1 km radius of home. Respondents were also asked to report their use of prescribed meds—drugs for anxiety, insomnia, and depression, collectively known as psychotropic drugs; high blood pressure and asthma drugs—if applicable, for periods ranging from within the past week up to more than a year ago or never. They were also asked how often they spent time, or exercised outdoors, in green spaces, during May and September, with options ranging from never to 5 or more times a week. And they were asked whether they could see green or blue spaces from any of their windows at home, and if so, how often they took in these views, with options ranging from seldom to often. Green areas were defined as forests, gardens, parks, castle parks, cemeteries, zoos, herbaceous vegetation associations such as natural grassland and moors, and wetlands. Blue areas were defined as sea, lakes, and rivers. Potentially influential factors, including health behaviors, outdoor air pollution and noise, and household income and educational attainment were also considered. The final analysis included approximately 6000 participants who provided complete information. This showed that the amount of residential green and blue spaces, or views of them from home, weren't associated with the use of prescription meds for mental health, insomnia, high blood pressure or asthma. But the frequency of green space visits was. Compared with less than one weekly visit, visiting 3-4 times weekly was associated with 33% lower odds of using mental health meds, 36% lower odds of using blood pressure meds, and 26% lower odds of using asthma meds. The equivalent figures for visiting at least 5 times a week were, respectively, 22%, 41%, and 24% lower. These observed associations were weakened when weight (BMI) was factored in, particularly for asthma meds, as obesity is a known risk factor for asthma, point out the researchers. The effects of visiting green spaces were also stronger among those reporting the lowest annual household income ( below €30, 000). But overall, the associations found didn't depend on household income and educational attainment. This is an observational study, and so can't establish cause and effect. No information was available on illness severity, and better health may enable a person to spend more time outdoors. Finland has high forest cover, while Finnish cities are relatively green, making it easy for those willing to use green spaces to access them with minimal effort, they add. But they conclude: "Mounting scientific evidence supporting the health benefits of nature exposure is likely to increase the supply of high quality green spaces in urban environments and promote their active use. This might be one way to improve health and welfare in cities." <|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 Fishing is widely known to magnify fluctuations in targeted populations. These fluctuations are correlated with population shifts towards young, small, and more quickly maturing individuals. However, the existence and nature of the mechanistic basis for these correlations and their potential ecosystem impacts remain highly uncertain. Here, we elucidate this basis and associated impacts by showing how fishing can increase fluctuations in fishes and their ecosystem, particularly when coupled with decreasing body sizes and advancing maturation characteristic of the life-history changes induced by fishing. More specifically, using an empirically parameterized network model of a well-studied lake ecosystem, we show how fishing may both increase fluctuations in fish abundances and also, when accompanied by decreasing body size of adults, further decrease fish abundance and increase temporal variability of fishes’ food resources and their ecosystem. In contrast, advanced maturation has relatively little effect except to increase variability in juvenile populations. Our findings illustrate how different mechanisms underlying life-history changes that may arise as evolutionary responses to intensive, size-selective fishing can rapidly and continuously destabilize and degrade ecosystems even after fishing has ceased. This research helps better predict how life-history changes may reduce fishes’ resilience to fishing and ecosystems’ resistance to environmental variations. Introduction Commercial fishing is widely thought to magnify fluctuations in the abundance of the targeted population as suggested by variations in larval abundances 1 . While such fluctuations could, in principle, arise from varying fishing pressure or increased environmental variation, these fluctuations have been found most clearly correlated with shifts of fish life histories towards young, small, and more quickly maturing individuals 2 . Namely, age truncation of populations can lead to increasing instability in population dynamics owing the changes in intrinsic population growth rates 2 . However, the existence and nature of the mechanistic basis for the correlation between population age and size structure and instability of population dynamics as well as its potential ecosystem impacts remain poorly understood. Fishing alters age and size composition of the targeted population directly through removal of those ages and sizes specifically selected by fishing gears. However, numerous commercially exploited fish populations show not only demographic shifts in population structure but also trends in fish life-histories towards earlier maturation and declining adult body size 3 . While such changes can be also induced by increasing water temperatures 4 , most of the observed trends correlate positively with fishing pressure suggesting that the phenotypic changes are induced by fishing and potentially be, or at least resemble, evolutionary responses to fisheries-induced selection 5 , 6 . Quantifying ecological feedbacks of such life-history changes are key to understanding how these changes translate into species’ viability and recovery 7 . Such understanding may help people to manage the stability of fish populations including their resistance and resilience to exploitation and natural disturbances. Here, we use a network approach 8 to mechanistically explore the effects of fisheries-induced shifts in fish demography and life history on the dynamics of harvested species and the ecosystem. We elucidate potential causes of such effects by comparing ecosystem dynamics across periods before, during, and after fishing, in the absence and presence of life-history changes induced by fishing. We further explore the responsible mechanisms by disentangling the relative roles of life-history changes in fishes’ body size and maturation as well as the demographic effects of fishing mediated through biomass removal and fishing selectivity. The robustness of the results derived based on deterministic food web dynamics is also explored with respect to alternative levels of environmental stochasticity associated with ecosystem primary productivity. Our methods integrate two different and well-established components that model basic mechanisms responsible for the abundance of fishes in ecosystems. One component describes food-web dynamics 9 . The other describes how fishing impacts vary with the life stage of the fishes. Food web dynamics are based on consumer-resource interactions where the abundance of a species is determined by the balance of gains from consuming resources (e.g., feeding) and losses to metabolism and other consumers (e.g., predators 10 , 11 ). Key parameters such as metabolic and feeding rates are widely measured and remarkably well estimated from each species’ mean body size 12 , 13 . An allometric trophic network model 14 (ATN) based on this approach has been extended and specifically parameterized for the Lake Constance (LC) ecosystem at the Northern foot of the European Alps 9 . The LC ATN model accurately simulates the seasonal dynamics of the plankton community’s biomass and productivity including 20 functional guilds of bacteria, phytoplankton, and zooplankton fed upon by 4 functional guilds of fish 9 . Here, we extend the LC ATN model by separating each of the two most common and commercially fished species in LC-the piscivorous Eurasian perch ( Perca fluviatilis ; hereafter denoted as perch) and planktivorous whitefish ( Coregonus lavaretus )-into five life stages (total of 10 functional guilds) including larvae, juveniles, 2 years, 3 years, and 4 years or older (4+) ( Fig. 1 ). We model the dynamics of these stages by modifying a size-structured biomass model that is a less fully age-structured version of a physiologically-structured population model 15 . In contrast to the original version’s application of all adults’ energy beyond maintenance costs to reproduction, our modification allows adults to continue growing while also reproducing. We parameterized the stages using empirically measured growth parameters of the species in LC and a widely used and empirically accurate model of body size as a function of the fishes’ age 16 . Fishing-induced life-history changes were estimated using empirical observations of the effects of fishing on body size and maturation age 6 , 17 . Fishing mortality was parameterized according to observed fishing pressure in LC 18 . Figure 1: Lake Constance food web. Five guilds of algae (Alg1-5), bacteria (Bac), autotrophic picoplankton (APP), heterotrophic nanoflagellates (HNF), five guilds of ciliates (Cil1-5), four guilds of rotifers (Rot1-3, Asp), herbivorous crustacean (Dap), carnivorous crustacean (Cyc, Lep), whitefish larvae (Wht0), perch larvae (Per0), whitefish juveniles (Wht1), perch juveniles (Per1), and 2, 3, and", "role": "user" }, { "content": "Intense fishing of primarily larger fish not only makes fish populations smaller, it changes the remaining fish. When the fish which have a chance to reproduce before being caught are smaller and have reached sexual maturity earlier, these characteristics are passed down to future generations. In many fish populations targeted by intense fishing, e.g., Atlantic cod across the west coast of North America, the sizes of fish have been observed to have decreased and the age of sexual maturity to have reduced. Fish are often at the top of the food web in the aquatic ecosystem, so changes in fish can have broader consequences which involve the entire ecosystem. Together with her American and German colleagues, Academy of Finland Research Fellow Anna Kuparinen from the University of Helsinki studied how fishing changes the ways aquatic ecosystems function. The researchers used computer-generated simulations to help them model the interactions between species and the flow of energy through the food web as well as the overall dynamics of the ecosystem. The research focused on the fishing of perch and whitefish in Lake Constance, which borders Switzerland, Germany and Austria. Simulations describing the development of the ecosystem targeted by fishing indicated that once intense fishing causes fish to become smaller and reach sexual maturity earlier, the production of plankton in the lake becomes unstable. Similarly, the sizes of the fish populations and their production of offspring fluctuate greatly from one year to the next. \"If the changes in fish are genetic, the stability of the fish populations and the lake ecosystem cannot be regained even if fishing was permanently ended. The study demonstrates how important it is to consider the entire ecosystem and indirect impacts on other species when the impact of fishing is evaluated. For example, the production of offspring among perch is more dependent on the fluctuations of the production of plankton in the lake than the number of female fish producing eggs,\" says Anna Kuparinen. \"The many food chains leading to fish form complex food webs. The better we understand this complexity, the better we understand how fishing impacts fish and the environment,\" says Professor Neo Martinez from the University of Arizona, US. ", "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 Fishing is widely known to magnify fluctuations in targeted populations. These fluctuations are correlated with population shifts towards young, small, and more quickly maturing individuals. However, the existence and nature of the mechanistic basis for these correlations and their potential ecosystem impacts remain highly uncertain. Here, we elucidate this basis and associated impacts by showing how fishing can increase fluctuations in fishes and their ecosystem, particularly when coupled with decreasing body sizes and advancing maturation characteristic of the life-history changes induced by fishing. More specifically, using an empirically parameterized network model of a well-studied lake ecosystem, we show how fishing may both increase fluctuations in fish abundances and also, when accompanied by decreasing body size of adults, further decrease fish abundance and increase temporal variability of fishes’ food resources and their ecosystem. In contrast, advanced maturation has relatively little effect except to increase variability in juvenile populations. Our findings illustrate how different mechanisms underlying life-history changes that may arise as evolutionary responses to intensive, size-selective fishing can rapidly and continuously destabilize and degrade ecosystems even after fishing has ceased. This research helps better predict how life-history changes may reduce fishes’ resilience to fishing and ecosystems’ resistance to environmental variations. Introduction Commercial fishing is widely thought to magnify fluctuations in the abundance of the targeted population as suggested by variations in larval abundances 1 . While such fluctuations could, in principle, arise from varying fishing pressure or increased environmental variation, these fluctuations have been found most clearly correlated with shifts of fish life histories towards young, small, and more quickly maturing individuals 2 . Namely, age truncation of populations can lead to increasing instability in population dynamics owing the changes in intrinsic population growth rates 2 . However, the existence and nature of the mechanistic basis for the correlation between population age and size structure and instability of population dynamics as well as its potential ecosystem impacts remain poorly understood. Fishing alters age and size composition of the targeted population directly through removal of those ages and sizes specifically selected by fishing gears. However, numerous commercially exploited fish populations show not only demographic shifts in population structure but also trends in fish life-histories towards earlier maturation and declining adult body size 3 . While such changes can be also induced by increasing water temperatures 4 , most of the observed trends correlate positively with fishing pressure suggesting that the phenotypic changes are induced by fishing and potentially be, or at least resemble, evolutionary responses to fisheries-induced selection 5 , 6 . Quantifying ecological feedbacks of such life-history changes are key to understanding how these changes translate into species’ viability and recovery 7 . Such understanding may help people to manage the stability of fish populations including their resistance and resilience to exploitation and natural disturbances. Here, we use a network approach 8 to mechanistically explore the effects of fisheries-induced shifts in fish demography and life history on the dynamics of harvested species and the ecosystem. We elucidate potential causes of such effects by comparing ecosystem dynamics across periods before, during, and after fishing, in the absence and presence of life-history changes induced by fishing. We further explore the responsible mechanisms by disentangling the relative roles of life-history changes in fishes’ body size and maturation as well as the demographic effects of fishing mediated through biomass removal and fishing selectivity. The robustness of the results derived based on deterministic food web dynamics is also explored with respect to alternative levels of environmental stochasticity associated with ecosystem primary productivity. Our methods integrate two different and well-established components that model basic mechanisms responsible for the abundance of fishes in ecosystems. One component describes food-web dynamics 9 . The other describes how fishing impacts vary with the life stage of the fishes. Food web dynamics are based on consumer-resource interactions where the abundance of a species is determined by the balance of gains from consuming resources (e.g., feeding) and losses to metabolism and other consumers (e.g., predators 10 , 11 ). Key parameters such as metabolic and feeding rates are widely measured and remarkably well estimated from each species’ mean body size 12 , 13 . An allometric trophic network model 14 (ATN) based on this approach has been extended and specifically parameterized for the Lake Constance (LC) ecosystem at the Northern foot of the European Alps 9 . The LC ATN model accurately simulates the seasonal dynamics of the plankton community’s biomass and productivity including 20 functional guilds of bacteria, phytoplankton, and zooplankton fed upon by 4 functional guilds of fish 9 . Here, we extend the LC ATN model by separating each of the two most common and commercially fished species in LC-the piscivorous Eurasian perch ( Perca fluviatilis ; hereafter denoted as perch) and planktivorous whitefish ( Coregonus lavaretus )-into five life stages (total of 10 functional guilds) including larvae, juveniles, 2 years, 3 years, and 4 years or older (4+) ( Fig. 1 ). We model the dynamics of these stages by modifying a size-structured biomass model that is a less fully age-structured version of a physiologically-structured population model 15 . In contrast to the original version’s application of all adults’ energy beyond maintenance costs to reproduction, our modification allows adults to continue growing while also reproducing. We parameterized the stages using empirically measured growth parameters of the species in LC and a widely used and empirically accurate model of body size as a function of the fishes’ age 16 . Fishing-induced life-history changes were estimated using empirical observations of the effects of fishing on body size and maturation age 6 , 17 . Fishing mortality was parameterized according to observed fishing pressure in LC 18 . Figure 1: Lake Constance food web. Five guilds of algae (Alg1-5), bacteria (Bac), autotrophic picoplankton (APP), heterotrophic nanoflagellates (HNF), five guilds of ciliates (Cil1-5), four guilds of rotifers (Rot1-3, Asp), herbivorous crustacean (Dap), carnivorous crustacean (Cyc, Lep), whitefish larvae (Wht0), perch larvae (Per0), whitefish juveniles (Wht1), perch juveniles (Per1), and 2, 3, and<|im_end|> <|im_start|>assistant Intense fishing of primarily larger fish not only makes fish populations smaller, it changes the remaining fish. When the fish which have a chance to reproduce before being caught are smaller and have reached sexual maturity earlier, these characteristics are passed down to future generations. In many fish populations targeted by intense fishing, e.g., Atlantic cod across the west coast of North America, the sizes of fish have been observed to have decreased and the age of sexual maturity to have reduced. Fish are often at the top of the food web in the aquatic ecosystem, so changes in fish can have broader consequences which involve the entire ecosystem. Together with her American and German colleagues, Academy of Finland Research Fellow Anna Kuparinen from the University of Helsinki studied how fishing changes the ways aquatic ecosystems function. The researchers used computer-generated simulations to help them model the interactions between species and the flow of energy through the food web as well as the overall dynamics of the ecosystem. The research focused on the fishing of perch and whitefish in Lake Constance, which borders Switzerland, Germany and Austria. Simulations describing the development of the ecosystem targeted by fishing indicated that once intense fishing causes fish to become smaller and reach sexual maturity earlier, the production of plankton in the lake becomes unstable. Similarly, the sizes of the fish populations and their production of offspring fluctuate greatly from one year to the next. "If the changes in fish are genetic, the stability of the fish populations and the lake ecosystem cannot be regained even if fishing was permanently ended. The study demonstrates how important it is to consider the entire ecosystem and indirect impacts on other species when the impact of fishing is evaluated. For example, the production of offspring among perch is more dependent on the fluctuations of the production of plankton in the lake than the number of female fish producing eggs," says Anna Kuparinen. "The many food chains leading to fish form complex food webs. The better we understand this complexity, the better we understand how fishing impacts fish and the environment," says Professor Neo Martinez from the University of Arizona, US. <|im_end|>

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1,745

[ { "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 light field print (LFP) displays three-dimensional (3D) information to the naked-eye observer under ambient white light illumination. Changing perspectives of a 3D image are seen by the observer from varying angles. However, LFPs appear pixelated due to limited resolution and misalignment between their lenses and colour pixels. A promising solution to create high-resolution LFPs is through the use of advanced nanofabrication techniques. Here, we use two-photon polymerization lithography as a one-step nanoscale 3D printer to directly fabricate LFPs out of transparent resin. This approach produces simultaneously high spatial resolution (29–45 µm) and high angular resolution (~1.6°) images with smooth motion parallax across 15 × 15 views. Notably, the smallest colour pixel consists of only a single nanopillar (~300 nm diameter). Our LFP signifies a step towards hyper-realistic 3D images that can be applied in print media and security tags for high-value goods. Introduction Commonly available prints have a fixed two-dimensional (2D) appearance as they store only intensity and colour information. Unfortunately, these prints lack a vital piece of information—the directional control of light rays 1 , 2 , 3 , 4 —to display a three-dimensional (3D) image. With no ability to discriminate the direction of light rays, the prints appear unchanged to an observer from all viewing angles. On the other hand, light field prints (LFPs) encode directional information, which enables them to display changing perspectives of a 3D image seen from varying viewing angles. This technique of displaying a 3D image was discovered in 1908 by the Nobel Laureate, Gabriel Lippmann 5 . He proposed using an array of tiny lenses on film to record a scene, so that each lens formed its own sub-image with a slightly shifted perspective. The film would then be illuminated under diffuse light to reconstruct an integral 3D image of the scene. LFPs are autostereoscopic as their 3D images are visible to the naked eye under incoherent and unpolarized illumination, which gives them an advantage over stereoscopic prints 6 , 7 that require viewing through a pair of anaglyph glasses or orthogonally polarized filters. LFPs also do not require laser illumination used in conventional holograms 8 . However, LFPs appear pixelated because of low spatial resolution and low angular resolution caused by fabrication limitations. Spatial resolution is limited by the centre-to-centre separation between lenses, and angular resolution is limited by the density of pixels under each lens 9 , 10 . To create high-resolution LFPs, we leverage on advanced nanofabrication techniques in structural colour printing 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 . Structural colour prints with plasmonic nanostructures 16 , 18 can attain a pixel resolution of ~100,000 dots per inch, which is several orders of magnitude higher than that of conventional inkjet prints 17 . Though inkjet printers are capable of printing LFPs for art 25 , their pixel resolution is insufficient for optical security devices 26 that require the spatial resolution to be <50 µm (i.e. beyond the resolving power of human vision). Moreover, misregistration between colour layers is an issue in these printers, but not in nanofabrication tools, such as electron beam lithography that position plasmonic colour pixels without misregistration 14 . Jiang et al. demonstrated high-resolution multi-colour motion effects by bonding a microlens array onto a plasmonic colour print 27 . However, this approach is relatively complicated because it requires multiple processing steps and manual alignment between the microlenses and pixels. Accurate alignment is essential to reconstruct clear 3D images but doing manual alignment at the nanoscale is challenging as it relies on delicate movements and visual inspection. As manual alignment has been done for regular arrays of microlenses and colour pixels, an alternative alignment approach is thus needed for irregular arrays that have a pseudorandom arrangement 28 . In this work, we use two-photon polymerization lithography (TPL) to fabricate high-resolution LFPs in one patterning step that circumvents the need for doing manual alignment. The microlenses and structural colour pixels of our LFPs are aligned automatically in the TPL system (Nanoscribe GmbH Photonic Professional GT system), which can position each volumetric pixel exposed by the laser up to an accuracy of 10 nm. As TPL is an additive manufacturing technology, we fabricate the microlenses and structural colour pixels in discrete slicing height steps of 20 and 300 nm, respectively. The microlenses and structural colour pixels are made of the same low refractive index material, IP-Dip photoresist ( n ~1.55). Unlike plasmonic colour pixels, our structural colour pixels do not require additional metal deposition, which makes the TPL system only necessary for fabricating LFPs. The microlenses and structural colour pixels are fabricated together in a pseudorandom arrangement, which can minimize undesired moiré patterns and also encode secret information for security applications. More importantly, our LFP displays simultaneously high spatial resolution (29–45 µm) and high angular resolution (~1.6°) images with smooth motion parallax that appear unpixellated to the naked eye, even up close. Results Design concepts We propose the working principle of our LFP: A white light source is used to illuminate the structural colour pixels, which function as colour filters that transmit varying intensities of visible wavelengths within a range of angles collected by the microlenses. The microlenses then project the collected light to an observer who sees the colours of selected pixels at the corresponding viewpoint in the far field. All these selected pixels form a complete 3D image (Fig. 1a ). The design of our LFP was inspired by Thiele et al.’s compound microlens system 29 . Instead of a compound system, we designed our system (Fig. 1b ) with a hollow tower to support a spherical plano-convex microlens above a block of structural colour pixels that contains an array of nanopillars 8 , 30 , 31 . We refer to this system as a display unit. Our LFP comprised 65 × 65 display units placed in a pseudorandom arrangement with centre-to-centre separation between 29", "role": "user" }, { "content": "Wouldn't it be amazing if printed images can look three-dimensional (3D)? Unfortunately, conventional prints like photographs display two-dimensional (2D) images with a fixed appearance as they contain only intensity and color information. These prints are unable to display a 3D image because they lack directional control of light rays, hence resulting in the loss of depth information. To address this problem, a team of researchers from the Singapore University of Technology and Design (SUTD) used a nanoscale 3D printing technique to create high-resolution light field prints (LFP). The LFP comprises an array of microlenses aligned on top of an array of structural color pixels. When the LFP is illuminated by ordinary white light, a 3D image is displayed. The 3D image is autostereoscopic, which means that it can be viewed without needing to wear special glasses. The image changes appearance as it is viewed from varying angles, which gives the LFP a special 3D visual effect. More importantly, high-resolution LFPs are needed to display ultra-realistic 3D images that have potential applications in artworks and security items. By using nanoscale 3D printing to create LFPs, the team achieved a maximum pixel resolution of 25,400 dots per inch (dpi), which surpasses the pixel resolution of consumer inkjet printers ~1,200 dpi. The structural color pixels in the LFP are made of nanopillars (~300nm diameter). Perhaps the most remarkable result is that each color pixel can be represented by a single nanopillar to produce the LFP at its maximum resolution. SUTD Associate Professor Joel Yang, who is the principal investigator of this research, remarked: \"This is possibly the first time that 3D printing is used to entirely create a multi-colored light field print (LFP) in a single step, without the use of dyes, and without the need for manual alignment of microlenses to the color pixels. The prints are embedded with up to 225 frames within a single LFP to generate smooth viewing transitions at unprecedented resolution. These effects will lead to 2D prints that produce ultra-realistic 3D visuals in future.\" The team anticipates that high-resolution LFPs will become more readily available in the market when nanotechnology allows greater scalability and throughput. This 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 A light field print (LFP) displays three-dimensional (3D) information to the naked-eye observer under ambient white light illumination. Changing perspectives of a 3D image are seen by the observer from varying angles. However, LFPs appear pixelated due to limited resolution and misalignment between their lenses and colour pixels. A promising solution to create high-resolution LFPs is through the use of advanced nanofabrication techniques. Here, we use two-photon polymerization lithography as a one-step nanoscale 3D printer to directly fabricate LFPs out of transparent resin. This approach produces simultaneously high spatial resolution (29–45 µm) and high angular resolution (~1.6°) images with smooth motion parallax across 15 × 15 views. Notably, the smallest colour pixel consists of only a single nanopillar (~300 nm diameter). Our LFP signifies a step towards hyper-realistic 3D images that can be applied in print media and security tags for high-value goods. Introduction Commonly available prints have a fixed two-dimensional (2D) appearance as they store only intensity and colour information. Unfortunately, these prints lack a vital piece of information—the directional control of light rays 1 , 2 , 3 , 4 —to display a three-dimensional (3D) image. With no ability to discriminate the direction of light rays, the prints appear unchanged to an observer from all viewing angles. On the other hand, light field prints (LFPs) encode directional information, which enables them to display changing perspectives of a 3D image seen from varying viewing angles. This technique of displaying a 3D image was discovered in 1908 by the Nobel Laureate, Gabriel Lippmann 5 . He proposed using an array of tiny lenses on film to record a scene, so that each lens formed its own sub-image with a slightly shifted perspective. The film would then be illuminated under diffuse light to reconstruct an integral 3D image of the scene. LFPs are autostereoscopic as their 3D images are visible to the naked eye under incoherent and unpolarized illumination, which gives them an advantage over stereoscopic prints 6 , 7 that require viewing through a pair of anaglyph glasses or orthogonally polarized filters. LFPs also do not require laser illumination used in conventional holograms 8 . However, LFPs appear pixelated because of low spatial resolution and low angular resolution caused by fabrication limitations. Spatial resolution is limited by the centre-to-centre separation between lenses, and angular resolution is limited by the density of pixels under each lens 9 , 10 . To create high-resolution LFPs, we leverage on advanced nanofabrication techniques in structural colour printing 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 . Structural colour prints with plasmonic nanostructures 16 , 18 can attain a pixel resolution of ~100,000 dots per inch, which is several orders of magnitude higher than that of conventional inkjet prints 17 . Though inkjet printers are capable of printing LFPs for art 25 , their pixel resolution is insufficient for optical security devices 26 that require the spatial resolution to be <50 µm (i.e. beyond the resolving power of human vision). Moreover, misregistration between colour layers is an issue in these printers, but not in nanofabrication tools, such as electron beam lithography that position plasmonic colour pixels without misregistration 14 . Jiang et al. demonstrated high-resolution multi-colour motion effects by bonding a microlens array onto a plasmonic colour print 27 . However, this approach is relatively complicated because it requires multiple processing steps and manual alignment between the microlenses and pixels. Accurate alignment is essential to reconstruct clear 3D images but doing manual alignment at the nanoscale is challenging as it relies on delicate movements and visual inspection. As manual alignment has been done for regular arrays of microlenses and colour pixels, an alternative alignment approach is thus needed for irregular arrays that have a pseudorandom arrangement 28 . In this work, we use two-photon polymerization lithography (TPL) to fabricate high-resolution LFPs in one patterning step that circumvents the need for doing manual alignment. The microlenses and structural colour pixels of our LFPs are aligned automatically in the TPL system (Nanoscribe GmbH Photonic Professional GT system), which can position each volumetric pixel exposed by the laser up to an accuracy of 10 nm. As TPL is an additive manufacturing technology, we fabricate the microlenses and structural colour pixels in discrete slicing height steps of 20 and 300 nm, respectively. The microlenses and structural colour pixels are made of the same low refractive index material, IP-Dip photoresist ( n ~1.55). Unlike plasmonic colour pixels, our structural colour pixels do not require additional metal deposition, which makes the TPL system only necessary for fabricating LFPs. The microlenses and structural colour pixels are fabricated together in a pseudorandom arrangement, which can minimize undesired moiré patterns and also encode secret information for security applications. More importantly, our LFP displays simultaneously high spatial resolution (29–45 µm) and high angular resolution (~1.6°) images with smooth motion parallax that appear unpixellated to the naked eye, even up close. Results Design concepts We propose the working principle of our LFP: A white light source is used to illuminate the structural colour pixels, which function as colour filters that transmit varying intensities of visible wavelengths within a range of angles collected by the microlenses. The microlenses then project the collected light to an observer who sees the colours of selected pixels at the corresponding viewpoint in the far field. All these selected pixels form a complete 3D image (Fig. 1a ). The design of our LFP was inspired by Thiele et al.’s compound microlens system 29 . Instead of a compound system, we designed our system (Fig. 1b ) with a hollow tower to support a spherical plano-convex microlens above a block of structural colour pixels that contains an array of nanopillars 8 , 30 , 31 . We refer to this system as a display unit. Our LFP comprised 65 × 65 display units placed in a pseudorandom arrangement with centre-to-centre separation between 29<|im_end|> <|im_start|>assistant Wouldn't it be amazing if printed images can look three-dimensional (3D)? Unfortunately, conventional prints like photographs display two-dimensional (2D) images with a fixed appearance as they contain only intensity and color information. These prints are unable to display a 3D image because they lack directional control of light rays, hence resulting in the loss of depth information. To address this problem, a team of researchers from the Singapore University of Technology and Design (SUTD) used a nanoscale 3D printing technique to create high-resolution light field prints (LFP). The LFP comprises an array of microlenses aligned on top of an array of structural color pixels. When the LFP is illuminated by ordinary white light, a 3D image is displayed. The 3D image is autostereoscopic, which means that it can be viewed without needing to wear special glasses. The image changes appearance as it is viewed from varying angles, which gives the LFP a special 3D visual effect. More importantly, high-resolution LFPs are needed to display ultra-realistic 3D images that have potential applications in artworks and security items. By using nanoscale 3D printing to create LFPs, the team achieved a maximum pixel resolution of 25,400 dots per inch (dpi), which surpasses the pixel resolution of consumer inkjet printers ~1,200 dpi. The structural color pixels in the LFP are made of nanopillars (~300nm diameter). Perhaps the most remarkable result is that each color pixel can be represented by a single nanopillar to produce the LFP at its maximum resolution. SUTD Associate Professor Joel Yang, who is the principal investigator of this research, remarked: "This is possibly the first time that 3D printing is used to entirely create a multi-colored light field print (LFP) in a single step, without the use of dyes, and without the need for manual alignment of microlenses to the color pixels. The prints are embedded with up to 225 frames within a single LFP to generate smooth viewing transitions at unprecedented resolution. These effects will lead to 2D prints that produce ultra-realistic 3D visuals in future." The team anticipates that high-resolution LFPs will become more readily available in the market when nanotechnology allows greater scalability and throughput. This research was published in Nature Communications. <|im_end|>

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445, 11960, 82, 5101, 13252, 660, 1606, 315, 3428, 29079, 11175, 323, 3428, 20932, 11175, 9057, 555, 59251, 9669, 13, 75797, 11175, 374, 7347, 555, 279, 12541, 4791, 21911, 265, 25768, 1990, 36057, 11, 323, 20932, 11175, 374, 7347, 555, 279, 17915, 315, 16128, 1234, 1855, 18848, 220, 24, 1174, 220, 605, 662, 2057, 1893, 1579, 64036, 445, 11960, 82, 11, 584, 33164, 389, 11084, 20622, 1073, 29997, 367, 12823, 304, 24693, 12745, 18991, 220, 806, 1174, 220, 717, 1174, 220, 1032, 1174, 220, 975, 1174, 220, 868, 1174, 220, 845, 1174, 220, 1114, 1174, 220, 972, 1174, 220, 777, 1174, 220, 508, 1174, 220, 1691, 1174, 220, 1313, 1174, 220, 1419, 1174, 220, 1187, 662, 73800, 12745, 24370, 449, 628, 300, 74689, 51593, 47194, 220, 845, 1174, 220, 972, 649, 36861, 264, 13252, 11175, 315, 4056, 1041, 11, 931, 32094, 824, 17560, 11, 902, 374, 3892, 10373, 315, 26703, 5190, 1109, 430, 315, 21349, 27513, 15769, 24370, 220, 1114, 662, 18056, 27513, 15769, 57053, 527, 13171, 315, 18991, 445, 11960, 82, 369, 1989, 220, 914, 1174, 872, 13252, 11175, 374, 39413, 369, 29393, 4868, 7766, 220, 1627, 430, 1397, 279, 29079, 11175, 311, 387, 366, 1135, 64012, 76, 320, 72, 1770, 13, 7953, 279, 53583, 2410, 315, 3823, 11376, 570, 23674, 11, 5906, 26947, 1990, 12745, 13931, 374, 459, 4360, 304, 1521, 57053, 11, 719, 539, 304, 20622, 1073, 29997, 367, 7526, 11, 1778, 439, 17130, 24310, 46282, 5814, 430, 2361, 628, 300, 74689, 12745, 16128, 2085, 5906, 26947, 220, 975, 662, 61922, 1880, 453, 13, 21091, 1579, 64036, 7447, 20024, 414, 11633, 6372, 555, 64186, 264, 19748, 1098, 729, 1358, 8800, 264, 628, 300, 74689, 12745, 1194, 220, 1544, 662, 4452, 11, 420, 5603, 374, 12309, 17395, 1606, 433, 7612, 5361, 8863, 7504, 323, 11630, 17632, 1990, 279, 19748, 1098, 4377, 323, 16128, 13, 11683, 62259, 17632, 374, 7718, 311, 44928, 2867, 220, 18, 35, 5448, 719, 3815, 11630, 17632, 520, 279, 20622, 437, 2296, 374, 17436, 439, 433, 34744, 389, 36301, 19567, 323, 9302, 26767, 13, 1666, 11630, 17632, 706, 1027, 2884, 369, 5912, 18893, 315, 19748, 1098, 4377, 323, 12745, 16128, 11, 459, 10778, 17632, 5603, 374, 8617, 4460, 369, 42408, 18893, 430, 617, 264, 51743, 269, 2255, 27204, 220, 1591, 662, 763, 420, 990, 11, 584, 1005, 1403, 63837, 26934, 47393, 2065, 46282, 5814, 320, 78610, 8, 311, 13354, 349, 1579, 64036, 445, 11960, 82, 304, 832, 93093, 1251, 3094, 430, 10408, 48764, 279, 1205, 369, 3815, 11630, 17632, 13, 578, 19748, 1098, 4377, 323, 24693, 12745, 16128, 315, 1057, 445, 11960, 82, 527, 27210, 9651, 304, 279, 350, 2989, 1887, 320, 45, 44705, 3191, 32577, 18235, 14338, 21931, 12177, 1887, 705, 902, 649, 2361, 1855, 63920, 16743, 13252, 15246, 555, 279, 21120, 709, 311, 459, 13708, 315, 220, 605, 26807, 13, 1666, 350, 2989, 374, 459, 64338, 15266, 5557, 11, 584, 13354, 349, 279, 19748, 1098, 4377, 323, 24693, 12745, 16128, 304, 44279, 86015, 2673, 7504, 315, 220, 508, 323, 220, 3101, 26807, 11, 15947, 13, 578, 19748, 1098, 4377, 323, 24693, 12745, 16128, 527, 1903, 315, 279, 1890, 3428, 19914, 3104, 1963, 3769, 11, 6933, 9607, 575, 6685, 417, 380, 320, 308, 4056, 16, 13, 2131, 570, 27140, 628, 300, 74689, 12745, 16128, 11, 1057, 24693, 12745, 16128, 656, 539, 1397, 5217, 9501, 65374, 11, 902, 3727, 279, 350, 2989, 1887, 1193, 5995, 369, 13354, 1113, 445, 11960, 82, 13, 578, 19748, 1098, 4377, 323, 24693, 12745, 16128, 527, 70554, 3871, 304, 264, 51743, 269, 2255, 27204, 11, 902, 649, 30437, 56838, 2757, 4647, 404, 978, 12912, 323, 1101, 16559, 6367, 2038, 369, 4868, 8522, 13, 4497, 23659, 11, 1057, 445, 11960, 19207, 25291, 1579, 29079, 11175, 320, 1682, 4235, 1774, 64012, 76, 8, 323, 1579, 20932, 11175, 31857, 16, 13, 21, 11877, 8, 5448, 449, 11113, 11633, 1370, 45268, 430, 5101, 22355, 953, 616, 660, 311, 279, 19557, 8071, 11, 1524, 709, 3345, 13, 18591, 7127, 19476, 1226, 30714, 279, 3318, 17966, 315, 1057, 445, 11960, 25, 362, 4251, 3177, 2592, 374, 1511, 311, 88682, 279, 24693, 12745, 16128, 11, 902, 734, 439, 12745, 13711, 430, 30382, 29865, 25228, 1385, 315, 9621, 93959, 2949, 264, 2134, 315, 27030, 14890, 555, 279, 19748, 1098, 4377, 13, 578, 19748, 1098, 4377, 1243, 2447, 279, 14890, 3177, 311, 459, 22842, 889, 16008, 279, 27230, 315, 4183, 16128, 520, 279, 12435, 59485, 304, 279, 3117, 2115, 13, 2052, 1521, 4183, 16128, 1376, 264, 4686, 220, 18, 35, 2217, 320, 30035, 13, 220, 16, 64, 7609, 578, 2955, 315, 1057, 445, 11960, 574, 14948, 555, 666, 25641, 1880, 453, 14639, 82, 24549, 19748, 1098, 729, 1887, 220, 1682, 662, 12361, 315, 264, 24549, 1887, 11, 584, 6319, 1057, 1887, 320, 30035, 13, 220, 16, 65, 883, 449, 264, 42902, 21970, 311, 1862, 264, 65251, 85428, 12, 12296, 327, 19748, 1098, 729, 3485, 264, 2565, 315, 24693, 12745, 16128, 430, 5727, 459, 1358, 315, 76307, 484, 1590, 220, 23, 1174, 220, 966, 1174, 220, 2148, 662, 1226, 8464, 311, 420, 1887, 439, 264, 3113, 5089, 13, 5751, 445, 11960, 40056, 220, 2397, 25800, 220, 2397, 3113, 8316, 9277, 304, 264, 51743, 269, 2255, 27204, 449, 12541, 4791, 21911, 265, 25768, 1990, 220, 1682, 128257, 198, 128256, 78191, 198, 29089, 77, 956, 433, 387, 8056, 422, 17124, 5448, 649, 1427, 2380, 33520, 320, 18, 35, 12106, 19173, 11, 21349, 24370, 1093, 25232, 3113, 1403, 33520, 320, 17, 35, 8, 5448, 449, 264, 8521, 11341, 439, 814, 6782, 1193, 21261, 323, 1933, 2038, 13, 4314, 24370, 527, 12153, 311, 3113, 264, 220, 18, 35, 2217, 1606, 814, 6996, 73945, 2585, 315, 3177, 45220, 11, 16472, 13239, 304, 279, 4814, 315, 8149, 2038, 13, 2057, 2686, 420, 3575, 11, 264, 2128, 315, 12074, 505, 279, 21181, 3907, 315, 12053, 323, 7127, 320, 50, 1406, 35, 8, 1511, 264, 20622, 437, 2296, 220, 18, 35, 18991, 15105, 311, 1893, 1579, 64036, 3177, 2115, 24370, 320, 43, 11960, 570, 578, 445, 11960, 41095, 459, 1358, 315, 19748, 1098, 4377, 27210, 389, 1948, 315, 459, 1358, 315, 24693, 1933, 16128, 13, 3277, 279, 445, 11960, 374, 75648, 555, 19664, 4251, 3177, 11, 264, 220, 18, 35, 2217, 374, 12882, 13, 578, 220, 18, 35, 2217, 374, 3154, 537, 486, 84667, 11, 902, 3445, 430, 433, 649, 387, 19894, 2085, 33921, 311, 10051, 3361, 29247, 13, 578, 2217, 4442, 11341, 439, 433, 374, 19894, 505, 29865, 27030, 11, 902, 6835, 279, 445, 11960, 264, 3361, 220, 18, 35, 9302, 2515, 13, 4497, 23659, 11, 1579, 64036, 445, 11960, 82, 527, 4460, 311, 3113, 24955, 75895, 4633, 220, 18, 35, 5448, 430, 617, 4754, 8522, 304, 97549, 323, 4868, 3673, 13, 3296, 1701, 20622, 437, 2296, 220, 18, 35, 18991, 311, 1893, 445, 11960, 82, 11, 279, 2128, 17427, 264, 7340, 13252, 11175, 315, 220, 914, 11, 3443, 32094, 824, 17560, 320, 79129, 705, 902, 53120, 288, 279, 13252, 11175, 315, 11761, 27513, 15769, 57053, 4056, 16, 11, 1049, 51842, 13, 578, 24693, 1933, 16128, 304, 279, 445, 11960, 527, 1903, 315, 76307, 484, 1590, 31857, 3101, 20211, 23899, 570, 19292, 279, 1455, 23649, 1121, 374, 430, 1855, 1933, 13252, 649, 387, 15609, 555, 264, 3254, 76307, 484, 277, 311, 8356, 279, 445, 11960, 520, 1202, 7340, 11175, 13, 328, 1406, 35, 33468, 17054, 39447, 25482, 11, 889, 374, 279, 12717, 49581, 315, 420, 3495, 11, 61414, 25, 330, 2028, 374, 11000, 279, 1176, 892, 430, 220, 18, 35, 18991, 374, 1511, 311, 11622, 1893, 264, 7447, 58822, 3177, 2115, 1194, 320, 43, 11960, 8, 304, 264, 3254, 3094, 11, 2085, 279, 1005, 315, 294, 9891, 11, 323, 2085, 279, 1205, 369, 11630, 17632, 315, 19748, 1098, 4377, 311, 279, 1933, 16128, 13, 578, 24370, 527, 23711, 449, 709, 311, 220, 11057, 14418, 2949, 264, 3254, 445, 11960, 311, 7068, 11113, 20705, 34692, 520, 31069, 11175, 13, 4314, 6372, 690, 3063, 311, 220, 17, 35, 24370, 430, 8356, 24955, 75895, 4633, 220, 18, 35, 54077, 304, 3938, 1210, 578, 2128, 16961, 988, 430, 1579, 64036, 445, 11960, 82, 690, 3719, 810, 31368, 2561, 304, 279, 3157, 994, 20622, 52536, 6276, 7191, 94840, 323, 64862, 13, 1115, 3495, 574, 4756, 304, 22037, 26545, 13, 220, 128257, 198 ]

1,887

[ { "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 Lateral variations of seismic wave speeds and attenuation (dissipation of strain energy) in the Earth’s upper mantle have the potential to map key characteristics such as temperature, major-element composition, melt fraction and water content 1 , 2 , 3 . The inversion of these data into meaningful representations of physical properties requires a robust understanding of the micromechanical processes that affect the propagation of seismic waves 2 , 3 . Structurally bound water (hydroxyl) is believed to affect seismic properties 2 , 3 but this has yet to be experimentally quantified. Here we present a comprehensive low-frequency forced-oscillation assessment of the seismic properties of olivine as a function of water content within the under-saturated regime that is relevant to the Earth’s interior. Our results demonstrate that wave speeds and attenuation are in fact strikingly insensitive to water content. Rather, the redox conditions imposed by the choice of metal sleeving, and the associated defect chemistry, appear to have a substantial influence on the seismic properties. These findings suggest that elevated water contents are not responsible for low-velocity or high-attenuation structures in the upper mantle. Instead, the high attenuation observed in hydrous and oxidized regions of the upper mantle (such as above subduction zones) may reflect the prevailing oxygen fugacity. In addition, these data provide no support for the hypothesis whereby a sharp lithosphere–asthenosphere boundary is explained by enhanced grain boundary sliding in the presence of water. Main Lattice defects and the structure and composition of grain boundaries in olivine strongly influence the stiffness and strength of the mantle from infinitesimal strains (elastic/anelastic) 4 , 5 , 6 , to large-strain viscous rheology 7 . Central to experimental efforts in quantifying these effects is understanding the influence of hydrogen-related defects on both diffusional and dislocation-governed processes 8 , 9 . It has been suggested, mainly by analogy with observations of water-enhanced viscous deformation of olivine, that the potential seismological importance of water in the mantle might involve either an increase in defect mobility through increased vacancy populations, or water-enhanced diffusivities facilitating grain boundary sliding 2 , 10 , 11 . Substantially modified seismic properties in the presence of water have been observed previously at low frequencies, but only in a single exploratory study conducted under water-saturated conditions 12 . Accordingly, hypotheses concerning water-enhanced grain boundary sliding as an explanation for the sharp lithosphere–asthenosphere boundary 10 , 11 , and the more general seismological mapping of mantle water contents 2 , remain to be experimentally tested. Water is conventionally introduced into experimental specimens through the use of solid buffers containing hydrated phases 9 , or as excess fluid, ensuring high water fugacity ( ) and water-saturated conditions during mechanical testing 9 , 12 . However, free fluid phases are not expected under upper-mantle conditions. Conducting experiments under a more relevant water-undersaturated environment requires conditions sufficiently oxidizing to ensure that > (see Methods), for the decoration of intrinsic and extrinsic defects with H + . A recent experimental campaign 13 used the energetically favoured Ti-clinohumite-like defect (‘Ti-OH’) 14 , 15 , 16 (Ti located on a metal site, charge balanced by a doubly protonated Si vacancy) to assess the sensitivity of large-strain creep in olivine to small (and undersaturated) water concentrations. A conspicuous modification of large-strain rheology was observed in the presence of low concentrations of this defect, with a near-linear enhancement of strain rate in dislocation creep occurring as a function of increasing hydroxyl content, inferred to be due to the increased concentration of associated Si vacancies 13 . Motivated by the scant experimental data on the influence of water on seismic properties, here we build upon the work of ref. 13 to explore the micro-strain anelastic effects of changes in and that are associated with water-undersaturated conditions. We isostatically hot-pressed, and then mechanically tested under a range of conditions, eight polycrystalline olivine specimens containing different types of hydrated defects in various concentrations. We used different metal sleeves surrounding the olivine specimens during testing to vary the imposed redox conditions 13 —a Pt sleeve to create relatively oxidizing conditions, a Ni 70 /Fe 30 (‘NiFe’) sleeve to produce more-reducing conditions, or a Ni sleeve for an intermediate . The sample suite consisted of undoped and Ti-doped solgel olivine of Fo 90 composition (containing 90% forsterite) 13 , Ti-doped forsterite and a reconstituted San Carlos olivine (see Extended Data Table 1 for sample compositions). Each specimen was mechanically tested in torsional forced oscillation at periods representative of the seismic band (1–1,000 s), using a confining pressure of 200 MPa and temperatures up to 1,200 °C (see Methods for details). Fourier-transform infrared (FTIR) spectroscopy was used to identify the hydrous defect and quantify the water content of each specimen after mechanical testing. The FTIR spectra ( Fig. 1a ) of Ti-bearing specimens are dominated by absorption bands at 3,572 cm −1 and 3,525 cm −1 , attributed to the Ti-OH defect 14 , 15 , for which a site-specific calibration factor 16 was used to infer the concentration of chemically bound hydroxyl. The residual broadband absorbance is attributed to the presence of molecular water, and higher concentrations of molecular water are prominent in Ti-free specimens. Additional hydrated defects associated with Si vacancies (at 3,612 cm −1 ) and trivalent ions (at 3,350 cm −1 ) can also be observed in some specimens. The specimen tested within a NiFe-sleeve shows no absorbance within the range 4,000–3,000 cm −1 , indicating the absence of both chemically bound hydroxyl and molecular water. Figure 1: Seismic properties of all specimens. FTIR spectra for all specimens are shown in a , with the corresponding shear modulus in b and dissipation data in c for a representative temperature of 1,100 °C. Pt-sleeved specimens are represented in blue, Ni-sleeved in purple and NiFe-sleeved in red. In a , peak (1) represents a secondary hydrous phase at 3,690 cm −1 , peaks (2) and (3) show Ti-OH 14 , 15 , 16 and peak (4) shows OH associated with trivalent ions 14", "role": "user" }, { "content": "When an earthquake strikes, nearby seismometers pick up its vibrations in the form of seismic waves. In addition to revealing the epicenter of a quake, seismic waves can give scientists a way to map the interior structures of the Earth, much like a CT scan images the body. By measuring the velocity at which seismic waves travel at various depths, scientists can determine the types of rocks and other materials that lie beneath the Earth's surface. The accuracy of such seismic maps depends on scientists' understanding of how various materials affect seismic waves' speeds. Now researchers at MIT and the Australian National University have found that seismic waves are essentially blind to a very common substance found throughout the Earth's interior: water. Their findings, published today in the journal Nature, go against a general assumption that seismic imaging can pick up signs of water deep within the Earth's upper mantle. In fact, the team found that even trace amounts of water have no effect on the speed at which seismic waves travel. The results may help scientists reinterpret seismic maps of the Earth's interior. For instance, in places such as midocean ridges, magma from deep within the Earth erupts through massive cracks in the seafloor, spreading away from the ridge and eventually solidifying as new oceanic crust. The process of melting at tens of kilometers below the surface removes tiny amounts of water that are found in rocks at greater depth. Scientists have thought that seismic images showed this \"wet-dry\" transition, corresponding to the transition from rigid tectonic plates to deformable mantle beneath. However, the team's findings suggest that seismic imaging may be picking up signs of not water, but rather, melt - tiny pockets of molten rock. \"If we see very strong variations [in seismic velocities], it's more likely that they're due to melt,\" says Ulrich Faul, a research scientist in MIT's Department of Earth, Atmospheric, and Planetary Sciences. \"Water, based on these experiments, is no longer a major player in that sense. This will shift how we interpret images of the interior of the Earth.\" Faul's co-authors are lead author Christopher Cline, along with Emmanuel David, Andrew Berry, and Ian Jackson, of the Australian National University. A seismic twist Faul, Cline, and their colleagues originally set out to determine exactly how water affects seismic wave speeds. They assumed, as most researchers have, that seismic imaging can \"see\" water, in the form of hydroxyl groups within individual mineral grains in rocks, and as molecular-scale pockets of water trapped between these grains. Water, even in tiny amounts, has been known to weaken rocks deep in the Earth's interior. \"It was known that water has a strong effect in very small quantities on the properties of rocks,\" Faul says. \"From there, the inference was that water also affects seismic wave speeds substantially.\" To measure the extent to which water affects seismic wave speeds, the team produced different samples of olivine - a mineral that constitutes the majority of Earth's upper mantle and determines its properties. They trapped various amounts of water within each sample, and then placed the samples one at a time in a machine engineered to slowly twist a rock, similar to twisting a rubber band. The experiments were done in a furnace at high pressures and temperatures, in order to simulate conditions deep within the Earth. \"We twist the sample at one end and measure the magnitude and time delay of the resulting strain at the other end,\" Faul says. \"This simulates propagation of seismic waves through the Earth. The magnitude of this strain is similar to the width of a thin human hair - not very easy to measure at a pressure of 2,000 times atmospheric pressure and a temperature that approaches the melting temperature of steel.\" The team expected to find a correlation between the amount of water in a given sample and the speed at which seismic waves would propagate through that sample. When the initial samples did not show the anticipated behavior, the researchers modified the composition and measured again, but they kept getting the same negative result. Eventually it became inescapable that the original hypothesis was incorrect. \"From our [twisting] measurements, the rocks behaved as if they were dry, even though we could clearly analyze the water in there,\" Faul says. \"At that point, we knew water makes no difference.\" A rock, encased Another unexpected outcome of the experiments was that seismic wave velocity appeared to depend on a rock's oxidation state. All rocks on Earth contain certain amounts of iron, at various states of oxidation, just as metallic iron on a car can rust when exposed to a certain amount of oxygen. The researchers found, almost unintentionally, that the oxidation of iron in olivine affects the way seismic waves travel through the rock. Cline and Faul came to this conclusion after having to reconfigure their experimental setup. To carry out their experiments, the team typically encases each rock sample in a cylinder made from nickel and iron. However, in measuring each sample's water content in this cylinder, they found that hydrogen atoms in water tended to escape out of the rock, through the metal casing. To contain hydrogen, they switched their casing to one made from platinum. To their surprise they found that the type of metal surrounding the samples affected their seismic properties. Separate experiments showed that what in fact changed was the amount of Fe3+ in olivine. Normally the oxidation state of iron in olivine is 2+. As it turns out, the presence of Fe3+ produces imperfections which affect seismic wave speeds. Faul says that the group's findings suggest that seismic waves may be used to map levels of oxidation, such as at subduction zones - regions in the Earth where oceanic plates sink down into the mantle. Based on their results, however, seismic imaging cannot be used to image the distribution of water in the Earth's interior. What some scientists interpreted as water may in fact be melt - an insight that may change our understanding of how the Earth shifts its tectonic plates over time. \"An underlying question is what lubricates tectonic plates on Earth,\" Faul says. \"Our work points toward the importance of small amounts of melt at the base of tectonic plates, rather than a wet mantle beneath dry plates. Overall these results may help to illuminate volatile cycling between the interior and the surface of the Earth.\" ", "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 Lateral variations of seismic wave speeds and attenuation (dissipation of strain energy) in the Earth’s upper mantle have the potential to map key characteristics such as temperature, major-element composition, melt fraction and water content 1 , 2 , 3 . The inversion of these data into meaningful representations of physical properties requires a robust understanding of the micromechanical processes that affect the propagation of seismic waves 2 , 3 . Structurally bound water (hydroxyl) is believed to affect seismic properties 2 , 3 but this has yet to be experimentally quantified. Here we present a comprehensive low-frequency forced-oscillation assessment of the seismic properties of olivine as a function of water content within the under-saturated regime that is relevant to the Earth’s interior. Our results demonstrate that wave speeds and attenuation are in fact strikingly insensitive to water content. Rather, the redox conditions imposed by the choice of metal sleeving, and the associated defect chemistry, appear to have a substantial influence on the seismic properties. These findings suggest that elevated water contents are not responsible for low-velocity or high-attenuation structures in the upper mantle. Instead, the high attenuation observed in hydrous and oxidized regions of the upper mantle (such as above subduction zones) may reflect the prevailing oxygen fugacity. In addition, these data provide no support for the hypothesis whereby a sharp lithosphere–asthenosphere boundary is explained by enhanced grain boundary sliding in the presence of water. Main Lattice defects and the structure and composition of grain boundaries in olivine strongly influence the stiffness and strength of the mantle from infinitesimal strains (elastic/anelastic) 4 , 5 , 6 , to large-strain viscous rheology 7 . Central to experimental efforts in quantifying these effects is understanding the influence of hydrogen-related defects on both diffusional and dislocation-governed processes 8 , 9 . It has been suggested, mainly by analogy with observations of water-enhanced viscous deformation of olivine, that the potential seismological importance of water in the mantle might involve either an increase in defect mobility through increased vacancy populations, or water-enhanced diffusivities facilitating grain boundary sliding 2 , 10 , 11 . Substantially modified seismic properties in the presence of water have been observed previously at low frequencies, but only in a single exploratory study conducted under water-saturated conditions 12 . Accordingly, hypotheses concerning water-enhanced grain boundary sliding as an explanation for the sharp lithosphere–asthenosphere boundary 10 , 11 , and the more general seismological mapping of mantle water contents 2 , remain to be experimentally tested. Water is conventionally introduced into experimental specimens through the use of solid buffers containing hydrated phases 9 , or as excess fluid, ensuring high water fugacity ( ) and water-saturated conditions during mechanical testing 9 , 12 . However, free fluid phases are not expected under upper-mantle conditions. Conducting experiments under a more relevant water-undersaturated environment requires conditions sufficiently oxidizing to ensure that > (see Methods), for the decoration of intrinsic and extrinsic defects with H + . A recent experimental campaign 13 used the energetically favoured Ti-clinohumite-like defect (‘Ti-OH’) 14 , 15 , 16 (Ti located on a metal site, charge balanced by a doubly protonated Si vacancy) to assess the sensitivity of large-strain creep in olivine to small (and undersaturated) water concentrations. A conspicuous modification of large-strain rheology was observed in the presence of low concentrations of this defect, with a near-linear enhancement of strain rate in dislocation creep occurring as a function of increasing hydroxyl content, inferred to be due to the increased concentration of associated Si vacancies 13 . Motivated by the scant experimental data on the influence of water on seismic properties, here we build upon the work of ref. 13 to explore the micro-strain anelastic effects of changes in and that are associated with water-undersaturated conditions. We isostatically hot-pressed, and then mechanically tested under a range of conditions, eight polycrystalline olivine specimens containing different types of hydrated defects in various concentrations. We used different metal sleeves surrounding the olivine specimens during testing to vary the imposed redox conditions 13 —a Pt sleeve to create relatively oxidizing conditions, a Ni 70 /Fe 30 (‘NiFe’) sleeve to produce more-reducing conditions, or a Ni sleeve for an intermediate . The sample suite consisted of undoped and Ti-doped solgel olivine of Fo 90 composition (containing 90% forsterite) 13 , Ti-doped forsterite and a reconstituted San Carlos olivine (see Extended Data Table 1 for sample compositions). Each specimen was mechanically tested in torsional forced oscillation at periods representative of the seismic band (1–1,000 s), using a confining pressure of 200 MPa and temperatures up to 1,200 °C (see Methods for details). Fourier-transform infrared (FTIR) spectroscopy was used to identify the hydrous defect and quantify the water content of each specimen after mechanical testing. The FTIR spectra ( Fig. 1a ) of Ti-bearing specimens are dominated by absorption bands at 3,572 cm −1 and 3,525 cm −1 , attributed to the Ti-OH defect 14 , 15 , for which a site-specific calibration factor 16 was used to infer the concentration of chemically bound hydroxyl. The residual broadband absorbance is attributed to the presence of molecular water, and higher concentrations of molecular water are prominent in Ti-free specimens. Additional hydrated defects associated with Si vacancies (at 3,612 cm −1 ) and trivalent ions (at 3,350 cm −1 ) can also be observed in some specimens. The specimen tested within a NiFe-sleeve shows no absorbance within the range 4,000–3,000 cm −1 , indicating the absence of both chemically bound hydroxyl and molecular water. Figure 1: Seismic properties of all specimens. FTIR spectra for all specimens are shown in a , with the corresponding shear modulus in b and dissipation data in c for a representative temperature of 1,100 °C. Pt-sleeved specimens are represented in blue, Ni-sleeved in purple and NiFe-sleeved in red. In a , peak (1) represents a secondary hydrous phase at 3,690 cm −1 , peaks (2) and (3) show Ti-OH 14 , 15 , 16 and peak (4) shows OH associated with trivalent ions 14<|im_end|> <|im_start|>assistant When an earthquake strikes, nearby seismometers pick up its vibrations in the form of seismic waves. In addition to revealing the epicenter of a quake, seismic waves can give scientists a way to map the interior structures of the Earth, much like a CT scan images the body. By measuring the velocity at which seismic waves travel at various depths, scientists can determine the types of rocks and other materials that lie beneath the Earth's surface. The accuracy of such seismic maps depends on scientists' understanding of how various materials affect seismic waves' speeds. Now researchers at MIT and the Australian National University have found that seismic waves are essentially blind to a very common substance found throughout the Earth's interior: water. Their findings, published today in the journal Nature, go against a general assumption that seismic imaging can pick up signs of water deep within the Earth's upper mantle. In fact, the team found that even trace amounts of water have no effect on the speed at which seismic waves travel. The results may help scientists reinterpret seismic maps of the Earth's interior. For instance, in places such as midocean ridges, magma from deep within the Earth erupts through massive cracks in the seafloor, spreading away from the ridge and eventually solidifying as new oceanic crust. The process of melting at tens of kilometers below the surface removes tiny amounts of water that are found in rocks at greater depth. Scientists have thought that seismic images showed this "wet-dry" transition, corresponding to the transition from rigid tectonic plates to deformable mantle beneath. However, the team's findings suggest that seismic imaging may be picking up signs of not water, but rather, melt - tiny pockets of molten rock. "If we see very strong variations [in seismic velocities], it's more likely that they're due to melt," says Ulrich Faul, a research scientist in MIT's Department of Earth, Atmospheric, and Planetary Sciences. "Water, based on these experiments, is no longer a major player in that sense. This will shift how we interpret images of the interior of the Earth." Faul's co-authors are lead author Christopher Cline, along with Emmanuel David, Andrew Berry, and Ian Jackson, of the Australian National University. A seismic twist Faul, Cline, and their colleagues originally set out to determine exactly how water affects seismic wave speeds. They assumed, as most researchers have, that seismic imaging can "see" water, in the form of hydroxyl groups within individual mineral grains in rocks, and as molecular-scale pockets of water trapped between these grains. Water, even in tiny amounts, has been known to weaken rocks deep in the Earth's interior. "It was known that water has a strong effect in very small quantities on the properties of rocks," Faul says. "From there, the inference was that water also affects seismic wave speeds substantially." To measure the extent to which water affects seismic wave speeds, the team produced different samples of olivine - a mineral that constitutes the majority of Earth's upper mantle and determines its properties. They trapped various amounts of water within each sample, and then placed the samples one at a time in a machine engineered to slowly twist a rock, similar to twisting a rubber band. The experiments were done in a furnace at high pressures and temperatures, in order to simulate conditions deep within the Earth. "We twist the sample at one end and measure the magnitude and time delay of the resulting strain at the other end," Faul says. "This simulates propagation of seismic waves through the Earth. The magnitude of this strain is similar to the width of a thin human hair - not very easy to measure at a pressure of 2,000 times atmospheric pressure and a temperature that approaches the melting temperature of steel." The team expected to find a correlation between the amount of water in a given sample and the speed at which seismic waves would propagate through that sample. When the initial samples did not show the anticipated behavior, the researchers modified the composition and measured again, but they kept getting the same negative result. Eventually it became inescapable that the original hypothesis was incorrect. "From our [twisting] measurements, the rocks behaved as if they were dry, even though we could clearly analyze the water in there," Faul says. "At that point, we knew water makes no difference." A rock, encased Another unexpected outcome of the experiments was that seismic wave velocity appeared to depend on a rock's oxidation state. All rocks on Earth contain certain amounts of iron, at various states of oxidation, just as metallic iron on a car can rust when exposed to a certain amount of oxygen. The researchers found, almost unintentionally, that the oxidation of iron in olivine affects the way seismic waves travel through the rock. Cline and Faul came to this conclusion after having to reconfigure their experimental setup. To carry out their experiments, the team typically encases each rock sample in a cylinder made from nickel and iron. However, in measuring each sample's water content in this cylinder, they found that hydrogen atoms in water tended to escape out of the rock, through the metal casing. To contain hydrogen, they switched their casing to one made from platinum. To their surprise they found that the type of metal surrounding the samples affected their seismic properties. Separate experiments showed that what in fact changed was the amount of Fe3+ in olivine. Normally the oxidation state of iron in olivine is 2+. As it turns out, the presence of Fe3+ produces imperfections which affect seismic wave speeds. Faul says that the group's findings suggest that seismic waves may be used to map levels of oxidation, such as at subduction zones - regions in the Earth where oceanic plates sink down into the mantle. Based on their results, however, seismic imaging cannot be used to image the distribution of water in the Earth's interior. What some scientists interpreted as water may in fact be melt - an insight that may change our understanding of how the Earth shifts its tectonic plates over time. "An underlying question is what lubricates tectonic plates on Earth," Faul says. "Our work points toward the importance of small amounts of melt at the base of tectonic plates, rather than a wet mantle beneath dry plates. Overall these results may help to illuminate volatile cycling between the interior and the surface of the Earth." <|im_end|>

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2,711

[ { "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 Warming-induced global water cycle changes pose a significant challenge to global ecosystems and human society. However, quantifying historical water cycle change is difficult owing to a dearth of direct observations, particularly over the ocean, where 77% and 85% of global precipitation and evaporation occur, respectively 1 , 2 , 3 . Air–sea fluxes of freshwater imprint on ocean salinity such that mean salinity is lowest in the warmest and coldest parts of the ocean, and is highest at intermediate temperatures 4 . Here we track salinity trends in the warm, salty fraction of the ocean, and quantify the observed net poleward transport of freshwater in the Earth system from 1970 to 2014. Over this period, poleward freshwater transport from warm to cold ocean regions has occurred at a rate of 34–62 milli-sverdrups (mSv = 10 3 m 3 s −1 ), a rate that is not replicated in the current generation of climate models (the Climate Model Intercomparison Project Phase 6 (CMIP6)). In CMIP6 models, surface freshwater flux intensification in warm ocean regions leads to an approximately equivalent change in ocean freshwater content, with little impact from ocean mixing and circulation. Should this partition of processes hold for the real world, the implication is that the historical surface flux amplification is weaker (0.3–4.6%) in CMIP6 compared with observations (3.0–7.4%). These results establish a historical constraint on poleward freshwater transport that will assist in addressing biases in climate models. Main The global water cycle represents the sustained transport of freshwater through the lithosphere, hydrosphere, biosphere and atmosphere, and underpins the foundation of human society and ecological systems 1 . Understanding the response of the global water cycle to long-term global warming is critically important to mitigating the impacts of climate change. However, direct observations of rainfall are sparse, particularly over the ocean, which hosts 77% of global rainfall and 85% of surface evaporation 1 , 2 , 3 . Limited rainfall and evaporation observations, combined with substantial variance across atmospheric reanalysis products 4 , 5 , 6 , have made direct measurements of long-term changes to the global water cycle challenging. As a result, some of our understanding of changes to the water cycle has been shaped by proxies for rainfall measurements over the ocean, including salinity. As water associated with the hydrological cycle transits through the ocean, it generates a signature of ocean salinification and freshening, both at the surface 7 , 8 and the interior 9 , 10 . Using in situ salinity observations and ocean models, a growing body of research has identified a ‘wet gets wetter, dry gets drier’ paradigm, wherein the global water cycle intensifies owing to global warming 7 , 11 , 12 , 13 , with some estimates suggesting a water cycle intensification of 2–4% relative to the 1950 ocean state 8 , 10 , 14 . This intensification manifests as increasingly salty subtropical oceans and increasingly fresh tropical and subpolar oceans. Observed ocean salinity change has a large-scale coherent pattern through depth 15 , 16 (Fig. 1 ). The Indo-Pacific basin has well-defined regions of freshening and salinification, whereas the Atlantic basin is broadly salinifying in warmer temperature zones (compare Fig. 1a, b with Fig. 1c, d ). Subsurface salinity changes seem to be related to surface patterns of precipitation, river runoff and evaporation ( \$P-E+R\$ ) in observations and climate models (hatched line plots in Fig. 1 ). There are also significant differences between estimates of ocean salinity changes in observations (Fig. 1a, c ) and climate models over the same period (Fig. 1b, d ). Such differences between observations and models in Eulerian diagnostics have motivated past research to use water-mass-based diagnostics to frame ocean salinity changes, for instance, by quantifying mean salinity, S , in temperature, T , (or density) layers (known as the T – S curve of the ocean) 9 , 17 , 18 . Fig. 1: Coherent patterns of historical salinity change in observed and modelled zonally averaged salinity. a – d , Bottom panels: zonally averaged salinity tendency, in grams per kilogram per year from 1970 to 2014, in composite observations (IAP 14 , 21 and EN4 23 ) ( a , c ) and in the CMIP6 multi-model mean (MMM) 24 ( b , d ) in the Atlantic ( a , b ) and Indo-Pacific ( c , d ) basins. Top panels: hatched line plots show the time-mean, zonally integrated surface precipitation and river runoff minus evaporation ( P − E + R ), in sverdrups per degree of latitude in the corresponding basins from ERA5 reanalysis 26 from 1979 to 2014 ( a , c ) and the CMIP6 MMM pre-industrial control run ( b , d ). Stippling in b and d indicates regions for which more than 2/3 of the CMIP6 models agree on the sign of the salinity tendency. Black contour lines indicate zonally averaged temperature percentiles with the warmest 2% of the ocean bound by the 2% contour, the warmest 6% by the 6% contour and so on. Here we track salinity changes in these percentile layers. Full size image Tracking the global T – S curve over time provides information about salinity changes in different climatic regions based on temperature. However, simply computing trends of absolute salinity at constant conservative temperature ignores ocean warming that moves the underlying T – S curve 19 , yielding anomalously large salinity tendencies at constant T (Extended Data Fig. 2 ). In this work, we analyse salinity changes at constant temperature percentile rather than constant temperature 20 . That is, we organize the ocean from warmest to coldest and track changes at a fixed accumulated volume (for example, by tracking salinity changes in the warmest 6% of the ocean by volume). Temperature-percentile surfaces occupy the same volume over time, and outcrop in roughly the same climatic region even as the ocean warms (for instance, Extended Data Fig. 3 exhibits the poleward migration of temperature-percentile outcrops compared with the equivalent isotherms).", "role": "user" }, { "content": "The global water cycle—that is, the constant movement of freshwater between the clouds, land and the ocean—plays an important role in our daily lives. This delicate system transports water from the ocean to the land, helping to make our environment habitable and soil fertile. But rising global temperatures have been making this system more extreme: water is moving away from dry regions towards wet regions, causing droughts to worsen in parts of the globe, while intensifying rainfall events and flooding in others. In other words, wet areas are getting wetter, and dry areas are getting drier. Up until now, changes to the cycle have been difficult to directly observe, with around 80 percent of global rainfall and evaporation happening over the ocean. But a new UNSW-led study, published today in Nature, has used changing patterns of salt in the ocean to estimate how much ocean freshwater has moved from the equator to the poles since 1970. The findings show that between two and four times more freshwater has moved than climate models anticipated—giving us insights about how the global water cycle is amplifying as a whole. \"We already knew from previous work that the global water cycle was intensifying,\" says lead author of the study Dr. Taimoor Sohail, a mathematician and postdoctoral research associate at UNSW Science. \"We just didn't know by how much. \"The movement of freshwater from warm to cold areas forms the lion's share of water transport. Our findings paint a picture of the larger changes happening in the global water cycle.\" The team reached their findings by analyzing observations from three historical data sets covering the period 1970-2014. But instead of focusing on direct rainfall observations—which can be hard to measure across the ocean—they focused on a more unusual aspect: how salty the water was in each ocean area. \"In warmer regions, evaporation removes fresh water from the ocean leaving salt behind, making the ocean saltier,\" says co-author Jan Zika, an associate professor in the UNSW School of Mathematics and Statistics. \"The water cycle takes that fresh water to colder regions where it falls as rain, diluting the ocean and making it less salty.\" In other words, the water cycle leaves a signature on the ocean salt pattern—and by measuring these patterns, researchers can trace how the cycle changes over time. The team estimate that between 1970 and 2014, an extra 46,000-77,000 cubic kilometers of freshwater was transported from the equator to the poles than expected—that's around 18-30 centimeters of freshwater from tropical and sub-tropical regions, or roughly 123 times the water in Sydney Harbour. \"Changes to the water cycle can have a critical impact on infrastructure, agriculture, and biodiversity,\" says Dr. Sohail. \"It's therefore important to understand the way the climate change is impacting the water cycle now and into the future. \"This finding gives us an idea of how much this limb of the water cycle is changing, and can help us improve future climate change models.\" Improving future projections When Dr. Sohail and the team compared their findings to 20 different climate models, they found that all the models had underestimated the actual change in warm-cold freshwater transfer. Dr. Sohail says the findings could mean we're underestimating the impacts of climate change on rainfall. \"Findings like ours are how we improve these models,\" says Dr. Sohail. \"Each new generation of modeling adapts past models with real data, finding areas that we can improve upon in future models. This is a natural evolution in climate modeling.\" Scientists are now using the sixth generation of climate modeling (called the Sixth Climate Model Intercomparison Project, or 'CMIP6'), which incorporated updates from the fifth generation. This newest finding is a demonstration of the scientific process at work—and could help improve future estimates. \"Establishing the change in warm-to-cold freshwater transport means we can move forward and continue to make these important projections about how climate change is likely to impact our global water cycle,\" says Dr. Sohail. \"In 10 or 20 years from now, scientists can use this reference to find out how much these patterns are further changing over 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 Warming-induced global water cycle changes pose a significant challenge to global ecosystems and human society. However, quantifying historical water cycle change is difficult owing to a dearth of direct observations, particularly over the ocean, where 77% and 85% of global precipitation and evaporation occur, respectively 1 , 2 , 3 . Air–sea fluxes of freshwater imprint on ocean salinity such that mean salinity is lowest in the warmest and coldest parts of the ocean, and is highest at intermediate temperatures 4 . Here we track salinity trends in the warm, salty fraction of the ocean, and quantify the observed net poleward transport of freshwater in the Earth system from 1970 to 2014. Over this period, poleward freshwater transport from warm to cold ocean regions has occurred at a rate of 34–62 milli-sverdrups (mSv = 10 3 m 3 s −1 ), a rate that is not replicated in the current generation of climate models (the Climate Model Intercomparison Project Phase 6 (CMIP6)). In CMIP6 models, surface freshwater flux intensification in warm ocean regions leads to an approximately equivalent change in ocean freshwater content, with little impact from ocean mixing and circulation. Should this partition of processes hold for the real world, the implication is that the historical surface flux amplification is weaker (0.3–4.6%) in CMIP6 compared with observations (3.0–7.4%). These results establish a historical constraint on poleward freshwater transport that will assist in addressing biases in climate models. Main The global water cycle represents the sustained transport of freshwater through the lithosphere, hydrosphere, biosphere and atmosphere, and underpins the foundation of human society and ecological systems 1 . Understanding the response of the global water cycle to long-term global warming is critically important to mitigating the impacts of climate change. However, direct observations of rainfall are sparse, particularly over the ocean, which hosts 77% of global rainfall and 85% of surface evaporation 1 , 2 , 3 . Limited rainfall and evaporation observations, combined with substantial variance across atmospheric reanalysis products 4 , 5 , 6 , have made direct measurements of long-term changes to the global water cycle challenging. As a result, some of our understanding of changes to the water cycle has been shaped by proxies for rainfall measurements over the ocean, including salinity. As water associated with the hydrological cycle transits through the ocean, it generates a signature of ocean salinification and freshening, both at the surface 7 , 8 and the interior 9 , 10 . Using in situ salinity observations and ocean models, a growing body of research has identified a ‘wet gets wetter, dry gets drier’ paradigm, wherein the global water cycle intensifies owing to global warming 7 , 11 , 12 , 13 , with some estimates suggesting a water cycle intensification of 2–4% relative to the 1950 ocean state 8 , 10 , 14 . This intensification manifests as increasingly salty subtropical oceans and increasingly fresh tropical and subpolar oceans. Observed ocean salinity change has a large-scale coherent pattern through depth 15 , 16 (Fig. 1 ). The Indo-Pacific basin has well-defined regions of freshening and salinification, whereas the Atlantic basin is broadly salinifying in warmer temperature zones (compare Fig. 1a, b with Fig. 1c, d ). Subsurface salinity changes seem to be related to surface patterns of precipitation, river runoff and evaporation ( $P-E+R$ ) in observations and climate models (hatched line plots in Fig. 1 ). There are also significant differences between estimates of ocean salinity changes in observations (Fig. 1a, c ) and climate models over the same period (Fig. 1b, d ). Such differences between observations and models in Eulerian diagnostics have motivated past research to use water-mass-based diagnostics to frame ocean salinity changes, for instance, by quantifying mean salinity, S , in temperature, T , (or density) layers (known as the T – S curve of the ocean) 9 , 17 , 18 . Fig. 1: Coherent patterns of historical salinity change in observed and modelled zonally averaged salinity. a – d , Bottom panels: zonally averaged salinity tendency, in grams per kilogram per year from 1970 to 2014, in composite observations (IAP 14 , 21 and EN4 23 ) ( a , c ) and in the CMIP6 multi-model mean (MMM) 24 ( b , d ) in the Atlantic ( a , b ) and Indo-Pacific ( c , d ) basins. Top panels: hatched line plots show the time-mean, zonally integrated surface precipitation and river runoff minus evaporation ( P − E + R ), in sverdrups per degree of latitude in the corresponding basins from ERA5 reanalysis 26 from 1979 to 2014 ( a , c ) and the CMIP6 MMM pre-industrial control run ( b , d ). Stippling in b and d indicates regions for which more than 2/3 of the CMIP6 models agree on the sign of the salinity tendency. Black contour lines indicate zonally averaged temperature percentiles with the warmest 2% of the ocean bound by the 2% contour, the warmest 6% by the 6% contour and so on. Here we track salinity changes in these percentile layers. Full size image Tracking the global T – S curve over time provides information about salinity changes in different climatic regions based on temperature. However, simply computing trends of absolute salinity at constant conservative temperature ignores ocean warming that moves the underlying T – S curve 19 , yielding anomalously large salinity tendencies at constant T (Extended Data Fig. 2 ). In this work, we analyse salinity changes at constant temperature percentile rather than constant temperature 20 . That is, we organize the ocean from warmest to coldest and track changes at a fixed accumulated volume (for example, by tracking salinity changes in the warmest 6% of the ocean by volume). Temperature-percentile surfaces occupy the same volume over time, and outcrop in roughly the same climatic region even as the ocean warms (for instance, Extended Data Fig. 3 exhibits the poleward migration of temperature-percentile outcrops compared with the equivalent isotherms).<|im_end|> <|im_start|>assistant The global water cycle—that is, the constant movement of freshwater between the clouds, land and the ocean—plays an important role in our daily lives. This delicate system transports water from the ocean to the land, helping to make our environment habitable and soil fertile. But rising global temperatures have been making this system more extreme: water is moving away from dry regions towards wet regions, causing droughts to worsen in parts of the globe, while intensifying rainfall events and flooding in others. In other words, wet areas are getting wetter, and dry areas are getting drier. Up until now, changes to the cycle have been difficult to directly observe, with around 80 percent of global rainfall and evaporation happening over the ocean. But a new UNSW-led study, published today in Nature, has used changing patterns of salt in the ocean to estimate how much ocean freshwater has moved from the equator to the poles since 1970. The findings show that between two and four times more freshwater has moved than climate models anticipated—giving us insights about how the global water cycle is amplifying as a whole. "We already knew from previous work that the global water cycle was intensifying," says lead author of the study Dr. Taimoor Sohail, a mathematician and postdoctoral research associate at UNSW Science. "We just didn't know by how much. "The movement of freshwater from warm to cold areas forms the lion's share of water transport. Our findings paint a picture of the larger changes happening in the global water cycle." The team reached their findings by analyzing observations from three historical data sets covering the period 1970-2014. But instead of focusing on direct rainfall observations—which can be hard to measure across the ocean—they focused on a more unusual aspect: how salty the water was in each ocean area. "In warmer regions, evaporation removes fresh water from the ocean leaving salt behind, making the ocean saltier," says co-author Jan Zika, an associate professor in the UNSW School of Mathematics and Statistics. "The water cycle takes that fresh water to colder regions where it falls as rain, diluting the ocean and making it less salty." In other words, the water cycle leaves a signature on the ocean salt pattern—and by measuring these patterns, researchers can trace how the cycle changes over time. The team estimate that between 1970 and 2014, an extra 46,000-77,000 cubic kilometers of freshwater was transported from the equator to the poles than expected—that's around 18-30 centimeters of freshwater from tropical and sub-tropical regions, or roughly 123 times the water in Sydney Harbour. "Changes to the water cycle can have a critical impact on infrastructure, agriculture, and biodiversity," says Dr. Sohail. "It's therefore important to understand the way the climate change is impacting the water cycle now and into the future. "This finding gives us an idea of how much this limb of the water cycle is changing, and can help us improve future climate change models." Improving future projections When Dr. Sohail and the team compared their findings to 20 different climate models, they found that all the models had underestimated the actual change in warm-cold freshwater transfer. Dr. Sohail says the findings could mean we're underestimating the impacts of climate change on rainfall. "Findings like ours are how we improve these models," says Dr. Sohail. "Each new generation of modeling adapts past models with real data, finding areas that we can improve upon in future models. This is a natural evolution in climate modeling." Scientists are now using the sixth generation of climate modeling (called the Sixth Climate Model Intercomparison Project, or 'CMIP6'), which incorporated updates from the fifth generation. This newest finding is a demonstration of the scientific process at work—and could help improve future estimates. "Establishing the change in warm-to-cold freshwater transport means we can move forward and continue to make these important projections about how climate change is likely to impact our global water cycle," says Dr. Sohail. "In 10 or 20 years from now, scientists can use this reference to find out how much these patterns are further changing over time." <|im_end|>

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11, 2737, 4371, 13797, 13, 1666, 3090, 5938, 449, 279, 17055, 31356, 11008, 1380, 1220, 1555, 279, 18435, 11, 433, 27983, 264, 12223, 315, 18435, 4371, 258, 2461, 323, 7878, 6147, 11, 2225, 520, 279, 7479, 220, 22, 1174, 220, 23, 323, 279, 15135, 220, 24, 1174, 220, 605, 662, 12362, 304, 10109, 4371, 13797, 24654, 323, 18435, 4211, 11, 264, 7982, 2547, 315, 3495, 706, 11054, 264, 3451, 86, 295, 5334, 14739, 466, 11, 9235, 5334, 294, 7401, 529, 49340, 11, 42418, 279, 3728, 3090, 11008, 25228, 9803, 56612, 311, 3728, 24808, 220, 22, 1174, 220, 806, 1174, 220, 717, 1174, 220, 1032, 1174, 449, 1063, 17989, 23377, 264, 3090, 11008, 25228, 2461, 315, 220, 17, 4235, 19, 4, 8844, 311, 279, 220, 6280, 15, 18435, 1614, 220, 23, 1174, 220, 605, 1174, 220, 975, 662, 1115, 25228, 2461, 84332, 439, 15098, 74975, 42129, 51172, 54280, 323, 15098, 7878, 35148, 323, 1207, 79, 7569, 54280, 13, 51541, 2841, 18435, 4371, 13797, 2349, 706, 264, 3544, 13230, 56887, 5497, 1555, 8149, 220, 868, 1174, 220, 845, 320, 30035, 13, 220, 16, 7609, 578, 76985, 64976, 58309, 706, 1664, 39817, 13918, 315, 7878, 6147, 323, 4371, 258, 2461, 11, 20444, 279, 23179, 58309, 374, 44029, 4371, 258, 7922, 304, 46039, 9499, 26467, 320, 19484, 23966, 13, 220, 16, 64, 11, 293, 449, 23966, 13, 220, 16, 66, 11, 294, 7609, 3804, 40846, 4371, 13797, 4442, 2873, 311, 387, 5552, 311, 7479, 12912, 315, 61050, 11, 15140, 79152, 323, 3721, 96649, 320, 18240, 47, 13737, 10, 49, 58858, 883, 304, 24654, 323, 10182, 4211, 320, 71, 35344, 1584, 31794, 304, 23966, 13, 220, 16, 7609, 2684, 527, 1101, 5199, 12062, 1990, 17989, 315, 18435, 4371, 13797, 4442, 304, 24654, 320, 30035, 13, 220, 16, 64, 11, 272, 883, 323, 10182, 4211, 927, 279, 1890, 4261, 320, 30035, 13, 220, 16, 65, 11, 294, 7609, 15483, 12062, 1990, 24654, 323, 4211, 304, 81118, 1122, 50518, 617, 27762, 3347, 3495, 311, 1005, 3090, 1474, 395, 6108, 50518, 311, 4124, 18435, 4371, 13797, 4442, 11, 369, 2937, 11, 555, 10484, 7922, 3152, 4371, 13797, 11, 328, 1174, 304, 9499, 11, 350, 1174, 320, 269, 17915, 8, 13931, 320, 5391, 439, 279, 350, 1389, 328, 16029, 315, 279, 18435, 8, 220, 24, 1174, 220, 1114, 1174, 220, 972, 662, 23966, 13, 220, 16, 25, 3623, 38638, 12912, 315, 13970, 4371, 13797, 2349, 304, 13468, 323, 1646, 839, 1167, 263, 750, 37956, 4371, 13797, 13, 264, 1389, 294, 1174, 26821, 21988, 25, 1167, 263, 750, 37956, 4371, 13797, 31954, 11, 304, 34419, 824, 15395, 13255, 824, 1060, 505, 220, 4468, 15, 311, 220, 679, 19, 11, 304, 28814, 24654, 320, 40, 2599, 220, 975, 1174, 220, 1691, 323, 5301, 19, 220, 1419, 883, 320, 264, 1174, 272, 883, 323, 304, 279, 18582, 3378, 21, 7447, 29344, 3152, 320, 87773, 8, 220, 1187, 320, 293, 1174, 294, 883, 304, 279, 23179, 320, 264, 1174, 293, 883, 323, 76985, 64976, 320, 272, 1174, 294, 883, 3122, 1354, 13, 7054, 21988, 25, 305, 35344, 1584, 31794, 1501, 279, 892, 84096, 11, 1167, 263, 750, 18751, 7479, 61050, 323, 15140, 79152, 28382, 3721, 96649, 320, 393, 25173, 469, 489, 432, 7026, 304, 274, 424, 3696, 8772, 824, 8547, 315, 21518, 304, 279, 12435, 3122, 1354, 505, 45120, 20, 312, 35584, 220, 1627, 505, 220, 4468, 24, 311, 220, 679, 19, 320, 264, 1174, 272, 883, 323, 279, 18582, 3378, 21, 57205, 864, 18251, 47479, 2585, 1629, 320, 293, 1174, 294, 7609, 800, 575, 12127, 304, 293, 323, 294, 15151, 13918, 369, 902, 810, 1109, 220, 17, 14, 18, 315, 279, 18582, 3378, 21, 4211, 7655, 389, 279, 1879, 315, 279, 4371, 13797, 31954, 13, 5348, 42533, 5238, 13519, 1167, 263, 750, 37956, 9499, 3346, 3742, 449, 279, 8369, 478, 220, 17, 4, 315, 279, 18435, 6965, 555, 279, 220, 17, 4, 42533, 11, 279, 8369, 478, 220, 21, 4, 555, 279, 220, 21, 4, 42533, 323, 779, 389, 13, 5810, 584, 3839, 4371, 13797, 4442, 304, 1521, 66257, 13931, 13, 8797, 1404, 2217, 47170, 279, 3728, 350, 1389, 328, 16029, 927, 892, 5825, 2038, 922, 4371, 13797, 4442, 304, 2204, 11323, 780, 13918, 3196, 389, 9499, 13, 4452, 11, 5042, 25213, 18845, 315, 10973, 4371, 13797, 520, 6926, 15692, 9499, 49378, 18435, 24808, 430, 11031, 279, 16940, 350, 1389, 328, 16029, 220, 777, 1174, 78504, 70673, 7162, 3544, 4371, 13797, 61555, 520, 6926, 350, 320, 54290, 2956, 23966, 13, 220, 17, 7609, 763, 420, 990, 11, 584, 49586, 4371, 13797, 4442, 520, 6926, 9499, 66257, 4856, 1109, 6926, 9499, 220, 508, 662, 3011, 374, 11, 584, 31335, 279, 18435, 505, 8369, 478, 311, 1400, 5086, 323, 3839, 4442, 520, 264, 8521, 41165, 8286, 320, 2000, 3187, 11, 555, 15194, 4371, 13797, 4442, 304, 279, 8369, 478, 220, 21, 4, 315, 279, 18435, 555, 8286, 570, 38122, 71724, 458, 27529, 48678, 279, 1890, 8286, 927, 892, 11, 323, 704, 35247, 304, 17715, 279, 1890, 11323, 780, 5654, 1524, 439, 279, 18435, 4208, 1026, 320, 2000, 2937, 11, 41665, 2956, 23966, 13, 220, 18, 50829, 279, 26078, 1637, 12172, 315, 9499, 71724, 458, 704, 66, 3787, 7863, 449, 279, 13890, 374, 1605, 1026, 570, 128257, 198, 128256, 78191, 198, 791, 3728, 3090, 11008, 41128, 374, 11, 279, 6926, 7351, 315, 80744, 1990, 279, 30614, 11, 4363, 323, 279, 18435, 2345, 28897, 459, 3062, 3560, 304, 1057, 7446, 6439, 13, 1115, 36301, 1887, 69169, 3090, 505, 279, 18435, 311, 279, 4363, 11, 10695, 311, 1304, 1057, 4676, 14464, 481, 323, 17614, 70225, 13, 2030, 16448, 3728, 20472, 617, 1027, 3339, 420, 1887, 810, 14560, 25, 3090, 374, 7366, 3201, 505, 9235, 13918, 7119, 14739, 13918, 11, 14718, 37846, 82, 311, 47293, 268, 304, 5596, 315, 279, 24867, 11, 1418, 25228, 7922, 53958, 4455, 323, 39262, 304, 3885, 13, 763, 1023, 4339, 11, 14739, 5789, 527, 3794, 14739, 466, 11, 323, 9235, 5789, 527, 3794, 294, 7401, 13, 3216, 3156, 1457, 11, 4442, 311, 279, 11008, 617, 1027, 5107, 311, 6089, 23846, 11, 449, 2212, 220, 1490, 3346, 315, 3728, 53958, 323, 3721, 96649, 12765, 927, 279, 18435, 13, 2030, 264, 502, 47083, 54, 35054, 4007, 11, 4756, 3432, 304, 22037, 11, 706, 1511, 10223, 12912, 315, 12290, 304, 279, 18435, 311, 16430, 1268, 1790, 18435, 80744, 706, 7882, 505, 279, 3312, 859, 311, 279, 51879, 2533, 220, 4468, 15, 13, 578, 14955, 1501, 430, 1990, 1403, 323, 3116, 3115, 810, 80744, 706, 7882, 1109, 10182, 4211, 30199, 2345, 70, 2299, 603, 26793, 922, 1268, 279, 3728, 3090, 11008, 374, 23201, 7922, 439, 264, 4459, 13, 330, 1687, 2736, 7020, 505, 3766, 990, 430, 279, 3728, 3090, 11008, 574, 25228, 7922, 1359, 2795, 3063, 3229, 315, 279, 4007, 2999, 13, 350, 2706, 10922, 2100, 71, 607, 11, 264, 21651, 1122, 323, 1772, 38083, 278, 3495, 22712, 520, 47083, 54, 10170, 13, 330, 1687, 1120, 3287, 956, 1440, 555, 1268, 1790, 13, 330, 791, 7351, 315, 80744, 505, 8369, 311, 9439, 5789, 7739, 279, 40132, 596, 4430, 315, 3090, 7710, 13, 5751, 14955, 6308, 264, 6945, 315, 279, 8294, 4442, 12765, 304, 279, 3728, 3090, 11008, 1210, 578, 2128, 8813, 872, 14955, 555, 42118, 24654, 505, 2380, 13970, 828, 7437, 18702, 279, 4261, 220, 4468, 15, 12, 679, 19, 13, 2030, 4619, 315, 21760, 389, 2167, 53958, 24654, 50004, 649, 387, 2653, 311, 6767, 4028, 279, 18435, 71201, 10968, 389, 264, 810, 19018, 13189, 25, 1268, 74975, 279, 3090, 574, 304, 1855, 18435, 3158, 13, 330, 644, 46039, 13918, 11, 3721, 96649, 29260, 7878, 3090, 505, 279, 18435, 9564, 12290, 4920, 11, 3339, 279, 18435, 12290, 1291, 1359, 2795, 1080, 43802, 4448, 82026, 11, 459, 22712, 14561, 304, 279, 47083, 54, 6150, 315, 50895, 323, 25647, 13, 330, 791, 3090, 11008, 5097, 430, 7878, 3090, 311, 76214, 13918, 1405, 433, 17503, 439, 11422, 11, 19371, 10831, 279, 18435, 323, 3339, 433, 2753, 74975, 1210, 763, 1023, 4339, 11, 279, 3090, 11008, 11141, 264, 12223, 389, 279, 18435, 12290, 5497, 17223, 555, 30090, 1521, 12912, 11, 12074, 649, 11917, 1268, 279, 11008, 4442, 927, 892, 13, 578, 2128, 16430, 430, 1990, 220, 4468, 15, 323, 220, 679, 19, 11, 459, 5066, 220, 2790, 11, 931, 12, 2813, 11, 931, 41999, 41668, 315, 80744, 574, 40460, 505, 279, 3312, 859, 311, 279, 51879, 1109, 3685, 41128, 596, 2212, 220, 972, 12, 966, 2960, 55336, 315, 80744, 505, 35148, 323, 1207, 2442, 51172, 13918, 11, 477, 17715, 220, 4513, 3115, 279, 3090, 304, 21972, 63107, 13, 330, 11569, 311, 279, 3090, 11008, 649, 617, 264, 9200, 5536, 389, 14054, 11, 30029, 11, 323, 73119, 1359, 2795, 2999, 13, 2100, 71, 607, 13, 330, 2181, 596, 9093, 3062, 311, 3619, 279, 1648, 279, 10182, 2349, 374, 74055, 279, 3090, 11008, 1457, 323, 1139, 279, 3938, 13, 330, 2028, 9455, 6835, 603, 459, 4623, 315, 1268, 1790, 420, 48694, 315, 279, 3090, 11008, 374, 10223, 11, 323, 649, 1520, 603, 7417, 3938, 10182, 2349, 4211, 1210, 22728, 4504, 3938, 41579, 3277, 2999, 13, 2100, 71, 607, 323, 279, 2128, 7863, 872, 14955, 311, 220, 508, 2204, 10182, 4211, 11, 814, 1766, 430, 682, 279, 4211, 1047, 87136, 279, 5150, 2349, 304, 8369, 1824, 820, 80744, 8481, 13, 2999, 13, 2100, 71, 607, 2795, 279, 14955, 1436, 3152, 584, 2351, 1234, 478, 79448, 279, 25949, 315, 10182, 2349, 389, 53958, 13, 330, 10086, 826, 1093, 11604, 527, 1268, 584, 7417, 1521, 4211, 1359, 2795, 2999, 13, 2100, 71, 607, 13, 330, 4959, 502, 9659, 315, 34579, 39732, 2641, 3347, 4211, 449, 1972, 828, 11, 9455, 5789, 430, 584, 649, 7417, 5304, 304, 3938, 4211, 13, 1115, 374, 264, 5933, 15740, 304, 10182, 34579, 1210, 57116, 527, 1457, 1701, 279, 26084, 9659, 315, 10182, 34579, 320, 44982, 279, 68077, 31636, 5008, 5783, 55805, 5907, 11, 477, 364, 10190, 3378, 21, 4670, 902, 32762, 9013, 505, 279, 18172, 9659, 13, 1115, 24519, 9455, 374, 264, 30816, 315, 279, 12624, 1920, 520, 990, 17223, 1436, 1520, 7417, 3938, 17989, 13, 330, 69320, 287, 279, 2349, 304, 8369, 4791, 1824, 820, 80744, 7710, 3445, 584, 649, 3351, 4741, 323, 3136, 311, 1304, 1521, 3062, 41579, 922, 1268, 10182, 2349, 374, 4461, 311, 5536, 1057, 3728, 3090, 11008, 1359, 2795, 2999, 13, 2100, 71, 607, 13, 330, 644, 220, 605, 477, 220, 508, 1667, 505, 1457, 11, 14248, 649, 1005, 420, 5905, 311, 1505, 704, 1268, 1790, 1521, 12912, 527, 4726, 10223, 927, 892, 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 Molecular electronics aims to miniaturize electronic devices by using subnanometre-scale active components 1 , 2 , 3 . A single-molecule diode, a circuit element that directs current flow 4 , was first proposed more than 40 years ago 5 and consisted of an asymmetric molecule comprising a donor–bridge–acceptor architecture to mimic a semiconductor p–n junction. Several single-molecule diodes have since been realized in junctions featuring asymmetric molecular backbones 6 , 7 , 8 , molecule–electrode linkers 9 or electrode materials 10 . Despite these advances, molecular diodes have had limited potential for applications due to their low conductance, low rectification ratios, extreme sensitivity to the junction structure and high operating voltages 7 , 8 , 9 , 11 , 12 . Here, we demonstrate a powerful approach to induce current rectification in symmetric single-molecule junctions using two electrodes of the same metal, but breaking symmetry by exposing considerably different electrode areas to an ionic solution. This allows us to control the junction's electrostatic environment in an asymmetric fashion by simply changing the bias polarity. With this method, we reliably and reproducibly achieve rectification ratios in excess of 200 at voltages as low as 370 mV using a symmetric oligomer of thiophene-1,1-dioxide 13 , 14 . By taking advantage of the changes in the junction environment induced by the presence of an ionic solution, this method provides a general route for tuning nonlinear nanoscale device phenomena, which could potentially be applied in systems beyond single-molecule junctions. Main In this Letter we use the scanning tunnelling microscope-based break junction technique 15 (STM-BJ) to rapidly and reproducibly measure the conductance ( G = I / V ) and current–voltage ( I – V ) characteristics of thousands of single-molecule junctions (see Methods and Supplementary Fig. 1 ). Using this technique, we demonstrate rectification in single-molecule junctions by carrying out measurements in propylene carbonate (PC), a polar solvent. We use an STM tip insulated with Apiezon wax 16 to reduce its area to ∼ 1 µm 2 and a gold substrate with an area greater than 1 cm 2 ( Fig. 1a ). The insulation on the tip serves to reduce any background capacitive and Faradaic electrochemical currents stemming from the electrolyte, but, more importantly, it gives us control of the electrostatic environment around the tip and substrate. Figure 1: Environmentally enabled single-molecule diodes. a , TDO n molecular structure (alkyl side chains omitted for clarity) and schematic of the molecular junction created using asymmetric area electrodes (not drawn to scale). b , Log-binned conductance histograms for TDO4 taken at −180 mV and +180 mV, created using 3,000 traces each and 100 bins/decade. Arrows indicate the most probably measured conductance at each bias. Inset: Sample conductance versus displacement traces, laterally offset for clarity. c , Two-dimensional absolute current versus voltage histogram for TDO5 in PC. Inset: Examples of exceptionally rectifying junctions (three selected traces). d , Two-dimensional absolute current versus voltage histogram for TDO5 in TCB. Average I – V s for TDO5 are overlaid on c and d in black. Full size image We first demonstrate exceptionally high and statistically reproducible single-molecule junction rectification in an oligomer consisting of four thiophene-1,1-dioxide units flanked by two gold-binding methyl-sulphide-bearing thiophenes 13 (TDO4, Fig. 1a ). Sample conductance versus displacement traces for TDO4 measured in PC are shown in the inset to Fig. 1b . Under the conditions described above, there is a significant difference in the single-molecule junction conductance measurements when performed at +180 mV or −180 mV (tip relative to substrate). When thousands of conductance traces are compiled, without data selection, into one-dimensional log-binned conductance histograms ( Fig. 1b ), it is clear that the conductance measured at −180 mV exceeds that measured at +180 mV by a factor of 3.25. This is a significant difference for such a low-bias measurement. This bias polarity-dependent conductance is not observed when TDO4 is measured in a nonpolar and non-ionic solvent (1,2,4-trichlorobenzene, TCB, Supplementary Fig. 2 ). We next demonstrate the highest achieved rectification ratios in single-molecule junctions by performing I – V measurements on TDO5 ( Fig. 1a ) in PC. Thousands of individual I – V s were obtained, and only traces containing a molecular feature that sustained the entire voltage ramp were considered (typically ∼ 500–1,000 traces per molecule, see Methods ). These traces were then overlaid and compiled into a two-dimensional current versus voltage histogram ( Fig. 1c ). The plot illustrates a clear asymmetry in current with bias sign, showing a much higher current (flowing from tip to substrate) at negative voltages than at positive voltages (tip relative to substrate). Results from analogous I – V measurements in TCB, where no asymmetry is observed, are shown in Fig. 1d . To obtain a quantitative value for the rectification ratio ( I on / I off ), each vertical slice of the two-dimensional histogram was fit with a Gaussian, and a most probable current value was determined at each voltage to obtain an average I – V curve (overlays in Fig. 1c,d ). In PC, a rectification ratio for TDO5 greater than 200 at ±370 mV is observed. Although this ‘average’ rectification ratio is already the highest reported for single-molecule junctions, several single-trace plots of these junctions display exceptionally high rectifying behaviour, in excess of 500, as shown in the inset of Fig. 1c . Although high rectification ratios have been observed in systems consisting of many-molecule junctions 17 , 18 , the number of molecules involved in transport is generally unknown in these systems. Moreover, past reports have relied on asymmetric molecules, electrodes and chemical linker groups, unlike the design described here. We hypothesize that the highly asymmetric nature of the I – V curves is due to the formation of an asymmetric, bias-dependent electric double layer. We note that a polar ion-soluble solvent is essential to observing rectification ( Supplementary Fig. 3 ). Indeed, measurements in PC with an added electrolyte ( Supplementary Fig. 4 ) do not differ significantly", "role": "user" }, { "content": "A team of researchers from Berkeley Lab and Columbia University has passed a major milestone in molecular electronics with the creation of the world's highest-performance single-molecule diode. Working at Berkeley Lab's Molecular Foundry, a U.S. Department of Energy (DOE) Office of Science User Facility, the team used a combination of gold electrodes and an ionic solution to create a single-molecule diode that outperforms the best of its predecessors by a factor of 50. \"Using a single symmetric molecule, an ionic solution and two gold electrodes of dramatically different exposed surface areas, we were able to create a diode that resulted in a rectification ratio, the ratio of forward to reverse current at fixed voltage, in excess of 200, which is a record for single-molecule devices,\" says Jeff Neaton, Director of the Molecular Foundry, a senior faculty scientist with Berkeley Lab's Materials Sciences Division and the Department of Physics at the University of California Berkeley, and a member of the Kavli Energy Nanoscience Institute at Berkeley (Kavli ENSI). \"The asymmetry necessary for diode behavior originates with the different exposed electrode areas and the ionic solution,\" he says. \"This leads to different electrostatic environments surrounding the two electrodes and superlative single-molecule device behavior.\" With \"smaller and faster\" as the driving mantra of the electronics industry, single-molecule devices represent the ultimate limit in electronic miniaturization. In 1974, molecular electronics pioneers Mark Ratner and Arieh Aviram theorized that an asymmetric molecule could act as a rectifier, a one-way conductor of electric current. Since then, development of functional single-molecule electronic devices has been a major pursuit with diodes - one of the most widely used electronic components - being at the top of the list. A typical diode consists of a silicon p-n junction between a pair of electrodes (anode and cathode) that serves as the \"valve\" of an electrical circuit, directing the flow of current by allowing it to pass through in only one \"forward\" direction. The asymmetry of a p-n junction presents the electrons with an \"on/off\" transport environment. Scientists have previously fashioned single-molecule diodes either through the chemical synthesis of special asymmetric molecules that are analogous to a p-n junction; or through the use of symmetric molecules with different metals as the two electrodes. However, the resulting asymmetric junctions yielded low rectification ratios, and low forward current. Neaton and his colleagues at Columbia University have discovered a way to address both deficiencies. \"Electron flow at molecular length-scales is dominated by quantum tunneling,\" Neaton explains. \"The efficiency of the tunneling process depends intimately on the degree of alignment of the molecule's discrete energy levels with the electrode's continuous spectrum. In a molecular rectifier, this alignment is enhanced for positive voltage, leading to an increase in tunneling, and is reduced for negative voltage. At the Molecular Foundry we developed an approach to accurately compute energy-level alignment and tunneling probability in single-molecule junctions. This method allowed myself and Zhenfei Liu to understand the diode behavior quantitatively.\" In collaboration with Columbia University's Latha Venkataraman and Luis Campos and their respective research groups, Neaton and Liu fabricated a high-performing rectifier from junctions made of symmetric molecules with molecular resonance in nearly perfect alignment with the Fermi electron energy levels of the gold electrodes. Symmetry was broken by a substantial difference in the size of the area on each gold electrode that was exposed to the ionic solution. Owing to the asymmetric electrode area, the ionic solution, and the junction energy level alignment, a positive voltage increases current substantially; a negative voltage suppresses it equally significantly. Schematic of the molecular junction created using asymmetric area electrodes which functions as a diode, allowing current to flow in one direction only. Credit: courtesy of Berkeley Lab and Columbia University \"The ionic solution, combined with the asymmetry in electrode areas, allows us to control the junction's electrostatic environment simply by changing the bias polarity,\" Neaton says. \"In addition to breaking symmetry, double layers formed by ionic solution also generate dipole differences at the two electrodes, which is the underlying reason behind the asymmetric shift of molecular resonance. The Columbia group's experiments showed that with the same molecule and electrode setup, a non-ionic solution yields no rectification at all.\" The Berkeley Lab-Columbia University team believes their new approach to a single-molecule diode provides a general route for tuning nonlinear nanoscale-device phenomena that could be applied to systems beyond single-molecule junctions and two-terminal devices. \"We expect the understanding gained from this work to be applicable to ionic liquid gating in other contexts, and mechanisms to be generalized to devices fabricated from two-dimensional materials,\" Neaton says. \"Beyond devices, these tiny molecular circuits are petri dishes for revealing and designing new routes to charge and energy flow at the nanoscale. What is exciting to me about this field is its multidisciplinary nature - the need for both physics and chemistry - and the strong beneficial coupling between experiment and theory. \"With the increasing level of experimental control at the single-molecule level, and improvements in theoretical understanding and computational speed and accuracy, we're just at the tip of the iceberg with what we can understand and control at these small length scales.\" Neaton, Venkataraman and Campos are the corresponding authors of a paper describing this research in Nature Nanotechnology. The paper is titled \"Single-molecule diodes with high rectificationratios through environmental control.\" Other co-authors are Brian Capozzi, Jianlong Xia, Olgun Adak, Emma Dell, Zhen-Fei Liu and Jeffrey Taylor. ", "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 Molecular electronics aims to miniaturize electronic devices by using subnanometre-scale active components 1 , 2 , 3 . A single-molecule diode, a circuit element that directs current flow 4 , was first proposed more than 40 years ago 5 and consisted of an asymmetric molecule comprising a donor–bridge–acceptor architecture to mimic a semiconductor p–n junction. Several single-molecule diodes have since been realized in junctions featuring asymmetric molecular backbones 6 , 7 , 8 , molecule–electrode linkers 9 or electrode materials 10 . Despite these advances, molecular diodes have had limited potential for applications due to their low conductance, low rectification ratios, extreme sensitivity to the junction structure and high operating voltages 7 , 8 , 9 , 11 , 12 . Here, we demonstrate a powerful approach to induce current rectification in symmetric single-molecule junctions using two electrodes of the same metal, but breaking symmetry by exposing considerably different electrode areas to an ionic solution. This allows us to control the junction's electrostatic environment in an asymmetric fashion by simply changing the bias polarity. With this method, we reliably and reproducibly achieve rectification ratios in excess of 200 at voltages as low as 370 mV using a symmetric oligomer of thiophene-1,1-dioxide 13 , 14 . By taking advantage of the changes in the junction environment induced by the presence of an ionic solution, this method provides a general route for tuning nonlinear nanoscale device phenomena, which could potentially be applied in systems beyond single-molecule junctions. Main In this Letter we use the scanning tunnelling microscope-based break junction technique 15 (STM-BJ) to rapidly and reproducibly measure the conductance ( G = I / V ) and current–voltage ( I – V ) characteristics of thousands of single-molecule junctions (see Methods and Supplementary Fig. 1 ). Using this technique, we demonstrate rectification in single-molecule junctions by carrying out measurements in propylene carbonate (PC), a polar solvent. We use an STM tip insulated with Apiezon wax 16 to reduce its area to ∼ 1 µm 2 and a gold substrate with an area greater than 1 cm 2 ( Fig. 1a ). The insulation on the tip serves to reduce any background capacitive and Faradaic electrochemical currents stemming from the electrolyte, but, more importantly, it gives us control of the electrostatic environment around the tip and substrate. Figure 1: Environmentally enabled single-molecule diodes. a , TDO n molecular structure (alkyl side chains omitted for clarity) and schematic of the molecular junction created using asymmetric area electrodes (not drawn to scale). b , Log-binned conductance histograms for TDO4 taken at −180 mV and +180 mV, created using 3,000 traces each and 100 bins/decade. Arrows indicate the most probably measured conductance at each bias. Inset: Sample conductance versus displacement traces, laterally offset for clarity. c , Two-dimensional absolute current versus voltage histogram for TDO5 in PC. Inset: Examples of exceptionally rectifying junctions (three selected traces). d , Two-dimensional absolute current versus voltage histogram for TDO5 in TCB. Average I – V s for TDO5 are overlaid on c and d in black. Full size image We first demonstrate exceptionally high and statistically reproducible single-molecule junction rectification in an oligomer consisting of four thiophene-1,1-dioxide units flanked by two gold-binding methyl-sulphide-bearing thiophenes 13 (TDO4, Fig. 1a ). Sample conductance versus displacement traces for TDO4 measured in PC are shown in the inset to Fig. 1b . Under the conditions described above, there is a significant difference in the single-molecule junction conductance measurements when performed at +180 mV or −180 mV (tip relative to substrate). When thousands of conductance traces are compiled, without data selection, into one-dimensional log-binned conductance histograms ( Fig. 1b ), it is clear that the conductance measured at −180 mV exceeds that measured at +180 mV by a factor of 3.25. This is a significant difference for such a low-bias measurement. This bias polarity-dependent conductance is not observed when TDO4 is measured in a nonpolar and non-ionic solvent (1,2,4-trichlorobenzene, TCB, Supplementary Fig. 2 ). We next demonstrate the highest achieved rectification ratios in single-molecule junctions by performing I – V measurements on TDO5 ( Fig. 1a ) in PC. Thousands of individual I – V s were obtained, and only traces containing a molecular feature that sustained the entire voltage ramp were considered (typically ∼ 500–1,000 traces per molecule, see Methods ). These traces were then overlaid and compiled into a two-dimensional current versus voltage histogram ( Fig. 1c ). The plot illustrates a clear asymmetry in current with bias sign, showing a much higher current (flowing from tip to substrate) at negative voltages than at positive voltages (tip relative to substrate). Results from analogous I – V measurements in TCB, where no asymmetry is observed, are shown in Fig. 1d . To obtain a quantitative value for the rectification ratio ( I on / I off ), each vertical slice of the two-dimensional histogram was fit with a Gaussian, and a most probable current value was determined at each voltage to obtain an average I – V curve (overlays in Fig. 1c,d ). In PC, a rectification ratio for TDO5 greater than 200 at ±370 mV is observed. Although this ‘average’ rectification ratio is already the highest reported for single-molecule junctions, several single-trace plots of these junctions display exceptionally high rectifying behaviour, in excess of 500, as shown in the inset of Fig. 1c . Although high rectification ratios have been observed in systems consisting of many-molecule junctions 17 , 18 , the number of molecules involved in transport is generally unknown in these systems. Moreover, past reports have relied on asymmetric molecules, electrodes and chemical linker groups, unlike the design described here. We hypothesize that the highly asymmetric nature of the I – V curves is due to the formation of an asymmetric, bias-dependent electric double layer. We note that a polar ion-soluble solvent is essential to observing rectification ( Supplementary Fig. 3 ). Indeed, measurements in PC with an added electrolyte ( Supplementary Fig. 4 ) do not differ significantly<|im_end|> <|im_start|>assistant A team of researchers from Berkeley Lab and Columbia University has passed a major milestone in molecular electronics with the creation of the world's highest-performance single-molecule diode. Working at Berkeley Lab's Molecular Foundry, a U.S. Department of Energy (DOE) Office of Science User Facility, the team used a combination of gold electrodes and an ionic solution to create a single-molecule diode that outperforms the best of its predecessors by a factor of 50. "Using a single symmetric molecule, an ionic solution and two gold electrodes of dramatically different exposed surface areas, we were able to create a diode that resulted in a rectification ratio, the ratio of forward to reverse current at fixed voltage, in excess of 200, which is a record for single-molecule devices," says Jeff Neaton, Director of the Molecular Foundry, a senior faculty scientist with Berkeley Lab's Materials Sciences Division and the Department of Physics at the University of California Berkeley, and a member of the Kavli Energy Nanoscience Institute at Berkeley (Kavli ENSI). "The asymmetry necessary for diode behavior originates with the different exposed electrode areas and the ionic solution," he says. "This leads to different electrostatic environments surrounding the two electrodes and superlative single-molecule device behavior." With "smaller and faster" as the driving mantra of the electronics industry, single-molecule devices represent the ultimate limit in electronic miniaturization. In 1974, molecular electronics pioneers Mark Ratner and Arieh Aviram theorized that an asymmetric molecule could act as a rectifier, a one-way conductor of electric current. Since then, development of functional single-molecule electronic devices has been a major pursuit with diodes - one of the most widely used electronic components - being at the top of the list. A typical diode consists of a silicon p-n junction between a pair of electrodes (anode and cathode) that serves as the "valve" of an electrical circuit, directing the flow of current by allowing it to pass through in only one "forward" direction. The asymmetry of a p-n junction presents the electrons with an "on/off" transport environment. Scientists have previously fashioned single-molecule diodes either through the chemical synthesis of special asymmetric molecules that are analogous to a p-n junction; or through the use of symmetric molecules with different metals as the two electrodes. However, the resulting asymmetric junctions yielded low rectification ratios, and low forward current. Neaton and his colleagues at Columbia University have discovered a way to address both deficiencies. "Electron flow at molecular length-scales is dominated by quantum tunneling," Neaton explains. "The efficiency of the tunneling process depends intimately on the degree of alignment of the molecule's discrete energy levels with the electrode's continuous spectrum. In a molecular rectifier, this alignment is enhanced for positive voltage, leading to an increase in tunneling, and is reduced for negative voltage. At the Molecular Foundry we developed an approach to accurately compute energy-level alignment and tunneling probability in single-molecule junctions. This method allowed myself and Zhenfei Liu to understand the diode behavior quantitatively." In collaboration with Columbia University's Latha Venkataraman and Luis Campos and their respective research groups, Neaton and Liu fabricated a high-performing rectifier from junctions made of symmetric molecules with molecular resonance in nearly perfect alignment with the Fermi electron energy levels of the gold electrodes. Symmetry was broken by a substantial difference in the size of the area on each gold electrode that was exposed to the ionic solution. Owing to the asymmetric electrode area, the ionic solution, and the junction energy level alignment, a positive voltage increases current substantially; a negative voltage suppresses it equally significantly. Schematic of the molecular junction created using asymmetric area electrodes which functions as a diode, allowing current to flow in one direction only. Credit: courtesy of Berkeley Lab and Columbia University "The ionic solution, combined with the asymmetry in electrode areas, allows us to control the junction's electrostatic environment simply by changing the bias polarity," Neaton says. "In addition to breaking symmetry, double layers formed by ionic solution also generate dipole differences at the two electrodes, which is the underlying reason behind the asymmetric shift of molecular resonance. The Columbia group's experiments showed that with the same molecule and electrode setup, a non-ionic solution yields no rectification at all." The Berkeley Lab-Columbia University team believes their new approach to a single-molecule diode provides a general route for tuning nonlinear nanoscale-device phenomena that could be applied to systems beyond single-molecule junctions and two-terminal devices. "We expect the understanding gained from this work to be applicable to ionic liquid gating in other contexts, and mechanisms to be generalized to devices fabricated from two-dimensional materials," Neaton says. "Beyond devices, these tiny molecular circuits are petri dishes for revealing and designing new routes to charge and energy flow at the nanoscale. What is exciting to me about this field is its multidisciplinary nature - the need for both physics and chemistry - and the strong beneficial coupling between experiment and theory. "With the increasing level of experimental control at the single-molecule level, and improvements in theoretical understanding and computational speed and accuracy, we're just at the tip of the iceberg with what we can understand and control at these small length scales." Neaton, Venkataraman and Campos are the corresponding authors of a paper describing this research in Nature Nanotechnology. The paper is titled "Single-molecule diodes with high rectificationratios through environmental control." Other co-authors are Brian Capozzi, Jianlong Xia, Olgun Adak, Emma Dell, Zhen-Fei Liu and Jeffrey Taylor. <|im_end|>

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2,607

[ { "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 Learning and memory processes can be influenced by recent experience, but the mechanisms involved are poorly understood. Enhanced plasticity during critical periods of early life is linked to differentiating parvalbumin (PV)-interneuron networks 1 , 2 , 3 , 4 , 5 , 6 , 7 , suggesting that recent experience may modulate learning by targeting the differentiation state of PV neurons 8 , 9 , 10 , 11 in the adult. Here we show that environmental enrichment and Pavlovian contextual fear conditioning induce opposite, sustained and reversible hippocampal PV-network configurations in adult mice. Specifically, enrichment promotes the emergence of large fractions of low-differentiation (low PV and GAD67 expression) basket cells with low excitatory-to-inhibitory synaptic-density ratios, whereas fear conditioning leads to large fractions of high-differentiation (high PV and GAD67 expression) basket cells with high excitatory-to-inhibitory synaptic-density ratios. Pharmacogenetic inhibition or activation of PV neurons was sufficient to induce such opposite low-PV-network or high-PV-network configurations, respectively. The low-PV-network configuration enhanced structural synaptic plasticity 12 , 13 , and memory consolidation and retrieval, whereas these were reduced by the high-PV-network configuration. We then show that maze navigation learning 14 induces a hippocampal low-PV-network configuration paralleled by enhanced memory and structural synaptic plasticity throughout training, followed by a shift to a high-PV-network configuration after learning completion. The shift to a low-PV-network configuration specifically involved increased vasoactive intestinal polypeptide (VIP)-positive GABAergic boutons and synaptic transmission onto PV neurons 15 , 16 . Closely comparable low- and high-PV-network configurations involving VIP boutons were specifically induced in primary motor cortex upon rotarod motor learning 17 , 18 . These results uncover a network plasticity mechanism induced after learning through VIP–PV microcircuit modulation 19 , and involving large, sustained and reversible shifts in the configuration of PV basket-cell networks in the adult. This novel form of experience-related plasticity in the adult modulates memory consolidation, retrieval and learning, and might be harnessed for therapeutic strategies to promote cognitive enhancement and neuroprotection. Main To determine whether plasticity and learning in the adult may involve alterations in the differentiation state of PV-positive GABA (γ-aminobutyric acid)-ergic interneurons, we monitored PV immunoreactivity in ensembles of genetically identified PV neurons near the pyramidal cell layer in dorsal hippocampal area CA3b ( Supplementary Discussion ). We initially compared cage control to environmentally enriched, and to contextually fear conditioned mice. The environmental enrichment protocol enhances hippocampal plasticity and learning 12 , 13 , whereas fear specifically restricted to training context depends on enhanced filopodial synapses onto PV neurons by hippocampal mossy fibres upon contextual fear conditioning 20 . The PV-neuron group with lowest PV signals (low-PV) represented 2± 0.8% of the total number of PV neurons, whereas the group with highest PV levels (high-PV) represented 19± 2% of the total number of PV neurons ( n = 15 mice). Housing mice under environmentally enriched conditions induced a robust increase in low-PV neurons, whereas contextual fear conditioning greatly enhanced high-PV-neuron contents ( Fig. 1a and Supplementary discussion ). Total numbers of PV neurons were not affected by these experimental conditions (CA3b PV-neuron numbers per 50,000 μm 2 within 150 μm of the pyramidal cell layer were 20.0 ± 0.9 (control), 19.3 ± 1.4 (environmentally enriched) and 21.2 ± 1.7 (contextual fear conditioning); n = 18 mice each). Under all experimental conditions, PV immunoreactivity in individual interneurons was closely correlated to GAD67 immunoreactivity (Pearson correlation, 0.92; Fig. 1b and Extended Data Fig. 2 ). GAD67 is a key GABA-synthesizing enzyme that links synaptic activity to GABA levels, regulates PV neuron synaptogenesis and is a differentiation marker of PV neurons 21 . An analysis of PV neurons in postnatal hippocampal CA3b revealed that at the time of eye opening, PV distributions resemble the low-PV configuration induced in the adult after environmental enrichment ( Fig. 1c and Extended Data Fig. 3 ). Figure 1: Differentiation plasticity of hippocampal parvalbumin-expressing basket-cell networks in adult mice. a , Experience-related plasticity of PV neurons. Arrows, high-PV-signal (dark blue), intermediate high-PV-signal (blue), intermediate low-PV-signal (gold) and low-PV-signal (yellow) neurons. White arrows indicate PV basket-cell terminals. Relative contents of PV neurons in control (Ctrl), environmentally enriched (EE, 3 weeks) and contextually fear conditioned (cFC, day1) mice. n = 15 mice each (50 neurons per mouse). b , Differentiation plasticity of PV neurons in the adult. PV- and GAD67-signal relationship in individual PV neurons from Ctrl, EE and cFC mice. n = 5 mice each (50 neurons per mouse). c , PV-network configuration during maturation of hippocampal CA3 (CA3b). n = 8 mice each. Colours as in a . d , PV immunoreactivity in Soma (So), dendrites (Den) and terminal boutons (Bask) of individual PV-expressing basket cells. n = 8–10 dendrite stretches or 30–50 boutons per cell. e , PV-bouton distribution at individual pyramidal neuron perisomatic baskets. n = 60 neurons (3 mice) each. Colours as in a . f , PV-bouton labelling intensities at axon initial segments (chandelier cells). n = 60 AIS (3 mice) each. Colours as in a . g , PV-network configuration correlated to memory consolidation and retrieval (left, FOR), and synapse turnover (right). n = 8 mice cFC, and 3 mice and 40 mossy-fibre terminals each (mossy-fibre-terminal active-zone densities). Colours as in a . NS, not significant. Values are means ± s.e.m. Scale bars, 20 μm ( a , d ); 10 μm ( b ); 5 μm ( e , f ). * P < 0.05; ** P < 0.01; *** P < 0.001. PowerPoint slide Full size image To investigate how defined subpopulations of PV neurons are influenced by experience, we analysed presynaptic terminals of basket and chandelier cells, the two main subpopulations of hippocampal PV neurons in CA3. PV immunoreactivity signals were comparable at soma, axonal boutons and dendrites of individual PV basket cells ( Fig. 1d ). Perisomatic PV-bouton immunoreactivity distributions for individual baskets were closely comparable to those of the whole PV network for each experimental condition ( Figs 1e and Extended Data Fig. 4a, b ). This was in contrast to the distribution of", "role": "user" }, { "content": "Neurobiologist from the Friedrich Miescher Institute for Biomedical Research show how a network of neurons in hippocampus and cortex switches states to turn on and off learning in the adult. They further show how a stimulating environment promotes this switch, and thus learning. Their findings are published today in the renowned journal Nature and have far reaching implications also for diseases where learning and memory is impaired, such as Alzheimer's or dementia. Learning to ride a bike, to ski or swim: After many days and weeks of practice, trial and error, we usually master a skill and never forget how to do it. What is also common knowledge is that motivation and a supportive environment usually help: learning how to ski in the extreme cold will take much longer than on a sunny day with an understanding teacher. While we can observe these phenomena over and over again with many tasks at hand, we still don't understand fully, what mechanisms in the brain first enable learning and then allow the switch to the state where \"we just know\", and hardly forget. Pico Caroni and his team at the Friedrich Miescher Institute for Biomedical Research in Basel could now show that networks of specific cells in the brain regions relevant for each particular type of learning, switch first to a \"learning state\" and then to a \"learnt state\", and how the environment and experience modulate these processes. In a study published today in the renowned scientific journal Nature, they could show that so called basked cells, inhibitory neurons assembled in a network to modulate the function of excitatory neurons in brain regions such as the hippocampus, switch between three states during a learning experience. From a neutral state, many basket cells de-differentiate as the learning experience starts. This facilitates local formation and remodeling of new connections, new synapses; the network is plastic and conducive to learning and memory of new relationships potentially important to master the task at hand. As soon as the task has been successfully learned, this initial switch is reversed, and many basket cells switch to a highly differentiated state. The local network loses its ability to form new synapses, but at the same time enhances the function of strong synapses involved in the newly learned skill; the network loses its plasticity, but consolidates its gains. Learning is complete, the ability to perform the task stable. Finally, the cells revert to the neutral state again, ready for the next task to learn. Caroni and his team further showed that the learning environment influences the state of the basket cells. In an environment rich in stimuli and diverse experiences, a large fraction of the basket cells are in a low differentiation state, ready for learning. Importantly, the scientists show that they can pharmacogenetically switch the different basket cells, thereby inducing the predicted outcomes in the ability to learn. Inhibition of basket cells decreased their differentiation and increased the ability to learn, whereas activation of basket cells increased their differentiation state and reduced learning and memory skills. These findings are ground-breaking in several ways. First, for a long time the scientific community believed that plasticity of neuronal connections in brain regions such as the hippocampus is permanently reduced in the adult. Caroni and his team now show that the same cells that ease learning and plasticity of neuronal connections in the young are involved in the same processes at an older age. Second, the scientists could show how the environment and experience influence plasticity and learning. \"In dementia and Alzheimer's disease, stimulating activities have been proposed as therapeutic approaches to slow down the disease,\" comments Caroni, \"our results provide now a scientific rational for such a therapeutic tactic. Being able to reversibly induce basket cell network states that modulate learning and memory formation might be harnessed for therapeutic strategies in these 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 Learning and memory processes can be influenced by recent experience, but the mechanisms involved are poorly understood. Enhanced plasticity during critical periods of early life is linked to differentiating parvalbumin (PV)-interneuron networks 1 , 2 , 3 , 4 , 5 , 6 , 7 , suggesting that recent experience may modulate learning by targeting the differentiation state of PV neurons 8 , 9 , 10 , 11 in the adult. Here we show that environmental enrichment and Pavlovian contextual fear conditioning induce opposite, sustained and reversible hippocampal PV-network configurations in adult mice. Specifically, enrichment promotes the emergence of large fractions of low-differentiation (low PV and GAD67 expression) basket cells with low excitatory-to-inhibitory synaptic-density ratios, whereas fear conditioning leads to large fractions of high-differentiation (high PV and GAD67 expression) basket cells with high excitatory-to-inhibitory synaptic-density ratios. Pharmacogenetic inhibition or activation of PV neurons was sufficient to induce such opposite low-PV-network or high-PV-network configurations, respectively. The low-PV-network configuration enhanced structural synaptic plasticity 12 , 13 , and memory consolidation and retrieval, whereas these were reduced by the high-PV-network configuration. We then show that maze navigation learning 14 induces a hippocampal low-PV-network configuration paralleled by enhanced memory and structural synaptic plasticity throughout training, followed by a shift to a high-PV-network configuration after learning completion. The shift to a low-PV-network configuration specifically involved increased vasoactive intestinal polypeptide (VIP)-positive GABAergic boutons and synaptic transmission onto PV neurons 15 , 16 . Closely comparable low- and high-PV-network configurations involving VIP boutons were specifically induced in primary motor cortex upon rotarod motor learning 17 , 18 . These results uncover a network plasticity mechanism induced after learning through VIP–PV microcircuit modulation 19 , and involving large, sustained and reversible shifts in the configuration of PV basket-cell networks in the adult. This novel form of experience-related plasticity in the adult modulates memory consolidation, retrieval and learning, and might be harnessed for therapeutic strategies to promote cognitive enhancement and neuroprotection. Main To determine whether plasticity and learning in the adult may involve alterations in the differentiation state of PV-positive GABA (γ-aminobutyric acid)-ergic interneurons, we monitored PV immunoreactivity in ensembles of genetically identified PV neurons near the pyramidal cell layer in dorsal hippocampal area CA3b ( Supplementary Discussion ). We initially compared cage control to environmentally enriched, and to contextually fear conditioned mice. The environmental enrichment protocol enhances hippocampal plasticity and learning 12 , 13 , whereas fear specifically restricted to training context depends on enhanced filopodial synapses onto PV neurons by hippocampal mossy fibres upon contextual fear conditioning 20 . The PV-neuron group with lowest PV signals (low-PV) represented 2± 0.8% of the total number of PV neurons, whereas the group with highest PV levels (high-PV) represented 19± 2% of the total number of PV neurons ( n = 15 mice). Housing mice under environmentally enriched conditions induced a robust increase in low-PV neurons, whereas contextual fear conditioning greatly enhanced high-PV-neuron contents ( Fig. 1a and Supplementary discussion ). Total numbers of PV neurons were not affected by these experimental conditions (CA3b PV-neuron numbers per 50,000 μm 2 within 150 μm of the pyramidal cell layer were 20.0 ± 0.9 (control), 19.3 ± 1.4 (environmentally enriched) and 21.2 ± 1.7 (contextual fear conditioning); n = 18 mice each). Under all experimental conditions, PV immunoreactivity in individual interneurons was closely correlated to GAD67 immunoreactivity (Pearson correlation, 0.92; Fig. 1b and Extended Data Fig. 2 ). GAD67 is a key GABA-synthesizing enzyme that links synaptic activity to GABA levels, regulates PV neuron synaptogenesis and is a differentiation marker of PV neurons 21 . An analysis of PV neurons in postnatal hippocampal CA3b revealed that at the time of eye opening, PV distributions resemble the low-PV configuration induced in the adult after environmental enrichment ( Fig. 1c and Extended Data Fig. 3 ). Figure 1: Differentiation plasticity of hippocampal parvalbumin-expressing basket-cell networks in adult mice. a , Experience-related plasticity of PV neurons. Arrows, high-PV-signal (dark blue), intermediate high-PV-signal (blue), intermediate low-PV-signal (gold) and low-PV-signal (yellow) neurons. White arrows indicate PV basket-cell terminals. Relative contents of PV neurons in control (Ctrl), environmentally enriched (EE, 3 weeks) and contextually fear conditioned (cFC, day1) mice. n = 15 mice each (50 neurons per mouse). b , Differentiation plasticity of PV neurons in the adult. PV- and GAD67-signal relationship in individual PV neurons from Ctrl, EE and cFC mice. n = 5 mice each (50 neurons per mouse). c , PV-network configuration during maturation of hippocampal CA3 (CA3b). n = 8 mice each. Colours as in a . d , PV immunoreactivity in Soma (So), dendrites (Den) and terminal boutons (Bask) of individual PV-expressing basket cells. n = 8–10 dendrite stretches or 30–50 boutons per cell. e , PV-bouton distribution at individual pyramidal neuron perisomatic baskets. n = 60 neurons (3 mice) each. Colours as in a . f , PV-bouton labelling intensities at axon initial segments (chandelier cells). n = 60 AIS (3 mice) each. Colours as in a . g , PV-network configuration correlated to memory consolidation and retrieval (left, FOR), and synapse turnover (right). n = 8 mice cFC, and 3 mice and 40 mossy-fibre terminals each (mossy-fibre-terminal active-zone densities). Colours as in a . NS, not significant. Values are means ± s.e.m. Scale bars, 20 μm ( a , d ); 10 μm ( b ); 5 μm ( e , f ). * P < 0.05; ** P < 0.01; *** P < 0.001. PowerPoint slide Full size image To investigate how defined subpopulations of PV neurons are influenced by experience, we analysed presynaptic terminals of basket and chandelier cells, the two main subpopulations of hippocampal PV neurons in CA3. PV immunoreactivity signals were comparable at soma, axonal boutons and dendrites of individual PV basket cells ( Fig. 1d ). Perisomatic PV-bouton immunoreactivity distributions for individual baskets were closely comparable to those of the whole PV network for each experimental condition ( Figs 1e and Extended Data Fig. 4a, b ). This was in contrast to the distribution of<|im_end|> <|im_start|>assistant Neurobiologist from the Friedrich Miescher Institute for Biomedical Research show how a network of neurons in hippocampus and cortex switches states to turn on and off learning in the adult. They further show how a stimulating environment promotes this switch, and thus learning. Their findings are published today in the renowned journal Nature and have far reaching implications also for diseases where learning and memory is impaired, such as Alzheimer's or dementia. Learning to ride a bike, to ski or swim: After many days and weeks of practice, trial and error, we usually master a skill and never forget how to do it. What is also common knowledge is that motivation and a supportive environment usually help: learning how to ski in the extreme cold will take much longer than on a sunny day with an understanding teacher. While we can observe these phenomena over and over again with many tasks at hand, we still don't understand fully, what mechanisms in the brain first enable learning and then allow the switch to the state where "we just know", and hardly forget. Pico Caroni and his team at the Friedrich Miescher Institute for Biomedical Research in Basel could now show that networks of specific cells in the brain regions relevant for each particular type of learning, switch first to a "learning state" and then to a "learnt state", and how the environment and experience modulate these processes. In a study published today in the renowned scientific journal Nature, they could show that so called basked cells, inhibitory neurons assembled in a network to modulate the function of excitatory neurons in brain regions such as the hippocampus, switch between three states during a learning experience. From a neutral state, many basket cells de-differentiate as the learning experience starts. This facilitates local formation and remodeling of new connections, new synapses; the network is plastic and conducive to learning and memory of new relationships potentially important to master the task at hand. As soon as the task has been successfully learned, this initial switch is reversed, and many basket cells switch to a highly differentiated state. The local network loses its ability to form new synapses, but at the same time enhances the function of strong synapses involved in the newly learned skill; the network loses its plasticity, but consolidates its gains. Learning is complete, the ability to perform the task stable. Finally, the cells revert to the neutral state again, ready for the next task to learn. Caroni and his team further showed that the learning environment influences the state of the basket cells. In an environment rich in stimuli and diverse experiences, a large fraction of the basket cells are in a low differentiation state, ready for learning. Importantly, the scientists show that they can pharmacogenetically switch the different basket cells, thereby inducing the predicted outcomes in the ability to learn. Inhibition of basket cells decreased their differentiation and increased the ability to learn, whereas activation of basket cells increased their differentiation state and reduced learning and memory skills. These findings are ground-breaking in several ways. First, for a long time the scientific community believed that plasticity of neuronal connections in brain regions such as the hippocampus is permanently reduced in the adult. Caroni and his team now show that the same cells that ease learning and plasticity of neuronal connections in the young are involved in the same processes at an older age. Second, the scientists could show how the environment and experience influence plasticity and learning. "In dementia and Alzheimer's disease, stimulating activities have been proposed as therapeutic approaches to slow down the disease," comments Caroni, "our results provide now a scientific rational for such a therapeutic tactic. Being able to reversibly induce basket cell network states that modulate learning and memory formation might be harnessed for therapeutic strategies in these 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 A substantial area of the new almond plantations in Spain is under irrigation but because of water scarcity, deficit irrigation (DI) strategies have to be adopted. This study assesses the long-term sustainability of different DI strategies over 6 years (2014–2019) on a mature almond [ Prunus dulcis (Mill) D.A. Web] orchard in southern Spain. Four irrigation treatments were imposed: full irrigation (FI); two moderate DI, (SDI M ) and (RDI M ), where applied irrigation was 65% of FI but differed in the seasonal water distribution; and a severe DI, where applied irrigation was 35% of FI. The results emphasise the key role of soil water storage and the importance to consider crop evapotranspiration (ET C ) as the principal driving variable of productivity instead of irrigation in many situations. Soil water partially buffered the irrigation reductions imposed, leading to no significant differences in yield performance between the two different moderate DI treatments. The water production functions (yield versus applied irrigation and yield versus ET C ) did not show statistical differences when comparing the first (2014–2016) against that of the second triennia (2017–2019), suggesting the non-existence of exhaustion or adaptation phenomena that could jeopardize the longer term sustainability of DI strategies. Average annual ET C ranged from 580 mm in the RDI S treatment to a maximum value of 1300 mm, yielding between 1370 and 2750 kg ha −1 of nuts, and showed that water deficits caused yield losses ranging from 0.05 to 0.35 kg m −3 of irrigation water depending on the irrigation level. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Almond [ Prunus dulcis (Mill) D.A. Web] is the most important tree nut species with a worldwide kernel production exceeding 1,240,400 t in the world (International Nut and Dried Fruit Council 2018 ). Spain has the largest almond cultivated area with more than 700,000 ha (MAPA 2018 ) but is third in terms of production, well behind USA and Australia (International Nut and Dried Fruit Council 2018 ). This is explained by the fact that most of the almond acreage in Spain is made up of traditional rainfed orchards grown in marginal agricultural areas, where the trees are sparsely planted and small (orchards with under 15–25% ground cover) and low-yielding (kernel yields below 200 kg ha −1 ). By contrast, the intensive almond orchards typical of California are abundantly irrigated, have ground canopy cover (usually > 60%) and yield over 2000 kg ha −1 (Almond Board of California 2019 ). However, the picture is rapidly changing in Spain in the last years, as high international prices and other factors are promoting plantation of new intensive orchards under irrigation, which have reached more than 110 000 ha in 2018 (MAPA 2018 ). The annual irrigation requirements of intensive mature almond orchards in California can exceed 1300 mm (Goldhamer and Fereres 2017 ). Spanish intensive orchards can also achieve similar levels of consumptive water use (López-López et al. 2018a ). However, irrigation water restrictions are common in the majority of the almond growing areas in Spain, where periodic droughts force the Water Authorities to supply irrigations quotas below the crop water requirements of fully matured orchards. This anticipated levels of irrigation supply varied depending on the river basin conditions, but common irrigation water supplies range between 250 and 600 mm. The effects of deficit irrigation on tree growth and yield have been the focus of several studies. Some of them have identified the rapid nut growth in spring and the post-harvest period as the most critical stages for yield determination when water shortage causes nut shedding and affects flower differentiation, respectively (Fereres et al. 1981 ; Girona et al. 1997 ; Esparza et al. 2001 ). On the contrary, kernel filling is recognised as a less sensitive phenological phase, thus deficit irrigation (DI) strategies are usually applied during that stage, even though nut size and weight can be reduced (Goldhamer and Viveros 2000 ; Girona et al. 2005 ; Egea et al. 2010 ). Water production functions define the relationships between crop productivity and water at any supply level (i.e. precipitation, irrigation, crop evapotranspiration (ET C ) or transpiration) and appeared first in field crops (Stewart and Hagan 1973 ). Developing yield-ET C production functions in tree crops is particularly challenging both because it requires long-term experiments in order to account for the effects of alternate bearing and due to the difficulties in measuring ET C in orchards. However, it is a powerful tool that allows the generalisation of the relationship between crop yield and evapotranspiration for orchards differing in canopy cover, locations and years. Long-term exposure to DI might modify the shape of the yield-ET C production functions. On the one hand, water stress-induced reduction in tree photosynthesis can have cumulative effects leading to a depletion of carbohydrate reserves limiting yield potential. This idea was suggested by Girona et al. ( 2005 ), who observed a more detrimental almond yield response to water stress in the last biennium of a four-year experiment. Also, a continued exposure to water stress over several years could ultimately affect vegetative growth, spurs positions renewal and spurs rate mortality (Egea et al. 2010 ; Lampinen et al. 2011 , 2018 ; Tombesi et al. 2017 ). This would result in a decline of nut load over time as might have occurred in the 3 year DI experiment by Esparza et al. ( 2001 ). On the other hand, trees might exhibit positive adaptative responses to recurrent water stress through osmotic adjustment and changes in the elasticity of tissues (Kozlowski and Pallardy 2002 ). In addition, trees under water stress can change root/shoot allocation ratios, promoting additional soil exploration and an increase in water extraction from the soil thus improving tree water status (Hsiao 1973 ; Sharp and Davies 1979 ; Bradford and Hsiao 1982 ; Kozlowski and Pallardy 2002 ; Rahman and Hasegawa 2012 ). In the light of", "role": "user" }, { "content": "Spain boasts the largest cultivated area of almond trees in the world, with more than 700,000 ha (MAPA, 2018), but ranks third in terms of production. How can this be? Actually it's easy to explain: most of the country's cultivated area of almond trees is comprised of traditional rainfed orchards and located in marginal areas featuring a low density of trees per hectare. Over the last decade, however, the nut's surging prices have given rise to intensive almond tree plantations characterized by a high density of trees per hectare and the employment of fertilization and irrigation, yielding endless rows of white when the trees are in bloom. Knowing what the future of these plantations will be like in a country where the availability of water for irrigation is limited is one of the main tasks tackled by agronomic research. The recent establishment of this type of plantation makes it difficult to conduct long-term studies on them. The creation of these new plantations requires significant investments that are not recovered for several years, so studying the productive sustainability of the crop over the life of the plantation is of the utmost importance. One of the questions to be answered in this context is whether the widespread practice of deficit irrigation (i.e. irrigation below the crop's needs) can lead to a drop in productivity in the long term. In order to answer this question, a team formed by researcher Álvaro López Bernal and Professor Elías Fereres, with the María de Maeztu Unit of Excellence—Department of Agronomy at the UCO (DAUCO), together with researchers from IFAPA and the CSIC's Institute of Sustainable Agriculture (IAS—CSIC), have analyzed the response of almond production under different deficit irrigation strategies between 2014 and 2019. To analyze the response to irrigation, crop production functions were constructedrepresentinghow almond yield varies in response tothe amount of water used seasonally in the form of applied irrigation, plot evapotranspiration(plot evaporation plus transpiration from the leaves of the plant itself) and tree transpiration. The production functions of this trial were obtained based onfour irrigation treatments: a control treatment, in which total irrigation does not limit crop evapotranspiration; two moderate deficit treatments,applying 65% of the control irrigation; and a severe deficit irrigation treatment, at 35%. Comparing the data obtained for the initial (2014-2016) and final (2017-2019) three-year periods, it was shown that the production functions were practically identical. This result suggests that, based on the conditions and duration of the trial, \"the deficit irrigation treatments implemented make it possible to maintain sustained production over time, without a gradual drop in production,\" says López Bernal. Therefore, the deficit irrigated trees in this study did not exhibit signs of reserve depletion or a reduction in the renewal capacity of the mixed bunches and May clusters yieldingflowers and fruit. Although the difference in production between the fully irrigated treatment and the more severe deficit irrigation was significant (2,660 vs. 1,430 kg of almond kernels per year), thestudy suggests that the productive capacity of the trees remained stable over the six years of the experiment even for those subjected to severe deficit irrigation. It is important to bear in mind that the grower's water supply in Spain is more similar to that of deficit irrigation treatments than to any of the others, hence the importance of knowing what happens to production under these water conditions. It should be noted that this study sheds light on the effects of this practice over a longer period than those that had been analyzed to date. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract A substantial area of the new almond plantations in Spain is under irrigation but because of water scarcity, deficit irrigation (DI) strategies have to be adopted. This study assesses the long-term sustainability of different DI strategies over 6 years (2014–2019) on a mature almond [ Prunus dulcis (Mill) D.A. Web] orchard in southern Spain. Four irrigation treatments were imposed: full irrigation (FI); two moderate DI, (SDI M ) and (RDI M ), where applied irrigation was 65% of FI but differed in the seasonal water distribution; and a severe DI, where applied irrigation was 35% of FI. The results emphasise the key role of soil water storage and the importance to consider crop evapotranspiration (ET C ) as the principal driving variable of productivity instead of irrigation in many situations. Soil water partially buffered the irrigation reductions imposed, leading to no significant differences in yield performance between the two different moderate DI treatments. The water production functions (yield versus applied irrigation and yield versus ET C ) did not show statistical differences when comparing the first (2014–2016) against that of the second triennia (2017–2019), suggesting the non-existence of exhaustion or adaptation phenomena that could jeopardize the longer term sustainability of DI strategies. Average annual ET C ranged from 580 mm in the RDI S treatment to a maximum value of 1300 mm, yielding between 1370 and 2750 kg ha −1 of nuts, and showed that water deficits caused yield losses ranging from 0.05 to 0.35 kg m −3 of irrigation water depending on the irrigation level. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Almond [ Prunus dulcis (Mill) D.A. Web] is the most important tree nut species with a worldwide kernel production exceeding 1,240,400 t in the world (International Nut and Dried Fruit Council 2018 ). Spain has the largest almond cultivated area with more than 700,000 ha (MAPA 2018 ) but is third in terms of production, well behind USA and Australia (International Nut and Dried Fruit Council 2018 ). This is explained by the fact that most of the almond acreage in Spain is made up of traditional rainfed orchards grown in marginal agricultural areas, where the trees are sparsely planted and small (orchards with under 15–25% ground cover) and low-yielding (kernel yields below 200 kg ha −1 ). By contrast, the intensive almond orchards typical of California are abundantly irrigated, have ground canopy cover (usually > 60%) and yield over 2000 kg ha −1 (Almond Board of California 2019 ). However, the picture is rapidly changing in Spain in the last years, as high international prices and other factors are promoting plantation of new intensive orchards under irrigation, which have reached more than 110 000 ha in 2018 (MAPA 2018 ). The annual irrigation requirements of intensive mature almond orchards in California can exceed 1300 mm (Goldhamer and Fereres 2017 ). Spanish intensive orchards can also achieve similar levels of consumptive water use (López-López et al. 2018a ). However, irrigation water restrictions are common in the majority of the almond growing areas in Spain, where periodic droughts force the Water Authorities to supply irrigations quotas below the crop water requirements of fully matured orchards. This anticipated levels of irrigation supply varied depending on the river basin conditions, but common irrigation water supplies range between 250 and 600 mm. The effects of deficit irrigation on tree growth and yield have been the focus of several studies. Some of them have identified the rapid nut growth in spring and the post-harvest period as the most critical stages for yield determination when water shortage causes nut shedding and affects flower differentiation, respectively (Fereres et al. 1981 ; Girona et al. 1997 ; Esparza et al. 2001 ). On the contrary, kernel filling is recognised as a less sensitive phenological phase, thus deficit irrigation (DI) strategies are usually applied during that stage, even though nut size and weight can be reduced (Goldhamer and Viveros 2000 ; Girona et al. 2005 ; Egea et al. 2010 ). Water production functions define the relationships between crop productivity and water at any supply level (i.e. precipitation, irrigation, crop evapotranspiration (ET C ) or transpiration) and appeared first in field crops (Stewart and Hagan 1973 ). Developing yield-ET C production functions in tree crops is particularly challenging both because it requires long-term experiments in order to account for the effects of alternate bearing and due to the difficulties in measuring ET C in orchards. However, it is a powerful tool that allows the generalisation of the relationship between crop yield and evapotranspiration for orchards differing in canopy cover, locations and years. Long-term exposure to DI might modify the shape of the yield-ET C production functions. On the one hand, water stress-induced reduction in tree photosynthesis can have cumulative effects leading to a depletion of carbohydrate reserves limiting yield potential. This idea was suggested by Girona et al. ( 2005 ), who observed a more detrimental almond yield response to water stress in the last biennium of a four-year experiment. Also, a continued exposure to water stress over several years could ultimately affect vegetative growth, spurs positions renewal and spurs rate mortality (Egea et al. 2010 ; Lampinen et al. 2011 , 2018 ; Tombesi et al. 2017 ). This would result in a decline of nut load over time as might have occurred in the 3 year DI experiment by Esparza et al. ( 2001 ). On the other hand, trees might exhibit positive adaptative responses to recurrent water stress through osmotic adjustment and changes in the elasticity of tissues (Kozlowski and Pallardy 2002 ). In addition, trees under water stress can change root/shoot allocation ratios, promoting additional soil exploration and an increase in water extraction from the soil thus improving tree water status (Hsiao 1973 ; Sharp and Davies 1979 ; Bradford and Hsiao 1982 ; Kozlowski and Pallardy 2002 ; Rahman and Hasegawa 2012 ). In the light of<|im_end|> <|im_start|>assistant Spain boasts the largest cultivated area of almond trees in the world, with more than 700,000 ha (MAPA, 2018), but ranks third in terms of production. How can this be? Actually it's easy to explain: most of the country's cultivated area of almond trees is comprised of traditional rainfed orchards and located in marginal areas featuring a low density of trees per hectare. Over the last decade, however, the nut's surging prices have given rise to intensive almond tree plantations characterized by a high density of trees per hectare and the employment of fertilization and irrigation, yielding endless rows of white when the trees are in bloom. Knowing what the future of these plantations will be like in a country where the availability of water for irrigation is limited is one of the main tasks tackled by agronomic research. The recent establishment of this type of plantation makes it difficult to conduct long-term studies on them. The creation of these new plantations requires significant investments that are not recovered for several years, so studying the productive sustainability of the crop over the life of the plantation is of the utmost importance. One of the questions to be answered in this context is whether the widespread practice of deficit irrigation (i.e. irrigation below the crop's needs) can lead to a drop in productivity in the long term. In order to answer this question, a team formed by researcher Álvaro López Bernal and Professor Elías Fereres, with the María de Maeztu Unit of Excellence—Department of Agronomy at the UCO (DAUCO), together with researchers from IFAPA and the CSIC's Institute of Sustainable Agriculture (IAS—CSIC), have analyzed the response of almond production under different deficit irrigation strategies between 2014 and 2019. To analyze the response to irrigation, crop production functions were constructedrepresentinghow almond yield varies in response tothe amount of water used seasonally in the form of applied irrigation, plot evapotranspiration(plot evaporation plus transpiration from the leaves of the plant itself) and tree transpiration. The production functions of this trial were obtained based onfour irrigation treatments: a control treatment, in which total irrigation does not limit crop evapotranspiration; two moderate deficit treatments,applying 65% of the control irrigation; and a severe deficit irrigation treatment, at 35%. Comparing the data obtained for the initial (2014-2016) and final (2017-2019) three-year periods, it was shown that the production functions were practically identical. This result suggests that, based on the conditions and duration of the trial, "the deficit irrigation treatments implemented make it possible to maintain sustained production over time, without a gradual drop in production," says López Bernal. Therefore, the deficit irrigated trees in this study did not exhibit signs of reserve depletion or a reduction in the renewal capacity of the mixed bunches and May clusters yieldingflowers and fruit. Although the difference in production between the fully irrigated treatment and the more severe deficit irrigation was significant (2,660 vs. 1,430 kg of almond kernels per year), thestudy suggests that the productive capacity of the trees remained stable over the six years of the experiment even for those subjected to severe deficit irrigation. It is important to bear in mind that the grower's water supply in Spain is more similar to that of deficit irrigation treatments than to any of the others, hence the importance of knowing what happens to production under these water conditions. It should be noted that this study sheds light on the effects of this practice over a longer period than those that had been analyzed to date. <|im_end|>

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2,123

[ { "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 Health systems have improved their abilities to identify, diagnose, treat and, increasingly, achieve viral suppression among people living with HIV (PLHIV). Despite these advances, a higher burden of multimorbidity and poorer health-related quality of life are reported by many PLHIV in comparison to people without HIV. Stigma and discrimination further exacerbate these poor outcomes. A global multidisciplinary group of HIV experts developed a consensus statement identifying key issues that health systems must address in order to move beyond the HIV field’s longtime emphasis on viral suppression to instead deliver integrated, person-centered healthcare for PLHIV throughout their lives. Introduction Following the introduction of highly effective antiretroviral therapy (ART) in 1996, the global scale-up of ART resulted in substantial declines in AIDS-related morbidity and mortality. By the end of 2019, 67% of the world’s estimated 38 million people living with HIV (PLHIV) had initiated ART, with 59% achieving viral suppression 1 . The life expectancy for PLHIV who are diagnosed early and are able to take continuous ART now approaches that of the general population 2 . Yet, despite viral suppression, PLHIV often report poor well-being and health-related quality of life (HRQoL) 3 , 4 , 5 , 6 , 7 . Factors negatively affecting the HRQoL of PLHIV include multimorbidity, drug and alcohol dependence, poverty, social isolation, difficulties disclosing HIV status, and persecution due to discriminatory laws and attitudes 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 . HIV-related stigma and discrimination negatively affect the HRQoL of PLHIV through multiple pathways, including social rejection, low self-esteem, and barriers to accessing health and support services 15 , 16 , 17 . These problems call for a broad health system response to the health-related needs of PLHIV. This includes the provision of integrated services for the prevention and management of communicable and non-communicable diseases, along with psychosocial and other support to address common psychological, social, and access challenges. Approaching the healthcare of PLHIV holistically, with decision-making driven by the person’s priorities rather than by a pathogen-specific paradigm, has the potential to yield better overall health outcomes 18 . Comprehensive, multidisciplinary healthcare for PLHIV requires an integrated, person-centered approach. This is likely to enhance HRQoL and contribute to improvements in population-level health across all domains, including infectious and noncommunicable diseases, mental health, and sexual and reproductive health. Achieving consistent, long-term virological suppression has become a key marker of successful HIV care 19 , 20 . Whilst access to effective ART for all remains essential, it should be seen as one aspect of a more multifaceted definition of success. The central goal should be integrated, person-centered healthcare that promotes the importance of HRQoL, recognizing the right of all people to enjoy “the highest attainable standard of physical and mental health” 21 . The World Health Organization (WHO) Global health sector strategy on HIV 2016–2021 briefly addresses the non-HIV-specific chronic care needs of PLHIV although without mention of HRQoL 22 . UNAIDS has included a general health target for PLHIV in its strategic guidance for the first time in 2021. It calls for 90% of PLHIV to “have access to integrated or linked services for HIV treatment and cardiovascular diseases, cervical cancer, mental health, diabetes diagnosis and treatment, education on healthy lifestyle counseling, smoking cessation advice and physical exercise” 23 . Recently, national and regional initiatives have promoted a more person-centered HIV care agenda 24 , 25 . This reflects the global movement towards person-centered care for illness in general. A body of evidence, including studies of PLHIV, exists to underpin the concept and practice, which is largely, but not exclusively, from high-income coutries 26 . Person-centered healthcare must value the social networks of patients, promote quality of life, and reform structurally to improve patients’ experience interacting with the healthcare system, including respect for and protection of human rights. However, there is not yet a common understanding of what the core values and practices of person-centered, holistic care for PLHIV should encompass, or how aspects of this issue may be context-specific. As a first step in achieving a common understanding, a multidisciplinary expert panel was convened to engage in a Delphi process to develop a consensus statement on the role of health systems in advancing the long-term well-being of PLHIV from a patient-centered perspective. The overarching purpose of the consensus statement is to guide global, regional, national, and subnational stakeholders in improving health system responses to achieve the best possible long-term health outcomes for PLHIV, including HRQoL outcomes. This article reports on the consensus development process and the agreed-upon consensus points. Methodology We employed a standard six-stage Delphi process 27 , 28 , including the definition of the problem and identification of experts (Stages 1 and 2, concurrently), three survey rounds (Stages 3–5), and actions based on the findings (i.e., endorsement of consensus statements and recommendations; Stage 6) 29 . (Further details of the methodology for this Delphi study are presented in the Supplementary Information.) The research team (J.V.L., K.S.) established an expert panel comprised of 44 individuals with expertise in the long-term health needs of PLHIV. The expert panel encompassed diverse disciplinary and geographical perspectives, as well as wide-ranging lived experiences (Table 1 , Table 2 ). Eleven expert panel members, including two people living openly with HIV, served as members of a steering committee that was tasked with providing conceptual guidance for this project (J.A., R.B.L.*, G.B., G.C., N.D.*, M.J.F., R.H., A.K.*, J.V.L.*, C.S., K.S.) (project co-chairs denoted by *). Three teams of steering committee members led scoping reviews of the literature on multimorbidity (G.B., A.K.), HRQoL (M.J.F., R.H.), and stigma and discrimination (J.A., G.C.) in order to identify priority issues to consider for the consensus statement. Specifically, the main findings from the respective reviews guided decision-making regarding potential consensus points. In particular, issues thought to be difficult to address or inadequately addressed (e.g., measurement of health-related quality of life, approaches to addressing stigma) were deemed important by the steering committee and expert panel members alike", "role": "user" }, { "content": "Since antiretroviral therapy (ART) for HIV was introduced in 1996, AIDS-related morbidity and mortality has declined significantly. People living with HIV are now expected to live nearly as long as people without HIV. Despite these advances, those living with HIV often report poor well-being and health-related quality of life. To guide stakeholders in improving health system responses to achieve the best possible long-term health outcomes for people living with HIV, a global multidisciplinary group of HIV experts led by CUNY SPH Senior Scholar Jeffrey Lazarus and including Distinguished Professor Denis Nash and Associate Professor Diana Romero developed a consensus statement identifying the key issues health systems must address in order to move beyond the longtime emphasis on viral suppression to instead deliver integrated, person-centered healthcare for people living with HIV throughout their lives. Following a rigorous, multi-stage Delphi process, the research team established a diverse panel of experts with expertise in the long-term health needs of people living with HIV. The panel reviewed the literature on multimorbidity and stigma and discrimination in order to identify priority issues to incorporate in the Delphi process to develop a consensus statement. \"An important strength of this consensus statement is that it was generated through this rigorous process, incorporating quantitative and qualitative data from experts from over 20 countries,\" says Dr. Romero. The panel found that multimorbidity, health-related quality of life, and stigma and discrimination continue to be major issues for people living with HIV, including those who have achieved viral suppression and in particular those from marginalized populations. \"These factors can lead to depression, social isolation and barriers in accessing health and support services,\" says Dr. Lazarus, who is also associate professor at the Barcelona Institute for Global Health. \"Many of these issues are not currently addressed in HIV monitoring, strategies or guideline.\" 'There is ample evidence that addressing things like mental health, stigma reduction, quality of life, and in many settings, housing and food security, will also improve HIV outcomes like adherence to antiretroviral medications and viral suppression,\" Dr. Nash says. \"The field of HIV implementation science can play a key role in assessing the impact of strategies integrated into HIV service delivery to mitigate these issues.\" The World Health Organization (WHO) and UNAIDS should create new HIV monitoring processes and guidelines, and Member States should commit to report on the indicators and implement policies to enhance health system performance and ensure the long-term well-being of the millions of people around the world living with HIV, the authors note. ", "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 Health systems have improved their abilities to identify, diagnose, treat and, increasingly, achieve viral suppression among people living with HIV (PLHIV). Despite these advances, a higher burden of multimorbidity and poorer health-related quality of life are reported by many PLHIV in comparison to people without HIV. Stigma and discrimination further exacerbate these poor outcomes. A global multidisciplinary group of HIV experts developed a consensus statement identifying key issues that health systems must address in order to move beyond the HIV field’s longtime emphasis on viral suppression to instead deliver integrated, person-centered healthcare for PLHIV throughout their lives. Introduction Following the introduction of highly effective antiretroviral therapy (ART) in 1996, the global scale-up of ART resulted in substantial declines in AIDS-related morbidity and mortality. By the end of 2019, 67% of the world’s estimated 38 million people living with HIV (PLHIV) had initiated ART, with 59% achieving viral suppression 1 . The life expectancy for PLHIV who are diagnosed early and are able to take continuous ART now approaches that of the general population 2 . Yet, despite viral suppression, PLHIV often report poor well-being and health-related quality of life (HRQoL) 3 , 4 , 5 , 6 , 7 . Factors negatively affecting the HRQoL of PLHIV include multimorbidity, drug and alcohol dependence, poverty, social isolation, difficulties disclosing HIV status, and persecution due to discriminatory laws and attitudes 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 . HIV-related stigma and discrimination negatively affect the HRQoL of PLHIV through multiple pathways, including social rejection, low self-esteem, and barriers to accessing health and support services 15 , 16 , 17 . These problems call for a broad health system response to the health-related needs of PLHIV. This includes the provision of integrated services for the prevention and management of communicable and non-communicable diseases, along with psychosocial and other support to address common psychological, social, and access challenges. Approaching the healthcare of PLHIV holistically, with decision-making driven by the person’s priorities rather than by a pathogen-specific paradigm, has the potential to yield better overall health outcomes 18 . Comprehensive, multidisciplinary healthcare for PLHIV requires an integrated, person-centered approach. This is likely to enhance HRQoL and contribute to improvements in population-level health across all domains, including infectious and noncommunicable diseases, mental health, and sexual and reproductive health. Achieving consistent, long-term virological suppression has become a key marker of successful HIV care 19 , 20 . Whilst access to effective ART for all remains essential, it should be seen as one aspect of a more multifaceted definition of success. The central goal should be integrated, person-centered healthcare that promotes the importance of HRQoL, recognizing the right of all people to enjoy “the highest attainable standard of physical and mental health” 21 . The World Health Organization (WHO) Global health sector strategy on HIV 2016–2021 briefly addresses the non-HIV-specific chronic care needs of PLHIV although without mention of HRQoL 22 . UNAIDS has included a general health target for PLHIV in its strategic guidance for the first time in 2021. It calls for 90% of PLHIV to “have access to integrated or linked services for HIV treatment and cardiovascular diseases, cervical cancer, mental health, diabetes diagnosis and treatment, education on healthy lifestyle counseling, smoking cessation advice and physical exercise” 23 . Recently, national and regional initiatives have promoted a more person-centered HIV care agenda 24 , 25 . This reflects the global movement towards person-centered care for illness in general. A body of evidence, including studies of PLHIV, exists to underpin the concept and practice, which is largely, but not exclusively, from high-income coutries 26 . Person-centered healthcare must value the social networks of patients, promote quality of life, and reform structurally to improve patients’ experience interacting with the healthcare system, including respect for and protection of human rights. However, there is not yet a common understanding of what the core values and practices of person-centered, holistic care for PLHIV should encompass, or how aspects of this issue may be context-specific. As a first step in achieving a common understanding, a multidisciplinary expert panel was convened to engage in a Delphi process to develop a consensus statement on the role of health systems in advancing the long-term well-being of PLHIV from a patient-centered perspective. The overarching purpose of the consensus statement is to guide global, regional, national, and subnational stakeholders in improving health system responses to achieve the best possible long-term health outcomes for PLHIV, including HRQoL outcomes. This article reports on the consensus development process and the agreed-upon consensus points. Methodology We employed a standard six-stage Delphi process 27 , 28 , including the definition of the problem and identification of experts (Stages 1 and 2, concurrently), three survey rounds (Stages 3–5), and actions based on the findings (i.e., endorsement of consensus statements and recommendations; Stage 6) 29 . (Further details of the methodology for this Delphi study are presented in the Supplementary Information.) The research team (J.V.L., K.S.) established an expert panel comprised of 44 individuals with expertise in the long-term health needs of PLHIV. The expert panel encompassed diverse disciplinary and geographical perspectives, as well as wide-ranging lived experiences (Table 1 , Table 2 ). Eleven expert panel members, including two people living openly with HIV, served as members of a steering committee that was tasked with providing conceptual guidance for this project (J.A., R.B.L.*, G.B., G.C., N.D.*, M.J.F., R.H., A.K.*, J.V.L.*, C.S., K.S.) (project co-chairs denoted by *). Three teams of steering committee members led scoping reviews of the literature on multimorbidity (G.B., A.K.), HRQoL (M.J.F., R.H.), and stigma and discrimination (J.A., G.C.) in order to identify priority issues to consider for the consensus statement. Specifically, the main findings from the respective reviews guided decision-making regarding potential consensus points. In particular, issues thought to be difficult to address or inadequately addressed (e.g., measurement of health-related quality of life, approaches to addressing stigma) were deemed important by the steering committee and expert panel members alike<|im_end|> <|im_start|>assistant Since antiretroviral therapy (ART) for HIV was introduced in 1996, AIDS-related morbidity and mortality has declined significantly. People living with HIV are now expected to live nearly as long as people without HIV. Despite these advances, those living with HIV often report poor well-being and health-related quality of life. To guide stakeholders in improving health system responses to achieve the best possible long-term health outcomes for people living with HIV, a global multidisciplinary group of HIV experts led by CUNY SPH Senior Scholar Jeffrey Lazarus and including Distinguished Professor Denis Nash and Associate Professor Diana Romero developed a consensus statement identifying the key issues health systems must address in order to move beyond the longtime emphasis on viral suppression to instead deliver integrated, person-centered healthcare for people living with HIV throughout their lives. Following a rigorous, multi-stage Delphi process, the research team established a diverse panel of experts with expertise in the long-term health needs of people living with HIV. The panel reviewed the literature on multimorbidity and stigma and discrimination in order to identify priority issues to incorporate in the Delphi process to develop a consensus statement. "An important strength of this consensus statement is that it was generated through this rigorous process, incorporating quantitative and qualitative data from experts from over 20 countries," says Dr. Romero. The panel found that multimorbidity, health-related quality of life, and stigma and discrimination continue to be major issues for people living with HIV, including those who have achieved viral suppression and in particular those from marginalized populations. "These factors can lead to depression, social isolation and barriers in accessing health and support services," says Dr. Lazarus, who is also associate professor at the Barcelona Institute for Global Health. "Many of these issues are not currently addressed in HIV monitoring, strategies or guideline." 'There is ample evidence that addressing things like mental health, stigma reduction, quality of life, and in many settings, housing and food security, will also improve HIV outcomes like adherence to antiretroviral medications and viral suppression," Dr. Nash says. "The field of HIV implementation science can play a key role in assessing the impact of strategies integrated into HIV service delivery to mitigate these issues." The World Health Organization (WHO) and UNAIDS should create new HIV monitoring processes and guidelines, and Member States should commit to report on the indicators and implement policies to enhance health system performance and ensure the long-term well-being of the millions of people around the world living with HIV, the authors note. <|im_end|>

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1,918

[ { "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 prevalent model for cataract formation in the eye lens posits that damaged crystallin proteins form light-scattering aggregates. The α-crystallins are thought to counteract this process as chaperones by sequestering misfolded crystallin proteins. In this scenario, chaperone pool depletion would result in lens opacification. Here we analyze lenses from different mouse strains that develop early-onset cataract due to point mutations in α-, β-, or γ-crystallin proteins. We find that these mutant crystallins are unstable in vitro; in the lens, their levels are substantially reduced, and they do not accumulate in the water-insoluble fraction. Instead, all the other crystallin proteins, including the α-crystallins, are found to precipitate. The changes in protein composition and spatial organization of the crystallins observed in the mutant lenses suggest that the imbalance in the lenticular proteome and altered crystallin interactions are the bases for cataract formation, rather than the aggregation propensity of the mutant crystallins. Main Cataract, the opacity of the eye lens, is the most frequent eye disorder in the human population 1 . Age-dependent modifications play a major role in cataract formation, with genetic and environmental factors decreasing the age of onset of cataract formation 2 , 3 , 4 . Mendelian mutations leading to congenital cataracts lead to an early onset of this disease. The eye lens is a unique tissue, as its proteins are not degraded over a lifetime. The oldest lens proteins are formed early during embryonic development 5 . Moreover, the protein content of the vertebrate lens is exceptionally high. It contains up to 450 milligrams per milliliter protein 3 , similar to the concentrations found in protein crystals 6 . About 90% of the lens proteins are members of the α-, β-, and γ-crystallin families 6 . In most mammals, these crystallin proteins are encoded by 16 genes, and numerous mutations have been identified in these isoforms that are causative for congenital cataracts 7 , 8 . Several processes leading to age-related cataracts have been discussed, including crystallin oxidation 9 , truncation 10 , and posttranslational modifications 11 , such as phosphorylation 12 and proteolysis 13 . As there is no general protein turnover in the eye lens, damaged proteins will accumulate during aging. In hereditary cataracts, the situation is thought to be aggravated by the aggregation of conformationally destabilized crystallin variants, including the formation of amyloid-like structures 14 , 15 that impair vision at an early age 16 . In the current model of cataractogenesis, the polydisperse α-crystallins (also referred to as αL-crystallin) are thought to act as molecular chaperones, preventing the formation of unspecific agglomerates by binding and sequestering non-native crystallin proteins into high molecular weight (HMW) particles 17 . The polydispersity of α-crystallins further blocks the formation of micro protein crystals, thus guaranteeing eye lens transparency 18 , 19 , 20 , 21 , 22 . As the capacity of α-crystallins to bind aggregation-prone proteins becomes limited 23 , saturation of the chaperone pool will result in the formation of large, light-scattering aggregates. However, some previously reported findings do not really fit this titration model. Day and Clayton showed that the mouse Cat Fr mutation (affecting the Mip ( Aqp0 ) gene) leads to congenital cataract 24 . The mutant lenses contained less protein than the wild type, and all crystallins were affected. At that time, no specific conclusions about the mechanism could be reached. For the Gja8 D47A mutation, affecting connexin50, the β- and γ-crystallins have been shown to be reduced in the lenses of mutant mice 25 . More recently, Posner et al found that in the zebrafish cloche mutant, the levels of mRNA of crystallin genes were changed 26 . The changes were linked to reduced eye and lens size, and cataract was likely to be caused by abnormal protein aggregation. Here, we test the titration model of cataractogenesis 17 , 23 using hereditary congenital cataract variants in mouse strains carrying point mutations in individual crystallin isoforms. Our analyses show that the mutated crystallin proteins are depleted in the eye lens and do not aggregate; however, there are changes in the protein composition and in the higher-order organization of crystallins, with aggregation of the other, non-mutated crystallins. These findings challenge existing models for cataract formation, including the presumed role of α-crystallins as general eye lens chaperones. Our observations indicate that an imbalance in the lenticular proteome is a major contributor to cataract formation, and all eye lens crystallins, including the α-crystallins, are components of the aggregates. Results Experimental strategy To study the effects of aging on lens protein homeostasis, we analyzed the protein composition of eye lenses from wild-type and three mutant mouse strains with early-onset hereditary cataract. The mutant mouse strains have point mutations that cover the three crystallin families and are established models for hereditary cataracts in humans 7 . The eye lenses of a mouse strain with a mutation in the major α-crystallin isoform ( Cryaa V124E/V124E ) is characterized by a progressive nuclear cataract and zonular opacity 27 . In the βA2-crystallin mutant ( Cryba2 S47P/S47P ), a cortical opacity is observed in younger animals, resulting in total cataract at the age of 6 months 28 . The γD-crystallin mutant mouse ( Crygd V76D/V76D ) exhibits a strong nuclear and milky cortical cataract at the age of 3 months 29 . The experimental procedure used for the analysis of the mouse eye lenses, as used in the field, is shown schematically in Fig. 1a 30 , 31 , 32 , 33 . For analysis of the entire proteome, the intact eye lenses were mechanically homogenized in the presence of a physiological buffer and separated into the water-soluble and water-insoluble fractions by means of centrifugation. The water-soluble fraction contained the β- and γ-crystallins, but also the αL-crystallin, which comprises the αA-crystallin and αB-crystallin isoforms at a 3:1 ratio, and HMW particles consisting of protein complexes larger than 700 kDa of the α-crystallins and other crystallins 34 . The water-insoluble fraction comprised a mixture of lens proteins not soluble in", "role": "user" }, { "content": "Cataracts are the most common eye ailment in humans. However, the exact processes leading to this condition are not fully understood. A team of researchers headed by the Technical University of Munich (TUM) has now discovered that the composition of the protein solution plays a decisive role. Their conclusions are contrary to prevailing opinion in the field. The cells in the lens consist of a highly concentrated protein solution that is normally clear. \"When the balance of the proteins in the lens is destroyed, they clump together and the lens becomes cloudy,\" says Prof. Johannes Buchner of the Chair of Biotechnology at TUM. This results in the condition known as cataracts. The clouding can have different causes. Because the proteins in the lens are formed in the embryo and are not replaced, damage can accumulate over the years, ultimately causing the lens to cloud over. That is why cataracts occur mainly in older people. But some individuals have a genetic predisposition to the eye condition, in which proteins in the lens mutate. In these cases, cataracts are present at birth or appear during childhood. Unstable proteins eliminated immediately The scientists studied strains of mice affected by hereditary cataracts. They worked with the research group surrounding Jochen Graw, an expert in eye lenses who until 2019 was a professor at the Institute of Development Genetics at Helmholtz Zentrum München. Until now, the prevailing view said that only the defective proteins in the eye were reacting with one another and forming clumps. But Buchner's team has now shown that, in the mice with \"genetic cataracts\", this was not the case. \"We discovered that the mutated, unstable proteins in the lens were not there,\" says Buchner. \"They are eliminated immediately.\" Instead the 'healthy' proteins clump together. \"Our model, based on these new insights, says that the balance between the various proteins, or their ratios to one another, is important. When one of these components is missing, the remaining ones interact and form clumps.\" Important step for cataract treatment Many studies have been carried out to understand the causes of cataracts. \"But never before has there been such a comprehensive investigation of the lenses in mice, comparing wild populations and mutants,\" says Buchner. The new insights are an important step in the search for new treatment methods for cataracts. The most common method is surgery, in which artificial lenses are implanted in the eye. \"If you understand exactly what is happening, you can also think about ways that might use medication to disrupt the bad interactions,\" says Buchner. \"But we have a long way to go—and first we need to show that the proposed model also applies to the lens in the human eye.\" ", "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 prevalent model for cataract formation in the eye lens posits that damaged crystallin proteins form light-scattering aggregates. The α-crystallins are thought to counteract this process as chaperones by sequestering misfolded crystallin proteins. In this scenario, chaperone pool depletion would result in lens opacification. Here we analyze lenses from different mouse strains that develop early-onset cataract due to point mutations in α-, β-, or γ-crystallin proteins. We find that these mutant crystallins are unstable in vitro; in the lens, their levels are substantially reduced, and they do not accumulate in the water-insoluble fraction. Instead, all the other crystallin proteins, including the α-crystallins, are found to precipitate. The changes in protein composition and spatial organization of the crystallins observed in the mutant lenses suggest that the imbalance in the lenticular proteome and altered crystallin interactions are the bases for cataract formation, rather than the aggregation propensity of the mutant crystallins. Main Cataract, the opacity of the eye lens, is the most frequent eye disorder in the human population 1 . Age-dependent modifications play a major role in cataract formation, with genetic and environmental factors decreasing the age of onset of cataract formation 2 , 3 , 4 . Mendelian mutations leading to congenital cataracts lead to an early onset of this disease. The eye lens is a unique tissue, as its proteins are not degraded over a lifetime. The oldest lens proteins are formed early during embryonic development 5 . Moreover, the protein content of the vertebrate lens is exceptionally high. It contains up to 450 milligrams per milliliter protein 3 , similar to the concentrations found in protein crystals 6 . About 90% of the lens proteins are members of the α-, β-, and γ-crystallin families 6 . In most mammals, these crystallin proteins are encoded by 16 genes, and numerous mutations have been identified in these isoforms that are causative for congenital cataracts 7 , 8 . Several processes leading to age-related cataracts have been discussed, including crystallin oxidation 9 , truncation 10 , and posttranslational modifications 11 , such as phosphorylation 12 and proteolysis 13 . As there is no general protein turnover in the eye lens, damaged proteins will accumulate during aging. In hereditary cataracts, the situation is thought to be aggravated by the aggregation of conformationally destabilized crystallin variants, including the formation of amyloid-like structures 14 , 15 that impair vision at an early age 16 . In the current model of cataractogenesis, the polydisperse α-crystallins (also referred to as αL-crystallin) are thought to act as molecular chaperones, preventing the formation of unspecific agglomerates by binding and sequestering non-native crystallin proteins into high molecular weight (HMW) particles 17 . The polydispersity of α-crystallins further blocks the formation of micro protein crystals, thus guaranteeing eye lens transparency 18 , 19 , 20 , 21 , 22 . As the capacity of α-crystallins to bind aggregation-prone proteins becomes limited 23 , saturation of the chaperone pool will result in the formation of large, light-scattering aggregates. However, some previously reported findings do not really fit this titration model. Day and Clayton showed that the mouse Cat Fr mutation (affecting the Mip ( Aqp0 ) gene) leads to congenital cataract 24 . The mutant lenses contained less protein than the wild type, and all crystallins were affected. At that time, no specific conclusions about the mechanism could be reached. For the Gja8 D47A mutation, affecting connexin50, the β- and γ-crystallins have been shown to be reduced in the lenses of mutant mice 25 . More recently, Posner et al found that in the zebrafish cloche mutant, the levels of mRNA of crystallin genes were changed 26 . The changes were linked to reduced eye and lens size, and cataract was likely to be caused by abnormal protein aggregation. Here, we test the titration model of cataractogenesis 17 , 23 using hereditary congenital cataract variants in mouse strains carrying point mutations in individual crystallin isoforms. Our analyses show that the mutated crystallin proteins are depleted in the eye lens and do not aggregate; however, there are changes in the protein composition and in the higher-order organization of crystallins, with aggregation of the other, non-mutated crystallins. These findings challenge existing models for cataract formation, including the presumed role of α-crystallins as general eye lens chaperones. Our observations indicate that an imbalance in the lenticular proteome is a major contributor to cataract formation, and all eye lens crystallins, including the α-crystallins, are components of the aggregates. Results Experimental strategy To study the effects of aging on lens protein homeostasis, we analyzed the protein composition of eye lenses from wild-type and three mutant mouse strains with early-onset hereditary cataract. The mutant mouse strains have point mutations that cover the three crystallin families and are established models for hereditary cataracts in humans 7 . The eye lenses of a mouse strain with a mutation in the major α-crystallin isoform ( Cryaa V124E/V124E ) is characterized by a progressive nuclear cataract and zonular opacity 27 . In the βA2-crystallin mutant ( Cryba2 S47P/S47P ), a cortical opacity is observed in younger animals, resulting in total cataract at the age of 6 months 28 . The γD-crystallin mutant mouse ( Crygd V76D/V76D ) exhibits a strong nuclear and milky cortical cataract at the age of 3 months 29 . The experimental procedure used for the analysis of the mouse eye lenses, as used in the field, is shown schematically in Fig. 1a 30 , 31 , 32 , 33 . For analysis of the entire proteome, the intact eye lenses were mechanically homogenized in the presence of a physiological buffer and separated into the water-soluble and water-insoluble fractions by means of centrifugation. The water-soluble fraction contained the β- and γ-crystallins, but also the αL-crystallin, which comprises the αA-crystallin and αB-crystallin isoforms at a 3:1 ratio, and HMW particles consisting of protein complexes larger than 700 kDa of the α-crystallins and other crystallins 34 . The water-insoluble fraction comprised a mixture of lens proteins not soluble in<|im_end|> <|im_start|>assistant Cataracts are the most common eye ailment in humans. However, the exact processes leading to this condition are not fully understood. A team of researchers headed by the Technical University of Munich (TUM) has now discovered that the composition of the protein solution plays a decisive role. Their conclusions are contrary to prevailing opinion in the field. The cells in the lens consist of a highly concentrated protein solution that is normally clear. "When the balance of the proteins in the lens is destroyed, they clump together and the lens becomes cloudy," says Prof. Johannes Buchner of the Chair of Biotechnology at TUM. This results in the condition known as cataracts. The clouding can have different causes. Because the proteins in the lens are formed in the embryo and are not replaced, damage can accumulate over the years, ultimately causing the lens to cloud over. That is why cataracts occur mainly in older people. But some individuals have a genetic predisposition to the eye condition, in which proteins in the lens mutate. In these cases, cataracts are present at birth or appear during childhood. Unstable proteins eliminated immediately The scientists studied strains of mice affected by hereditary cataracts. They worked with the research group surrounding Jochen Graw, an expert in eye lenses who until 2019 was a professor at the Institute of Development Genetics at Helmholtz Zentrum München. Until now, the prevailing view said that only the defective proteins in the eye were reacting with one another and forming clumps. But Buchner's team has now shown that, in the mice with "genetic cataracts", this was not the case. "We discovered that the mutated, unstable proteins in the lens were not there," says Buchner. "They are eliminated immediately." Instead the 'healthy' proteins clump together. "Our model, based on these new insights, says that the balance between the various proteins, or their ratios to one another, is important. When one of these components is missing, the remaining ones interact and form clumps." Important step for cataract treatment Many studies have been carried out to understand the causes of cataracts. "But never before has there been such a comprehensive investigation of the lenses in mice, comparing wild populations and mutants," says Buchner. The new insights are an important step in the search for new treatment methods for cataracts. The most common method is surgery, in which artificial lenses are implanted in the eye. "If you understand exactly what is happening, you can also think about ways that might use medication to disrupt the bad interactions," says Buchner. "But we have a long way to go—and first we need to show that the proposed model also applies to the lens in the human eye." <|im_end|>

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2,036

[ { "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 Black carbon (BC) is a recalcitrant form of organic carbon (OC) produced by landscape fires. BC is an important component of the global carbon cycle because, compared to unburned biogenic OC, it is selectively conserved in terrestrial and oceanic pools. Here we show that the dissolved BC (DBC) content of dissolved OC (DOC) is twice greater in major (sub)tropical and high-latitude rivers than in major temperate rivers, with further significant differences between biomes. We estimate that rivers export 18 ± 4 Tg DBC year −1 globally and that, including particulate BC fluxes, total riverine export amounts to 43 ± 15 Tg BC year −1 (12 ± 5% of the OC flux). While rivers export ~1% of the OC sequestered by terrestrial vegetation, our estimates suggest that 34 ± 26% of the BC produced by landscape fires has an oceanic fate. Biogeochemical models require modification to account for the unique dynamics of BC and to predict the response of recalcitrant OC export to changing environmental conditions. Introduction Globally, terrestrial net primary production (NPP) sequesters around 60 Pg C year −1 from the atmosphere to stocks of organic carbon (OC) in biomass 1 , 2 , 3 . The majority of this carbon returns to the atmosphere from the terrestrial biosphere over decadal timescales, through fire emissions, herbivory or by entering soils as dead organic matter and undergoing microbial decomposition 4 , 5 , 6 . Only around 1% of terrestrial NPP is exported to the global oceans by rivers (300–800 Tg C year −1 ) 7 , 8 , 9 . Some fractions of the exported OC are bio-labile and thus drive coastal and marine food webs, while other major fractions are biologically recalcitrant and have potential for long-term storage in oceanic pools 10 , 11 , 12 , 13 , 14 , 15 . Black carbon (BC) is a quantitatively significant by-product of incomplete combustion of terrestrial OC. Around 40–215 Tg BC year −1 are generated by the incomplete combustion of biomass during landscape fires, forming a major component of residual charcoal and ash deposits (see “Methods”) 16 . An additional 2–29 Tg BC year −1 are emitted as soot (aerosol) from landscape fires and fossil fuel combustion 17 , 18 . The BC produced by landscape fires has three potential fates. First, it can be mineralised through biotic or abiotic processes 19 , 20 , such as microbial decomposition or combustion during subsequent fires 21 , 22 . Second, it can reach deep soil stores where its decomposition is exceptionally limited 23 , 24 . Third, it can be exported to the global oceans as a fraction of riverine dissolved organic carbon (DOC) or particulate organic carbon (POC) 25 , 26 . BC is among the most recalcitrant forms of OC in the Earth System 27 , 28 . Its poly-condensed aromatic molecular structure renders it relatively inaccessible to microbial organisms 19 , 20 , 29 . Owing to its biological recalcitrance, BC accumulates in Earth’s major OC pools 27 , 28 , 30 , 31 , 32 . Despite the annual production of BC equating to <0.5% of OC production by the terrestrial biosphere (~60 Pg C year −1 ) 1 , 2 , 3 and marine organisms (~13 Pg C year −1 ) 2 , BC constitutes ~5–18% of global soil OC stocks 33 , ~2–5% of oceanic DOC stocks 34 , 35 and ~5–30% of the OC in ocean sediments 27 , 36 , 37 (Fig. 1 ). Estimates of the BC contribution to global oceanic DOC stocks do not differ substantially from estimates of the total terrigenous fraction of DOC (<5%) 14 . Similarly, estimates of the BC contribution to the global stock of OC in oceanic sediments do not differ substantially from estimates of the terrigenous fraction of the total OC in oceanic seciments (approximately one-third) 36 , 38 . Hence, a considerable fraction of the terrigenous OC stored in the global oceans is thought to have been altered by fire (Fig. 1 ). The residence time of oceanic BC stocks is on the order of millennia to tens of millennia 30 , 35 , 39 , 40 , likely an order of magnitude longer than soil BC stocks (centuries to millennia) 19 , 20 and multiple orders of magnitude longer than terrestrial OC (decades to centuries) 4 , 5 , 6 . Hence, the production of BC and its subsequent export to the global oceans significantly extends the residence time of terrigenous carbon in the Earth System. Fig. 1: Global dynamics of black carbon (BC) and organic carbon (OC). DOC dissolved organic carbon, DBC dissolved black carbon, POC particulate organic carbon, PBC particulate black carbon. The relative size of the stocks and fluxes of OC and BC in soils, sediments, dissolved organic matter and suspended particulates are indicated by the size of the circles (stocks) and triangles (fluxes). BC is selectively preserved across the land-to-ocean aquatic continuum and thus represents a large fraction of the terrigenous OC in ocean pools. Rivers are the primary source of oceanic BC, though small additional fluxes of aerosol BC (soot) to the ocean surface are not shown. The estimates for each stock and flux are provided in Supplementary Dataset along with references to source data. Full size image Riverine dissolved black carbon (DBC) is chiefly a by-product of the decomposition of soil BC stocks, which are maintained by landscape fires and by small aerosol fluxes to the land surface 41 , 42 (Fig. 1 ). Like OC more generally, the rate at which soil BC degrades is moderated by environmental factors, such as temperature, hydrology, soil characteristics (e.g. clay content, mineralogy and pH) and land use 33 , 42 , 43 , 44 , 45 . Nonetheless, the disproportionate effect of these factors on rates of soil BC decomposition relative to bulk soil OC decomposition has been shown to drive variation in the DBC content of riverine DOC at regional scales 42 , 45 . In", "role": "user" }, { "content": "The extent to which rivers transport burned carbon to oceans—where it can be stored for tens of millennia—is revealed in new research led by the University of East Anglia (UEA). The study, published today in Nature Communications, calculates how much burned carbon is being flushed out by rivers and locked up in the oceans. Oceans store a surprising amount of carbon from burned vegetation, for example as a result of wildfires and managed burning. The research team describe it as a natural—if unexpected—quirk of the Earth system. The international interdisciplinary team, including collaborators from the Universities of Exeter, Swansea, Zurich, Oldenburg and Florida International, studied the amount of dissolved carbon flowing through 78 rivers on every continent except Antarctica. Lead researcher Dr. Matthew Jones, of the Tyndall Centre for Climate Change Research at UEA, said: \"Fires leave behind carbon-rich materials, like charcoal and ash, which break down very slowly in soils. We care about this burned carbon because it is essentially 'locked out' of the atmosphere for the distant future—it breaks down to greenhouse gases extremely slowly in comparison to most unburned carbon. \"We know that this burned carbon takes about 10 times longer to break down in the oceans than on land. Rivers are the conveyor belts that shift carbon from the land to the oceans, so they determine how long it takes for burned carbon to break down. So, we set out to estimate how much burned carbon reaches the oceans via rivers.\" Based on a large dataset of 409 observations from 78 rivers around the world, the researchers analysed how the burned fraction of dissolved carbon in rivers varies at different latitudes and in different ecosystems. They then upscaled their findings to estimate that 18 million tonnes of dissolved burned carbon are transported annually by rivers. When combined with the burned carbon that is exported with sediments, the estimate rises to 43 million tonnes of burned carbon per year. Dr. Jones said: \"We found that a surprising amount—around 12% per cent—of all carbon flowing through rivers comes from burned vegetation. \"While fires emit two billion tonnes of carbon each year, they also leave behind around 250 million tonnes of carbon as burned residues, like charcoal and ash. Around half of the carbon in these residues is in the particularly long-lived form of 'black carbon', and we show that about one-third of all black carbon reaches the oceans.\" \"This is a good thing because that carbon gets locked up and stored for very long periods—it takes tens of millennia for black carbon to degrade to carbon dioxide in the oceans. By comparison, only about one per cent of carbon taken up by land plants ends up in the ocean. \"With wildfires anticipated to increase in the future because of climate change, we can expect more burned carbon to be flushed out by rivers and locked up in the oceans. \"It's a natural quirk of the Earth system—a moderating 'negative feedback' of the warming climate that could trap some extra carbon in a more fire-prone world.\" 'Fires prime terrestrial organic carbon for riverine export to the global oceans' is published in the journal Nature Communications on Wednesday, June 3, 2020. ", "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 Black carbon (BC) is a recalcitrant form of organic carbon (OC) produced by landscape fires. BC is an important component of the global carbon cycle because, compared to unburned biogenic OC, it is selectively conserved in terrestrial and oceanic pools. Here we show that the dissolved BC (DBC) content of dissolved OC (DOC) is twice greater in major (sub)tropical and high-latitude rivers than in major temperate rivers, with further significant differences between biomes. We estimate that rivers export 18 ± 4 Tg DBC year −1 globally and that, including particulate BC fluxes, total riverine export amounts to 43 ± 15 Tg BC year −1 (12 ± 5% of the OC flux). While rivers export ~1% of the OC sequestered by terrestrial vegetation, our estimates suggest that 34 ± 26% of the BC produced by landscape fires has an oceanic fate. Biogeochemical models require modification to account for the unique dynamics of BC and to predict the response of recalcitrant OC export to changing environmental conditions. Introduction Globally, terrestrial net primary production (NPP) sequesters around 60 Pg C year −1 from the atmosphere to stocks of organic carbon (OC) in biomass 1 , 2 , 3 . The majority of this carbon returns to the atmosphere from the terrestrial biosphere over decadal timescales, through fire emissions, herbivory or by entering soils as dead organic matter and undergoing microbial decomposition 4 , 5 , 6 . Only around 1% of terrestrial NPP is exported to the global oceans by rivers (300–800 Tg C year −1 ) 7 , 8 , 9 . Some fractions of the exported OC are bio-labile and thus drive coastal and marine food webs, while other major fractions are biologically recalcitrant and have potential for long-term storage in oceanic pools 10 , 11 , 12 , 13 , 14 , 15 . Black carbon (BC) is a quantitatively significant by-product of incomplete combustion of terrestrial OC. Around 40–215 Tg BC year −1 are generated by the incomplete combustion of biomass during landscape fires, forming a major component of residual charcoal and ash deposits (see “Methods”) 16 . An additional 2–29 Tg BC year −1 are emitted as soot (aerosol) from landscape fires and fossil fuel combustion 17 , 18 . The BC produced by landscape fires has three potential fates. First, it can be mineralised through biotic or abiotic processes 19 , 20 , such as microbial decomposition or combustion during subsequent fires 21 , 22 . Second, it can reach deep soil stores where its decomposition is exceptionally limited 23 , 24 . Third, it can be exported to the global oceans as a fraction of riverine dissolved organic carbon (DOC) or particulate organic carbon (POC) 25 , 26 . BC is among the most recalcitrant forms of OC in the Earth System 27 , 28 . Its poly-condensed aromatic molecular structure renders it relatively inaccessible to microbial organisms 19 , 20 , 29 . Owing to its biological recalcitrance, BC accumulates in Earth’s major OC pools 27 , 28 , 30 , 31 , 32 . Despite the annual production of BC equating to <0.5% of OC production by the terrestrial biosphere (~60 Pg C year −1 ) 1 , 2 , 3 and marine organisms (~13 Pg C year −1 ) 2 , BC constitutes ~5–18% of global soil OC stocks 33 , ~2–5% of oceanic DOC stocks 34 , 35 and ~5–30% of the OC in ocean sediments 27 , 36 , 37 (Fig. 1 ). Estimates of the BC contribution to global oceanic DOC stocks do not differ substantially from estimates of the total terrigenous fraction of DOC (<5%) 14 . Similarly, estimates of the BC contribution to the global stock of OC in oceanic sediments do not differ substantially from estimates of the terrigenous fraction of the total OC in oceanic seciments (approximately one-third) 36 , 38 . Hence, a considerable fraction of the terrigenous OC stored in the global oceans is thought to have been altered by fire (Fig. 1 ). The residence time of oceanic BC stocks is on the order of millennia to tens of millennia 30 , 35 , 39 , 40 , likely an order of magnitude longer than soil BC stocks (centuries to millennia) 19 , 20 and multiple orders of magnitude longer than terrestrial OC (decades to centuries) 4 , 5 , 6 . Hence, the production of BC and its subsequent export to the global oceans significantly extends the residence time of terrigenous carbon in the Earth System. Fig. 1: Global dynamics of black carbon (BC) and organic carbon (OC). DOC dissolved organic carbon, DBC dissolved black carbon, POC particulate organic carbon, PBC particulate black carbon. The relative size of the stocks and fluxes of OC and BC in soils, sediments, dissolved organic matter and suspended particulates are indicated by the size of the circles (stocks) and triangles (fluxes). BC is selectively preserved across the land-to-ocean aquatic continuum and thus represents a large fraction of the terrigenous OC in ocean pools. Rivers are the primary source of oceanic BC, though small additional fluxes of aerosol BC (soot) to the ocean surface are not shown. The estimates for each stock and flux are provided in Supplementary Dataset along with references to source data. Full size image Riverine dissolved black carbon (DBC) is chiefly a by-product of the decomposition of soil BC stocks, which are maintained by landscape fires and by small aerosol fluxes to the land surface 41 , 42 (Fig. 1 ). Like OC more generally, the rate at which soil BC degrades is moderated by environmental factors, such as temperature, hydrology, soil characteristics (e.g. clay content, mineralogy and pH) and land use 33 , 42 , 43 , 44 , 45 . Nonetheless, the disproportionate effect of these factors on rates of soil BC decomposition relative to bulk soil OC decomposition has been shown to drive variation in the DBC content of riverine DOC at regional scales 42 , 45 . In<|im_end|> <|im_start|>assistant The extent to which rivers transport burned carbon to oceans—where it can be stored for tens of millennia—is revealed in new research led by the University of East Anglia (UEA). The study, published today in Nature Communications, calculates how much burned carbon is being flushed out by rivers and locked up in the oceans. Oceans store a surprising amount of carbon from burned vegetation, for example as a result of wildfires and managed burning. The research team describe it as a natural—if unexpected—quirk of the Earth system. The international interdisciplinary team, including collaborators from the Universities of Exeter, Swansea, Zurich, Oldenburg and Florida International, studied the amount of dissolved carbon flowing through 78 rivers on every continent except Antarctica. Lead researcher Dr. Matthew Jones, of the Tyndall Centre for Climate Change Research at UEA, said: "Fires leave behind carbon-rich materials, like charcoal and ash, which break down very slowly in soils. We care about this burned carbon because it is essentially 'locked out' of the atmosphere for the distant future—it breaks down to greenhouse gases extremely slowly in comparison to most unburned carbon. "We know that this burned carbon takes about 10 times longer to break down in the oceans than on land. Rivers are the conveyor belts that shift carbon from the land to the oceans, so they determine how long it takes for burned carbon to break down. So, we set out to estimate how much burned carbon reaches the oceans via rivers." Based on a large dataset of 409 observations from 78 rivers around the world, the researchers analysed how the burned fraction of dissolved carbon in rivers varies at different latitudes and in different ecosystems. They then upscaled their findings to estimate that 18 million tonnes of dissolved burned carbon are transported annually by rivers. When combined with the burned carbon that is exported with sediments, the estimate rises to 43 million tonnes of burned carbon per year. Dr. Jones said: "We found that a surprising amount—around 12% per cent—of all carbon flowing through rivers comes from burned vegetation. "While fires emit two billion tonnes of carbon each year, they also leave behind around 250 million tonnes of carbon as burned residues, like charcoal and ash. Around half of the carbon in these residues is in the particularly long-lived form of 'black carbon', and we show that about one-third of all black carbon reaches the oceans." "This is a good thing because that carbon gets locked up and stored for very long periods—it takes tens of millennia for black carbon to degrade to carbon dioxide in the oceans. By comparison, only about one per cent of carbon taken up by land plants ends up in the ocean. "With wildfires anticipated to increase in the future because of climate change, we can expect more burned carbon to be flushed out by rivers and locked up in the oceans. "It's a natural quirk of the Earth system—a moderating 'negative feedback' of the warming climate that could trap some extra carbon in a more fire-prone world." 'Fires prime terrestrial organic carbon for riverine export to the global oceans' is published in the journal Nature Communications on Wednesday, June 3, 2020. <|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 Angle-closure glaucoma (ACG) is a subset of glaucoma affecting 16 million people 1 , 2 , 3 . Although 4 million people are bilaterally blind from ACG 4 , 5 , the causative molecular mechanisms of ACG remain to be defined. High intraocular pressure induces glaucoma in ACG. High intraocular pressure traditionally was suggested to result from the iris blocking or closing the angle of the eye, thereby limiting aqueous humor drainage. Eyes from individuals with ACG often have a modestly decreased axial length, shallow anterior chamber and relatively large lens, features that predispose to angle closure 6 . Here we show that genetic alteration of a previously unidentified serine protease (PRSS56) alters axial length and causes a mouse phenotype resembling ACG. Mutations affecting this protease also cause a severe decrease of axial length in individuals with posterior microphthalmia. Together, these data suggest that alterations of this serine protease may contribute to a spectrum of human ocular conditions including reduced ocular size and ACG. Main The genetic and molecular mechanisms of intraocular pressure (IOP) elevation in ACG are not understood and likely involve a variety of physiological disturbances 7 , 8 . Mechanistically, IOP elevation is now known to be more complicated than simple blockage of aqueous humor (AqH) drainage by the iris, and reduced ocular dimensions alone are not sufficient to elevate IOP 7 . To identify new genes and mechanisms that impact IOP elevation, we conducted an N -ethyl- N -nitrosourea (ENU) mutagenesis screen 9 (Online Methods). We identified mutant mice with elevated IOP but otherwise grossly normal eyes ( Fig. 1a ). We named the recessively inherited mutant allele that underlies this phenotype 'glaucoma relevant mutant 4' ( Grm4 ). The incidence of high IOP in homozygous Grm4 mutants increased with age (detected in ∼ 50% of mice at 3 months and ∼ 90% of mice at 12 months of age; Fig. 1b,c ), and the anterior chambers became enlarged in some eyes at around 3 months of age. A histological analysis showed that the angles were not occluded with abnormal tissue (synechia) and had a readily detectable trabecular meshwork and Schlemm's canal (two important drainage structures; Fig. 1d ). Despite this, compromised AqH drainage (outflow) contributes to the IOP elevation ( Fig. 1e ). After IOP elevation, Grm4 mutants developed glaucomatous neurodegeneration, which is characterized by retinal ganglion cell death and optic nerve atrophy ( Fig. 1f and Supplementary Fig. 1 ). Figure 1: Grm4 mutant mice have normal angle tissues and exhibit high IOP. ( a ) We subjected mice to slit-lamp examination by broad-beam illumination to assess ocular structures including the iris, pupil and lens. We compared mutant mice (Mut) to age-matched wild-type (WT) mice. Representative eyes of mice of the indicated ages are shown. We detected no obvious structural abnormalities in mutant eyes. ( b , c ) IOP distributions for wild-type and mutant mice. Mutant eyes had significantly higher IOP compared to wild-type at all ages ( t test P < 0.0001). In the box plots ( c ), the green line and surrounding diamonds represent the mean ± s.e.m. (total n ≥ 170 for each genotype, and total n ≥ 30 for each group). ( d ) Histological analysis of angles showing well-formed trabecular meshwork (TM) and Schlemm's canal (SC, arrowheads) drainage tissues. There was no abnormal tissue obstructing the angle recess (arrow). ( e ) Mean outflow facility ± s.d. of wild-type and mutant eyes. Total outflow (Ct) is significantly reduced in mutant mice (* P < 0.0001, t test, n = 6 for each genotype). ( f ) Histological assessment of optic nerve heads. Mutant but not wild-type eyes exhibit hallmarks of glaucomatous nerve damage, including optic nerve excavation (asterisk) and thinning of the nerve fiber layer with age (arrow heads). V, blood vessels. Scale bar, 50 μm. Full size image Although mutant eyes appeared grossly normal in size ( Fig. 2a,b ), measurement of enucleated eyes identified a variable reduction of axial length, with values that overlap with controls. On average, the axial length of a randomly selected set of adult mutant eyes was 4.4% shorter than that of wild-type littermate controls at 2 months of age (with a range of 0–10% shorter axial lengths; t test P = 0.015; Fig. 2c ). The lens diameter was not different between these groups ( t test P = 0.21; Fig. 2d ), suggesting that the lens occupies a greater proportion of the ocular volume in mutants. These differences in ocular size occur after birth, and there was no difference in axial length at postnatal day (P) 7, a 3.8% difference at P13 and a 5.1% difference at P20 ( Fig. 2e,f ). Many human eyes with ACG have a reduced axial length and increased lens-to-ocular volume 2 , 3 , 6 . Figure 2: Grm4 mutant eyes have short axial length. ( a ) Photographs showing no obvious difference in ocular size between wild-type and mutant mice. ( b ) Close evaluation of enucleated eyes indicates that mutant eyes with a largely B6 strain background (>99% B6; Online Methods) are slightly smaller than wild-type eyes. ( c ) The mutant eyes are about 4.4% shorter than wild-type eyes (* P = 0.015, t test). ( d ) The lens diameter of the wild-type and mutant eyes was the same ( P = 0.27, t test). ( e , f ) The differences in ocular size occured after postnatal day 7. The ocular axial length and equatorial diameter was significantly smaller at P13 and P20 ( P < 0.01, t test). All histograms are mean ± s.d. and n ≥ 6 for all groups. Scale bars in b , 1 mm. Full size image Because angle closure is dynamic and is affected by ocular anatomy and unknown physiologic factors, we next evaluated the angle and iris in vivo . Gonioscopy allowed viewing of the drainage structures in the angles of all wild-type mice. In contrast, the iris prevented us", "role": "user" }, { "content": "Jackson Laboratory researchers and their collaborators have reported their discovery of a gene implicated in an acute and severe form of glaucoma known as angle-closure glaucoma (ACG). The gene's activity points to previously unsuspected mechanisms involved in both ACG and infant eye development. Glaucoma is one of the most common eye diseases and a leading cause of blindness. An increase in fluid pressure in the eye (intraocular pressure or IOP) leads to damage to the optic nerve, causing loss of vision. Most people with the more familiar chronic (open-angle) glaucoma don't even know they have the disease until it's detected in an eye exam. The condition develops slowly and can usually be managed with eyedrops and laser surgery. But ACG can be another story: acute attacks of ACG are a medical emergency. Sudden, debilitating symptoms include severe eye pain, headache, blurred vision, nausea and vomiting, and without prompt intervention to reduce IOP, very rapid loss of vision can occur. Simon W.M. John, Ph.D., the Jackson Laboratory professor and Howard Hughes Medical Investigator who led the glaucoma research team, describes ACG as \"a particularly severe and debilitating subtype of glaucoma, which is very poorly understood at the molecular level.\" ACG, which affects about 16 million people worldwide, accounts for half of all glaucoma blindness. ACG patients typically have eyes that are slightly smaller than normal, with a lens that is large for the size of the eye, and an abnormally short axial (front-to-back) length of the eye. These features predispose to blockage or closing of the angle of the eye, which contains an important drain for ocular fluid. As a result, the fluid does not drain properly and can quickly build up, sharply raising IOP. However, notes study author Sai Nair, Ph.D., project head and associate research scientist in the John lab, \"It's now clear that the mechanisms of IOP elevation are more complicated than simple blockage by the iris, and must include other physiological disturbances.\" The research team identified a mouse strain that has anatomical features similar to those seen in patients with ACG, and that develops high IOP. Because this IOP elevation causes the optic nerve to degenerate, these mice represent an important and much needed mouse model for ACG. Further, studies in the mouse suggest that depending on genetic background, the mutated gene can cause variable reduction in axial length, ranging from modest to severe. In collaboration with Mounira Hmani-Aifa and colleagues at Université de Sfax in Tunisia, they found that mutation in the same gene can result in severe reduction in axial length in people with extreme hyperopia. In finding a genetic mutation in the mice that produces a previously unknown protein (one that acts as a protease to break down other proteins), the researchers make the first link between the protein's activity and ACG, as well as eye development in infants. The John research group also included Zain Ali, Alison Kearney, Danilo Macalinao, Ioan Cosma, Gareth Howell and Richard Smith. Funding was provided by the National Eye Institute, the Barbara and Joseph Cohen Foundation and the Tunisian Ministère de l'Enseignement Supérieur, de la Recherche Scientifique et de la Technologie. This is the third major paper on glaucoma to come out of the John lab since early March. In the Journal of Clinical Investigation, the researchers reported on their new analysis technique that detects early stages of glaucoma in mice, and on their success in blocking the disease by targeting some of the molecular events in those early stages. And a paper in Science demonstrated their findings that RNA granules—key players in messenger RNA (mRNA) processing—can affect eye development, leading to juvenile cataracts and glaucoma in humans and mice. ", "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 Angle-closure glaucoma (ACG) is a subset of glaucoma affecting 16 million people 1 , 2 , 3 . Although 4 million people are bilaterally blind from ACG 4 , 5 , the causative molecular mechanisms of ACG remain to be defined. High intraocular pressure induces glaucoma in ACG. High intraocular pressure traditionally was suggested to result from the iris blocking or closing the angle of the eye, thereby limiting aqueous humor drainage. Eyes from individuals with ACG often have a modestly decreased axial length, shallow anterior chamber and relatively large lens, features that predispose to angle closure 6 . Here we show that genetic alteration of a previously unidentified serine protease (PRSS56) alters axial length and causes a mouse phenotype resembling ACG. Mutations affecting this protease also cause a severe decrease of axial length in individuals with posterior microphthalmia. Together, these data suggest that alterations of this serine protease may contribute to a spectrum of human ocular conditions including reduced ocular size and ACG. Main The genetic and molecular mechanisms of intraocular pressure (IOP) elevation in ACG are not understood and likely involve a variety of physiological disturbances 7 , 8 . Mechanistically, IOP elevation is now known to be more complicated than simple blockage of aqueous humor (AqH) drainage by the iris, and reduced ocular dimensions alone are not sufficient to elevate IOP 7 . To identify new genes and mechanisms that impact IOP elevation, we conducted an N -ethyl- N -nitrosourea (ENU) mutagenesis screen 9 (Online Methods). We identified mutant mice with elevated IOP but otherwise grossly normal eyes ( Fig. 1a ). We named the recessively inherited mutant allele that underlies this phenotype 'glaucoma relevant mutant 4' ( Grm4 ). The incidence of high IOP in homozygous Grm4 mutants increased with age (detected in ∼ 50% of mice at 3 months and ∼ 90% of mice at 12 months of age; Fig. 1b,c ), and the anterior chambers became enlarged in some eyes at around 3 months of age. A histological analysis showed that the angles were not occluded with abnormal tissue (synechia) and had a readily detectable trabecular meshwork and Schlemm's canal (two important drainage structures; Fig. 1d ). Despite this, compromised AqH drainage (outflow) contributes to the IOP elevation ( Fig. 1e ). After IOP elevation, Grm4 mutants developed glaucomatous neurodegeneration, which is characterized by retinal ganglion cell death and optic nerve atrophy ( Fig. 1f and Supplementary Fig. 1 ). Figure 1: Grm4 mutant mice have normal angle tissues and exhibit high IOP. ( a ) We subjected mice to slit-lamp examination by broad-beam illumination to assess ocular structures including the iris, pupil and lens. We compared mutant mice (Mut) to age-matched wild-type (WT) mice. Representative eyes of mice of the indicated ages are shown. We detected no obvious structural abnormalities in mutant eyes. ( b , c ) IOP distributions for wild-type and mutant mice. Mutant eyes had significantly higher IOP compared to wild-type at all ages ( t test P < 0.0001). In the box plots ( c ), the green line and surrounding diamonds represent the mean ± s.e.m. (total n ≥ 170 for each genotype, and total n ≥ 30 for each group). ( d ) Histological analysis of angles showing well-formed trabecular meshwork (TM) and Schlemm's canal (SC, arrowheads) drainage tissues. There was no abnormal tissue obstructing the angle recess (arrow). ( e ) Mean outflow facility ± s.d. of wild-type and mutant eyes. Total outflow (Ct) is significantly reduced in mutant mice (* P < 0.0001, t test, n = 6 for each genotype). ( f ) Histological assessment of optic nerve heads. Mutant but not wild-type eyes exhibit hallmarks of glaucomatous nerve damage, including optic nerve excavation (asterisk) and thinning of the nerve fiber layer with age (arrow heads). V, blood vessels. Scale bar, 50 μm. Full size image Although mutant eyes appeared grossly normal in size ( Fig. 2a,b ), measurement of enucleated eyes identified a variable reduction of axial length, with values that overlap with controls. On average, the axial length of a randomly selected set of adult mutant eyes was 4.4% shorter than that of wild-type littermate controls at 2 months of age (with a range of 0–10% shorter axial lengths; t test P = 0.015; Fig. 2c ). The lens diameter was not different between these groups ( t test P = 0.21; Fig. 2d ), suggesting that the lens occupies a greater proportion of the ocular volume in mutants. These differences in ocular size occur after birth, and there was no difference in axial length at postnatal day (P) 7, a 3.8% difference at P13 and a 5.1% difference at P20 ( Fig. 2e,f ). Many human eyes with ACG have a reduced axial length and increased lens-to-ocular volume 2 , 3 , 6 . Figure 2: Grm4 mutant eyes have short axial length. ( a ) Photographs showing no obvious difference in ocular size between wild-type and mutant mice. ( b ) Close evaluation of enucleated eyes indicates that mutant eyes with a largely B6 strain background (>99% B6; Online Methods) are slightly smaller than wild-type eyes. ( c ) The mutant eyes are about 4.4% shorter than wild-type eyes (* P = 0.015, t test). ( d ) The lens diameter of the wild-type and mutant eyes was the same ( P = 0.27, t test). ( e , f ) The differences in ocular size occured after postnatal day 7. The ocular axial length and equatorial diameter was significantly smaller at P13 and P20 ( P < 0.01, t test). All histograms are mean ± s.d. and n ≥ 6 for all groups. Scale bars in b , 1 mm. Full size image Because angle closure is dynamic and is affected by ocular anatomy and unknown physiologic factors, we next evaluated the angle and iris in vivo . Gonioscopy allowed viewing of the drainage structures in the angles of all wild-type mice. In contrast, the iris prevented us<|im_end|> <|im_start|>assistant Jackson Laboratory researchers and their collaborators have reported their discovery of a gene implicated in an acute and severe form of glaucoma known as angle-closure glaucoma (ACG). The gene's activity points to previously unsuspected mechanisms involved in both ACG and infant eye development. Glaucoma is one of the most common eye diseases and a leading cause of blindness. An increase in fluid pressure in the eye (intraocular pressure or IOP) leads to damage to the optic nerve, causing loss of vision. Most people with the more familiar chronic (open-angle) glaucoma don't even know they have the disease until it's detected in an eye exam. The condition develops slowly and can usually be managed with eyedrops and laser surgery. But ACG can be another story: acute attacks of ACG are a medical emergency. Sudden, debilitating symptoms include severe eye pain, headache, blurred vision, nausea and vomiting, and without prompt intervention to reduce IOP, very rapid loss of vision can occur. Simon W.M. John, Ph.D., the Jackson Laboratory professor and Howard Hughes Medical Investigator who led the glaucoma research team, describes ACG as "a particularly severe and debilitating subtype of glaucoma, which is very poorly understood at the molecular level." ACG, which affects about 16 million people worldwide, accounts for half of all glaucoma blindness. ACG patients typically have eyes that are slightly smaller than normal, with a lens that is large for the size of the eye, and an abnormally short axial (front-to-back) length of the eye. These features predispose to blockage or closing of the angle of the eye, which contains an important drain for ocular fluid. As a result, the fluid does not drain properly and can quickly build up, sharply raising IOP. However, notes study author Sai Nair, Ph.D., project head and associate research scientist in the John lab, "It's now clear that the mechanisms of IOP elevation are more complicated than simple blockage by the iris, and must include other physiological disturbances." The research team identified a mouse strain that has anatomical features similar to those seen in patients with ACG, and that develops high IOP. Because this IOP elevation causes the optic nerve to degenerate, these mice represent an important and much needed mouse model for ACG. Further, studies in the mouse suggest that depending on genetic background, the mutated gene can cause variable reduction in axial length, ranging from modest to severe. In collaboration with Mounira Hmani-Aifa and colleagues at Université de Sfax in Tunisia, they found that mutation in the same gene can result in severe reduction in axial length in people with extreme hyperopia. In finding a genetic mutation in the mice that produces a previously unknown protein (one that acts as a protease to break down other proteins), the researchers make the first link between the protein's activity and ACG, as well as eye development in infants. The John research group also included Zain Ali, Alison Kearney, Danilo Macalinao, Ioan Cosma, Gareth Howell and Richard Smith. Funding was provided by the National Eye Institute, the Barbara and Joseph Cohen Foundation and the Tunisian Ministère de l'Enseignement Supérieur, de la Recherche Scientifique et de la Technologie. This is the third major paper on glaucoma to come out of the John lab since early March. In the Journal of Clinical Investigation, the researchers reported on their new analysis technique that detects early stages of glaucoma in mice, and on their success in blocking the disease by targeting some of the molecular events in those early stages. And a paper in Science demonstrated their findings that RNA granules—key players in messenger RNA (mRNA) processing—can affect eye development, leading to juvenile cataracts and glaucoma in humans and mice. <|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 Objective The gut microbiota has been suggested to play a role in autism spectrum disorder (ASD). We postulate that children with ASD harbour an altered developmental profile of the gut microbiota distinct from that of typically developing (TD) children. Here, we aimed to characterise compositional and functional alterations in gut microbiome in association with age in children with ASD and to identify novel faecal bacterial markers for predicting ASD. Design We performed deep metagenomic sequencing in faecal samples of 146 Chinese children (72 ASD and 74 TD children). We compared gut microbial composition and functions between children with ASD and TD children. Candidate bacteria markers were identified and validated by metagenomic analysis. Gut microbiota development in relation to chronological age was assessed using random forest model. Results ASD and chronological age had the most significant and largest impacts on children’s faecal microbiome while diet showed no correlation. Children with ASD had significant alterations in faecal microbiome composition compared with TD children characterised by increased bacterial richness (p=0.021) and altered microbiome composition (p<0.05). Five bacterial species were identified to distinguish gut microbes in ASD and TD children, with areas under the receiver operating curve (AUC) of 82.6% and 76.2% in the discovery cohort and validation cohort, respectively. Multiple neurotransmitter biosynthesis related pathways in the gut microbiome were depleted in children with ASD compared with TD children (p<0.05). Developing dynamics of growth-associated gut bacteria (age-discriminatory species) seen in TD children were lost in children with ASD across the early-life age spectrum. Conclusions Gut microbiome in Chinese children with ASD was altered in composition, ecological network and functionality compared with TD children. We identified novel bacterial markers for prediction of ASD and demonstrated persistent underdevelopment of the gut microbiota in children with ASD which lagged behind their respective age-matched peers. intestinal microbiology Data availability statement Data are available in a public, open access repository. (Raw sequence) data that support the findings of this study have been deposited in (NCBI) with the (PRJNA686821) accession codes [ ] googletag.cmd.push(function() { googletag.display(\"dfp-ad-mpu\"); }); Statistics from Altmetric.com See more details Picked up by 27 news outlets Blogged by 2 Tweeted by 148 On 5 Facebook pages Reddited by 4 104 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 intestinal microbiology Significance of this study What is already known on this subject? Alterations in faecal bacteriome have been reported in children with autism spectrum disorder (ASD), but causality is yet to be established in humans. The microbiota–gut–brain axis, the bidirectional communication pathway between gut bacteria and the central nervous system, has a profound effect on social behaviours. However, data on gut microbiome development during early age in children with ASD are lacking. What are the new findings? Gut microbiome composition was not associated with diet in this cohort. We identiﬁed five bacteria markers that differentiate children with ASD from typically developing (TD) children in a discovery set (AUC 82.6%) and validated the findings in an independent cohort (AUC 76.2%). Microbial functions relating to neurotransmitter biosynthesis are significantly decreased in children with ASD compared with TD children. We demonstrated for the first time persistent under-development of gut microbiome in children with ASD relative to age-matched and gender-matched TD children. How might it impact on clinical practice in the foreseeable future? Our study supports the potential role of non-invasive prediction of ASD based on faecal bacteria markers and age-related bacteria development profile. Future therapeutics targeting reconstitution of gut microbiota in early life and increasing abundance of neurotransmitter-synthesised bacteria such as Faecalibacterium should be explored for ASD. Introduction Autism spectrum disorder (ASD) is a group of neurodevelopmental conditions that begins in early life and is characterised by impaired social communication and interactions as well as stereotyped, repetitive behaviour. 1 The prevalence of ASD in children and adolescents is 0.36% in Asia 2 and 1.85% in western countries. 3 Over the past two decades, the incidence of ASD in China has increased from 2.80 per 10 000 in 2000 to 63 per 10 000 in 2015. 4 5 Genetic research has highlighted the importance of de novo mutations in ASD 6 but no single gene has been identified that substantially increases the risk of ASD. Apart from genetic factors, the gut microbiota has been suggested to play a role in ASD. The community of microorganisms in the gastrointestinal (GI) tract is known to influence brain physiology and social-behaviour via a diverse set of pathways, 7 8 including immune activation, production of microbial metabolites and peptides and production of various neurotransmitters and neuromodulators. 9 In early childhood during a period of behavioural and biological development, gut microbes are thought to be essential in development by assisting in energy metabolism and modulating the immune system. 10 Subramanian et al previously described an assembly of gut bacteria that matured with chronological age in healthy children and a comparatively ‘immature’ microbiota profile in malnourished children. 11 In addition to biological underdevelopment, it was also revealed that the development of gut microbiota has a close relationship with cognitive development. 12 Age-related change of bacteria alpha diversity was reported in ASD but developmental trajectory of gut microbiota in ASD has not been reported. 13 Microbiota maturity may provide a microbial measure of children development as a way of classifying health or disease states and provide new insight on disease occurrence, progress and treatment of disease. Given that the gut microbiome has been linked to brain function via the gut-brain axis, we hypothesise that an underdeveloped gut microbiota may be associated with ASD. Currently, diagnosing ASD can be challenging because there is no definitive medical test and diagnosis is based on physician assessment. Potential faecal bacteria biomarkers used to predict ASD can therefore facilitate early treatment", "role": "user" }, { "content": "Children with autism seem to have a distinctive and underdeveloped range and volume of gut bacteria (microbiome) that isn't related to their diet, suggests a small study published online in the journal Gut. They have significantly fewer bacteria linked to neurotransmitter activity and 5 species of bacteria that aren't typically found in the guts of children without the condition, suggesting that there may be a characteristic microbial profile for autism, which may pave the way for treatment early on, say the researchers. Apart from genetic factors, it has been suggested that the gut microbiome may have a part to play in autism spectrum disorders. And the evidence suggests that the pathway between gut bacteria and the central nervous system, referred to as the gut-brain axis, has a profound effect on social behaviours. Diagnosing autism spectrum disorder can be difficult, because there is no definitive medical test and diagnosis is based on physician assessment. The researchers therefore wanted to see if 3-6 year olds with autism might harbour a microbiome that differs significantly from that of typically developing children, which might be used to facilitate early treatment. They compared the range, volume, and associated functions of bacteria in the stool samples of 128 Chinese children, 64 of whom had autism spectrum disorder and 64 of whom didn't. The factors most strongly and independently associated with microbiome composition in the stool samples were age, autism, and weight (BMI). Diet wasn't an influential factor. The stool samples of children with autism displayed a greater variety of microbes than those matched for age and weight who didn't have the condition. Clostridium, Dialister and Coprobacillus were enriched in children with autism while Faecalibacterium was significantly decreased. Several Clostridium species enriched in children with autism closely interacted with each other and formed a connected group. Clostridia species have been linked with autism via the production of clostridial toxins which can damage the central nervous system, point out the researchers. And the gut microbiome composition in children with autism differed substantially from that of children without the condition, with five bacterial species largely accounting for the difference: Alistipes indistinctus; candidate division_TM7_ isolate_TM7c (single cell organism); Streptococcus cristatus; Eubacterium limosum; and Streptococcus oligofermentans. These differences were further confirmed in a separate group of 18 children, 8 with autism and 10 without. Importantly, bacteria associated with neurotransmitter activities were substantially reduced in children with autism. Some 26 age-related bacterial species were identified as proxies of typical development of the gut microbiome by age. But these associations were absent in children with autism, suggesting abnormal development of the gut microbiome during the early life of these children, say the researchers. This is a small study and the gut microbiome can vary according to geographical region. Nevertheless, the researchers write: \"Our study shows for the first time that the gut microbiota of children with [autism] is abnormally developed and lags that of age-matched peers. \"As development of microbial communities within the [gastrointestinal] tract during childhood represents a critical window of human growth and health, shifts in the gut microbiota during early life development may have important functional roles in the pathogenesis of [autism spectrum disorder] and thus warrants extensive investigation.\" And they conclude: \"Our study supports the potential role of non-invasive prediction of [autism spectrum disorder] based on faecal bacteria markers and age-related bacteria development profile. \"Future therapeutics targeting reconstitution of gut microbiota in early life and increasing abundance of neurotransmitter-synthesised bacteria such as Faecalibacterium should be explored for [autism spectrum disorder].\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Objective The gut microbiota has been suggested to play a role in autism spectrum disorder (ASD). We postulate that children with ASD harbour an altered developmental profile of the gut microbiota distinct from that of typically developing (TD) children. Here, we aimed to characterise compositional and functional alterations in gut microbiome in association with age in children with ASD and to identify novel faecal bacterial markers for predicting ASD. Design We performed deep metagenomic sequencing in faecal samples of 146 Chinese children (72 ASD and 74 TD children). We compared gut microbial composition and functions between children with ASD and TD children. Candidate bacteria markers were identified and validated by metagenomic analysis. Gut microbiota development in relation to chronological age was assessed using random forest model. Results ASD and chronological age had the most significant and largest impacts on children’s faecal microbiome while diet showed no correlation. Children with ASD had significant alterations in faecal microbiome composition compared with TD children characterised by increased bacterial richness (p=0.021) and altered microbiome composition (p<0.05). Five bacterial species were identified to distinguish gut microbes in ASD and TD children, with areas under the receiver operating curve (AUC) of 82.6% and 76.2% in the discovery cohort and validation cohort, respectively. Multiple neurotransmitter biosynthesis related pathways in the gut microbiome were depleted in children with ASD compared with TD children (p<0.05). Developing dynamics of growth-associated gut bacteria (age-discriminatory species) seen in TD children were lost in children with ASD across the early-life age spectrum. Conclusions Gut microbiome in Chinese children with ASD was altered in composition, ecological network and functionality compared with TD children. We identified novel bacterial markers for prediction of ASD and demonstrated persistent underdevelopment of the gut microbiota in children with ASD which lagged behind their respective age-matched peers. intestinal microbiology Data availability statement Data are available in a public, open access repository. (Raw sequence) data that support the findings of this study have been deposited in (NCBI) with the (PRJNA686821) accession codes [ ] googletag.cmd.push(function() { googletag.display("dfp-ad-mpu"); }); Statistics from Altmetric.com See more details Picked up by 27 news outlets Blogged by 2 Tweeted by 148 On 5 Facebook pages Reddited by 4 104 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 intestinal microbiology Significance of this study What is already known on this subject? Alterations in faecal bacteriome have been reported in children with autism spectrum disorder (ASD), but causality is yet to be established in humans. The microbiota–gut–brain axis, the bidirectional communication pathway between gut bacteria and the central nervous system, has a profound effect on social behaviours. However, data on gut microbiome development during early age in children with ASD are lacking. What are the new findings? Gut microbiome composition was not associated with diet in this cohort. We identiﬁed five bacteria markers that differentiate children with ASD from typically developing (TD) children in a discovery set (AUC 82.6%) and validated the findings in an independent cohort (AUC 76.2%). Microbial functions relating to neurotransmitter biosynthesis are significantly decreased in children with ASD compared with TD children. We demonstrated for the first time persistent under-development of gut microbiome in children with ASD relative to age-matched and gender-matched TD children. How might it impact on clinical practice in the foreseeable future? Our study supports the potential role of non-invasive prediction of ASD based on faecal bacteria markers and age-related bacteria development profile. Future therapeutics targeting reconstitution of gut microbiota in early life and increasing abundance of neurotransmitter-synthesised bacteria such as Faecalibacterium should be explored for ASD. Introduction Autism spectrum disorder (ASD) is a group of neurodevelopmental conditions that begins in early life and is characterised by impaired social communication and interactions as well as stereotyped, repetitive behaviour. 1 The prevalence of ASD in children and adolescents is 0.36% in Asia 2 and 1.85% in western countries. 3 Over the past two decades, the incidence of ASD in China has increased from 2.80 per 10 000 in 2000 to 63 per 10 000 in 2015. 4 5 Genetic research has highlighted the importance of de novo mutations in ASD 6 but no single gene has been identified that substantially increases the risk of ASD. Apart from genetic factors, the gut microbiota has been suggested to play a role in ASD. The community of microorganisms in the gastrointestinal (GI) tract is known to influence brain physiology and social-behaviour via a diverse set of pathways, 7 8 including immune activation, production of microbial metabolites and peptides and production of various neurotransmitters and neuromodulators. 9 In early childhood during a period of behavioural and biological development, gut microbes are thought to be essential in development by assisting in energy metabolism and modulating the immune system. 10 Subramanian et al previously described an assembly of gut bacteria that matured with chronological age in healthy children and a comparatively ‘immature’ microbiota profile in malnourished children. 11 In addition to biological underdevelopment, it was also revealed that the development of gut microbiota has a close relationship with cognitive development. 12 Age-related change of bacteria alpha diversity was reported in ASD but developmental trajectory of gut microbiota in ASD has not been reported. 13 Microbiota maturity may provide a microbial measure of children development as a way of classifying health or disease states and provide new insight on disease occurrence, progress and treatment of disease. Given that the gut microbiome has been linked to brain function via the gut-brain axis, we hypothesise that an underdeveloped gut microbiota may be associated with ASD. Currently, diagnosing ASD can be challenging because there is no definitive medical test and diagnosis is based on physician assessment. Potential faecal bacteria biomarkers used to predict ASD can therefore facilitate early treatment<|im_end|> <|im_start|>assistant Children with autism seem to have a distinctive and underdeveloped range and volume of gut bacteria (microbiome) that isn't related to their diet, suggests a small study published online in the journal Gut. They have significantly fewer bacteria linked to neurotransmitter activity and 5 species of bacteria that aren't typically found in the guts of children without the condition, suggesting that there may be a characteristic microbial profile for autism, which may pave the way for treatment early on, say the researchers. Apart from genetic factors, it has been suggested that the gut microbiome may have a part to play in autism spectrum disorders. And the evidence suggests that the pathway between gut bacteria and the central nervous system, referred to as the gut-brain axis, has a profound effect on social behaviours. Diagnosing autism spectrum disorder can be difficult, because there is no definitive medical test and diagnosis is based on physician assessment. The researchers therefore wanted to see if 3-6 year olds with autism might harbour a microbiome that differs significantly from that of typically developing children, which might be used to facilitate early treatment. They compared the range, volume, and associated functions of bacteria in the stool samples of 128 Chinese children, 64 of whom had autism spectrum disorder and 64 of whom didn't. The factors most strongly and independently associated with microbiome composition in the stool samples were age, autism, and weight (BMI). Diet wasn't an influential factor. The stool samples of children with autism displayed a greater variety of microbes than those matched for age and weight who didn't have the condition. Clostridium, Dialister and Coprobacillus were enriched in children with autism while Faecalibacterium was significantly decreased. Several Clostridium species enriched in children with autism closely interacted with each other and formed a connected group. Clostridia species have been linked with autism via the production of clostridial toxins which can damage the central nervous system, point out the researchers. And the gut microbiome composition in children with autism differed substantially from that of children without the condition, with five bacterial species largely accounting for the difference: Alistipes indistinctus; candidate division_TM7_ isolate_TM7c (single cell organism); Streptococcus cristatus; Eubacterium limosum; and Streptococcus oligofermentans. These differences were further confirmed in a separate group of 18 children, 8 with autism and 10 without. Importantly, bacteria associated with neurotransmitter activities were substantially reduced in children with autism. Some 26 age-related bacterial species were identified as proxies of typical development of the gut microbiome by age. But these associations were absent in children with autism, suggesting abnormal development of the gut microbiome during the early life of these children, say the researchers. This is a small study and the gut microbiome can vary according to geographical region. Nevertheless, the researchers write: "Our study shows for the first time that the gut microbiota of children with [autism] is abnormally developed and lags that of age-matched peers. "As development of microbial communities within the [gastrointestinal] tract during childhood represents a critical window of human growth and health, shifts in the gut microbiota during early life development may have important functional roles in the pathogenesis of [autism spectrum disorder] and thus warrants extensive investigation." And they conclude: "Our study supports the potential role of non-invasive prediction of [autism spectrum disorder] based on faecal bacteria markers and age-related bacteria development profile. "Future therapeutics targeting reconstitution of gut microbiota in early life and increasing abundance of neurotransmitter-synthesised bacteria such as Faecalibacterium should be explored for [autism spectrum disorder]." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Developmental nicotine exposure causes persistent changes in cortical neuron morphology and in behavior. We used microarray screening to identify master transcriptional or epigenetic regulators mediating these effects of nicotine and discovered increases in Ash2l mRNA, encoding a component of a histone methyltransferase complex. We therefore examined genome-wide changes in trimethylation of histone H3 on Lys4 (H3K4me3), a mark induced by the Ash2l complex associated with increased gene transcription. A large proportion of regulated promoter sites were involved in synapse maintenance. We found that Mef2c interacts with Ash2l and mediates changes in H3K4me3. Knockdown of Ash2l or Mef2c abolished nicotine-mediated alterations of dendritic complexity in vitro and in vivo , and attenuated nicotine-dependent changes in passive avoidance behavior. In contrast, overexpression mimicked nicotine-mediated alterations of neuronal structure and passive avoidance behavior. These studies identify Ash2l as a target induced by nicotinic stimulation that couples developmental nicotine exposure to changes in brain epigenetic marks, neuronal structure and behavior. Main High affinity nicotinic acetylcholine receptors (nAChRs) are involved in early brain development, nicotine-mediated alterations of neuronal structure, and persistent changes in behavior 1 , 2 . Developmental nicotine exposure induces structural and synaptic changes in the developing brain 3 , and these changes persist into later life 4 . Accordingly, developmental exposure to nicotine is associated with many deleterious effects, including deficits in learning and later development of psychiatric disorders 5 , 6 , 7 ; however, the molecular mechanisms underlying these effects of cholinergic signaling on early brain development are largely unknown. We used microarray screening to detect long-term changes in gene expression with the goal of identifying pleiotropic master transcriptional regulators responsible for persistent morphological alterations of cortical neurons. Among identified genes that could alter a transcriptional program, Ash2l , encoding a component of a histone methyltransferase complex, was upregulated by nicotine exposure during development. We therefore used next-generation sequencing to determine whether nicotine could alter histone methylation associated with promoter regions of ensembles of genes involved in neuronal structure. Developmental nicotine exposure enriched trimethylated H3K4 (H3K4me3) at promoter regions of multiple genes involved in development and maintenance of excitatory synapses, including the gene encoding the transcription factor Mef2c, which assembles with Ash2l in a histone methyltransferase complex. This study thus identifies Ash2l as a regulator of neuronal morphology during early brain development and reveals a new molecular mechanism underlying the long-term consequences of developmental nicotine exposure. Results Developmental nicotine treatment alters neuronal morphology Exposure to tobacco smoke during human development can alter cortical structure as measured by diffusion tensor imaging (DTI) 8 . Since nicotine can alter dendritic spine numbers and neuronal morphology 1 , we determined whether nicotine in tobacco smoke could underlie changes in cortical fractional anisotropy measured by DTI. Among regimens used to deliver nicotine during development 7 , drinking water administration results in detectable blood levels in the dam and the offspring and has minimal stressful effects 9 . We therefore exposed mice to saccharin or nicotine (200 μg/ml) from the time of conception through weaning, postnatal day (P) 21, and measured fractional anisotropy at 3 months of age. This regimen results in persistent neurochemical and behavioral changes in exposed pups, with no effects on maternal behavior 10 . Developmental nicotine exposure induced significant increases in fractional anisotropy in a number of cortical areas, largely in gray matter ( Fig. 1a,b ). To determine whether changes in gray matter such as spine density and dendritic arborization underlie the increased fractional anisotropy, we labeled neurons diolistically with DiI and performed Sholl analysis and spine counting in mice exposed to nicotine throughout pre- and postnatal development as in the DTI study, as well as in an additional group that was treated only from birth to weaning (postnatal exposure), a critical period for cortical development dependent on acetylcholine signaling 11 . Nicotine significantly increased spine density in both the pre- and postnatal nicotine treated group and in the postnatal-only nicotine treated group ( Fig. 1c ). There was a significant effect of nicotine treatment on dendritic complexity across rostral, medial and caudal regions of cortex ( Fig. 1d–f ) and across all cortical layers, as demonstrated by a significant nicotine treatment by dendritic complexity interaction in each cortical layer compared to the saccharin-treated group ( Fig. 1g–i ). These results are consistent with previous studies showing that nicotine can induce persistent changes in spine density 3 , 4 . Postnatal-only nicotine-treated mice also showed an increase in dendritic complexity across all cortical regions and layers ( Supplementary Fig. 1 ). Figure 1: Morphological changes in cortical neurons induced by developmental nicotine exposure. Voxel-based analysis of fractional anisotropy changes induced by nicotine treatment during development measured by DTI; diagram from the Paxinos atlas 43 identifies affected regions. Two-tailed t -tests of average fractional anisotropy values in nicotine (Nic) and saccharin (Sac) groups indicate a significant difference ( n = 5 brains per condition; t (23) = 3.31, P = 0.00306) in cortical regions investigated, including ( a ) somatosensory cortex and ( b ) sensory cortex; ** P < 0.01. ( c ) Nicotine significantly increased spine density in treated groups compared to controls as measured by two-tailed t -test (pre- and postnatal: Sac, n = 26 slices from 6 mice, Nic, n = 25 slices from 5 mice, t 49 = 5.151, P = 0.00000460; postnatal-only: Sac, n = 19 slices from 6 mice, Nic, n = 29 slices from 6 mice, t 46 = 4.96, P = 0.0000100; *** P < 0.001). ( d – i ) The number of intersections was assessed for the apical dendritic tree as measured by one-way ANOVA followed by LSD test. Scale bar, 12 μm. ( d ) Frontal cortical regions. F (1,113) = 9.02, P = 0.00329. The parietal ( e ) and occipital ( f ) regions of cortex showed a significantly higher number of intersections following nicotine exposure compared to the control group. ( e ) F (1,48) = 31.9; P = 0.00000085. ( f ) F (1,38)", "role": "user" }, { "content": "Early exposure to nicotine can trigger widespread genetic changes that affect formation of connections between brain cells long after birth, a new Yale-led study has found. The finding helps explains why maternal smoking has been linked to behavioral changes such as attention deficit and hyperactivity disorder, addiction and conduct disorder. Nicotine does this by affecting a master regulator of DNA packaging, which in turn influences activity of genes crucial to the formation and stabilization of synapses between brain cells, according to the study published online May 30 in the journal Nature Neuroscience. \"When this regulator is induced in mice, they pay attention to a stimulus they should ignore,'' said Marina Picciotto, the Charles B.G. Murphy Professor of Psychiatry, professor in the Child Study Center and the Departments of Neuroscience and Pharmacology, and senior author of the paper. An inability to focus is the hallmark of attention deficit hyperactivity disorder and other behavioral disorders, which have been linked to maternal smoking and exposure to second-hand smoke. However, scientists did not understand how early environmental exposure to smoking could create behavioral problems years later. Picciotto's lab found that mice exposed to nicotine during early development did indeed develop behavioral problems that mimic symptoms of attention deficit disorder in humans. They then did extensive genomic screening of mice exposed to nicotine and found higher levels of activity in a key regulator of histone methylation—a process that controls gene expression by changing the DNA wrapping around chromosomes. The researchers found that genes essential to the creation of brain synapses were heavily effected. Furthermore, the scientists found that these genetic changes were maintained even in adult mice. However, when researchers inhibited the master regulator of histone methylation, these adult mice were calmer and no longer reacted to a stimulus they should ignore. In a final test, they triggered expression of this regulator in mice never exposed to nicotine, and the mice exhibited behavior that mimicked attention deficit disorder. \"It is exciting to find a signal that could explain the long-lasting effects of nicotine on brain cell structure and behavior,\" Picciotto said. \"It was even more intriguing to find a regulator of gene expression that responds to a stimulus like nicotine and may change synapse and brain activity during development.\" ", "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 Developmental nicotine exposure causes persistent changes in cortical neuron morphology and in behavior. We used microarray screening to identify master transcriptional or epigenetic regulators mediating these effects of nicotine and discovered increases in Ash2l mRNA, encoding a component of a histone methyltransferase complex. We therefore examined genome-wide changes in trimethylation of histone H3 on Lys4 (H3K4me3), a mark induced by the Ash2l complex associated with increased gene transcription. A large proportion of regulated promoter sites were involved in synapse maintenance. We found that Mef2c interacts with Ash2l and mediates changes in H3K4me3. Knockdown of Ash2l or Mef2c abolished nicotine-mediated alterations of dendritic complexity in vitro and in vivo , and attenuated nicotine-dependent changes in passive avoidance behavior. In contrast, overexpression mimicked nicotine-mediated alterations of neuronal structure and passive avoidance behavior. These studies identify Ash2l as a target induced by nicotinic stimulation that couples developmental nicotine exposure to changes in brain epigenetic marks, neuronal structure and behavior. Main High affinity nicotinic acetylcholine receptors (nAChRs) are involved in early brain development, nicotine-mediated alterations of neuronal structure, and persistent changes in behavior 1 , 2 . Developmental nicotine exposure induces structural and synaptic changes in the developing brain 3 , and these changes persist into later life 4 . Accordingly, developmental exposure to nicotine is associated with many deleterious effects, including deficits in learning and later development of psychiatric disorders 5 , 6 , 7 ; however, the molecular mechanisms underlying these effects of cholinergic signaling on early brain development are largely unknown. We used microarray screening to detect long-term changes in gene expression with the goal of identifying pleiotropic master transcriptional regulators responsible for persistent morphological alterations of cortical neurons. Among identified genes that could alter a transcriptional program, Ash2l , encoding a component of a histone methyltransferase complex, was upregulated by nicotine exposure during development. We therefore used next-generation sequencing to determine whether nicotine could alter histone methylation associated with promoter regions of ensembles of genes involved in neuronal structure. Developmental nicotine exposure enriched trimethylated H3K4 (H3K4me3) at promoter regions of multiple genes involved in development and maintenance of excitatory synapses, including the gene encoding the transcription factor Mef2c, which assembles with Ash2l in a histone methyltransferase complex. This study thus identifies Ash2l as a regulator of neuronal morphology during early brain development and reveals a new molecular mechanism underlying the long-term consequences of developmental nicotine exposure. Results Developmental nicotine treatment alters neuronal morphology Exposure to tobacco smoke during human development can alter cortical structure as measured by diffusion tensor imaging (DTI) 8 . Since nicotine can alter dendritic spine numbers and neuronal morphology 1 , we determined whether nicotine in tobacco smoke could underlie changes in cortical fractional anisotropy measured by DTI. Among regimens used to deliver nicotine during development 7 , drinking water administration results in detectable blood levels in the dam and the offspring and has minimal stressful effects 9 . We therefore exposed mice to saccharin or nicotine (200 μg/ml) from the time of conception through weaning, postnatal day (P) 21, and measured fractional anisotropy at 3 months of age. This regimen results in persistent neurochemical and behavioral changes in exposed pups, with no effects on maternal behavior 10 . Developmental nicotine exposure induced significant increases in fractional anisotropy in a number of cortical areas, largely in gray matter ( Fig. 1a,b ). To determine whether changes in gray matter such as spine density and dendritic arborization underlie the increased fractional anisotropy, we labeled neurons diolistically with DiI and performed Sholl analysis and spine counting in mice exposed to nicotine throughout pre- and postnatal development as in the DTI study, as well as in an additional group that was treated only from birth to weaning (postnatal exposure), a critical period for cortical development dependent on acetylcholine signaling 11 . Nicotine significantly increased spine density in both the pre- and postnatal nicotine treated group and in the postnatal-only nicotine treated group ( Fig. 1c ). There was a significant effect of nicotine treatment on dendritic complexity across rostral, medial and caudal regions of cortex ( Fig. 1d–f ) and across all cortical layers, as demonstrated by a significant nicotine treatment by dendritic complexity interaction in each cortical layer compared to the saccharin-treated group ( Fig. 1g–i ). These results are consistent with previous studies showing that nicotine can induce persistent changes in spine density 3 , 4 . Postnatal-only nicotine-treated mice also showed an increase in dendritic complexity across all cortical regions and layers ( Supplementary Fig. 1 ). Figure 1: Morphological changes in cortical neurons induced by developmental nicotine exposure. Voxel-based analysis of fractional anisotropy changes induced by nicotine treatment during development measured by DTI; diagram from the Paxinos atlas 43 identifies affected regions. Two-tailed t -tests of average fractional anisotropy values in nicotine (Nic) and saccharin (Sac) groups indicate a significant difference ( n = 5 brains per condition; t (23) = 3.31, P = 0.00306) in cortical regions investigated, including ( a ) somatosensory cortex and ( b ) sensory cortex; ** P < 0.01. ( c ) Nicotine significantly increased spine density in treated groups compared to controls as measured by two-tailed t -test (pre- and postnatal: Sac, n = 26 slices from 6 mice, Nic, n = 25 slices from 5 mice, t 49 = 5.151, P = 0.00000460; postnatal-only: Sac, n = 19 slices from 6 mice, Nic, n = 29 slices from 6 mice, t 46 = 4.96, P = 0.0000100; *** P < 0.001). ( d – i ) The number of intersections was assessed for the apical dendritic tree as measured by one-way ANOVA followed by LSD test. Scale bar, 12 μm. ( d ) Frontal cortical regions. F (1,113) = 9.02, P = 0.00329. The parietal ( e ) and occipital ( f ) regions of cortex showed a significantly higher number of intersections following nicotine exposure compared to the control group. ( e ) F (1,48) = 31.9; P = 0.00000085. ( f ) F (1,38)<|im_end|> <|im_start|>assistant Early exposure to nicotine can trigger widespread genetic changes that affect formation of connections between brain cells long after birth, a new Yale-led study has found. The finding helps explains why maternal smoking has been linked to behavioral changes such as attention deficit and hyperactivity disorder, addiction and conduct disorder. Nicotine does this by affecting a master regulator of DNA packaging, which in turn influences activity of genes crucial to the formation and stabilization of synapses between brain cells, according to the study published online May 30 in the journal Nature Neuroscience. "When this regulator is induced in mice, they pay attention to a stimulus they should ignore,'' said Marina Picciotto, the Charles B.G. Murphy Professor of Psychiatry, professor in the Child Study Center and the Departments of Neuroscience and Pharmacology, and senior author of the paper. An inability to focus is the hallmark of attention deficit hyperactivity disorder and other behavioral disorders, which have been linked to maternal smoking and exposure to second-hand smoke. However, scientists did not understand how early environmental exposure to smoking could create behavioral problems years later. Picciotto's lab found that mice exposed to nicotine during early development did indeed develop behavioral problems that mimic symptoms of attention deficit disorder in humans. They then did extensive genomic screening of mice exposed to nicotine and found higher levels of activity in a key regulator of histone methylation—a process that controls gene expression by changing the DNA wrapping around chromosomes. The researchers found that genes essential to the creation of brain synapses were heavily effected. Furthermore, the scientists found that these genetic changes were maintained even in adult mice. However, when researchers inhibited the master regulator of histone methylation, these adult mice were calmer and no longer reacted to a stimulus they should ignore. In a final test, they triggered expression of this regulator in mice never exposed to nicotine, and the mice exhibited behavior that mimicked attention deficit disorder. "It is exciting to find a signal that could explain the long-lasting effects of nicotine on brain cell structure and behavior," Picciotto said. "It was even more intriguing to find a regulator of gene expression that responds to a stimulus like nicotine and may change synapse and brain activity during development." <|im_end|>

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79390, 11, 2737, 279, 15207, 11418, 279, 46940, 8331, 386, 830, 17, 66, 11, 902, 439, 41794, 449, 14937, 17, 75, 304, 264, 13034, 606, 79574, 25163, 521, 6485, 13, 1115, 4007, 8617, 36611, 14937, 17, 75, 439, 264, 40704, 315, 79402, 79612, 2391, 4216, 8271, 4500, 323, 21667, 264, 502, 31206, 17383, 16940, 279, 1317, 9860, 16296, 315, 48006, 50011, 14675, 13, 18591, 11050, 278, 50011, 6514, 88687, 79402, 79612, 71866, 311, 27531, 16603, 2391, 3823, 4500, 649, 11857, 83619, 6070, 439, 17303, 555, 58430, 16000, 32758, 320, 10822, 40, 8, 220, 23, 662, 8876, 50011, 649, 11857, 90052, 50308, 35776, 5219, 323, 79402, 79612, 220, 16, 1174, 584, 11075, 3508, 50011, 304, 27531, 16603, 1436, 1234, 11828, 4442, 304, 83619, 69309, 459, 285, 354, 18237, 17303, 555, 26065, 40, 13, 22395, 1239, 46697, 1511, 311, 6493, 50011, 2391, 4500, 220, 22, 1174, 16558, 3090, 8735, 3135, 304, 11388, 481, 6680, 5990, 304, 279, 3824, 323, 279, 46471, 323, 706, 17832, 46883, 6372, 220, 24, 662, 1226, 9093, 15246, 24548, 311, 11347, 1799, 258, 477, 50011, 320, 1049, 33983, 70, 60648, 8, 505, 279, 892, 315, 43656, 1555, 584, 44159, 11, 1772, 74439, 1938, 320, 47, 8, 220, 1691, 11, 323, 17303, 69309, 459, 285, 354, 18237, 520, 220, 18, 4038, 315, 4325, 13, 1115, 68128, 3135, 304, 26048, 18247, 32056, 323, 36695, 4442, 304, 15246, 90821, 11, 449, 912, 6372, 389, 50150, 7865, 220, 605, 662, 11050, 278, 50011, 14675, 36572, 5199, 12992, 304, 69309, 459, 285, 354, 18237, 304, 264, 1396, 315, 83619, 5789, 11, 14090, 304, 18004, 5030, 320, 23966, 13, 220, 16, 64, 8568, 7609, 2057, 8417, 3508, 4442, 304, 18004, 5030, 1778, 439, 35776, 17915, 323, 90052, 50308, 802, 9552, 2065, 1234, 11828, 279, 7319, 69309, 459, 285, 354, 18237, 11, 584, 30929, 34313, 1891, 35775, 2740, 449, 7923, 40, 323, 10887, 1443, 980, 6492, 323, 35776, 26060, 304, 24548, 15246, 311, 50011, 6957, 864, 12, 323, 1772, 74439, 4500, 439, 304, 279, 26065, 40, 4007, 11, 439, 1664, 439, 304, 459, 5217, 1912, 430, 574, 12020, 1193, 505, 7342, 311, 584, 44159, 320, 2252, 74439, 14675, 705, 264, 9200, 4261, 369, 83619, 4500, 18222, 389, 1645, 87348, 331, 22671, 43080, 220, 806, 662, 18011, 40253, 12207, 7319, 35776, 17915, 304, 2225, 279, 864, 12, 323, 1772, 74439, 50011, 12020, 1912, 323, 304, 279, 1772, 74439, 15744, 50011, 12020, 1912, 320, 23966, 13, 220, 16, 66, 7609, 2684, 574, 264, 5199, 2515, 315, 50011, 6514, 389, 90052, 50308, 23965, 4028, 938, 56070, 11, 97348, 323, 2211, 664, 278, 13918, 315, 49370, 320, 23966, 13, 220, 16, 67, 4235, 69, 883, 323, 4028, 682, 83619, 13931, 11, 439, 21091, 555, 264, 5199, 50011, 6514, 555, 90052, 50308, 23965, 16628, 304, 1855, 83619, 6324, 7863, 311, 279, 11347, 1799, 258, 88186, 1912, 320, 23966, 13, 220, 16, 70, 4235, 72, 7609, 4314, 3135, 527, 13263, 449, 3766, 7978, 9204, 430, 50011, 649, 49853, 26048, 4442, 304, 35776, 17915, 220, 18, 1174, 220, 19, 662, 3962, 74439, 15744, 50011, 88186, 24548, 1101, 8710, 459, 5376, 304, 90052, 50308, 23965, 4028, 682, 83619, 13918, 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11, 308, 284, 220, 1627, 35354, 505, 220, 21, 24548, 11, 18011, 11, 308, 284, 220, 914, 35354, 505, 220, 20, 24548, 11, 259, 220, 2491, 284, 220, 20, 13, 9690, 11, 393, 284, 220, 15, 13, 931, 8759, 1399, 26, 1772, 74439, 15744, 25, 23916, 11, 308, 284, 220, 777, 35354, 505, 220, 21, 24548, 11, 18011, 11, 308, 284, 220, 1682, 35354, 505, 220, 21, 24548, 11, 259, 220, 2790, 284, 220, 19, 13, 4161, 11, 393, 284, 220, 15, 13, 931, 7755, 15, 26, 17601, 393, 366, 220, 15, 13, 4119, 570, 320, 294, 1389, 602, 883, 578, 1396, 315, 65357, 574, 32448, 369, 279, 1469, 950, 90052, 50308, 5021, 439, 17303, 555, 832, 27896, 2147, 46, 13114, 8272, 555, 72170, 1296, 13, 25635, 3703, 11, 220, 717, 33983, 76, 13, 320, 294, 883, 15248, 278, 83619, 13918, 13, 435, 320, 16, 11, 8190, 8, 284, 220, 24, 13, 2437, 11, 393, 284, 220, 15, 13, 6268, 1682, 13, 578, 1370, 3978, 278, 320, 384, 883, 323, 3056, 575, 2223, 320, 282, 883, 13918, 315, 49370, 8710, 264, 12207, 5190, 1396, 315, 65357, 2768, 50011, 14675, 7863, 311, 279, 2585, 1912, 13, 320, 384, 883, 435, 320, 16, 11, 2166, 8, 284, 220, 2148, 13, 24, 26, 393, 284, 220, 15, 13, 931, 931, 5313, 13, 320, 282, 883, 435, 320, 16, 11, 1987, 8, 128257, 198, 128256, 78191, 198, 42298, 14675, 311, 50011, 649, 8346, 24716, 19465, 4442, 430, 7958, 18488, 315, 13537, 1990, 8271, 7917, 1317, 1306, 7342, 11, 264, 502, 44552, 35054, 4007, 706, 1766, 13, 578, 9455, 8779, 15100, 3249, 50150, 20149, 706, 1027, 10815, 311, 36695, 4442, 1778, 439, 6666, 29287, 323, 17508, 7323, 19823, 11, 27471, 323, 6929, 19823, 13, 18011, 40253, 1587, 420, 555, 28987, 264, 7491, 40704, 315, 15922, 24066, 11, 902, 304, 2543, 34453, 5820, 315, 21389, 16996, 311, 279, 18488, 323, 83938, 315, 6925, 79390, 1990, 8271, 7917, 11, 4184, 311, 279, 4007, 4756, 2930, 3297, 220, 966, 304, 279, 8486, 22037, 85879, 13, 330, 4599, 420, 40704, 374, 36572, 304, 24548, 11, 814, 2343, 6666, 311, 264, 39535, 814, 1288, 10240, 41610, 1071, 52636, 26987, 5979, 36726, 11, 279, 15274, 426, 1246, 13, 31053, 17054, 315, 69244, 11, 14561, 304, 279, 9576, 19723, 5955, 323, 279, 85608, 315, 85879, 323, 71881, 2508, 11, 323, 10195, 3229, 315, 279, 5684, 13, 1556, 38550, 311, 5357, 374, 279, 98799, 315, 6666, 29287, 17508, 7323, 19823, 323, 1023, 36695, 24673, 11, 902, 617, 1027, 10815, 311, 50150, 20149, 323, 14675, 311, 2132, 25417, 16603, 13, 4452, 11, 14248, 1550, 539, 3619, 1268, 4216, 12434, 14675, 311, 20149, 1436, 1893, 36695, 5435, 1667, 3010, 13, 26987, 5979, 36726, 596, 10278, 1766, 430, 24548, 15246, 311, 50011, 2391, 4216, 4500, 1550, 13118, 2274, 36695, 5435, 430, 56459, 13803, 315, 6666, 29287, 19823, 304, 12966, 13, 2435, 1243, 1550, 16781, 81064, 23061, 315, 24548, 15246, 311, 50011, 323, 1766, 5190, 5990, 315, 5820, 304, 264, 1401, 40704, 315, 13034, 606, 21747, 79933, 29096, 1920, 430, 11835, 15207, 7645, 555, 10223, 279, 15922, 42295, 2212, 83181, 13, 578, 12074, 1766, 430, 21389, 7718, 311, 279, 9886, 315, 8271, 6925, 79390, 1051, 17345, 89589, 13, 24296, 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1,883

[ { "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 Fault-tolerant quantum memory plays a key role in interfacing quantum computers with quantum networks to construct quantum computer networks. Manipulation of spin quantum memory generally requires a magnetic field, which hinders the integration with superconducting qubits. Completely zero-field operation is desirable for scaling up a quantum computer based on superconducting qubits. Here we demonstrate quantum error correction to protect the nuclear spin of the nitrogen as a quantum memory in a diamond nitrogen-vacancy center with two nuclear spins of the surrounding carbon isotopes under a zero magnetic field. The quantum error correction makes quantum memory resilient against operational or environmental errors without the need for magnetic fields and opens a way toward distributed quantum computation and a quantum internet with memory-based quantum interfaces or quantum repeaters. Introduction Nuclear spins around a nitrogen-vacancy (NV) center 1 , 2 , 3 in diamond (Fig. 1a ) have long coherence times: over 10 seconds for nitrogen and carbon nuclear spins 4 , 5 and ~1.9 min for carbon nuclear spin pairs 6 . Thus, such spins are promising as quantum memories for quantum repeaters 7 and quantum computers 8 . However, changes in magnetic fields such as external noise fields or hyperfine fields by the electron spin due to optical excitation cause either a bit-flip or phase-flip error. To avoid such errors, various kinds of quantum error correction (QEC) 9 have been demonstrated 10 , 11 , 12 . Waldherr et al. 10 demonstrated QEC with nitrogen and two carbon nuclear spins, Taminiau et al. demonstrated QEC with an NV electron and two carbon nuclear spins 11 , and Cramer et al. demonstrated a stabilizer code with three carbon isotopes 12 . However, these demonstrations were carried out under relatively strong magnetic fields such as 6200 Gauss with individual error corrections 10 or 403 Gauss with repetitive error corrections based on dynamical decoupling 11 , 12 . Under the magnetic fields, an increase in the fidelity of the controlled-phase (C-Z) gate by increasing the external magnetic field strongly depends on the carbon position relative to the NV center unless the field is well aligned to the hyperfine field (see discussion section and Supplementary Note 1 ) (Fig. 1b, c ). In contrast, the fidelity can be increased independent of the carbon position under a zero magnetic field, where the hyperfine field uniquely defines the quantization axis, which allows time-reversal operation in any timing, resulting in high fidelity single nuclear spin manipulation conditioned by the NV electron, as discussed later. The application of an external magnetic field also limits the integration with other physical qubits. For example, superconducting qubits, which we believe are the most promising candidates for quantum computers, become unstable by the application of a magnetic field due to the penetration of magnetic flux into the superconductor or the Josephson junction. The accessible magnetic field is ~100 Gauss even in the plane of the superconducting loop 13 , 14 , 15 , 16 , 17 unless using exotic junctions such as semiconductor nanowires. Although a flux qubit relies on applying external magnetic fields, it is usually <1 Gauss to introduce a half flux in the loop to stabilize the qubit, and the application of higher magnetic fields beyond a half-flux field reduces the supercurrent in the junction 18 . A zero magnetic field is also advantageous for qubit integration because a spatially uniform magnetic field can be easily obtained compared to individually tuned magnetic fields. A flux qubit working under a completely zero magnetic field with a ferromagnetic π-shifted Josephson junction, which does not require any precise tuning of the flux in a qubit loop by individual coil currents, is under development toward large-scale integration of quantum computers with flexible layout 19 , 20 . To further extend the scale of quantum computers in size and that of quantum communications 21 in distance, it is desirable to use spins in diamond, which serve as quantum interfaces 22 , 23 , 24 , 25 with long-time memory and excellent optical accessibility for connecting quantum computers to optical quantum networks 26 . Li et al. 27 recently demonstrated coherent coupling of a single NV center spin to a superconducting flux qubit via a nanomechanical resonator and Scarlino et al. demonstrated coherent coupling of a semiconductor double quantum dot charge qubit to a superconducting transmon qubit via a microwave photon 28 , which also operate under a zero magnetic field. Furthermore, it is essential to provide error tolerance not only to the NISQ (noisy intermediate-scale quantum) 29 based on stabilizer codes such as surface codes 30 , 31 , 32 , 33 , 34 , 35 but also to the quantum interface, which should also work under a zero magnetic field for stable and reliable operations with flexible layout. In this report, we first demonstrate the quantum operation of the electron and nuclear spins and their correlated operations based on the geometric phase in the absence of a magnetic field. We then demonstrate the most fundamental three-qubit QEC 36 for either a bit-flip or phase-flip error using three nuclear spins on nitrogen and two carbon isotopes in the vicinity of an NV center. Fig. 1: Carbon spin manipulation with and without magnetic field. a Schematic structure of a nitrogen-vacancy center in diamond, where carbon (C) adjacent to a vacancy (e) is replaced by impurity nitrogen (N), whose spin error is protected by two carbon isotope spins serving as ancilla qubits for quantum error correction. The green-colored 13 C atoms’ placement is just an artistic choice. b Quantization axis of carbon nuclear spins, which is determined by the hyperfine field by the electron spin as well as the external magnetic field if applied. c Simulated Rabi frequency dependence of the fidelity (F) of the holonomic controlled-phase gate based on the geometric phase between two carbon nuclear spins ( 13 C 1 , 1.14 MHz; 13 C 2 , 0.33 MHz) under a zero magnetic field (blue line), 100 Gauss (green line), 1000 gauss (red line),", "role": "user" }, { "content": "Quantum computing holds the potential to be a game-changing future technology in fields ranging from chemistry to cryptography to finance to pharmaceuticals. Compared to conventional computers, scientists suggest that quantum computers could operate many thousand times faster. To harness this power, scientists today are looking at ways to construct quantum computer networks. Fault-tolerant quantum memory, which responds well when hardware or software malfunctions occur, will play an important role in these networks. A research team from Yokohama National University is exploring quantum memory that is resilient against operational or environmental errors. The research team reported their findings on April 27, 2022 in the journal Communications Physics. For quantum computers to reach their full potential, scientists need to be able to construct quantum networks. In these networks, fault-tolerant quantum memory is essential. When scientists manipulate spin quantum memory, a magnetic field is required. The magnetic field hinders the integration with the superconducting quantum bits, or qubits. The qubits in quantum computing are basic units of information, similar to the binary digits, or bits, in conventional computers. To scale up a quantum computer based on superconducting qubits, scientists need to operate under a zero magnetic field. In their search to further the technology toward an fault-tolerant quantum computer, the research team studied nitrogen-vacancy centers in diamond. Nitrogen-vacancy centers hold promise in a range of applications including quantum computing. Using a diamond nitrogen-vacancy center with two nuclear spins of the surrounding carbon isotopes, the team demonstrated quantum error correction in quantum memory. They tested a three-qubit quantum error correction against both a bit-flip or phase-flip error, under a zero magnetic field. The bit-flip or phase-flip errors can occur when there are changes in the magnetic field. To achieve a zero magnetic field, the team used a three-dimensional coil to cancel out the residual magnetic field including the geomagnetic field. This quantum memory is error-correction coded to correct errors automatically as they occur. Previous research had demonstrated quantum error correction, but it was all carried out under relatively strong magnetic fields. The Yokohama National University research team is the first to demonstrate the quantum operation of the electron and nuclear spins in the absence of a magnetic field. \"The quantum error correction makes quantum memory resilient against operational or environmental errors without the need for magnetic fields and opens a way toward distributed quantum computation and a quantum internet with memory-based quantum interfaces or quantum repeaters,\" said Hideo Kosaka, a professor at Yokohama University and lead author on the study. The team's demonstration can be applied to the construction of a large-scale distributed quantum computer and a long-haul quantum communication network by connecting quantum systems vulnerable to a magnetic field, such as superconducting qubits with spin-based quantum memories. Looking ahead, the research team has plans to take the technology a step further. \"We want to develop a quantum interface between superconducting and photonic qubits to realize an fault-tolerant large-scale quantum computer,\" said Kosaka. ", "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 Fault-tolerant quantum memory plays a key role in interfacing quantum computers with quantum networks to construct quantum computer networks. Manipulation of spin quantum memory generally requires a magnetic field, which hinders the integration with superconducting qubits. Completely zero-field operation is desirable for scaling up a quantum computer based on superconducting qubits. Here we demonstrate quantum error correction to protect the nuclear spin of the nitrogen as a quantum memory in a diamond nitrogen-vacancy center with two nuclear spins of the surrounding carbon isotopes under a zero magnetic field. The quantum error correction makes quantum memory resilient against operational or environmental errors without the need for magnetic fields and opens a way toward distributed quantum computation and a quantum internet with memory-based quantum interfaces or quantum repeaters. Introduction Nuclear spins around a nitrogen-vacancy (NV) center 1 , 2 , 3 in diamond (Fig. 1a ) have long coherence times: over 10 seconds for nitrogen and carbon nuclear spins 4 , 5 and ~1.9 min for carbon nuclear spin pairs 6 . Thus, such spins are promising as quantum memories for quantum repeaters 7 and quantum computers 8 . However, changes in magnetic fields such as external noise fields or hyperfine fields by the electron spin due to optical excitation cause either a bit-flip or phase-flip error. To avoid such errors, various kinds of quantum error correction (QEC) 9 have been demonstrated 10 , 11 , 12 . Waldherr et al. 10 demonstrated QEC with nitrogen and two carbon nuclear spins, Taminiau et al. demonstrated QEC with an NV electron and two carbon nuclear spins 11 , and Cramer et al. demonstrated a stabilizer code with three carbon isotopes 12 . However, these demonstrations were carried out under relatively strong magnetic fields such as 6200 Gauss with individual error corrections 10 or 403 Gauss with repetitive error corrections based on dynamical decoupling 11 , 12 . Under the magnetic fields, an increase in the fidelity of the controlled-phase (C-Z) gate by increasing the external magnetic field strongly depends on the carbon position relative to the NV center unless the field is well aligned to the hyperfine field (see discussion section and Supplementary Note 1 ) (Fig. 1b, c ). In contrast, the fidelity can be increased independent of the carbon position under a zero magnetic field, where the hyperfine field uniquely defines the quantization axis, which allows time-reversal operation in any timing, resulting in high fidelity single nuclear spin manipulation conditioned by the NV electron, as discussed later. The application of an external magnetic field also limits the integration with other physical qubits. For example, superconducting qubits, which we believe are the most promising candidates for quantum computers, become unstable by the application of a magnetic field due to the penetration of magnetic flux into the superconductor or the Josephson junction. The accessible magnetic field is ~100 Gauss even in the plane of the superconducting loop 13 , 14 , 15 , 16 , 17 unless using exotic junctions such as semiconductor nanowires. Although a flux qubit relies on applying external magnetic fields, it is usually <1 Gauss to introduce a half flux in the loop to stabilize the qubit, and the application of higher magnetic fields beyond a half-flux field reduces the supercurrent in the junction 18 . A zero magnetic field is also advantageous for qubit integration because a spatially uniform magnetic field can be easily obtained compared to individually tuned magnetic fields. A flux qubit working under a completely zero magnetic field with a ferromagnetic π-shifted Josephson junction, which does not require any precise tuning of the flux in a qubit loop by individual coil currents, is under development toward large-scale integration of quantum computers with flexible layout 19 , 20 . To further extend the scale of quantum computers in size and that of quantum communications 21 in distance, it is desirable to use spins in diamond, which serve as quantum interfaces 22 , 23 , 24 , 25 with long-time memory and excellent optical accessibility for connecting quantum computers to optical quantum networks 26 . Li et al. 27 recently demonstrated coherent coupling of a single NV center spin to a superconducting flux qubit via a nanomechanical resonator and Scarlino et al. demonstrated coherent coupling of a semiconductor double quantum dot charge qubit to a superconducting transmon qubit via a microwave photon 28 , which also operate under a zero magnetic field. Furthermore, it is essential to provide error tolerance not only to the NISQ (noisy intermediate-scale quantum) 29 based on stabilizer codes such as surface codes 30 , 31 , 32 , 33 , 34 , 35 but also to the quantum interface, which should also work under a zero magnetic field for stable and reliable operations with flexible layout. In this report, we first demonstrate the quantum operation of the electron and nuclear spins and their correlated operations based on the geometric phase in the absence of a magnetic field. We then demonstrate the most fundamental three-qubit QEC 36 for either a bit-flip or phase-flip error using three nuclear spins on nitrogen and two carbon isotopes in the vicinity of an NV center. Fig. 1: Carbon spin manipulation with and without magnetic field. a Schematic structure of a nitrogen-vacancy center in diamond, where carbon (C) adjacent to a vacancy (e) is replaced by impurity nitrogen (N), whose spin error is protected by two carbon isotope spins serving as ancilla qubits for quantum error correction. The green-colored 13 C atoms’ placement is just an artistic choice. b Quantization axis of carbon nuclear spins, which is determined by the hyperfine field by the electron spin as well as the external magnetic field if applied. c Simulated Rabi frequency dependence of the fidelity (F) of the holonomic controlled-phase gate based on the geometric phase between two carbon nuclear spins ( 13 C 1 , 1.14 MHz; 13 C 2 , 0.33 MHz) under a zero magnetic field (blue line), 100 Gauss (green line), 1000 gauss (red line),<|im_end|> <|im_start|>assistant Quantum computing holds the potential to be a game-changing future technology in fields ranging from chemistry to cryptography to finance to pharmaceuticals. Compared to conventional computers, scientists suggest that quantum computers could operate many thousand times faster. To harness this power, scientists today are looking at ways to construct quantum computer networks. Fault-tolerant quantum memory, which responds well when hardware or software malfunctions occur, will play an important role in these networks. A research team from Yokohama National University is exploring quantum memory that is resilient against operational or environmental errors. The research team reported their findings on April 27, 2022 in the journal Communications Physics. For quantum computers to reach their full potential, scientists need to be able to construct quantum networks. In these networks, fault-tolerant quantum memory is essential. When scientists manipulate spin quantum memory, a magnetic field is required. The magnetic field hinders the integration with the superconducting quantum bits, or qubits. The qubits in quantum computing are basic units of information, similar to the binary digits, or bits, in conventional computers. To scale up a quantum computer based on superconducting qubits, scientists need to operate under a zero magnetic field. In their search to further the technology toward an fault-tolerant quantum computer, the research team studied nitrogen-vacancy centers in diamond. Nitrogen-vacancy centers hold promise in a range of applications including quantum computing. Using a diamond nitrogen-vacancy center with two nuclear spins of the surrounding carbon isotopes, the team demonstrated quantum error correction in quantum memory. They tested a three-qubit quantum error correction against both a bit-flip or phase-flip error, under a zero magnetic field. The bit-flip or phase-flip errors can occur when there are changes in the magnetic field. To achieve a zero magnetic field, the team used a three-dimensional coil to cancel out the residual magnetic field including the geomagnetic field. This quantum memory is error-correction coded to correct errors automatically as they occur. Previous research had demonstrated quantum error correction, but it was all carried out under relatively strong magnetic fields. The Yokohama National University research team is the first to demonstrate the quantum operation of the electron and nuclear spins in the absence of a magnetic field. "The quantum error correction makes quantum memory resilient against operational or environmental errors without the need for magnetic fields and opens a way toward distributed quantum computation and a quantum internet with memory-based quantum interfaces or quantum repeaters," said Hideo Kosaka, a professor at Yokohama University and lead author on the study. The team's demonstration can be applied to the construction of a large-scale distributed quantum computer and a long-haul quantum communication network by connecting quantum systems vulnerable to a magnetic field, such as superconducting qubits with spin-based quantum memories. Looking ahead, the research team has plans to take the technology a step further. "We want to develop a quantum interface between superconducting and photonic qubits to realize an fault-tolerant large-scale quantum computer," said Kosaka. <|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 Although research on human-mediated exchanges of species has substantially intensified during the last centuries, we know surprisingly little about temporal dynamics of alien species accumulations across regions and taxa. Using a novel database of 45,813 first records of 16,926 established alien species, we show that the annual rate of first records worldwide has increased during the last 200 years, with 37% of all first records reported most recently (1970–2014). Inter-continental and inter-taxonomic variation can be largely attributed to the diaspora of European settlers in the nineteenth century and to the acceleration in trade in the twentieth century. For all taxonomic groups, the increase in numbers of alien species does not show any sign of saturation and most taxa even show increases in the rate of first records over time. This highlights that past efforts to mitigate invasions have not been effective enough to keep up with increasing globalization. Introduction The rate at which humans translocate species beyond their native ranges has substantially increased during the last centuries 1 , 2 , 3 . The unprecedented intensity of human-mediated species exchange leads to the homogenization of floras and faunas 4 , re-defines the classical boundaries of biogeography 5 and has far-reaching implications for native biota, ecosystem functioning, human health and economy 6 , 7 , 8 . However, although the general rise in the number of alien species is undisputed, we know little about the temporal dynamics of alien species accumulation and how this might vary among taxonomic groups and geographic regions. A wide range of motivations underlie the introduction of alien species and the relative importance of these vary considerably in space and time, and among taxonomic groups 9 . For example, many alien species of taxa such as mammals, plants or birds were released by European explorers and settlers all over the world during 1500–1800 (ref. 9 ). In the nineteenth century, numerous plants have been brought to Europe for ornamental purposes 10 , whereas currently bird species are intensively traded in South East Asia, where the accidental or deliberate release of individuals supports the establishment of alien populations 3 . In addition, most alien species of taxa, such as insects, algae and crustaceans, have been introduced recently through trade and the transport of goods and people 11 . Differences in the pathways and distribution of alien species introductions suggest that the chronology of invasion probably varies among taxonomic groups and regions, yet a comprehensive analysis of global invasion dynamics of the last centuries is still lacking. Furthermore, we have as yet only limited understanding of whether current rates of alien species accumulation may show signs of saturation or whether we can expect biological invasions to continue at the same rate seen in the past. To address these gaps in our knowledge, we compiled a global data set of regional first records of alien species that are now established (following the criteria in ref. 12 ) in multiple geographic regions worldwide (countries and sub-national regions such as islands). This data set of 45,813 first records of 16,926 established alien species from a wide range of taxonomic groups is invaluable for assessing taxonomic and geographic variation in alien species accumulations, and for testing for evidence of slowdown in the accumulation rates. It covers 282 non-overlapping regions from all continents, with particularly intense sampling in Europe, North America and Oceania, and from well-studied taxa such as vascular plants, mammals, insects, birds and fishes ( Fig. 1 and Supplementary Fig. 1 ). This data set allows us to analyse variations in the rate of alien species introductions across space and time in a consistent way over large geographic scales. In particular, we test the following predictions: (1) rates of introductions for species often intentionally introduced such as mammals, birds and vascular plants should decline in recent years as a result of increased awareness of their impacts and tighter biosecurity regulations; (2) rates of introductions for taxonomic groups primarily introduced accidentally such as invertebrates or algae should show steep increases in recent times, as these species are more difficult to regulate and are closely associated with increasing trade; and (3) significant geographic differences in the rates of alien species introductions should be apparent, reflecting variations in socio-economic histories and the strength of biosecurity regulations. We find that the number of established alien species and for most taxonomic groups even the rate of introduction increased until recently with no sign of saturation. We can therefore expect many more invasions to happen in the near future. Figure 1: Number of first records of established alien species per region (mainlands and islands) for major taxonomic groups. ( a – f ) Colour and size of circles indicate the number of first records of established alien species. Circles denote first records on small islands and archipelagos otherwise not visible. The world maps were created using the ‘maptools’ package 40 of the open source software R 36 . Full size image Results Global patterns of alien species introductions The global rate of first records (measured as the number of first records of established alien species per time unit) remained low between 1500 and 1800 (on average 7.7 first records annually, Fig. 2a ). Since 1800, first records have increased constantly, only slowing during the two World Wars, to a maximum of 585 in 1996 (reflecting on average more than 1.5 new records per day). Our data set does not cover all alien species recorded in every region of the world and thus inevitably underestimates first record rates. The continuous rise in first record rates during the last 200 years is consistent across taxa ( Fig. 2 ), except for mammals and fishes, whose rates have declined in recent decades ( Fig. 2e,i ). Remarkably, barring mammals and fish, there is no clear indication of a slowdown in the first records rates of alien species: rather, they are still increasing. This trend was consistent for both mainlands and islands ( Supplementary Fig. 2 ). Figure 2: Global temporal", "role": "user" }, { "content": "The number of alien species is increasing globally, and does not show any sign of saturation, finds an international team involving UCL researchers. Led by scientists from Senckenberg, Germany, and the University of Vienna, Austria, the team found that during the last 200 years, the number of new established alien species has grown continuously worldwide, with more than a third of all first introductions recorded between 1970 and 2014. The study, published today in Nature Communications, shows that individual trends differ among taxonomic groups, which can be attributed to human activities, but overall, alien species numbers are increasing for all groups of organisms. \"We observe distinct increases in first record rates of vascular plants, birds and mammals in the 19th century, probably as a result of the spread of horticulture and attempts at supposedly beneficial introductions during the period of European colonial expansion. The rates of new introductions of other organisms such as algae, molluscs or insects increased steeply after 1950, most likely because of the ongoing globalisation of trade,\" explained study co-author Professor Tim Blackburn (UCL Genetics, Evolution & Environment). Although it was already known that the number of alien species has increased during the last 50 years, it remained unclear whether or not the accumulation of alien species has already reached a point of slow-down. Dr Hanno Seebens (Senckenberg, Germany), first author of the study, said: \"For all groups of organisms on all continents, the number of alien species has increased continuously during the last 200 years. For most groups, the rate of introduction is highest in recent years. Barring mammals and fishes, there are no signs of a slow-down in the arrival of aliens, and we have to expect more new invasions in the near future.\" This conclusion results from of a large collaborative effort by 45 scientists from all over the world, who established a database of the date an alien species was first detected in a region outside the species' native range. Using more than 45,000 of these first records of more than 16,000 alien species, they analysed the accumulation of alien species over the last few centuries. The scientists found that 37% of all recorded alien species were introduced between 1970-2014 and thus recently. The peak came in 1996, when 585 new alien species were recorded worldwide, or more than 1.5 new alien species per day. \"As the date of first record is not available for most alien species, these numbers are clearly underestimating the full extent of alien species introductions\", said senior study author Dr Franz Essl (University of Vienna, Austria). The team say the unprecedented increase in alien species numbers can lead to an increase in regional species richness but also lead to a variety of negative impacts on native ecosystems, including the global homogenisation of floras and faunas, and the global extinction of native species. For this reason, various laws are currently in force globally attempting to mitigate the introduction of new alien species. \"However our results show that the past efforts have not been effective enough to keep up with ongoing globalisation. There is an urgent need to implement more effective prevention policies at all scales,\" concluded Dr Essl. ", "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 research on human-mediated exchanges of species has substantially intensified during the last centuries, we know surprisingly little about temporal dynamics of alien species accumulations across regions and taxa. Using a novel database of 45,813 first records of 16,926 established alien species, we show that the annual rate of first records worldwide has increased during the last 200 years, with 37% of all first records reported most recently (1970–2014). Inter-continental and inter-taxonomic variation can be largely attributed to the diaspora of European settlers in the nineteenth century and to the acceleration in trade in the twentieth century. For all taxonomic groups, the increase in numbers of alien species does not show any sign of saturation and most taxa even show increases in the rate of first records over time. This highlights that past efforts to mitigate invasions have not been effective enough to keep up with increasing globalization. Introduction The rate at which humans translocate species beyond their native ranges has substantially increased during the last centuries 1 , 2 , 3 . The unprecedented intensity of human-mediated species exchange leads to the homogenization of floras and faunas 4 , re-defines the classical boundaries of biogeography 5 and has far-reaching implications for native biota, ecosystem functioning, human health and economy 6 , 7 , 8 . However, although the general rise in the number of alien species is undisputed, we know little about the temporal dynamics of alien species accumulation and how this might vary among taxonomic groups and geographic regions. A wide range of motivations underlie the introduction of alien species and the relative importance of these vary considerably in space and time, and among taxonomic groups 9 . For example, many alien species of taxa such as mammals, plants or birds were released by European explorers and settlers all over the world during 1500–1800 (ref. 9 ). In the nineteenth century, numerous plants have been brought to Europe for ornamental purposes 10 , whereas currently bird species are intensively traded in South East Asia, where the accidental or deliberate release of individuals supports the establishment of alien populations 3 . In addition, most alien species of taxa, such as insects, algae and crustaceans, have been introduced recently through trade and the transport of goods and people 11 . Differences in the pathways and distribution of alien species introductions suggest that the chronology of invasion probably varies among taxonomic groups and regions, yet a comprehensive analysis of global invasion dynamics of the last centuries is still lacking. Furthermore, we have as yet only limited understanding of whether current rates of alien species accumulation may show signs of saturation or whether we can expect biological invasions to continue at the same rate seen in the past. To address these gaps in our knowledge, we compiled a global data set of regional first records of alien species that are now established (following the criteria in ref. 12 ) in multiple geographic regions worldwide (countries and sub-national regions such as islands). This data set of 45,813 first records of 16,926 established alien species from a wide range of taxonomic groups is invaluable for assessing taxonomic and geographic variation in alien species accumulations, and for testing for evidence of slowdown in the accumulation rates. It covers 282 non-overlapping regions from all continents, with particularly intense sampling in Europe, North America and Oceania, and from well-studied taxa such as vascular plants, mammals, insects, birds and fishes ( Fig. 1 and Supplementary Fig. 1 ). This data set allows us to analyse variations in the rate of alien species introductions across space and time in a consistent way over large geographic scales. In particular, we test the following predictions: (1) rates of introductions for species often intentionally introduced such as mammals, birds and vascular plants should decline in recent years as a result of increased awareness of their impacts and tighter biosecurity regulations; (2) rates of introductions for taxonomic groups primarily introduced accidentally such as invertebrates or algae should show steep increases in recent times, as these species are more difficult to regulate and are closely associated with increasing trade; and (3) significant geographic differences in the rates of alien species introductions should be apparent, reflecting variations in socio-economic histories and the strength of biosecurity regulations. We find that the number of established alien species and for most taxonomic groups even the rate of introduction increased until recently with no sign of saturation. We can therefore expect many more invasions to happen in the near future. Figure 1: Number of first records of established alien species per region (mainlands and islands) for major taxonomic groups. ( a – f ) Colour and size of circles indicate the number of first records of established alien species. Circles denote first records on small islands and archipelagos otherwise not visible. The world maps were created using the ‘maptools’ package 40 of the open source software R 36 . Full size image Results Global patterns of alien species introductions The global rate of first records (measured as the number of first records of established alien species per time unit) remained low between 1500 and 1800 (on average 7.7 first records annually, Fig. 2a ). Since 1800, first records have increased constantly, only slowing during the two World Wars, to a maximum of 585 in 1996 (reflecting on average more than 1.5 new records per day). Our data set does not cover all alien species recorded in every region of the world and thus inevitably underestimates first record rates. The continuous rise in first record rates during the last 200 years is consistent across taxa ( Fig. 2 ), except for mammals and fishes, whose rates have declined in recent decades ( Fig. 2e,i ). Remarkably, barring mammals and fish, there is no clear indication of a slowdown in the first records rates of alien species: rather, they are still increasing. This trend was consistent for both mainlands and islands ( Supplementary Fig. 2 ). Figure 2: Global temporal<|im_end|> <|im_start|>assistant The number of alien species is increasing globally, and does not show any sign of saturation, finds an international team involving UCL researchers. Led by scientists from Senckenberg, Germany, and the University of Vienna, Austria, the team found that during the last 200 years, the number of new established alien species has grown continuously worldwide, with more than a third of all first introductions recorded between 1970 and 2014. The study, published today in Nature Communications, shows that individual trends differ among taxonomic groups, which can be attributed to human activities, but overall, alien species numbers are increasing for all groups of organisms. "We observe distinct increases in first record rates of vascular plants, birds and mammals in the 19th century, probably as a result of the spread of horticulture and attempts at supposedly beneficial introductions during the period of European colonial expansion. The rates of new introductions of other organisms such as algae, molluscs or insects increased steeply after 1950, most likely because of the ongoing globalisation of trade," explained study co-author Professor Tim Blackburn (UCL Genetics, Evolution & Environment). Although it was already known that the number of alien species has increased during the last 50 years, it remained unclear whether or not the accumulation of alien species has already reached a point of slow-down. Dr Hanno Seebens (Senckenberg, Germany), first author of the study, said: "For all groups of organisms on all continents, the number of alien species has increased continuously during the last 200 years. For most groups, the rate of introduction is highest in recent years. Barring mammals and fishes, there are no signs of a slow-down in the arrival of aliens, and we have to expect more new invasions in the near future." This conclusion results from of a large collaborative effort by 45 scientists from all over the world, who established a database of the date an alien species was first detected in a region outside the species' native range. Using more than 45,000 of these first records of more than 16,000 alien species, they analysed the accumulation of alien species over the last few centuries. The scientists found that 37% of all recorded alien species were introduced between 1970-2014 and thus recently. The peak came in 1996, when 585 new alien species were recorded worldwide, or more than 1.5 new alien species per day. "As the date of first record is not available for most alien species, these numbers are clearly underestimating the full extent of alien species introductions", said senior study author Dr Franz Essl (University of Vienna, Austria). The team say the unprecedented increase in alien species numbers can lead to an increase in regional species richness but also lead to a variety of negative impacts on native ecosystems, including the global homogenisation of floras and faunas, and the global extinction of native species. For this reason, various laws are currently in force globally attempting to mitigate the introduction of new alien species. "However our results show that the past efforts have not been effective enough to keep up with ongoing globalisation. There is an urgent need to implement more effective prevention policies at all scales," concluded Dr Essl. <|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 Electric components based on fibers or textiles have been investigated owing to their potential applications in wearable devices. High performance on response to gas, drape-ability and washing durability are of important for gas sensors based on fiber substrates. In this report, we demonstrate the bendable and washable electronic textile ( e -textile) gas sensors composed of reduced graphene oxides (RGOs) using commercially available yarn and molecular glue through an electrostatic self-assembly. The e -textile gas sensor possesses chemical durability to several detergent washing treatments and mechanical stability under 1,000 bending tests at an extreme bending radius of 1 mm as well as a high response to NO 2 gas at room temperature with selectivity to other gases such as acetone, ethanol, ethylene and CO 2 . Introduction Fiber-shaped electric components such as thin film transistors (TFTs) 1 , 2 , 3 , light-emitting diodes (LEDs) 4 , energy harvesters 5 , energy storage devices 6 , 7 , 8 and sensors 3 , 9 , 10 with high performance and flexibility are of great interest owing to their potential applications in portable devices and wearable electronics. Fiber-based gas sensors are expected to have a large number of advantages including excellent drapability, pliability, durability, a light weight and low cost 11 . Moreover, compared with conventional solid-state gas sensors or recently explored gas sensors prepared on flexible film or paper, fiber-based gas sensors can be integrated into textiles in various forms 12 . Thus far, several fiber sensors based on conducting polymers and metal oxides have been developed 13 , 14 , 15 . However, these sensors are unsuitable for flexible and wearable gas sensors owing to their poor mechanical/chemical durability and operation at high temperature. As an alternative approach, graphene and its derivatives have been the focus of research owing to their ultra-high surface area, excellent electrical properties and good selectivity without the need for a catalyst or modification 16 , 17 . Additionally, they show high mechanical strength with flexibility 18 , 19 , which makes them ideal candidate materials for high-performance flexible gas sensors 20 , 21 , 22 , 23 . Results Recently, graphene fibers and yarns have been developed for various applications, such as fiber-based supercapacitors, dye-sensitized photovoltaic cells (DSSCs) and photo-detectors 24 , 25 , 26 . However, there have been no reports to date on graphene yarn-based gas sensors. We previously reported an efficient graphene oxide (GO) wrapping method using biomolecules, i.e., bovine serum albumin (BSA), as a mediator for electrostatic self-assembly between the GO and various types of yarn, including cotton, polyester and nylon 27 . This method was found to be effective for the preparation of ultrasensitive gas sensors and pliable electronic wires owing to their highly flexible and conducting properties. Herein, we demonstrate the effectiveness of wearable gas sensors based on reduced graphene oxide-decorated yarn (RGOY) with ultra-sensitivity at room temperature using a robust fiber wrapping method ( Fig. 1a ). RGOY gas sensors including RGO-decorated cotton yarn (RGOCY) and RGO-decorated polyester yarn (RGOPY) were obtained from GO wrapping through an electrostatic self-assembly using BSA and a low-temperature reduction. RGOCY and RGOPY 1-m long can be wound on a bobbin without damage ( Fig. 1b ) and were embroidered into commercial textile fabric and connected with electronic components to demonstrate a gas sensor device that turns on an LED light upon exposure to a certain gas concentration ( Fig. 1c,d ). These sensors can selectively detect NO 2 gas down to 250 parts-per-billion (ppb) at room temperature with a –6.0% response, which is a three-fold higher response compared with an RGO gas sensor prepared on a flat substrate 28 . Furthermore, the sensors exhibit high reliability under several washing treatments and more than 1,000 bending tests with an extreme bending radius of as low as 1.0 mm and provide a constant response for long-term (seven days) gas monitoring. Figure 1 Fabric gas sensor with reduced graphene oxide applied. ( a ) Schematic illustration of RGOY gas sensor prepared from microfiber bundles (light grey cylinders) wrapped with RGO (dark grey hexagon patches). The red, blue, black and white spheres indicate oxygen, nitrogen, carbon and hydrogen atoms, respectively. ( b ) Photograph of RGOCY and RGOPY wound on a plastic bobbin. ( c ) RGOCY gas sensor system integrated into a fabric. ( d ) Demonstration of wearable gas sensing and alarm system. All parts of this figure were drawn and photographed by the authors. Full size image Both cotton yarn (CY) and polyester yarn (PY) were used as templates for fabricating yarn wrapped with RGOs. Briefly, a dip-coating process was employed to coat an adhesive thin layer of BSA on the surface of both types of yarn. The resulting BSA-coated yarn (BSAY) was then wrapped with GO sheets through electrostatic self-assembly. Finally, graphene oxide yarn (GOY) was reduced using a low-temperature chemical reduction method. More details regarding the fabrication of RGOCY and RGOPY through a flow process can be found in our previous work and are provided in the supporting information ( Fig. S1 ) 27 . After chemical reduction, the color of the CY and PY changed from white to black. SEM images of RGOCY and RGOPY composed of single RGO microfibers with a diameter of 10 μm are shown in Fig. 2 . The enlarged images ( Fig. 2c,f ) show numerous wrinkles and ripples around the individual fibers, which are attributed to the successful wrapping of the RGO sheets onto the CY and PY. Figure 2 SEM images of RGOCY and RGOPY. ( a, d ) SEM images of single RGOCY and RGOPY (scale bar = 500 and 250 \\micro m). ( b, e ) SEM images of RGOCY and RGOPY micro fibrils (scale bar =5 \\micro m). ( c, f ) HR-SEM images of micro fibril surface of RGOCY and RGOPY (scale bar = 500 nm). Numerous wrinkles were observed, indicating that RGO is well-wrapped around the yarn. Full size image The RGOY was further characterized using", "role": "user" }, { "content": "Scientists in Korea have developed wearable, graphene-coated fabrics that can detect dangerous gases present in the air, alerting the wearer by turning on an LED light. The researchers, from the Electronics and Telecommunications Research Institute and Konkuk University in the Republic of Korea, coated cotton and polyester yarn with a nanoglue called bovine serum albumin (BSA). The yarns were then wrapped in graphene oxide sheets. Graphene is an incredibly strong one-atom-thick layer of carbon, and is known for its excellent conductive properties of heat and electricity. The graphene sheets stuck very well to the nanoglue—so much so that further testing showed the fabrics retained their electrical conducting properties after 1,000 consecutive cycles of bending and straightening and ten washing tests with various chemical detergents. Finally, the graphene oxide yarns were exposed to a chemical reduction process, which involves the gaining of electrons. The reduced-graphene-oxide-coated materials were found to be particularly sensitive to detecting nitrogen dioxide, a pollutant gas commonly found in vehicle exhaust that also results from fossil fuel combustion. Prolonged exposure to nitrogen dioxide can be dangerous to human health, causing many respiratory-related illnesses. Exposure of these specially-treated fabrics to nitrogen dioxide led to a change in the electrical resistance of the reduced graphene oxide. The fabrics were so sensitive that 30 minutes of exposure to 0.25 parts per million of nitrogen dioxide (just under five times above the acceptable standard set by the U.S. Environmental Protection Agency) elicited a response. The fabrics were three times as sensitive to nitrogen dioxide in air compared to another reduced graphene oxide sensor previously prepared on a flat material. Dr Hyung-Kun Lee is measuring the fiber sensor. Credit: ETRI The new technology, according to the researchers, can be immediately adopted in related industries because the coating process is a simple one, making it suitable for mass production. It would allow outdoor wearers to receive relevant information about air quality. The materials could also be incorporated with air-purifying filters to act as \"smart filters\" that can both detect and filter harmful gas from air. \"This sensor can bring a significant change to our daily life since it was developed with flexible and widely used fibers, unlike the gas sensors invariably developed with the existing solid substrates,\" says Dr. Hyung-Kun Lee, who led this research initiative. The study was published on June 4 in the online edition of Scientific Reports, a journal from the publishers of Nature. Dr Hyung-Kun Lee is pointing the graph to monitor the experimental result. Credit: ETRI ", "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 Electric components based on fibers or textiles have been investigated owing to their potential applications in wearable devices. High performance on response to gas, drape-ability and washing durability are of important for gas sensors based on fiber substrates. In this report, we demonstrate the bendable and washable electronic textile ( e -textile) gas sensors composed of reduced graphene oxides (RGOs) using commercially available yarn and molecular glue through an electrostatic self-assembly. The e -textile gas sensor possesses chemical durability to several detergent washing treatments and mechanical stability under 1,000 bending tests at an extreme bending radius of 1 mm as well as a high response to NO 2 gas at room temperature with selectivity to other gases such as acetone, ethanol, ethylene and CO 2 . Introduction Fiber-shaped electric components such as thin film transistors (TFTs) 1 , 2 , 3 , light-emitting diodes (LEDs) 4 , energy harvesters 5 , energy storage devices 6 , 7 , 8 and sensors 3 , 9 , 10 with high performance and flexibility are of great interest owing to their potential applications in portable devices and wearable electronics. Fiber-based gas sensors are expected to have a large number of advantages including excellent drapability, pliability, durability, a light weight and low cost 11 . Moreover, compared with conventional solid-state gas sensors or recently explored gas sensors prepared on flexible film or paper, fiber-based gas sensors can be integrated into textiles in various forms 12 . Thus far, several fiber sensors based on conducting polymers and metal oxides have been developed 13 , 14 , 15 . However, these sensors are unsuitable for flexible and wearable gas sensors owing to their poor mechanical/chemical durability and operation at high temperature. As an alternative approach, graphene and its derivatives have been the focus of research owing to their ultra-high surface area, excellent electrical properties and good selectivity without the need for a catalyst or modification 16 , 17 . Additionally, they show high mechanical strength with flexibility 18 , 19 , which makes them ideal candidate materials for high-performance flexible gas sensors 20 , 21 , 22 , 23 . Results Recently, graphene fibers and yarns have been developed for various applications, such as fiber-based supercapacitors, dye-sensitized photovoltaic cells (DSSCs) and photo-detectors 24 , 25 , 26 . However, there have been no reports to date on graphene yarn-based gas sensors. We previously reported an efficient graphene oxide (GO) wrapping method using biomolecules, i.e., bovine serum albumin (BSA), as a mediator for electrostatic self-assembly between the GO and various types of yarn, including cotton, polyester and nylon 27 . This method was found to be effective for the preparation of ultrasensitive gas sensors and pliable electronic wires owing to their highly flexible and conducting properties. Herein, we demonstrate the effectiveness of wearable gas sensors based on reduced graphene oxide-decorated yarn (RGOY) with ultra-sensitivity at room temperature using a robust fiber wrapping method ( Fig. 1a ). RGOY gas sensors including RGO-decorated cotton yarn (RGOCY) and RGO-decorated polyester yarn (RGOPY) were obtained from GO wrapping through an electrostatic self-assembly using BSA and a low-temperature reduction. RGOCY and RGOPY 1-m long can be wound on a bobbin without damage ( Fig. 1b ) and were embroidered into commercial textile fabric and connected with electronic components to demonstrate a gas sensor device that turns on an LED light upon exposure to a certain gas concentration ( Fig. 1c,d ). These sensors can selectively detect NO 2 gas down to 250 parts-per-billion (ppb) at room temperature with a –6.0% response, which is a three-fold higher response compared with an RGO gas sensor prepared on a flat substrate 28 . Furthermore, the sensors exhibit high reliability under several washing treatments and more than 1,000 bending tests with an extreme bending radius of as low as 1.0 mm and provide a constant response for long-term (seven days) gas monitoring. Figure 1 Fabric gas sensor with reduced graphene oxide applied. ( a ) Schematic illustration of RGOY gas sensor prepared from microfiber bundles (light grey cylinders) wrapped with RGO (dark grey hexagon patches). The red, blue, black and white spheres indicate oxygen, nitrogen, carbon and hydrogen atoms, respectively. ( b ) Photograph of RGOCY and RGOPY wound on a plastic bobbin. ( c ) RGOCY gas sensor system integrated into a fabric. ( d ) Demonstration of wearable gas sensing and alarm system. All parts of this figure were drawn and photographed by the authors. Full size image Both cotton yarn (CY) and polyester yarn (PY) were used as templates for fabricating yarn wrapped with RGOs. Briefly, a dip-coating process was employed to coat an adhesive thin layer of BSA on the surface of both types of yarn. The resulting BSA-coated yarn (BSAY) was then wrapped with GO sheets through electrostatic self-assembly. Finally, graphene oxide yarn (GOY) was reduced using a low-temperature chemical reduction method. More details regarding the fabrication of RGOCY and RGOPY through a flow process can be found in our previous work and are provided in the supporting information ( Fig. S1 ) 27 . After chemical reduction, the color of the CY and PY changed from white to black. SEM images of RGOCY and RGOPY composed of single RGO microfibers with a diameter of 10 μm are shown in Fig. 2 . The enlarged images ( Fig. 2c,f ) show numerous wrinkles and ripples around the individual fibers, which are attributed to the successful wrapping of the RGO sheets onto the CY and PY. Figure 2 SEM images of RGOCY and RGOPY. ( a, d ) SEM images of single RGOCY and RGOPY (scale bar = 500 and 250 \micro m). ( b, e ) SEM images of RGOCY and RGOPY micro fibrils (scale bar =5 \micro m). ( c, f ) HR-SEM images of micro fibril surface of RGOCY and RGOPY (scale bar = 500 nm). Numerous wrinkles were observed, indicating that RGO is well-wrapped around the yarn. Full size image The RGOY was further characterized using<|im_end|> <|im_start|>assistant Scientists in Korea have developed wearable, graphene-coated fabrics that can detect dangerous gases present in the air, alerting the wearer by turning on an LED light. The researchers, from the Electronics and Telecommunications Research Institute and Konkuk University in the Republic of Korea, coated cotton and polyester yarn with a nanoglue called bovine serum albumin (BSA). The yarns were then wrapped in graphene oxide sheets. Graphene is an incredibly strong one-atom-thick layer of carbon, and is known for its excellent conductive properties of heat and electricity. The graphene sheets stuck very well to the nanoglue—so much so that further testing showed the fabrics retained their electrical conducting properties after 1,000 consecutive cycles of bending and straightening and ten washing tests with various chemical detergents. Finally, the graphene oxide yarns were exposed to a chemical reduction process, which involves the gaining of electrons. The reduced-graphene-oxide-coated materials were found to be particularly sensitive to detecting nitrogen dioxide, a pollutant gas commonly found in vehicle exhaust that also results from fossil fuel combustion. Prolonged exposure to nitrogen dioxide can be dangerous to human health, causing many respiratory-related illnesses. Exposure of these specially-treated fabrics to nitrogen dioxide led to a change in the electrical resistance of the reduced graphene oxide. The fabrics were so sensitive that 30 minutes of exposure to 0.25 parts per million of nitrogen dioxide (just under five times above the acceptable standard set by the U.S. Environmental Protection Agency) elicited a response. The fabrics were three times as sensitive to nitrogen dioxide in air compared to another reduced graphene oxide sensor previously prepared on a flat material. Dr Hyung-Kun Lee is measuring the fiber sensor. Credit: ETRI The new technology, according to the researchers, can be immediately adopted in related industries because the coating process is a simple one, making it suitable for mass production. It would allow outdoor wearers to receive relevant information about air quality. The materials could also be incorporated with air-purifying filters to act as "smart filters" that can both detect and filter harmful gas from air. "This sensor can bring a significant change to our daily life since it was developed with flexible and widely used fibers, unlike the gas sensors invariably developed with the existing solid substrates," says Dr. Hyung-Kun Lee, who led this research initiative. The study was published on June 4 in the online edition of Scientific Reports, a journal from the publishers of Nature. Dr Hyung-Kun Lee is pointing the graph to monitor the experimental result. Credit: ETRI <|im_end|>

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1,915

[ { "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 Phytochrome proteins detect red/far-red light to guide the growth, motion, development and reproduction in plants, fungi, and bacteria. Bacterial phytochromes commonly function as an entrance signal in two-component sensory systems. Despite the availability of three-dimensional structures of phytochromes and other two-component proteins, the conformational changes, which lead to activation of the protein, are not understood. We reveal cryo electron microscopy structures of the complete phytochrome from Deinoccocus radiodurans in its resting and photoactivated states at 3.6 Å and 3.5 Å resolution, respectively. Upon photoactivation, the photosensory core module hardly changes its tertiary domain arrangement, but the connector helices between the photosensory and the histidine kinase modules open up like a zipper, causing asymmetry and disorder in the effector domains. The structures provide a framework for atom-scale understanding of signaling in phytochromes, visualize allosteric communication over several nanometers, and suggest that disorder in the dimeric arrangement of the effector domains is important for phosphatase activity in a two-component system. The results have implications for the development of optogenetic applications. Introduction Light is essential for life and all living organisms have developed intricate systems to detect and adapt to it. At the molecular level, this is achieved by photoreceptor proteins. Phytochromes are a protein superfamily in bacteria, plants, and fungi, and function by photoswitching between states that absorb red light (Pr) and far-red light (Pfr) 1 , 2 , 3 , 4 , 5 , 6 . These states have differential signaling activity. Conserved over the entire superfamily and exemplified by the phytochrome from D. radiodurans , phytochromes share a photosensory core module, consisting of PAS, GAF, and PHY domains and a bilin chromophore (Fig. 1 ), which is connected to a variable effector module via helical linkers 3 . The structure of the photosensory core is very similar in plant and bacterial phytochromes 7 , 8 , 9 , 10 , 11 , 12 , 13 but diverges in the context of full-length proteins 14 . Phytochromes are highly interesting targets for gene optimization of plants, are used as near-infrared fluorescent markers in microscopy 15 , and have been utilized in optogenetic applications 16 , 17 . Fig. 1: Spectra and function of Dr BphP and Dr BphP- Dr RR. a The domain organization and the linker configuration are shown with the position of the biliverdin (BV) chromophore indicated. CA catalytic ATP-binding, DHp dimerization and histidine phosphotransfer, GAF cGMP phosphodiesterase-adenylate cyclase FhlA, HK histidine kinase, PAS Per-ARNT-Sim, PHY phytochrome-specific, PSM photosensory module, REC receiver domain, RR response regulator. b Absorption spectra of both proteins recorded in dark (D) or after saturating 655 nm red light (R). The spectra are normalized at the peak at 700 nm of the corresponding dark spectrum. Source data are provided as a Source Data file. c Dark reversion of Dr BphP and Dr BphP- Dr RR. Response regulator fusion increases the Dr BphP dark reversion, which resembles the addition of soluble Dr RR to Dr BphP (see Supplementary Fig. 1b ) 35 . Source data are provided as a Source Data file. d Phos-tag assay of phosphatase activity 35 . In the assay, the retention of phosphorylated protein is slower than its non-phosphorylated counterparts. Here, all samples were supplemented with the same amount of phospho- Dr RR (p- Dr RR) and the change in its final amount implies either kinase (increase) or phosphatase (decrease) activity. The gel shows that Dr BphP- Dr RR dephosphorylates p- Dr RR in its red light-illuminated state (lane R) and the activity is stalled in the darkness (lane D). The phosphatase activity of the fusion protein resembles that of Dr BphP, although is generally weaker because of competition between the fused and free Dr RR. See Supplementary Fig. 1c for an extended gel. Source data are provided as a Source Data file. Full size image Many bacteriophytochromes are histidine kinases or phosphatases in two-component systems (TCSs) 18 , 19 . TCSs sense environmental cues in all kingdoms of life. They are particularly important in microorganisms and plants, where they provide for cell growth, survival, and pathogenicity, and are implicated in multidrug and antibiotic resistance 20 . TCSs consist of sensor kinases, which send phospho-signals to so-called response regulators. A highly pertinent question is how the kinases achieve this signal transduction at the atomic level. Crystal structures of proteins involved in TCS have resulted in a number of partially conflicting conformational mechanisms for signal transduction 21 , 22 , 23 , 24 , 25 , 26 , one of which is that the region around the active site for phosphate transfer is destabilized 27 . Opposing the notion that one clearly defined cascade of structural changes leads to signaling, it has been proposed that allosteric coupling between the different modules controls the activity of the effector domains 25 , 28 , but a structural understanding of this concept is missing. Reminiscent of the state-of-the-art for TCSs, the conformational changes that guide phytochrome activation are not understood. Structures have been obtained for the photosensory core fragment of bacteriophytochromes in Pr and Pfr states 10 , 11 , 12 , pinpointing isomerization of the D-ring of the bilin cofactor and refolding of the so-called PHY tongue, which is a hairpin structure that extends from the PHY domain onto the chromophore region, as outstanding features of the photoconversion 13 . Finer mechanistic insight near the chromophore has been obtained using spectroscopy and crystallography 29 , 30 , 31 , 32 . Signal transduction from the photosensory core to the effector domains has been proposed to be guided by a monomerization mechanism 33 , or by a shift of register in the dimeric binding interface of the sensor-effector linker 34 . However, solid progress is limited by a lack of structures of full-length phytochromes in active and resting states. In this work, we use single-particle cryo-electron microscopy (cryo-EM) to solve the structure of the full-length phytochrome from D. radiodurans ( Dr BphP) in the resting (Pr) and photoactivated (Pfr) states. We present models in both", "role": "user" }, { "content": "Scientist have revealed both dark adapted and light-activated structures of a red photosensory protein, phytochrome. According to the results of the study, almost non-existent structural changes in the regulatory domains can cause large changes elsewhere. The study is published in Nature Communications. 'Nobody has succeeded in this before' Plants and bacteria adapt to light environment by using various photoreceptor proteins. Phytochromes are a group of photoreceptors that respond to red and far-red light. The function of phytochromes have been studied extensively. Still, their full and biologically relevant structures have remained elusive. Now, full-length structures of a model bacterial phytochrome, DrBphP, from Deinococcus radiodurans have been revealed in two activity states. \"Although many groups have tried, nobody has succeeded [in solving] a crystal structure of a full-length phytochrome,\" explains Heikki Takala from the University of Jyväskylä. \"We therefore decided to apply cryo-electron microscopy to this model phytochrome.\" Light-triggered structural changes revealed by cryogenic electron microscopy An international team, including the groups of Dr. Heikki Takala and Prof. Janne Ihalainen from the University of Jyväskylä, have now successfully uncovered the structure of DrBphP. By using single particle cryo-electron microscopy (cryo-EM), they found out that the structure of the full-length phytochrome is a symmetrical and relatively well-defined dimer in the dark-adapted state. However, when illuminated with red light, its output histidine kinase module becomes asymmetrical and less defined. Unlike predicted in previous studies, the light-induced structural changes in the photosensory module were small but amplified only at the output module. \"These results show that almost non-existent structural changes in the regulatory domains can cause large changes elsewhere, giving valuable information about signal propagation and allostery in sensory proteins,\" concludes Prof. Janne Ihalainen, one of the senior scientists on the team. ", "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 Phytochrome proteins detect red/far-red light to guide the growth, motion, development and reproduction in plants, fungi, and bacteria. Bacterial phytochromes commonly function as an entrance signal in two-component sensory systems. Despite the availability of three-dimensional structures of phytochromes and other two-component proteins, the conformational changes, which lead to activation of the protein, are not understood. We reveal cryo electron microscopy structures of the complete phytochrome from Deinoccocus radiodurans in its resting and photoactivated states at 3.6 Å and 3.5 Å resolution, respectively. Upon photoactivation, the photosensory core module hardly changes its tertiary domain arrangement, but the connector helices between the photosensory and the histidine kinase modules open up like a zipper, causing asymmetry and disorder in the effector domains. The structures provide a framework for atom-scale understanding of signaling in phytochromes, visualize allosteric communication over several nanometers, and suggest that disorder in the dimeric arrangement of the effector domains is important for phosphatase activity in a two-component system. The results have implications for the development of optogenetic applications. Introduction Light is essential for life and all living organisms have developed intricate systems to detect and adapt to it. At the molecular level, this is achieved by photoreceptor proteins. Phytochromes are a protein superfamily in bacteria, plants, and fungi, and function by photoswitching between states that absorb red light (Pr) and far-red light (Pfr) 1 , 2 , 3 , 4 , 5 , 6 . These states have differential signaling activity. Conserved over the entire superfamily and exemplified by the phytochrome from D. radiodurans , phytochromes share a photosensory core module, consisting of PAS, GAF, and PHY domains and a bilin chromophore (Fig. 1 ), which is connected to a variable effector module via helical linkers 3 . The structure of the photosensory core is very similar in plant and bacterial phytochromes 7 , 8 , 9 , 10 , 11 , 12 , 13 but diverges in the context of full-length proteins 14 . Phytochromes are highly interesting targets for gene optimization of plants, are used as near-infrared fluorescent markers in microscopy 15 , and have been utilized in optogenetic applications 16 , 17 . Fig. 1: Spectra and function of Dr BphP and Dr BphP- Dr RR. a The domain organization and the linker configuration are shown with the position of the biliverdin (BV) chromophore indicated. CA catalytic ATP-binding, DHp dimerization and histidine phosphotransfer, GAF cGMP phosphodiesterase-adenylate cyclase FhlA, HK histidine kinase, PAS Per-ARNT-Sim, PHY phytochrome-specific, PSM photosensory module, REC receiver domain, RR response regulator. b Absorption spectra of both proteins recorded in dark (D) or after saturating 655 nm red light (R). The spectra are normalized at the peak at 700 nm of the corresponding dark spectrum. Source data are provided as a Source Data file. c Dark reversion of Dr BphP and Dr BphP- Dr RR. Response regulator fusion increases the Dr BphP dark reversion, which resembles the addition of soluble Dr RR to Dr BphP (see Supplementary Fig. 1b ) 35 . Source data are provided as a Source Data file. d Phos-tag assay of phosphatase activity 35 . In the assay, the retention of phosphorylated protein is slower than its non-phosphorylated counterparts. Here, all samples were supplemented with the same amount of phospho- Dr RR (p- Dr RR) and the change in its final amount implies either kinase (increase) or phosphatase (decrease) activity. The gel shows that Dr BphP- Dr RR dephosphorylates p- Dr RR in its red light-illuminated state (lane R) and the activity is stalled in the darkness (lane D). The phosphatase activity of the fusion protein resembles that of Dr BphP, although is generally weaker because of competition between the fused and free Dr RR. See Supplementary Fig. 1c for an extended gel. Source data are provided as a Source Data file. Full size image Many bacteriophytochromes are histidine kinases or phosphatases in two-component systems (TCSs) 18 , 19 . TCSs sense environmental cues in all kingdoms of life. They are particularly important in microorganisms and plants, where they provide for cell growth, survival, and pathogenicity, and are implicated in multidrug and antibiotic resistance 20 . TCSs consist of sensor kinases, which send phospho-signals to so-called response regulators. A highly pertinent question is how the kinases achieve this signal transduction at the atomic level. Crystal structures of proteins involved in TCS have resulted in a number of partially conflicting conformational mechanisms for signal transduction 21 , 22 , 23 , 24 , 25 , 26 , one of which is that the region around the active site for phosphate transfer is destabilized 27 . Opposing the notion that one clearly defined cascade of structural changes leads to signaling, it has been proposed that allosteric coupling between the different modules controls the activity of the effector domains 25 , 28 , but a structural understanding of this concept is missing. Reminiscent of the state-of-the-art for TCSs, the conformational changes that guide phytochrome activation are not understood. Structures have been obtained for the photosensory core fragment of bacteriophytochromes in Pr and Pfr states 10 , 11 , 12 , pinpointing isomerization of the D-ring of the bilin cofactor and refolding of the so-called PHY tongue, which is a hairpin structure that extends from the PHY domain onto the chromophore region, as outstanding features of the photoconversion 13 . Finer mechanistic insight near the chromophore has been obtained using spectroscopy and crystallography 29 , 30 , 31 , 32 . Signal transduction from the photosensory core to the effector domains has been proposed to be guided by a monomerization mechanism 33 , or by a shift of register in the dimeric binding interface of the sensor-effector linker 34 . However, solid progress is limited by a lack of structures of full-length phytochromes in active and resting states. In this work, we use single-particle cryo-electron microscopy (cryo-EM) to solve the structure of the full-length phytochrome from D. radiodurans ( Dr BphP) in the resting (Pr) and photoactivated (Pfr) states. We present models in both<|im_end|> <|im_start|>assistant Scientist have revealed both dark adapted and light-activated structures of a red photosensory protein, phytochrome. According to the results of the study, almost non-existent structural changes in the regulatory domains can cause large changes elsewhere. The study is published in Nature Communications. 'Nobody has succeeded in this before' Plants and bacteria adapt to light environment by using various photoreceptor proteins. Phytochromes are a group of photoreceptors that respond to red and far-red light. The function of phytochromes have been studied extensively. Still, their full and biologically relevant structures have remained elusive. Now, full-length structures of a model bacterial phytochrome, DrBphP, from Deinococcus radiodurans have been revealed in two activity states. "Although many groups have tried, nobody has succeeded [in solving] a crystal structure of a full-length phytochrome," explains Heikki Takala from the University of Jyväskylä. "We therefore decided to apply cryo-electron microscopy to this model phytochrome." Light-triggered structural changes revealed by cryogenic electron microscopy An international team, including the groups of Dr. Heikki Takala and Prof. Janne Ihalainen from the University of Jyväskylä, have now successfully uncovered the structure of DrBphP. By using single particle cryo-electron microscopy (cryo-EM), they found out that the structure of the full-length phytochrome is a symmetrical and relatively well-defined dimer in the dark-adapted state. However, when illuminated with red light, its output histidine kinase module becomes asymmetrical and less defined. Unlike predicted in previous studies, the light-induced structural changes in the photosensory module were small but amplified only at the output module. "These results show that almost non-existent structural changes in the regulatory domains can cause large changes elsewhere, giving valuable information about signal propagation and allostery in sensory proteins," concludes Prof. Janne Ihalainen, one of the senior scientists on the team. <|im_end|>

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2077, 40242, 13, 362, 7701, 62623, 3488, 374, 1268, 279, 24890, 2315, 11322, 420, 8450, 1380, 23985, 520, 279, 25524, 2237, 13, 29016, 14726, 315, 28896, 6532, 304, 350, 6546, 617, 19543, 304, 264, 1396, 315, 26310, 52133, 390, 1659, 278, 24717, 369, 8450, 1380, 23985, 220, 1691, 1174, 220, 1313, 1174, 220, 1419, 1174, 220, 1187, 1174, 220, 914, 1174, 220, 1627, 1174, 832, 315, 902, 374, 430, 279, 5654, 2212, 279, 4642, 2816, 369, 79106, 8481, 374, 72257, 1534, 220, 1544, 662, 29710, 14759, 279, 23035, 430, 832, 9539, 4613, 43118, 315, 24693, 4442, 11767, 311, 43080, 11, 433, 706, 1027, 11223, 430, 63747, 3751, 292, 59086, 1990, 279, 2204, 13761, 11835, 279, 5820, 315, 279, 3369, 1279, 31576, 220, 914, 1174, 220, 1591, 1174, 719, 264, 24693, 8830, 315, 420, 7434, 374, 7554, 13, 5031, 85703, 1189, 315, 279, 1614, 8838, 10826, 38921, 369, 350, 6546, 82, 11, 279, 390, 1659, 278, 4442, 430, 8641, 37555, 998, 33002, 15449, 527, 539, 16365, 13, 71150, 617, 1027, 12457, 369, 279, 7397, 729, 683, 6332, 12569, 315, 17854, 72, 118930, 998, 41484, 288, 304, 2394, 323, 393, 1658, 5415, 220, 605, 1174, 220, 806, 1174, 220, 717, 1174, 67638, 287, 374, 26429, 2065, 315, 279, 423, 77029, 315, 279, 106407, 69903, 5739, 323, 2098, 15345, 315, 279, 779, 19434, 58341, 25466, 11, 902, 374, 264, 7013, 13576, 6070, 430, 2289, 505, 279, 58341, 8106, 8800, 279, 22083, 5237, 461, 5654, 11, 439, 19310, 4519, 315, 279, 6685, 74825, 220, 1032, 662, 5767, 261, 7852, 4633, 20616, 3221, 279, 22083, 5237, 461, 706, 1027, 12457, 1701, 66425, 51856, 323, 26110, 848, 1976, 88, 220, 1682, 1174, 220, 966, 1174, 220, 2148, 1174, 220, 843, 662, 28329, 1380, 23985, 505, 279, 7397, 729, 683, 6332, 311, 279, 3369, 1279, 31576, 706, 1027, 11223, 311, 387, 33687, 555, 264, 1647, 26429, 2065, 17383, 220, 1644, 1174, 477, 555, 264, 6541, 315, 4254, 304, 279, 294, 3212, 292, 11212, 3834, 315, 279, 12271, 53465, 1279, 86845, 220, 1958, 662, 4452, 11, 6573, 5208, 374, 7347, 555, 264, 6996, 315, 14726, 315, 2539, 30425, 37555, 998, 41484, 288, 304, 4642, 323, 41219, 5415, 13, 763, 420, 990, 11, 584, 1005, 3254, 2320, 7203, 16106, 78, 37081, 2298, 92914, 320, 62238, 78, 12, 2783, 8, 311, 11886, 279, 6070, 315, 279, 2539, 30425, 37555, 998, 33002, 505, 423, 13, 12164, 347, 324, 598, 320, 2999, 426, 764, 47, 8, 304, 279, 41219, 320, 3617, 8, 323, 6685, 31262, 320, 47, 1658, 8, 5415, 13, 1226, 3118, 4211, 304, 2225, 128257, 198, 128256, 78191, 198, 51665, 380, 617, 10675, 2225, 6453, 30464, 323, 3177, 12, 31262, 14726, 315, 264, 2579, 7397, 729, 683, 13128, 11, 37555, 998, 33002, 13, 10771, 311, 279, 3135, 315, 279, 4007, 11, 4661, 2536, 60928, 24693, 4442, 304, 279, 23331, 31576, 649, 5353, 3544, 4442, 18403, 13, 578, 4007, 374, 4756, 304, 22037, 26545, 13, 364, 57813, 706, 26399, 304, 420, 1603, 6, 50298, 323, 24032, 10737, 311, 3177, 4676, 555, 1701, 5370, 4604, 461, 15709, 28896, 13, 93682, 998, 41484, 288, 527, 264, 1912, 315, 4604, 461, 58650, 430, 6013, 311, 2579, 323, 3117, 32698, 3177, 13, 578, 734, 315, 37555, 998, 41484, 288, 617, 1027, 20041, 42817, 13, 16782, 11, 872, 2539, 323, 6160, 30450, 9959, 14726, 617, 14958, 66684, 13, 4800, 11, 2539, 30425, 14726, 315, 264, 1646, 45964, 37555, 998, 33002, 11, 2999, 33, 764, 47, 11, 505, 1611, 258, 511, 92411, 12164, 347, 324, 598, 617, 1027, 10675, 304, 1403, 5820, 5415, 13, 330, 16179, 1690, 5315, 617, 6818, 11, 19093, 706, 26399, 510, 258, 22581, 60, 264, 26110, 6070, 315, 264, 2539, 30425, 37555, 998, 33002, 1359, 15100, 1283, 84641, 34390, 6181, 505, 279, 3907, 315, 622, 88, 73150, 4991, 4010, 2357, 13, 330, 1687, 9093, 6773, 311, 3881, 16106, 78, 37081, 2298, 92914, 311, 420, 1646, 37555, 998, 33002, 1210, 8828, 59087, 291, 24693, 4442, 10675, 555, 16106, 29569, 17130, 92914, 1556, 6625, 2128, 11, 2737, 279, 5315, 315, 2999, 13, 1283, 84641, 34390, 6181, 323, 8626, 13, 4448, 818, 358, 12130, 56764, 505, 279, 3907, 315, 622, 88, 73150, 4991, 4010, 2357, 11, 617, 1457, 7946, 43522, 279, 6070, 315, 2999, 33, 764, 47, 13, 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1,915

[ { "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 More than half of Earth’s freshwater resources are held by the Antarctic Ice Sheet, which thus represents by far the largest potential source for global sea-level rise under future warming conditions 1 . Its long-term stability determines the fate of our coastal cities and cultural heritage. Feedbacks between ice, atmosphere, ocean, and the solid Earth give rise to potential nonlinearities in its response to temperature changes. So far, we are lacking a comprehensive stability analysis of the Antarctic Ice Sheet for different amounts of global warming. Here we show that the Antarctic Ice Sheet exhibits a multitude of temperature thresholds beyond which ice loss is irreversible. Consistent with palaeodata 2 we find, using the Parallel Ice Sheet Model 3 , 4 , 5 , that at global warming levels around 2 degrees Celsius above pre-industrial levels, West Antarctica is committed to long-term partial collapse owing to the marine ice-sheet instability. Between 6 and 9 degrees of warming above pre-industrial levels, the loss of more than 70 per cent of the present-day ice volume is triggered, mainly caused by the surface elevation feedback. At more than 10 degrees of warming above pre-industrial levels, Antarctica is committed to become virtually ice-free. The ice sheet’s temperature sensitivity is 1.3 metres of sea-level equivalent per degree of warming up to 2 degrees above pre-industrial levels, almost doubling to 2.4 metres per degree of warming between 2 and 6 degrees and increasing to about 10 metres per degree of warming between 6 and 9 degrees. Each of these thresholds gives rise to hysteresis behaviour: that is, the currently observed ice-sheet configuration is not regained even if temperatures are reversed to present-day levels. In particular, the West Antarctic Ice Sheet does not regrow to its modern extent until temperatures are at least one degree Celsius lower than pre-industrial levels. Our results show that if the Paris Agreement is not met, Antarctica’s long-term sea-level contribution will dramatically increase and exceed that of all other sources. Main The Antarctic Ice Sheet comprises an ice mass equivalent to 58 m of global sea-level rise 1 . Its future evolution and the associated sea-level change are therefore of profound importance to coastal populations, ecosystems and economies. Over the past decades, the ice sheet has been losing mass at an accelerating rate 6 , 7 . Although the current net mass loss from Antarctica is small compared to the other sea-level rise contributions, it is likely to increase with progressing global warming 8 . Snowfall can be expected to increase in a warming atmosphere 9 , but this additional accumulation is likely to be counteracted and eventually overcompensated by ice dynamical effects 10 . The long-term stability of the Antarctic Ice Sheet under a changing climate is the subject of ongoing research. It will be determined by the interplay between a number of negative (dampening) and positive (amplifying) feedbacks 8 . The latter might eventually lead to the crossing of critical thresholds, with the ice sheet entering into an irreversible dynamic, committing it to a specific amount of sea-level contribution. One such self-amplifying feedback is the so-called surface-melt–elevation feedback. Whereas at present in Antarctica there is very little surface melt, it might increase with strong global warming. The resulting lowered surface elevation exposes the ice to warmer temperatures through the atmospheric lapse rate, in turn leading to more melting 11 , 12 , 13 , 14 . Once a critical temperature threshold is crossed, this melt-induced lowering of the ice-sheet surface elevation can trigger accelerated ice loss. In addition, the ice flow is generally accelerated under warmer temperatures, as viscosity decreases and deformation rates for a given stress increase. Through enhanced strain heating, this effect facilitates basal sliding and sped-up ice stream flow and might eventually result in a runaway process known as “creep instability” 15 . Regions of the ice sheet that rest on bedrock below sea level are prone to additional feedback mechanisms, which can potentially drive the collapse of Antarctic Ice Sheet basins. Such regions—termed marine ice-sheet regions—can be found in most of West Antarctica as well as in substantial parts of East Antarctica (for example, the Aurora and Wilkes subglacial basins). One self-reinforcing feedback mechanism associated with these regions is the marine ice-sheet instability, which implies a potential for irreversible grounding-line retreat on retrograde sloping bedrock 8 , 16 , 17 . However, in the presence of sufficiently large ice-shelf buttressing, grounding lines on retrograde bed slopes can be conditionally stable 18 . A potential negative feedback is introduced by solid-Earth rebound: marine ice-sheet mass loss leads to a drop in sea level at the grounding line as a response to post-glacial rebound of the unloaded crust. This can effectively reduce the ice outflow, thereby acting as a stabilizing mechanism 19 . There are several further positive and negative feedback mechanisms caused by the interaction of the Antarctic Ice Sheet with the surrounding ocean, sea ice, atmosphere and the solid Earth 20 . These, however, are not included in the analysis presented here because, as discussed below, they either require a deeper understanding or they can be expected to have a less substantial impact on the long-term stability of the ice sheet. Here we investigate the long-term response of the Antarctic Ice Sheet to various levels of warming with the fully dynamic Parallel Ice Sheet Model (PISM 3 , 4 , 5 ). Owing to the interplay between the dampening and amplifying feedbacks, the response of the Antarctic ice volume to temperature change is expected to be highly nonlinear, and critical threshold behaviour might occur 21 , 22 , leading to committed sea-level contribution upon transgression. This implies the existence of a hysteresis, that is, a path-dependent difference between multiple stable ice-sheet states, similar to what has been shown for the Greenland Ice Sheet 23 . As yet, however, large uncertainties remain concerning the warming levels at which these thresholds are reached and which regions of Antarctica could undergo irreversible ice loss under future warming 21", "role": "user" }, { "content": "The warmer it gets, the faster Antarctica loses ice—and much of it will disappear forever. Consequences for the world's coastal cities and cultural heritage sites would be detrimental, from London to Mumbai, and from New York to Shanghai. That's the conclusion of a team of researchers from the Potsdam Institute for Climate Impact Research, Potsdam University and New York's Columbia University in their new study, published in Nature, on how much warming the Antarctic ice sheet can survive. In around 1 million hours of computation time, their unprecedentedly detailed simulations delineate where, exactly, and at which warming levels the ice would become unstable and eventually melt and drain into the ocean. They find a delicate concert of accelerating and moderating effects, but the main conclusion is that unmitigated climate change would have dire long-term consequences: If the global mean temperature is sustained long enough at four degrees above pre-industrial levels, Antarctic melting alone could eventually raise global sea levels by more than six meters. \"Antarctica holds more than half of Earth's fresh water, frozen in a vast ice-sheet which is nearly five kilometers thick,\" explains Ricarda Winkelmann, researcher at the Potsdam Institute for Climate Impact Research (PIK) and University of Potsdam, and corresponding author of the study. \"As the surrounding ocean water and atmosphere warm due to human greenhouse-gas emissions, the white cap on the South Pole loses mass and eventually becomes unstable. Because of its sheer magnitude, Antarctica's potential for sea-level contribution is enormous: We find that already at 2 degrees of warming, melting and the accelerated ice flow into the ocean will, eventually, entail 2.5 meters of global sea level rise just from Antarctica alone. At 4 degrees, it will be 6.5 meters and at 6 degrees almost 12 meters if these temperature levels would be sustained long enough.\" Long-term change: it's not rapid, but it's forever The paper's title refers to the complex physical phenomenon of hysteresis. In this case, that translates into irreversibility. Anders Levermann, co-author and researcher at PIK and Columbia University describes: \"Antarctica is basically our ultimate heritage from an earlier time in Earth's history. It's been around for roughly 34 million years. Now, our simulations show that once it's melted, it does not regrow to its initial state even if temperatures eventually sink again. Indeed, temperatures would have to go back to pre-industrial levels to allow its full recovery—a highly unlikely scenario. In other words: What we lose of Antarctica now is lost forever.\" The reasons behind this irreversibility are self-enforcing mechanisms in the ice sheets' behavior under warming conditions. Co-author Torsten Albrecht lays out: \"In West Antarctica for instance, the main driver of ice loss is warm ocean water leading to higher melting underneath the ice shelves, which in turn can destabilize the grounded ice sheet. That makes glaciers the size of Florida slide into the ocean. Once temperatures cross the threshold of six degrees above pre-industrial levels, effects from the ice surface become more dominant: As the gigantic mountains of ice slowly sink to lower heights where the air is warmer, this leads to more melt at the ice surface—just as we observe in Greenland.\" The animation shows the modelled long-term evolution of the Antarctic Ice Sheet under steadily increasing temperatures.The upper panel shows the ice sheet's surface elevation change (in meters; grey shading), the ocean-induced melting at the base of the floating ice shelves (in meters per year; purple-orange shading), as well as the topography of the bed underneath the ice sheet and the surrounding ocean (in meters above the present-day sea level; blue-brown shading).The lower panel shows the total sea-level relevant ice volume change (in meters of sea-level equivalent ; blue curve) and total ice mass flux (in gigatons per year; purple curve).Abbreviations: EAIS, East Antarctic Ice Sheet; WAIS, West Antarctic Ice Sheet; IS, ice shelf; FRIS, Filchner-Ronne Ice Shelf.For full details, please refer to the publication below. Credit: This video is supplement to the following article: Julius Garbe, Torsten Albrecht, Anders Levermann, Jonathan F. Donges, Ricarda Winkelmann (2020): The hysteresis of the Antarctic Ice Sheet. Nature [DOI:10.1038/s41586-020-2727-5] The fate of New York, Tokyo, Hamburg is in our hands Ice loss and melting have accelerated significantly over the last decades in Antarctica. The authors, however, have explicitly not addressed the question of time scale in their work, but rather assess the critical warming levels at which parts of the Antarctic ice sheet become unstable. Winkelmann explains this approach: \"In the end, it is our burning of coal and oil that determines ongoing and future greenhouse-gas emissions and therefore, if and when critical temperature thresholds in Antarctica are crossed. And even if the ice loss happens on long time scales, the respective carbon dioxide levels can already be reached in the near future. We decide now whether we manage to halt the warming. So Antarctica's fate really lies in our hands—and with it that of our cities and cultural sites across the globe, from Rio de Janeiro's Copacabana to Sydney's Opera House. Thus, this study really is another exclamation mark behind the importance of the Paris Climate Accord: Keep global warming below two degrees.\" Levermann adds: \"If we give up the Paris Agreement, we give up Hamburg, Tokyo and New York.\" ", "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 More than half of Earth’s freshwater resources are held by the Antarctic Ice Sheet, which thus represents by far the largest potential source for global sea-level rise under future warming conditions 1 . Its long-term stability determines the fate of our coastal cities and cultural heritage. Feedbacks between ice, atmosphere, ocean, and the solid Earth give rise to potential nonlinearities in its response to temperature changes. So far, we are lacking a comprehensive stability analysis of the Antarctic Ice Sheet for different amounts of global warming. Here we show that the Antarctic Ice Sheet exhibits a multitude of temperature thresholds beyond which ice loss is irreversible. Consistent with palaeodata 2 we find, using the Parallel Ice Sheet Model 3 , 4 , 5 , that at global warming levels around 2 degrees Celsius above pre-industrial levels, West Antarctica is committed to long-term partial collapse owing to the marine ice-sheet instability. Between 6 and 9 degrees of warming above pre-industrial levels, the loss of more than 70 per cent of the present-day ice volume is triggered, mainly caused by the surface elevation feedback. At more than 10 degrees of warming above pre-industrial levels, Antarctica is committed to become virtually ice-free. The ice sheet’s temperature sensitivity is 1.3 metres of sea-level equivalent per degree of warming up to 2 degrees above pre-industrial levels, almost doubling to 2.4 metres per degree of warming between 2 and 6 degrees and increasing to about 10 metres per degree of warming between 6 and 9 degrees. Each of these thresholds gives rise to hysteresis behaviour: that is, the currently observed ice-sheet configuration is not regained even if temperatures are reversed to present-day levels. In particular, the West Antarctic Ice Sheet does not regrow to its modern extent until temperatures are at least one degree Celsius lower than pre-industrial levels. Our results show that if the Paris Agreement is not met, Antarctica’s long-term sea-level contribution will dramatically increase and exceed that of all other sources. Main The Antarctic Ice Sheet comprises an ice mass equivalent to 58 m of global sea-level rise 1 . Its future evolution and the associated sea-level change are therefore of profound importance to coastal populations, ecosystems and economies. Over the past decades, the ice sheet has been losing mass at an accelerating rate 6 , 7 . Although the current net mass loss from Antarctica is small compared to the other sea-level rise contributions, it is likely to increase with progressing global warming 8 . Snowfall can be expected to increase in a warming atmosphere 9 , but this additional accumulation is likely to be counteracted and eventually overcompensated by ice dynamical effects 10 . The long-term stability of the Antarctic Ice Sheet under a changing climate is the subject of ongoing research. It will be determined by the interplay between a number of negative (dampening) and positive (amplifying) feedbacks 8 . The latter might eventually lead to the crossing of critical thresholds, with the ice sheet entering into an irreversible dynamic, committing it to a specific amount of sea-level contribution. One such self-amplifying feedback is the so-called surface-melt–elevation feedback. Whereas at present in Antarctica there is very little surface melt, it might increase with strong global warming. The resulting lowered surface elevation exposes the ice to warmer temperatures through the atmospheric lapse rate, in turn leading to more melting 11 , 12 , 13 , 14 . Once a critical temperature threshold is crossed, this melt-induced lowering of the ice-sheet surface elevation can trigger accelerated ice loss. In addition, the ice flow is generally accelerated under warmer temperatures, as viscosity decreases and deformation rates for a given stress increase. Through enhanced strain heating, this effect facilitates basal sliding and sped-up ice stream flow and might eventually result in a runaway process known as “creep instability” 15 . Regions of the ice sheet that rest on bedrock below sea level are prone to additional feedback mechanisms, which can potentially drive the collapse of Antarctic Ice Sheet basins. Such regions—termed marine ice-sheet regions—can be found in most of West Antarctica as well as in substantial parts of East Antarctica (for example, the Aurora and Wilkes subglacial basins). One self-reinforcing feedback mechanism associated with these regions is the marine ice-sheet instability, which implies a potential for irreversible grounding-line retreat on retrograde sloping bedrock 8 , 16 , 17 . However, in the presence of sufficiently large ice-shelf buttressing, grounding lines on retrograde bed slopes can be conditionally stable 18 . A potential negative feedback is introduced by solid-Earth rebound: marine ice-sheet mass loss leads to a drop in sea level at the grounding line as a response to post-glacial rebound of the unloaded crust. This can effectively reduce the ice outflow, thereby acting as a stabilizing mechanism 19 . There are several further positive and negative feedback mechanisms caused by the interaction of the Antarctic Ice Sheet with the surrounding ocean, sea ice, atmosphere and the solid Earth 20 . These, however, are not included in the analysis presented here because, as discussed below, they either require a deeper understanding or they can be expected to have a less substantial impact on the long-term stability of the ice sheet. Here we investigate the long-term response of the Antarctic Ice Sheet to various levels of warming with the fully dynamic Parallel Ice Sheet Model (PISM 3 , 4 , 5 ). Owing to the interplay between the dampening and amplifying feedbacks, the response of the Antarctic ice volume to temperature change is expected to be highly nonlinear, and critical threshold behaviour might occur 21 , 22 , leading to committed sea-level contribution upon transgression. This implies the existence of a hysteresis, that is, a path-dependent difference between multiple stable ice-sheet states, similar to what has been shown for the Greenland Ice Sheet 23 . As yet, however, large uncertainties remain concerning the warming levels at which these thresholds are reached and which regions of Antarctica could undergo irreversible ice loss under future warming 21<|im_end|> <|im_start|>assistant The warmer it gets, the faster Antarctica loses ice—and much of it will disappear forever. Consequences for the world's coastal cities and cultural heritage sites would be detrimental, from London to Mumbai, and from New York to Shanghai. That's the conclusion of a team of researchers from the Potsdam Institute for Climate Impact Research, Potsdam University and New York's Columbia University in their new study, published in Nature, on how much warming the Antarctic ice sheet can survive. In around 1 million hours of computation time, their unprecedentedly detailed simulations delineate where, exactly, and at which warming levels the ice would become unstable and eventually melt and drain into the ocean. They find a delicate concert of accelerating and moderating effects, but the main conclusion is that unmitigated climate change would have dire long-term consequences: If the global mean temperature is sustained long enough at four degrees above pre-industrial levels, Antarctic melting alone could eventually raise global sea levels by more than six meters. "Antarctica holds more than half of Earth's fresh water, frozen in a vast ice-sheet which is nearly five kilometers thick," explains Ricarda Winkelmann, researcher at the Potsdam Institute for Climate Impact Research (PIK) and University of Potsdam, and corresponding author of the study. "As the surrounding ocean water and atmosphere warm due to human greenhouse-gas emissions, the white cap on the South Pole loses mass and eventually becomes unstable. Because of its sheer magnitude, Antarctica's potential for sea-level contribution is enormous: We find that already at 2 degrees of warming, melting and the accelerated ice flow into the ocean will, eventually, entail 2.5 meters of global sea level rise just from Antarctica alone. At 4 degrees, it will be 6.5 meters and at 6 degrees almost 12 meters if these temperature levels would be sustained long enough." Long-term change: it's not rapid, but it's forever The paper's title refers to the complex physical phenomenon of hysteresis. In this case, that translates into irreversibility. Anders Levermann, co-author and researcher at PIK and Columbia University describes: "Antarctica is basically our ultimate heritage from an earlier time in Earth's history. It's been around for roughly 34 million years. Now, our simulations show that once it's melted, it does not regrow to its initial state even if temperatures eventually sink again. Indeed, temperatures would have to go back to pre-industrial levels to allow its full recovery—a highly unlikely scenario. In other words: What we lose of Antarctica now is lost forever." The reasons behind this irreversibility are self-enforcing mechanisms in the ice sheets' behavior under warming conditions. Co-author Torsten Albrecht lays out: "In West Antarctica for instance, the main driver of ice loss is warm ocean water leading to higher melting underneath the ice shelves, which in turn can destabilize the grounded ice sheet. That makes glaciers the size of Florida slide into the ocean. Once temperatures cross the threshold of six degrees above pre-industrial levels, effects from the ice surface become more dominant: As the gigantic mountains of ice slowly sink to lower heights where the air is warmer, this leads to more melt at the ice surface—just as we observe in Greenland." The animation shows the modelled long-term evolution of the Antarctic Ice Sheet under steadily increasing temperatures.The upper panel shows the ice sheet's surface elevation change (in meters; grey shading), the ocean-induced melting at the base of the floating ice shelves (in meters per year; purple-orange shading), as well as the topography of the bed underneath the ice sheet and the surrounding ocean (in meters above the present-day sea level; blue-brown shading).The lower panel shows the total sea-level relevant ice volume change (in meters of sea-level equivalent ; blue curve) and total ice mass flux (in gigatons per year; purple curve).Abbreviations: EAIS, East Antarctic Ice Sheet; WAIS, West Antarctic Ice Sheet; IS, ice shelf; FRIS, Filchner-Ronne Ice Shelf.For full details, please refer to the publication below. Credit: This video is supplement to the following article: Julius Garbe, Torsten Albrecht, Anders Levermann, Jonathan F. Donges, Ricarda Winkelmann (2020): The hysteresis of the Antarctic Ice Sheet. Nature [DOI:10.1038/s41586-020-2727-5] The fate of New York, Tokyo, Hamburg is in our hands Ice loss and melting have accelerated significantly over the last decades in Antarctica. The authors, however, have explicitly not addressed the question of time scale in their work, but rather assess the critical warming levels at which parts of the Antarctic ice sheet become unstable. Winkelmann explains this approach: "In the end, it is our burning of coal and oil that determines ongoing and future greenhouse-gas emissions and therefore, if and when critical temperature thresholds in Antarctica are crossed. And even if the ice loss happens on long time scales, the respective carbon dioxide levels can already be reached in the near future. We decide now whether we manage to halt the warming. So Antarctica's fate really lies in our hands—and with it that of our cities and cultural sites across the globe, from Rio de Janeiro's Copacabana to Sydney's Opera House. Thus, this study really is another exclamation mark behind the importance of the Paris Climate Accord: Keep global warming below two degrees." Levermann adds: "If we give up the Paris Agreement, we give up Hamburg, Tokyo and New York." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In recent years, complex nanocomposites formed by Ag nanoparticles coupled to an α-Ag 2 WO 4 semiconductor network have emerged as promising bactericides, where the semiconductor attracts bacterial agents and Ag nanoparticles neutralize them. However, the production rate of such materials has been limited to transmission electron microscope processing, making it difficult to cross the barrier from basic research to real applications. The interaction between pulsed laser radiation and α-Ag 2 WO 4 has revealed a new processing alternative to scale up the production of the nanocomposite resulting in a 32-fold improvement of bactericidal performance, and at the same time obtaining a new class of spherical Ag x W y O z nanoparticles. Introduction The ever-increasing use of semiconductors in daily human life has brought a wave of new materials with a wide range of technological applications. In particular, one of the semiconductor families that has attracted the most attention in recent years is the family of ternary tungsten oxides, such as metal tungstates (with the general formula MWO 4 ), which are a class of functional materials with fascinating properties at the cutting edge of fundamental science, as well as having many potential applications that are studied and applied widely in many fields 1 , 2 , 3 . Within this family of materials, silver tungstate (α-Ag 2 WO 4 ) is an important inorganic material that has attracted significant attention owing to its applications in photocalalysts, photoswitches, or as an alternative to conventional wide band gap semiconductors 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 . Recent studies have demonstrated that crystals of α-Ag 2 WO 4 showed a metal nanoparticle growth attached to the semiconductor framework, which in the near future may lead to outstanding applications due to Ag segregation, such as photocatalysis, ozone sensing and bacteriocidicity 3 , 5 , 8 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 . Despite the great potential for growing novel metal nanoparticles on the framework of tungstate semiconductors, the ability to grow and control their molecular structure has been limited to Transmission Electron Microscopy (TEM) processing 2 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 . It is of exceptional scientific importance to scale up the production of the assembly under non-special conditions, and at the same time the methodology should provide enough versatility to be extensible to a wide range of materials. In this context, ultrashort laser irradiation over the sample in air may represent an alternative, as it can be easily integrated within a production process. Other alternatives may be electron beam machining. The influence of laser irradiation over materials promotes a complex interplay between various physical and chemical mechanisms associated with sub-nanosecond timescale processes, influencing the constituent elements of materials in an intense way, which may result in the emergence of changes in the macroscopic behavior of materials due to internal modifications. In this sense, the current scientific literature demonstrates an ever-increasing use of femtosecond laser radiation in processing materials, the induction of a nanometric structure in bulk materials being its most popular use for obtaining novel species that present highly attractive properties for technological advances 32 , 33 , 34 , 35 , 36 , 37 . However, the ease with which the structure of materials can be modified at nanometric scales also allows the manufacture of novel complex nanoensembles 38 , 39 , 40 , 41 . Nowadays, the femtosecond laser-matter interactions that lead to the production of such promising materials are still not fully understood. However, the reliability and versatility of using pulsed laser radiation for nanomaterials has led to an exponential growth in its use 42 , 43 , 44 . Based on this fact, in this communication we seek to fulfill a three-fold objective. The first is to report the novel formation of Ag and (Ag x W y O z ) nanoparticles from α-Ag 2 WO 4 by laser-assisted irradiation, where a large amount of material is created and non-special conditions are required, rather than irradiating the α-Ag 2 WO 4 sample in air. These results are compared with those obtained in previous theoretical and experimental studies on the response triggered by electron beam irradiation on α-Ag 2 WO 4 . Second, based on this comparison, an explanation is given to unveil the formation of Ag nanoparticles occurring along the laser interaction. The third aim is to demonstrate that laser-irradiated samples have a much higher bactericidal activity than samples treated with electron beams. We believe that these novel results are of outstanding relevance, since they may inspire the efficient synthesis of nanocompounds and contribute to broadening the fundamental knowledge on the effect of laser-matter interactions. Experimental Results In this proof-of-concept experiment to demonstrate the ability of the femtosecond laser to increase the efficiency of the production of nanoparticles over large areas of α-Ag 2 WO 4 and test its bactericidal activity, an 8 mm × 8 mm portion of the surface of each sample was irradiated. The samples were then characterized by high resolution TEM (HR-TEM) and analyzed by energy dispersive X-ray spectroscopy (EDS). In parallel, bactericidal activity was tested by bringing the treated samples into contact with Planktonic cultures of Methicillin-Resistant Staphylococcus Aureus ATCC 33591 (MRSA), and then analyzing them by scanning microscopy (SEM) and confocal laser scanning microscopy (CLSM). Material characterization Powder and pellet samples of α-Ag 2 WO 4 were prepared and irradiated following two different routes. Protocol I consisted in irradiating the sample with a spot diameter in the order of 20 µm at a fluence of about 60 J/cm 2 . In protocol II the sample was irradiated with a spot diameter of approximately 84 µm at a fluence of about 3.6 J/cm 2 . The samples were then characterized by HR-TEM and analyzed by EDS. In protocol I, two different chemical regions", "role": "user" }, { "content": "In recent decades, research groups in the field of materials science have invested time and resources to answer the following question: Is it possible to develop new techniques to produce silver particles on a nanometric scale (i.e., one billionth of a meter), thus enhancing the optical, catalytic and bactericidal properties of silver? A group of Brazilian investigators reports new developments. In a research carried out within the Center for Development of Functional Materials (CDMF), the researchers developed a new technological approach to generate silver nanoparticles with 32 times the bactericidal capacity of those currently used in food packaging, orthotics, and hospital and medical materials, among others. The results of the study were published in Scientific Reports. Professor Elson Longo of UFSCar says that CDMF's researchers developed an innovative method of obtaining nanocomposites three years ago. These nanocomposites comprised silver nanoparticles coupled to a silver tungstate semiconductor crystal by transmission electron microscopy. However, the high cost of transmission electron microscopes limited plans of large-scale production of these materials for real-world applications. \"The transmission electron microscope used to obtain this material costs approximately 1.3 million euros,\" Longo said. The technique involved electron-beam irradiation of silver tungstate, which resulted in promising bactericides whereby the silver tungstate semiconductor attracts bacterial agents that are then are neutralized by silver nanoparticles. To scale up production of these nanocomposites using a more competitive method, the researchers developed a novel technique consisting of pulsed laser irradiation of a silver tungstate semiconductor, with each pulse lasting only a femtosecond—one millionth of one billionth of a second (10-15 s). Analysis of the irradiated samples showed that interaction between the silver tungstate semiconductor and the femtosecond laser gave rise to large numbers of microstructures, which they characterized by transmission electron microscopy and found to be of two different types. \"The new technique we developed resulted both in silver nanoparticles left on the semiconductor and in silver clusters,\" said the coordinator of the FAPESP-funded research center. To measure the bactericidal activity of the materials, the researchers placed samples of them in contact with methicillin-resistant strains of Staphylococcus aureus (MRSA), a bacterium that is resistant to numerous antibiotics and is frequently at the root of hospital-acquired infections. Microscopic analysis showed a 32-fold increase in bactericidal activity for the laser-irradiated samples compared with silver nanoparticles produced by electron-beam irradiation. \"The new technique offers the possibility of obtaining high-performance bactericidal compounds that are easy to produce,\" Longo said. Potential applications The researchers have applied for a patent on the new technique and the two new classes of silver nanoparticle obtained by the technique. The idea is to license the technology to Nanox, a spinoff from CDMF based in São Carlos, São Paulo State, and supported by FAPESP's Innovative Research in Small Business Program (PIPE). \"Nanox already sells silver nanoparticles worldwide and could benefit a great deal from the new technique for obtaining the material,\" Longo said. The researchers plan to evaluate use of the material in dental prosthetics and have begun trials to investigate the action of nanocomposites in cancer cells. Preliminary results of the experiments suggest the nanoparticles can eliminate tumor cells without affecting healthy cells. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In recent years, complex nanocomposites formed by Ag nanoparticles coupled to an α-Ag 2 WO 4 semiconductor network have emerged as promising bactericides, where the semiconductor attracts bacterial agents and Ag nanoparticles neutralize them. However, the production rate of such materials has been limited to transmission electron microscope processing, making it difficult to cross the barrier from basic research to real applications. The interaction between pulsed laser radiation and α-Ag 2 WO 4 has revealed a new processing alternative to scale up the production of the nanocomposite resulting in a 32-fold improvement of bactericidal performance, and at the same time obtaining a new class of spherical Ag x W y O z nanoparticles. Introduction The ever-increasing use of semiconductors in daily human life has brought a wave of new materials with a wide range of technological applications. In particular, one of the semiconductor families that has attracted the most attention in recent years is the family of ternary tungsten oxides, such as metal tungstates (with the general formula MWO 4 ), which are a class of functional materials with fascinating properties at the cutting edge of fundamental science, as well as having many potential applications that are studied and applied widely in many fields 1 , 2 , 3 . Within this family of materials, silver tungstate (α-Ag 2 WO 4 ) is an important inorganic material that has attracted significant attention owing to its applications in photocalalysts, photoswitches, or as an alternative to conventional wide band gap semiconductors 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 . Recent studies have demonstrated that crystals of α-Ag 2 WO 4 showed a metal nanoparticle growth attached to the semiconductor framework, which in the near future may lead to outstanding applications due to Ag segregation, such as photocatalysis, ozone sensing and bacteriocidicity 3 , 5 , 8 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 . Despite the great potential for growing novel metal nanoparticles on the framework of tungstate semiconductors, the ability to grow and control their molecular structure has been limited to Transmission Electron Microscopy (TEM) processing 2 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 . It is of exceptional scientific importance to scale up the production of the assembly under non-special conditions, and at the same time the methodology should provide enough versatility to be extensible to a wide range of materials. In this context, ultrashort laser irradiation over the sample in air may represent an alternative, as it can be easily integrated within a production process. Other alternatives may be electron beam machining. The influence of laser irradiation over materials promotes a complex interplay between various physical and chemical mechanisms associated with sub-nanosecond timescale processes, influencing the constituent elements of materials in an intense way, which may result in the emergence of changes in the macroscopic behavior of materials due to internal modifications. In this sense, the current scientific literature demonstrates an ever-increasing use of femtosecond laser radiation in processing materials, the induction of a nanometric structure in bulk materials being its most popular use for obtaining novel species that present highly attractive properties for technological advances 32 , 33 , 34 , 35 , 36 , 37 . However, the ease with which the structure of materials can be modified at nanometric scales also allows the manufacture of novel complex nanoensembles 38 , 39 , 40 , 41 . Nowadays, the femtosecond laser-matter interactions that lead to the production of such promising materials are still not fully understood. However, the reliability and versatility of using pulsed laser radiation for nanomaterials has led to an exponential growth in its use 42 , 43 , 44 . Based on this fact, in this communication we seek to fulfill a three-fold objective. The first is to report the novel formation of Ag and (Ag x W y O z ) nanoparticles from α-Ag 2 WO 4 by laser-assisted irradiation, where a large amount of material is created and non-special conditions are required, rather than irradiating the α-Ag 2 WO 4 sample in air. These results are compared with those obtained in previous theoretical and experimental studies on the response triggered by electron beam irradiation on α-Ag 2 WO 4 . Second, based on this comparison, an explanation is given to unveil the formation of Ag nanoparticles occurring along the laser interaction. The third aim is to demonstrate that laser-irradiated samples have a much higher bactericidal activity than samples treated with electron beams. We believe that these novel results are of outstanding relevance, since they may inspire the efficient synthesis of nanocompounds and contribute to broadening the fundamental knowledge on the effect of laser-matter interactions. Experimental Results In this proof-of-concept experiment to demonstrate the ability of the femtosecond laser to increase the efficiency of the production of nanoparticles over large areas of α-Ag 2 WO 4 and test its bactericidal activity, an 8 mm × 8 mm portion of the surface of each sample was irradiated. The samples were then characterized by high resolution TEM (HR-TEM) and analyzed by energy dispersive X-ray spectroscopy (EDS). In parallel, bactericidal activity was tested by bringing the treated samples into contact with Planktonic cultures of Methicillin-Resistant Staphylococcus Aureus ATCC 33591 (MRSA), and then analyzing them by scanning microscopy (SEM) and confocal laser scanning microscopy (CLSM). Material characterization Powder and pellet samples of α-Ag 2 WO 4 were prepared and irradiated following two different routes. Protocol I consisted in irradiating the sample with a spot diameter in the order of 20 µm at a fluence of about 60 J/cm 2 . In protocol II the sample was irradiated with a spot diameter of approximately 84 µm at a fluence of about 3.6 J/cm 2 . The samples were then characterized by HR-TEM and analyzed by EDS. In protocol I, two different chemical regions<|im_end|> <|im_start|>assistant In recent decades, research groups in the field of materials science have invested time and resources to answer the following question: Is it possible to develop new techniques to produce silver particles on a nanometric scale (i.e., one billionth of a meter), thus enhancing the optical, catalytic and bactericidal properties of silver? A group of Brazilian investigators reports new developments. In a research carried out within the Center for Development of Functional Materials (CDMF), the researchers developed a new technological approach to generate silver nanoparticles with 32 times the bactericidal capacity of those currently used in food packaging, orthotics, and hospital and medical materials, among others. The results of the study were published in Scientific Reports. Professor Elson Longo of UFSCar says that CDMF's researchers developed an innovative method of obtaining nanocomposites three years ago. These nanocomposites comprised silver nanoparticles coupled to a silver tungstate semiconductor crystal by transmission electron microscopy. However, the high cost of transmission electron microscopes limited plans of large-scale production of these materials for real-world applications. "The transmission electron microscope used to obtain this material costs approximately 1.3 million euros," Longo said. The technique involved electron-beam irradiation of silver tungstate, which resulted in promising bactericides whereby the silver tungstate semiconductor attracts bacterial agents that are then are neutralized by silver nanoparticles. To scale up production of these nanocomposites using a more competitive method, the researchers developed a novel technique consisting of pulsed laser irradiation of a silver tungstate semiconductor, with each pulse lasting only a femtosecond—one millionth of one billionth of a second (10-15 s). Analysis of the irradiated samples showed that interaction between the silver tungstate semiconductor and the femtosecond laser gave rise to large numbers of microstructures, which they characterized by transmission electron microscopy and found to be of two different types. "The new technique we developed resulted both in silver nanoparticles left on the semiconductor and in silver clusters," said the coordinator of the FAPESP-funded research center. To measure the bactericidal activity of the materials, the researchers placed samples of them in contact with methicillin-resistant strains of Staphylococcus aureus (MRSA), a bacterium that is resistant to numerous antibiotics and is frequently at the root of hospital-acquired infections. Microscopic analysis showed a 32-fold increase in bactericidal activity for the laser-irradiated samples compared with silver nanoparticles produced by electron-beam irradiation. "The new technique offers the possibility of obtaining high-performance bactericidal compounds that are easy to produce," Longo said. Potential applications The researchers have applied for a patent on the new technique and the two new classes of silver nanoparticle obtained by the technique. The idea is to license the technology to Nanox, a spinoff from CDMF based in São Carlos, São Paulo State, and supported by FAPESP's Innovative Research in Small Business Program (PIPE). "Nanox already sells silver nanoparticles worldwide and could benefit a great deal from the new technique for obtaining the material," Longo said. The researchers plan to evaluate use of the material in dental prosthetics and have begun trials to investigate the action of nanocomposites in cancer cells. Preliminary results of the experiments suggest the nanoparticles can eliminate tumor cells without affecting healthy cells. <|im_end|>

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2,030

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The olefin metathesis reaction of two unsaturated substrates is one of the most powerful carbon–carbon-bond-forming reactions in organic chemistry. Specifically, the catalytic olefin metathesis reaction has led to profound developments in the synthesis of molecules relevant to the petroleum, materials, agricultural and pharmaceutical industries 1 . These reactions are characterized by their use of discrete metal alkylidene catalysts that operate via a well-established mechanism 2 . While the corresponding carbonyl–olefin metathesis reaction can also be used to construct carbon–carbon bonds, currently available methods are scarce and severely hampered by either harsh reaction conditions or the required use of stoichiometric transition metals as reagents. To date, no general protocol for catalytic carbonyl–olefin metathesis has been reported. Here we demonstrate a catalytic carbonyl–olefin ring-closing metathesis reaction that uses iron, an Earth-abundant and environmentally benign transition metal, as a catalyst. This transformation accommodates a variety of substrates and is distinguished by its operational simplicity, mild reaction conditions, high functional-group tolerance, and amenability to gram-scale synthesis. We anticipate that these characteristics, coupled with the efficiency of this reaction, will allow for further advances in areas that have historically been enhanced by olefin metathesis. Main Classified by their mechanistic profile, metathesis reactions most often proceed through a [2+2] cycloaddition to form a 4-atom cyclic intermediate, followed by [2+2] cycloreversion, resulting in an exchange of reactive partners 3 , 4 , 5 , 6 . Included in this mode of reactivity are classical olefination reactions ( Fig. 1a ), in which highly polarized nucleophilic components add to carbonyl derivatives to give cyclic intermediates 7 , 8 , 9 . These compounds then fragment to produce olefins and a metal or main-group oxo species, the latter being the thermodynamic driving force for the reaction. The utility of this chemistry is often hampered by harsh conditions, the need for pre-functionalized intermediates and the production of excess quantities of waste products. A revolutionary development in this regard was the establishment of the catalytic olefin–olefin metathesis reaction, in which transition-metal alkylidenes facilitate [2+2] cycloadditions and subsequent [2+2] cycloreversions from simple olefin starting materials ( Fig. 1b ). Since its discovery, olefin metathesis has led to marked advances in the fields of organic chemistry as well as chemical biology, and allowed entry into previously inaccessible complex molecules. Although it was discovered at around the same time, the corresponding carbonyl–olefin metathesis ( Fig. 1c ) is much less developed 10 . To date, no catalytic protocol of general synthetic utility exists for carbonyl–olefin metathesis reactions, and, furthermore, available procedures rely on harsh reaction conditions or the use of stoichiometric metal reagents. The earliest reported examples for carbonyl–olefin metathesis reactions involve a two-step sequence including a photoinduced [2+2] cycloaddition, followed by a subsequent acidic and/or thermal fragmentation step to induce cycloreversion to the corresponding metathesis products ( Fig. 1c ) 10 , 11 , 12 . The success of this photolysis–pyrolysis series is often impeded by harsh reaction conditions, which are prone to result in competing polymerization or regeneration of starting carbonyl–olefin pairs. Importantly, stoichiometric amounts of catalysts originally developed for olefin metathesis ( Fig. 1b ) were found to be able to mediate carbonyl–olefin metathesis reactions. In this case, the cycloreversion step results in the formation of a kinetically inert metal–oxo complex, precluding regeneration of the metal alkylidene and prohibiting catalyst turnover ( Fig. 1c ) 13 . Figure 1: Olefination and metathesis reactions for the formation of alkenes. a , Summary of traditional olefination reactions in organic synthesis. b , Olefin–olefin metathesis catalysed by ruthenium, molybdenum and tungsten complexes. c , Modes of carbonyl–olefin metathesis, including two-step photochemical cycloaddition/thermolysis cycloreversion, stoichiometric transition-metal-mediated, organocatalytic, and the new iron( III )-catalysed processes described herein. R, R 1 , R 2 , R 3 , R 4 , generic substituent. cat., catalyst. PowerPoint slide Full size image Alternatively, titanium-based Tebbe and Petasis reagents have been used in excess to induce initial olefin metathesis and subsequent carbonyl olefination reactions, resulting in the formation of carbonyl–olefin metathesis products 14 , 15 . In addition to this titanium alkylidene approach, Brønsted and Lewis acids are also reported to effect carbonyl–olefin metathesis reactions of simple acetophenone and benzaldehyde derivatives, although limited in scope 16 , 17 , 18 , 19 . An important contribution in carbonyl–olefin metathesis reactions was reported recently, wherein an organocatalysed (3+2)/retro-(3+2) cycloaddition process allowed the ring-opening metathesis of cyclopropenes to give γ,δ-unsaturated aldehydes, which constitute formal carbonyl–olefin metathesis products ( Fig. 1c ) 20 . Although a remarkable advance, only highly strained cyclopropenes are applicable as olefinic components. As such, a general catalytic protocol has yet to be developed. Despite the development of the methods described earlier, the only protocol for carbonyl–olefin metathesis that has been applied to the synthesis of biologically active natural products and pharmaceutically relevant compounds 21 , 22 is the stoichiometric metal-mediated approach ( Fig. 1c ), further illustrating the need for a general catalytic system. We describe a Lewis-acid-catalysed carbonyl–olefin ring-closing metathesis reaction for the direct synthesis of functionalized carbocycles, representing a major advance in carbonyl–olefin metathesis. At the outset of our investigations, we envisioned an efficient design principle for catalytic carbonyl–olefin metathesis based on the in situ formation of oxetanes as reactive intermediates ( II ) ( Fig. 1c ). This approach fundamentally differs from stoichiometric carbonyl–olefin metathesis protocols proceeding via intermediate metalla-oxetanes using metal-alkylidene reagents. While these result in the formation of kinetically inert metal–oxo complexes upon retro-cycloaddition that ultimately prohibit a catalytic process, the corresponding oxetane intermediates ( II ) are able to undergo direct fragmentation to the desired carbonyl–olefin metathesis products, thus enabling catalyst turnover. This conceptually simple design principle for catalytic carbonyl–olefin metathesis relies on several fundamental requirements to achieve a viable synthetic strategy. In particular, a potent catalyst needs to be identified that has the capability of efficiently promoting both the [2+2] cycloaddition as well as the subsequent [2+2] cycloreversion step. Additionally, potential competing side reactions upon [2+2] cycloreversion, such as polymerization and regeneration of starting materials, need to be reduced. Similarly,", "role": "user" }, { "content": "(Phys.org)—Olefin metathesis reactions where two allyls switch substituent groups, has proved to be a useful carbon-carbon bond forming reaction for drug discovery and other industrial processes. The carbonyl-olefin metathesis reaction was discovered around the same time as the olefin metathesis reaction, but has had limited applicability due to harsh reaction conditions and stringent reactant requirements. Until now, there have been no examples of catalysts for this reaction that are generalizable. In a report in Nature, Jacob R. Ludwig, Paul M. Zimmerman, Joseph B. Gianino & Corinna S. Schindler of the University of Michigan have successfully found a Lewis acid catalyst that successfully exacts a carbonyl-olefin ring-closing metathesis reaction for the direct synthesis of functionalized carbocycles. Furthermore, the catalyst uses iron, which is abundant and environmentally safe, and works under mild conditions for a variety of functional groups and at gram-level scales. The olefin reaction mechanism involves a metal-catalyzed [2+2] cycloaddition of two allyls to form a four-member cyclic intermediate in which the metal is one of the members of the four-member ring. This is followed by a [2+2] cycloreversion resulting in products that have exchanged substituents. Carbonyl olefin metathesis reactions operate similarly. There are three carbonyl olefin metathesis reactions have been observed, but each has its limitations. One involves a two-step photochemical cycloaddition followed by a thermolysis cycloreversion. Another involves a stoichiometric amount of transition-metal catalyst. Another reaction involves an organocatalyst that requires a cyclopropene reactant. All of these are limited in scope and, in the case of the photochemical reaction, require prohibitively harsh conditions. The reaction involving a stoichiometric amount of transition-metal catalyst is the most versatile, but it produces a metal-oxo complex that consumes the catalyst. Ludwing, et al. wanted to look for ways to form an in situ oxetane intermediate, a four-member cyclic intermediate with the oxygen as one of the atoms instead of a metal. This would avoid the formation of products that consume the catalyst. In general, they needed a catalyst that promotes [2+2] cycloaddition and [2+2] cyclorevrsion, does not promote side reactions such as polymerization or reforming reactants, and is chemoselective. They decided to investigate metal-derived Lewis acids. To test various Lewis acid catalysts, they reacted a β-ketoester with a pendant isoprenyl group with MClx Lewis acids. They tested AlCl3, TiCl4, SnCl4, FeCl2, ZnCl2, SnCl2, and FeCl3. They found that FeCl3 formed the desired products and that optimal reaction conditions were 5 mol% FeCl3 in dicholorethane at room temperature for one-to-twelve hours. Once a catalyst was determined and reaction conditions were optimized, the next step was to test the generalizability of the reaction. Ludwig, et al. looked at various arene groups. Their reaction conditions worked with electron withdrawing and donating groups producing products in good yield. They then changed the β-substitution on the β-ketoesters and found the reaction worked with a variety of substituents. They also looked at the effects of incorporating a heteroatom, changing structural motifs, and changing the pendant isoprenyl group. Overall, the FeCl3 catalyst showed remarkable versatility in the variety of reactions that were successfully completed. These reactions provided insight into the carbonyl-olefin reaction mechanism. The reaction either proceeds via a carbocation intermediate or in a concerted fashion that involves metal coordination to FeCl3. Subsequent studies using a mechanistic probe to trap the product that would be formed from a carbocation intermediate showed no results, thus demonstrating that a concerted and metal coordinated mechanism is likely. Computational studies indicate that the reaction mechanism is likely a concerted carbon-oxygen bond breakage and carbon-carbon bond formation mechanism that occurs asynchronously. Carbonyl-olefin metathesis reactions had been limited in scope, but this study demonstrates a catalyst and optimal reaction conditions that are generalizable for a variety of reactants opening the door for the synthesis of complex compounds. The reaction is practically useful as iron is an earth-abundant metal and is environmentally safe, and the reactions are scalable. ", "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 olefin metathesis reaction of two unsaturated substrates is one of the most powerful carbon–carbon-bond-forming reactions in organic chemistry. Specifically, the catalytic olefin metathesis reaction has led to profound developments in the synthesis of molecules relevant to the petroleum, materials, agricultural and pharmaceutical industries 1 . These reactions are characterized by their use of discrete metal alkylidene catalysts that operate via a well-established mechanism 2 . While the corresponding carbonyl–olefin metathesis reaction can also be used to construct carbon–carbon bonds, currently available methods are scarce and severely hampered by either harsh reaction conditions or the required use of stoichiometric transition metals as reagents. To date, no general protocol for catalytic carbonyl–olefin metathesis has been reported. Here we demonstrate a catalytic carbonyl–olefin ring-closing metathesis reaction that uses iron, an Earth-abundant and environmentally benign transition metal, as a catalyst. This transformation accommodates a variety of substrates and is distinguished by its operational simplicity, mild reaction conditions, high functional-group tolerance, and amenability to gram-scale synthesis. We anticipate that these characteristics, coupled with the efficiency of this reaction, will allow for further advances in areas that have historically been enhanced by olefin metathesis. Main Classified by their mechanistic profile, metathesis reactions most often proceed through a [2+2] cycloaddition to form a 4-atom cyclic intermediate, followed by [2+2] cycloreversion, resulting in an exchange of reactive partners 3 , 4 , 5 , 6 . Included in this mode of reactivity are classical olefination reactions ( Fig. 1a ), in which highly polarized nucleophilic components add to carbonyl derivatives to give cyclic intermediates 7 , 8 , 9 . These compounds then fragment to produce olefins and a metal or main-group oxo species, the latter being the thermodynamic driving force for the reaction. The utility of this chemistry is often hampered by harsh conditions, the need for pre-functionalized intermediates and the production of excess quantities of waste products. A revolutionary development in this regard was the establishment of the catalytic olefin–olefin metathesis reaction, in which transition-metal alkylidenes facilitate [2+2] cycloadditions and subsequent [2+2] cycloreversions from simple olefin starting materials ( Fig. 1b ). Since its discovery, olefin metathesis has led to marked advances in the fields of organic chemistry as well as chemical biology, and allowed entry into previously inaccessible complex molecules. Although it was discovered at around the same time, the corresponding carbonyl–olefin metathesis ( Fig. 1c ) is much less developed 10 . To date, no catalytic protocol of general synthetic utility exists for carbonyl–olefin metathesis reactions, and, furthermore, available procedures rely on harsh reaction conditions or the use of stoichiometric metal reagents. The earliest reported examples for carbonyl–olefin metathesis reactions involve a two-step sequence including a photoinduced [2+2] cycloaddition, followed by a subsequent acidic and/or thermal fragmentation step to induce cycloreversion to the corresponding metathesis products ( Fig. 1c ) 10 , 11 , 12 . The success of this photolysis–pyrolysis series is often impeded by harsh reaction conditions, which are prone to result in competing polymerization or regeneration of starting carbonyl–olefin pairs. Importantly, stoichiometric amounts of catalysts originally developed for olefin metathesis ( Fig. 1b ) were found to be able to mediate carbonyl–olefin metathesis reactions. In this case, the cycloreversion step results in the formation of a kinetically inert metal–oxo complex, precluding regeneration of the metal alkylidene and prohibiting catalyst turnover ( Fig. 1c ) 13 . Figure 1: Olefination and metathesis reactions for the formation of alkenes. a , Summary of traditional olefination reactions in organic synthesis. b , Olefin–olefin metathesis catalysed by ruthenium, molybdenum and tungsten complexes. c , Modes of carbonyl–olefin metathesis, including two-step photochemical cycloaddition/thermolysis cycloreversion, stoichiometric transition-metal-mediated, organocatalytic, and the new iron( III )-catalysed processes described herein. R, R 1 , R 2 , R 3 , R 4 , generic substituent. cat., catalyst. PowerPoint slide Full size image Alternatively, titanium-based Tebbe and Petasis reagents have been used in excess to induce initial olefin metathesis and subsequent carbonyl olefination reactions, resulting in the formation of carbonyl–olefin metathesis products 14 , 15 . In addition to this titanium alkylidene approach, Brønsted and Lewis acids are also reported to effect carbonyl–olefin metathesis reactions of simple acetophenone and benzaldehyde derivatives, although limited in scope 16 , 17 , 18 , 19 . An important contribution in carbonyl–olefin metathesis reactions was reported recently, wherein an organocatalysed (3+2)/retro-(3+2) cycloaddition process allowed the ring-opening metathesis of cyclopropenes to give γ,δ-unsaturated aldehydes, which constitute formal carbonyl–olefin metathesis products ( Fig. 1c ) 20 . Although a remarkable advance, only highly strained cyclopropenes are applicable as olefinic components. As such, a general catalytic protocol has yet to be developed. Despite the development of the methods described earlier, the only protocol for carbonyl–olefin metathesis that has been applied to the synthesis of biologically active natural products and pharmaceutically relevant compounds 21 , 22 is the stoichiometric metal-mediated approach ( Fig. 1c ), further illustrating the need for a general catalytic system. We describe a Lewis-acid-catalysed carbonyl–olefin ring-closing metathesis reaction for the direct synthesis of functionalized carbocycles, representing a major advance in carbonyl–olefin metathesis. At the outset of our investigations, we envisioned an efficient design principle for catalytic carbonyl–olefin metathesis based on the in situ formation of oxetanes as reactive intermediates ( II ) ( Fig. 1c ). This approach fundamentally differs from stoichiometric carbonyl–olefin metathesis protocols proceeding via intermediate metalla-oxetanes using metal-alkylidene reagents. While these result in the formation of kinetically inert metal–oxo complexes upon retro-cycloaddition that ultimately prohibit a catalytic process, the corresponding oxetane intermediates ( II ) are able to undergo direct fragmentation to the desired carbonyl–olefin metathesis products, thus enabling catalyst turnover. This conceptually simple design principle for catalytic carbonyl–olefin metathesis relies on several fundamental requirements to achieve a viable synthetic strategy. In particular, a potent catalyst needs to be identified that has the capability of efficiently promoting both the [2+2] cycloaddition as well as the subsequent [2+2] cycloreversion step. Additionally, potential competing side reactions upon [2+2] cycloreversion, such as polymerization and regeneration of starting materials, need to be reduced. Similarly,<|im_end|> <|im_start|>assistant (Phys.org)—Olefin metathesis reactions where two allyls switch substituent groups, has proved to be a useful carbon-carbon bond forming reaction for drug discovery and other industrial processes. The carbonyl-olefin metathesis reaction was discovered around the same time as the olefin metathesis reaction, but has had limited applicability due to harsh reaction conditions and stringent reactant requirements. Until now, there have been no examples of catalysts for this reaction that are generalizable. In a report in Nature, Jacob R. Ludwig, Paul M. Zimmerman, Joseph B. Gianino & Corinna S. Schindler of the University of Michigan have successfully found a Lewis acid catalyst that successfully exacts a carbonyl-olefin ring-closing metathesis reaction for the direct synthesis of functionalized carbocycles. Furthermore, the catalyst uses iron, which is abundant and environmentally safe, and works under mild conditions for a variety of functional groups and at gram-level scales. The olefin reaction mechanism involves a metal-catalyzed [2+2] cycloaddition of two allyls to form a four-member cyclic intermediate in which the metal is one of the members of the four-member ring. This is followed by a [2+2] cycloreversion resulting in products that have exchanged substituents. Carbonyl olefin metathesis reactions operate similarly. There are three carbonyl olefin metathesis reactions have been observed, but each has its limitations. One involves a two-step photochemical cycloaddition followed by a thermolysis cycloreversion. Another involves a stoichiometric amount of transition-metal catalyst. Another reaction involves an organocatalyst that requires a cyclopropene reactant. All of these are limited in scope and, in the case of the photochemical reaction, require prohibitively harsh conditions. The reaction involving a stoichiometric amount of transition-metal catalyst is the most versatile, but it produces a metal-oxo complex that consumes the catalyst. Ludwing, et al. wanted to look for ways to form an in situ oxetane intermediate, a four-member cyclic intermediate with the oxygen as one of the atoms instead of a metal. This would avoid the formation of products that consume the catalyst. In general, they needed a catalyst that promotes [2+2] cycloaddition and [2+2] cyclorevrsion, does not promote side reactions such as polymerization or reforming reactants, and is chemoselective. They decided to investigate metal-derived Lewis acids. To test various Lewis acid catalysts, they reacted a β-ketoester with a pendant isoprenyl group with MClx Lewis acids. They tested AlCl3, TiCl4, SnCl4, FeCl2, ZnCl2, SnCl2, and FeCl3. They found that FeCl3 formed the desired products and that optimal reaction conditions were 5 mol% FeCl3 in dicholorethane at room temperature for one-to-twelve hours. Once a catalyst was determined and reaction conditions were optimized, the next step was to test the generalizability of the reaction. Ludwig, et al. looked at various arene groups. Their reaction conditions worked with electron withdrawing and donating groups producing products in good yield. They then changed the β-substitution on the β-ketoesters and found the reaction worked with a variety of substituents. They also looked at the effects of incorporating a heteroatom, changing structural motifs, and changing the pendant isoprenyl group. Overall, the FeCl3 catalyst showed remarkable versatility in the variety of reactions that were successfully completed. These reactions provided insight into the carbonyl-olefin reaction mechanism. The reaction either proceeds via a carbocation intermediate or in a concerted fashion that involves metal coordination to FeCl3. Subsequent studies using a mechanistic probe to trap the product that would be formed from a carbocation intermediate showed no results, thus demonstrating that a concerted and metal coordinated mechanism is likely. Computational studies indicate that the reaction mechanism is likely a concerted carbon-oxygen bond breakage and carbon-carbon bond formation mechanism that occurs asynchronously. Carbonyl-olefin metathesis reactions had been limited in scope, but this study demonstrates a catalyst and optimal reaction conditions that are generalizable for a variety of reactants opening the door for the synthesis of complex compounds. The reaction is practically useful as iron is an earth-abundant metal and is environmentally safe, and the reactions are scalable. <|im_end|>

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323, 17876, 35872, 3633, 75, 32878, 69, 2617, 25481, 11, 13239, 304, 279, 18488, 315, 35872, 3633, 75, 4235, 1286, 5589, 2322, 589, 14093, 3956, 220, 975, 1174, 220, 868, 662, 763, 5369, 311, 420, 71404, 58998, 4010, 307, 1994, 5603, 11, 3320, 6282, 77, 24836, 323, 21256, 33969, 527, 1101, 5068, 311, 2515, 35872, 3633, 75, 4235, 1286, 5589, 2322, 589, 14093, 25481, 315, 4382, 65802, 5237, 268, 606, 323, 72046, 278, 86836, 43645, 11, 8051, 7347, 304, 7036, 220, 845, 1174, 220, 1114, 1174, 220, 972, 1174, 220, 777, 662, 1556, 3062, 19035, 304, 35872, 3633, 75, 4235, 1286, 5589, 2322, 589, 14093, 25481, 574, 5068, 6051, 11, 42418, 459, 2942, 511, 4306, 1065, 291, 320, 18, 10, 17, 5738, 2171, 299, 8172, 18, 10, 17, 8, 44448, 385, 723, 684, 1920, 5535, 279, 10264, 86308, 2322, 589, 14093, 315, 44448, 385, 2741, 22383, 311, 3041, 63127, 11, 86486, 12, 11099, 35467, 453, 80660, 5919, 11, 902, 35256, 16287, 35872, 3633, 75, 4235, 1286, 5589, 2322, 589, 14093, 3956, 320, 23966, 13, 220, 16, 66, 883, 220, 508, 662, 10541, 264, 23649, 12178, 11, 1193, 7701, 73779, 44448, 385, 2741, 22383, 527, 8581, 439, 32878, 5589, 292, 6956, 13, 1666, 1778, 11, 264, 4689, 34454, 70504, 11766, 706, 3686, 311, 387, 8040, 13, 18185, 279, 4500, 315, 279, 5528, 7633, 6931, 11, 279, 1193, 11766, 369, 35872, 3633, 75, 4235, 1286, 5589, 2322, 589, 14093, 430, 706, 1027, 9435, 311, 279, 39975, 315, 6160, 30450, 4642, 5933, 3956, 323, 15430, 25297, 2740, 9959, 32246, 220, 1691, 1174, 220, 1313, 374, 279, 43132, 41652, 24264, 9501, 82076, 5603, 320, 23966, 13, 220, 16, 66, 7026, 4726, 94012, 279, 1205, 369, 264, 4689, 34454, 70504, 1887, 13, 1226, 7664, 264, 21256, 38698, 307, 1824, 4306, 1065, 291, 35872, 3633, 75, 4235, 1286, 5589, 10264, 1824, 18310, 2322, 589, 14093, 13010, 369, 279, 2167, 39975, 315, 16003, 1534, 35872, 511, 16182, 11, 14393, 264, 3682, 12178, 304, 35872, 3633, 75, 4235, 1286, 5589, 2322, 589, 14093, 13, 2468, 279, 68864, 315, 1057, 26969, 11, 584, 74389, 459, 11297, 2955, 17966, 369, 34454, 70504, 35872, 3633, 75, 4235, 1286, 5589, 2322, 589, 14093, 3196, 389, 279, 304, 10109, 18488, 315, 19488, 295, 14997, 439, 56563, 55275, 988, 320, 8105, 883, 320, 23966, 13, 220, 16, 66, 7609, 1115, 5603, 43593, 44642, 505, 43132, 41652, 24264, 35872, 3633, 75, 4235, 1286, 5589, 2322, 589, 14093, 32885, 39547, 4669, 29539, 2322, 21575, 12, 5241, 295, 14997, 1701, 9501, 12, 1727, 4010, 307, 1994, 312, 55975, 13, 6104, 1521, 1121, 304, 279, 18488, 315, 24890, 37774, 81073, 9501, 4235, 5241, 78, 69125, 5304, 17189, 1824, 3418, 385, 723, 684, 430, 13967, 48486, 264, 34454, 70504, 1920, 11, 279, 12435, 19488, 295, 2194, 55275, 988, 320, 8105, 883, 527, 3025, 311, 37771, 2167, 88452, 311, 279, 12974, 35872, 3633, 75, 4235, 1286, 5589, 2322, 589, 14093, 3956, 11, 8617, 28462, 51483, 48639, 13, 1115, 7434, 1870, 4382, 2955, 17966, 369, 34454, 70504, 35872, 3633, 75, 4235, 1286, 5589, 2322, 589, 14093, 34744, 389, 3892, 16188, 8670, 311, 11322, 264, 31528, 28367, 8446, 13, 763, 4040, 11, 264, 36875, 51483, 3966, 311, 387, 11054, 430, 706, 279, 23099, 315, 30820, 22923, 2225, 279, 510, 17, 10, 17, 60, 44448, 385, 723, 684, 439, 1664, 439, 279, 17876, 510, 17, 10, 17, 60, 44448, 20763, 4464, 3094, 13, 23212, 11, 4754, 27260, 3185, 25481, 5304, 510, 17, 10, 17, 60, 44448, 20763, 4464, 11, 1778, 439, 47393, 2065, 323, 60517, 315, 6041, 7384, 11, 1205, 311, 387, 11293, 13, 35339, 11, 128257, 198, 128256, 78191, 198, 7, 67171, 2726, 68850, 46, 273, 5589, 2322, 589, 14093, 25481, 1405, 1403, 31953, 4835, 3480, 32434, 11942, 5315, 11, 706, 19168, 311, 387, 264, 5505, 12782, 24948, 6098, 11049, 30164, 13010, 369, 5623, 18841, 323, 1023, 13076, 11618, 13, 578, 35872, 3633, 75, 12, 1286, 5589, 2322, 589, 14093, 13010, 574, 11352, 2212, 279, 1890, 892, 439, 279, 32878, 5589, 2322, 589, 14093, 13010, 11, 719, 706, 1047, 7347, 4666, 2968, 4245, 311, 25984, 13010, 4787, 323, 70099, 14085, 519, 8670, 13, 30070, 1457, 11, 1070, 617, 1027, 912, 10507, 315, 51483, 82, 369, 420, 13010, 430, 527, 4689, 8499, 13, 763, 264, 1934, 304, 22037, 11, 25537, 432, 13, 85550, 11, 7043, 386, 13, 66758, 11, 15466, 426, 13, 79704, 3394, 612, 4563, 258, 3458, 328, 13, 5124, 485, 1565, 315, 279, 3907, 315, 14972, 617, 7946, 1766, 264, 21256, 13935, 51483, 430, 7946, 4839, 82, 264, 35872, 3633, 75, 12, 1286, 5589, 10264, 1824, 18310, 2322, 589, 14093, 13010, 369, 279, 2167, 39975, 315, 16003, 1534, 35872, 511, 16182, 13, 24296, 11, 279, 51483, 5829, 11245, 11, 902, 374, 44611, 323, 57340, 6220, 11, 323, 4375, 1234, 23900, 4787, 369, 264, 8205, 315, 16003, 5315, 323, 520, 23882, 11852, 29505, 13, 578, 32878, 5589, 13010, 17383, 18065, 264, 9501, 1824, 4306, 88, 16284, 510, 17, 10, 17, 60, 44448, 385, 723, 684, 315, 1403, 31953, 4835, 311, 1376, 264, 3116, 44650, 77102, 29539, 304, 902, 279, 9501, 374, 832, 315, 279, 3697, 315, 279, 3116, 44650, 10264, 13, 1115, 374, 8272, 555, 264, 510, 17, 10, 17, 60, 44448, 20763, 4464, 13239, 304, 3956, 430, 617, 48501, 32434, 84, 812, 13, 69577, 3633, 75, 32878, 5589, 2322, 589, 14093, 25481, 14816, 30293, 13, 2684, 527, 2380, 35872, 3633, 75, 32878, 5589, 2322, 589, 14093, 25481, 617, 1027, 13468, 11, 719, 1855, 706, 1202, 9669, 13, 3861, 18065, 264, 1403, 30308, 6685, 32056, 44448, 385, 723, 684, 8272, 555, 264, 30945, 337, 4548, 44448, 20763, 4464, 13, 13596, 18065, 264, 43132, 41652, 24264, 3392, 315, 9320, 89932, 51483, 13, 13596, 13010, 18065, 459, 2942, 511, 4306, 599, 430, 7612, 264, 44448, 385, 2741, 1994, 14085, 519, 13, 2052, 315, 1521, 527, 7347, 304, 7036, 323, 11, 304, 279, 1162, 315, 279, 6685, 32056, 13010, 11, 1397, 48486, 3210, 25984, 4787, 13, 578, 13010, 16239, 264, 43132, 41652, 24264, 3392, 315, 9320, 89932, 51483, 374, 279, 1455, 33045, 11, 719, 433, 19159, 264, 9501, 12, 5241, 78, 6485, 430, 60606, 279, 51483, 13, 46270, 24510, 11, 1880, 453, 13, 4934, 311, 1427, 369, 5627, 311, 1376, 459, 304, 10109, 19488, 295, 2194, 29539, 11, 264, 3116, 44650, 77102, 29539, 449, 279, 24463, 439, 832, 315, 279, 33299, 4619, 315, 264, 9501, 13, 1115, 1053, 5766, 279, 18488, 315, 3956, 430, 25024, 279, 51483, 13, 763, 4689, 11, 814, 4460, 264, 51483, 430, 39990, 510, 17, 10, 17, 60, 44448, 385, 723, 684, 323, 510, 17, 10, 17, 60, 44448, 385, 7430, 5544, 290, 11, 1587, 539, 12192, 3185, 25481, 1778, 439, 47393, 2065, 477, 15180, 287, 14085, 1821, 11, 323, 374, 8590, 974, 772, 535, 13, 2435, 6773, 311, 19874, 9501, 72286, 21256, 33969, 13, 2057, 1296, 5370, 21256, 13935, 51483, 82, 11, 814, 55841, 264, 34318, 12934, 11269, 5302, 449, 264, 42844, 374, 454, 1466, 4010, 1912, 449, 386, 5176, 87, 21256, 33969, 13, 2435, 12793, 1708, 5176, 18, 11, 23126, 5176, 19, 11, 13358, 5176, 19, 11, 3926, 5176, 17, 11, 127265, 5176, 17, 11, 13358, 5176, 17, 11, 323, 3926, 5176, 18, 13, 2435, 1766, 430, 3926, 5176, 18, 14454, 279, 12974, 3956, 323, 430, 23669, 13010, 4787, 1051, 220, 20, 22337, 4, 3926, 5176, 18, 304, 29953, 337, 461, 86185, 520, 3130, 9499, 369, 832, 4791, 98662, 21903, 4207, 13, 9843, 264, 51483, 574, 11075, 323, 13010, 4787, 1051, 34440, 11, 279, 1828, 3094, 574, 311, 1296, 279, 4689, 450, 2968, 315, 279, 13010, 13, 85550, 11, 1880, 453, 13, 7111, 520, 5370, 527, 818, 5315, 13, 11205, 13010, 4787, 6575, 449, 17130, 84060, 323, 61959, 5315, 17843, 3956, 304, 1695, 7692, 13, 2435, 1243, 5614, 279, 34318, 18451, 10663, 389, 279, 34318, 12934, 11269, 76802, 323, 1766, 279, 13010, 6575, 449, 264, 8205, 315, 32434, 84, 812, 13, 2435, 1101, 7111, 520, 279, 6372, 315, 52913, 264, 30548, 78, 22612, 11, 10223, 24693, 84989, 11, 323, 10223, 279, 42844, 374, 454, 1466, 4010, 1912, 13, 28993, 11, 279, 3926, 5176, 18, 51483, 8710, 23649, 60112, 304, 279, 8205, 315, 25481, 430, 1051, 7946, 8308, 13, 4314, 25481, 3984, 20616, 1139, 279, 35872, 3633, 75, 12, 1286, 5589, 13010, 17383, 13, 578, 13010, 3060, 34555, 4669, 264, 35872, 2328, 29539, 477, 304, 264, 97666, 11401, 430, 18065, 9501, 38793, 311, 3926, 5176, 18, 13, 3804, 72457, 7978, 1701, 264, 7852, 4633, 22477, 311, 23709, 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 The mechanisms by which hypoxic tumours evade immunological pressure and anti-tumour immunity remain elusive. Here, we report that two hypoxia-responsive microRNAs, miR-25 and miR-93, are important for establishing an immunosuppressive tumour microenvironment by downregulating expression of the DNA sensor cGAS. Mechanistically, miR-25/93 targets NCOA3, an epigenetic factor that maintains basal levels of cGAS expression, leading to repression of cGAS during hypoxia. This allows hypoxic tumour cells to escape immunological responses induced by damage-associated molecular pattern molecules, specifically the release of mitochondrial DNA. Moreover, restoring cGAS expression results in an anti-tumour immune response. Clinically, decreased levels of cGAS are associated with poor prognosis for patients with breast cancer harbouring high levels of miR-25/93. Together, these data suggest that inactivation of the cGAS pathway plays a critical role in tumour progression, and reveal a direct link between hypoxia-responsive miRNAs and adaptive immune responses to the hypoxic tumour microenvironment, thus unveiling potential new therapeutic strategies. Main The ability of cancer cells to evade immune responses is critical for the emergence of malignant phenotypes 1 . Cancer cells can escape both innate and adaptive immune responses by deregulating immune effector cells and immunosuppressive cells, as well as molecules responsible for cancer cell recognition and elimination 2 . Hypoxia contributes to immunosuppression within tumours, helping shield cancer cells from immune attack and inhibiting immune killing functions 3 , 4 , 5 . For example, immunosuppressive cells (for example, regulatory T cells) accumulate within hypoxic regions of tumours where they promote tumour progression 6 , 7 , 8 , 9 and activate immune tolerance mechanisms that enable cancer cells to evade host immunosurveillance. Despite recent advances, the molecular mechanisms underlying hypoxia-induced immune escape are not yet fully understood. MicroRNAs (miRNAs) regulate a variety of cellular processes, including immune cell differentiation, immune responses to infection, and the development of immune disorders 10 , 11 . In the context of tumorigenesis, dysregulated miRNAs promote tumour progression by regulating cancer pathways associated with tumour malignancy 12 . A recent screen for hypoxia-regulated miRNAs in breast cancer cells revealed that hypoxia modulates miRNA function during breast cancer progression 13 . Hypoxia-responsive miRNAs regulate a complex spectrum of candidate target genes, including those involved in proliferation, apoptosis, metabolism and migration 14 . Here we identify hypoxia-responsive miR-25 and miR-93 as critical factors in suppressing the expression of cyclic GMP-AMP synthase (cGAS) through a pathway that requires TET1 and NCOA3. In this way, these miRNAs promote immune escape of hypoxic tumours from damage-associated molecular pattern molecule (DAMP)-induced immunological stress, ultimately leading to the formation of an immunosuppressive tumour microenvironment. RESULTS Hypoxia signalling induces immunosuppressive phenotypes Recent findings suggest that hypoxia/HIF-1 signalling suppresses host defence against cancer 9 , 15 . To prove this concept, we examined associations between hypoxic tumours and immunosuppression. We identified hypoxic breast tumour samples on the basis of levels of HIF-1α and assessed the expression of an array of inflammatory and immune mediators. This analysis revealed decreased levels of Ifn - g , an anti-tumour factor, as well as decreased levels of several factors known to drive anti-tumour immunity, such as Il-12 , Cxcl10 , Ifit1 and Tbx21 (ref. 16 ). In contrast, Il-10 , a tumour-promoting factor, as well as Il-1β and Il-17 , were increased ( Fig. 1a–c ). As a second means of studying hypoxic cancer cells, we subcutaneously inoculated wild-type mice with murine breast cancer cells (E0771) that overexpress a constitutively active form of HIF-1α (ref. 17 ). Because hypoxia results in the recruitment of immunosuppressive cells 4 , we characterized tumour-infiltrating immune cells (TICs). Fluorescence-activated cell sorting (FACS) analysis of tumour biopsies indicated an increase in CD11b + Ly6G − Ly6C high monocytic myeloid-derived suppressor cells (MDSCs) in HIF-1α-overexpressing tumours (compared with control tumours), whereas HIF-1α did not affect levels of CD11b + F4/80 + tumour-associated macrophages or CD11b + Ly6G + Ly6C low granulocytic MDSCs ( Supplementary Fig. 1a–c ). The population of effector CD8 + T cells was decreased in HIF-1α-overexpressing tumours, accompanied by a change in the percentage of tumour-infiltrating CD8 + T cells, whereas the percentage of CD4 + T cells remained the same ( Fig. 1d and Supplementary Fig. 1d, e ). Furthermore, we found greater numbers of CD4 + Foxp3 + regulatory T cells (Tregs) in HIF-1α-overexpressing tumours ( Fig. 1e ), consistent with previous reports showing enhanced recruitment of Tregs by hypoxia 9 , 18 . We also analysed these tumours and consistently observed immunosuppressive gene expression profiles, as shown by decreased levels of anti-tumour immunity factors and increased levels of tumour-promoting factors ( Fig. 1f, g ). Collectively, these results indicate that hypoxia/HIF-1α promotes immunosuppression during breast cancer formation in vivo . Figure 1: miR-25/93 induced by hypoxia drives immunosuppression. ( a ) Top: correlation between regions of hypoxia (defined by hypoxyprobe) and regions of high HIF-1α in murine tumour samples. Bottom: screening for hypoxic murine tumour samples. Endogenous HIF-1α was used as an indicator for hypoxia. E0771 cells were used for tumour formation. Scale bars, 50 μm. N, non-hypoxic sample; H, hypoxic sample. ( b , c ) Gene expression analysis for selected genes responsible for either anti-tumour immunity or tumour-promoting effects in hypoxic tumour samples, compared with non-hypoxic tumour samples. Anti-tumour immunity factors include Ifn - g , Il-12 , Cxcl10 , lfit1 and Tbx21 . Tumour-promoting factors include Il-10 , Il-1 and Il-17 . ( d ) The percentage of effector CD8 + cytotoxic T cells was decreased in HIF-1α-overexpressing tumours. Changes in effector CD8 + cytotoxic T cells were normalized to total CD8 + T-cell proportions. Effector CD8 + cytotoxic T cells were defined by the production of TNF (also known as TNF-α) and IFN-γ. E0771 cells expressing HIF-1α or empty vector were used for tumour formation. ( e ) HIF-1α-overexpressing tumours showed significantly higher recruitment of CD4 + Foxp3 + Tregs. ( f ) Gene expression analysis for anti-tumour immunity factors in whole-tumour homogenates derived from HIF-1α-overexpressing tumours or control tumours. ( g ) The level of tumour-promoting factors", "role": "user" }, { "content": "The immune system automatically destroys dysfunctional cells such as cancer cells, but cancerous tumors often survive nonetheless. A new study by Salk scientists shows one method by which fast-growing tumors evade anti-tumor immunity. The Salk team uncovered two gene-regulating molecules that alter cell signaling within tumor cells to survive and subvert the body's normal immune response, according to a September 18, 2017, paper in Nature Cell Biology. The discovery could one day point to a new target for cancer treatment in various types of cancer. \"The immunological pressure occurring during tumor progression might be harmful for the tumor to prosper,\" says Salk Professor Juan Carlos Izpisua Belmonte, senior author of the work and holder of the Roger Guillemin Chair. \"However, the cancer cells find a way to evade such a condition by restraining the anti-tumor immune response.\" Cancerous tumors often grow so fast that they use up their available blood supply, creating a low-oxygen environment called hypoxia. Cells normally start to self-destruct under hypoxia, but in some tumors, the microenvironment surrounding hypoxic tumor tissue has been found to help shield the tumor. \"Our findings actually indicate how cancer cells respond to a changing microenvironment and suppress anti-tumor immunity through intrinsic signaling,\" says Izpisua Belmonte. The answer was through microRNAs. MicroRNAs—small, noncoding RNA molecules that regulate genes by silencing RNA—have increasingly been implicated in tumor survival and progression. To better understand the connection between microRNAs and tumor survival, the researchers screened different tumor types for altered levels of microRNAs. They identified two microRNAs—miR25 and miR93— whose levels increased in hypoxic tumors. The team then measured levels of those two microRNAs in the tumors of 148 cancer patients and found that tumors with high levels of miR25 and miR93 led to a worse prognosis in patients compared to tumors with lower levels. The reverse was true for another molecule called cGAS: the lower the level of cGAS in a tumor, the worse the prognosis for the patient. Previous research has shown that cGAS acts as an alarm for the immune system by detecting mitochondrial DNA floating around the cell—a sign of tissue damage—and activating the body's immune response. \"Given these results, we wondered if these two microRNA molecules, miR25 and miR93, could be lowering cGAS levels to create a protective immunity shield for the tumor,\" says Min-Zu (Michael) Wu, first author of the paper and a research associate in Salk's Gene Expression Laboratory. That is exactly what the team confirmed with further experiments. Using mouse models and tissue samples, the researchers found that a low-oxygen (hypoxia) state triggered miR25 and miR93 to set off a chain of cell signaling that ultimately lowered cGAS levels. If the researchers inhibited miR25 and miR93 in tumor cells, then cGAS levels remained high in low-oxygen (hypoxic) tumors. Researchers could slow tumor growth in mice if they inhibited miR25 and miR93. Yet, in immune-deficient mice, the effect of inhibiting miR25 and miR93 was diminished, further indicating that miR25 and miR93 help promote tumor growth by influencing the immune system. Identifying miR25 and miR93 may help researchers pinpoint a good target to try to boost cGAS levels and block tumor evasion of the immune response. However, the team says directly targeting microRNA in treatment can be tricky. Targeting the intermediate players in the signaling between the two microRNAs and cGAS may be easier. \"To follow up this study, we're now investigating the different immune cells that can contribute to cancer anti-tumor immunity,\" adds Wu. ", "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 mechanisms by which hypoxic tumours evade immunological pressure and anti-tumour immunity remain elusive. Here, we report that two hypoxia-responsive microRNAs, miR-25 and miR-93, are important for establishing an immunosuppressive tumour microenvironment by downregulating expression of the DNA sensor cGAS. Mechanistically, miR-25/93 targets NCOA3, an epigenetic factor that maintains basal levels of cGAS expression, leading to repression of cGAS during hypoxia. This allows hypoxic tumour cells to escape immunological responses induced by damage-associated molecular pattern molecules, specifically the release of mitochondrial DNA. Moreover, restoring cGAS expression results in an anti-tumour immune response. Clinically, decreased levels of cGAS are associated with poor prognosis for patients with breast cancer harbouring high levels of miR-25/93. Together, these data suggest that inactivation of the cGAS pathway plays a critical role in tumour progression, and reveal a direct link between hypoxia-responsive miRNAs and adaptive immune responses to the hypoxic tumour microenvironment, thus unveiling potential new therapeutic strategies. Main The ability of cancer cells to evade immune responses is critical for the emergence of malignant phenotypes 1 . Cancer cells can escape both innate and adaptive immune responses by deregulating immune effector cells and immunosuppressive cells, as well as molecules responsible for cancer cell recognition and elimination 2 . Hypoxia contributes to immunosuppression within tumours, helping shield cancer cells from immune attack and inhibiting immune killing functions 3 , 4 , 5 . For example, immunosuppressive cells (for example, regulatory T cells) accumulate within hypoxic regions of tumours where they promote tumour progression 6 , 7 , 8 , 9 and activate immune tolerance mechanisms that enable cancer cells to evade host immunosurveillance. Despite recent advances, the molecular mechanisms underlying hypoxia-induced immune escape are not yet fully understood. MicroRNAs (miRNAs) regulate a variety of cellular processes, including immune cell differentiation, immune responses to infection, and the development of immune disorders 10 , 11 . In the context of tumorigenesis, dysregulated miRNAs promote tumour progression by regulating cancer pathways associated with tumour malignancy 12 . A recent screen for hypoxia-regulated miRNAs in breast cancer cells revealed that hypoxia modulates miRNA function during breast cancer progression 13 . Hypoxia-responsive miRNAs regulate a complex spectrum of candidate target genes, including those involved in proliferation, apoptosis, metabolism and migration 14 . Here we identify hypoxia-responsive miR-25 and miR-93 as critical factors in suppressing the expression of cyclic GMP-AMP synthase (cGAS) through a pathway that requires TET1 and NCOA3. In this way, these miRNAs promote immune escape of hypoxic tumours from damage-associated molecular pattern molecule (DAMP)-induced immunological stress, ultimately leading to the formation of an immunosuppressive tumour microenvironment. RESULTS Hypoxia signalling induces immunosuppressive phenotypes Recent findings suggest that hypoxia/HIF-1 signalling suppresses host defence against cancer 9 , 15 . To prove this concept, we examined associations between hypoxic tumours and immunosuppression. We identified hypoxic breast tumour samples on the basis of levels of HIF-1α and assessed the expression of an array of inflammatory and immune mediators. This analysis revealed decreased levels of Ifn - g , an anti-tumour factor, as well as decreased levels of several factors known to drive anti-tumour immunity, such as Il-12 , Cxcl10 , Ifit1 and Tbx21 (ref. 16 ). In contrast, Il-10 , a tumour-promoting factor, as well as Il-1β and Il-17 , were increased ( Fig. 1a–c ). As a second means of studying hypoxic cancer cells, we subcutaneously inoculated wild-type mice with murine breast cancer cells (E0771) that overexpress a constitutively active form of HIF-1α (ref. 17 ). Because hypoxia results in the recruitment of immunosuppressive cells 4 , we characterized tumour-infiltrating immune cells (TICs). Fluorescence-activated cell sorting (FACS) analysis of tumour biopsies indicated an increase in CD11b + Ly6G − Ly6C high monocytic myeloid-derived suppressor cells (MDSCs) in HIF-1α-overexpressing tumours (compared with control tumours), whereas HIF-1α did not affect levels of CD11b + F4/80 + tumour-associated macrophages or CD11b + Ly6G + Ly6C low granulocytic MDSCs ( Supplementary Fig. 1a–c ). The population of effector CD8 + T cells was decreased in HIF-1α-overexpressing tumours, accompanied by a change in the percentage of tumour-infiltrating CD8 + T cells, whereas the percentage of CD4 + T cells remained the same ( Fig. 1d and Supplementary Fig. 1d, e ). Furthermore, we found greater numbers of CD4 + Foxp3 + regulatory T cells (Tregs) in HIF-1α-overexpressing tumours ( Fig. 1e ), consistent with previous reports showing enhanced recruitment of Tregs by hypoxia 9 , 18 . We also analysed these tumours and consistently observed immunosuppressive gene expression profiles, as shown by decreased levels of anti-tumour immunity factors and increased levels of tumour-promoting factors ( Fig. 1f, g ). Collectively, these results indicate that hypoxia/HIF-1α promotes immunosuppression during breast cancer formation in vivo . Figure 1: miR-25/93 induced by hypoxia drives immunosuppression. ( a ) Top: correlation between regions of hypoxia (defined by hypoxyprobe) and regions of high HIF-1α in murine tumour samples. Bottom: screening for hypoxic murine tumour samples. Endogenous HIF-1α was used as an indicator for hypoxia. E0771 cells were used for tumour formation. Scale bars, 50 μm. N, non-hypoxic sample; H, hypoxic sample. ( b , c ) Gene expression analysis for selected genes responsible for either anti-tumour immunity or tumour-promoting effects in hypoxic tumour samples, compared with non-hypoxic tumour samples. Anti-tumour immunity factors include Ifn - g , Il-12 , Cxcl10 , lfit1 and Tbx21 . Tumour-promoting factors include Il-10 , Il-1 and Il-17 . ( d ) The percentage of effector CD8 + cytotoxic T cells was decreased in HIF-1α-overexpressing tumours. Changes in effector CD8 + cytotoxic T cells were normalized to total CD8 + T-cell proportions. Effector CD8 + cytotoxic T cells were defined by the production of TNF (also known as TNF-α) and IFN-γ. E0771 cells expressing HIF-1α or empty vector were used for tumour formation. ( e ) HIF-1α-overexpressing tumours showed significantly higher recruitment of CD4 + Foxp3 + Tregs. ( f ) Gene expression analysis for anti-tumour immunity factors in whole-tumour homogenates derived from HIF-1α-overexpressing tumours or control tumours. ( g ) The level of tumour-promoting factors<|im_end|> <|im_start|>assistant The immune system automatically destroys dysfunctional cells such as cancer cells, but cancerous tumors often survive nonetheless. A new study by Salk scientists shows one method by which fast-growing tumors evade anti-tumor immunity. The Salk team uncovered two gene-regulating molecules that alter cell signaling within tumor cells to survive and subvert the body's normal immune response, according to a September 18, 2017, paper in Nature Cell Biology. The discovery could one day point to a new target for cancer treatment in various types of cancer. "The immunological pressure occurring during tumor progression might be harmful for the tumor to prosper," says Salk Professor Juan Carlos Izpisua Belmonte, senior author of the work and holder of the Roger Guillemin Chair. "However, the cancer cells find a way to evade such a condition by restraining the anti-tumor immune response." Cancerous tumors often grow so fast that they use up their available blood supply, creating a low-oxygen environment called hypoxia. Cells normally start to self-destruct under hypoxia, but in some tumors, the microenvironment surrounding hypoxic tumor tissue has been found to help shield the tumor. "Our findings actually indicate how cancer cells respond to a changing microenvironment and suppress anti-tumor immunity through intrinsic signaling," says Izpisua Belmonte. The answer was through microRNAs. MicroRNAs—small, noncoding RNA molecules that regulate genes by silencing RNA—have increasingly been implicated in tumor survival and progression. To better understand the connection between microRNAs and tumor survival, the researchers screened different tumor types for altered levels of microRNAs. They identified two microRNAs—miR25 and miR93— whose levels increased in hypoxic tumors. The team then measured levels of those two microRNAs in the tumors of 148 cancer patients and found that tumors with high levels of miR25 and miR93 led to a worse prognosis in patients compared to tumors with lower levels. The reverse was true for another molecule called cGAS: the lower the level of cGAS in a tumor, the worse the prognosis for the patient. Previous research has shown that cGAS acts as an alarm for the immune system by detecting mitochondrial DNA floating around the cell—a sign of tissue damage—and activating the body's immune response. "Given these results, we wondered if these two microRNA molecules, miR25 and miR93, could be lowering cGAS levels to create a protective immunity shield for the tumor," says Min-Zu (Michael) Wu, first author of the paper and a research associate in Salk's Gene Expression Laboratory. That is exactly what the team confirmed with further experiments. Using mouse models and tissue samples, the researchers found that a low-oxygen (hypoxia) state triggered miR25 and miR93 to set off a chain of cell signaling that ultimately lowered cGAS levels. If the researchers inhibited miR25 and miR93 in tumor cells, then cGAS levels remained high in low-oxygen (hypoxic) tumors. Researchers could slow tumor growth in mice if they inhibited miR25 and miR93. Yet, in immune-deficient mice, the effect of inhibiting miR25 and miR93 was diminished, further indicating that miR25 and miR93 help promote tumor growth by influencing the immune system. Identifying miR25 and miR93 may help researchers pinpoint a good target to try to boost cGAS levels and block tumor evasion of the immune response. However, the team says directly targeting microRNA in treatment can be tricky. Targeting the intermediate players in the signaling between the two microRNAs and cGAS may be easier. "To follow up this study, we're now investigating the different immune cells that can contribute to cancer anti-tumor immunity," adds Wu. <|im_end|>

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2,450

[ { "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 Coffee is a widely consumed beverage that is naturally bitter and contains caffeine. Genome-wide association studies (GWAS) of coffee drinking have identified genetic variants involved in caffeine-related pathways but not in taste perception. The taste of coffee can be altered by addition of milk/sweetener, which has not been accounted for in GWAS. Using UK and US cohorts, we test the hypotheses that genetic variants related to taste are more strongly associated with consumption of black coffee than with consumption of coffee with milk or sweetener and that genetic variants related to caffeine pathways are not differentially associated with the type of coffee consumed independent of caffeine content. Contrary to our hypotheses, genetically inferred caffeine sensitivity was more strongly associated with coffee taste preferences than with genetically inferred bitter taste perception. These findings extended to tea and dark chocolate. Taste preferences and physiological caffeine effects intertwine in a way that is difficult to distinguish for individuals which may represent conditioned taste preferences. Introduction Coffee and tea are among the most widely consumed beverages in the world 1 . The consumption of these plant-based beverages has been associated with a lower risk of chronic diseases such as type 2 diabetes, cardiovascular diseases, and several types of cancer 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 . Although plausible underlying biological mechanisms have been identified, more research is needed to establish the causal role of these beverages in human health 10 . Thus, understanding determinants of beverage choice and consumption level is important to inform research and public health strategies. Genome-wide association studies (GWAS) of coffee and tea drinking behavior have identified genetic variants involved in the metabolism and physiological effects of caffeine as determinants of the amount of these beverages consumed (Supplementary Table S1 ) 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 . Furthermore, a variant near a gene encoding an olfactory receptor ( OR5M8 ) has been associated with coffee intake. As coffee and tea have a bitter taste, it is also plausible that genetic variants related to bitter taste perception affect coffee and tea consumption. However, none of the loci identified in GWAS of coffee and tea intake overlap with TAS2R loci associated with taste perception of bitter compounds including propylthiouracil (PROP)/phenylthiocarbamide (PTC), caffeine, and quinine in GWAS (Supplementary Table S1 ) 22 , 23 , 24 , 25 . Caffeine seeking behavior might explain the persistent consumption of coffee and tea despite their bitter taste 21 , 26 . However, the taste of these beverages is easily manipulated by the addition of sweetener and milk; behaviors not previously accounted for in GWAS or the vast majority of epidemiological studies. The current study uses genetic, dietary, and food preference (“liking”) data available from the UK Biobank (UKB) and two US cohorts, the Nurses’ Health Study (NHS) and Health Professionals Follow-up study (HPFS). We first test the hypothesis that published GWAS-confirmed variants related to taste are more strongly associated with black coffee consumption than with the consumption of total coffee or coffee with added sweetener or milk because their effects would not be masked by coffee taste manipulation. We focus on coffee but extend this hypothesis to tea since we expect similar but weaker associations of taste-related genetic variants with tea consumption, because tea is reportedly less bitter than coffee 27 , 28 . As a negative control, we also examine published GWAS-confirmed loci involved in the metabolism and physiology of caffeine which we would not expect to be differentially associated with type of coffee and tea consumed independent of caffeine content. Second, we examine whether there are shared genetic determinants of coffee and tea traits with other bitter tasting foods; specifically, beer and dark chocolate. Finally, we perform GWAS of liking or consumption of specific types of coffee and tea (e.g., with sugar versus without sugar) that may yield genetic variants not reported previously by GWAS of total coffee and tea consumption. Methods UK biobank In 2006–2010, the UKB recruited over 502,633 participants aged 37–73 years at 22 centers across England, Wales, and Scotland 29 . Participants provided informed written consent, completed touchscreen questionnaires on sociodemographic factors, lifestyle, and medical history followed by an interviewer-administered questionnaire, physical assessment, and biospecimen collection 30 . Subsets of the cohort have returned for follow-up assessments and have completed additional on-line questionnaires. The latter are the primary source of data for the current analysis. This study was covered by the generic ethical approval for UKB studies from the National Research Ethics Service Committee North West–Haydock (approval letter dated 17th June 2011, Ref 11/NW/0382), and all study procedures were performed in accordance with the World Medical Association Declaration of Helsinki ethical principles for medical research. Coffee and tea consumption In 2009–2012, a subset of 122,292 participants who completed the baseline assessment center visit also completed at least two of five on-line 24 h dietary recalls 31 , 32 . Detailed collection methods for coffee and tea intake and methods for estimating added milk and sweetener are provided in Supplementary Methods S2 . Briefly, participants reporting consumption of coffee were probed for details concerning quantity (0.5–6 + cups/day), brew type (instant, filtered, espresso, cappuccino, latte, and other), and whether the coffee was decaffeinated (yes, no, varied) and sweetened (half, 1, 2, 3 + teaspoons or “varied” for sugar and artificial sweetener). Categorical measures of coffee quantity were converted to cups/day by using the midpoint of each category; those reporting 6 + cups/day were assigned an intake of 6 cups/day. Those reporting consumption of instant, filtered, espresso or other coffee were additionally asked if milk was added (yes, no, varied). Participants reporting consumption of tea were probed for details concerning quantity (1–6 + cups/day), brew type (green, black, rooibos, herbal and other), and whether it was decaffeinated (black tea only) and sweetened. Those reporting consumption of black or rooibos tea were additionally asked if milk was added.", "role": "user" }, { "content": "People who like to drink their coffee black also prefer dark chocolate, a new Northwestern Medicine study found. The reason is in their genes. Northwestern scientists have found coffee drinkers who have a genetic variant that reflects a faster metabolism of caffeine prefer bitter, black coffee. And the same genetic variant is found in people who prefer the more bitter dark chocolate over the more mellow milk chocolate. The reason is not because they love the taste, but rather because they associate the bitter flavor with the boost in mental alertness they expect from caffeine. \"That is interesting because these gene variants are related to faster metabolism of caffeine and are not related to taste,\" said lead study author Marilyn Cornelis, associate professor of preventive medicine in nutrition. \"These individuals metabolize caffeine faster, so the stimulating effects wear off faster as well. So, they need to drink more.\" \"Our interpretation is these people equate caffeine's natural bitterness with a psycho-stimulation effect,\" Cornelis said. \"They learn to associate bitterness with caffeine and the boost they feel. We are seeing a learned effect. When they think of caffeine, they think of a bitter taste, so they enjoy dark coffee and, likewise, dark chocolate.\" The paper was published Dec. 13 in Scientific Reports. The dark chocolate connection also may be related to the fact that dark chocolate contains a small amount of caffeine but predominantly theobromine, a caffeine-related compound, also a psychostimulant. Why does this matter? Coffee and dark chocolate consumption have been shown to lower the risk of certain diseases. Moderate coffee consumption lowers the risk of Parkinson's disease, cardiovascular diseases, type 2 diabetes and several types of cancer. Dark chocolate appears to lower the risk of heart disease. Currently, when scientists study the health benefits of coffee and dark chocolate, they must rely on epidemiological studies, which only confer an association with health benefits rather than a stronger causal link. Cornelis's new research shows these genetic variants can be used more precisely to study the relationship between coffee and health benefits. Previously, scientists were using the genetic markers for coffee drinkers in general. The new findings suggest they are stronger markers for particular types of coffee drinkers—black coffee drinkers. This impacts the interpretation of these genetic studies of coffee and health. \"Drinking black coffee versus coffee with cream and sugar is very different for your health,\" Cornelis said. \"The person who wants black coffee is different from a person who wants coffee with cream and sugar. Based on our findings, the person who drinks black coffee also prefers other bitter foods like dark chocolate. So, we are drilling down into a more precise way to measure the actual health benefits of this beverage and other food.\" The benefits of black coffee are based on moderate consumption of two to three cups a day, Cornelis said. The current study used genetic, dietary and food preference data available from the UK Biobank and two U.S. cohorts, the Nurses' Health Study and Health Professionals Follow-up study. The paper is titled \"Genetic determinants of liking and intake of coffee and other bitter foods and beverages.\" ", "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 Coffee is a widely consumed beverage that is naturally bitter and contains caffeine. Genome-wide association studies (GWAS) of coffee drinking have identified genetic variants involved in caffeine-related pathways but not in taste perception. The taste of coffee can be altered by addition of milk/sweetener, which has not been accounted for in GWAS. Using UK and US cohorts, we test the hypotheses that genetic variants related to taste are more strongly associated with consumption of black coffee than with consumption of coffee with milk or sweetener and that genetic variants related to caffeine pathways are not differentially associated with the type of coffee consumed independent of caffeine content. Contrary to our hypotheses, genetically inferred caffeine sensitivity was more strongly associated with coffee taste preferences than with genetically inferred bitter taste perception. These findings extended to tea and dark chocolate. Taste preferences and physiological caffeine effects intertwine in a way that is difficult to distinguish for individuals which may represent conditioned taste preferences. Introduction Coffee and tea are among the most widely consumed beverages in the world 1 . The consumption of these plant-based beverages has been associated with a lower risk of chronic diseases such as type 2 diabetes, cardiovascular diseases, and several types of cancer 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 . Although plausible underlying biological mechanisms have been identified, more research is needed to establish the causal role of these beverages in human health 10 . Thus, understanding determinants of beverage choice and consumption level is important to inform research and public health strategies. Genome-wide association studies (GWAS) of coffee and tea drinking behavior have identified genetic variants involved in the metabolism and physiological effects of caffeine as determinants of the amount of these beverages consumed (Supplementary Table S1 ) 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 . Furthermore, a variant near a gene encoding an olfactory receptor ( OR5M8 ) has been associated with coffee intake. As coffee and tea have a bitter taste, it is also plausible that genetic variants related to bitter taste perception affect coffee and tea consumption. However, none of the loci identified in GWAS of coffee and tea intake overlap with TAS2R loci associated with taste perception of bitter compounds including propylthiouracil (PROP)/phenylthiocarbamide (PTC), caffeine, and quinine in GWAS (Supplementary Table S1 ) 22 , 23 , 24 , 25 . Caffeine seeking behavior might explain the persistent consumption of coffee and tea despite their bitter taste 21 , 26 . However, the taste of these beverages is easily manipulated by the addition of sweetener and milk; behaviors not previously accounted for in GWAS or the vast majority of epidemiological studies. The current study uses genetic, dietary, and food preference (“liking”) data available from the UK Biobank (UKB) and two US cohorts, the Nurses’ Health Study (NHS) and Health Professionals Follow-up study (HPFS). We first test the hypothesis that published GWAS-confirmed variants related to taste are more strongly associated with black coffee consumption than with the consumption of total coffee or coffee with added sweetener or milk because their effects would not be masked by coffee taste manipulation. We focus on coffee but extend this hypothesis to tea since we expect similar but weaker associations of taste-related genetic variants with tea consumption, because tea is reportedly less bitter than coffee 27 , 28 . As a negative control, we also examine published GWAS-confirmed loci involved in the metabolism and physiology of caffeine which we would not expect to be differentially associated with type of coffee and tea consumed independent of caffeine content. Second, we examine whether there are shared genetic determinants of coffee and tea traits with other bitter tasting foods; specifically, beer and dark chocolate. Finally, we perform GWAS of liking or consumption of specific types of coffee and tea (e.g., with sugar versus without sugar) that may yield genetic variants not reported previously by GWAS of total coffee and tea consumption. Methods UK biobank In 2006–2010, the UKB recruited over 502,633 participants aged 37–73 years at 22 centers across England, Wales, and Scotland 29 . Participants provided informed written consent, completed touchscreen questionnaires on sociodemographic factors, lifestyle, and medical history followed by an interviewer-administered questionnaire, physical assessment, and biospecimen collection 30 . Subsets of the cohort have returned for follow-up assessments and have completed additional on-line questionnaires. The latter are the primary source of data for the current analysis. This study was covered by the generic ethical approval for UKB studies from the National Research Ethics Service Committee North West–Haydock (approval letter dated 17th June 2011, Ref 11/NW/0382), and all study procedures were performed in accordance with the World Medical Association Declaration of Helsinki ethical principles for medical research. Coffee and tea consumption In 2009–2012, a subset of 122,292 participants who completed the baseline assessment center visit also completed at least two of five on-line 24 h dietary recalls 31 , 32 . Detailed collection methods for coffee and tea intake and methods for estimating added milk and sweetener are provided in Supplementary Methods S2 . Briefly, participants reporting consumption of coffee were probed for details concerning quantity (0.5–6 + cups/day), brew type (instant, filtered, espresso, cappuccino, latte, and other), and whether the coffee was decaffeinated (yes, no, varied) and sweetened (half, 1, 2, 3 + teaspoons or “varied” for sugar and artificial sweetener). Categorical measures of coffee quantity were converted to cups/day by using the midpoint of each category; those reporting 6 + cups/day were assigned an intake of 6 cups/day. Those reporting consumption of instant, filtered, espresso or other coffee were additionally asked if milk was added (yes, no, varied). Participants reporting consumption of tea were probed for details concerning quantity (1–6 + cups/day), brew type (green, black, rooibos, herbal and other), and whether it was decaffeinated (black tea only) and sweetened. Those reporting consumption of black or rooibos tea were additionally asked if milk was added.<|im_end|> <|im_start|>assistant People who like to drink their coffee black also prefer dark chocolate, a new Northwestern Medicine study found. The reason is in their genes. Northwestern scientists have found coffee drinkers who have a genetic variant that reflects a faster metabolism of caffeine prefer bitter, black coffee. And the same genetic variant is found in people who prefer the more bitter dark chocolate over the more mellow milk chocolate. The reason is not because they love the taste, but rather because they associate the bitter flavor with the boost in mental alertness they expect from caffeine. "That is interesting because these gene variants are related to faster metabolism of caffeine and are not related to taste," said lead study author Marilyn Cornelis, associate professor of preventive medicine in nutrition. "These individuals metabolize caffeine faster, so the stimulating effects wear off faster as well. So, they need to drink more." "Our interpretation is these people equate caffeine's natural bitterness with a psycho-stimulation effect," Cornelis said. "They learn to associate bitterness with caffeine and the boost they feel. We are seeing a learned effect. When they think of caffeine, they think of a bitter taste, so they enjoy dark coffee and, likewise, dark chocolate." The paper was published Dec. 13 in Scientific Reports. The dark chocolate connection also may be related to the fact that dark chocolate contains a small amount of caffeine but predominantly theobromine, a caffeine-related compound, also a psychostimulant. Why does this matter? Coffee and dark chocolate consumption have been shown to lower the risk of certain diseases. Moderate coffee consumption lowers the risk of Parkinson's disease, cardiovascular diseases, type 2 diabetes and several types of cancer. Dark chocolate appears to lower the risk of heart disease. Currently, when scientists study the health benefits of coffee and dark chocolate, they must rely on epidemiological studies, which only confer an association with health benefits rather than a stronger causal link. Cornelis's new research shows these genetic variants can be used more precisely to study the relationship between coffee and health benefits. Previously, scientists were using the genetic markers for coffee drinkers in general. The new findings suggest they are stronger markers for particular types of coffee drinkers—black coffee drinkers. This impacts the interpretation of these genetic studies of coffee and health. "Drinking black coffee versus coffee with cream and sugar is very different for your health," Cornelis said. "The person who wants black coffee is different from a person who wants coffee with cream and sugar. Based on our findings, the person who drinks black coffee also prefers other bitter foods like dark chocolate. So, we are drilling down into a more precise way to measure the actual health benefits of this beverage and other food." The benefits of black coffee are based on moderate consumption of two to three cups a day, Cornelis said. The current study used genetic, dietary and food preference data available from the UK Biobank and two U.S. cohorts, the Nurses' Health Study and Health Professionals Follow-up study. The paper is titled "Genetic determinants of liking and intake of coffee and other bitter foods and beverages." <|im_end|>

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1,968

[ { "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 Research on halophilic microorganisms is important due to their relation to fundamental questions of survival of living organisms in a hostile environment. Here we introduce a novel method to stain halophiles with MitoTracker fluorescent dyes in their growth medium. The method is based on membrane-potential sensitive dyes, which were originally used to label mitochondria in eukaryotic cells. We demonstrate that these fluorescent dyes provide high staining efficiency and are beneficial for multi-staining purposes due to the spectral range covered (from orange to deep red). In contrast with other fluorescent dyes used so far, MitoTracker does not affect growth rate, and remains in cells after several washing steps and several generations in cell culture. The suggested dyes were tested on three archaeal ( Hbt. salinarum, Haloferax sp., Halorubrum sp .) and two bacterial ( Salicola sp., Halomonas sp .) strains of halophilic microorganisms. The new staining approach provides new insights into biology of Hbt. salinarum . We demonstrated the interconversion of rod-shaped cells of Hbt. salinarium to spheroplasts and submicron-sized spheres, as well as the cytoplasmic integrity of giant rod Hbt. salinarum species. By expanding the variety of tools available for halophile detection, MitoTracker dyes overcome long-standing limitations in fluorescence microscopy studies of halophiles. Introduction Halophiles are organisms that can thrive in extreme conditions of high salt concentrations. Most of these organisms belong to the archaea or bacteria life domains. Exposed to a hostile environment, halophiles evolved unique biomechanisms, which make them very exciting scientific objects. Probably, the most important is the example of bacteriorhodopsin – a photoactivatable retinal membrane protein with unique properties, including stability at high concentration of salt (up to 5M), protease resistance, tolerance to high temperatures (upto 140 °C when dry) 1 and to a broad range of pH (at least 3–10) 2 . Bacteriorhodopsin has become the most studied membrane protein, often serving as a “model” for all other membrane proteins (see for instance 3 , 4 , 5 , 6 , 7 , 8 ). In recent decades, halophiles have attracted additional scientific interest due to their isolation from Earth’s subsurface halites, in some cases >250 million years old 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 . Being buried in brine-filled fluid inclusions, halophiles are able to survive for millennia under conditions of extremely high ionic strength, elevated temperatures and nutrients depletion. Genome studies showed that spore formation is not possible for halophilic archaea 21 , thus, their survival mechanisms remain unclear 22 . Halites were discovered on the surface of Mars by the Opportunity and Spirit rovers and in meteorite samples 23 , 24 , 25 , 26 , 27 , 28 , 29 . It was shown that they can hypothetically play protective role against radiation 30 or biochemical degradation 19 and potentially harbour halobacteria 31 . Thus, sensitive detection of living halophiles in hypersaline medium with minimal influence on their viability is a question of great interest for further exploration of microbial life on Earth and elsewhere. An additional interest associated with halophiles arises from their role in microbial communities of natural and man-made hypersaline environments 32 , especially in the case of hydrocarbonoclastic communities, which are potentially applicable for bioremediation of oil pollutions 33 . Fluorescent staining can provide a sensitive method for detection of halophilic species (i.e. via flow cytometry) in environmental samples, and can also be used for their analysis via fluorescence microscopy. The main challenge in relation to the fluorescent staining of halophiles is the high ionic strength of the medium and in some cases hostile pH 34 of their natural environment, which are inappropriate for conventional antibodies and dyes 35 . The low permeability of the halobacterial S-layer to macromolecules can additionally complicate immunostaining. The list of staining approaches for halophiles is currently rather limited. Most of them require fixation (i.e. immunostaining 36 , 37 , DAPI 38 , 39 , and FISH 38 , 40 ) or the use of DNA-targeted intercalating dyes (i.e. LIVE&DEAD kit 35 , 39 , 41 , 42 , 43 , 44 , 45 , Acridine Orange 43 , 46 , Hoechst 47 ). The latter approach is unsafe due to interference with the cellular DNA processing machinery, which can result in complete loss of cell viability (for review see 48 , 49 ). It has been shown that Acridine Orange and its derivatives can additionally stain archaeal phospholipids 50 . Several other approaches for staining halophiles that have been recently suggested 44 , 51 remain limited to particular applications. Genetic modification of archaea with GFP for its fluorescent visualization 44 , 52 is also worth mentioning, although it is not straightforward for detection purposes. Notably, no dyes for long-term staining without cytotoxic side-effects have been found; the field is dominated by DNA-staining dyes, which has cytotoxicity as an intrinsic limitation. Here we suggest a new method for staining living halobacteria cells with fluorescent dyes in their growth medium. We show that dyes designed to specifically stain mitochondria in mammalian eukaryotic cells (MitoTracker Orange CMTMRos, MitoTracker Red CMXRos and MitoTracker Deep Red FM) easily permeate the S-layer of Hbt. salinarum and cause stable bright staining of the archaeon. Even without removal of the residual, non-incorporated MitoTracker dye, the signal-to-noise ratio (SNR) is sufficient for clear cell detection and fluorescence microscopy. To test our staining procedure we investigate the conversion of Hbt. salinarum cells into spheroplasts via exposure to an EDTA-containing solution. In the case of MitoTracker Orange CMTMRos we also show that it does not have an effect on the cell’s growth rate. The staining remains bright during long observations (hours to days) and is inherited in cell division. The new method of staining allowed us to detect the development of viable spheres of submicron size (herein called “microspheres” to highlight the difference between them and spheroplasts) from rod-shaped Hbt. salinarum after the exposure to EDTA, which was previously assumed to result only in", "role": "user" }, { "content": "Researchers from MIPT and their colleagues from Research Center Juelich (Germany) and Dmitry Mendeleev University of Chemical Technology of Russia have described a new method for studying microorganisms that can survive in extreme conditions. The scientists identified a fluorescent dye that enabled them to observe the life cycle of bacteria in real time. Halophiles, which is the ancient Greek for \"salt-loving,\" are microorganisms that thrive in high salt concentrations. Their ability to survive in hostile environments makes halophiles important scientific objects, for both theoretical and applied studies. This line of enquiry may eventually facilitate the search for extraterrestrial life, shed light on the history of the Earth, and provide data sought by biotech specialists. The authors of the paper, who work at MIPT's Laboratory for Advanced Studies of Membrane Proteins, point out that these organisms can be used for many purposes, including cleaning up oil spills. However, this research is facing a number of obstacles, not least of them being that microbiological experiments are technically quite challenging. To study microorganisms in their natural environment, dyes are required—ideally, selective ones. With their help, much more data can be obtained, compared to when an unstained medium is examined. However, well-established fluorescent labels and antibodies that dyes use to bind with a given substance often fail to work in salty environments. Additional difficulties are posed by the halophiles' thick membrane. \"Despite all the hard work, scientists have so far been unable to find a substance that would enable them to observe these organisms 'live,\" the way they really are. Instead, bacteria had to undergo harmful preparation,\" says Ivan Maslov, a fifth-year MIPT student and co-author of the study. Video showing how bacteria change their shape from rods to spheres in a hostile medium. Credit: Ivan Maslov et al./Scientific Reports In the new paper published in Scientific Reports, the international research team described a solution to this issue. Their experiments showed that there is no need to synthesize new types of dyes: Previously created substances for labeling mitochondria in eukaryotic cells demonstrated positive results in halophiles as well. There are two major types of cells: prokaryotes and eukaryotes. Prokaryotes, represented by bacteria, lack nuclei, and other membrane-bound structures. Eukaryotes—animal, plant, and fungal cells—have nuclei and various organelles. Among them are mitochondria, which are used to generate adenosine triphosphate molecules—a universal energy source consumed in various cellular processes. Interestingly, the modern view on the subject suggests that mitochondria were originally free-living bacteria and only later became symbionts of eukaryotic cells. Even now, they still have their own DNA. MitoTracker dyes proved to be successful in staining a wide range of microorganisms: Halobacterium salinarium, Haloferax sp., Halorubrum sp., Salicola sp., and Halomonas sp. (the letters \"sp\" mean \"one of the species\"). The experiments conducted by the researchers demonstrated that it is possible not only to obtain clear photos and keep count of the cells, but also to observe the transformation of Halobacterium salinarium. When exposed to hostile chemical treatment, the cells changed their shape: From rod-shaped, they turned into spheres. The team even made a video recording of that process. The new method will be effective in labeling microorganisms in their natural environment, be it in a saline deposit on Earth or in a Martian soil sample retrieved by a rover. It will also help study the behavior of these bacteria with minimum distortions of the results. \"Halophiles are often found in ancient saline deposits that have been building up for millions of years. Our method helps locate these organisms in mineral formations and study them. This can shed light on the origin of life on Earth. According to one theory, life was brought to our planet from elsewhere in the form of bacteria,\" comments Valentin Borshchevskiy, lead author of the study and deputy head of the Laboratory for Advanced Studies of Membrane Proteins, MIPT. ", "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 Research on halophilic microorganisms is important due to their relation to fundamental questions of survival of living organisms in a hostile environment. Here we introduce a novel method to stain halophiles with MitoTracker fluorescent dyes in their growth medium. The method is based on membrane-potential sensitive dyes, which were originally used to label mitochondria in eukaryotic cells. We demonstrate that these fluorescent dyes provide high staining efficiency and are beneficial for multi-staining purposes due to the spectral range covered (from orange to deep red). In contrast with other fluorescent dyes used so far, MitoTracker does not affect growth rate, and remains in cells after several washing steps and several generations in cell culture. The suggested dyes were tested on three archaeal ( Hbt. salinarum, Haloferax sp., Halorubrum sp .) and two bacterial ( Salicola sp., Halomonas sp .) strains of halophilic microorganisms. The new staining approach provides new insights into biology of Hbt. salinarum . We demonstrated the interconversion of rod-shaped cells of Hbt. salinarium to spheroplasts and submicron-sized spheres, as well as the cytoplasmic integrity of giant rod Hbt. salinarum species. By expanding the variety of tools available for halophile detection, MitoTracker dyes overcome long-standing limitations in fluorescence microscopy studies of halophiles. Introduction Halophiles are organisms that can thrive in extreme conditions of high salt concentrations. Most of these organisms belong to the archaea or bacteria life domains. Exposed to a hostile environment, halophiles evolved unique biomechanisms, which make them very exciting scientific objects. Probably, the most important is the example of bacteriorhodopsin – a photoactivatable retinal membrane protein with unique properties, including stability at high concentration of salt (up to 5M), protease resistance, tolerance to high temperatures (upto 140 °C when dry) 1 and to a broad range of pH (at least 3–10) 2 . Bacteriorhodopsin has become the most studied membrane protein, often serving as a “model” for all other membrane proteins (see for instance 3 , 4 , 5 , 6 , 7 , 8 ). In recent decades, halophiles have attracted additional scientific interest due to their isolation from Earth’s subsurface halites, in some cases >250 million years old 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 . Being buried in brine-filled fluid inclusions, halophiles are able to survive for millennia under conditions of extremely high ionic strength, elevated temperatures and nutrients depletion. Genome studies showed that spore formation is not possible for halophilic archaea 21 , thus, their survival mechanisms remain unclear 22 . Halites were discovered on the surface of Mars by the Opportunity and Spirit rovers and in meteorite samples 23 , 24 , 25 , 26 , 27 , 28 , 29 . It was shown that they can hypothetically play protective role against radiation 30 or biochemical degradation 19 and potentially harbour halobacteria 31 . Thus, sensitive detection of living halophiles in hypersaline medium with minimal influence on their viability is a question of great interest for further exploration of microbial life on Earth and elsewhere. An additional interest associated with halophiles arises from their role in microbial communities of natural and man-made hypersaline environments 32 , especially in the case of hydrocarbonoclastic communities, which are potentially applicable for bioremediation of oil pollutions 33 . Fluorescent staining can provide a sensitive method for detection of halophilic species (i.e. via flow cytometry) in environmental samples, and can also be used for their analysis via fluorescence microscopy. The main challenge in relation to the fluorescent staining of halophiles is the high ionic strength of the medium and in some cases hostile pH 34 of their natural environment, which are inappropriate for conventional antibodies and dyes 35 . The low permeability of the halobacterial S-layer to macromolecules can additionally complicate immunostaining. The list of staining approaches for halophiles is currently rather limited. Most of them require fixation (i.e. immunostaining 36 , 37 , DAPI 38 , 39 , and FISH 38 , 40 ) or the use of DNA-targeted intercalating dyes (i.e. LIVE&DEAD kit 35 , 39 , 41 , 42 , 43 , 44 , 45 , Acridine Orange 43 , 46 , Hoechst 47 ). The latter approach is unsafe due to interference with the cellular DNA processing machinery, which can result in complete loss of cell viability (for review see 48 , 49 ). It has been shown that Acridine Orange and its derivatives can additionally stain archaeal phospholipids 50 . Several other approaches for staining halophiles that have been recently suggested 44 , 51 remain limited to particular applications. Genetic modification of archaea with GFP for its fluorescent visualization 44 , 52 is also worth mentioning, although it is not straightforward for detection purposes. Notably, no dyes for long-term staining without cytotoxic side-effects have been found; the field is dominated by DNA-staining dyes, which has cytotoxicity as an intrinsic limitation. Here we suggest a new method for staining living halobacteria cells with fluorescent dyes in their growth medium. We show that dyes designed to specifically stain mitochondria in mammalian eukaryotic cells (MitoTracker Orange CMTMRos, MitoTracker Red CMXRos and MitoTracker Deep Red FM) easily permeate the S-layer of Hbt. salinarum and cause stable bright staining of the archaeon. Even without removal of the residual, non-incorporated MitoTracker dye, the signal-to-noise ratio (SNR) is sufficient for clear cell detection and fluorescence microscopy. To test our staining procedure we investigate the conversion of Hbt. salinarum cells into spheroplasts via exposure to an EDTA-containing solution. In the case of MitoTracker Orange CMTMRos we also show that it does not have an effect on the cell’s growth rate. The staining remains bright during long observations (hours to days) and is inherited in cell division. The new method of staining allowed us to detect the development of viable spheres of submicron size (herein called “microspheres” to highlight the difference between them and spheroplasts) from rod-shaped Hbt. salinarum after the exposure to EDTA, which was previously assumed to result only in<|im_end|> <|im_start|>assistant Researchers from MIPT and their colleagues from Research Center Juelich (Germany) and Dmitry Mendeleev University of Chemical Technology of Russia have described a new method for studying microorganisms that can survive in extreme conditions. The scientists identified a fluorescent dye that enabled them to observe the life cycle of bacteria in real time. Halophiles, which is the ancient Greek for "salt-loving," are microorganisms that thrive in high salt concentrations. Their ability to survive in hostile environments makes halophiles important scientific objects, for both theoretical and applied studies. This line of enquiry may eventually facilitate the search for extraterrestrial life, shed light on the history of the Earth, and provide data sought by biotech specialists. The authors of the paper, who work at MIPT's Laboratory for Advanced Studies of Membrane Proteins, point out that these organisms can be used for many purposes, including cleaning up oil spills. However, this research is facing a number of obstacles, not least of them being that microbiological experiments are technically quite challenging. To study microorganisms in their natural environment, dyes are required—ideally, selective ones. With their help, much more data can be obtained, compared to when an unstained medium is examined. However, well-established fluorescent labels and antibodies that dyes use to bind with a given substance often fail to work in salty environments. Additional difficulties are posed by the halophiles' thick membrane. "Despite all the hard work, scientists have so far been unable to find a substance that would enable them to observe these organisms 'live," the way they really are. Instead, bacteria had to undergo harmful preparation," says Ivan Maslov, a fifth-year MIPT student and co-author of the study. Video showing how bacteria change their shape from rods to spheres in a hostile medium. Credit: Ivan Maslov et al./Scientific Reports In the new paper published in Scientific Reports, the international research team described a solution to this issue. Their experiments showed that there is no need to synthesize new types of dyes: Previously created substances for labeling mitochondria in eukaryotic cells demonstrated positive results in halophiles as well. There are two major types of cells: prokaryotes and eukaryotes. Prokaryotes, represented by bacteria, lack nuclei, and other membrane-bound structures. Eukaryotes—animal, plant, and fungal cells—have nuclei and various organelles. Among them are mitochondria, which are used to generate adenosine triphosphate molecules—a universal energy source consumed in various cellular processes. Interestingly, the modern view on the subject suggests that mitochondria were originally free-living bacteria and only later became symbionts of eukaryotic cells. Even now, they still have their own DNA. MitoTracker dyes proved to be successful in staining a wide range of microorganisms: Halobacterium salinarium, Haloferax sp., Halorubrum sp., Salicola sp., and Halomonas sp. (the letters "sp" mean "one of the species"). The experiments conducted by the researchers demonstrated that it is possible not only to obtain clear photos and keep count of the cells, but also to observe the transformation of Halobacterium salinarium. When exposed to hostile chemical treatment, the cells changed their shape: From rod-shaped, they turned into spheres. The team even made a video recording of that process. The new method will be effective in labeling microorganisms in their natural environment, be it in a saline deposit on Earth or in a Martian soil sample retrieved by a rover. It will also help study the behavior of these bacteria with minimum distortions of the results. "Halophiles are often found in ancient saline deposits that have been building up for millions of years. Our method helps locate these organisms in mineral formations and study them. This can shed light on the origin of life on Earth. According to one theory, life was brought to our planet from elsewhere in the form of bacteria," comments Valentin Borshchevskiy, lead author of the study and deputy head of the Laboratory for Advanced Studies of Membrane Proteins, MIPT. <|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 ALLO-715 is a first-in-class, allogeneic, anti-BCMA CAR T cell therapy engineered to abrogate graft-versus-host disease and minimize CAR T rejection. We evaluated escalating doses of ALLO-715 after lymphodepletion with an anti-CD52 antibody (ALLO-647)-containing regimen in 43 patients with relapsed/refractory multiple myeloma as part A of the ongoing first-in-human phase 1 UNIVERSAL trial. Primary objectives included determination of the safety and tolerability of ALLO-715 and the safety profile of the ALLO-647-containing lymphodepletion regimen. Key secondary endpoints were response rate and duration of response. Grade ≥3 adverse events were reported in 38 (88.0%) of patients. Cytokine release syndrome was observed in 24 patients (55.8%), with 1 grade ≥3 event (2.3%) and neurotoxicity in 6 patients (14%), with no grade ≥3 events. Infections occurred in 23 patients (53.5%), with 10 (23.3%) of grade ≥3. Overall, 24 patients (55.8%) had a response. Among patients treated with 320 × 10 6 CAR + T cells and a fludarabine-, cyclophosphamide- and ALLO-647-based lymphodepletion regimen ( n = 24), 17 (70.8%) had a response including 11 (45.8%) with very good partial response or better and 6 (25%) with a complete response/stringent complete response. The median duration of response was 8.3 months. These initial results support the feasibility and safety of allogeneic CAR T cell therapy for myeloma. See clinicaltrials.gov registration NCT04093596 . Main Multiple myeloma (MM) remains an incurable cancer despite recent advances in treatment. The mainstay of MM treatment includes immunomodulatory drugs, proteasome inhibitors and anti-CD38 monoclonal antibodies. Although these have prolonged survival, patients eventually relapse, with each subsequent line of therapy rendering a patient more refractory to treatment 1 . Therapies targeting the B cell maturation antigen (BCMA) superfamily have emerged as a new class of therapy for treatment of myeloma. BCMA is a member of the tumor necrosis factor receptor (TNFR) superfamily (TNFRSF) that is expressed primarily on mature B lymphocytes and plasma cells 2 . BCMA maintains survival and proliferation of these cell types by binding to B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) and is specifically implicated in the survival and proliferation of MM cells 3 , 4 . Multiple modalities targeting BCMA have demonstrated activity including antibody–drug conjugates (ADCs) 5 , bispecific antibodies 6 , 7 and autologous chimeric antigen receptor (CAR) T cell therapy 8 , 9 . High overall response rates (ORRs) and duration of response (DOR) are seen, particularly with autologous BCMA-targeted CAR T cell therapies. As of December 2022, the US Food and Drug Administration (FDA) has approved four different BCMA-targeted therapies for treatment of patients with relapsed/refractory myeloma who have been treated with a proteasome inhibitor (PI), immunomodulator (IMiD) and anti-CD38 monoclonal antibody, including belantamab mafodotin-blmf, idecabtagene vicleucel (ide-cel), ciltacabtagene autoleucel (cilta-cel) and teclistamab ( ) 5 , 8 , 9 . Belantamab mafodotin-blmf is a BCMA-directed antibody conjugated to a microtubule inhibitor (accelerated approval; approval rescinded in December 2022) and at approved doses achieved an ORR of 32% and the median DOR (mDOR) of 11 months 5 , 10 . Teclistamab, a bispecific antibody that targets both BCMA and CD3 (accelerated approval; full approval pending) and results from the phase 1/2 MajesTEC-1 study, showed an ORR of 63% and mDOR of 18.4 months 11 , 12 . Ide-cel and cilta-cel are autologous CAR T cell therapies targeting BCMA. Ide-cel achieved an ORR of 72% and an mDOR of 11 months 8 , 13 , whereas cilta-cel has a reported ORR of 98% and the mDOR has not yet been reached 9 , 14 . Although the recent FDA approvals of autologous BCMA-targeted CAR T cell therapies mark an important treatment advance for patients with MM, there are several logistical challenges to autologous CAR T that may prevent widespread access to CAR T therapy. These include the number of cells available and suitable for collection possibly being scarce because patients are often lymphopenic 15 , 16 , manufacturing constraints and, perhaps most importantly, because of the lengthy vein-to-vein time, which makes bridging therapy necessary for most patients. These factors have resulted in wait lists for treatment and some patients die before they can receive treatment 17 . Allogeneic CAR T cell therapy aims to bridge these logistical hurdles by being an off-the-shelf CAR T product that can be accessed without the need for leukapheresis and the subsequent lengthy manufacturing times 18 . Previous studies of donor-derived, allogeneic anti-CD19 CAR T therapy have reported complete responses in patients with heavily pretreated B cell acute lymphoblastic leukemia and this efficacy has been associated with a manageable safety profile 19 , 20 . ALLO-715 contains an integrated, self-inactivating, third-generation, recombinant lentiviral vector that expresses a second-generation anti-BCMA CAR containing a single-chain variable fragment (scFv) derived from a human anti-BCMA antibody and the intracellular domains of 4-1BB and CD3ζ (Extended Data Fig. 1 ). The extracellular region of the BCMA CAR also contains two mimotopes that confer susceptibility to the anti-CD20 monoclonal antibody rituximab and functions as an intracellular off-switch in the presence of rituximab 21 , 22 . There are two additional changes using the transcription activator-like effector nuclease (TALEN) technology: (1) knockout of the T cell receptor alpha constant (TRAC) and (2) knockout of cluster of differentiation (CD) 52. Knocking out TRAC reduces the risk of graft-versus-host disease (GvHD) by reducing the expression of the T cell receptor (TCR)-αβ complex at the cell surface, to prevent TCR-αβ-mediated recognition of histocompatibility antigens. CD52 is a cell-surface glycoprotein found on a variety of host immune cell types, including lymphocytes, monocytes, macrophages, eosinophils and dendritic cells; host immune cells can mediate a host-versus-graft reaction, leading to the elimination of ALLO-715. CD52 + cells can be effectively depleted by anti-CD52 antibodies such as ALLO-647, a therapeutic immunoglobulin G1 monoclonal antibody. Inactivation of CD52 in the CAR T cells enables cell expansion and persistence of ALLO-715 in patients who are lymphodepleted with ALLO-647. UNIVERSAL is a first-in-human phase 1 trial of ALLO-715 ( NCT04093596 ) in patients who have relapsed and refractory myeloma. UNIVERSAL consists of three parts: parts A,", "role": "user" }, { "content": "A team of medical specialists working at Memorial Sloan Kettering Cancer Center in New York has found that donated white blood cells can be used effectively as part of CAR T cell therapy to treat myeloma patients. In their study, published in the journal Nature Medicine, the group gave patients varying amounts of donated CAR T cells as a treatment option in a phase I clinical trial for myeloma, which occurs in plasma cells in bone marrow. Jennifer Brudno and James Kochenderfer with the U.S. National Institutes of Health published a News & Views article in the same journal issue outlining how chimeric antigen receptor (CAR) T cell therapies work and discussing the work done by the team in New York. CAR T cell therapy involves removing T cells from a cancer patient, modifying them genetically to more specifically target cancer cells, and then injecting them back into the same patient. CAR T cell therapy is highly effective for some patients. The downside is that it is time-consuming to grow the cells after alteration, ruling it out for some patients, and it can be expensive, as well. In this new effort, the researchers took a different approach, using previously altered cells donated by healthy volunteers. As part of the research, the team in New York ran a phase I clinical trial called UNIVERSAL to find out if the approach is feasible. The trial involved giving varying amounts of altered cultivated cells to 43 myeloma patients, each of whom had either not responded well to other treatments or who had relapsed. Also, an additional genetic modification was made to the donated cells to make them less likely to be targeted by the immune system. Each patient was also given antibodies to reduce the chances of the immune system targeting the donated cells. Testing showed that just over half of the volunteer patients (55%) had a positive response to the therapy. The therapy was also found to be both safe and feasible. The researchers suggest that their trial was a success and plan to continue their work with the goal of improving results. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract ALLO-715 is a first-in-class, allogeneic, anti-BCMA CAR T cell therapy engineered to abrogate graft-versus-host disease and minimize CAR T rejection. We evaluated escalating doses of ALLO-715 after lymphodepletion with an anti-CD52 antibody (ALLO-647)-containing regimen in 43 patients with relapsed/refractory multiple myeloma as part A of the ongoing first-in-human phase 1 UNIVERSAL trial. Primary objectives included determination of the safety and tolerability of ALLO-715 and the safety profile of the ALLO-647-containing lymphodepletion regimen. Key secondary endpoints were response rate and duration of response. Grade ≥3 adverse events were reported in 38 (88.0%) of patients. Cytokine release syndrome was observed in 24 patients (55.8%), with 1 grade ≥3 event (2.3%) and neurotoxicity in 6 patients (14%), with no grade ≥3 events. Infections occurred in 23 patients (53.5%), with 10 (23.3%) of grade ≥3. Overall, 24 patients (55.8%) had a response. Among patients treated with 320 × 10 6 CAR + T cells and a fludarabine-, cyclophosphamide- and ALLO-647-based lymphodepletion regimen ( n = 24), 17 (70.8%) had a response including 11 (45.8%) with very good partial response or better and 6 (25%) with a complete response/stringent complete response. The median duration of response was 8.3 months. These initial results support the feasibility and safety of allogeneic CAR T cell therapy for myeloma. See clinicaltrials.gov registration NCT04093596 . Main Multiple myeloma (MM) remains an incurable cancer despite recent advances in treatment. The mainstay of MM treatment includes immunomodulatory drugs, proteasome inhibitors and anti-CD38 monoclonal antibodies. Although these have prolonged survival, patients eventually relapse, with each subsequent line of therapy rendering a patient more refractory to treatment 1 . Therapies targeting the B cell maturation antigen (BCMA) superfamily have emerged as a new class of therapy for treatment of myeloma. BCMA is a member of the tumor necrosis factor receptor (TNFR) superfamily (TNFRSF) that is expressed primarily on mature B lymphocytes and plasma cells 2 . BCMA maintains survival and proliferation of these cell types by binding to B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) and is specifically implicated in the survival and proliferation of MM cells 3 , 4 . Multiple modalities targeting BCMA have demonstrated activity including antibody–drug conjugates (ADCs) 5 , bispecific antibodies 6 , 7 and autologous chimeric antigen receptor (CAR) T cell therapy 8 , 9 . High overall response rates (ORRs) and duration of response (DOR) are seen, particularly with autologous BCMA-targeted CAR T cell therapies. As of December 2022, the US Food and Drug Administration (FDA) has approved four different BCMA-targeted therapies for treatment of patients with relapsed/refractory myeloma who have been treated with a proteasome inhibitor (PI), immunomodulator (IMiD) and anti-CD38 monoclonal antibody, including belantamab mafodotin-blmf, idecabtagene vicleucel (ide-cel), ciltacabtagene autoleucel (cilta-cel) and teclistamab ( ) 5 , 8 , 9 . Belantamab mafodotin-blmf is a BCMA-directed antibody conjugated to a microtubule inhibitor (accelerated approval; approval rescinded in December 2022) and at approved doses achieved an ORR of 32% and the median DOR (mDOR) of 11 months 5 , 10 . Teclistamab, a bispecific antibody that targets both BCMA and CD3 (accelerated approval; full approval pending) and results from the phase 1/2 MajesTEC-1 study, showed an ORR of 63% and mDOR of 18.4 months 11 , 12 . Ide-cel and cilta-cel are autologous CAR T cell therapies targeting BCMA. Ide-cel achieved an ORR of 72% and an mDOR of 11 months 8 , 13 , whereas cilta-cel has a reported ORR of 98% and the mDOR has not yet been reached 9 , 14 . Although the recent FDA approvals of autologous BCMA-targeted CAR T cell therapies mark an important treatment advance for patients with MM, there are several logistical challenges to autologous CAR T that may prevent widespread access to CAR T therapy. These include the number of cells available and suitable for collection possibly being scarce because patients are often lymphopenic 15 , 16 , manufacturing constraints and, perhaps most importantly, because of the lengthy vein-to-vein time, which makes bridging therapy necessary for most patients. These factors have resulted in wait lists for treatment and some patients die before they can receive treatment 17 . Allogeneic CAR T cell therapy aims to bridge these logistical hurdles by being an off-the-shelf CAR T product that can be accessed without the need for leukapheresis and the subsequent lengthy manufacturing times 18 . Previous studies of donor-derived, allogeneic anti-CD19 CAR T therapy have reported complete responses in patients with heavily pretreated B cell acute lymphoblastic leukemia and this efficacy has been associated with a manageable safety profile 19 , 20 . ALLO-715 contains an integrated, self-inactivating, third-generation, recombinant lentiviral vector that expresses a second-generation anti-BCMA CAR containing a single-chain variable fragment (scFv) derived from a human anti-BCMA antibody and the intracellular domains of 4-1BB and CD3ζ (Extended Data Fig. 1 ). The extracellular region of the BCMA CAR also contains two mimotopes that confer susceptibility to the anti-CD20 monoclonal antibody rituximab and functions as an intracellular off-switch in the presence of rituximab 21 , 22 . There are two additional changes using the transcription activator-like effector nuclease (TALEN) technology: (1) knockout of the T cell receptor alpha constant (TRAC) and (2) knockout of cluster of differentiation (CD) 52. Knocking out TRAC reduces the risk of graft-versus-host disease (GvHD) by reducing the expression of the T cell receptor (TCR)-αβ complex at the cell surface, to prevent TCR-αβ-mediated recognition of histocompatibility antigens. CD52 is a cell-surface glycoprotein found on a variety of host immune cell types, including lymphocytes, monocytes, macrophages, eosinophils and dendritic cells; host immune cells can mediate a host-versus-graft reaction, leading to the elimination of ALLO-715. CD52 + cells can be effectively depleted by anti-CD52 antibodies such as ALLO-647, a therapeutic immunoglobulin G1 monoclonal antibody. Inactivation of CD52 in the CAR T cells enables cell expansion and persistence of ALLO-715 in patients who are lymphodepleted with ALLO-647. UNIVERSAL is a first-in-human phase 1 trial of ALLO-715 ( NCT04093596 ) in patients who have relapsed and refractory myeloma. UNIVERSAL consists of three parts: parts A,<|im_end|> <|im_start|>assistant A team of medical specialists working at Memorial Sloan Kettering Cancer Center in New York has found that donated white blood cells can be used effectively as part of CAR T cell therapy to treat myeloma patients. In their study, published in the journal Nature Medicine, the group gave patients varying amounts of donated CAR T cells as a treatment option in a phase I clinical trial for myeloma, which occurs in plasma cells in bone marrow. Jennifer Brudno and James Kochenderfer with the U.S. National Institutes of Health published a News & Views article in the same journal issue outlining how chimeric antigen receptor (CAR) T cell therapies work and discussing the work done by the team in New York. CAR T cell therapy involves removing T cells from a cancer patient, modifying them genetically to more specifically target cancer cells, and then injecting them back into the same patient. CAR T cell therapy is highly effective for some patients. The downside is that it is time-consuming to grow the cells after alteration, ruling it out for some patients, and it can be expensive, as well. In this new effort, the researchers took a different approach, using previously altered cells donated by healthy volunteers. As part of the research, the team in New York ran a phase I clinical trial called UNIVERSAL to find out if the approach is feasible. The trial involved giving varying amounts of altered cultivated cells to 43 myeloma patients, each of whom had either not responded well to other treatments or who had relapsed. Also, an additional genetic modification was made to the donated cells to make them less likely to be targeted by the immune system. Each patient was also given antibodies to reduce the chances of the immune system targeting the donated cells. Testing showed that just over half of the volunteer patients (55%) had a positive response to the therapy. The therapy was also found to be both safe and feasible. The researchers suggest that their trial was a success and plan to continue their work with the goal of improving results. <|im_end|>

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2,079

[ { "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 Flaring and warping of the disk of the Milky Way have been inferred from observations of atomic hydrogen 1 , 2 but stars associated with flaring have not hitherto been reported. In the area beyond the Galactic centre the stars are largely hidden from view by dust, and the kinematic distances of the gas cannot be estimated. Thirty-two possible Cepheid stars (young pulsating variable stars) in the direction of the Galactic bulge were recently identified 3 . With their well-calibrated period–luminosity relationships, Cepheid stars are useful distance indicators 4 . When observations of these stars are made in two colours, so that their distance and reddening can be determined simultaneously, the problems of dust obscuration are minimized. Here we report that five of the candidates are classical Cepheid stars. These five stars are distributed from approximately one to two kiloparsecs above and below the plane of the Galaxy, at radial distances of about 13 to 22 kiloparsecs from the centre. The presence of these relatively young (less than 130 million years old) stars so far from the Galactic plane is puzzling, unless they are in the flared outer disk. If so, they may be associated with the outer molecular arm 5 . Main We derived the distances for the five Cepheids from near-infrared photometry obtained with the Infrared Survey Facility (IRSF) and we used radial velocities from the Southern African Large Telescope (SALT) to determine the kinematics (see Methods)—both telescopes are at the South African Astronomical Observatory (SAAO), Sutherland, in South Africa. From these data we were able to ascertain the population to which the Cepheids belong. The other 27 Cepheid candidates are either better assigned to a different class (such as anomalous Cepheids) or else their classification as classical Cepheids is uncertain. Table 1 lists the derived distances and various other parameters for the Cepheids. They are at about the distance and position at which a stream associated with the Sagittarius (Sgr) dwarf galaxy crosses the plane 6 , but the low radial velocity (mean heliocentric radial velocity after correction for the effects of stellar pulsation of V R = 4 ± 8 km s −1 , see Table 1 ) is completely different from that expected for members of the Sgr dwarf stream (about 150 km s −1 ) 6 , 7 and the Cepheids are clearly Galactic. They cannot be in the Galactic bulge because their distances from the centre put them far beyond the bulge and the velocity dispersion of the five stars, 16 ± 5 km s −1 (much of which is observational), is much smaller than expected for bulge objects (>60 km s −1 ) 8 . Furthermore, these short-period Cepheids will be relatively young (about 100 million years (Myr) old), and, although there is a young component, including Cepheids 9 , in the innermost regions of the bulge, the bulk of the population is old (about 10 billion years (Gyr) old) 8 . Figure 1 shows the positions of the five stars in comparison to catalogued Cepheids. The various sources of uncertainty for the distances of the Cepheids are discussed in the Methods, but the reddening law and reddening corrections presented the biggest challenge and are the primary contributors to the error bars shown in the figure. Table 1 Data for individual Cepheids Full size table Figure 1: Schematic of the Galaxy. The positions of the Cepheids (open circles with assumed maximum uncertainties of ±0.2 mag) are compared to the location of the H i gas. The solid and dashed curves are model fits, S and N1, respectively, from ref. 1 at three times the HWHM above and below the Galactic plane. We note that figures 1 and 2 of ref. 2 show the H i flare in the relevant region extending up to about 2 kpc. The dark grey points are previously known Galactic Cepheids 10 and the approximate regions surveyed by OGLE (2 < | b | < 6) are shown in light grey on either side of the plane. The positions of the Sun and Galactic centre are indicated by the star symbols. PowerPoint slide Full size image There is almost no information on gas or stars in the Galactic disk immediately behind (Galactic longitude l ± 15°) the Galactic centre. The atomic hydrogen observations 2 on either side of the centre, but away from the central region itself, suggest that the gaseous disk of the Milky Way at l ≈ 0 is not warped but shows a marked flaring at Galactocentric radii ( R , the distance from a star to the centre of the Galaxy) of 15 kiloparsecs (kpc) and more; we note that the details are model dependent. The thickness of the gaseous disk 1 , 2 increases from 60 parsecs (pc) half-width at half-maximum (HWHM) at R = 4 kpc to 2.7 kpc at R = 30 kpc and, especially at positive Galactic longitudes 1 , there is a marked increase from about 0.4 kpc at R = 15 kpc to about 1.0 kpc at R = 20 kpc. Therefore we found the Cepheids at exactly the distance predicted for this increase in disk thickness, as can be seen in Fig. 1 . The absence of Cepheids nearer the Sun is consistent with the lower HWHM in these regions, whereas the absence of more distant Cepheids is partly due to the decreasing density at larger distances from the centre and partly the consequence of the Optical Gravitational Lensing Experiment (OGLE) observational cut-off. So the relatively narrow range of distances is consistent with our hypothesis that these stars are in the flared disk. In the Methods we also show that the numbers of Cepheids observed is consistent with expectations from a flared disk. Cepheids are usually associated with spiral arms and the distances of these five are similar to that expected for the far outer molecular spiral arm of the Galaxy 5 where it passes behind the central region of the Galaxy; the HWHM of this", "role": "user" }, { "content": "South African astronomers have discovered the very first known stars in the flared disk of our Milky Way Galaxy. These stars are situated on the far side of our Galaxy, 80 thousand light years from the Earth and beyond the Galactic Centre. The discovery is important because stars like these will allow astronomers to test theoretical ideas about how galaxies, like the Milky Way in which we live, formed. In particular these stars, which are close to the effective edge of the Milky Way, will help astronomers trace the distribution of the very mysterious dark matter. Dark matter is known to be an important component of all galaxies, but its nature and distribution remain elusive. The five stars involved in this discovery are very special ones, known as Cepheid variables, whose brightness changes regularly on a cycle time of a few days. These Cepheid variables have characteristics that allow their distances to be measured accurately. A team of astronomers led by Prof. Michael Feast used observations made with the Southern African Large Telescope (SALT) and the Infrared Survey Facility (IRSF), both at the South African Astronomical Observatory's (SAAO) site at Sutherland in the Northern Cape, to determine the distances of these stars and hence their locations within our Galaxy. The majority of stars in our Galaxy, including our own sun, are distributed in a flat disk (see illustration). Early in the 21st century radio astronomers discovered that hydrogen gas, of which the Galaxy contains a great deal, flared away from the disk at large distances from the Galactic centre, but until now no one knew that stars did the same thing. An infrared image (left) of the Cepheid named OGLE-BLG-CEP-32 and the stars which surround it, together with its SALT spectrum (insert right). These were used to show that the Cepheid was in the flare of the Galactic disk. Credit: Whitelock et al The team who made the discovery are from South Africa and Japan: Prof Michael Feast (University of Cape Town – UCT, SAAO), Dr John Menzies (SAAO), Dr Noriyuki Matsunaga (the University of Tokyo, Japan) and Prof Patricia Whitelock (SAAO, UCT). These results will be published in detail on 15 May, in the international journal 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 Flaring and warping of the disk of the Milky Way have been inferred from observations of atomic hydrogen 1 , 2 but stars associated with flaring have not hitherto been reported. In the area beyond the Galactic centre the stars are largely hidden from view by dust, and the kinematic distances of the gas cannot be estimated. Thirty-two possible Cepheid stars (young pulsating variable stars) in the direction of the Galactic bulge were recently identified 3 . With their well-calibrated period–luminosity relationships, Cepheid stars are useful distance indicators 4 . When observations of these stars are made in two colours, so that their distance and reddening can be determined simultaneously, the problems of dust obscuration are minimized. Here we report that five of the candidates are classical Cepheid stars. These five stars are distributed from approximately one to two kiloparsecs above and below the plane of the Galaxy, at radial distances of about 13 to 22 kiloparsecs from the centre. The presence of these relatively young (less than 130 million years old) stars so far from the Galactic plane is puzzling, unless they are in the flared outer disk. If so, they may be associated with the outer molecular arm 5 . Main We derived the distances for the five Cepheids from near-infrared photometry obtained with the Infrared Survey Facility (IRSF) and we used radial velocities from the Southern African Large Telescope (SALT) to determine the kinematics (see Methods)—both telescopes are at the South African Astronomical Observatory (SAAO), Sutherland, in South Africa. From these data we were able to ascertain the population to which the Cepheids belong. The other 27 Cepheid candidates are either better assigned to a different class (such as anomalous Cepheids) or else their classification as classical Cepheids is uncertain. Table 1 lists the derived distances and various other parameters for the Cepheids. They are at about the distance and position at which a stream associated with the Sagittarius (Sgr) dwarf galaxy crosses the plane 6 , but the low radial velocity (mean heliocentric radial velocity after correction for the effects of stellar pulsation of V R = 4 ± 8 km s −1 , see Table 1 ) is completely different from that expected for members of the Sgr dwarf stream (about 150 km s −1 ) 6 , 7 and the Cepheids are clearly Galactic. They cannot be in the Galactic bulge because their distances from the centre put them far beyond the bulge and the velocity dispersion of the five stars, 16 ± 5 km s −1 (much of which is observational), is much smaller than expected for bulge objects (>60 km s −1 ) 8 . Furthermore, these short-period Cepheids will be relatively young (about 100 million years (Myr) old), and, although there is a young component, including Cepheids 9 , in the innermost regions of the bulge, the bulk of the population is old (about 10 billion years (Gyr) old) 8 . Figure 1 shows the positions of the five stars in comparison to catalogued Cepheids. The various sources of uncertainty for the distances of the Cepheids are discussed in the Methods, but the reddening law and reddening corrections presented the biggest challenge and are the primary contributors to the error bars shown in the figure. Table 1 Data for individual Cepheids Full size table Figure 1: Schematic of the Galaxy. The positions of the Cepheids (open circles with assumed maximum uncertainties of ±0.2 mag) are compared to the location of the H i gas. The solid and dashed curves are model fits, S and N1, respectively, from ref. 1 at three times the HWHM above and below the Galactic plane. We note that figures 1 and 2 of ref. 2 show the H i flare in the relevant region extending up to about 2 kpc. The dark grey points are previously known Galactic Cepheids 10 and the approximate regions surveyed by OGLE (2 < | b | < 6) are shown in light grey on either side of the plane. The positions of the Sun and Galactic centre are indicated by the star symbols. PowerPoint slide Full size image There is almost no information on gas or stars in the Galactic disk immediately behind (Galactic longitude l ± 15°) the Galactic centre. The atomic hydrogen observations 2 on either side of the centre, but away from the central region itself, suggest that the gaseous disk of the Milky Way at l ≈ 0 is not warped but shows a marked flaring at Galactocentric radii ( R , the distance from a star to the centre of the Galaxy) of 15 kiloparsecs (kpc) and more; we note that the details are model dependent. The thickness of the gaseous disk 1 , 2 increases from 60 parsecs (pc) half-width at half-maximum (HWHM) at R = 4 kpc to 2.7 kpc at R = 30 kpc and, especially at positive Galactic longitudes 1 , there is a marked increase from about 0.4 kpc at R = 15 kpc to about 1.0 kpc at R = 20 kpc. Therefore we found the Cepheids at exactly the distance predicted for this increase in disk thickness, as can be seen in Fig. 1 . The absence of Cepheids nearer the Sun is consistent with the lower HWHM in these regions, whereas the absence of more distant Cepheids is partly due to the decreasing density at larger distances from the centre and partly the consequence of the Optical Gravitational Lensing Experiment (OGLE) observational cut-off. So the relatively narrow range of distances is consistent with our hypothesis that these stars are in the flared disk. In the Methods we also show that the numbers of Cepheids observed is consistent with expectations from a flared disk. Cepheids are usually associated with spiral arms and the distances of these five are similar to that expected for the far outer molecular spiral arm of the Galaxy 5 where it passes behind the central region of the Galaxy; the HWHM of this<|im_end|> <|im_start|>assistant South African astronomers have discovered the very first known stars in the flared disk of our Milky Way Galaxy. These stars are situated on the far side of our Galaxy, 80 thousand light years from the Earth and beyond the Galactic Centre. The discovery is important because stars like these will allow astronomers to test theoretical ideas about how galaxies, like the Milky Way in which we live, formed. In particular these stars, which are close to the effective edge of the Milky Way, will help astronomers trace the distribution of the very mysterious dark matter. Dark matter is known to be an important component of all galaxies, but its nature and distribution remain elusive. The five stars involved in this discovery are very special ones, known as Cepheid variables, whose brightness changes regularly on a cycle time of a few days. These Cepheid variables have characteristics that allow their distances to be measured accurately. A team of astronomers led by Prof. Michael Feast used observations made with the Southern African Large Telescope (SALT) and the Infrared Survey Facility (IRSF), both at the South African Astronomical Observatory's (SAAO) site at Sutherland in the Northern Cape, to determine the distances of these stars and hence their locations within our Galaxy. The majority of stars in our Galaxy, including our own sun, are distributed in a flat disk (see illustration). Early in the 21st century radio astronomers discovered that hydrogen gas, of which the Galaxy contains a great deal, flared away from the disk at large distances from the Galactic centre, but until now no one knew that stars did the same thing. An infrared image (left) of the Cepheid named OGLE-BLG-CEP-32 and the stars which surround it, together with its SALT spectrum (insert right). These were used to show that the Cepheid was in the flare of the Galactic disk. Credit: Whitelock et al The team who made the discovery are from South Africa and Japan: Prof Michael Feast (University of Cape Town – UCT, SAAO), Dr John Menzies (SAAO), Dr Noriyuki Matsunaga (the University of Tokyo, Japan) and Prof Patricia Whitelock (SAAO, UCT). These results will be published in detail on 15 May, in the international journal Nature. <|im_end|>

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1,838

[ { "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 evaluate the impact of a multicomponent intervention (Stand More AT (SMArT) Work) designed to reduce sitting time on short (three months), medium (six months), and longer term (12 months) changes in occupational, daily, and prolonged sitting, standing, and physical activity, and physical, psychological, and work related health. Design Cluster two arm randomised controlled trial. Setting National Health Service trust, England. Participants 37 office clusters (146 participants) of desk based workers: 19 clusters (77 participants) were randomised to the intervention and 18 (69 participants) to control. Interventions The intervention group received a height adjustable workstation, a brief seminar with supporting leaflet, workstation instructions with sitting and standing targets, feedback on sitting and physical activity at three time points, posters, action planning and goal setting booklet, self monitoring and prompt tool, and coaching sessions (month 1 and every three months thereafter). The control group continued with usual practice. Main outcome measures The primary outcome was occupational sitting time (thigh worn accelerometer). Secondary outcomes were objectively measured daily sitting, prolonged sitting (≥30 minutes), and standing time, physical activity, musculoskeletal problems, self reported work related health (job performance, job satisfaction, work engagement, occupational fatigue, sickness presenteeism, and sickness absenteeism), cognitive function, and self reported psychological measures (mood and affective states, quality of life) assessed at 3, 6, and 12 months. Data were analysed using generalised estimating equation models, accounting for clustering. Results A significant difference between groups (in favour of the intervention group) was found in occupational sitting time at 12 months (−83.28 min/workday, 95% confidence interval −116.57 to −49.98, P=0.001). Differences between groups (in favour of the intervention group compared with control) were observed for occupational sitting time at three months (−50.62 min/workday, −78.71 to −22.54, P<0.001) and six months (−64.40 min/workday, −97.31 to −31.50, P<0.001) and daily sitting time at six months (−59.32 min/day, −88.40 to −30.25, P<0.001) and 12 months (−82.39 min/day, −114.54 to −50.26, P=0.001). Group differences (in favour of the intervention group compared with control) were found for prolonged sitting time, standing time, job performance, work engagement, occupational fatigue, sickness presenteeism, daily anxiety, and quality of life. No differences were seen for sickness absenteeism. Conclusions SMArT Work successfully reduced sitting time over the short, medium, and longer term, and positive changes were observed in work related and psychological health. Trial registration Current Controlled Trials ISRCTN10967042 . Download figure Open in new tab Download powerpoint Introduction A wealth of epidemiological evidence shows that sedentary behaviour is associated with an increased risk of chronic disease (type 2 diabetes, cardiovascular disease, some cancers) and mortality, often independently of body mass index (BMI) and physical activity, 1 2 3 4 poor mental health, 5 6 and a lower quality of life. 7 Office workers are one of the most sedentary populations, spending 70-85% of time at work sitting. 8 9 It has also been reported that over a third of their total sitting time at work is accumulated in bouts of prolonged sitting (>30 minutes). 8 Occupational sedentary behaviour specifically has been associated with an increased risk of diabetes and mortality 10 and musculoskeletal problems such as neck and shoulder pain, 11 as well as being detrimental for important work related outcomes such as engagement 12 and presenteeism. 13 Research on outcomes such as work engagement and presenteeism is, however, limited. These links between sedentary behaviour and health and work related outcomes are important because the estimated costs of presenteeism and absenteeism in the United Kingdom are reported to be more than £30bn ($39bn; €34bn), with presenteeism costing over twice as much as absenteeism. 14 More positively, reductions in sitting and breaking up sitting through standing and walking in acute experimental settings have led to improvements in important cardiometabolic markers of health such as glucose and insulin levels and blood pressure, 15 16 17 18 19 20 21 22 and feelings of fatigue and vigour. 23 24 In response to this evidence, interventions to reduce sitting time in the workplace have received increasing attention in recent years. 25 These have focused on numerous strategies, including physical changes to the workplace, such as providing height adjustable desks to enable sitting or standing, pedalling workstations, treadmill desks, policy changes, information provision, counselling, and computer prompts. 25 While positive findings were observed for some strategies in terms of reducing sitting time, particularly the provision of height adjustable desks, the quality of evidence was considered low for most studies owing to non-powered small studies and studies with a high risk of bias. 25 Furthermore, interventions have typically been evaluated over the short term, so knowledge on longer term effectiveness is lacking. Although some studies have examined the impact of sitting reduction interventions on work related outcomes such as job performance and productivity, 25 26 presenteeism, 26 and absenteeism, 26 27 it is difficult to draw conclusions across these studies owing to the limitations in study designs. The Stand Up Victoria study was one recent example that addressed these limitations. This was a multicomponent intervention in Australia, and effectiveness was tested within a cluster randomised controlled trial over 12 months. 28 Components comprised a group based workshop, feedback on sitting behaviour, provision of a height adjustable desk attachment, goal setting, and ongoing support for three months in the form of emails or individual coaching sessions. The intervention was successful in reducing daily sitting and sitting at work 29 and led to small improvements in glucose levels and cardiometabolic risk. 30 However, high quality designs remain scarce and studies in the UK are lacking. The Stand More At Work (SMArT Work) intervention was designed in response to this need and was developed using guidance from the Behaviour Change Wheel 31 (a framework for designing interventions) after formative research with office workers. 32 We undertook a cluster randomised controlled trial to test the impact of the SMArT Work intervention over the short (three months), medium (six months), and longer term (12 months) in a sample of office workers working within the English National Health Service, the largest", "role": "user" }, { "content": "Sit-stand workstations that allow employees to stand, as well as sit, while working on a computer reduce daily sitting time and appear to have a positive impact on job performance and psychological health, finds a trial published by The BMJ today. The results show that employees who used the workstations for 12 months, on average, reduced their sitting time by more than an hour a day, with potentially meaningful benefits. High levels of sedentary behaviour (sitting) have been associated with an increased risk of chronic diseases (type 2 diabetes, heart disease, and some cancers) as well as death and have been shown to be detrimental for work related outcomes such as feelings of engagement and presenteeism (going to work despite illness). Office workers are one of the most sedentary populations, spending 70-85% of time at work sitting, but studies looking at ways to reduce sitting in the workplace have been deemed low quality. So a team of researchers based in the UK, with collaborators in Australia, set out to evaluate the impact of (Stand More AT (SMArT) Work) an intervention designed to reduce sitting time at work. The trial involved 146 office workers based at the University Hospitals of Leicester NHS Trust of whom 77 were randomly assigned to the intervention group and 69 to the control group over a 12 month period. The average age of participants was 41 years, 78% reported being of white European ethnicity, and the majority (80%) were women. The intervention group were given a height adjustable workstation, a brief seminar with supporting leaflet, and workstation instructions with sitting and standing targets. They also received feedback on sitting and physical activity, an action planning and goal setting booklet, a self monitoring and prompt tool, and coaching sessions. The control group carried on working as usual. Workers' sitting time was measured using a device worn on the thigh at the start of the study (baseline) and at 3, 6, and 12 months. Daily physical activity levels and questions about work (eg. job performance, engagement) and health (eg. mood, quality of life) were also recorded. At the start of the study, overall sitting time was 9.7 hours per day. The results show that sitting time was lower by 50.62 minutes per day at 3 months, 64.40 minutes per day at 6 months, and 82.39 minutes per day at 12 months in the intervention group compared with the control group. Prolonged sitting time was also reduced in the intervention group. The reduction in sitting was largely replaced by time spent standing rather than moving, as stepping time and physical activity remained unchanged. The results also suggest improvements in job performance, work engagement, occupational fatigue, presenteeism, daily anxiety and quality of life, but no notable changes were found for job satisfaction, cognitive function, and sickness absence. The authors say this was a well-designed trial and their results remained largely unchanged after further analyses. But they acknowledge that their findings may not apply to other organisations, and that self-reporting of work related outcomes may have affected the results. Nevertheless, they say the SMArT Work successfully reduced sitting time over the short, medium, and longer term, and positive changes were observed in work related and psychological health. And they suggest future research should assess the longer term health benefits of displacing sitting with standing and how best to promote movement rather than just standing while at work. In a linked editorial, Dr. Cindy Gray at the University of Glasgow says this is an important study that demonstrates lasting reductions in sedentary behaviour and other work-related benefits. But she questions the potential health gains of simply replacing sitting with standing. The intervention did not increase potentially more beneficial physical activity. She also questions SMArT Work's transferability and suitability for other types of employees, including shift workers, as well as its cost-effectiveness, which she says should be addressed in future research. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Objectives To evaluate the impact of a multicomponent intervention (Stand More AT (SMArT) Work) designed to reduce sitting time on short (three months), medium (six months), and longer term (12 months) changes in occupational, daily, and prolonged sitting, standing, and physical activity, and physical, psychological, and work related health. Design Cluster two arm randomised controlled trial. Setting National Health Service trust, England. Participants 37 office clusters (146 participants) of desk based workers: 19 clusters (77 participants) were randomised to the intervention and 18 (69 participants) to control. Interventions The intervention group received a height adjustable workstation, a brief seminar with supporting leaflet, workstation instructions with sitting and standing targets, feedback on sitting and physical activity at three time points, posters, action planning and goal setting booklet, self monitoring and prompt tool, and coaching sessions (month 1 and every three months thereafter). The control group continued with usual practice. Main outcome measures The primary outcome was occupational sitting time (thigh worn accelerometer). Secondary outcomes were objectively measured daily sitting, prolonged sitting (≥30 minutes), and standing time, physical activity, musculoskeletal problems, self reported work related health (job performance, job satisfaction, work engagement, occupational fatigue, sickness presenteeism, and sickness absenteeism), cognitive function, and self reported psychological measures (mood and affective states, quality of life) assessed at 3, 6, and 12 months. Data were analysed using generalised estimating equation models, accounting for clustering. Results A significant difference between groups (in favour of the intervention group) was found in occupational sitting time at 12 months (−83.28 min/workday, 95% confidence interval −116.57 to −49.98, P=0.001). Differences between groups (in favour of the intervention group compared with control) were observed for occupational sitting time at three months (−50.62 min/workday, −78.71 to −22.54, P<0.001) and six months (−64.40 min/workday, −97.31 to −31.50, P<0.001) and daily sitting time at six months (−59.32 min/day, −88.40 to −30.25, P<0.001) and 12 months (−82.39 min/day, −114.54 to −50.26, P=0.001). Group differences (in favour of the intervention group compared with control) were found for prolonged sitting time, standing time, job performance, work engagement, occupational fatigue, sickness presenteeism, daily anxiety, and quality of life. No differences were seen for sickness absenteeism. Conclusions SMArT Work successfully reduced sitting time over the short, medium, and longer term, and positive changes were observed in work related and psychological health. Trial registration Current Controlled Trials ISRCTN10967042 . Download figure Open in new tab Download powerpoint Introduction A wealth of epidemiological evidence shows that sedentary behaviour is associated with an increased risk of chronic disease (type 2 diabetes, cardiovascular disease, some cancers) and mortality, often independently of body mass index (BMI) and physical activity, 1 2 3 4 poor mental health, 5 6 and a lower quality of life. 7 Office workers are one of the most sedentary populations, spending 70-85% of time at work sitting. 8 9 It has also been reported that over a third of their total sitting time at work is accumulated in bouts of prolonged sitting (>30 minutes). 8 Occupational sedentary behaviour specifically has been associated with an increased risk of diabetes and mortality 10 and musculoskeletal problems such as neck and shoulder pain, 11 as well as being detrimental for important work related outcomes such as engagement 12 and presenteeism. 13 Research on outcomes such as work engagement and presenteeism is, however, limited. These links between sedentary behaviour and health and work related outcomes are important because the estimated costs of presenteeism and absenteeism in the United Kingdom are reported to be more than £30bn ($39bn; €34bn), with presenteeism costing over twice as much as absenteeism. 14 More positively, reductions in sitting and breaking up sitting through standing and walking in acute experimental settings have led to improvements in important cardiometabolic markers of health such as glucose and insulin levels and blood pressure, 15 16 17 18 19 20 21 22 and feelings of fatigue and vigour. 23 24 In response to this evidence, interventions to reduce sitting time in the workplace have received increasing attention in recent years. 25 These have focused on numerous strategies, including physical changes to the workplace, such as providing height adjustable desks to enable sitting or standing, pedalling workstations, treadmill desks, policy changes, information provision, counselling, and computer prompts. 25 While positive findings were observed for some strategies in terms of reducing sitting time, particularly the provision of height adjustable desks, the quality of evidence was considered low for most studies owing to non-powered small studies and studies with a high risk of bias. 25 Furthermore, interventions have typically been evaluated over the short term, so knowledge on longer term effectiveness is lacking. Although some studies have examined the impact of sitting reduction interventions on work related outcomes such as job performance and productivity, 25 26 presenteeism, 26 and absenteeism, 26 27 it is difficult to draw conclusions across these studies owing to the limitations in study designs. The Stand Up Victoria study was one recent example that addressed these limitations. This was a multicomponent intervention in Australia, and effectiveness was tested within a cluster randomised controlled trial over 12 months. 28 Components comprised a group based workshop, feedback on sitting behaviour, provision of a height adjustable desk attachment, goal setting, and ongoing support for three months in the form of emails or individual coaching sessions. The intervention was successful in reducing daily sitting and sitting at work 29 and led to small improvements in glucose levels and cardiometabolic risk. 30 However, high quality designs remain scarce and studies in the UK are lacking. The Stand More At Work (SMArT Work) intervention was designed in response to this need and was developed using guidance from the Behaviour Change Wheel 31 (a framework for designing interventions) after formative research with office workers. 32 We undertook a cluster randomised controlled trial to test the impact of the SMArT Work intervention over the short (three months), medium (six months), and longer term (12 months) in a sample of office workers working within the English National Health Service, the largest<|im_end|> <|im_start|>assistant Sit-stand workstations that allow employees to stand, as well as sit, while working on a computer reduce daily sitting time and appear to have a positive impact on job performance and psychological health, finds a trial published by The BMJ today. The results show that employees who used the workstations for 12 months, on average, reduced their sitting time by more than an hour a day, with potentially meaningful benefits. High levels of sedentary behaviour (sitting) have been associated with an increased risk of chronic diseases (type 2 diabetes, heart disease, and some cancers) as well as death and have been shown to be detrimental for work related outcomes such as feelings of engagement and presenteeism (going to work despite illness). Office workers are one of the most sedentary populations, spending 70-85% of time at work sitting, but studies looking at ways to reduce sitting in the workplace have been deemed low quality. So a team of researchers based in the UK, with collaborators in Australia, set out to evaluate the impact of (Stand More AT (SMArT) Work) an intervention designed to reduce sitting time at work. The trial involved 146 office workers based at the University Hospitals of Leicester NHS Trust of whom 77 were randomly assigned to the intervention group and 69 to the control group over a 12 month period. The average age of participants was 41 years, 78% reported being of white European ethnicity, and the majority (80%) were women. The intervention group were given a height adjustable workstation, a brief seminar with supporting leaflet, and workstation instructions with sitting and standing targets. They also received feedback on sitting and physical activity, an action planning and goal setting booklet, a self monitoring and prompt tool, and coaching sessions. The control group carried on working as usual. Workers' sitting time was measured using a device worn on the thigh at the start of the study (baseline) and at 3, 6, and 12 months. Daily physical activity levels and questions about work (eg. job performance, engagement) and health (eg. mood, quality of life) were also recorded. At the start of the study, overall sitting time was 9.7 hours per day. The results show that sitting time was lower by 50.62 minutes per day at 3 months, 64.40 minutes per day at 6 months, and 82.39 minutes per day at 12 months in the intervention group compared with the control group. Prolonged sitting time was also reduced in the intervention group. The reduction in sitting was largely replaced by time spent standing rather than moving, as stepping time and physical activity remained unchanged. The results also suggest improvements in job performance, work engagement, occupational fatigue, presenteeism, daily anxiety and quality of life, but no notable changes were found for job satisfaction, cognitive function, and sickness absence. The authors say this was a well-designed trial and their results remained largely unchanged after further analyses. But they acknowledge that their findings may not apply to other organisations, and that self-reporting of work related outcomes may have affected the results. Nevertheless, they say the SMArT Work successfully reduced sitting time over the short, medium, and longer term, and positive changes were observed in work related and psychological health. And they suggest future research should assess the longer term health benefits of displacing sitting with standing and how best to promote movement rather than just standing while at work. In a linked editorial, Dr. Cindy Gray at the University of Glasgow says this is an important study that demonstrates lasting reductions in sedentary behaviour and other work-related benefits. But she questions the potential health gains of simply replacing sitting with standing. The intervention did not increase potentially more beneficial physical activity. She also questions SMArT Work's transferability and suitability for other types of employees, including shift workers, as well as its cost-effectiveness, which she says should be addressed in future research. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Spillover of parasites at the domestic animal - wildlife interface is a pervasive threat to animal health. Cat and dog fleas ( Ctenocephalides felis and C. canis ) are among the world’s most invasive and economically important ectoparasites. Although both species are presumed to infest a diversity of host species across the globe, knowledge on their distributions in wildlife is poor. We built a global dataset of wild mammal host associations for cat and dog fleas, and used Bayesian hierarchical models to identify traits that predict wildlife infestation probability. We complemented this by calculating functional-phylogenetic host specificity to assess whether fleas are restricted to hosts with similar evolutionary histories, diet or habitat niches. Results Over 130 wildlife species have been found to harbour cat fleas, representing nearly 20% of all mammal species sampled for fleas. Phylogenetic models indicate cat fleas are capable of infesting a broad diversity of wild mammal species through ecological fitting. Those that use anthropogenic habitats are at highest risk. Dog fleas, by contrast, have been recorded in 31 mammal species that are primarily restricted to certain phylogenetic clades, including canids, felids and murids. Both flea species are commonly reported infesting mammals that are feral (free-roaming cats and dogs) or introduced (red foxes, black rats and brown rats), suggesting the breakdown of barriers between wildlife and invasive reservoir species will increase spillover at the domestic animal - wildlife interface. Conclusions Our empirical evidence shows that cat fleas are incredibly host-generalist, likely exhibiting a host range that is among the broadest of all ectoparasites. Reducing wild species’ contact rates with domestic animals across natural and anthropogenic habitats, together with mitigating impacts of invasive reservoir hosts, will be crucial for reducing invasive flea infestations in wild mammals. Background Animals closely associated with humans can act as reservoir hosts that spread parasites to wildlife [ 1 , 2 , 3 ]. Spillover of parasites (i.e. the transmission of a parasite from one host species to another) between domestic and wild animals is an increasing threat to animal health, and understanding factors that drive this process is crucial [ 4 , 5 , 6 ]. Yet while conversion of natural habitat into production zones, habitat fragmentation and global urbanisation increase contact rates between domestic and wild animals [ 7 , 8 ], patterns of parasite sharing at the domestic animal - wildlife interface are poorly resolved. Cat fleas ( Ctenocephalides felis ) and related dog fleas ( C. canis ) are blood-feeding ectoparasites causing enormous grievances for pets worldwide [ 9 , 10 , 11 , 12 ]. Flea control relies on mass use of preventative drugs, equating to hundreds of dollars spent by owners each year [ 13 ]. In addition to pets, C. felis and C. canis are presumed to infest a diversity of wild species. Control of parasite spread and infestation-related morbidity are therefore multifaceted problems [ 14 , 15 , 16 , 17 ]. The potential for urban-wildlife parasite exchange represents a considerable One Health threat, especially since fleas can transmit harmful bacteria (some of them being zoonotic [ 18 , 19 ]). Despite the pervasive risk for flea spillover between domestic and wild animals, there is a dearth of knowledge on C. felis and C. canis distributions among wildlife [ 10 , 20 , 21 ]. Predicting parasite spread requires an understanding of wildlife characteristics that enable host shifting [ 22 ]. The human-induced range expansion of domestic animals and other non-native species that act as viable hosts for fleas (including foxes, rabbits and rats [ 23 , 24 , 25 ]) has led to the encroachment of potential reservoir host species into almost all terrestrial environments [ 26 , 27 , 28 ]. Close proximity between natural and anthropogenic habitats might increase exposure to feral and domestic animals [ 29 , 30 , 31 ] and could be a key predictor of C. felis and C. canis infestation in wildlife. However, other host attributes, such as body mass, diet and phylogenetic ancestry, can be informative for predicting whether hosts share parasite species [ 3 , 32 ]. These attributes may facilitate flea exchange, as factors regulating habitat use are important drivers of ectoparasite infestation [ 33 , 34 , 35 ]. How historical and ecological species traits facilitate or inhibit flea infestation is not known. Moreover, information on infestation rates in wildlife species is scattered throughout the literature. We use a systematic literature search and web scraping tools to build a global database of C. felis and C. canis infestations in wildlife species. Using Bayesian hierarchical models, we incorporate mammalian trait data to ask if extrinsic (habitat use, diet breadth) and intrinsic (phylogenetic ancestry, body mass) host attributes act as drivers of flea infestation risk. We use host specificity analyses and null models to assess whether fleas infest species that are more similar in their phylogenetic ancestry, habitat use or diet than expected by chance. If habitat use is a key driver of infestation risk, we expect that use of anthropogenic habitats will increase species’ infestation probability and that both flea species will infest hosts that exhibit more similar habitats than expected by chance. Results Introduced mammals as reservoir hosts for fleas at the domestic-animal wildlife interfac e Both flea species infest wildlife on all continents apart from Antarctica (Fig. 1 ). In total, 138 (20%) out of 685 sampled wild mammal species harboured cat fleas ( Ctenocephalides felis ) and 31 (4%) harboured dog fleas ( C. canis ). Species most frequently reported to be associated with C. felis were all invasive mammals, including feral cats (26 out of 446 total flea-host-location observations; ranging all sampled continents), feral dogs (21 observations), red foxes ( Vulpes vulpes ; 19 observations), black rats ( Rattus rattus species complex; 16 observations), brown rats ( Rattus norvegicus ; 14 records) and European rabbits ( Oryctolagus cuniculus ; 9 observations; Table 1 ). Likewise, C. canis was commonly reported infesting feral mammals, including red foxes (22 observations),", "role": "user" }, { "content": "Fleas from domestic pets are infesting native wildlife and feral animals in all continents except Antarctica, a new study reveals. The University of Queensland-led global study found domestic pet fleas feeding on species as diverse as Australian brushtail possums, coyotes, golden jackals and Iberian lynx. UQ School of Veterinary Science researcher Dr. Nicholas Clark said the potential for urban-wildlife parasite exchange represented a considerable threat, especially since fleas could transmit harmful bacteria including those causing bubonic plague and typhus. The study showed that so-called cat fleas – the main flea species found on domestic dogs and cats— were infesting more than 130 wildlife species around the world, representing nearly 20 per cent of all mammal species sampled. \"Dog fleas are less widespread and to date they've been reported on 31 mammal species,\" he said. \"Both flea species are commonly reported infesting free-roaming (feral) cats and dogs or introduced mammals such as red foxes, black rats and brown rats.\" The breakdown of barriers between wildlife and invasive species had increased the transfer of fleas between domestic animals and wildlife. Credit: University of Queensland parasites from domestic pets affecting wildlife worldwide. Credit: University of Queensland Dr. Clark said this was a threat to One Health – a concept from the Centres of Disease Control and Prevention that recognises that the health of people is linked to the health of animals and the environment, and requires a global effort to address. University of Sydney researcher Associate Professor Jan Šlapeta said that despite the extensive risk for flea spill-over between domestic and wild animals, there was a lack of knowledge on cat and dog flea distributions among wildlife. \"This study is the first to uncover the magnitude and geographic spread of the wildlife occurrences of domestic dog and cat fleas,\" he said. \"We have provided tangible evidence that invasive species contribute to the spread of the most common parasites from domestic pets.\" Dr. Clark said that reducing contact between wild species and domestic animals would be crucial to manage invasive flea infestations in wild animals. ", "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 Spillover of parasites at the domestic animal - wildlife interface is a pervasive threat to animal health. Cat and dog fleas ( Ctenocephalides felis and C. canis ) are among the world’s most invasive and economically important ectoparasites. Although both species are presumed to infest a diversity of host species across the globe, knowledge on their distributions in wildlife is poor. We built a global dataset of wild mammal host associations for cat and dog fleas, and used Bayesian hierarchical models to identify traits that predict wildlife infestation probability. We complemented this by calculating functional-phylogenetic host specificity to assess whether fleas are restricted to hosts with similar evolutionary histories, diet or habitat niches. Results Over 130 wildlife species have been found to harbour cat fleas, representing nearly 20% of all mammal species sampled for fleas. Phylogenetic models indicate cat fleas are capable of infesting a broad diversity of wild mammal species through ecological fitting. Those that use anthropogenic habitats are at highest risk. Dog fleas, by contrast, have been recorded in 31 mammal species that are primarily restricted to certain phylogenetic clades, including canids, felids and murids. Both flea species are commonly reported infesting mammals that are feral (free-roaming cats and dogs) or introduced (red foxes, black rats and brown rats), suggesting the breakdown of barriers between wildlife and invasive reservoir species will increase spillover at the domestic animal - wildlife interface. Conclusions Our empirical evidence shows that cat fleas are incredibly host-generalist, likely exhibiting a host range that is among the broadest of all ectoparasites. Reducing wild species’ contact rates with domestic animals across natural and anthropogenic habitats, together with mitigating impacts of invasive reservoir hosts, will be crucial for reducing invasive flea infestations in wild mammals. Background Animals closely associated with humans can act as reservoir hosts that spread parasites to wildlife [ 1 , 2 , 3 ]. Spillover of parasites (i.e. the transmission of a parasite from one host species to another) between domestic and wild animals is an increasing threat to animal health, and understanding factors that drive this process is crucial [ 4 , 5 , 6 ]. Yet while conversion of natural habitat into production zones, habitat fragmentation and global urbanisation increase contact rates between domestic and wild animals [ 7 , 8 ], patterns of parasite sharing at the domestic animal - wildlife interface are poorly resolved. Cat fleas ( Ctenocephalides felis ) and related dog fleas ( C. canis ) are blood-feeding ectoparasites causing enormous grievances for pets worldwide [ 9 , 10 , 11 , 12 ]. Flea control relies on mass use of preventative drugs, equating to hundreds of dollars spent by owners each year [ 13 ]. In addition to pets, C. felis and C. canis are presumed to infest a diversity of wild species. Control of parasite spread and infestation-related morbidity are therefore multifaceted problems [ 14 , 15 , 16 , 17 ]. The potential for urban-wildlife parasite exchange represents a considerable One Health threat, especially since fleas can transmit harmful bacteria (some of them being zoonotic [ 18 , 19 ]). Despite the pervasive risk for flea spillover between domestic and wild animals, there is a dearth of knowledge on C. felis and C. canis distributions among wildlife [ 10 , 20 , 21 ]. Predicting parasite spread requires an understanding of wildlife characteristics that enable host shifting [ 22 ]. The human-induced range expansion of domestic animals and other non-native species that act as viable hosts for fleas (including foxes, rabbits and rats [ 23 , 24 , 25 ]) has led to the encroachment of potential reservoir host species into almost all terrestrial environments [ 26 , 27 , 28 ]. Close proximity between natural and anthropogenic habitats might increase exposure to feral and domestic animals [ 29 , 30 , 31 ] and could be a key predictor of C. felis and C. canis infestation in wildlife. However, other host attributes, such as body mass, diet and phylogenetic ancestry, can be informative for predicting whether hosts share parasite species [ 3 , 32 ]. These attributes may facilitate flea exchange, as factors regulating habitat use are important drivers of ectoparasite infestation [ 33 , 34 , 35 ]. How historical and ecological species traits facilitate or inhibit flea infestation is not known. Moreover, information on infestation rates in wildlife species is scattered throughout the literature. We use a systematic literature search and web scraping tools to build a global database of C. felis and C. canis infestations in wildlife species. Using Bayesian hierarchical models, we incorporate mammalian trait data to ask if extrinsic (habitat use, diet breadth) and intrinsic (phylogenetic ancestry, body mass) host attributes act as drivers of flea infestation risk. We use host specificity analyses and null models to assess whether fleas infest species that are more similar in their phylogenetic ancestry, habitat use or diet than expected by chance. If habitat use is a key driver of infestation risk, we expect that use of anthropogenic habitats will increase species’ infestation probability and that both flea species will infest hosts that exhibit more similar habitats than expected by chance. Results Introduced mammals as reservoir hosts for fleas at the domestic-animal wildlife interfac e Both flea species infest wildlife on all continents apart from Antarctica (Fig. 1 ). In total, 138 (20%) out of 685 sampled wild mammal species harboured cat fleas ( Ctenocephalides felis ) and 31 (4%) harboured dog fleas ( C. canis ). Species most frequently reported to be associated with C. felis were all invasive mammals, including feral cats (26 out of 446 total flea-host-location observations; ranging all sampled continents), feral dogs (21 observations), red foxes ( Vulpes vulpes ; 19 observations), black rats ( Rattus rattus species complex; 16 observations), brown rats ( Rattus norvegicus ; 14 records) and European rabbits ( Oryctolagus cuniculus ; 9 observations; Table 1 ). Likewise, C. canis was commonly reported infesting feral mammals, including red foxes (22 observations),<|im_end|> <|im_start|>assistant Fleas from domestic pets are infesting native wildlife and feral animals in all continents except Antarctica, a new study reveals. The University of Queensland-led global study found domestic pet fleas feeding on species as diverse as Australian brushtail possums, coyotes, golden jackals and Iberian lynx. UQ School of Veterinary Science researcher Dr. Nicholas Clark said the potential for urban-wildlife parasite exchange represented a considerable threat, especially since fleas could transmit harmful bacteria including those causing bubonic plague and typhus. The study showed that so-called cat fleas – the main flea species found on domestic dogs and cats— were infesting more than 130 wildlife species around the world, representing nearly 20 per cent of all mammal species sampled. "Dog fleas are less widespread and to date they've been reported on 31 mammal species," he said. "Both flea species are commonly reported infesting free-roaming (feral) cats and dogs or introduced mammals such as red foxes, black rats and brown rats." The breakdown of barriers between wildlife and invasive species had increased the transfer of fleas between domestic animals and wildlife. Credit: University of Queensland parasites from domestic pets affecting wildlife worldwide. Credit: University of Queensland Dr. Clark said this was a threat to One Health – a concept from the Centres of Disease Control and Prevention that recognises that the health of people is linked to the health of animals and the environment, and requires a global effort to address. University of Sydney researcher Associate Professor Jan Šlapeta said that despite the extensive risk for flea spill-over between domestic and wild animals, there was a lack of knowledge on cat and dog flea distributions among wildlife. "This study is the first to uncover the magnitude and geographic spread of the wildlife occurrences of domestic dog and cat fleas," he said. "We have provided tangible evidence that invasive species contribute to the spread of the most common parasites from domestic pets." Dr. Clark said that reducing contact between wild species and domestic animals would be crucial to manage invasive flea infestations in wild animals. <|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 Diacylglycerol (DAG) is a versatile lipid whose 1,2- sn -stereoisomer serves both as second messenger in signal transduction pathways that control vital cellular processes, and as metabolic precursor for downstream signaling lipids such as phosphatidic acid. Effector proteins translocate to available DAG pools in the membranes by using conserved homology 1 (C1) domains as DAG-sensing modules. Yet, how C1 domains recognize and capture DAG in the complex environment of a biological membrane has remained unresolved for the 40 years since the discovery of Protein Kinase C (PKC) as the first member of the DAG effector cohort. Herein, we report the high-resolution crystal structures of a C1 domain (C1B from PKCδ) complexed to DAG and to each of four potent PKC agonists that produce different biological readouts and that command intense therapeutic interest. This structural information details the mechanisms of stereospecific recognition of DAG by the C1 domains, the functional properties of the lipid-binding site, and the identities of the key residues required for the recognition and capture of DAG and exogenous agonists. Moreover, the structures of the five C1 domain complexes provide the high-resolution guides for the design of agents that modulate the activities of DAG effector proteins. Introduction The impressive diversity of DAG signaling output is mediated via its interactions with seven families of effector proteins that execute broad sets of regulatory functions 1 . These include protein phosphorylation (PKCs and PKDs 2 , 3 ); DAG phosphorylation (DGKs 4 ); RacGTPase regulation (Chimaerins 5 ); Ras guanine nucleotide exchange factor activation (RasGRPs 6 ); Cdc42-mediated cytoskeletal reorganization (MRCK 7 ); and assembly of scaffolds that potentiate synaptic vesicle fusion and neurotransmitter release (Munc13s 8 ). PKCs define a central DAG-sensing node in intracellular phosphoinositide signaling pathways that regulate cell growth, differentiation, apoptosis, and motility 9 . Shortly after their discovery, PKCs were identified as cellular receptors for tumor-promoting phorbol esters 10 that bind C1 domains in lieu of DAG. These observations, combined with the central roles executed by PKCs in intracellular signaling established their DAG-sensing function as an attractive target for therapeutic intervention, with considerable promise in the treatment of Alzheimer’s disease 11 , HIV/AIDS 12 , 13 , and cancer 14 , 15 . However, the structural basis of DAG recognition by the C1 domains has remained elusive, and the strategies for therapeutic agent design deployed to date all relied on modeling studies (reviewed in 16 ) based on the single available crystal structure of the C1 domain complexed to a ligand that does not activate PKC 17 . Herein, we have overcome these well-documented challenges 18 , 19 , 20 that have hindered the crystallization of extremely hydrophobic C1-ligand complexes for almost three decades. This advance enabled us to determine high-resolution structures of C1 bound to the endogenous agonist DAG and to each of four exogenous agonists of therapeutic interest. Collectively, our findings: (i) provide a structural rationale for the consensus amino acid sequence of DAG-sensitive C1 domains; (ii) provide insight into the origins of DAG sensitivity; and (iii) reveal how the unique hydrophilic/hydrophobic properties of the ligand-binding groove enable C1 domains to accommodate chemically diverse ligands. Results and discussion Structure of the C1Bδ-DAG complex C1 domains form complexes with their ligands in the membrane environment, and dodecylphosphocholine (DPC) is an effective membrane mimic that faithfully reproduces the functional properties of C1 domains with respect to ligand-binding interactions 21 , 22 . For structural studies, we formed the complex between the C1B domain of PKCδ (C1Bδ) and a synthetic DAG analog (di-octanoyl- sn -1,2-glycerol) in the presence of DPC micelles. The structure of the C1Bδ-DAG complex was refined to 1.75 Å with R work = 0.214 and R free = 0.246 (Supplementary Table 1 ). The H3 space group unit cell (89 × 89 × 219 Å, Fig. 1a ) contains a total of 72 protein chains contributed by nine asymmetric units (AUs) with eight C1Bδ molecules per AU (Fig. 1b ). Fig. 1: Arrangement of protein chains, lipid, and detergent molecules in the unit cell and the asymmetric unit of the C1Bδ-DAG complex crystal (PDB ID: 7L92). a The unit cell contains 72 DAG-complexed C1Bδ chains and 18/54 DAG/DPC molecules that peripherally associate with the protein surface. Structural Zn 2+ ions of C1Bδ are shown as black spheres. b The asymmetric unit comprises 8 C1Bδ protein chains with 8 DAG molecules captured within a well-defined groove, and 2/6 peripheral DAG/DPC molecules. c Space-filling representation of the two distinct DAG/DPC micelles. Full size image The organization of the protein crystal lattice is unprecedented as it contains two distinct lipid-detergent micelles located at symmetry elements in the crystal. Micelle 1 is composed of 12 DAG and 12 DPC ordered molecules, and micelle 2 composed of 18 DAG and 6 DPC ordered molecules (Fig. 1c ), in addition to fully or partially disordered lipids. We speculate that the micelles help nucleate the crystallization, as all of the protein subunits are arranged with their lipid sensing loops directly binding to DAG within micelles (Supplementary Fig. 1a, b ). Each C1Bδ protein chain has a DAG molecule captured within a groove formed by its membrane-binding loop regions (Fig. 1b and Supplementary Fig. 1c, d ). The well-defined glycerol ester moieties of this tightly bound ‘intra-loop’ DAG refined with B-factors (18–26 Å 2 ) comparable to those of the surrounding protein residues (17–23 Å 2 ). In addition, each AU contains two less-ordered peripheral DAG and six DPC molecules associated with the amphiphilic protein surface (Supplementary Fig. 1e, f ). There is little variability among DAG-complexed C1Bδ chains within the asymmetric unit, as evidenced by low pairwise backbone r.m.s.d values of 0.3–0.6 Å (Fig. 2a ). The most variable region is located between helix α1 and the C-terminal Cysteine residue that coordinates a structural Zn 2+ ion. According to solution NMR, this region undergoes conformational exchange on the μs-ms timescale 21 , 23 . We crystallized apo C1Bδ under conditions similar to those used for the C1Bδ-DAG complex (but without", "role": "user" }, { "content": "In a major advance for rational drug design, a Texas A&M AgriLife team has described several protein structures of a crucial player in cellular processes. The advance could bring new ideas for treatments of diseases such as Alzheimer's, AIDS, cancer and others. Specifically, the work describes the C1 domain of protein kinase C, PKC, which helps regulate the protein's activity in organisms. In the structures, the C1 domain wraps around different molecules of intense therapeutic interest, providing the first reliable, atomic-resolution guide for designing drug candidates. Published May 16 in Nature Communications, the research was directed by Tatyana Igumenova, Ph.D., associate professor in the Department of Biochemistry and Biophysics in the Texas A&M College of Agriculture and Life Sciences. The project's primary author is Sachin Katti, Ph.D., a postdoctoral fellow working with Igumenova. The study involved a collaboration with Inna Krieger, Ph.D., research assistant professor, and James Sacchettini, Ph.D., professor, both in the Department of Biochemistry and Biophysics. One of the most sought-after protein structures A healthy cell responds to chemical signals in precise, intricate ways. Receiving chemical inputs from the cell's environment and forwarding them to the central control systems within the cell nucleus is the task of specialized proteins such as PKC. Improper PKC activity shows up in many human diseases. As a result, there is much interest in finding ways to fine-tune PKC activity with drugs. The design of such drugs will offer new approaches for treating Alzheimer's disease, AIDS, cancer and more. \"Protein kinase C is one of the most intensely studied proteins in cell biology and pharmacology,\" Igumenova said. \"A major hurdle has been the lack of precise structural information to guide drug design efforts.\" One complication for drug design is that the PKC family has 11 members. Different PKC family members can have opposite physiological effects, so a successful drug candidate must be selective about which PKC it targets. To do that, drug candidates must fit a target PKC like a key to a lock. But determining the 3D structure of a PKC \"on-switch\"—the C1 domain—bound to PKC activators has not been easy. Protein structures are typically solved using X-ray crystallography. The technique involves using X-rays to determine the position of atoms in a crystal. For this method, researchers need to create conditions where the protein of interest crystallizes. Yet intense efforts in many research labs over the past three decades failed to yield crystals of C1 domains bound to relevant ligands. Because of this lack of progress, multiple researchers pronounced the task impossible, Igumenova said. Crystals of a domain of protein kinase C spontaneously formed in Katti’s NMR sample tube. Credit: Sachin Katti. Solving a 30-year problem Accepting the problem as challenging, Katti and Igumenova decided instead to study the molecules in solution using nuclear magnetic resonance, NMR, spectroscopy. This involved finding the right components to mimic cell membranes, where the C1 domain would encounter ligands. \"Then, one fine day, Sachin discovered crystals forming in an old NMR tube,\" Igumenova said. \"I give all the credit to Sachin, who basically said, 'I'm going to go and test them and see if they are actually the protein.' And he was right. It gave us confidence that crystallization is possible.\" In turn, Katti gives credence to the insights obtained from NMR, and a bit of luck. \"I think that's the beauty of doing research where you have to use multiple approaches,\" he said. \"You never know when one approach is going to be useful for doing something with other approaches.\" Insights from NMR and X-ray crystallography The new protein structures, along with the team's NMR results, have already yielded interesting information. One long-standing mystery has been how C1 domains can accommodate ligands that have very different chemical structures, Igumenova said. \"Our previous NMR work indicated that the loops of the C1 domain that bind ligands are very dynamic,\" Igumenova said. \"This C1 domain is like a PAC-man. It binds the membrane, and then it searches for a ligand. Once it finds the ligand, it latches on.\" In addition, the structure shows that the ligand-binding groove has a \"water-loving,\" or hydrophilic, surface at the bottom, and \"water-repelling,\" or hydrophobic, surface at the top. \"If you think about a lipid molecule, the head group is hydrophilic and the tail is hydrophobic,\" Igumenova said. \"So, when C1 domains bind lipid ligands, the patterns match.\" The team's results include the structure of a C1 domain bound to its natural ligand, diacylglycerol. In addition, the team describes several other structures of C1 that include different compounds of pharmacological interest. The work also provides a method for testing different drug candidates, Katti said. \"If you want to study fish, you want to study them in water,\" Katti said. \"Now we know how to create a membrane-like environment where these very hydrophobic compounds can be tested for C1 binding.\" Next, Katti and Igumenova plan to explore C1 domains from other PKC family members. \"It's important for us to focus on C1 domains because they have inherent differences that can be exploited to achieve selectivity,\" Igumenova said. \"What we are finding now is that not all C1 domains are created equal.\" ", "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 Diacylglycerol (DAG) is a versatile lipid whose 1,2- sn -stereoisomer serves both as second messenger in signal transduction pathways that control vital cellular processes, and as metabolic precursor for downstream signaling lipids such as phosphatidic acid. Effector proteins translocate to available DAG pools in the membranes by using conserved homology 1 (C1) domains as DAG-sensing modules. Yet, how C1 domains recognize and capture DAG in the complex environment of a biological membrane has remained unresolved for the 40 years since the discovery of Protein Kinase C (PKC) as the first member of the DAG effector cohort. Herein, we report the high-resolution crystal structures of a C1 domain (C1B from PKCδ) complexed to DAG and to each of four potent PKC agonists that produce different biological readouts and that command intense therapeutic interest. This structural information details the mechanisms of stereospecific recognition of DAG by the C1 domains, the functional properties of the lipid-binding site, and the identities of the key residues required for the recognition and capture of DAG and exogenous agonists. Moreover, the structures of the five C1 domain complexes provide the high-resolution guides for the design of agents that modulate the activities of DAG effector proteins. Introduction The impressive diversity of DAG signaling output is mediated via its interactions with seven families of effector proteins that execute broad sets of regulatory functions 1 . These include protein phosphorylation (PKCs and PKDs 2 , 3 ); DAG phosphorylation (DGKs 4 ); RacGTPase regulation (Chimaerins 5 ); Ras guanine nucleotide exchange factor activation (RasGRPs 6 ); Cdc42-mediated cytoskeletal reorganization (MRCK 7 ); and assembly of scaffolds that potentiate synaptic vesicle fusion and neurotransmitter release (Munc13s 8 ). PKCs define a central DAG-sensing node in intracellular phosphoinositide signaling pathways that regulate cell growth, differentiation, apoptosis, and motility 9 . Shortly after their discovery, PKCs were identified as cellular receptors for tumor-promoting phorbol esters 10 that bind C1 domains in lieu of DAG. These observations, combined with the central roles executed by PKCs in intracellular signaling established their DAG-sensing function as an attractive target for therapeutic intervention, with considerable promise in the treatment of Alzheimer’s disease 11 , HIV/AIDS 12 , 13 , and cancer 14 , 15 . However, the structural basis of DAG recognition by the C1 domains has remained elusive, and the strategies for therapeutic agent design deployed to date all relied on modeling studies (reviewed in 16 ) based on the single available crystal structure of the C1 domain complexed to a ligand that does not activate PKC 17 . Herein, we have overcome these well-documented challenges 18 , 19 , 20 that have hindered the crystallization of extremely hydrophobic C1-ligand complexes for almost three decades. This advance enabled us to determine high-resolution structures of C1 bound to the endogenous agonist DAG and to each of four exogenous agonists of therapeutic interest. Collectively, our findings: (i) provide a structural rationale for the consensus amino acid sequence of DAG-sensitive C1 domains; (ii) provide insight into the origins of DAG sensitivity; and (iii) reveal how the unique hydrophilic/hydrophobic properties of the ligand-binding groove enable C1 domains to accommodate chemically diverse ligands. Results and discussion Structure of the C1Bδ-DAG complex C1 domains form complexes with their ligands in the membrane environment, and dodecylphosphocholine (DPC) is an effective membrane mimic that faithfully reproduces the functional properties of C1 domains with respect to ligand-binding interactions 21 , 22 . For structural studies, we formed the complex between the C1B domain of PKCδ (C1Bδ) and a synthetic DAG analog (di-octanoyl- sn -1,2-glycerol) in the presence of DPC micelles. The structure of the C1Bδ-DAG complex was refined to 1.75 Å with R work = 0.214 and R free = 0.246 (Supplementary Table 1 ). The H3 space group unit cell (89 × 89 × 219 Å, Fig. 1a ) contains a total of 72 protein chains contributed by nine asymmetric units (AUs) with eight C1Bδ molecules per AU (Fig. 1b ). Fig. 1: Arrangement of protein chains, lipid, and detergent molecules in the unit cell and the asymmetric unit of the C1Bδ-DAG complex crystal (PDB ID: 7L92). a The unit cell contains 72 DAG-complexed C1Bδ chains and 18/54 DAG/DPC molecules that peripherally associate with the protein surface. Structural Zn 2+ ions of C1Bδ are shown as black spheres. b The asymmetric unit comprises 8 C1Bδ protein chains with 8 DAG molecules captured within a well-defined groove, and 2/6 peripheral DAG/DPC molecules. c Space-filling representation of the two distinct DAG/DPC micelles. Full size image The organization of the protein crystal lattice is unprecedented as it contains two distinct lipid-detergent micelles located at symmetry elements in the crystal. Micelle 1 is composed of 12 DAG and 12 DPC ordered molecules, and micelle 2 composed of 18 DAG and 6 DPC ordered molecules (Fig. 1c ), in addition to fully or partially disordered lipids. We speculate that the micelles help nucleate the crystallization, as all of the protein subunits are arranged with their lipid sensing loops directly binding to DAG within micelles (Supplementary Fig. 1a, b ). Each C1Bδ protein chain has a DAG molecule captured within a groove formed by its membrane-binding loop regions (Fig. 1b and Supplementary Fig. 1c, d ). The well-defined glycerol ester moieties of this tightly bound ‘intra-loop’ DAG refined with B-factors (18–26 Å 2 ) comparable to those of the surrounding protein residues (17–23 Å 2 ). In addition, each AU contains two less-ordered peripheral DAG and six DPC molecules associated with the amphiphilic protein surface (Supplementary Fig. 1e, f ). There is little variability among DAG-complexed C1Bδ chains within the asymmetric unit, as evidenced by low pairwise backbone r.m.s.d values of 0.3–0.6 Å (Fig. 2a ). The most variable region is located between helix α1 and the C-terminal Cysteine residue that coordinates a structural Zn 2+ ion. According to solution NMR, this region undergoes conformational exchange on the μs-ms timescale 21 , 23 . We crystallized apo C1Bδ under conditions similar to those used for the C1Bδ-DAG complex (but without<|im_end|> <|im_start|>assistant In a major advance for rational drug design, a Texas A&M AgriLife team has described several protein structures of a crucial player in cellular processes. The advance could bring new ideas for treatments of diseases such as Alzheimer's, AIDS, cancer and others. Specifically, the work describes the C1 domain of protein kinase C, PKC, which helps regulate the protein's activity in organisms. In the structures, the C1 domain wraps around different molecules of intense therapeutic interest, providing the first reliable, atomic-resolution guide for designing drug candidates. Published May 16 in Nature Communications, the research was directed by Tatyana Igumenova, Ph.D., associate professor in the Department of Biochemistry and Biophysics in the Texas A&M College of Agriculture and Life Sciences. The project's primary author is Sachin Katti, Ph.D., a postdoctoral fellow working with Igumenova. The study involved a collaboration with Inna Krieger, Ph.D., research assistant professor, and James Sacchettini, Ph.D., professor, both in the Department of Biochemistry and Biophysics. One of the most sought-after protein structures A healthy cell responds to chemical signals in precise, intricate ways. Receiving chemical inputs from the cell's environment and forwarding them to the central control systems within the cell nucleus is the task of specialized proteins such as PKC. Improper PKC activity shows up in many human diseases. As a result, there is much interest in finding ways to fine-tune PKC activity with drugs. The design of such drugs will offer new approaches for treating Alzheimer's disease, AIDS, cancer and more. "Protein kinase C is one of the most intensely studied proteins in cell biology and pharmacology," Igumenova said. "A major hurdle has been the lack of precise structural information to guide drug design efforts." One complication for drug design is that the PKC family has 11 members. Different PKC family members can have opposite physiological effects, so a successful drug candidate must be selective about which PKC it targets. To do that, drug candidates must fit a target PKC like a key to a lock. But determining the 3D structure of a PKC "on-switch"—the C1 domain—bound to PKC activators has not been easy. Protein structures are typically solved using X-ray crystallography. The technique involves using X-rays to determine the position of atoms in a crystal. For this method, researchers need to create conditions where the protein of interest crystallizes. Yet intense efforts in many research labs over the past three decades failed to yield crystals of C1 domains bound to relevant ligands. Because of this lack of progress, multiple researchers pronounced the task impossible, Igumenova said. Crystals of a domain of protein kinase C spontaneously formed in Katti’s NMR sample tube. Credit: Sachin Katti. Solving a 30-year problem Accepting the problem as challenging, Katti and Igumenova decided instead to study the molecules in solution using nuclear magnetic resonance, NMR, spectroscopy. This involved finding the right components to mimic cell membranes, where the C1 domain would encounter ligands. "Then, one fine day, Sachin discovered crystals forming in an old NMR tube," Igumenova said. "I give all the credit to Sachin, who basically said, 'I'm going to go and test them and see if they are actually the protein.' And he was right. It gave us confidence that crystallization is possible." In turn, Katti gives credence to the insights obtained from NMR, and a bit of luck. "I think that's the beauty of doing research where you have to use multiple approaches," he said. "You never know when one approach is going to be useful for doing something with other approaches." Insights from NMR and X-ray crystallography The new protein structures, along with the team's NMR results, have already yielded interesting information. One long-standing mystery has been how C1 domains can accommodate ligands that have very different chemical structures, Igumenova said. "Our previous NMR work indicated that the loops of the C1 domain that bind ligands are very dynamic," Igumenova said. "This C1 domain is like a PAC-man. It binds the membrane, and then it searches for a ligand. Once it finds the ligand, it latches on." In addition, the structure shows that the ligand-binding groove has a "water-loving," or hydrophilic, surface at the bottom, and "water-repelling," or hydrophobic, surface at the top. "If you think about a lipid molecule, the head group is hydrophilic and the tail is hydrophobic," Igumenova said. "So, when C1 domains bind lipid ligands, the patterns match." The team's results include the structure of a C1 domain bound to its natural ligand, diacylglycerol. In addition, the team describes several other structures of C1 that include different compounds of pharmacological interest. The work also provides a method for testing different drug candidates, Katti said. "If you want to study fish, you want to study them in water," Katti said. "Now we know how to create a membrane-like environment where these very hydrophobic compounds can be tested for C1 binding." Next, Katti and Igumenova plan to explore C1 domains from other PKC family members. "It's important for us to focus on C1 domains because they have inherent differences that can be exploited to achieve selectivity," Igumenova said. "What we are finding now is that not all C1 domains are created equal." <|im_end|>

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2,692

[ { "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 Direct lineage conversion offers a new strategy for tissue regeneration and disease modelling. Despite recent success in directly reprogramming fibroblasts into various cell types, the precise changes that occur as fibroblasts progressively convert to the target cell fates remain unclear. The inherent heterogeneity and asynchronous nature of the reprogramming process renders it difficult to study this process using bulk genomic techniques. Here we used single-cell RNA sequencing to overcome this limitation and analysed global transcriptome changes at early stages during the reprogramming of mouse fibroblasts into induced cardiomyocytes (iCMs) 1 , 2 , 3 , 4 . Using unsupervised dimensionality reduction and clustering algorithms, we identified molecularly distinct subpopulations of cells during reprogramming. We also constructed routes of iCM formation, and delineated the relationship between cell proliferation and iCM induction. Further analysis of global gene expression changes during reprogramming revealed unexpected downregulation of factors involved in mRNA processing and splicing. Detailed functional analysis of the top candidate splicing factor, Ptbp1, revealed that it is a critical barrier for the acquisition of cardiomyocyte-specific splicing patterns in fibroblasts. Concomitantly, Ptbp1 depletion promoted cardiac transcriptome acquisition and increased iCM reprogramming efficiency. Additional quantitative analysis of our dataset revealed a strong correlation between the expression of each reprogramming factor and the progress of individual cells through the reprogramming process, and led to the discovery of new surface markers for the enrichment of iCMs. In summary, our single-cell transcriptomics approaches enabled us to reconstruct the reprogramming trajectory and to uncover intermediate cell populations, gene pathways and regulators involved in iCM induction. Main Direct cardiac reprogramming that converts scar-forming fibroblasts into iCMs shows promise as an approach to replenish lost cardiomyocytes in diseased hearts 1 , 2 , 3 , 4 . Considerable efforts have been made to improve the efficiency and unravel the underlying mechanism 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 . However, it still remains unknown how the conversion of fibroblast into cardiomyocyte is achieved without following conventional cardiomyocyte specification and differentiation process. This is partly because the starting fibroblasts exhibit molecular heterogeneity that is mostly uncharacterized, and the reprogramming population contains fully, partially and unconverted cells. Traditional population-based genome-wide approaches are incapable of resolving this unsynchronized cell-fate-switching process. Therefore, we leveraged the power of single-cell transcriptomics to better investigate the reprogramming of iCMs that is mediated by Mef2c, Gata4 and Tbx5. Previous studies have indicated that a snapshot of an unsynchronized biological process can capture cells at different stages of the process 16 . Because the emergence of iCMs occurs as early as day 3 (refs 1 , 11 , 12 , 13 , 14 , 15 ), we reasoned that day-3 reprogramming fibroblasts contain a wide spectrum of cells that are transitioning from fibroblast to iCM. We therefore performed single-cell RNA sequencing (RNA-seq) on day-3 cardiac fibroblasts infected with separate Mef2c, Gata4 and Tbx5 viral constructs (hereafter M + G + T) from seven independent experiments (for experimental design, see Extended Data Fig. 1 ), followed by a series of quality control steps ( Extended Data Fig. 1 , Methods and Supplementary Tables 1, 2 ). Extensive data normalization was performed to correct for technical variations and batch effects ( Extended Data Figs 1 , 2 and Methods). After comparing the entire set of single-cell RNA-seq data to bulk RNA-seq data of endogenous cardiac fibroblasts and cardiomyocytes that were obtained from parallel experiments, we detected a group of resident or circulating immune or immune-like cells ( Extended Data Fig. 3 ) that were not included in the subsequent analyses. Unsupervised hierarchical clustering and principal component analysis (PCA) on the remaining 454 non-immune cells revealed three gene clusters that account for most of the variability in the data: cardiomyocyte-, fibroblast- and cell-cycle-related genes ( Fig. 1a, b and Extended Data Fig. 4a–c ). On the basis of the expression of cell-cycle-related genes, the cells were grouped into cell-cycle-active (CCA) and cell-cycle-inactive (CCI) populations ( Fig. 1a ); this was confirmed by the molecular signature of the cells in their proliferation states ( Extended Data Fig. 4d–g , proliferating or non-proliferating). Within CCA and CCI populations, hierarchical clustering further identified four subpopulations based on differential expression of fibroblast versus cardiomyocyte genes: fibroblasts, intermediate fibroblasts, pre-iCMs and iCMs ( Fig. 1a ). When plotted using PCA or t -distributed stochastic neighbour embedding analysis, a stepwise transcriptome shift from fibroblast to intermediate fibroblast to pre-iCM to iCM was evident ( Fig. 1c and Extended Data Fig. 4h, i ). We also analysed the reprogramming process as a continuous transition using SLICER (selective locally linear inference of cellular expression relationships) 17 , an algorithm for inferring nonlinear cellular trajectories ( Fig. 1d, e ). The trajectory built by SLICER suggested that fibroblasts, intermediate fibroblasts, pre-iCMs and iCMs form a continuum on the bottom CCI path, representing an iCM-reprogramming route. We further calculated the pseudotime for each cell on the trajectory by defining a starting fibroblast and measuring the distance of each single cell to the starting cell along the reprogramming route ( Fig. 1e ). We then examined the distribution of cells along the pseudotime line by plotting the ‘free energy’ (max(density) − density) of the trajectory and discovered a peak (lowest density) in pre-iCM state ( Fig. 1f ). These data suggest that the pre-iCM stage is an unstable cell state seeking to settle into a more stable state, such as the iCM state, consistent with the PCA and hierarchical clustering analysis showing that pre-iCMs express both cardiomyocyte and fibroblast markers as an intermediate cell type and our other experimental evidence ( Fig. 1a–c and Extended Data Fig. 4j–o ). To experimentally test the iCM route, we performed population-based gene expression profiling at reprogramming days 0, 3, 5, 7, 10 and 14 ( Fig. 1g, h and Extended Data Fig. 4p–v ). PCA generated a pattern showing an oriented path during reprogramming ( Fig. 1g and Extended Data Fig. 4p–s", "role": "user" }, { "content": "Reversing scar tissue after a heart attack to create healthy heart muscle: this would be a game-changer in the field of cardiology and regenerative medicine. In the lab, scientists have shown it's possible to change fibroblasts (scar tissue cells) into cardiomyocytes (heart muscle cells), but sorting out the details of how this happens hasn't been easy, and using this kind of approach in clinics or even other basic research projects has proven elusive. Now, in a new study published today in Nature, UNC researchers report a breakthrough. They have used single cell RNA sequencing technology in combination with mathematical modeling and genetic and chemical approaches to delineate the step-by-step molecular changes that occur during cell fate conversion from fibroblast to cardiomyocyte. The scientists, led by Li Qian, PhD, assistant professor of pathology and laboratory medicine at the UNC School of Medicine, not only successfully reconstructed the routes a single cell could take in this process but also identified underlying molecular pathways and key regulators important for the transformation from one cell type to another. \"We used direct cardiac reprogramming as an example in this study,\" said Qian, the senior author of this paper and member of the UNC McAllister Heart Institute, \"But the pipelines and methods we've established here can be used in any other reprogramming process, and potentially other unsynchronized and heterogeneous biological processes.\" When we are babies, embryonic stem cells throughout our bodies gradually change into a variety of highly specialized cell types, such as neurons, blood cells, and heart muscle cells. For a long time, scientists thought these specific cell types were terminal; they could not change again or be reverted back to a state between embryonic and their final differentiated stage. Recent discoveries, though, show it's possible to revert terminally differentiated somatic cells to a pluripotent state - a kind of \"master\" cell that can self-produce and potentially turn into any kind of cell in the body. Scientists have also figured out how to convert one kind of differentiated somatic cell type into another without detouring through the pluripotent stage or the original progenitor stage. Such findings shifted the paradigm of cellular hierarchy and revolutionized stem cell research and the field of regenerative medicine. Yet, figuring out how to study the specifics of these processes to leverage them for clinical and basic research has been difficult. Direct cardiac reprogramming, a promising approach for cardiac regeneration and disease modeling that the Qian Lab has pioneered and fine-tuned in the past several years, involves direct conversion of cardiac non-myocytes into induced cardiomyocytes (iCMs) that closely resemble endogenous CMs. Like any reprogramming process, the many cells that are being reprogrammed don't do so at the same time. \"It's an 'asynchronous' process,\" Qian said. \"Conversions occur at different intervals. So, at any stage, the cell population always contains unconverted, partially reprogrammed, and fully reprogrammed cells. Therefore, cellular reprogramming is 'heterogeneous,' which makes it difficult to study using traditional approaches.\" In this study, by using microfluidic single-cell RNA sequencing techniques, Qian's lab addressed the two main issues of 'asynchronous' programming and heterogeneous cell populations. They analyzed global transcriptome changes during fate conversion from fibroblasts to iCMs. Using mathematical algorithms, they identified molecularly distinct subpopulations of cells along the reprogramming pipeline. Then they re-constructed routes of iCM formation based on simulation and experimental validation. These routes provided them an unprecedented high-resolution roadmap for further studies on the mechanisms of cell conversion. \"Some of what we found is clinically important,\" Qian said, \"For example, we know that after a heart attack, cardiac fibroblasts around the injured area are immediately activated and become highly proliferative but this proliferative capacity decreases over time. How to take advantage of the varied cell cycle status of fibroblasts over the progression of a heart attack and its aftermath would certainly broaden the application of cellular reprogramming for patients and optimize outcomes.\" Cardiofibroblasts that Li Qian's lab changed into iCMs -- induced cardiomyocytes that compose healthy heart muscle. Credit: Qian Lab, UNC School of Medicine Qian added, \"We demonstrated the routes between cell proliferation and cell reprogramming. We also showed experimental evidence that altering the cell cycle statuses of starting fibroblasts would change the outcomes of new myocyte formation.\" Her team discovered that the molecular features of subpopulations of fibroblasts were differentially suppressed during reprogramming, suggesting that the susceptibility of cells to be reprogrammed varies. Interestingly, this susceptibility coincides with the timing of cardiomyocyte differentiation during heart development. The signatures in the intermediate populations that seem to appear earlier in heart development were more resistant to the alterations. This suggests that the recent epigenetic memories of cells might be more easily erased, and so the fibroblast subpopulations with such epigenetic features are more easily converted into cardiomyocytes. \"Manipulating epigenetic memories - not just changing their current epigenetic status - could be crucial for altering a cell's fate for therapeutic value,\" Qian said. With further analysis of global gene expression changes during reprogramming, researchers identified an unexpected down-regulation of factors involved in mRNA processing and splicing. \"This is a big surprise to us,\" Qian said. \"We found that some of the basic cell machinery is dramatically changed, like the machinery for protein production, transportation and degradation, and as we document in detail - mRNA splicing machinery.\" The team continued with detailed functional analysis of the top candidate - the splicing factor called Ptbp1. Evidence suggests it as a critical barrier to the acquisition of cardiomyocyte-specific splicing patterns in fibroblasts. Qian's research showed that Ptbp1 depletion promoted the formation of more iCMs. \"The new knowledge learned from our mechanistic studies of how a single splicing factor regulates the fate conversion from fibroblast to cardiomyocyte is really a bonus to us,\" Qian continued. \"Without the unbiased nature of this approach, we would not gain such fresh, valuable information about the reprogramming process. And that's the beauty of our platform.\" Additional quantitative analysis revealed a strong correlation between the expression of each reprogramming factor and the progress of individual cells through the reprogramming process, and led to the discovery of new surface markers for enrichment of iCMs. Qian said, \"I believe the interdisciplinary approaches in this paper are very powerful. They helped us identify previously unrecognized functions or mechanisms, as well as better understand the nature of a cell and the progression of a disease. Ultimately, this approach could benefit not only heart disease patients, but also patients with cancers, diabetes, neurological diseases, and other conditions. We are very excited about the road ahead.\" ", "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 Direct lineage conversion offers a new strategy for tissue regeneration and disease modelling. Despite recent success in directly reprogramming fibroblasts into various cell types, the precise changes that occur as fibroblasts progressively convert to the target cell fates remain unclear. The inherent heterogeneity and asynchronous nature of the reprogramming process renders it difficult to study this process using bulk genomic techniques. Here we used single-cell RNA sequencing to overcome this limitation and analysed global transcriptome changes at early stages during the reprogramming of mouse fibroblasts into induced cardiomyocytes (iCMs) 1 , 2 , 3 , 4 . Using unsupervised dimensionality reduction and clustering algorithms, we identified molecularly distinct subpopulations of cells during reprogramming. We also constructed routes of iCM formation, and delineated the relationship between cell proliferation and iCM induction. Further analysis of global gene expression changes during reprogramming revealed unexpected downregulation of factors involved in mRNA processing and splicing. Detailed functional analysis of the top candidate splicing factor, Ptbp1, revealed that it is a critical barrier for the acquisition of cardiomyocyte-specific splicing patterns in fibroblasts. Concomitantly, Ptbp1 depletion promoted cardiac transcriptome acquisition and increased iCM reprogramming efficiency. Additional quantitative analysis of our dataset revealed a strong correlation between the expression of each reprogramming factor and the progress of individual cells through the reprogramming process, and led to the discovery of new surface markers for the enrichment of iCMs. In summary, our single-cell transcriptomics approaches enabled us to reconstruct the reprogramming trajectory and to uncover intermediate cell populations, gene pathways and regulators involved in iCM induction. Main Direct cardiac reprogramming that converts scar-forming fibroblasts into iCMs shows promise as an approach to replenish lost cardiomyocytes in diseased hearts 1 , 2 , 3 , 4 . Considerable efforts have been made to improve the efficiency and unravel the underlying mechanism 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 . However, it still remains unknown how the conversion of fibroblast into cardiomyocyte is achieved without following conventional cardiomyocyte specification and differentiation process. This is partly because the starting fibroblasts exhibit molecular heterogeneity that is mostly uncharacterized, and the reprogramming population contains fully, partially and unconverted cells. Traditional population-based genome-wide approaches are incapable of resolving this unsynchronized cell-fate-switching process. Therefore, we leveraged the power of single-cell transcriptomics to better investigate the reprogramming of iCMs that is mediated by Mef2c, Gata4 and Tbx5. Previous studies have indicated that a snapshot of an unsynchronized biological process can capture cells at different stages of the process 16 . Because the emergence of iCMs occurs as early as day 3 (refs 1 , 11 , 12 , 13 , 14 , 15 ), we reasoned that day-3 reprogramming fibroblasts contain a wide spectrum of cells that are transitioning from fibroblast to iCM. We therefore performed single-cell RNA sequencing (RNA-seq) on day-3 cardiac fibroblasts infected with separate Mef2c, Gata4 and Tbx5 viral constructs (hereafter M + G + T) from seven independent experiments (for experimental design, see Extended Data Fig. 1 ), followed by a series of quality control steps ( Extended Data Fig. 1 , Methods and Supplementary Tables 1, 2 ). Extensive data normalization was performed to correct for technical variations and batch effects ( Extended Data Figs 1 , 2 and Methods). After comparing the entire set of single-cell RNA-seq data to bulk RNA-seq data of endogenous cardiac fibroblasts and cardiomyocytes that were obtained from parallel experiments, we detected a group of resident or circulating immune or immune-like cells ( Extended Data Fig. 3 ) that were not included in the subsequent analyses. Unsupervised hierarchical clustering and principal component analysis (PCA) on the remaining 454 non-immune cells revealed three gene clusters that account for most of the variability in the data: cardiomyocyte-, fibroblast- and cell-cycle-related genes ( Fig. 1a, b and Extended Data Fig. 4a–c ). On the basis of the expression of cell-cycle-related genes, the cells were grouped into cell-cycle-active (CCA) and cell-cycle-inactive (CCI) populations ( Fig. 1a ); this was confirmed by the molecular signature of the cells in their proliferation states ( Extended Data Fig. 4d–g , proliferating or non-proliferating). Within CCA and CCI populations, hierarchical clustering further identified four subpopulations based on differential expression of fibroblast versus cardiomyocyte genes: fibroblasts, intermediate fibroblasts, pre-iCMs and iCMs ( Fig. 1a ). When plotted using PCA or t -distributed stochastic neighbour embedding analysis, a stepwise transcriptome shift from fibroblast to intermediate fibroblast to pre-iCM to iCM was evident ( Fig. 1c and Extended Data Fig. 4h, i ). We also analysed the reprogramming process as a continuous transition using SLICER (selective locally linear inference of cellular expression relationships) 17 , an algorithm for inferring nonlinear cellular trajectories ( Fig. 1d, e ). The trajectory built by SLICER suggested that fibroblasts, intermediate fibroblasts, pre-iCMs and iCMs form a continuum on the bottom CCI path, representing an iCM-reprogramming route. We further calculated the pseudotime for each cell on the trajectory by defining a starting fibroblast and measuring the distance of each single cell to the starting cell along the reprogramming route ( Fig. 1e ). We then examined the distribution of cells along the pseudotime line by plotting the ‘free energy’ (max(density) − density) of the trajectory and discovered a peak (lowest density) in pre-iCM state ( Fig. 1f ). These data suggest that the pre-iCM stage is an unstable cell state seeking to settle into a more stable state, such as the iCM state, consistent with the PCA and hierarchical clustering analysis showing that pre-iCMs express both cardiomyocyte and fibroblast markers as an intermediate cell type and our other experimental evidence ( Fig. 1a–c and Extended Data Fig. 4j–o ). To experimentally test the iCM route, we performed population-based gene expression profiling at reprogramming days 0, 3, 5, 7, 10 and 14 ( Fig. 1g, h and Extended Data Fig. 4p–v ). PCA generated a pattern showing an oriented path during reprogramming ( Fig. 1g and Extended Data Fig. 4p–s<|im_end|> <|im_start|>assistant Reversing scar tissue after a heart attack to create healthy heart muscle: this would be a game-changer in the field of cardiology and regenerative medicine. In the lab, scientists have shown it's possible to change fibroblasts (scar tissue cells) into cardiomyocytes (heart muscle cells), but sorting out the details of how this happens hasn't been easy, and using this kind of approach in clinics or even other basic research projects has proven elusive. Now, in a new study published today in Nature, UNC researchers report a breakthrough. They have used single cell RNA sequencing technology in combination with mathematical modeling and genetic and chemical approaches to delineate the step-by-step molecular changes that occur during cell fate conversion from fibroblast to cardiomyocyte. The scientists, led by Li Qian, PhD, assistant professor of pathology and laboratory medicine at the UNC School of Medicine, not only successfully reconstructed the routes a single cell could take in this process but also identified underlying molecular pathways and key regulators important for the transformation from one cell type to another. "We used direct cardiac reprogramming as an example in this study," said Qian, the senior author of this paper and member of the UNC McAllister Heart Institute, "But the pipelines and methods we've established here can be used in any other reprogramming process, and potentially other unsynchronized and heterogeneous biological processes." When we are babies, embryonic stem cells throughout our bodies gradually change into a variety of highly specialized cell types, such as neurons, blood cells, and heart muscle cells. For a long time, scientists thought these specific cell types were terminal; they could not change again or be reverted back to a state between embryonic and their final differentiated stage. Recent discoveries, though, show it's possible to revert terminally differentiated somatic cells to a pluripotent state - a kind of "master" cell that can self-produce and potentially turn into any kind of cell in the body. Scientists have also figured out how to convert one kind of differentiated somatic cell type into another without detouring through the pluripotent stage or the original progenitor stage. Such findings shifted the paradigm of cellular hierarchy and revolutionized stem cell research and the field of regenerative medicine. Yet, figuring out how to study the specifics of these processes to leverage them for clinical and basic research has been difficult. Direct cardiac reprogramming, a promising approach for cardiac regeneration and disease modeling that the Qian Lab has pioneered and fine-tuned in the past several years, involves direct conversion of cardiac non-myocytes into induced cardiomyocytes (iCMs) that closely resemble endogenous CMs. Like any reprogramming process, the many cells that are being reprogrammed don't do so at the same time. "It's an 'asynchronous' process," Qian said. "Conversions occur at different intervals. So, at any stage, the cell population always contains unconverted, partially reprogrammed, and fully reprogrammed cells. Therefore, cellular reprogramming is 'heterogeneous,' which makes it difficult to study using traditional approaches." In this study, by using microfluidic single-cell RNA sequencing techniques, Qian's lab addressed the two main issues of 'asynchronous' programming and heterogeneous cell populations. They analyzed global transcriptome changes during fate conversion from fibroblasts to iCMs. Using mathematical algorithms, they identified molecularly distinct subpopulations of cells along the reprogramming pipeline. Then they re-constructed routes of iCM formation based on simulation and experimental validation. These routes provided them an unprecedented high-resolution roadmap for further studies on the mechanisms of cell conversion. "Some of what we found is clinically important," Qian said, "For example, we know that after a heart attack, cardiac fibroblasts around the injured area are immediately activated and become highly proliferative but this proliferative capacity decreases over time. How to take advantage of the varied cell cycle status of fibroblasts over the progression of a heart attack and its aftermath would certainly broaden the application of cellular reprogramming for patients and optimize outcomes." Cardiofibroblasts that Li Qian's lab changed into iCMs -- induced cardiomyocytes that compose healthy heart muscle. Credit: Qian Lab, UNC School of Medicine Qian added, "We demonstrated the routes between cell proliferation and cell reprogramming. We also showed experimental evidence that altering the cell cycle statuses of starting fibroblasts would change the outcomes of new myocyte formation." Her team discovered that the molecular features of subpopulations of fibroblasts were differentially suppressed during reprogramming, suggesting that the susceptibility of cells to be reprogrammed varies. Interestingly, this susceptibility coincides with the timing of cardiomyocyte differentiation during heart development. The signatures in the intermediate populations that seem to appear earlier in heart development were more resistant to the alterations. This suggests that the recent epigenetic memories of cells might be more easily erased, and so the fibroblast subpopulations with such epigenetic features are more easily converted into cardiomyocytes. "Manipulating epigenetic memories - not just changing their current epigenetic status - could be crucial for altering a cell's fate for therapeutic value," Qian said. With further analysis of global gene expression changes during reprogramming, researchers identified an unexpected down-regulation of factors involved in mRNA processing and splicing. "This is a big surprise to us," Qian said. "We found that some of the basic cell machinery is dramatically changed, like the machinery for protein production, transportation and degradation, and as we document in detail - mRNA splicing machinery." The team continued with detailed functional analysis of the top candidate - the splicing factor called Ptbp1. Evidence suggests it as a critical barrier to the acquisition of cardiomyocyte-specific splicing patterns in fibroblasts. Qian's research showed that Ptbp1 depletion promoted the formation of more iCMs. "The new knowledge learned from our mechanistic studies of how a single splicing factor regulates the fate conversion from fibroblast to cardiomyocyte is really a bonus to us," Qian continued. "Without the unbiased nature of this approach, we would not gain such fresh, valuable information about the reprogramming process. And that's the beauty of our platform." Additional quantitative analysis revealed a strong correlation between the expression of each reprogramming factor and the progress of individual cells through the reprogramming process, and led to the discovery of new surface markers for enrichment of iCMs. Qian said, "I believe the interdisciplinary approaches in this paper are very powerful. They helped us identify previously unrecognized functions or mechanisms, as well as better understand the nature of a cell and the progression of a disease. Ultimately, this approach could benefit not only heart disease patients, but also patients with cancers, diabetes, neurological diseases, and other conditions. We are very excited about the road ahead." <|im_end|>

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2,876

[ { "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 Objective To determine the efficacy and safety of awake prone positioning versus usual care in non-intubated adults with hypoxemic respiratory failure due to covid-19. Design Systematic review with frequentist and bayesian meta-analyses. Study eligibility Randomized trials comparing awake prone positioning versus usual care in adults with covid-19 related hypoxemic respiratory failure. Information sources were Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to 4 March 2022. Data extraction and synthesis Two reviewers independently extracted data and assessed risk of bias. Random effects meta-analyses were performed for the primary and secondary outcomes. Bayesian meta-analyses were performed for endotracheal intubation and mortality outcomes. GRADE certainty of evidence was assessed for outcomes. Main outcome measures The primary outcome was endotracheal intubation. Secondary outcomes were mortality, ventilator-free days, intensive care unit (ICU) and hospital length of stay, escalation of oxygen modality, change in oxygenation and respiratory rate, and adverse events. Results 17 trials (2931 patients) met the eligibility criteria. 12 trials were at low risk of bias, three had some concerns, and two were at high risk. Awake prone positioning reduced the risk of endotracheal intubation compared with usual care (crude average 24.2% v 29.8%, relative risk 0.83, 95% confidence interval 0.73 to 0.94; high certainty). This translates to 55 fewer intubations per 1000 patients (95% confidence interval 87 to 19 fewer intubations). Awake prone positioning did not significantly affect secondary outcomes, including mortality (15.6% v 17.2%, relative risk 0.90, 0.76 to 1.07; high certainty), ventilator-free days (mean difference 0.97 days, 95% confidence interval −0.5 to 3.4; low certainty), ICU length of stay (−2.1 days, −4.5 to 0.4; low certainty), hospital length of stay (−0.09 days, −0.69 to 0.51; moderate certainty), and escalation of oxygen modality (21.4% v 23.0%, relative risk 1.04, 0.74 to 1.44; low certainty). Adverse events related to awake prone positioning were uncommon. Bayesian meta-analysis showed a high probability of benefit with awake prone positioning for endotracheal intubation (non-informative prior, mean relative risk 0.83, 95% credible interval 0.70 to 0.97; posterior probability for relative risk <0.95=96%) but lower probability for mortality (0.90, 0.73 to 1.13; <0.95=68%). Conclusions Awake prone positioning compared with usual care reduces the risk of endotracheal intubation in adults with hypoxemic respiratory failure due to covid-19 but probably has little to no effect on mortality or other outcomes. Systematic review registration PROSPERO CRD42022314856. Introduction Patients with covid-19 can develop hypoxemic respiratory failure, potentially necessitating admission to hospital for supplemental oxygen or to an intensive care unit (ICU) for mechanical ventilation. 1 2 3 Although most patients have mild disease, some will develop severe disease, including acute respiratory distress syndrome. 2 Interventions aimed at limiting illness severity and reducing the need for invasive mechanical ventilation are needed. Non-pharmacological interventions such as prone positioning are life saving for patients with moderate-severe acute respiratory distress syndrome receiving mechanical ventilation. 4 5 6 Although high certainty evidence exists for the use of prone positioning in patients receiving invasive ventilation for non-covid-19 related acute respiratory distress syndrome, 5 6 it is unclear whether awake prone positioning improves outcomes in spontaneously breathing non-intubated patients with covid-19. Previous systematic reviews and meta-analyses of observational studies suggested that awake prone positioning was associated with improved oxygenation and low endotracheal intubation rates. 7 8 9 10 Despite these outcomes, the tolerability, safety, and efficacy of awake prone positioning remains unclear in patients with covid-19 related hypoxemic respiratory failure. A prospective meta-analysis of six individual randomized controlled trials reported a reduction in the risk of treatment failure (ie, a composite outcome of intubation or death) and a reduction in the risk of endotracheal intubation. The results of this prospective meta-analysis must be interpreted cautiously as the effect was probably driven by one of the included randomized controlled trials. 11 Two recent systematic reviews and meta-analyses had limitations, such as being driven by the results of the prospective meta-analysis 12 or combining both observational and randomized studies. 10 Moreover, a comprehensive systematic review on awake prone positioning in patients with covid-19 that also incorporates recent trials is needed. Given the uncertainty about the clinical benefits of awake prone positioning 13 and recent evidence from three trials with more than 900 additional patients, 14 15 16 we performed a systematic review and meta-analysis. We used both frequentist and bayesian methods to evaluate the efficacy and safety of awake prone positioning compared with usual care in trials of non-intubated adults with hypoxemic respiratory failure due to covid-19. Methods We conducted this systematic review and meta-analysis according to the Cochrane Handbook for Systematic Reviews of Interventions, 17 adhered to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) (see supplemental eMethods 1), 18 and prospectively registered the protocol on PROSPERO. Search strategy and study selection The Cochrane Central Register of Controlled Trials, Embase, and Medline were systematically searched from inception to 4 March 2022. We also searched the preprint server medrxiv for relevant unpublished studies and ClinicalTrials.gov for ongoing or recently completed trials. The reference lists of included studies were reviewed for any additional eligible studies. A medical librarian designed the search strategy for all databases. A second medical librarian subsequently and independently reviewed the search strategy. 19 The search terms are available in supplemental eMethods 2. Two reviewers independently, and in duplicate, screened the list of titles and abstracts. Reviewers assessed the full texts of potentially eligible studies. To be eligible for inclusion the studies needed to use a randomized controlled trial design, including cluster randomized controlled trials and quasi-randomized controlled trials using the Cochrane suggested definitions of these study types 17 20 21 ; include hospital patients with hypoxemic respiratory failure due to covid-19; compare awake prone positioning with usual care (no prone positioning); and report on at least one of the outcomes of interest. Reviewers excluded non-randomized studies. Outcomes The primary outcome was endotracheal intubation at the longest time point reported. Secondary outcomes included mortality at the longest reported interval, hospital length of stay, ICU length of stay, invasive ventilator-free days, escalation of", "role": "user" }, { "content": "Patients admitted to the hospital with severe breathing difficulties due to COVID-19 are less likely to need a breathing tube if they lie face down in a prone position, but evidence for its effect on mortality or other outcomes is inconclusive, suggests an in-depth analysis of the latest evidence published by The BMJ today. Since the 1970s, prone positioning has been standard care for patients with severe acute respiratory distress syndrome, as it encourages a larger part of the lung to expand, so patients can take bigger breaths. Usually, it is done for critically ill patients who are sedated and intubated (breathing through a tube attached to a mechanical ventilator). But in February, 2020, reports emerged that prone positioning of conscious patients with COVID-19 might also be helpful, and it was widely adopted. Since then, several studies have examined its effectiveness in conscious patients with COVID-19, but results have been conflicting. To try and resolve this uncertainty, researchers trawled databases for randomized trials comparing conscious prone positioning to usual care for adult patients with COVID-19 hypoxemic respiratory failure (a serious condition that develops when the lungs can't get enough oxygen into the blood). They found 17 suitable trials involving 2,931 non-intubated patients who were able to breathe without mechanical assistance and who spent an average of 2.8 hours per day lying prone. Twelve trials were at low risk of bias, three had some concerns, and two were at high risk, but the researchers were able to allow for that in their analysis. The main measure of interest was endotracheal intubation (a breathing tube inserted into the windpipe to allow mechanical ventilation). Other (secondary) outcomes included mortality, ventilator-free days, intensive care unit (ICU) and hospital length of stay, change in oxygenation and respiratory rate, and adverse events. High certainty evidence from a pooled analysis of 14 trials showed that conscious prone positioning reduced the risk of endotracheal intubation compared with usual care (24.2% with conscious prone positioning vs. 29.8% with usual care). On average, conscious prone positioning resulted in 55 fewer intubations per 1,000 patients. However, high certainty evidence from a pooled analysis of 13 trials evaluating mortality did not show a significant difference in mortality between the two groups (15.6% with conscious prone positioning vs. 17.2% with usual care), but the study may have lacked statistical power to detect a difference. Conscious prone positioning did not significantly affect other secondary outcomes either, including ventilator-free days, and length of stay in the ICU or hospital, based on low- and moderate-certainty evidence. The researchers acknowledge several limitations, such as lack of individual patient data, differences between the targeted and achieved duration of conscious prone positioning, and variation in the definition and reporting of certain outcomes across studies. But further sensitivity analysis supported these results, suggesting a high probability of benefit for the endotracheal intubation outcome and a low probability of benefit for mortality. As such, the researchers conclude, \"Conscious prone positioning compared with usual care reduces the risk of endotracheal intubation in adults with hypoxemic respiratory failure due to COVID-19 but probably has little to no effect on mortality or other outcomes.\" In a linked editorial, researchers point out that the benefits of prone positioning in patients with COVID-19 may be confined to those with more severe hypoxemia and longer duration of prone positioning, and they say it may be wise to focus efforts on these particular groups. Several unanswered questions remain, including the ideal daily duration of treatment, the level of hypoxemia that should prompt prone positioning, and how best to improve patient comfort and encourage adherence, they write. These questions may never be answered definitively in patients with COVID-19, as fortunately, far fewer are experiencing hypoxemic respiratory failure or critical illness, they explain. \"The pandemic should, however, renew interest and encourage further evaluation of conscious prone positioning—an intervention that may benefit a wide range of patients with hypoxemia,\" 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 Objective To determine the efficacy and safety of awake prone positioning versus usual care in non-intubated adults with hypoxemic respiratory failure due to covid-19. Design Systematic review with frequentist and bayesian meta-analyses. Study eligibility Randomized trials comparing awake prone positioning versus usual care in adults with covid-19 related hypoxemic respiratory failure. Information sources were Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to 4 March 2022. Data extraction and synthesis Two reviewers independently extracted data and assessed risk of bias. Random effects meta-analyses were performed for the primary and secondary outcomes. Bayesian meta-analyses were performed for endotracheal intubation and mortality outcomes. GRADE certainty of evidence was assessed for outcomes. Main outcome measures The primary outcome was endotracheal intubation. Secondary outcomes were mortality, ventilator-free days, intensive care unit (ICU) and hospital length of stay, escalation of oxygen modality, change in oxygenation and respiratory rate, and adverse events. Results 17 trials (2931 patients) met the eligibility criteria. 12 trials were at low risk of bias, three had some concerns, and two were at high risk. Awake prone positioning reduced the risk of endotracheal intubation compared with usual care (crude average 24.2% v 29.8%, relative risk 0.83, 95% confidence interval 0.73 to 0.94; high certainty). This translates to 55 fewer intubations per 1000 patients (95% confidence interval 87 to 19 fewer intubations). Awake prone positioning did not significantly affect secondary outcomes, including mortality (15.6% v 17.2%, relative risk 0.90, 0.76 to 1.07; high certainty), ventilator-free days (mean difference 0.97 days, 95% confidence interval −0.5 to 3.4; low certainty), ICU length of stay (−2.1 days, −4.5 to 0.4; low certainty), hospital length of stay (−0.09 days, −0.69 to 0.51; moderate certainty), and escalation of oxygen modality (21.4% v 23.0%, relative risk 1.04, 0.74 to 1.44; low certainty). Adverse events related to awake prone positioning were uncommon. Bayesian meta-analysis showed a high probability of benefit with awake prone positioning for endotracheal intubation (non-informative prior, mean relative risk 0.83, 95% credible interval 0.70 to 0.97; posterior probability for relative risk <0.95=96%) but lower probability for mortality (0.90, 0.73 to 1.13; <0.95=68%). Conclusions Awake prone positioning compared with usual care reduces the risk of endotracheal intubation in adults with hypoxemic respiratory failure due to covid-19 but probably has little to no effect on mortality or other outcomes. Systematic review registration PROSPERO CRD42022314856. Introduction Patients with covid-19 can develop hypoxemic respiratory failure, potentially necessitating admission to hospital for supplemental oxygen or to an intensive care unit (ICU) for mechanical ventilation. 1 2 3 Although most patients have mild disease, some will develop severe disease, including acute respiratory distress syndrome. 2 Interventions aimed at limiting illness severity and reducing the need for invasive mechanical ventilation are needed. Non-pharmacological interventions such as prone positioning are life saving for patients with moderate-severe acute respiratory distress syndrome receiving mechanical ventilation. 4 5 6 Although high certainty evidence exists for the use of prone positioning in patients receiving invasive ventilation for non-covid-19 related acute respiratory distress syndrome, 5 6 it is unclear whether awake prone positioning improves outcomes in spontaneously breathing non-intubated patients with covid-19. Previous systematic reviews and meta-analyses of observational studies suggested that awake prone positioning was associated with improved oxygenation and low endotracheal intubation rates. 7 8 9 10 Despite these outcomes, the tolerability, safety, and efficacy of awake prone positioning remains unclear in patients with covid-19 related hypoxemic respiratory failure. A prospective meta-analysis of six individual randomized controlled trials reported a reduction in the risk of treatment failure (ie, a composite outcome of intubation or death) and a reduction in the risk of endotracheal intubation. The results of this prospective meta-analysis must be interpreted cautiously as the effect was probably driven by one of the included randomized controlled trials. 11 Two recent systematic reviews and meta-analyses had limitations, such as being driven by the results of the prospective meta-analysis 12 or combining both observational and randomized studies. 10 Moreover, a comprehensive systematic review on awake prone positioning in patients with covid-19 that also incorporates recent trials is needed. Given the uncertainty about the clinical benefits of awake prone positioning 13 and recent evidence from three trials with more than 900 additional patients, 14 15 16 we performed a systematic review and meta-analysis. We used both frequentist and bayesian methods to evaluate the efficacy and safety of awake prone positioning compared with usual care in trials of non-intubated adults with hypoxemic respiratory failure due to covid-19. Methods We conducted this systematic review and meta-analysis according to the Cochrane Handbook for Systematic Reviews of Interventions, 17 adhered to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) (see supplemental eMethods 1), 18 and prospectively registered the protocol on PROSPERO. Search strategy and study selection The Cochrane Central Register of Controlled Trials, Embase, and Medline were systematically searched from inception to 4 March 2022. We also searched the preprint server medrxiv for relevant unpublished studies and ClinicalTrials.gov for ongoing or recently completed trials. The reference lists of included studies were reviewed for any additional eligible studies. A medical librarian designed the search strategy for all databases. A second medical librarian subsequently and independently reviewed the search strategy. 19 The search terms are available in supplemental eMethods 2. Two reviewers independently, and in duplicate, screened the list of titles and abstracts. Reviewers assessed the full texts of potentially eligible studies. To be eligible for inclusion the studies needed to use a randomized controlled trial design, including cluster randomized controlled trials and quasi-randomized controlled trials using the Cochrane suggested definitions of these study types 17 20 21 ; include hospital patients with hypoxemic respiratory failure due to covid-19; compare awake prone positioning with usual care (no prone positioning); and report on at least one of the outcomes of interest. Reviewers excluded non-randomized studies. Outcomes The primary outcome was endotracheal intubation at the longest time point reported. Secondary outcomes included mortality at the longest reported interval, hospital length of stay, ICU length of stay, invasive ventilator-free days, escalation of<|im_end|> <|im_start|>assistant Patients admitted to the hospital with severe breathing difficulties due to COVID-19 are less likely to need a breathing tube if they lie face down in a prone position, but evidence for its effect on mortality or other outcomes is inconclusive, suggests an in-depth analysis of the latest evidence published by The BMJ today. Since the 1970s, prone positioning has been standard care for patients with severe acute respiratory distress syndrome, as it encourages a larger part of the lung to expand, so patients can take bigger breaths. Usually, it is done for critically ill patients who are sedated and intubated (breathing through a tube attached to a mechanical ventilator). But in February, 2020, reports emerged that prone positioning of conscious patients with COVID-19 might also be helpful, and it was widely adopted. Since then, several studies have examined its effectiveness in conscious patients with COVID-19, but results have been conflicting. To try and resolve this uncertainty, researchers trawled databases for randomized trials comparing conscious prone positioning to usual care for adult patients with COVID-19 hypoxemic respiratory failure (a serious condition that develops when the lungs can't get enough oxygen into the blood). They found 17 suitable trials involving 2,931 non-intubated patients who were able to breathe without mechanical assistance and who spent an average of 2.8 hours per day lying prone. Twelve trials were at low risk of bias, three had some concerns, and two were at high risk, but the researchers were able to allow for that in their analysis. The main measure of interest was endotracheal intubation (a breathing tube inserted into the windpipe to allow mechanical ventilation). Other (secondary) outcomes included mortality, ventilator-free days, intensive care unit (ICU) and hospital length of stay, change in oxygenation and respiratory rate, and adverse events. High certainty evidence from a pooled analysis of 14 trials showed that conscious prone positioning reduced the risk of endotracheal intubation compared with usual care (24.2% with conscious prone positioning vs. 29.8% with usual care). On average, conscious prone positioning resulted in 55 fewer intubations per 1,000 patients. However, high certainty evidence from a pooled analysis of 13 trials evaluating mortality did not show a significant difference in mortality between the two groups (15.6% with conscious prone positioning vs. 17.2% with usual care), but the study may have lacked statistical power to detect a difference. Conscious prone positioning did not significantly affect other secondary outcomes either, including ventilator-free days, and length of stay in the ICU or hospital, based on low- and moderate-certainty evidence. The researchers acknowledge several limitations, such as lack of individual patient data, differences between the targeted and achieved duration of conscious prone positioning, and variation in the definition and reporting of certain outcomes across studies. But further sensitivity analysis supported these results, suggesting a high probability of benefit for the endotracheal intubation outcome and a low probability of benefit for mortality. As such, the researchers conclude, "Conscious prone positioning compared with usual care reduces the risk of endotracheal intubation in adults with hypoxemic respiratory failure due to COVID-19 but probably has little to no effect on mortality or other outcomes." In a linked editorial, researchers point out that the benefits of prone positioning in patients with COVID-19 may be confined to those with more severe hypoxemia and longer duration of prone positioning, and they say it may be wise to focus efforts on these particular groups. Several unanswered questions remain, including the ideal daily duration of treatment, the level of hypoxemia that should prompt prone positioning, and how best to improve patient comfort and encourage adherence, they write. These questions may never be answered definitively in patients with COVID-19, as fortunately, far fewer are experiencing hypoxemic respiratory failure or critical illness, they explain. "The pandemic should, however, renew interest and encourage further evaluation of conscious prone positioning—an intervention that may benefit a wide range of patients with hypoxemia," 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 Identifying stable polymorphisms is essential for understanding biodiversity. Distinctive polymorphisms are rare in nature because a superior morph should dominate a population. In addition to the three known mechanisms for polymorphism persistence, we recently reported a fourth mechanism: protection of the polymorphism by symbionts. Attending ants preferentially protect polymorphic aphid colonies consisting of green and red morphs. Here, we show that attending ants manipulate the reproductive rate of their preferred green morphs to equal that of the red morphs, leading to the persistence of the polymorphism within the colonies. We could not, however, explain how the ants maintained the polymorphism in aphid colonies regardless of inter-morph competition. Manipulation by symbionts may be important for the maintenance of polymorphisms and the resulting biodiversity in certain symbiotic systems. Introduction Many natural ecosystems exhibit fairly high biodiversity, and the reason for such high biodiversity is the most fundamental question in ecology and evolutionary biology 1 because interspecific competition excludes competing species 2 . However, natural communities consist of many competing species. A heritable genetic polymorphism is one such form of biodiversity for which persistence is difficult to explain. In this sense, the persistence of a polymorphism is a fundamentally important issue in ecology and evolution because it helps us understand the observed biodiversity in nature. Why does a polymorphism persist in a population? Previously, three major mechanisms were identified: (1) negative frequency-dependent selection, (2) balancing selection of two opposing factors, and (3) superdominance. Under negative frequency-dependence, any morph becomes advantageous when rare but disadvantageous when abundant 3 . Therefore, polymorphisms are stable because each morph is protected from extirpation. However, polymorphisms caused by two opposing factors are rather unstable because random processes (genetic drift) can easily lead to the extinction of any one morph. Therefore, an averaging mechanism that protects from random walk is necessary in these polymorphisms (e.g., spatial heterogeneity that yields patchy microhabitats) 4 . Superdominance is the phonemenon that the heterozygote shows a higher fitness than the homozygotes, and thus two alleles are maintained stably in a population. Recently, we found another mechanism for the maintenance of color polymorphism in an ant-aphid symbiotic system. The aphid Macrosiphoniella yomogicola has established an obligate symbiotic relationship with ants that promotes the survival of the aphid because the attending ants provide protection from strong predation 5 . M. yomogicola exhibits a heritable color polymorphism with green and red morphs (Fig. 1 ) 5 . We found that the attending ant Lasius japonicus (Fig. 1 ) is attracted to and most strongly guards a mixed aphid colony (approximately 65% green morph) 5 . Because L. japonicus most strongly protects the mixed aphid colonies, the color polymorphism in the aphid is maintained in a population. In fact, a previous study has shown that polymorphic aphid colonies showed lower mortality 6 . However, a stable polymorphism is not guaranteed in this symbiotic system. For example, if the morphs differ in competitive ability or growth rate, any aphid colony will soon lose the inferior morph. Here, we use the term “competitive ability” in a broad sense, and it includes differences in the rates of growth and reproduction even if actual competitive interactions (e.g., depriving a resource from the other morph) do not occur between the morphs. Note that any such difference between morphs leads to the exclusion of the inferior morphs. Surprisingly, nearly all colonies consist of both green and red morphs in the field. However, the mechanism that maintains these two morphs in a colony when the morphs present different reproductive rates has not been clarified. Figure 1 Red and green morphs of M. yomogicola with the attending ant L. japonicus . The top three aphids (small green and two large black) are green morphs, and the lower two aphids (small brown with an ant and a large brownish green) are red morphs. Photo by Ryota Kawauchiya. Full size image Ant-attended aphids are known to excrete high-quality honeydew when ants are present 7 , 8 . Ant attendance has a negative effect on the growth and reproduction of the attended aphids 9 . Therefore, trade-offs should occur between the quality of honeydew and the growth and fecundity of aphid individuals. Thus, if attending ants prefer the morph excreting a high-quality honeydew, such trade-offs and resulting competitive interactions are expected between the color morphs in M. yomogicola . The morph excreting high-quality honeydew is known to have a lower reproductive rate than the other morphs 9 , 10 . This fact implies that if the attending ants prefer one morph, this morph is expected to excrete high-quality honeydew. Note that honeydew quality is known to vary between preferred and non-preferred morphs 11 . Therefore, the preferred morph is expected to decrease in number over time and eventually disappear from a colony, even if the ants prefer them. Regardless of this inferior trait, the morph that is preferred by ants is more likely to survive from spring to autumn when M. yomogicola reproduces asexually and to late autumn when the aphid produces sexuparae. The mated sexual females lay eggs that will overwinter. Thus, a strong attractiveness to ants is important for an aphid clone. However, in our field, the coexistence of the two color morphs on every host plant continues from June (the appearances of alates) to November (the end of the season). How can the two color morphs achieve long-lasting coexistence on the same host plant when the competitive exclusion of the inferior morphs is expected? This study aims to understand the long-lasting coexistence of both color morphs in every colony of M. yomogicola on host plants. In this study, we investigated the population growth and parthenogenetic reproductive rates of both morphs of M. yomogicola under several experimental settings. First, we compared the reproductive rate of each monoclonal red morph and green morph on several cloned host plants. Second, we examined the difference in the reproductive rates between the color morphs using a single cloned host plant. Then, we measured the reproductive rate of each morph", "role": "user" }, { "content": "Symbiotic ants manipulate aphid reproduction rates to achieve a specific mix of green and red aphids, maintaining the inferior green aphids which produce the ants' favorite snack. Ants and aphids coexist in a symbiotic relationship that benefits both species. Ants protect aphids from predators, such as lady bugs and wasps, and aphids secrete nutritious honeydew for ants to eat. The aphid species Macrosiphoniella yomogicola comes in two \"morphs\" with distinct colors: red and green. When there is more than one physical trait of the same species, it is called polymorphism. Typically, competition for survival would lead to one morph dominating and the others disappearing from the gene pool. However, this rule can be broken in a few circumstances, including if an ant benefits from maintaining a mixture of color morphs. Previously, Associate Professor Eisuke Hasegawa of Hokkaido University and his colleagues had determined that Lasius japonicus ants prefer the nutrient-rich honeydew produced by green morphs. They also found that ants were most attracted to and most vigorously protected colonies with 65 percent green and 35 percent red aphids. In a new study published in the journal Scientific Reports, Hasegawa and his students, including Saori Watanabe, investigated how population growth of aphid morphs differs with or without the presence of ants. They found that ants actively manipulate morph populations by improving the reproduction rate of the inferior morph. In field experiments without the ants' presence, the red morphs had a much higher and superior reproduction rate than green morphs. Thus, red aphids should dominate. However, when ants were introduced to the experiment, the green morph reproduction rate equalized with the red morphs. The experimental evidence matches what researchers find in the wild: red and green morphs coexisting on the same plant shoots attended by ants. What remains a mystery is this: if the ants prefer the green morphs' honeydew, why keep the red morphs around at all? Hasegawa explains, \"We theorize that the red morphs are able to provide a benefit that the green morphs can't, such as suppressing the development of lower buds on host plants. This might help both the red and green aphids survive and reproduce throughout more of the year, which could maximize long-term harvest of honey-dew from the green aphids.\" \"In this case, the ants invest in a future benefit by sacrificing the present benefit,\" the researchers hypothesize. They plan to test this hypothesis 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 Identifying stable polymorphisms is essential for understanding biodiversity. Distinctive polymorphisms are rare in nature because a superior morph should dominate a population. In addition to the three known mechanisms for polymorphism persistence, we recently reported a fourth mechanism: protection of the polymorphism by symbionts. Attending ants preferentially protect polymorphic aphid colonies consisting of green and red morphs. Here, we show that attending ants manipulate the reproductive rate of their preferred green morphs to equal that of the red morphs, leading to the persistence of the polymorphism within the colonies. We could not, however, explain how the ants maintained the polymorphism in aphid colonies regardless of inter-morph competition. Manipulation by symbionts may be important for the maintenance of polymorphisms and the resulting biodiversity in certain symbiotic systems. Introduction Many natural ecosystems exhibit fairly high biodiversity, and the reason for such high biodiversity is the most fundamental question in ecology and evolutionary biology 1 because interspecific competition excludes competing species 2 . However, natural communities consist of many competing species. A heritable genetic polymorphism is one such form of biodiversity for which persistence is difficult to explain. In this sense, the persistence of a polymorphism is a fundamentally important issue in ecology and evolution because it helps us understand the observed biodiversity in nature. Why does a polymorphism persist in a population? Previously, three major mechanisms were identified: (1) negative frequency-dependent selection, (2) balancing selection of two opposing factors, and (3) superdominance. Under negative frequency-dependence, any morph becomes advantageous when rare but disadvantageous when abundant 3 . Therefore, polymorphisms are stable because each morph is protected from extirpation. However, polymorphisms caused by two opposing factors are rather unstable because random processes (genetic drift) can easily lead to the extinction of any one morph. Therefore, an averaging mechanism that protects from random walk is necessary in these polymorphisms (e.g., spatial heterogeneity that yields patchy microhabitats) 4 . Superdominance is the phonemenon that the heterozygote shows a higher fitness than the homozygotes, and thus two alleles are maintained stably in a population. Recently, we found another mechanism for the maintenance of color polymorphism in an ant-aphid symbiotic system. The aphid Macrosiphoniella yomogicola has established an obligate symbiotic relationship with ants that promotes the survival of the aphid because the attending ants provide protection from strong predation 5 . M. yomogicola exhibits a heritable color polymorphism with green and red morphs (Fig. 1 ) 5 . We found that the attending ant Lasius japonicus (Fig. 1 ) is attracted to and most strongly guards a mixed aphid colony (approximately 65% green morph) 5 . Because L. japonicus most strongly protects the mixed aphid colonies, the color polymorphism in the aphid is maintained in a population. In fact, a previous study has shown that polymorphic aphid colonies showed lower mortality 6 . However, a stable polymorphism is not guaranteed in this symbiotic system. For example, if the morphs differ in competitive ability or growth rate, any aphid colony will soon lose the inferior morph. Here, we use the term “competitive ability” in a broad sense, and it includes differences in the rates of growth and reproduction even if actual competitive interactions (e.g., depriving a resource from the other morph) do not occur between the morphs. Note that any such difference between morphs leads to the exclusion of the inferior morphs. Surprisingly, nearly all colonies consist of both green and red morphs in the field. However, the mechanism that maintains these two morphs in a colony when the morphs present different reproductive rates has not been clarified. Figure 1 Red and green morphs of M. yomogicola with the attending ant L. japonicus . The top three aphids (small green and two large black) are green morphs, and the lower two aphids (small brown with an ant and a large brownish green) are red morphs. Photo by Ryota Kawauchiya. Full size image Ant-attended aphids are known to excrete high-quality honeydew when ants are present 7 , 8 . Ant attendance has a negative effect on the growth and reproduction of the attended aphids 9 . Therefore, trade-offs should occur between the quality of honeydew and the growth and fecundity of aphid individuals. Thus, if attending ants prefer the morph excreting a high-quality honeydew, such trade-offs and resulting competitive interactions are expected between the color morphs in M. yomogicola . The morph excreting high-quality honeydew is known to have a lower reproductive rate than the other morphs 9 , 10 . This fact implies that if the attending ants prefer one morph, this morph is expected to excrete high-quality honeydew. Note that honeydew quality is known to vary between preferred and non-preferred morphs 11 . Therefore, the preferred morph is expected to decrease in number over time and eventually disappear from a colony, even if the ants prefer them. Regardless of this inferior trait, the morph that is preferred by ants is more likely to survive from spring to autumn when M. yomogicola reproduces asexually and to late autumn when the aphid produces sexuparae. The mated sexual females lay eggs that will overwinter. Thus, a strong attractiveness to ants is important for an aphid clone. However, in our field, the coexistence of the two color morphs on every host plant continues from June (the appearances of alates) to November (the end of the season). How can the two color morphs achieve long-lasting coexistence on the same host plant when the competitive exclusion of the inferior morphs is expected? This study aims to understand the long-lasting coexistence of both color morphs in every colony of M. yomogicola on host plants. In this study, we investigated the population growth and parthenogenetic reproductive rates of both morphs of M. yomogicola under several experimental settings. First, we compared the reproductive rate of each monoclonal red morph and green morph on several cloned host plants. Second, we examined the difference in the reproductive rates between the color morphs using a single cloned host plant. Then, we measured the reproductive rate of each morph<|im_end|> <|im_start|>assistant Symbiotic ants manipulate aphid reproduction rates to achieve a specific mix of green and red aphids, maintaining the inferior green aphids which produce the ants' favorite snack. Ants and aphids coexist in a symbiotic relationship that benefits both species. Ants protect aphids from predators, such as lady bugs and wasps, and aphids secrete nutritious honeydew for ants to eat. The aphid species Macrosiphoniella yomogicola comes in two "morphs" with distinct colors: red and green. When there is more than one physical trait of the same species, it is called polymorphism. Typically, competition for survival would lead to one morph dominating and the others disappearing from the gene pool. However, this rule can be broken in a few circumstances, including if an ant benefits from maintaining a mixture of color morphs. Previously, Associate Professor Eisuke Hasegawa of Hokkaido University and his colleagues had determined that Lasius japonicus ants prefer the nutrient-rich honeydew produced by green morphs. They also found that ants were most attracted to and most vigorously protected colonies with 65 percent green and 35 percent red aphids. In a new study published in the journal Scientific Reports, Hasegawa and his students, including Saori Watanabe, investigated how population growth of aphid morphs differs with or without the presence of ants. They found that ants actively manipulate morph populations by improving the reproduction rate of the inferior morph. In field experiments without the ants' presence, the red morphs had a much higher and superior reproduction rate than green morphs. Thus, red aphids should dominate. However, when ants were introduced to the experiment, the green morph reproduction rate equalized with the red morphs. The experimental evidence matches what researchers find in the wild: red and green morphs coexisting on the same plant shoots attended by ants. What remains a mystery is this: if the ants prefer the green morphs' honeydew, why keep the red morphs around at all? Hasegawa explains, "We theorize that the red morphs are able to provide a benefit that the green morphs can't, such as suppressing the development of lower buds on host plants. This might help both the red and green aphids survive and reproduce throughout more of the year, which could maximize long-term harvest of honey-dew from the green aphids." "In this case, the ants invest in a future benefit by sacrificing the present benefit," the researchers hypothesize. They plan to test this hypothesis next. <|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 Solvent-free chemical manufacturing is one of the awaited technologies for addressing an emergent issue of environmental pollution. Here, we report solvent-free autocatalytic supramolecular polymerization (SF-ASP), which provides an inhibition-free template-assisted catalytic organic transformation that takes great advantage of the fact that the product (template) undergoes a termination-free nucleation–elongation assembly (living supramolecular polymerization) under solvent-free conditions. SF-ASP allows for reductive cyclotetramerization of hydrogen-bonding phthalonitriles into the corresponding phthalocyanines in exceptionally high yields (>80%). SF-ASP requires the growing polymer to form hexagonally packed crystalline fibres, which possibly preorganize the phthalonitriles at their cross-sectional edges for their efficient transformation. With metal oleates, SF-ASP produces single-crystalline fibres of metallophthalocyanines again in exceptionally high yields, which grow in both directions without terminal coupling until the phthalonitrile precursors are completely consumed. By taking advantage of this living nature of polymerization, multistep SF-ASP without/with metal oleates allows for the precision synthesis of multi-block supramolecular copolymers. Main Considering an emergent environmental issue caused by plastic waste 1 , supramolecular polymers are promising candidates for next-generation materials because their intrinsically dynamic nature possibly allows for excellent recyclability and recombinant usage 2 , 3 . Historically, supramolecular polymerization has been extensively studied in solution, and its mechanistic interpretation has been greatly elaborated in the last decade 4 , 5 , 6 . Nevertheless, from a viewpoint of practical applications, supramolecular polymerization under solvent-free conditions is considered more advantageous, because produced superstructures can be directly used as they are without losing their structural integrity. Needless to say, this process is also preferred for realizing a sustainable society 7 , 8 . It should be noted that, in the early days of research on supramolecular polymerization, noncovalent polymeric structures were reported to form from hydrogen-bonding (H-bonding) molecules in their crystalline and liquid-crystalline assemblies 9 , 10 , 11 . However, because of a preconception that molecular assembling events are difficult to control under solvent-free conditions, most interest in supramolecular polymerization moved to its solution process 12 , 13 , 14 . Here, we report solvent-free ‘autocatalytic’ supramolecular polymerization (SF-ASP). Together with solvent-free chemical manufacturing, the concept of autocatalysis, which is inspired by nature, is an awaited green technology because of its potentially high selectivity and efficiency. A chemical reaction can be called ‘autocatalytic’ if a product of the reaction serves to catalyse its own formation. Ideally, autocatalytic chemical reactions are supposed to show a sigmoidal time-course profile for the change in product concentration because the product facilitates its own formation 15 . Autocatalysis has been implicated in the emergence of life 16 , 17 and is intrinsic to many biological processes, such as the self-replication of biomolecules 18 , 19 , 20 . As a general strategy of autocatalytic chemical transformation, the product is designed to serve as a template (T) that can reversibly preorganize reactants A and B in the form of a ternary complex [A•T•B], which facilitates the reaction between A and B to produce T•T (refs. 21 , 22 ). However, if T•T does not serve as the template, the expected autocatalytic behaviour would not emerge unless T•T dissociates into monomeric T. This is called ‘product inhibition’. In 2010, Otto and coworkers reported a seminal work that, in the reversible oxidative cyclization of a dithiol having a β -sheet-forming peptide spacer, macrocyclic products with certain ring sizes, such as cyclic hexamers and heptamers, are selectively produced with a typical sigmoidal time-course profile if a shear force is continuously applied to the reaction mixture 23 . Why does the shear force have to be applied? In this case, the macrocycles selectively produced serve to template the macrocyclization. However, they tend to stack into nanofibres in the reaction medium, and such nanofibres also tend to combine together at their cross-sectional edges. Consequently, the concentration of active templates decreases, thereby hampering the autocatalytic process. However, if a shear force is continuously applied, the nanofibres can be cut into numerous short pieces with active edges for templating the reaction 24 . The decrease in active template concentration due to product inhibition and/or template aggregation is an essential problem in nonbiological organic autocatalysis and usually makes the expected sigmoidal time-course profile very obscure 25 , 26 , 27 . Otto and coworkers successfully avoided this problem. However, because the oxidative cyclization they used is intrinsically reversible, they have also suggested a possibility that the observed selectivity might be partly due to an equilibrium shift caused by the removal of preferred products as nanofibres 23 . In contrast with organic autocatalysis described above, some inorganic nanocrystals are known to form in an inhibition-free autocatalytic manner, where precursor metal ions in aqueous media preferentially adsorb onto the surface of seed nanocrystals and are electronically reduced to become a part of the nanocrystals to grow 28 , 29 . How can inhibition-free organic autocatalysis be achieved? Autocatalysis generally requires high dilution to avoid the assembly of products that act as templates. This creates a high barrier for its practical application to the large-scale manufacturing of chemicals. In contrast, self-replication events in living organisms usually operate far from thermodynamic equilibrium and, along this line, artificial out-of-equilibrium systems using chemical fuels 30 , chemical oscillations 31 , kinetic trapping 32 , 33 and microfluidic diffusion 34 as driving forces have recently been investigated. The SF-ASP (Fig. 1a ) reported here is very unique, because the monomer is autocatalytically produced in situ from its precursor in a very high yield. The monomers for SF-ASP are phthalocyanine ( H PC C n ) derivatives (Fig. 1b , left), which are produced via reductive cyclotetramerization of their phthalonitrile (PN C n ) precursors (Fig. 1c ) that adopt a fan shape with H-bonding amide groups. In SF-ASP, H PC C n monomer, if any is produced, nucleates and initiates H-bonding-mediated supramolecular polymerization to give one-dimensional (1D) single-crystalline fibres, which possibly preorganize PN C n molecules via an H-bonding interaction at the cross-sectional fibre edges and efficiently template their reductive cyclotetramerization to give H PC C n in an autocatalytic manner (Fig.", "role": "user" }, { "content": "A polymer that catalyzes its own formation in an environmentally friendly solvent-free process has been developed by an all-RIKEN team of chemists. The discovery could lead to the development of inherently recyclable polymer materials that are made using a sustainable process. Polymers are ubiquitous today, but they are detrimental to the environment through the accumulation of plastic waste and the unsustainable nature of conventional polymer manufacture. Polymers are generally made by linking together strings of building blocks, known as monomers, using covalent bonds. But these strong bonds make it difficult to take used, end-of-life plastic items and de-polymerize them to recover the monomers for reuse. Supramolecular polymers, in contrast, consist of arrays of monomers held together by interactions such as hydrogen bonds, which are weaker, and hence more reversible, than covalent bonds. However, the solvents used for manufacturing supramolecular polymers limit their application and sustainability. \"Within two decades, solvent-free chemical manufacturing may be the only approved chemical processes, since the large volumes of solvent used in other manufacturing processes are too damaging to the environment,\" says Takuzo Aida from the RIKEN Center for Emergent Matter Science (CEMS). Aida's team has been investigating wedge-shaped molecules called phthalonitriles. Now, he and nine CEMS colleagues have discovered that these substances melt when heated and then form multiple thin green crystalline fibers, which are rod-shaped supramolecular polymers. The polymerization process is initiated when four of the wedge-shaped pieces come together to form a flat, circular disk. The disk-shaped assembly—the monomer—can then act as a template surface for the next four wedge-shaped precursor molecules to combine, adding a layer to the structure. This process is repeated, with each new layer of the polymer catalyzing the formation of the next, until long rod-like structures form (Fig. 1). The team named their process solvent-free autocatalytic supramolecular polymerization. \"The mechanical properties of the crystalline fibers of these supramolecular polymers are analogous to those of poly(alkyl methacrylates),\" Aida says. These conventional polymers are used for a range of applications, including plexiglass. The team could create more complex versions of their supramolecular polymers by adding alternate precursor molecules into the mix at certain time points, thereby forming 'block copolymers' with bands of different monomers along the length of each rod. Solvent-free autocatalytic supramolecular polymerization could be used to make supramolecular polymers from a range of starting materials. \"It may be applicable to the synthesis of polycyclic aromatic hydrocarbons and cyclic peptides,\" Aida says. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Solvent-free chemical manufacturing is one of the awaited technologies for addressing an emergent issue of environmental pollution. Here, we report solvent-free autocatalytic supramolecular polymerization (SF-ASP), which provides an inhibition-free template-assisted catalytic organic transformation that takes great advantage of the fact that the product (template) undergoes a termination-free nucleation–elongation assembly (living supramolecular polymerization) under solvent-free conditions. SF-ASP allows for reductive cyclotetramerization of hydrogen-bonding phthalonitriles into the corresponding phthalocyanines in exceptionally high yields (>80%). SF-ASP requires the growing polymer to form hexagonally packed crystalline fibres, which possibly preorganize the phthalonitriles at their cross-sectional edges for their efficient transformation. With metal oleates, SF-ASP produces single-crystalline fibres of metallophthalocyanines again in exceptionally high yields, which grow in both directions without terminal coupling until the phthalonitrile precursors are completely consumed. By taking advantage of this living nature of polymerization, multistep SF-ASP without/with metal oleates allows for the precision synthesis of multi-block supramolecular copolymers. Main Considering an emergent environmental issue caused by plastic waste 1 , supramolecular polymers are promising candidates for next-generation materials because their intrinsically dynamic nature possibly allows for excellent recyclability and recombinant usage 2 , 3 . Historically, supramolecular polymerization has been extensively studied in solution, and its mechanistic interpretation has been greatly elaborated in the last decade 4 , 5 , 6 . Nevertheless, from a viewpoint of practical applications, supramolecular polymerization under solvent-free conditions is considered more advantageous, because produced superstructures can be directly used as they are without losing their structural integrity. Needless to say, this process is also preferred for realizing a sustainable society 7 , 8 . It should be noted that, in the early days of research on supramolecular polymerization, noncovalent polymeric structures were reported to form from hydrogen-bonding (H-bonding) molecules in their crystalline and liquid-crystalline assemblies 9 , 10 , 11 . However, because of a preconception that molecular assembling events are difficult to control under solvent-free conditions, most interest in supramolecular polymerization moved to its solution process 12 , 13 , 14 . Here, we report solvent-free ‘autocatalytic’ supramolecular polymerization (SF-ASP). Together with solvent-free chemical manufacturing, the concept of autocatalysis, which is inspired by nature, is an awaited green technology because of its potentially high selectivity and efficiency. A chemical reaction can be called ‘autocatalytic’ if a product of the reaction serves to catalyse its own formation. Ideally, autocatalytic chemical reactions are supposed to show a sigmoidal time-course profile for the change in product concentration because the product facilitates its own formation 15 . Autocatalysis has been implicated in the emergence of life 16 , 17 and is intrinsic to many biological processes, such as the self-replication of biomolecules 18 , 19 , 20 . As a general strategy of autocatalytic chemical transformation, the product is designed to serve as a template (T) that can reversibly preorganize reactants A and B in the form of a ternary complex [A•T•B], which facilitates the reaction between A and B to produce T•T (refs. 21 , 22 ). However, if T•T does not serve as the template, the expected autocatalytic behaviour would not emerge unless T•T dissociates into monomeric T. This is called ‘product inhibition’. In 2010, Otto and coworkers reported a seminal work that, in the reversible oxidative cyclization of a dithiol having a β -sheet-forming peptide spacer, macrocyclic products with certain ring sizes, such as cyclic hexamers and heptamers, are selectively produced with a typical sigmoidal time-course profile if a shear force is continuously applied to the reaction mixture 23 . Why does the shear force have to be applied? In this case, the macrocycles selectively produced serve to template the macrocyclization. However, they tend to stack into nanofibres in the reaction medium, and such nanofibres also tend to combine together at their cross-sectional edges. Consequently, the concentration of active templates decreases, thereby hampering the autocatalytic process. However, if a shear force is continuously applied, the nanofibres can be cut into numerous short pieces with active edges for templating the reaction 24 . The decrease in active template concentration due to product inhibition and/or template aggregation is an essential problem in nonbiological organic autocatalysis and usually makes the expected sigmoidal time-course profile very obscure 25 , 26 , 27 . Otto and coworkers successfully avoided this problem. However, because the oxidative cyclization they used is intrinsically reversible, they have also suggested a possibility that the observed selectivity might be partly due to an equilibrium shift caused by the removal of preferred products as nanofibres 23 . In contrast with organic autocatalysis described above, some inorganic nanocrystals are known to form in an inhibition-free autocatalytic manner, where precursor metal ions in aqueous media preferentially adsorb onto the surface of seed nanocrystals and are electronically reduced to become a part of the nanocrystals to grow 28 , 29 . How can inhibition-free organic autocatalysis be achieved? Autocatalysis generally requires high dilution to avoid the assembly of products that act as templates. This creates a high barrier for its practical application to the large-scale manufacturing of chemicals. In contrast, self-replication events in living organisms usually operate far from thermodynamic equilibrium and, along this line, artificial out-of-equilibrium systems using chemical fuels 30 , chemical oscillations 31 , kinetic trapping 32 , 33 and microfluidic diffusion 34 as driving forces have recently been investigated. The SF-ASP (Fig. 1a ) reported here is very unique, because the monomer is autocatalytically produced in situ from its precursor in a very high yield. The monomers for SF-ASP are phthalocyanine ( H PC C n ) derivatives (Fig. 1b , left), which are produced via reductive cyclotetramerization of their phthalonitrile (PN C n ) precursors (Fig. 1c ) that adopt a fan shape with H-bonding amide groups. In SF-ASP, H PC C n monomer, if any is produced, nucleates and initiates H-bonding-mediated supramolecular polymerization to give one-dimensional (1D) single-crystalline fibres, which possibly preorganize PN C n molecules via an H-bonding interaction at the cross-sectional fibre edges and efficiently template their reductive cyclotetramerization to give H PC C n in an autocatalytic manner (Fig.<|im_end|> <|im_start|>assistant A polymer that catalyzes its own formation in an environmentally friendly solvent-free process has been developed by an all-RIKEN team of chemists. The discovery could lead to the development of inherently recyclable polymer materials that are made using a sustainable process. Polymers are ubiquitous today, but they are detrimental to the environment through the accumulation of plastic waste and the unsustainable nature of conventional polymer manufacture. Polymers are generally made by linking together strings of building blocks, known as monomers, using covalent bonds. But these strong bonds make it difficult to take used, end-of-life plastic items and de-polymerize them to recover the monomers for reuse. Supramolecular polymers, in contrast, consist of arrays of monomers held together by interactions such as hydrogen bonds, which are weaker, and hence more reversible, than covalent bonds. However, the solvents used for manufacturing supramolecular polymers limit their application and sustainability. "Within two decades, solvent-free chemical manufacturing may be the only approved chemical processes, since the large volumes of solvent used in other manufacturing processes are too damaging to the environment," says Takuzo Aida from the RIKEN Center for Emergent Matter Science (CEMS). Aida's team has been investigating wedge-shaped molecules called phthalonitriles. Now, he and nine CEMS colleagues have discovered that these substances melt when heated and then form multiple thin green crystalline fibers, which are rod-shaped supramolecular polymers. The polymerization process is initiated when four of the wedge-shaped pieces come together to form a flat, circular disk. The disk-shaped assembly—the monomer—can then act as a template surface for the next four wedge-shaped precursor molecules to combine, adding a layer to the structure. This process is repeated, with each new layer of the polymer catalyzing the formation of the next, until long rod-like structures form (Fig. 1). The team named their process solvent-free autocatalytic supramolecular polymerization. "The mechanical properties of the crystalline fibers of these supramolecular polymers are analogous to those of poly(alkyl methacrylates)," Aida says. These conventional polymers are used for a range of applications, including plexiglass. The team could create more complex versions of their supramolecular polymers by adding alternate precursor molecules into the mix at certain time points, thereby forming 'block copolymers' with bands of different monomers along the length of each rod. Solvent-free autocatalytic supramolecular polymerization could be used to make supramolecular polymers from a range of starting materials. "It may be applicable to the synthesis of polycyclic aromatic hydrocarbons and cyclic peptides," Aida says. <|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 Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD) 1 , 2 . These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case–control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer’s disease in seven independent case–control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3 , reveal that several variants in this gene increase risk for Alzheimer’s disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer’s disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer’s disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-β precursor protein (APP) and extracellular Aβ42 and Aβ40 (the 42- and 40-residue isoforms of the amyloid-β peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits. Main The identification of pathogenic mutations in APP , presenilin 1 ( PSEN1 ) and PSEN2 , and the association of apolipoprotein E ( APOE ) genotype with disease risk led to a better understanding of the pathobiology of Alzheimer’s disease, and the development of novel animal models and therapies for this disease 3 . Recent studies using next-generation sequencing have also identified a protective variant in APP 4 , and a low-frequency variant in TREM2 associated with Alzheimer’s disease risk 5 , 6 , 7 , 8 with odds ratio close to that of one APOE4 allele. These studies have led to the identification of functional variants with large effects on Alzheimer’s disease pathogenesis, in contrast to the loci identified through GWAS 1 , 2 . Low-frequency coding variants not detected by GWAS may be a source of functional variants with a large effect on LOAD risk 5 , 6 , 7 , 8 ; however, the identification of such variants remains challenging because most study designs require WES in very large data sets. One potential solution is to perform WES or whole-genome-sequencing in a highly selected population at increased risk for disease followed by a combination of genotyping and deep re-sequencing of the variant or gene of interest in large numbers of cases and controls. We reported previously that families with a clinical history of LOAD in four or more individuals are enriched for genetic risk variants in known Alzheimer’s disease and frontotemporal dementia (FTD) genes, but some of these families do not carry pathogenic mutations in the known Alzheimer’s disease or FTD genes 9 , 10 , suggesting that additional genes may contribute to LOAD risk. We ranked 868 LOAD families from the National Institute on Aging (NIA)-LOAD study based on number of affected individuals, number of generations affected, the number of affected and unaffected individuals with DNA available, the number of individuals with a definite or probable diagnosis of Alzheimer’s disease, early age at onset (AAO) and APOE genotype (discarding families in which APOE4 segregates with disease status), and 14 were selected to perform WES. In the 14 selected families, there were at least four affected individuals per family, with DNA available for at least three of these individuals. We sequenced at least two affected individuals per family, prioritizing distantly related affected individuals with the earliest AAO. We also sequenced one unaffected individual in nine families and two unaffected individuals in one family. In total, we performed WES on 29 affected individuals and 11 unaffected individuals from 14 families of European American ancestry ( Supplementary Table 1 and Supplementary Fig. 2 ). All variants shared by affected individuals but absent in unaffected individuals within a family, with a minor allele frequency (MAF) lower than 0.5% in the Exome Variant Server (EVS; ) were selected and genotyped in the remaining family members to determine segregation with disease ( Supplementary Information ). We next examined whether individual variants or variants in the same gene segregated with disease in more than one family. A single variant, rs145999145 (Val232Met, PLD3, chromosome 19q13.2), segregated with disease in two independent families ( Fig. 1 and Supplementary Fig. 1 ). We then sought to determine whether this variant was associated with increased risk for sporadic Alzheimer’s disease in seven independent data sets (4,998 Alzheimer’s disease cases and 6,356 controls of European descent from the Knight Alzheimer’s Disease Research Centre (ADRC), NIA-LOAD, NIA-UK data set, Cache-County study, the Universities of Toronto, Nottingham and Pittsburgh, the National Institutes of Mental Health (NIMH) Alzheimer’s disease series, and the Wellderly study 7 , 11 , 12 , 13 , 14 ; Extended Data Table 1 ). PLD3 ( V232M ) was associated with both Alzheimer’s disease risk ( P = 2.93 × 10 −05 , odds ratio = 2.10, 95% CI = 1.47–2.99; Table 1 ) and AAO ( P = 3 × 10 −3 ; Extended Data Fig. 1 ). The frequency of PLD3 ( V232M ) was higher in Alzheimer’s disease cases compared to controls in each age–gender–ethnicity matched data set, with a similar estimated odds ratio for each data set ( Extended Data Table 1 and Extended Data Fig. 2 ), suggesting", "role": "user" }, { "content": "(Medical Xpress)—A new study, part-funded by the Medical Research Council (MRC), the Wellcome Trust and Alzheimer's Research UK, has shown that a fault in a gene called phospholipase D3 (PLD3) can contribute to the overproduction of amyloid-beta in the brain. Increased levels of this chemical are associated with an increased chance of developing Alzheimer's disease and the results show that, in certain cases, this can double an individual's risk. An international team of researchers in the UK and the US have been using genome-wide association studies (GWAS) to identify common genetic traits in the population that can influence a person's risk of contracting Alzheimer's disease after the age of 60 (known as Late Onset Alzheimer's Disease or LOAD). They then cross-analysed the data from the GWAS studies using a process known as whole-exome sequencing on 14 families with four or more members affected by Alzheimer's. Focussing on families heavily affected by the disease, the team used a new process to identify less common genes that could have the most severe effect. By improving researchers' understanding of how this gene's activity is linked to amyloid-beta production and Alzheimer's disease, this study will open up new avenues of research for drug development and could potentially help identify people who are more vulnerable to the disease. Dr Carlos Cruchaga the study's lead author at Washington University School of Medicine in St. Louis said \"We were very excited to be able to identify a gene that contains some of these rare variants. And we were surprised to find that the effect of the gene was so large. After adjusting for other factors that can influence risk for the disease, we found that people with certain gene variants were twice as likely as those who didn't have the variants to develop Alzheimer's.\" Professor John Hardy who led the UK work at University College London (UCL) and was funded by the Medical Research Council and the Wellcome Trust said, \"The use of the new technologies of whole genome and whole-exome sequencing in Alzheimer's disease is now yielding a rich harvest of genetic variants which influence our risks of developing disease. These re-enforce the critical role of amyloid deposition and breakdown in the brain as one of the 'main events' that can cause Alzheimer's disease.\" Rebecca Wood, Chief Executive of Alzheimer's Research UK, the UK's leading dementia research charity, said, \"Advances in genetic technology are allowing researchers to understand more than ever about the genetic risk factors for the most common form of Alzheimer's. This announcement, made just off the back of the G8 dementia research summit, is a timely reminder of the progress that can be made by worldwide collaboration. We know that late-onset Alzheimer's is caused by a complex mix of risk factors, including both genetic and lifestyle. Understanding all of these risk factors and how they work together to affect someone's likelihood of developing Alzheimer's is incredibly important for developing interventions to slow the onset of the disease. Alzheimer's Research UK is proud to have contributed to this discovery, both by funding researchers and through the establishment of a DNA collection that has been used in many of the recent genetic discoveries in Alzheimer's.\" ", "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 Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD) 1 , 2 . These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case–control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer’s disease in seven independent case–control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3 , reveal that several variants in this gene increase risk for Alzheimer’s disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer’s disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer’s disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-β precursor protein (APP) and extracellular Aβ42 and Aβ40 (the 42- and 40-residue isoforms of the amyloid-β peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits. Main The identification of pathogenic mutations in APP , presenilin 1 ( PSEN1 ) and PSEN2 , and the association of apolipoprotein E ( APOE ) genotype with disease risk led to a better understanding of the pathobiology of Alzheimer’s disease, and the development of novel animal models and therapies for this disease 3 . Recent studies using next-generation sequencing have also identified a protective variant in APP 4 , and a low-frequency variant in TREM2 associated with Alzheimer’s disease risk 5 , 6 , 7 , 8 with odds ratio close to that of one APOE4 allele. These studies have led to the identification of functional variants with large effects on Alzheimer’s disease pathogenesis, in contrast to the loci identified through GWAS 1 , 2 . Low-frequency coding variants not detected by GWAS may be a source of functional variants with a large effect on LOAD risk 5 , 6 , 7 , 8 ; however, the identification of such variants remains challenging because most study designs require WES in very large data sets. One potential solution is to perform WES or whole-genome-sequencing in a highly selected population at increased risk for disease followed by a combination of genotyping and deep re-sequencing of the variant or gene of interest in large numbers of cases and controls. We reported previously that families with a clinical history of LOAD in four or more individuals are enriched for genetic risk variants in known Alzheimer’s disease and frontotemporal dementia (FTD) genes, but some of these families do not carry pathogenic mutations in the known Alzheimer’s disease or FTD genes 9 , 10 , suggesting that additional genes may contribute to LOAD risk. We ranked 868 LOAD families from the National Institute on Aging (NIA)-LOAD study based on number of affected individuals, number of generations affected, the number of affected and unaffected individuals with DNA available, the number of individuals with a definite or probable diagnosis of Alzheimer’s disease, early age at onset (AAO) and APOE genotype (discarding families in which APOE4 segregates with disease status), and 14 were selected to perform WES. In the 14 selected families, there were at least four affected individuals per family, with DNA available for at least three of these individuals. We sequenced at least two affected individuals per family, prioritizing distantly related affected individuals with the earliest AAO. We also sequenced one unaffected individual in nine families and two unaffected individuals in one family. In total, we performed WES on 29 affected individuals and 11 unaffected individuals from 14 families of European American ancestry ( Supplementary Table 1 and Supplementary Fig. 2 ). All variants shared by affected individuals but absent in unaffected individuals within a family, with a minor allele frequency (MAF) lower than 0.5% in the Exome Variant Server (EVS; ) were selected and genotyped in the remaining family members to determine segregation with disease ( Supplementary Information ). We next examined whether individual variants or variants in the same gene segregated with disease in more than one family. A single variant, rs145999145 (Val232Met, PLD3, chromosome 19q13.2), segregated with disease in two independent families ( Fig. 1 and Supplementary Fig. 1 ). We then sought to determine whether this variant was associated with increased risk for sporadic Alzheimer’s disease in seven independent data sets (4,998 Alzheimer’s disease cases and 6,356 controls of European descent from the Knight Alzheimer’s Disease Research Centre (ADRC), NIA-LOAD, NIA-UK data set, Cache-County study, the Universities of Toronto, Nottingham and Pittsburgh, the National Institutes of Mental Health (NIMH) Alzheimer’s disease series, and the Wellderly study 7 , 11 , 12 , 13 , 14 ; Extended Data Table 1 ). PLD3 ( V232M ) was associated with both Alzheimer’s disease risk ( P = 2.93 × 10 −05 , odds ratio = 2.10, 95% CI = 1.47–2.99; Table 1 ) and AAO ( P = 3 × 10 −3 ; Extended Data Fig. 1 ). The frequency of PLD3 ( V232M ) was higher in Alzheimer’s disease cases compared to controls in each age–gender–ethnicity matched data set, with a similar estimated odds ratio for each data set ( Extended Data Table 1 and Extended Data Fig. 2 ), suggesting<|im_end|> <|im_start|>assistant (Medical Xpress)—A new study, part-funded by the Medical Research Council (MRC), the Wellcome Trust and Alzheimer's Research UK, has shown that a fault in a gene called phospholipase D3 (PLD3) can contribute to the overproduction of amyloid-beta in the brain. Increased levels of this chemical are associated with an increased chance of developing Alzheimer's disease and the results show that, in certain cases, this can double an individual's risk. An international team of researchers in the UK and the US have been using genome-wide association studies (GWAS) to identify common genetic traits in the population that can influence a person's risk of contracting Alzheimer's disease after the age of 60 (known as Late Onset Alzheimer's Disease or LOAD). They then cross-analysed the data from the GWAS studies using a process known as whole-exome sequencing on 14 families with four or more members affected by Alzheimer's. Focussing on families heavily affected by the disease, the team used a new process to identify less common genes that could have the most severe effect. By improving researchers' understanding of how this gene's activity is linked to amyloid-beta production and Alzheimer's disease, this study will open up new avenues of research for drug development and could potentially help identify people who are more vulnerable to the disease. Dr Carlos Cruchaga the study's lead author at Washington University School of Medicine in St. Louis said "We were very excited to be able to identify a gene that contains some of these rare variants. And we were surprised to find that the effect of the gene was so large. After adjusting for other factors that can influence risk for the disease, we found that people with certain gene variants were twice as likely as those who didn't have the variants to develop Alzheimer's." Professor John Hardy who led the UK work at University College London (UCL) and was funded by the Medical Research Council and the Wellcome Trust said, "The use of the new technologies of whole genome and whole-exome sequencing in Alzheimer's disease is now yielding a rich harvest of genetic variants which influence our risks of developing disease. These re-enforce the critical role of amyloid deposition and breakdown in the brain as one of the 'main events' that can cause Alzheimer's disease." Rebecca Wood, Chief Executive of Alzheimer's Research UK, the UK's leading dementia research charity, said, "Advances in genetic technology are allowing researchers to understand more than ever about the genetic risk factors for the most common form of Alzheimer's. This announcement, made just off the back of the G8 dementia research summit, is a timely reminder of the progress that can be made by worldwide collaboration. We know that late-onset Alzheimer's is caused by a complex mix of risk factors, including both genetic and lifestyle. Understanding all of these risk factors and how they work together to affect someone's likelihood of developing Alzheimer's is incredibly important for developing interventions to slow the onset of the disease. Alzheimer's Research UK is proud to have contributed to this discovery, both by funding researchers and through the establishment of a DNA collection that has been used in many of the recent genetic discoveries in Alzheimer's." <|im_end|>

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2,037

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract When electrons in a solid are excited by light, they can alter the free energy landscape and access phases of matter that are out of reach in thermal equilibrium. This accessibility becomes important in the presence of phase competition, when one state of matter is preferred over another by only a small energy scale that, in principle, is surmountable by the excitation. Here, we study a layered compound, LaTe 3 , where a small lattice anisotropy in the a – c plane results in a unidirectional charge density wave (CDW) along the c axis 1 , 2 . Using ultrafast electron diffraction, we find that, after photoexcitation, the CDW along the c axis is weakened and a different competing CDW along the a axis subsequently emerges. The timescales characterizing the relaxation of this new CDW and the reestablishment of the original CDW are nearly identical, which points towards a strong competition between the two orders. The new density wave represents a transient non-equilibrium phase of matter with no equilibrium counterpart, and this study thus provides a framework for discovering similar states of matter that are ‘trapped’ under equilibrium conditions. Main A major theme in condensed matter physics is the relationship between proximal phases of matter, where one ordered ground state gives way to another as a function of some external parameter such as pressure, magnetic field, doping or disorder. It is in such a neighbourhood that we find colossal magnetoresistance in manganites 3 and unconventional superconductivity in heavy fermion, copper oxide and iron-based compounds 4 . In these materials, the nearby ground states can affect one another in several ways. For example, phases can compete, impeding the formation of one state in place of another. This scenario occurs, for example, in La 2− x Ba x CuO 4 at x = 1/8, where the development of alternating charge and spin-ordered regions prevents the onset of superconductivity 5 , 6 . On the other hand, fluctuations of an adjacent phase can help another be realized, such as in 3 He, where ferromagnetic spin fluctuations enable the atoms to form Cooper pairs and hence a p -wave superfluid 4 , 7 . In more complicated situations, such as in manganites, nanoscale phase separation occurs, where local insulating antiferromagnetism coexists next to patches of metallic ferromagnetism, resulting in large magnetic and electrical responses to small perturbations 3 . In each case, the macroscopic properties of a material are heavily influenced by the nearby presence of different phases. Intense light pulses have recently emerged as a tool to tune between neighbouring broken-symmetry phases of matter 8 , 9 , 10 , 11 , 12 , 13 . Conventionally, light pulses are used to restore symmetry, but in certain cases symmetries can also be broken. For example, exposing SrTiO 3 to mid-infrared radiation has led to ferroelectricity 8 , 9 , while ferromagnetism has been induced in a manganite with near-infrared light 11 . In this Letter, we examine a quasi-two-dimensional (2D) material, LaTe 3 , where a unidirectional charge density wave (CDW) phase is only present along the c axis, with no counterpart along the nearly equivalent, perpendicular a axis. We show that femtosecond light pulses can be used to break translational symmetry and unleash an a -axis CDW. Using ultrafast electron diffraction (UED), we visualize this process and track both order parameters simultaneously, gaining a unique perspective on both orders in the time domain. LaTe 3 is a member of the rare-earth tritellurides ( R Te 3 , where R denotes a rare-earth element). These materials possess a layered, quasi-tetragonal structure (Fig. 1a ) with a slight in-plane anisotropy ( a ≥ 0.997 c ; Supplementary Fig. 4b ) 2 , 14 , which leads to a preferred direction for the CDW order along the c axis. The Fermi surface, which is similar for all R Te 3 , arises from the nearly square-shaped Te sheets; the rare-earth atoms, with different radii, effectively serve to apply chemical pressure 1 , 15 . The normal-state Fermi surface is depicted in Fig. 1a , along with the CDW wavevector for LaTe 3 . Depending on the specific rare-earth element in R Te 3 , some of the members display a CDW only along the c direction while others have an additional CDW along the orthogonal a direction (Fig. 1b ). As one moves from lighter to heavier rare-earth elements, the transition temperature of the CDW along the c axis, T c 1 , decreases, while that along the a axis, T c 2 , is first finite in TbTe 3 and increases with atomic number (Fig. 1b ). This relationship strongly suggests that the two CDWs compete in equilibrium. The competition can be understood as follows. Once the c -axis CDW forms, large portions of the Fermi surface open up a gap; the corresponding loss of states near the Fermi energy therefore inhibits the formation of the a -axis CDW 15 . In the material we study here, LaTe 3 , T c 1 is estimated to be ~670 K (ref. 16 ), and a CDW along the a axis does not exist. Fig. 1: Observation of a transient CDW induced by an 80 fs, 800 nm laser pulse. a , Left: Schematic of the LaTe 3 crystal structure, where dashed lines indicate the unit cell. Middle: Schematic of the normal state Fermi surface arising from the planar Te sheets, which are nearly square-shaped with a slight in-plane anisotropy ( a = 0.997 c at room temperature 2 , 14 ). The wavevector q c of the equilibrium c -axis CDW is indicated. Right: Schematic of the ultrafast electron diffraction set-up in transmission mode. Both 26 keV and 3.1 MeV electrons were used (see Methods and Supplementary Note 1 ). Exfoliated samples were mounted on a 10-nm-thick silicon nitride window. CCD, charge-coupled device. b , Summary of the two CDW transition temperatures, T c 1 and T c 2 , across the rare-earth series.", "role": "user" }, { "content": "Adding energy to any material, such as by heating it, almost always makes its structure less orderly. Ice, for example, with its crystalline structure, melts to become liquid water, with no order at all. But in new experiments by physicists at MIT and elsewhere, the opposite happens: When a pattern called a charge density wave in a certain material is hit with a fast laser pulse, a whole new charge density wave is created—a highly ordered state, instead of the expected disorder. The surprising finding could help to reveal unseen properties in materials of all kinds. The discovery is being reported today in the journal Nature Physics, in a paper by MIT professors Nuh Gedik and Pablo Jarillo-Herrero, postdoc Anshul Kogar, graduate student Alfred Zong, and 17 others at MIT, Harvard University, SLAC National Accelerator Laboratory, Stanford University, and Argonne National Laboratory. The experiments made use of a material called lanthanum tritelluride, which naturally forms itself into a layered structure. In this material, a wavelike pattern of electrons in high- and low-density regions forms spontaneously but is confined to a single direction within the material. But when hit with an ultrafast burst of laser light—less than a picosecond long, or under one trillionth of a second—that pattern, called a charge density wave or CDW, is obliterated, and a new CDW, at right angles to the original, pops into existence. This new, perpendicular CDW is something that has never been observed before in this material. It exists for only a flash, disappearing within a few more picoseconds. As it disappears, the original one comes back into view, suggesting that its presence had been somehow suppressed by the new one. Gedik explains that in ordinary materials, the density of electrons within the material is constant throughout their volume, but in certain materials, when they are cooled below some specific temperature, the electrons organize themselves into a CDW with alternating regions of high and low electron density. In lanthanum tritelluride, or LaTe3, the CDW is along one fixed direction within the material. In the other two dimensions, the electron density remains constant, as in ordinary materials. The perpendicular version of the CDW that appears after the burst of laser light has never before been observed in this material, Gedik says. It \"just briefly flashes, and then it's gone,\" Kogar says, to be replaced by the original CDW pattern which immediately pops back into view. Gedik points out that \"this is quite unusual. In most cases, when you add energy to a material, you reduce order.\" \"It's as if these two [kinds of CDW] are competing—when one shows up, the other goes away,\" Kogar says. \"I think the really important concept here is phase competition.\" The idea that two possible states of matter might be in competition and that the dominant mode is suppressing one or more alternative modes is fairly common in quantum materials, the researchers say. This suggests that there may be latent states lurking unseen in many kinds of matter that could be unveiled if a way can be found to suppress the dominant state. That is what seems to be happening in the case of these competing CDW states, which are considered to be analogous to crystal structures because of the predictable, orderly patterns of their subatomic constituents. Normally, all stable materials are found in their minimum energy states—that is, of all possible configurations of their atoms and molecules, the material settles into the state that requires the least energy to maintain itself. But for a given chemical structure, there may be other possible configurations the material could potentially have, except that they are suppressed by the dominant, lowest-energy state. \"By knocking out that dominant state with light, maybe those other states can be realized,\" Gedik says. And because the new states appear and disappear so quickly, \"you can turn them on and off,\" which may prove useful for some information processing applications. The possibility that suppressing other phases might reveal entirely new material properties opens up many new areas of research, Kogar says. \"The goal is to find phases of material that can only exist out of equilibrium,\" he says—in other words, states that would never be attainable without a method, such as this system of fast laser pulses, for suppressing the dominant phase. Gedik adds that \"normally, to change the phase of a material you try chemical changes, or pressure, or magnetic fields. In this work, we are using light to make these changes.\" The new findings may help to better understand the role of phase competition in other systems. This in turn can help to answer questions like why superconductivity occurs in some materials at relatively high temperatures, and may help in the quest to discover even higher-temperature superconductors.Gedik says, \"What if all you need to do is shine light on a material, and this new state comes into being?\" The work was supported by the U.S. Department of Energy, SLAC National Accelerator Laboratory, the Skoltech-MIT NGP Program, the Center for Excitonics, and the Gordon and Betty Moore Foundation. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract When electrons in a solid are excited by light, they can alter the free energy landscape and access phases of matter that are out of reach in thermal equilibrium. This accessibility becomes important in the presence of phase competition, when one state of matter is preferred over another by only a small energy scale that, in principle, is surmountable by the excitation. Here, we study a layered compound, LaTe 3 , where a small lattice anisotropy in the a – c plane results in a unidirectional charge density wave (CDW) along the c axis 1 , 2 . Using ultrafast electron diffraction, we find that, after photoexcitation, the CDW along the c axis is weakened and a different competing CDW along the a axis subsequently emerges. The timescales characterizing the relaxation of this new CDW and the reestablishment of the original CDW are nearly identical, which points towards a strong competition between the two orders. The new density wave represents a transient non-equilibrium phase of matter with no equilibrium counterpart, and this study thus provides a framework for discovering similar states of matter that are ‘trapped’ under equilibrium conditions. Main A major theme in condensed matter physics is the relationship between proximal phases of matter, where one ordered ground state gives way to another as a function of some external parameter such as pressure, magnetic field, doping or disorder. It is in such a neighbourhood that we find colossal magnetoresistance in manganites 3 and unconventional superconductivity in heavy fermion, copper oxide and iron-based compounds 4 . In these materials, the nearby ground states can affect one another in several ways. For example, phases can compete, impeding the formation of one state in place of another. This scenario occurs, for example, in La 2− x Ba x CuO 4 at x = 1/8, where the development of alternating charge and spin-ordered regions prevents the onset of superconductivity 5 , 6 . On the other hand, fluctuations of an adjacent phase can help another be realized, such as in 3 He, where ferromagnetic spin fluctuations enable the atoms to form Cooper pairs and hence a p -wave superfluid 4 , 7 . In more complicated situations, such as in manganites, nanoscale phase separation occurs, where local insulating antiferromagnetism coexists next to patches of metallic ferromagnetism, resulting in large magnetic and electrical responses to small perturbations 3 . In each case, the macroscopic properties of a material are heavily influenced by the nearby presence of different phases. Intense light pulses have recently emerged as a tool to tune between neighbouring broken-symmetry phases of matter 8 , 9 , 10 , 11 , 12 , 13 . Conventionally, light pulses are used to restore symmetry, but in certain cases symmetries can also be broken. For example, exposing SrTiO 3 to mid-infrared radiation has led to ferroelectricity 8 , 9 , while ferromagnetism has been induced in a manganite with near-infrared light 11 . In this Letter, we examine a quasi-two-dimensional (2D) material, LaTe 3 , where a unidirectional charge density wave (CDW) phase is only present along the c axis, with no counterpart along the nearly equivalent, perpendicular a axis. We show that femtosecond light pulses can be used to break translational symmetry and unleash an a -axis CDW. Using ultrafast electron diffraction (UED), we visualize this process and track both order parameters simultaneously, gaining a unique perspective on both orders in the time domain. LaTe 3 is a member of the rare-earth tritellurides ( R Te 3 , where R denotes a rare-earth element). These materials possess a layered, quasi-tetragonal structure (Fig. 1a ) with a slight in-plane anisotropy ( a ≥ 0.997 c ; Supplementary Fig. 4b ) 2 , 14 , which leads to a preferred direction for the CDW order along the c axis. The Fermi surface, which is similar for all R Te 3 , arises from the nearly square-shaped Te sheets; the rare-earth atoms, with different radii, effectively serve to apply chemical pressure 1 , 15 . The normal-state Fermi surface is depicted in Fig. 1a , along with the CDW wavevector for LaTe 3 . Depending on the specific rare-earth element in R Te 3 , some of the members display a CDW only along the c direction while others have an additional CDW along the orthogonal a direction (Fig. 1b ). As one moves from lighter to heavier rare-earth elements, the transition temperature of the CDW along the c axis, T c 1 , decreases, while that along the a axis, T c 2 , is first finite in TbTe 3 and increases with atomic number (Fig. 1b ). This relationship strongly suggests that the two CDWs compete in equilibrium. The competition can be understood as follows. Once the c -axis CDW forms, large portions of the Fermi surface open up a gap; the corresponding loss of states near the Fermi energy therefore inhibits the formation of the a -axis CDW 15 . In the material we study here, LaTe 3 , T c 1 is estimated to be ~670 K (ref. 16 ), and a CDW along the a axis does not exist. Fig. 1: Observation of a transient CDW induced by an 80 fs, 800 nm laser pulse. a , Left: Schematic of the LaTe 3 crystal structure, where dashed lines indicate the unit cell. Middle: Schematic of the normal state Fermi surface arising from the planar Te sheets, which are nearly square-shaped with a slight in-plane anisotropy ( a = 0.997 c at room temperature 2 , 14 ). The wavevector q c of the equilibrium c -axis CDW is indicated. Right: Schematic of the ultrafast electron diffraction set-up in transmission mode. Both 26 keV and 3.1 MeV electrons were used (see Methods and Supplementary Note 1 ). Exfoliated samples were mounted on a 10-nm-thick silicon nitride window. CCD, charge-coupled device. b , Summary of the two CDW transition temperatures, T c 1 and T c 2 , across the rare-earth series.<|im_end|> <|im_start|>assistant Adding energy to any material, such as by heating it, almost always makes its structure less orderly. Ice, for example, with its crystalline structure, melts to become liquid water, with no order at all. But in new experiments by physicists at MIT and elsewhere, the opposite happens: When a pattern called a charge density wave in a certain material is hit with a fast laser pulse, a whole new charge density wave is created—a highly ordered state, instead of the expected disorder. The surprising finding could help to reveal unseen properties in materials of all kinds. The discovery is being reported today in the journal Nature Physics, in a paper by MIT professors Nuh Gedik and Pablo Jarillo-Herrero, postdoc Anshul Kogar, graduate student Alfred Zong, and 17 others at MIT, Harvard University, SLAC National Accelerator Laboratory, Stanford University, and Argonne National Laboratory. The experiments made use of a material called lanthanum tritelluride, which naturally forms itself into a layered structure. In this material, a wavelike pattern of electrons in high- and low-density regions forms spontaneously but is confined to a single direction within the material. But when hit with an ultrafast burst of laser light—less than a picosecond long, or under one trillionth of a second—that pattern, called a charge density wave or CDW, is obliterated, and a new CDW, at right angles to the original, pops into existence. This new, perpendicular CDW is something that has never been observed before in this material. It exists for only a flash, disappearing within a few more picoseconds. As it disappears, the original one comes back into view, suggesting that its presence had been somehow suppressed by the new one. Gedik explains that in ordinary materials, the density of electrons within the material is constant throughout their volume, but in certain materials, when they are cooled below some specific temperature, the electrons organize themselves into a CDW with alternating regions of high and low electron density. In lanthanum tritelluride, or LaTe3, the CDW is along one fixed direction within the material. In the other two dimensions, the electron density remains constant, as in ordinary materials. The perpendicular version of the CDW that appears after the burst of laser light has never before been observed in this material, Gedik says. It "just briefly flashes, and then it's gone," Kogar says, to be replaced by the original CDW pattern which immediately pops back into view. Gedik points out that "this is quite unusual. In most cases, when you add energy to a material, you reduce order." "It's as if these two [kinds of CDW] are competing—when one shows up, the other goes away," Kogar says. "I think the really important concept here is phase competition." The idea that two possible states of matter might be in competition and that the dominant mode is suppressing one or more alternative modes is fairly common in quantum materials, the researchers say. This suggests that there may be latent states lurking unseen in many kinds of matter that could be unveiled if a way can be found to suppress the dominant state. That is what seems to be happening in the case of these competing CDW states, which are considered to be analogous to crystal structures because of the predictable, orderly patterns of their subatomic constituents. Normally, all stable materials are found in their minimum energy states—that is, of all possible configurations of their atoms and molecules, the material settles into the state that requires the least energy to maintain itself. But for a given chemical structure, there may be other possible configurations the material could potentially have, except that they are suppressed by the dominant, lowest-energy state. "By knocking out that dominant state with light, maybe those other states can be realized," Gedik says. And because the new states appear and disappear so quickly, "you can turn them on and off," which may prove useful for some information processing applications. The possibility that suppressing other phases might reveal entirely new material properties opens up many new areas of research, Kogar says. "The goal is to find phases of material that can only exist out of equilibrium," he says—in other words, states that would never be attainable without a method, such as this system of fast laser pulses, for suppressing the dominant phase. Gedik adds that "normally, to change the phase of a material you try chemical changes, or pressure, or magnetic fields. In this work, we are using light to make these changes." The new findings may help to better understand the role of phase competition in other systems. This in turn can help to answer questions like why superconductivity occurs in some materials at relatively high temperatures, and may help in the quest to discover even higher-temperature superconductors.Gedik says, "What if all you need to do is shine light on a material, and this new state comes into being?" The work was supported by the U.S. Department of Energy, SLAC National Accelerator Laboratory, the Skoltech-MIT NGP Program, the Center for Excitonics, and the Gordon and Betty Moore Foundation. <|im_end|>

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2,446

[ { "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 Aims Women with gestational diabetes mellitus (GDM) have an increased risk of diabetes postpartum. We developed a score to predict the long-term risk of postpartum diabetes using clinical and anamnestic variables recorded during or shortly after delivery. Methods Data from 257 GDM women who were prospectively followed for diabetes outcome over 20 years of follow-up were used to develop and validate the risk score. Participants were divided into training and test sets. The risk score was calculated using Lasso Cox regression and divided into four risk categories, and its prediction performance was assessed in the test set. Results Postpartum diabetes developed in 110 women. The computed training set risk score of 5 × body mass index in early pregnancy (per kg/m 2 ) + 132 if GDM was treated with insulin (otherwise 0) + 44 if the woman had a family history of diabetes (otherwise 0) − 35 if the woman lactated (otherwise 0) had R 2 values of 0.23, 0.25, and 0.33 at 5, 10, and 15 years postpartum, respectively, and a C-Index of 0.75. Application of the risk score in the test set resulted in observed risk of postpartum diabetes at 5 years of 11 % for low risk scores ≤140, 29 % for scores 141–220, 64 % for scores 221–300, and 80 % for scores >300. Conclusions The derived risk score is easy to calculate, allows accurate prediction of GDM-related postpartum diabetes, and may thus be a useful prediction tool for clinicians and general practitioners. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Gestational diabetes mellitus (GDM) affects 2–6 % of all pregnancies in industrialized countries [ 1 ] and is associated with an increased risk of diabetes postpartum [ 2 , 3 ]. We have recently reported that lactation provides long-term protection against the development of postpartum diabetes in women with GDM, while insulin treatment during pregnancy and maternal obesity are associated with increased risk [ 4 ]. These findings indicate that further stratification of GDM women according to their actual postpartum diabetes risk is possible already shortly after delivery. We aimed to develop an easily applicable tool for diabetes risk stratification in GDM women, which may be helpful in clinical settings, particularly in the context of targeted and more efficient programs to detect and prevent the development of postpartum diabetes. For this purpose, we analyzed our data with a novel approach, using advanced statistical methods to obtain a risk score based on clinical and anamnestic variables that could improve long-term prediction of postpartum diabetes in women with GDM. Methods Participants The prospective German GDM study followed women with GDM from delivery for up to 20 years to detect the development of postpartum diabetes. A detailed description of the study design has been previously reported [ 4 – 6 ]. In brief, a total of 304 patients with GDM were recruited between 1989 and 1999 across Germany and followed up until 2014. Patients were followed for the development of diabetes postpartum by means of an OGTT at 2 and 9 months; 2, 5, 8, 11, 15, and 19 years after pregnancy; or until the diagnosis of diabetes. OGTTs were performed by the patient physician. In addition, if women presented with symptoms of diabetes between follow-up visits, physicians took blood glucose measurements to test for clinical diabetes. Postpartum diabetes onset was defined according to American Diabetes Association criteria, which included unequivocal hyperglycemia with acute metabolic decompensation or the observation of a 2-h plasma glucose level >200 mg/dL after an oral glucose challenge, or a random blood glucose level >200 mg/dL if accompanied by unequivocal symptoms. Since 1997, a fasting blood glucose level >126 mg/dL on two occasions also was included as a diabetes diagnosis criteria in the study. Postpartum diabetes developed in 147 women (48.4 %). The median postpartum follow-up time from delivery was 8.1 years for women who did not develop diabetes. Statistical analysis To develop the risk score, we made use of the following variables: the mother’s body mass index (BMI) in early pregnancy, GDM treatment (insulin or diet), family history of diabetes (yes vs. no), lactation duration (never, ≤3, or >3 months, coded as two dummy variables), and maternal age at delivery. These variables were collected by questionnaires or interviews and were chosen because they were easily ascertainable anamnestic information and had been previously associated with postpartum diabetes risk [ 4 , 7 ]. Of the 304 women with GDM, 257 were islet autoantibody negative and had complete data for the selected variables of interest; those 257 women were used to develop and validate the risk score (suppl. table S1). Of these women, 110 developed postpartum diabetes. In order to derive and test the prediction model in two independent data sets, the data were split into a training set (2/3; n = 171 women) and a test set (1/3; n = 86 women) using stratified random sampling. In the training set, the Lasso method for Cox regression [ 8 ] was used to reduce the final model to the most important variables to predict postpartum diabetes. We used a bootstrap approach to assess the robustness of the selection process with regard to the split into training and test sets. Therefore, we created 1000 different training sets of the same sample size (171 each) by sampling with replacement from the full data and assessed how often each risk factor was selected as a relevant predictor of diabetes development in those 1000 bootstrap data sets (Table 1 ). The risk score was calculated based on the regression coefficients of the variables chosen for the final model, rounded to two decimal places, and multiplied with the factor 100. Table 1 Description and modeling results of risk factors for postpartum development of diabetes after gestational diabetes Full size table The predictive performance of the risk score in the test set was assessed with three measures: R 2 at different times after delivery to assess the overall model performance [", "role": "user" }, { "content": "Gestational diabetes is one of the most common conditions that can occur during pregnancy. Although the symptoms generally disappear after delivery, women suffering from gestational diabetes are at increased risk of developing postpartum diabetes in the following years. Researchers at the Helmholtz Zentrum München have now developed an accurate method of predicting the probability of developing this progressive disease following childbirth. Their findings were published recently in Acta Diabetologica. For their study, the scientists from the Institute of Diabetes Research (IDF), Helmholtz Zentrum München, which is one of the partners of the German Center for Diabetes Research (DZD), collected data from 257 cases of gestational diabetes (a type of diabetes that affects women during pregnancy) which occurred between 1989 and 1999 and were followed up for a period of 20 years after delivery. One hundred and ten of the women observed during this period developed postpartum diabetes. In order to be able to predict in which mother the disease would manifest itself after delivery, the team headed by Prof. Anette-Gabriele Ziegler, Director of the Institute of Diabetes Research, tested various parameters that are known to play a significant role in the genesis of the disease. Personal risk is easy to calculate \"Body mass index (BMI) and genetic predisposition both play a role in our calculation, as does the question of whether the mother breastfed her baby and whether her gestational diabetes had to be treated with insulin,\" explains Meike Köhler, first author of the study. On the basis of these parameters, the researchers introduced a point system to enable them to predict a woman's likelihood of developing postpartum diabetes. For low-risk scores, the probability of developing diabetes within five years after delivery was only about eleven percent; in the medium-risk category it ranged from 29 to 64 percent, while for the highest-risk scores it was more than 80 percent. \"The test we developed is very easy to apply and in the future could be used in hospitals as a tool for predicting postpartum diabetes,\" Prof. Ziegler added. \"This means that both the doctor and the patient are aware of the respective risk, and it allows diabetes checks to be more closely tailored to the patient's individual needs.\" ", "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 Aims Women with gestational diabetes mellitus (GDM) have an increased risk of diabetes postpartum. We developed a score to predict the long-term risk of postpartum diabetes using clinical and anamnestic variables recorded during or shortly after delivery. Methods Data from 257 GDM women who were prospectively followed for diabetes outcome over 20 years of follow-up were used to develop and validate the risk score. Participants were divided into training and test sets. The risk score was calculated using Lasso Cox regression and divided into four risk categories, and its prediction performance was assessed in the test set. Results Postpartum diabetes developed in 110 women. The computed training set risk score of 5 × body mass index in early pregnancy (per kg/m 2 ) + 132 if GDM was treated with insulin (otherwise 0) + 44 if the woman had a family history of diabetes (otherwise 0) − 35 if the woman lactated (otherwise 0) had R 2 values of 0.23, 0.25, and 0.33 at 5, 10, and 15 years postpartum, respectively, and a C-Index of 0.75. Application of the risk score in the test set resulted in observed risk of postpartum diabetes at 5 years of 11 % for low risk scores ≤140, 29 % for scores 141–220, 64 % for scores 221–300, and 80 % for scores >300. Conclusions The derived risk score is easy to calculate, allows accurate prediction of GDM-related postpartum diabetes, and may thus be a useful prediction tool for clinicians and general practitioners. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Gestational diabetes mellitus (GDM) affects 2–6 % of all pregnancies in industrialized countries [ 1 ] and is associated with an increased risk of diabetes postpartum [ 2 , 3 ]. We have recently reported that lactation provides long-term protection against the development of postpartum diabetes in women with GDM, while insulin treatment during pregnancy and maternal obesity are associated with increased risk [ 4 ]. These findings indicate that further stratification of GDM women according to their actual postpartum diabetes risk is possible already shortly after delivery. We aimed to develop an easily applicable tool for diabetes risk stratification in GDM women, which may be helpful in clinical settings, particularly in the context of targeted and more efficient programs to detect and prevent the development of postpartum diabetes. For this purpose, we analyzed our data with a novel approach, using advanced statistical methods to obtain a risk score based on clinical and anamnestic variables that could improve long-term prediction of postpartum diabetes in women with GDM. Methods Participants The prospective German GDM study followed women with GDM from delivery for up to 20 years to detect the development of postpartum diabetes. A detailed description of the study design has been previously reported [ 4 – 6 ]. In brief, a total of 304 patients with GDM were recruited between 1989 and 1999 across Germany and followed up until 2014. Patients were followed for the development of diabetes postpartum by means of an OGTT at 2 and 9 months; 2, 5, 8, 11, 15, and 19 years after pregnancy; or until the diagnosis of diabetes. OGTTs were performed by the patient physician. In addition, if women presented with symptoms of diabetes between follow-up visits, physicians took blood glucose measurements to test for clinical diabetes. Postpartum diabetes onset was defined according to American Diabetes Association criteria, which included unequivocal hyperglycemia with acute metabolic decompensation or the observation of a 2-h plasma glucose level >200 mg/dL after an oral glucose challenge, or a random blood glucose level >200 mg/dL if accompanied by unequivocal symptoms. Since 1997, a fasting blood glucose level >126 mg/dL on two occasions also was included as a diabetes diagnosis criteria in the study. Postpartum diabetes developed in 147 women (48.4 %). The median postpartum follow-up time from delivery was 8.1 years for women who did not develop diabetes. Statistical analysis To develop the risk score, we made use of the following variables: the mother’s body mass index (BMI) in early pregnancy, GDM treatment (insulin or diet), family history of diabetes (yes vs. no), lactation duration (never, ≤3, or >3 months, coded as two dummy variables), and maternal age at delivery. These variables were collected by questionnaires or interviews and were chosen because they were easily ascertainable anamnestic information and had been previously associated with postpartum diabetes risk [ 4 , 7 ]. Of the 304 women with GDM, 257 were islet autoantibody negative and had complete data for the selected variables of interest; those 257 women were used to develop and validate the risk score (suppl. table S1). Of these women, 110 developed postpartum diabetes. In order to derive and test the prediction model in two independent data sets, the data were split into a training set (2/3; n = 171 women) and a test set (1/3; n = 86 women) using stratified random sampling. In the training set, the Lasso method for Cox regression [ 8 ] was used to reduce the final model to the most important variables to predict postpartum diabetes. We used a bootstrap approach to assess the robustness of the selection process with regard to the split into training and test sets. Therefore, we created 1000 different training sets of the same sample size (171 each) by sampling with replacement from the full data and assessed how often each risk factor was selected as a relevant predictor of diabetes development in those 1000 bootstrap data sets (Table 1 ). The risk score was calculated based on the regression coefficients of the variables chosen for the final model, rounded to two decimal places, and multiplied with the factor 100. Table 1 Description and modeling results of risk factors for postpartum development of diabetes after gestational diabetes Full size table The predictive performance of the risk score in the test set was assessed with three measures: R 2 at different times after delivery to assess the overall model performance [<|im_end|> <|im_start|>assistant Gestational diabetes is one of the most common conditions that can occur during pregnancy. Although the symptoms generally disappear after delivery, women suffering from gestational diabetes are at increased risk of developing postpartum diabetes in the following years. Researchers at the Helmholtz Zentrum München have now developed an accurate method of predicting the probability of developing this progressive disease following childbirth. Their findings were published recently in Acta Diabetologica. For their study, the scientists from the Institute of Diabetes Research (IDF), Helmholtz Zentrum München, which is one of the partners of the German Center for Diabetes Research (DZD), collected data from 257 cases of gestational diabetes (a type of diabetes that affects women during pregnancy) which occurred between 1989 and 1999 and were followed up for a period of 20 years after delivery. One hundred and ten of the women observed during this period developed postpartum diabetes. In order to be able to predict in which mother the disease would manifest itself after delivery, the team headed by Prof. Anette-Gabriele Ziegler, Director of the Institute of Diabetes Research, tested various parameters that are known to play a significant role in the genesis of the disease. Personal risk is easy to calculate "Body mass index (BMI) and genetic predisposition both play a role in our calculation, as does the question of whether the mother breastfed her baby and whether her gestational diabetes had to be treated with insulin," explains Meike Köhler, first author of the study. On the basis of these parameters, the researchers introduced a point system to enable them to predict a woman's likelihood of developing postpartum diabetes. For low-risk scores, the probability of developing diabetes within five years after delivery was only about eleven percent; in the medium-risk category it ranged from 29 to 64 percent, while for the highest-risk scores it was more than 80 percent. "The test we developed is very easy to apply and in the future could be used in hospitals as a tool for predicting postpartum diabetes," Prof. Ziegler added. "This means that both the doctor and the patient are aware of the respective risk, and it allows diabetes checks to be more closely tailored to the patient's individual needs." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract When two metal nanostructures are placed nanometres apart, their optically driven free electrons couple electrically across the gap. The resulting plasmons have enhanced optical fields of a specific colour tightly confined inside the gap. Many emerging nanophotonic technologies depend on the careful control of this plasmonic coupling, including optical nanoantennas for high-sensitivity chemical and biological sensors 1 , nanoscale control of active devices 2 , 3 , 4 , and improved photovoltaic devices 5 . But for subnanometre gaps, coherent quantum tunnelling becomes possible and the system enters a regime of extreme non-locality in which previous classical treatments 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 fail. Electron correlations across the gap that are driven by quantum tunnelling require a new description of non-local transport, which is crucial in nanoscale optoelectronics and single-molecule electronics. Here, by simultaneously measuring both the electrical and optical properties of two gold nanostructures with controllable subnanometre separation, we reveal the quantum regime of tunnelling plasmonics in unprecedented detail. All observed phenomena are in good agreement with recent quantum-based models of plasmonic systems 15 , which eliminate the singularities predicted by classical theories. These findings imply that tunnelling establishes a quantum limit for plasmonic field confinement of about 10 −8 λ 3 for visible light (of wavelength λ ). Our work thus prompts new theoretical and experimental investigations into quantum-domain plasmonic systems, and will affect the future of nanoplasmonic device engineering and nanoscale photochemistry. Main Subwavelength metallic structures can concentrate light into nanoscale dimensions well below the diffraction limit 16 owing to reduced field penetration through a dense electron sea. Nanocavities formed inside a nanogap control the coupling of localized plasmons, thus allowing cavity-tuning 6 , 7 , 8 targeted to desirable applications that exploit the enhanced optical fields. But as the cavity gaps shrink to atomic length scales, quantum effects emerge and standard classical approaches to describe the optics of these systems fail. One effect of confining electronic wavefunctions to small metallic nanoparticles is to slightly modify the screening that tunes the plasmons 17 . However, tunnelling plasmonics in the quantum regime has more profound effects that cannot be explained through hydrodynamic models that account for quantum effects through smearing of the electronic localization 18 . Recent theories show that quantum tunnelling across the cavity strongly modifies the optical response 19 , 20 , but computational limits restrict these quantum simulations to very small systems below a few nanometres in size. Furthermore, the extreme difficulty of creating and probing subnanometre cavities has limited experimental investigations of plasmonics in the quantum regime. Top-down and self-assembly nanofabrication achieves gaps as small as 0.5 nm between plasmonic nanoparticles 21 , 22 , but these fail to reach the quantum tunnelling regime. Small cavities are also accessed in scanning tunnelling microscopes and electro-migrated break-junctions which show optical mixing, emission and rectification phenomena 23 , 24 , 25 , 26 , but the effect of quantum tunnelling on optical plasmon coupling across subnanometre cavities remains unexplored. Here we present broadband optical spectra that probe dynamically controlled plasmonic cavities and reveal the onset of quantum-tunnelling-induced plasmonics in the subnanometre regime. Two gold-nanoparticle-terminated atomic force microscope (AFM) tips are oriented tip-to-tip ( Fig. 1a ). The tip apices define a cavity supporting plasmonic resonances created via strong coupling between localized plasmons on each tip 7 , 27 . This dual AFM tip configuration provides multiple advantages. First, independent nanometre-precision movement of both tips is possible with three-axis piezoelectric stages. Second, conductive AFM probes provide direct electrical connection to the tips, enabling simultaneous optical and electrical measurements. Third, the tips are in free space and illuminated from the side in a dark-field configuration ( Fig. 1b, c and Supplementary Information ). This arrangement provides (for the first time, to our knowledge) background-free broadband spectroscopic characterization of the tip–tip plasmonic nanocavity throughout the subnanometre regime. A supercontinuum laser (with polarization parallel to the tip–tip axis) is used as an excitation source, providing high-brightness illumination over a wide wavelength range (450–1,700 nm) and reducing integration times to a few milliseconds. The tips are aligned using a recently developed electrostatic-force technique 28 . The inter-tip separation d is initially set to 50 nm and then reduced while recording dark field scattering spectra and direct currents simultaneously. Figure 1: Formation and characterization of a nanoscale plasmonic cavity. a , Scheme for simultaneous optical and electrical measurements of plasmonic cavity formed between two Au-coated tips, shown in dark-field microscope images ( b ) and false-colour scanning electron microscope image ( c ) of a typical tip, end radius R = 150 nm. d , Measured dark field scattering spectra from one inter-tip cavity at different cavity widths d . Plasmonic cavity resonances are labelled A–C. PowerPoint slide Full size image Each piezoelectric scan investigates three interaction regimes: capacitive near-field coupling (50 nm > d > 1 nm), quantum regimes (1 nm > d > 0 nm) and physical contact with conductive coupling ( d ≤ 0 nm). Crucially, this set-up allows us to resolve the gradual transition between each regime dynamically. The measured dark-field scattering spectra ( Fig. 1d ) within the capacitive regime ( d ≈ 40 nm) show a single plasmonic scattering peak centred near λ = 750 nm (mode A). As d is reduced, this peak redshifts owing to increasing near-field interactions between the tip plasmons. As the cavity shrinks below 20 nm, a second scattering peak emerges at shorter wavelengths (mode B, λ = 550 nm) and quickly increases in intensity. Modes A and B smoothly redshift until an estimated separation d = 5 nm, whereupon attractive inter-tip forces overwhelm the AFM-cantilever restoring force and snap the tips into close proximity 29 . However no current flow is detectable because this snap-to-contact point does not coincide with conductive contact and the metal surfaces remain separated. Snap-to-contact reduces d to ∼ 1 nm, significantly increasing the plasmonic interaction and dramatically changing the plasmonic scattering resonances", "role": "user" }, { "content": "Even empty gaps have a colour. Now scientists have shown that quantum jumps of electrons can change the colour of gaps between nano-sized balls of gold. The new results, published today in the journal Nature, set a fundamental quantum limit on how tightly light can be trapped. The team from the Universities of Cambridge, the Basque Country and Paris have combined tour de force experiments with advanced theories to show how light interacts with matter at nanometre sizes. The work shows how they can literally see quantum mechanics in action in air at room temperature. Because electrons in a metal move easily, shining light onto a tiny crack pushes electric charges onto and off each crack face in turn, at optical frequencies. The oscillating charge across the gap produces a 'plasmonic' colour for the ghostly region in-between, but only when the gap is small enough. Team leader Professor Jeremy Baumberg from the University of Cambridge Cavendish Laboratory suggests we think of this like the tension building between a flirtatious couple staring into each other's eyes. As their faces get closer the tension mounts, and only a kiss discharges this energy. In the new experiments, the gap is shrunk below 1nm (1 billionth of a metre) which strongly reddens the gap colour as the charge builds up. However because electrons can jump across the gap by quantum tunnelling, the charge can drain away when the gap is below 0.35nm, seen as a blue-shifting of the colour. As Baumberg says, \"It is as if you can kiss without quite touching lips.\" Matt Hawkeye, from the experimental team at Cambridge, said: \"Lining up the two nano-balls of gold is like closing your eyes and touching together two needles strapped to the end of your fingers. It has taken years of practise to get good at it.\" Prof Javier Aizpurua, leader of the theoretical team from San Sebastian complains: \"Trying to model so many electrons oscillating inside the gold just cannot be done with existing theories.\" He has had to fuse classical and quantum views of the world to even predict the colour shifts seen in experiment. The new insights from this work suggest ways to measure the world down to the scale of single atoms and molecules, and strategies to make useful tiny devices. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract When two metal nanostructures are placed nanometres apart, their optically driven free electrons couple electrically across the gap. The resulting plasmons have enhanced optical fields of a specific colour tightly confined inside the gap. Many emerging nanophotonic technologies depend on the careful control of this plasmonic coupling, including optical nanoantennas for high-sensitivity chemical and biological sensors 1 , nanoscale control of active devices 2 , 3 , 4 , and improved photovoltaic devices 5 . But for subnanometre gaps, coherent quantum tunnelling becomes possible and the system enters a regime of extreme non-locality in which previous classical treatments 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 fail. Electron correlations across the gap that are driven by quantum tunnelling require a new description of non-local transport, which is crucial in nanoscale optoelectronics and single-molecule electronics. Here, by simultaneously measuring both the electrical and optical properties of two gold nanostructures with controllable subnanometre separation, we reveal the quantum regime of tunnelling plasmonics in unprecedented detail. All observed phenomena are in good agreement with recent quantum-based models of plasmonic systems 15 , which eliminate the singularities predicted by classical theories. These findings imply that tunnelling establishes a quantum limit for plasmonic field confinement of about 10 −8 λ 3 for visible light (of wavelength λ ). Our work thus prompts new theoretical and experimental investigations into quantum-domain plasmonic systems, and will affect the future of nanoplasmonic device engineering and nanoscale photochemistry. Main Subwavelength metallic structures can concentrate light into nanoscale dimensions well below the diffraction limit 16 owing to reduced field penetration through a dense electron sea. Nanocavities formed inside a nanogap control the coupling of localized plasmons, thus allowing cavity-tuning 6 , 7 , 8 targeted to desirable applications that exploit the enhanced optical fields. But as the cavity gaps shrink to atomic length scales, quantum effects emerge and standard classical approaches to describe the optics of these systems fail. One effect of confining electronic wavefunctions to small metallic nanoparticles is to slightly modify the screening that tunes the plasmons 17 . However, tunnelling plasmonics in the quantum regime has more profound effects that cannot be explained through hydrodynamic models that account for quantum effects through smearing of the electronic localization 18 . Recent theories show that quantum tunnelling across the cavity strongly modifies the optical response 19 , 20 , but computational limits restrict these quantum simulations to very small systems below a few nanometres in size. Furthermore, the extreme difficulty of creating and probing subnanometre cavities has limited experimental investigations of plasmonics in the quantum regime. Top-down and self-assembly nanofabrication achieves gaps as small as 0.5 nm between plasmonic nanoparticles 21 , 22 , but these fail to reach the quantum tunnelling regime. Small cavities are also accessed in scanning tunnelling microscopes and electro-migrated break-junctions which show optical mixing, emission and rectification phenomena 23 , 24 , 25 , 26 , but the effect of quantum tunnelling on optical plasmon coupling across subnanometre cavities remains unexplored. Here we present broadband optical spectra that probe dynamically controlled plasmonic cavities and reveal the onset of quantum-tunnelling-induced plasmonics in the subnanometre regime. Two gold-nanoparticle-terminated atomic force microscope (AFM) tips are oriented tip-to-tip ( Fig. 1a ). The tip apices define a cavity supporting plasmonic resonances created via strong coupling between localized plasmons on each tip 7 , 27 . This dual AFM tip configuration provides multiple advantages. First, independent nanometre-precision movement of both tips is possible with three-axis piezoelectric stages. Second, conductive AFM probes provide direct electrical connection to the tips, enabling simultaneous optical and electrical measurements. Third, the tips are in free space and illuminated from the side in a dark-field configuration ( Fig. 1b, c and Supplementary Information ). This arrangement provides (for the first time, to our knowledge) background-free broadband spectroscopic characterization of the tip–tip plasmonic nanocavity throughout the subnanometre regime. A supercontinuum laser (with polarization parallel to the tip–tip axis) is used as an excitation source, providing high-brightness illumination over a wide wavelength range (450–1,700 nm) and reducing integration times to a few milliseconds. The tips are aligned using a recently developed electrostatic-force technique 28 . The inter-tip separation d is initially set to 50 nm and then reduced while recording dark field scattering spectra and direct currents simultaneously. Figure 1: Formation and characterization of a nanoscale plasmonic cavity. a , Scheme for simultaneous optical and electrical measurements of plasmonic cavity formed between two Au-coated tips, shown in dark-field microscope images ( b ) and false-colour scanning electron microscope image ( c ) of a typical tip, end radius R = 150 nm. d , Measured dark field scattering spectra from one inter-tip cavity at different cavity widths d . Plasmonic cavity resonances are labelled A–C. PowerPoint slide Full size image Each piezoelectric scan investigates three interaction regimes: capacitive near-field coupling (50 nm > d > 1 nm), quantum regimes (1 nm > d > 0 nm) and physical contact with conductive coupling ( d ≤ 0 nm). Crucially, this set-up allows us to resolve the gradual transition between each regime dynamically. The measured dark-field scattering spectra ( Fig. 1d ) within the capacitive regime ( d ≈ 40 nm) show a single plasmonic scattering peak centred near λ = 750 nm (mode A). As d is reduced, this peak redshifts owing to increasing near-field interactions between the tip plasmons. As the cavity shrinks below 20 nm, a second scattering peak emerges at shorter wavelengths (mode B, λ = 550 nm) and quickly increases in intensity. Modes A and B smoothly redshift until an estimated separation d = 5 nm, whereupon attractive inter-tip forces overwhelm the AFM-cantilever restoring force and snap the tips into close proximity 29 . However no current flow is detectable because this snap-to-contact point does not coincide with conductive contact and the metal surfaces remain separated. Snap-to-contact reduces d to ∼ 1 nm, significantly increasing the plasmonic interaction and dramatically changing the plasmonic scattering resonances<|im_end|> <|im_start|>assistant Even empty gaps have a colour. Now scientists have shown that quantum jumps of electrons can change the colour of gaps between nano-sized balls of gold. The new results, published today in the journal Nature, set a fundamental quantum limit on how tightly light can be trapped. The team from the Universities of Cambridge, the Basque Country and Paris have combined tour de force experiments with advanced theories to show how light interacts with matter at nanometre sizes. The work shows how they can literally see quantum mechanics in action in air at room temperature. Because electrons in a metal move easily, shining light onto a tiny crack pushes electric charges onto and off each crack face in turn, at optical frequencies. The oscillating charge across the gap produces a 'plasmonic' colour for the ghostly region in-between, but only when the gap is small enough. Team leader Professor Jeremy Baumberg from the University of Cambridge Cavendish Laboratory suggests we think of this like the tension building between a flirtatious couple staring into each other's eyes. As their faces get closer the tension mounts, and only a kiss discharges this energy. In the new experiments, the gap is shrunk below 1nm (1 billionth of a metre) which strongly reddens the gap colour as the charge builds up. However because electrons can jump across the gap by quantum tunnelling, the charge can drain away when the gap is below 0.35nm, seen as a blue-shifting of the colour. As Baumberg says, "It is as if you can kiss without quite touching lips." Matt Hawkeye, from the experimental team at Cambridge, said: "Lining up the two nano-balls of gold is like closing your eyes and touching together two needles strapped to the end of your fingers. It has taken years of practise to get good at it." Prof Javier Aizpurua, leader of the theoretical team from San Sebastian complains: "Trying to model so many electrons oscillating inside the gold just cannot be done with existing theories." He has had to fuse classical and quantum views of the world to even predict the colour shifts seen in experiment. The new insights from this work suggest ways to measure the world down to the scale of single atoms and molecules, and strategies to make useful tiny devices. <|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 Single cell RNA-sequencing (scRNA-seq) technology has undergone rapid development in recent years, leading to an explosion in the number of tailored data analysis methods. However, the current lack of gold-standard benchmark datasets makes it difficult for researchers to systematically compare the performance of the many methods available. Here, we generated a realistic benchmark experiment that included single cells and admixtures of cells or RNA to create ‘pseudo cells’ from up to five distinct cancer cell lines. In total, 14 datasets were generated using both droplet and plate-based scRNA-seq protocols. We compared 3,913 combinations of data analysis methods for tasks ranging from normalization and imputation to clustering, trajectory analysis and data integration. Evaluation revealed pipelines suited to different types of data for different tasks. Our data and analysis provide a comprehensive framework for benchmarking most common scRNA-seq analysis steps. Main The rapid development of computational methods for single cell gene expression analysis has created a need for systematic benchmarking to understand the strengths and weaknesses of different algorithms. The performances of particular single cell RNA-seq analysis methods have been evaluated for tasks including normalization 1 , feature selection 2 , differential gene expression analysis 3 , clustering 4 , 5 and trajectory analysis 6 . These studies compare methods using either experimental data where cell type labels are available or simulated datasets. Such ground truth is, however, imperfect, with simulations relying on assumptions that may not reflect the true nature of scRNA-seq data, and, because they focus on specific tasks, these studies lack a complete picture of performance at the pipeline level. Considering the heterogeneity between scRNA-seq datasets in terms of the number of clusters (cell types or states) and the presence of various technical artifacts, we set out to design a realistic gold-standard scRNA-seq control experiment that combines ground truth with varying levels of biological complexity. Two strategies are commonly employed to create gold-standard gene expression datasets. The first, which has been widely adopted in scRNA-seq studies 7 , uses small collections of exogenous spike-in controls such as External RNA Control Consortium spike-ins (ERCCs) 8 that vary in expression in a predictable way. The second involves either the dilution of RNA from a reference sample or mixing of RNA or cells from two or more samples to induce systematic genome-wide changes. An early example from Brennecke et al. 9 involved a dilution series to explore the sensitivity of the Smart-seq protocol. Grün et al. 10 generated a benchmark dataset using single mouse embryonic stem cells together with bulk RNA extracted from the same population, diluted to single cell equivalent amounts to quantify biological and technical variability. A limitation of these experiments is their lack of biological heterogeneity, which makes them less useful for comparing analysis methods. Mixture designs, in which RNA or cells are mixed in different proportions to generate biological heterogeneity with in-built truth, have been successfully used to benchmark microarray 11 , RNA-seq 12 and scRNA-seq 13 data. To combine the strengths of these approaches, we designed a series of experiments using mixtures of either cells or RNA from up to five cancer cell lines that included a dilution series to simulate variations in the RNA content of different cells, as well as ERCC spike-in controls where possible. Data were generated across four single cell technology platforms. Our scRNA-seq mixology design simulates varying levels of biological noise, with sample sizes varying from around 200 cells to 4,000 cells and known population structure to allow benchmarking of different analysis tools. We specifically evaluated combinations of methods for normalization and imputation, clustering, trajectory analysis and data integration. The methods chosen for each task use different algorithms and are mostly implemented in R 14 and Bioconductor 15 for convenience. Results scRNA-seq mixology provides ground truth for benchmarking Our scRNA-seq benchmarking experiment spanned two plate-based (CEL-seq2 and SORT-seq) and two droplet-based (10× Chromium and Drop-seq) protocols and involved three different experimental designs with replicates, yielding 14 datasets in total (Supplementary Table 1 ). The experimental design involved single cells, mixtures of single cells and mixtures of RNA from up to five human lung adenocarcinoma cell lines ( Methods , Fig. 1a,b and Supplementary Fig. 1 ). Fig. 1: Overview of the scRNA-seq mixology experimental design and benchmark analysis. a , b , The benchmark experimental design involving single cells ( a ) and ‘pseudo cells’ ( b ). c , PCA plots from representative datasets for each design (normalized using scran) highlight the structure present in each experiment. The percentage of variation explained by each principal component (PC) is included in the respective axis labels, and sample sizes are indicated by n . d , Workflow for benchmarking different analysis tasks using the CellBench R package. Full size image The three designs incorporate ground truth in various ways. For the single cell datasets (Fig. 1a ), the ground truth is the cell line identity that can be determined for each cell on the basis of known genetic variation ( Methods ). For the ‘pseudo cell’ mixture datasets, the known composition of cells and RNA serves as ground truth. The ‘RNA mixture’ and ‘cell mixture’ datasets (Fig. 1b and Supplementary Fig. 1 ) contain 7 and 34 groups, respectively, that give a continuous structure. Moreover, the RNA mixture dataset contains technical replication and a dilution series (Fig. 1b ), which is ideal for benchmarking normalization and imputation methods that are intended to deal with such technical variability. The data characteristics and analysis tasks that each design is suited to benchmark are summarized in Supplementary Table 2 . By comparing a range of quality control metrics collected across datasets using scPipe 16 , we observed that data from all platforms were of consistently high quality in terms of their exon mapping rates and the total unique molecular identifier (UMI) counts per cell (Supplementary Fig. 2 ). We found substantial differences in the percentage of reads mapping to intron regions in datasets generated from different protocols and experimental designs (Supplementary Fig. 2a ). After", "role": "user" }, { "content": "A first-of-its-kind data analysis platform is enabling researchers to select the best tool for interpreting the overwhelming amounts of data generated by single-cell research. Accurately making sense of these datasets will help to explain the vital and varied roles cells play in health and disease. The platform, CellBench, was published today in Nature Methods. The freely accessible platform, which includes software and several gold standard datasets compares the performance of thousands of different single-cell analysis options, enabling researchers to identify the best method for the questions they wish to answer. The project was led by Associate Professor Matthew Ritchie and Mr Luyi Tian from the Walter and Eliza Hall Institute of Medical Research, along with Dr. Kim-Anh Lê Cao and Mr Al J Abadi at the University of Melbourne. Making sense of mass data Much is still unknown about the trillions of cells in the human body. In the quest to better understand cells and the role they play in health and disease, a technique called single-cell sequencing has become a hot research field. Over the past five years there has been an explosion of new analysis tools for interpreting single-cell data. This has left researchers with hundreds of options to choose between in the challenging task of interpreting large and complex biological datasets. Associate Professor Ritchie said the ability to identify and define each cell and its activity was invaluable for preventing and treating disease. \"The challenge is that a colossal amount of complex biological data is generated from single-cell studies. Our platform offers a solution to this by helping researchers accurately and efficiently make sense of the overwhelming amounts of information from their studies,\" he said. Ensuring gold standard analysis Dr. Kim-Anh Lê Cao said choosing the right data analysis tool is crucial for avoiding misleading results or the incorrect biological interpretation of data. \"One of the biggest challenges we face in this area of research is our ability to compare the efficiency of all analysis methods currently available. This can only be done if we have good data like CellBench to do this benchmarking. \"CellBench is already enabling researchers to choose the right analysis method and generate meaningful and accurate conclusions from their data,\" she said. Associate Professor Ritchie said it was clear there was a real demand for a single-cell analysis benchmarking tool because the team's study had already been downloaded more than 3,000 times on a preprint server for biology called bioRxiv and that their data had already featured in five other research studies. \"We're really pleased to see the rapid uptake and use of the data from our CellBench project,\" he said. The researchers hope the platform will serve to encourage more rigorous testing, leading to better quality data analysis methods being developed in the future. Ultimately, their hope is that the platform will assist researchers in making new discoveries and developing more effective therapies for the major health challenges of our 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 Single cell RNA-sequencing (scRNA-seq) technology has undergone rapid development in recent years, leading to an explosion in the number of tailored data analysis methods. However, the current lack of gold-standard benchmark datasets makes it difficult for researchers to systematically compare the performance of the many methods available. Here, we generated a realistic benchmark experiment that included single cells and admixtures of cells or RNA to create ‘pseudo cells’ from up to five distinct cancer cell lines. In total, 14 datasets were generated using both droplet and plate-based scRNA-seq protocols. We compared 3,913 combinations of data analysis methods for tasks ranging from normalization and imputation to clustering, trajectory analysis and data integration. Evaluation revealed pipelines suited to different types of data for different tasks. Our data and analysis provide a comprehensive framework for benchmarking most common scRNA-seq analysis steps. Main The rapid development of computational methods for single cell gene expression analysis has created a need for systematic benchmarking to understand the strengths and weaknesses of different algorithms. The performances of particular single cell RNA-seq analysis methods have been evaluated for tasks including normalization 1 , feature selection 2 , differential gene expression analysis 3 , clustering 4 , 5 and trajectory analysis 6 . These studies compare methods using either experimental data where cell type labels are available or simulated datasets. Such ground truth is, however, imperfect, with simulations relying on assumptions that may not reflect the true nature of scRNA-seq data, and, because they focus on specific tasks, these studies lack a complete picture of performance at the pipeline level. Considering the heterogeneity between scRNA-seq datasets in terms of the number of clusters (cell types or states) and the presence of various technical artifacts, we set out to design a realistic gold-standard scRNA-seq control experiment that combines ground truth with varying levels of biological complexity. Two strategies are commonly employed to create gold-standard gene expression datasets. The first, which has been widely adopted in scRNA-seq studies 7 , uses small collections of exogenous spike-in controls such as External RNA Control Consortium spike-ins (ERCCs) 8 that vary in expression in a predictable way. The second involves either the dilution of RNA from a reference sample or mixing of RNA or cells from two or more samples to induce systematic genome-wide changes. An early example from Brennecke et al. 9 involved a dilution series to explore the sensitivity of the Smart-seq protocol. Grün et al. 10 generated a benchmark dataset using single mouse embryonic stem cells together with bulk RNA extracted from the same population, diluted to single cell equivalent amounts to quantify biological and technical variability. A limitation of these experiments is their lack of biological heterogeneity, which makes them less useful for comparing analysis methods. Mixture designs, in which RNA or cells are mixed in different proportions to generate biological heterogeneity with in-built truth, have been successfully used to benchmark microarray 11 , RNA-seq 12 and scRNA-seq 13 data. To combine the strengths of these approaches, we designed a series of experiments using mixtures of either cells or RNA from up to five cancer cell lines that included a dilution series to simulate variations in the RNA content of different cells, as well as ERCC spike-in controls where possible. Data were generated across four single cell technology platforms. Our scRNA-seq mixology design simulates varying levels of biological noise, with sample sizes varying from around 200 cells to 4,000 cells and known population structure to allow benchmarking of different analysis tools. We specifically evaluated combinations of methods for normalization and imputation, clustering, trajectory analysis and data integration. The methods chosen for each task use different algorithms and are mostly implemented in R 14 and Bioconductor 15 for convenience. Results scRNA-seq mixology provides ground truth for benchmarking Our scRNA-seq benchmarking experiment spanned two plate-based (CEL-seq2 and SORT-seq) and two droplet-based (10× Chromium and Drop-seq) protocols and involved three different experimental designs with replicates, yielding 14 datasets in total (Supplementary Table 1 ). The experimental design involved single cells, mixtures of single cells and mixtures of RNA from up to five human lung adenocarcinoma cell lines ( Methods , Fig. 1a,b and Supplementary Fig. 1 ). Fig. 1: Overview of the scRNA-seq mixology experimental design and benchmark analysis. a , b , The benchmark experimental design involving single cells ( a ) and ‘pseudo cells’ ( b ). c , PCA plots from representative datasets for each design (normalized using scran) highlight the structure present in each experiment. The percentage of variation explained by each principal component (PC) is included in the respective axis labels, and sample sizes are indicated by n . d , Workflow for benchmarking different analysis tasks using the CellBench R package. Full size image The three designs incorporate ground truth in various ways. For the single cell datasets (Fig. 1a ), the ground truth is the cell line identity that can be determined for each cell on the basis of known genetic variation ( Methods ). For the ‘pseudo cell’ mixture datasets, the known composition of cells and RNA serves as ground truth. The ‘RNA mixture’ and ‘cell mixture’ datasets (Fig. 1b and Supplementary Fig. 1 ) contain 7 and 34 groups, respectively, that give a continuous structure. Moreover, the RNA mixture dataset contains technical replication and a dilution series (Fig. 1b ), which is ideal for benchmarking normalization and imputation methods that are intended to deal with such technical variability. The data characteristics and analysis tasks that each design is suited to benchmark are summarized in Supplementary Table 2 . By comparing a range of quality control metrics collected across datasets using scPipe 16 , we observed that data from all platforms were of consistently high quality in terms of their exon mapping rates and the total unique molecular identifier (UMI) counts per cell (Supplementary Fig. 2 ). We found substantial differences in the percentage of reads mapping to intron regions in datasets generated from different protocols and experimental designs (Supplementary Fig. 2a ). After<|im_end|> <|im_start|>assistant A first-of-its-kind data analysis platform is enabling researchers to select the best tool for interpreting the overwhelming amounts of data generated by single-cell research. Accurately making sense of these datasets will help to explain the vital and varied roles cells play in health and disease. The platform, CellBench, was published today in Nature Methods. The freely accessible platform, which includes software and several gold standard datasets compares the performance of thousands of different single-cell analysis options, enabling researchers to identify the best method for the questions they wish to answer. The project was led by Associate Professor Matthew Ritchie and Mr Luyi Tian from the Walter and Eliza Hall Institute of Medical Research, along with Dr. Kim-Anh Lê Cao and Mr Al J Abadi at the University of Melbourne. Making sense of mass data Much is still unknown about the trillions of cells in the human body. In the quest to better understand cells and the role they play in health and disease, a technique called single-cell sequencing has become a hot research field. Over the past five years there has been an explosion of new analysis tools for interpreting single-cell data. This has left researchers with hundreds of options to choose between in the challenging task of interpreting large and complex biological datasets. Associate Professor Ritchie said the ability to identify and define each cell and its activity was invaluable for preventing and treating disease. "The challenge is that a colossal amount of complex biological data is generated from single-cell studies. Our platform offers a solution to this by helping researchers accurately and efficiently make sense of the overwhelming amounts of information from their studies," he said. Ensuring gold standard analysis Dr. Kim-Anh Lê Cao said choosing the right data analysis tool is crucial for avoiding misleading results or the incorrect biological interpretation of data. "One of the biggest challenges we face in this area of research is our ability to compare the efficiency of all analysis methods currently available. This can only be done if we have good data like CellBench to do this benchmarking. "CellBench is already enabling researchers to choose the right analysis method and generate meaningful and accurate conclusions from their data," she said. Associate Professor Ritchie said it was clear there was a real demand for a single-cell analysis benchmarking tool because the team's study had already been downloaded more than 3,000 times on a preprint server for biology called bioRxiv and that their data had already featured in five other research studies. "We're really pleased to see the rapid uptake and use of the data from our CellBench project," he said. The researchers hope the platform will serve to encourage more rigorous testing, leading to better quality data analysis methods being developed in the future. Ultimately, their hope is that the platform will assist researchers in making new discoveries and developing more effective therapies for the major health challenges of our time. <|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 LEAP and TEACCH represent two comprehensive treatment models (CTMs) that have been widely used across several decades to educate young children with autism spectrum disorders. The purpose of this quasi-experimental study was to compare high fidelity LEAP (n = 22) and TEACCH (n = 25) classrooms to each other and a control condition (n = 28), in which teachers in high quality special education programs used non-model-specific practices. A total of 198 children were included in data analysis. Across conditions, children’s performances improved over time. This study raises issues of the replication of effects for CTMs, and whether having access to a high quality special education program is as beneficial as access to a specific CTM. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Providing children with autism spectrum disorders (ASD) access to high quality, early intervention results in improved developmental performance (Boyd et al. 2010 ; Dawson et al. 2010 ; Kasari et al. 2006 ; Landa et al. 2011 ; Stahmer and Ingersoll 2004 ). However, debate persists over which treatment approach(es) to use to attain that ultimate goal. Presently, there are two overarching categories of intervention approaches from which practitioners or families can select treatments—focused interventions or comprehensive treatment models (CTMs). Focused interventions refer to treatments that are typically shorter in duration and target discrete skills (e.g., communication or challenging behavior). CTMs employ focused intervention practices that are organized around a central theoretical or conceptual framework, are typically used with children for a longer period of time, and target multiple developmental domains (Odom et al. 2010a ). Most of the empirical support for autism-specific, evidence-based practices comes from the focused intervention literature (Odom et al. 2003 , 2010b ). For instance, Odom et al. ( 2010a ) identified 30 CTMs for individuals with ASD, and one of the resounding and surprising findings of their literature review was the lack of empirical evidence for the majority of CTMs. The most notable exception is the research related to the Lovaas Young Autism Project, with multiple studies (Eikeseth et al. 2002 ; Lovaas 1987 ; Smith et al. 2000 ) as well as meta-analyses (Eldevik et al. 2009 ; Reichow and Wolery 2009 ) demonstrating evidence for this CTM. However, the research on this model has been primarily conducted in clinic- or home-based settings. Like most children, those with ASD spend a great deal of their time in schools; therefore, it is of critical importance to establish the efficacy of school-based CTMs. Increasingly, leaders in the field are calling for comparative efficacy studies to determine the relative effects of treatments when compared to each other (Dingfelder and Mandell 2011 ; Sox and Greenfield 2009 ). Two CTMs that have a long history in the field, are used frequently, and have different conceptual frameworks are LEAP (Learning Experiences and Alternative Program for Preschoolers and their Parents) and the TEACCH Autism Program. The purpose of this study was to examine the relative effects of LEAP and TEACCH school-based CTMs when compared to each other and a control condition consisting of non-model-specific (NMS) special education programs. TEACCH and LEAP are two long-standing CTMs, their origins for individuals with ASD being traced to the 1970s and 1980s, respectively. Yet, the philosophical tenets as well as actual practices underlying these CTMs represent quite divergent approaches to educating children with ASD. TEACCH bases its conceptual orientation in cognitive-social learning theory and subscribes to a “culture of autism,” in which accommodations such as visual schedules and work systems (Hume and Odom 2007 ; Hume et al. 2012 ) are made to the environment versus the individual to promote the child’s engagement and learning (Mesibov and Shea 2010 ; Mesibov et al. 2005 ). While it is not a stated principle of TEACCH, in the context of schools, this has often manifested itself in children with ASD being educated together in classrooms that are separate from their typically developing peers. In contrast, LEAP bases its treatment approach on a blend of applied behavior analysis (ABA) as well as common tenets of early childhood education (ECE) (Strain and Hoyson 2000 ; Strain et al. 1985 ) with a goal of reducing children’s characteristics of autism that interfere with their learning opportunities. The LEAP model uses an inclusive education approach whereby children with ASD are taught alongside typically developing, same-aged peer confederates who become agents of social instruction and intervention. Thus, LEAP and TEACCH provide “naturally occurring” contrasts with the former model using an inclusive education approach and the latter primarily implemented in classroom settings emphasizing more structured, adult-led learning opportunities. Yet the evidence base for LEAP and TEACCH, at least until recently (see Strain and Bovey 2011 , for research on LEAP), has been relatively sparse and there still are no existing studies that have directly compared the two approaches. With TEACCH, some evidence exists which documents positive effects of this CTM when implemented in home (Ozonoff and Cathcart 1998 ), residential (Panerai et al. 1998 , 2002 ), and school settings with older students (Panerai et al. 2009 ). However, we are aware of only one study in which TEACCH was evaluated as a school-based CTM for preschool-aged children with ASD (Tsang et al. 2007 ). In this quasi-experimental study, which was conducted in China, Tsang et al. assigned a total of 34 preschool-aged children to a TEACCH (N = 18) or a services-as-usual (N = 16) control condition. Tsang and colleagues found some improvements in favor of the experimental group in certain developmental skills (e.g., fine and gross motor) but no group differences in the areas of socialization or communication. Obviously, issues of culture as well as differences in the education system limit any generalization of the study’s findings to children with ASD served in the US public school system. In contrast, a recent large-scale efficacy study of the LEAP model demonstrated positive effects in the domains of socialization, cognition, language and challenging behavior for preschool-aged children with", "role": "user" }, { "content": "Researchers at the University of North Carolina at Chapel Hill have found that preschoolers with Autism Spectrum Disorder (ASD) who receive high-quality early intervention benefit developmentally regardless of the treatment model used—a surprising result that may have important implications for special-education programs and school classrooms across the country. \"This is the first study designed to compare long-standing comprehensive treatment models for young children with ASD,\" said Brian Boyd, a fellow at UNC's Frank Porter Graham Child Development Institute (FPG) and one of the study's co-principal investigators. Boyd also is an assistant professor in occupational science and occupational therapy in UNC's School of Medicine. \"We know that more children are being diagnosed with ASD each year, and that it can cost an estimated $3.2 million to treat each child over a lifetime. Understanding that a child can benefit from a high-quality program, rather than a specialized program, may help reduce those costs by decreasing the need for teachers and other school practitioners to be trained to deliver multiple specialized services,\" Boyd said. He stressed it remains important to ensure educators are trained to provide high-quality programs that meet the special behavioral, communication and other needs of children with ASD. Previous research has shown that when children with ASD have access to early intervention via treatment programs, they improve developmentally. Until now, however, debate has persisted over which approach to use, said Boyd. The study appeared in the June issue of Journal of Autism and Developmental Disorders. Two frequently used comprehensive treatment models have a long history: LEAP (Learning Experiences and Alternative Program for Preschoolers and their Parents) and TEACCH (now known only by its acronym). FPG's study examined the relative effects of the LEAP and TEACCH school-based comprehensive treatment models when compared to each other and to special-education programs that do not use a specific model. The multisite study took place only in high-quality classrooms and enrolled 74 teachers and 198 3- to 5-year-olds in public school districts. The study found that children made gains over the school year regardless of the classroom's use of LEAP, TEACCH or no specific comprehensive treatment model. \"Each group of children showed significant positive change in autism severity, communication and fine- motor skills,\" said Kara Hume, FPG scientist and co-author. \"No statistically significant differences were found among models, which challenged our initial expectations—and likely the field's.\" \"This study may shift the field's thinking about comprehensive treatment models designed for young children with ASD,\" said co-author Samuel L. Odom, FPG's director and the study's principal investigator. \"Perhaps it's not the unique features of the models that most contribute to child gains but the common features of the models that most influence child growth.\" ", "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 LEAP and TEACCH represent two comprehensive treatment models (CTMs) that have been widely used across several decades to educate young children with autism spectrum disorders. The purpose of this quasi-experimental study was to compare high fidelity LEAP (n = 22) and TEACCH (n = 25) classrooms to each other and a control condition (n = 28), in which teachers in high quality special education programs used non-model-specific practices. A total of 198 children were included in data analysis. Across conditions, children’s performances improved over time. This study raises issues of the replication of effects for CTMs, and whether having access to a high quality special education program is as beneficial as access to a specific CTM. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Providing children with autism spectrum disorders (ASD) access to high quality, early intervention results in improved developmental performance (Boyd et al. 2010 ; Dawson et al. 2010 ; Kasari et al. 2006 ; Landa et al. 2011 ; Stahmer and Ingersoll 2004 ). However, debate persists over which treatment approach(es) to use to attain that ultimate goal. Presently, there are two overarching categories of intervention approaches from which practitioners or families can select treatments—focused interventions or comprehensive treatment models (CTMs). Focused interventions refer to treatments that are typically shorter in duration and target discrete skills (e.g., communication or challenging behavior). CTMs employ focused intervention practices that are organized around a central theoretical or conceptual framework, are typically used with children for a longer period of time, and target multiple developmental domains (Odom et al. 2010a ). Most of the empirical support for autism-specific, evidence-based practices comes from the focused intervention literature (Odom et al. 2003 , 2010b ). For instance, Odom et al. ( 2010a ) identified 30 CTMs for individuals with ASD, and one of the resounding and surprising findings of their literature review was the lack of empirical evidence for the majority of CTMs. The most notable exception is the research related to the Lovaas Young Autism Project, with multiple studies (Eikeseth et al. 2002 ; Lovaas 1987 ; Smith et al. 2000 ) as well as meta-analyses (Eldevik et al. 2009 ; Reichow and Wolery 2009 ) demonstrating evidence for this CTM. However, the research on this model has been primarily conducted in clinic- or home-based settings. Like most children, those with ASD spend a great deal of their time in schools; therefore, it is of critical importance to establish the efficacy of school-based CTMs. Increasingly, leaders in the field are calling for comparative efficacy studies to determine the relative effects of treatments when compared to each other (Dingfelder and Mandell 2011 ; Sox and Greenfield 2009 ). Two CTMs that have a long history in the field, are used frequently, and have different conceptual frameworks are LEAP (Learning Experiences and Alternative Program for Preschoolers and their Parents) and the TEACCH Autism Program. The purpose of this study was to examine the relative effects of LEAP and TEACCH school-based CTMs when compared to each other and a control condition consisting of non-model-specific (NMS) special education programs. TEACCH and LEAP are two long-standing CTMs, their origins for individuals with ASD being traced to the 1970s and 1980s, respectively. Yet, the philosophical tenets as well as actual practices underlying these CTMs represent quite divergent approaches to educating children with ASD. TEACCH bases its conceptual orientation in cognitive-social learning theory and subscribes to a “culture of autism,” in which accommodations such as visual schedules and work systems (Hume and Odom 2007 ; Hume et al. 2012 ) are made to the environment versus the individual to promote the child’s engagement and learning (Mesibov and Shea 2010 ; Mesibov et al. 2005 ). While it is not a stated principle of TEACCH, in the context of schools, this has often manifested itself in children with ASD being educated together in classrooms that are separate from their typically developing peers. In contrast, LEAP bases its treatment approach on a blend of applied behavior analysis (ABA) as well as common tenets of early childhood education (ECE) (Strain and Hoyson 2000 ; Strain et al. 1985 ) with a goal of reducing children’s characteristics of autism that interfere with their learning opportunities. The LEAP model uses an inclusive education approach whereby children with ASD are taught alongside typically developing, same-aged peer confederates who become agents of social instruction and intervention. Thus, LEAP and TEACCH provide “naturally occurring” contrasts with the former model using an inclusive education approach and the latter primarily implemented in classroom settings emphasizing more structured, adult-led learning opportunities. Yet the evidence base for LEAP and TEACCH, at least until recently (see Strain and Bovey 2011 , for research on LEAP), has been relatively sparse and there still are no existing studies that have directly compared the two approaches. With TEACCH, some evidence exists which documents positive effects of this CTM when implemented in home (Ozonoff and Cathcart 1998 ), residential (Panerai et al. 1998 , 2002 ), and school settings with older students (Panerai et al. 2009 ). However, we are aware of only one study in which TEACCH was evaluated as a school-based CTM for preschool-aged children with ASD (Tsang et al. 2007 ). In this quasi-experimental study, which was conducted in China, Tsang et al. assigned a total of 34 preschool-aged children to a TEACCH (N = 18) or a services-as-usual (N = 16) control condition. Tsang and colleagues found some improvements in favor of the experimental group in certain developmental skills (e.g., fine and gross motor) but no group differences in the areas of socialization or communication. Obviously, issues of culture as well as differences in the education system limit any generalization of the study’s findings to children with ASD served in the US public school system. In contrast, a recent large-scale efficacy study of the LEAP model demonstrated positive effects in the domains of socialization, cognition, language and challenging behavior for preschool-aged children with<|im_end|> <|im_start|>assistant Researchers at the University of North Carolina at Chapel Hill have found that preschoolers with Autism Spectrum Disorder (ASD) who receive high-quality early intervention benefit developmentally regardless of the treatment model used—a surprising result that may have important implications for special-education programs and school classrooms across the country. "This is the first study designed to compare long-standing comprehensive treatment models for young children with ASD," said Brian Boyd, a fellow at UNC's Frank Porter Graham Child Development Institute (FPG) and one of the study's co-principal investigators. Boyd also is an assistant professor in occupational science and occupational therapy in UNC's School of Medicine. "We know that more children are being diagnosed with ASD each year, and that it can cost an estimated $3.2 million to treat each child over a lifetime. Understanding that a child can benefit from a high-quality program, rather than a specialized program, may help reduce those costs by decreasing the need for teachers and other school practitioners to be trained to deliver multiple specialized services," Boyd said. He stressed it remains important to ensure educators are trained to provide high-quality programs that meet the special behavioral, communication and other needs of children with ASD. Previous research has shown that when children with ASD have access to early intervention via treatment programs, they improve developmentally. Until now, however, debate has persisted over which approach to use, said Boyd. The study appeared in the June issue of Journal of Autism and Developmental Disorders. Two frequently used comprehensive treatment models have a long history: LEAP (Learning Experiences and Alternative Program for Preschoolers and their Parents) and TEACCH (now known only by its acronym). FPG's study examined the relative effects of the LEAP and TEACCH school-based comprehensive treatment models when compared to each other and to special-education programs that do not use a specific model. The multisite study took place only in high-quality classrooms and enrolled 74 teachers and 198 3- to 5-year-olds in public school districts. The study found that children made gains over the school year regardless of the classroom's use of LEAP, TEACCH or no specific comprehensive treatment model. "Each group of children showed significant positive change in autism severity, communication and fine- motor skills," said Kara Hume, FPG scientist and co-author. "No statistically significant differences were found among models, which challenged our initial expectations—and likely the field's." "This study may shift the field's thinking about comprehensive treatment models designed for young children with ASD," said co-author Samuel L. Odom, FPG's director and the study's principal investigator. "Perhaps it's not the unique features of the models that most contribute to child gains but the common features of the models that most influence child growth." <|im_end|>

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1,957

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In the classic transistor, the number of electric charge carriers—and thus the electrical conductivity—is precisely controlled by external voltage, providing electrical switching capability. This simple but powerful feature is essential for information processing technology, and also provides a platform for fundamental physics research 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . As the number of charges essentially determines the electronic phase of a condensed-matter system, transistor operation enables reversible and isothermal changes in the system’s state, as successfully demonstrated in electric-field-induced ferromagnetism 2 , 3 , 4 and superconductivity 5 , 6 , 7 , 8 , 9 , 10 . However, this effect of the electric field is limited to a channel thickness of nanometres or less, owing to the presence of Thomas–Fermi screening. Here we show that this conventional picture does not apply to a class of materials characterized by inherent collective interactions between electrons and the crystal lattice. We prepared metal–insulator–semiconductor field-effect transistors based on vanadium dioxide—a strongly correlated material with a thermally driven, first-order metal–insulator transition well above room temperature 17 , 18 , 19 , 20 , 21 , 22 , 23 —and found that electrostatic charging at a surface drives all the previously localized charge carriers in the bulk material into motion, leading to the emergence of a three-dimensional metallic ground state. This non-local switching of the electronic state is achieved by applying a voltage of only about one volt. In a voltage-sweep measurement, the first-order nature of the metal–insulator transition provides a non-volatile memory effect, which is operable at room temperature. Our results demonstrate a conceptually new field-effect device, extending the concept of electric-field control to macroscopic phase control. Main Metal–insulator–semiconductor field-effect transistors (MISFETs) work by using the electrostatic charging effect of a capacitor: the number of charges at the topmost surface of a channel material is linearly and reversibly tuned by an external electric field, giving rise to isothermal electrical switching functions. In contrast, a MISFET based on a strongly correlated material (a ‘Mott transistor’) could have a different operation mechanism 11 , in which a small number of electrostatically doped carriers drive all pre-existing localized electrons in the material to be mobile. This occurs by the reduction of the effective Coulomb repulsion energy, as has recently been demonstrated in an FET based on an organic Mott insulator 12 . Several attempts have been made at Mott transistor operation, using correlated oxides such as perovskite manganite 13 , 14 or nickelate 15 , 16 ; yet none has succeeded in inducing a metallic ground state by an electric field. In this study, we focus on a classical simple oxide, VO 2 . A striking feature of this compound arises from its first-order metal–insulator transition (MIT) 17 , 18 , 19 , 20 ; above the transition temperature ( T MI ), the system behaves as a half-filled metal with a 3 d 1 ( S = 1/2) state, but below T MI , the system adopts the insulating ground state, at which the resistance changes abruptly by several orders of magnitude. The microscopic origin of this transition is the dimerization of V 4+ ions along the c -axis direction, and resulting lattice transformation from the high-temperature tetragonal (rutile) phase to the low-temperature monoclinic phase, where 3 d electrons are localized on V sites to form the spin singlet state ( Fig. 1a ). The driving mechanism of the MIT is still debated, but both strong electron correlation (Mott–Hubbard transition) and electron–lattice coupling (Peierls transition) are generally thought to be important 21 , 22 , 23 . Figure 1: The first-order metal–insulator transition in VO 2 . a , Schematic drawings of the thermally driven first-order metal–insulator transition (MIT) in VO 2 . b , Temperature dependence of the resistivity of strained 10-nm and relaxed 70-nm VO 2 films grown on TiO 2 substrates. c , Schematic of an electric-double-layer transistor (EDLT) based on VO 2 , potentially enabling electrical switching of the MIT between the metallic tetragonal phase and the insulating monoclinic phase. PowerPoint slide Full size image The T MI of VO 2 , in bulk (or relaxed thin-film) form, is well above room temperature ( T ∼ 340 K), and can be varied across a wide range by electron-doping 24 , or by epitaxial strain in thin films 25 . Figure 1b shows the typical temperature dependence of the resistivity ( ρ xx ) of relaxed and strained VO 2 films, with a clear thermal hysteresis originating from the first-order nature of the transition. The T MI is high enough to be of practical use; accordingly, many efforts have been devoted to external control of the MIT in VO 2 using, for example, photon irradiation 26 , 27 or current excitation 28 . The use of a purely electrostatic effect in an FET geometry has also been examined, owing to its great importance for practical applications, but so far, only small changes in the resistance and/or the T MI have been achieved 28 , 29 , 30 , possibly because of insufficient electric field available with conventional solid dielectrics. To maximize the electron density attainable by applying a static electric field, we have used a recently developed electric-double-layer transistor (EDLT) technique involving an organic ionic liquid, which enables us to tune the surface charge density up to 10 15 cm −2 (refs 3 , 8–10 , 15 , 16 ). We fabricated micro-patterned EDLTs with c -axis-oriented VO 2 epitaxial thin films 24 in a side-gate configuration (see Methods Summary and Supplementary Information section A for details.) Figure 1c shows a conceptual schematic of the device operation based on a VO 2 -EDLT, in which electronic and structural phase transitions are expected to occur simultaneously owing to collective electron–lattice interactions, as demonstrated in femtosecond pump–probe experiments 26 , 27 . To see the effect of", "role": "user" }, { "content": "The transistor is the ultimate on-off switch. When a voltage is applied to the surface of a semiconductor, current flows; when the voltage is reversed, current is blocked. Researchers have tried for decades to replicate these effects in transition metal oxides by using a voltage to convert the material from an insulator to a metal, but the induced change only occurs within a few atomic layers of the surface. Now, Masaki Nakano and colleagues at the RIKEN Advanced Science Institute in Wako have discovered that applying a voltage to a vanadium dioxide (VO2) film several tens of nanometers thick converts the entire film from an insulator to a metal. The findings point to the specific material properties needed to make such devices work. They may also lead to new types of 'smart' technology. The electronic properties of transition metal oxides can be tuned by changing their chemical composition or temperature. For example, VO2 is an insulator at room temperature, but heating it or replacing a small fraction of the vanadium atoms with tungsten (an electron donor) causes a phase transition where the vanadium ions, which are paired up at low temperature, unfasten into a different crystal structure in which electrons are mobile. In principle, applying a positive voltage to the surface of an insulating VO2 film can accomplish the same effect by inducing electrons to the surface, making this region metallic. Researchers have assumed that this charging effect would be limited to a few atomic layers just below the surface because the excess of electrons cancels out the applied electric field (an effect called screening). But Nakano and his colleagues found that the excess electrons were enough to 'trigger' the crystal structure change associated with metallic behavior (Fig. 1). \"The surface lattice distortion propagates through the entire film, followed by an electronic phase transition inside the bulk region,\" he says. The voltage-induced transition decreases VO2's resistance by a factor of 100. The team is actively seeking other materials like VO2, as well as technological applications. One is a heat switch. Since temperature determines if VO2 is a metal or an insulator, it also determines the frequency of light the material absorbs. VO2-coated glass could therefore act as a 'smart window', passing or blocking infrared light depending on the temperature outside. \"Normally, this switching temperature is fixed,\" says Nakano. \"Our device adds electrical switching functionality to a smart window, which is very promising for energy-saving applications.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In the classic transistor, the number of electric charge carriers—and thus the electrical conductivity—is precisely controlled by external voltage, providing electrical switching capability. This simple but powerful feature is essential for information processing technology, and also provides a platform for fundamental physics research 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . As the number of charges essentially determines the electronic phase of a condensed-matter system, transistor operation enables reversible and isothermal changes in the system’s state, as successfully demonstrated in electric-field-induced ferromagnetism 2 , 3 , 4 and superconductivity 5 , 6 , 7 , 8 , 9 , 10 . However, this effect of the electric field is limited to a channel thickness of nanometres or less, owing to the presence of Thomas–Fermi screening. Here we show that this conventional picture does not apply to a class of materials characterized by inherent collective interactions between electrons and the crystal lattice. We prepared metal–insulator–semiconductor field-effect transistors based on vanadium dioxide—a strongly correlated material with a thermally driven, first-order metal–insulator transition well above room temperature 17 , 18 , 19 , 20 , 21 , 22 , 23 —and found that electrostatic charging at a surface drives all the previously localized charge carriers in the bulk material into motion, leading to the emergence of a three-dimensional metallic ground state. This non-local switching of the electronic state is achieved by applying a voltage of only about one volt. In a voltage-sweep measurement, the first-order nature of the metal–insulator transition provides a non-volatile memory effect, which is operable at room temperature. Our results demonstrate a conceptually new field-effect device, extending the concept of electric-field control to macroscopic phase control. Main Metal–insulator–semiconductor field-effect transistors (MISFETs) work by using the electrostatic charging effect of a capacitor: the number of charges at the topmost surface of a channel material is linearly and reversibly tuned by an external electric field, giving rise to isothermal electrical switching functions. In contrast, a MISFET based on a strongly correlated material (a ‘Mott transistor’) could have a different operation mechanism 11 , in which a small number of electrostatically doped carriers drive all pre-existing localized electrons in the material to be mobile. This occurs by the reduction of the effective Coulomb repulsion energy, as has recently been demonstrated in an FET based on an organic Mott insulator 12 . Several attempts have been made at Mott transistor operation, using correlated oxides such as perovskite manganite 13 , 14 or nickelate 15 , 16 ; yet none has succeeded in inducing a metallic ground state by an electric field. In this study, we focus on a classical simple oxide, VO 2 . A striking feature of this compound arises from its first-order metal–insulator transition (MIT) 17 , 18 , 19 , 20 ; above the transition temperature ( T MI ), the system behaves as a half-filled metal with a 3 d 1 ( S = 1/2) state, but below T MI , the system adopts the insulating ground state, at which the resistance changes abruptly by several orders of magnitude. The microscopic origin of this transition is the dimerization of V 4+ ions along the c -axis direction, and resulting lattice transformation from the high-temperature tetragonal (rutile) phase to the low-temperature monoclinic phase, where 3 d electrons are localized on V sites to form the spin singlet state ( Fig. 1a ). The driving mechanism of the MIT is still debated, but both strong electron correlation (Mott–Hubbard transition) and electron–lattice coupling (Peierls transition) are generally thought to be important 21 , 22 , 23 . Figure 1: The first-order metal–insulator transition in VO 2 . a , Schematic drawings of the thermally driven first-order metal–insulator transition (MIT) in VO 2 . b , Temperature dependence of the resistivity of strained 10-nm and relaxed 70-nm VO 2 films grown on TiO 2 substrates. c , Schematic of an electric-double-layer transistor (EDLT) based on VO 2 , potentially enabling electrical switching of the MIT between the metallic tetragonal phase and the insulating monoclinic phase. PowerPoint slide Full size image The T MI of VO 2 , in bulk (or relaxed thin-film) form, is well above room temperature ( T ∼ 340 K), and can be varied across a wide range by electron-doping 24 , or by epitaxial strain in thin films 25 . Figure 1b shows the typical temperature dependence of the resistivity ( ρ xx ) of relaxed and strained VO 2 films, with a clear thermal hysteresis originating from the first-order nature of the transition. The T MI is high enough to be of practical use; accordingly, many efforts have been devoted to external control of the MIT in VO 2 using, for example, photon irradiation 26 , 27 or current excitation 28 . The use of a purely electrostatic effect in an FET geometry has also been examined, owing to its great importance for practical applications, but so far, only small changes in the resistance and/or the T MI have been achieved 28 , 29 , 30 , possibly because of insufficient electric field available with conventional solid dielectrics. To maximize the electron density attainable by applying a static electric field, we have used a recently developed electric-double-layer transistor (EDLT) technique involving an organic ionic liquid, which enables us to tune the surface charge density up to 10 15 cm −2 (refs 3 , 8–10 , 15 , 16 ). We fabricated micro-patterned EDLTs with c -axis-oriented VO 2 epitaxial thin films 24 in a side-gate configuration (see Methods Summary and Supplementary Information section A for details.) Figure 1c shows a conceptual schematic of the device operation based on a VO 2 -EDLT, in which electronic and structural phase transitions are expected to occur simultaneously owing to collective electron–lattice interactions, as demonstrated in femtosecond pump–probe experiments 26 , 27 . To see the effect of<|im_end|> <|im_start|>assistant The transistor is the ultimate on-off switch. When a voltage is applied to the surface of a semiconductor, current flows; when the voltage is reversed, current is blocked. Researchers have tried for decades to replicate these effects in transition metal oxides by using a voltage to convert the material from an insulator to a metal, but the induced change only occurs within a few atomic layers of the surface. Now, Masaki Nakano and colleagues at the RIKEN Advanced Science Institute in Wako have discovered that applying a voltage to a vanadium dioxide (VO2) film several tens of nanometers thick converts the entire film from an insulator to a metal. The findings point to the specific material properties needed to make such devices work. They may also lead to new types of 'smart' technology. The electronic properties of transition metal oxides can be tuned by changing their chemical composition or temperature. For example, VO2 is an insulator at room temperature, but heating it or replacing a small fraction of the vanadium atoms with tungsten (an electron donor) causes a phase transition where the vanadium ions, which are paired up at low temperature, unfasten into a different crystal structure in which electrons are mobile. In principle, applying a positive voltage to the surface of an insulating VO2 film can accomplish the same effect by inducing electrons to the surface, making this region metallic. Researchers have assumed that this charging effect would be limited to a few atomic layers just below the surface because the excess of electrons cancels out the applied electric field (an effect called screening). But Nakano and his colleagues found that the excess electrons were enough to 'trigger' the crystal structure change associated with metallic behavior (Fig. 1). "The surface lattice distortion propagates through the entire film, followed by an electronic phase transition inside the bulk region," he says. The voltage-induced transition decreases VO2's resistance by a factor of 100. The team is actively seeking other materials like VO2, as well as technological applications. One is a heat switch. Since temperature determines if VO2 is a metal or an insulator, it also determines the frequency of light the material absorbs. VO2-coated glass could therefore act as a 'smart window', passing or blocking infrared light depending on the temperature outside. "Normally, this switching temperature is fixed," says Nakano. "Our device adds electrical switching functionality to a smart window, which is very promising for energy-saving applications." <|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 Frequent social interactions, proximity to conspecifics, and group density are main drivers of infections and parasite transmissions. However, recent theoretical and empirical studies suggest that the health benefits of sociality and group living can outweigh the costs of infection and help social individuals fight infections or increase their infection-related tolerance level. Here, we combine the advantage of studying artificially created social work groups with different demographic compositions with free-range feeding and social behaviours in semi-captive Asian elephants ( Elephas maximus ), employed in timber logging in Myanmar. We examine the link between gastro-intestinal nematode load (strongyles and Strongyloides spp . ), estimated by faecal egg counts, and three different aspects of an elephant’s social world: individual solitary behaviour, work group size, and work group sex ratio. Controlling for sex, age, origin, time since last deworming treatment, year, human sampler bias, and individual identity, we found that infection by nematodes ranged from 0 to 2720 eggs/g between and within 26 male and 45 female elephants over the 4-year study period. However, such variation was not linked to any investigated measures of sociality in either males or females. Our findings highlight the need for finer-scale studies, establishing how sociality is limited by, mitigates, or protects against infection in different ecological contexts, to fully understand the mechanisms underlying these pathways. Significance statement Being social involves not only benefits, such as improved health, but also costs, including increased risk of parasitism and infectious disease. We studied the relationship between and three different sociality measures—solitary behaviour, group size, and the proportion of females to males within a group—and infection by gut nematodes (roundworms), using a unique study system of semi-captive working Asian elephants. Our system allows for observing how infection is linked to sociality measures across different social frameworks. We found that none of our social measures was associated with nematode infection in the studied elephants. Our results therefore suggest that here infection is not a large cost to group living, that it can be alleviated by the benefits of increased sociality, or that there are weak infection–sociality associations present which could not be captured and thus require finer-scale measures than those studied here. Overall, more studies are needed from a diverse range of systems that investigate specific aspects of social infection dynamics. Working on a manuscript? Avoid the common mistakes Introduction In social species, group living and social behaviours can promote reproduction and survival through numerous pathways, including increased offspring survival, increased access to potential mates and resources, protection from predation, and increased health via social support (reviewed in Cantor et al. 2021 ). However, the same mechanisms that offer these benefits—frequent social interactions, close proximity to conspecifics, and group density—also present costs, such as increased competition and conflict (Alexander 1974 ; Krause and Ruxton 2002 ) and risk of disease and parasite infection (McEwen 2012 ; Hawley et al. 2021 ). Different components of sociality affect parasite load in various ways. For instance, group size is positively related to intensities of non-mobile parasites, but negatively to intensities of mobile parasites (Patterson and Ruckstuhl 2013 ). When investigating host–parasite interactions, it is important to consider the three main components of disease, called the disease triangle: the host, the environment, and the pathogen/parasite (Scholthof 2007 ). Individual host characteristics such as age (Lynsdale et al. 2020 ) and sex (Hillegass et al. 2008 ), as well as behaviour and social status (Hawley et al. 2011 ; Keiser et al. 2016 ), can relate to transmission and infection risk. In addition, external factors, such as season or weather conditions, influence sickness behaviour and infection dynamics for environmentally transmitted parasites (Owen-Ashley and Wingfield 2006 ; Rödel and Starkloff 2014 ). Finally, parasites can influence host social behaviour to promote transmission of parasites from the infected to new hosts (Moore 2002 ; Hawley et al. 2021 ). The “classic” view of social–infection dynamics is that sociality is a main driver of infections (Rifkin et al. 2012 ; Patterson and Ruckstuhl 2013 ). This view has substantial support within the literature: Higher numbers of social contacts and frequent social interaction are generally linked to increased infection (Loehle 1995 ; Schmid-Hempel 2017 ), and the reverse for increasingly solitary behaviour. A recent review on over 200 associations between individual social network measures and parasite load has shown that, within individuals, social behaviour leads to an increased risk of parasite infection (Briard and Ezenwa 2021 ). However, a growing body of theoretical and empirical studies challenges the assumption that infection risk and social behaviour or group size always co-vary positively (Kappeler et al. 2015 ; Ezenwa et al. 2016 ). This “enhanced” view suggests that the health benefits of sociality and group living can outweigh the costs of infection and help social individuals resist or tolerate parasites and other infectious disease (Ezenwa et al. 2016 ). Several studies have demonstrated that positive social interactions can be related to lower infection risk and lower infestation with gastrointestinal parasites. Social support by known group members and strong social bonds with opposite-sex partners can reduce parasite infestation (Rödel and Starkloff 2014 ; Müller-Klein et al. 2019 ), though this effect can depend on various factors such as environmental conditions or pathogen-specific transmission routes (Balasubramaniam et al. 2016 ). The encounter-dilution effect describes the potentially positive effects of group living with regard to costs of parasite infection (Mooring and Hart 1992 ), where group members experience protection from parasites by diluting the risk of being preyed on by ectoparasites or vector species (Mooring and Hart 1992 ; Patterson and Ruckstuhl 2013 ). Additionally, social living per se can reduce the negative effects of parasite infestation and larger group size can mitigate the costs of infection with ectoparasites for group members (Almberg et al. 2015 ). Furthermore, the positive effects of group size have been proposed and described for endoparasites and other infectious diseases. Although re-infection with gastrointestinal nematodes is more likely for individuals in larger social groups, infected individuals benefit from larger intake of", "role": "user" }, { "content": "An international team of scientists found that sociality is not linked to intestinal nematode infection in Asian elephants. The researchers looked at loneliness and characteristics of the elephants' social groups and found no differences in infection levels. Social behaviors are common in group-living mammals, and it is often thought that sociality and group density are main drivers of infections and parasite transmissions. Recent research however suggests that the health benefits of sociality and group living can outweigh the costs of sociality and help social individuals to fight infections. \"Asian elephants are one of the world's largest and longest-living terrestrial mammals, and have a very complex social life. However, studying sociality and parasite infection in Asian elephants in the wild is very difficult, if not impossible, due to the dense forests they live in and large roaming distances,\" says Postdoctoral Researcher and one of the two lead authors of the study Martin Seltmann from the University of Turku. The researchers investigated three different aspects related to Asian elephants' social world: socialness vs loneliness, size of the group, and living in single vs mixed sex groups. \"We studied these characteristics in 71 Asian timber elephants living in their natural habitat in Myanmar. These elephants work in the timber industry, where they pull and push logs out of the forest. This is a unique research environment and population that allows us to study many elephants living in their natural environment, but at the same time have detailed information about their social lives and infection dynamics,\" says postdoctoral researcher Carly Lynsdale from the University of Helsinki, the other lead author of the study. These elephants are semi-captive and their access to social partners is somewhat limited by the working conditions. Their social behaviors do not correspond exactly to the social behaviors of truly wild elephants. However, spending much of their time free in their natural habitat allows the timber elephants to express many of their natural behaviors, which is often not the case in fully captive systems such as zoos. Elephants and their handlers on their way to work. Credit: Carly Lynsdale Parasite infection is strongly affected by anti-parasitic treatment Every elephant works together with an elephant handler (mahout), and this relationship can last a lifetime. Therefore, a handler knows very well about his elephant's behaviors and is able to give detailed information on its social interactions with other elephants. From 2014 to 2018, the scientists asked the handlers if their elephants have friends or if they prefer to stay alone. Furthermore, the team assessed the size of the elephants work groups as a measure of social group size and the number of males and females within the work group. In addition, the researchers counted the eggs of intestinal parasites (nematodes, or round worms) in fresh fecal samples. These egg counts are a reliable estimate of the extent of parasite infection. \"We found that veterinarian treatment against parasite infection affects levels of parasite infection, meaning the more recent the treatment took place, the lower the parasite infection. This is of course not surprising and is confirmed by past research, and it is good for the health of these elephants to see that this treatment works. When controlling for this effect, we did not find any relationship between our social measures and parasite infection,\" says Seltmann. An egg of intestinal parasite commonly found in elephant feces. Credit: Carly Lynsdale Though this study did not find evidence to support an association between nematode infection and sociality, there is increasing support for the view that costs of infection may in fact be minimized through socially-promoted resistance and/or tolerance pathways. The reasons underlying the absence of associations between infection and social behavior in elephants remain largely obscure. However, according to the scientists, the research adds to a bigger picture of how social relationships can help prevent or increase the risk of infection in group-living animals. \"Timber elephants live in mobile working units without strong competition or dominance hierarchies, and this may instead mean that intestinal parasites either do not present large sociality costs for these elephants or that these costs are mitigated by the social health benefits of group living more than in other host taxa. Additionally, there might have been weak infection—sociality associations present in this system that could not be captured by the study's design,\" says Lynsdale. The findings of this new study highlight the need for finer-scale studies, establishing how sociality is limited by, mitigates, or protects against infection in different ecological contexts, to fully understand the mechanisms underlying these pathways. The article was published in the topical collection \"Sociality and Disease\" in the journal Behavioral Ecology and Sociobiology. ", "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 Frequent social interactions, proximity to conspecifics, and group density are main drivers of infections and parasite transmissions. However, recent theoretical and empirical studies suggest that the health benefits of sociality and group living can outweigh the costs of infection and help social individuals fight infections or increase their infection-related tolerance level. Here, we combine the advantage of studying artificially created social work groups with different demographic compositions with free-range feeding and social behaviours in semi-captive Asian elephants ( Elephas maximus ), employed in timber logging in Myanmar. We examine the link between gastro-intestinal nematode load (strongyles and Strongyloides spp . ), estimated by faecal egg counts, and three different aspects of an elephant’s social world: individual solitary behaviour, work group size, and work group sex ratio. Controlling for sex, age, origin, time since last deworming treatment, year, human sampler bias, and individual identity, we found that infection by nematodes ranged from 0 to 2720 eggs/g between and within 26 male and 45 female elephants over the 4-year study period. However, such variation was not linked to any investigated measures of sociality in either males or females. Our findings highlight the need for finer-scale studies, establishing how sociality is limited by, mitigates, or protects against infection in different ecological contexts, to fully understand the mechanisms underlying these pathways. Significance statement Being social involves not only benefits, such as improved health, but also costs, including increased risk of parasitism and infectious disease. We studied the relationship between and three different sociality measures—solitary behaviour, group size, and the proportion of females to males within a group—and infection by gut nematodes (roundworms), using a unique study system of semi-captive working Asian elephants. Our system allows for observing how infection is linked to sociality measures across different social frameworks. We found that none of our social measures was associated with nematode infection in the studied elephants. Our results therefore suggest that here infection is not a large cost to group living, that it can be alleviated by the benefits of increased sociality, or that there are weak infection–sociality associations present which could not be captured and thus require finer-scale measures than those studied here. Overall, more studies are needed from a diverse range of systems that investigate specific aspects of social infection dynamics. Working on a manuscript? Avoid the common mistakes Introduction In social species, group living and social behaviours can promote reproduction and survival through numerous pathways, including increased offspring survival, increased access to potential mates and resources, protection from predation, and increased health via social support (reviewed in Cantor et al. 2021 ). However, the same mechanisms that offer these benefits—frequent social interactions, close proximity to conspecifics, and group density—also present costs, such as increased competition and conflict (Alexander 1974 ; Krause and Ruxton 2002 ) and risk of disease and parasite infection (McEwen 2012 ; Hawley et al. 2021 ). Different components of sociality affect parasite load in various ways. For instance, group size is positively related to intensities of non-mobile parasites, but negatively to intensities of mobile parasites (Patterson and Ruckstuhl 2013 ). When investigating host–parasite interactions, it is important to consider the three main components of disease, called the disease triangle: the host, the environment, and the pathogen/parasite (Scholthof 2007 ). Individual host characteristics such as age (Lynsdale et al. 2020 ) and sex (Hillegass et al. 2008 ), as well as behaviour and social status (Hawley et al. 2011 ; Keiser et al. 2016 ), can relate to transmission and infection risk. In addition, external factors, such as season or weather conditions, influence sickness behaviour and infection dynamics for environmentally transmitted parasites (Owen-Ashley and Wingfield 2006 ; Rödel and Starkloff 2014 ). Finally, parasites can influence host social behaviour to promote transmission of parasites from the infected to new hosts (Moore 2002 ; Hawley et al. 2021 ). The “classic” view of social–infection dynamics is that sociality is a main driver of infections (Rifkin et al. 2012 ; Patterson and Ruckstuhl 2013 ). This view has substantial support within the literature: Higher numbers of social contacts and frequent social interaction are generally linked to increased infection (Loehle 1995 ; Schmid-Hempel 2017 ), and the reverse for increasingly solitary behaviour. A recent review on over 200 associations between individual social network measures and parasite load has shown that, within individuals, social behaviour leads to an increased risk of parasite infection (Briard and Ezenwa 2021 ). However, a growing body of theoretical and empirical studies challenges the assumption that infection risk and social behaviour or group size always co-vary positively (Kappeler et al. 2015 ; Ezenwa et al. 2016 ). This “enhanced” view suggests that the health benefits of sociality and group living can outweigh the costs of infection and help social individuals resist or tolerate parasites and other infectious disease (Ezenwa et al. 2016 ). Several studies have demonstrated that positive social interactions can be related to lower infection risk and lower infestation with gastrointestinal parasites. Social support by known group members and strong social bonds with opposite-sex partners can reduce parasite infestation (Rödel and Starkloff 2014 ; Müller-Klein et al. 2019 ), though this effect can depend on various factors such as environmental conditions or pathogen-specific transmission routes (Balasubramaniam et al. 2016 ). The encounter-dilution effect describes the potentially positive effects of group living with regard to costs of parasite infection (Mooring and Hart 1992 ), where group members experience protection from parasites by diluting the risk of being preyed on by ectoparasites or vector species (Mooring and Hart 1992 ; Patterson and Ruckstuhl 2013 ). Additionally, social living per se can reduce the negative effects of parasite infestation and larger group size can mitigate the costs of infection with ectoparasites for group members (Almberg et al. 2015 ). Furthermore, the positive effects of group size have been proposed and described for endoparasites and other infectious diseases. Although re-infection with gastrointestinal nematodes is more likely for individuals in larger social groups, infected individuals benefit from larger intake of<|im_end|> <|im_start|>assistant An international team of scientists found that sociality is not linked to intestinal nematode infection in Asian elephants. The researchers looked at loneliness and characteristics of the elephants' social groups and found no differences in infection levels. Social behaviors are common in group-living mammals, and it is often thought that sociality and group density are main drivers of infections and parasite transmissions. Recent research however suggests that the health benefits of sociality and group living can outweigh the costs of sociality and help social individuals to fight infections. "Asian elephants are one of the world's largest and longest-living terrestrial mammals, and have a very complex social life. However, studying sociality and parasite infection in Asian elephants in the wild is very difficult, if not impossible, due to the dense forests they live in and large roaming distances," says Postdoctoral Researcher and one of the two lead authors of the study Martin Seltmann from the University of Turku. The researchers investigated three different aspects related to Asian elephants' social world: socialness vs loneliness, size of the group, and living in single vs mixed sex groups. "We studied these characteristics in 71 Asian timber elephants living in their natural habitat in Myanmar. These elephants work in the timber industry, where they pull and push logs out of the forest. This is a unique research environment and population that allows us to study many elephants living in their natural environment, but at the same time have detailed information about their social lives and infection dynamics," says postdoctoral researcher Carly Lynsdale from the University of Helsinki, the other lead author of the study. These elephants are semi-captive and their access to social partners is somewhat limited by the working conditions. Their social behaviors do not correspond exactly to the social behaviors of truly wild elephants. However, spending much of their time free in their natural habitat allows the timber elephants to express many of their natural behaviors, which is often not the case in fully captive systems such as zoos. Elephants and their handlers on their way to work. Credit: Carly Lynsdale Parasite infection is strongly affected by anti-parasitic treatment Every elephant works together with an elephant handler (mahout), and this relationship can last a lifetime. Therefore, a handler knows very well about his elephant's behaviors and is able to give detailed information on its social interactions with other elephants. From 2014 to 2018, the scientists asked the handlers if their elephants have friends or if they prefer to stay alone. Furthermore, the team assessed the size of the elephants work groups as a measure of social group size and the number of males and females within the work group. In addition, the researchers counted the eggs of intestinal parasites (nematodes, or round worms) in fresh fecal samples. These egg counts are a reliable estimate of the extent of parasite infection. "We found that veterinarian treatment against parasite infection affects levels of parasite infection, meaning the more recent the treatment took place, the lower the parasite infection. This is of course not surprising and is confirmed by past research, and it is good for the health of these elephants to see that this treatment works. When controlling for this effect, we did not find any relationship between our social measures and parasite infection," says Seltmann. An egg of intestinal parasite commonly found in elephant feces. Credit: Carly Lynsdale Though this study did not find evidence to support an association between nematode infection and sociality, there is increasing support for the view that costs of infection may in fact be minimized through socially-promoted resistance and/or tolerance pathways. The reasons underlying the absence of associations between infection and social behavior in elephants remain largely obscure. However, according to the scientists, the research adds to a bigger picture of how social relationships can help prevent or increase the risk of infection in group-living animals. "Timber elephants live in mobile working units without strong competition or dominance hierarchies, and this may instead mean that intestinal parasites either do not present large sociality costs for these elephants or that these costs are mitigated by the social health benefits of group living more than in other host taxa. Additionally, there might have been weak infection—sociality associations present in this system that could not be captured by the study's design," says Lynsdale. The findings of this new study highlight the need for finer-scale studies, establishing how sociality is limited by, mitigates, or protects against infection in different ecological contexts, to fully understand the mechanisms underlying these pathways. The article was published in the topical collection "Sociality and Disease" in the journal Behavioral Ecology and Sociobiology. <|im_end|>

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2,324

[ { "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 mobile phones continue to rapidly expand around the world, marketers are seeking to better understand the impact these devices have on consumer outcomes. One common but understudied area is how mobile phones may influence in-store behaviors. Although prior research has investigated the many shopping related activities consumers undertake on their phones, it is still estimated that nearly half of all in-store mobile phone use is unrelated to the shopping task. Therefore, this paper examines the impact of shopping-unrelated mobile phone use, a frequent but understudied phenomenon, on consumers’ ability to accurately manage in-store shopping plans. Using both field and experimental data, we demonstrate that shopping-unrelated mobile phone use negatively affects consumers’ ability to accurately carry out in-store shopping plans and is associated with an increase in unplanned purchasing. Furthermore, we find that consumers who are highly dependent upon mobile phones tend to be the most at risk of deviating from a shopping plan while engaging in shopping-unrelated mobile phone use. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes The proliferation of mobile phones has significantly altered the world in which we live. With their continual growth, mobile phones have found their way into almost all aspects of everyday life, from our sleep hygiene (e.g., the Sleepbot app) and dietary habits (e.g., the MyFitnessPal app) to our entertainment choices (e.g., mobile gaming, videos, and social media) and work practices (e.g., email, calendar apps). Today, it is estimated that 46% of all Americans check their phones at least 25 times per day (Deloitte 2017 ) with the average user spending approximately 3 h and 45 min daily on mobile phone use (Brustein 2014 ). While the rapid growth of mobile phones has changed our lives, marketers are struggling to fully understand the impact of mobile phones on consumer outcomes (Oddenino 2015 ). An understudied area is the role that mobile phones play in impacting in-store behaviors. It has been well documented that consumers use their mobile phones in retail environments with 93% of consumers admitting to using their phones while out shopping (Deloitte 2017 ). While prior work focuses on the many shopping related activities consumers complete on their phones (Google 2013 ; Nielsen 2015 ; Skrovan 2017 ), recent research notes that almost half of all in-store mobile phone use is unrelated to the shopping task (Martin 2016 ). Despite the prevalence of mobile phone use in stores, there is a dearth of knowledge on how these devices impact consumers. Therefore, this paper examines the impact of shopping-unrelated mobile phone use, a frequent but understudied phenomenon, on consumers’ ability to accurately carry out in-store shopping plans. Shopping-unrelated mobile phone use occurs when a consumer uses her mobile phone in a manner that is not directly related to the focal shopping trip. This includes engaging in private conversations, sending personal text messages, checking emails, surfing the Internet, listening to music, and playing games. Additionally, we are interested in adherence to shopping plans as this is an important consideration for marketers and retailers’ success. It is imperative for marketers to have a better understanding of factors associated with consumers’ successful implementation and deviations from their planned shopping behavior (Iyer and Ahlawat 1987 ). While consumers have always had to contend with some forms of distraction (e.g. listening to in-store music or shopping with others), it is critical to single out in-store phone use for at least two reasons. First, as we have noted before, mobile phones have become inextricably immersed into modern life, with some arguing that these devices have become necessities rather than luxury goods (Dreyfuss 2017 ). Given their ubiquity, mobile phones are quickly becoming the principal distractor for many consumers (Poppick 2016 ). Second, work in other fields suggests that mobile phones offer a unique form of interruption. For example, research on distracted driving notes that mobile phone conversations impact individuals differently in comparison to in-person conversations (Drews et al. 2008 ). Therefore, we investigate shopping-unrelated mobile phone use as a factor that can dramatically impact adherence to shopping plans. More specifically, in this paper we are interested in the following research questions related to shopping-unrelated mobile phone use: (1) Does shopping-unrelated mobile phone use impact consumers’ ability to accurately carry out in-store shopping plans? (2) Are some consumers more susceptible to shopping errors while engaging in shopping-unrelated mobile phone use? (3) Does intermittent as opposed to continuous shopping-unrelated mobile phone use impact consumers’ ability to carry-out shopping plans? Before beginning our focal investigation, we conducted a preliminary investigation to examine shoppers’ perceptions of positive and negative outcomes tied to shopping-unrelated mobile phone use. We utilized a critical incident technique (Flanagan 1954 ; Gremler 2004 ; Keaveney 1995 ) in which direct recollections and stories were collected from consumers regarding their in-store mobile phone use. We recruited fifty-four participants and asked them to think about a time they used their mobile phone in a shopping-unrelated manner in a retail setting. After recalling the situation in detail, we asked respondents to compare the outcomes of their described shopping trip with a similar trip in which they did not use their phones. Results showed that participants disagreed that they forgot more items than they normally would have if not using their phone, disagreed that they made more unplanned purchases than they normally would have had they not been using their phone, and disagreed that they lacked sufficient mental resources to focus on their shopping. Finally, participants agreed that there were no significant drawbacks to using their phones during the shopping trip. Footnote 1 These results suggest that consumers perceive little impact of shopping-unrelated mobile phone use on their ability to accurately complete their shopping trip. Building off of consumers’ general beliefs about in-store mobile phone use, the goal of this paper is to investigate shopping-unrelated phone use and examine if these devices are really as innocuous as consumers believe. We study the consequences of shopping-unrelated mobile phone use on shoppers’ ability to accurately", "role": "user" }, { "content": "In-store mobile phone use that is unrelated to shopping may be associated with an increase in unplanned purchases, according to a study published in the Journal of the Academy of Marketing Science. Dr. Michael Sciandra at Fairfield University, US and colleagues investigated the impact of mobile phone use on in-store shopping behaviour. They found that those who used mobile phones in store for purposes unrelated to shopping, such as making phone calls, sending text messages, checking emails or listening to music, were more likely to make unplanned purchases and forget items they had planned to buy. The authors observed this effect even when phones were only used for part of the shopping trip, suggesting that in-store mobile phone use may consume attentional resources even after the phone is put away. Dr. Michael Sciandra, corresponding author of the study said: \"Our finding that phone use that is unrelated to shopping negatively affects shopping behaviour was in stark contrast to beliefs held by consumers. The vast majority of shoppers we asked thought that mobile phones did not have any negative effect.\" The researchers asked 231 participants to complete a simulated shopping task. While the participants either refrained from using their phone, or used it for an unrelated task either constantly (simulated phone call) or intermittently, they were shown a first person perspective video of someone grocery shopping. The participants were given a shopping list of items and were asked to compare the list to the products the person in the video placed in the cart, or picked up and put down. The participants' mobile phone dependence was assessed via self-report. The authors found that consumers who are highly dependent upon mobile phones, characterized by excessive use of and reliance on the device, were the most at risk of deviating from a shopping plan while engaging in shopping-unrelated mobile phone use. Dr. Sciandra said: \"Mobile phones are quickly becoming the principal distractor for many consumers and they offer a unique form of interruption. Our findings may influence consumers' attitudes towards mobile phone use while shopping and persuade them to reflect on how these devices impact our lives, both positively and negatively.\" The authors note that part of the study is based on a simulated shopping experience only, therefore caution should be taken when applying these conclusions from this to real life settings. ", "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 mobile phones continue to rapidly expand around the world, marketers are seeking to better understand the impact these devices have on consumer outcomes. One common but understudied area is how mobile phones may influence in-store behaviors. Although prior research has investigated the many shopping related activities consumers undertake on their phones, it is still estimated that nearly half of all in-store mobile phone use is unrelated to the shopping task. Therefore, this paper examines the impact of shopping-unrelated mobile phone use, a frequent but understudied phenomenon, on consumers’ ability to accurately manage in-store shopping plans. Using both field and experimental data, we demonstrate that shopping-unrelated mobile phone use negatively affects consumers’ ability to accurately carry out in-store shopping plans and is associated with an increase in unplanned purchasing. Furthermore, we find that consumers who are highly dependent upon mobile phones tend to be the most at risk of deviating from a shopping plan while engaging in shopping-unrelated mobile phone use. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes The proliferation of mobile phones has significantly altered the world in which we live. With their continual growth, mobile phones have found their way into almost all aspects of everyday life, from our sleep hygiene (e.g., the Sleepbot app) and dietary habits (e.g., the MyFitnessPal app) to our entertainment choices (e.g., mobile gaming, videos, and social media) and work practices (e.g., email, calendar apps). Today, it is estimated that 46% of all Americans check their phones at least 25 times per day (Deloitte 2017 ) with the average user spending approximately 3 h and 45 min daily on mobile phone use (Brustein 2014 ). While the rapid growth of mobile phones has changed our lives, marketers are struggling to fully understand the impact of mobile phones on consumer outcomes (Oddenino 2015 ). An understudied area is the role that mobile phones play in impacting in-store behaviors. It has been well documented that consumers use their mobile phones in retail environments with 93% of consumers admitting to using their phones while out shopping (Deloitte 2017 ). While prior work focuses on the many shopping related activities consumers complete on their phones (Google 2013 ; Nielsen 2015 ; Skrovan 2017 ), recent research notes that almost half of all in-store mobile phone use is unrelated to the shopping task (Martin 2016 ). Despite the prevalence of mobile phone use in stores, there is a dearth of knowledge on how these devices impact consumers. Therefore, this paper examines the impact of shopping-unrelated mobile phone use, a frequent but understudied phenomenon, on consumers’ ability to accurately carry out in-store shopping plans. Shopping-unrelated mobile phone use occurs when a consumer uses her mobile phone in a manner that is not directly related to the focal shopping trip. This includes engaging in private conversations, sending personal text messages, checking emails, surfing the Internet, listening to music, and playing games. Additionally, we are interested in adherence to shopping plans as this is an important consideration for marketers and retailers’ success. It is imperative for marketers to have a better understanding of factors associated with consumers’ successful implementation and deviations from their planned shopping behavior (Iyer and Ahlawat 1987 ). While consumers have always had to contend with some forms of distraction (e.g. listening to in-store music or shopping with others), it is critical to single out in-store phone use for at least two reasons. First, as we have noted before, mobile phones have become inextricably immersed into modern life, with some arguing that these devices have become necessities rather than luxury goods (Dreyfuss 2017 ). Given their ubiquity, mobile phones are quickly becoming the principal distractor for many consumers (Poppick 2016 ). Second, work in other fields suggests that mobile phones offer a unique form of interruption. For example, research on distracted driving notes that mobile phone conversations impact individuals differently in comparison to in-person conversations (Drews et al. 2008 ). Therefore, we investigate shopping-unrelated mobile phone use as a factor that can dramatically impact adherence to shopping plans. More specifically, in this paper we are interested in the following research questions related to shopping-unrelated mobile phone use: (1) Does shopping-unrelated mobile phone use impact consumers’ ability to accurately carry out in-store shopping plans? (2) Are some consumers more susceptible to shopping errors while engaging in shopping-unrelated mobile phone use? (3) Does intermittent as opposed to continuous shopping-unrelated mobile phone use impact consumers’ ability to carry-out shopping plans? Before beginning our focal investigation, we conducted a preliminary investigation to examine shoppers’ perceptions of positive and negative outcomes tied to shopping-unrelated mobile phone use. We utilized a critical incident technique (Flanagan 1954 ; Gremler 2004 ; Keaveney 1995 ) in which direct recollections and stories were collected from consumers regarding their in-store mobile phone use. We recruited fifty-four participants and asked them to think about a time they used their mobile phone in a shopping-unrelated manner in a retail setting. After recalling the situation in detail, we asked respondents to compare the outcomes of their described shopping trip with a similar trip in which they did not use their phones. Results showed that participants disagreed that they forgot more items than they normally would have if not using their phone, disagreed that they made more unplanned purchases than they normally would have had they not been using their phone, and disagreed that they lacked sufficient mental resources to focus on their shopping. Finally, participants agreed that there were no significant drawbacks to using their phones during the shopping trip. Footnote 1 These results suggest that consumers perceive little impact of shopping-unrelated mobile phone use on their ability to accurately complete their shopping trip. Building off of consumers’ general beliefs about in-store mobile phone use, the goal of this paper is to investigate shopping-unrelated phone use and examine if these devices are really as innocuous as consumers believe. We study the consequences of shopping-unrelated mobile phone use on shoppers’ ability to accurately<|im_end|> <|im_start|>assistant In-store mobile phone use that is unrelated to shopping may be associated with an increase in unplanned purchases, according to a study published in the Journal of the Academy of Marketing Science. Dr. Michael Sciandra at Fairfield University, US and colleagues investigated the impact of mobile phone use on in-store shopping behaviour. They found that those who used mobile phones in store for purposes unrelated to shopping, such as making phone calls, sending text messages, checking emails or listening to music, were more likely to make unplanned purchases and forget items they had planned to buy. The authors observed this effect even when phones were only used for part of the shopping trip, suggesting that in-store mobile phone use may consume attentional resources even after the phone is put away. Dr. Michael Sciandra, corresponding author of the study said: "Our finding that phone use that is unrelated to shopping negatively affects shopping behaviour was in stark contrast to beliefs held by consumers. The vast majority of shoppers we asked thought that mobile phones did not have any negative effect." The researchers asked 231 participants to complete a simulated shopping task. While the participants either refrained from using their phone, or used it for an unrelated task either constantly (simulated phone call) or intermittently, they were shown a first person perspective video of someone grocery shopping. The participants were given a shopping list of items and were asked to compare the list to the products the person in the video placed in the cart, or picked up and put down. The participants' mobile phone dependence was assessed via self-report. The authors found that consumers who are highly dependent upon mobile phones, characterized by excessive use of and reliance on the device, were the most at risk of deviating from a shopping plan while engaging in shopping-unrelated mobile phone use. Dr. Sciandra said: "Mobile phones are quickly becoming the principal distractor for many consumers and they offer a unique form of interruption. Our findings may influence consumers' attitudes towards mobile phone use while shopping and persuade them to reflect on how these devices impact our lives, both positively and negatively." The authors note that part of the study is based on a simulated shopping experience only, therefore caution should be taken when applying these conclusions from this to real life settings. <|im_end|>

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1,737

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In the absence of antibiotic-mediated selection, sensitive bacteria are expected to displace their resistant counterparts if resistance genes are costly. However, many resistance genes persist for long periods in the absence of antibiotics. Horizontal gene transfer (primarily conjugation) could explain this persistence, but it has been suggested that very high conjugation rates would be required. Here, we show that common conjugal plasmids, even when costly, are indeed transferred at sufficiently high rates to be maintained in the absence of antibiotics in Escherichia coli . The notion is applicable to nine plasmids from six major incompatibility groups and mixed populations carrying multiple plasmids. These results suggest that reducing antibiotic use alone is likely insufficient for reversing resistance. Therefore, combining conjugation inhibition and promoting plasmid loss would be an effective strategy to limit conjugation-assisted persistence of antibiotic resistance. Introduction Eliminating antibiotic use is an appealing strategy to promote resistance reversal, or the elimination of resistant bacteria by displacing them with their sensitive counterparts 1 , 2 , 3 (Fig. 1 a). Indeed, resistance genes often carry a fitness cost, giving the sensitive strains a growth advantage 4 , 5 , 6 . In the absence of selection for antibiotic resistance, competition between the two populations would presumably eliminate the resistant strain over time 5 , 7 . However, despite its conceptual simplicity, this approach has been largely unsuccessful 8 , 9 , 10 . Several factors can enable the persistence of resistance in the absence of selection. For instance, co-selection could propagate genetically linked resistance genes 11 , 12 . Also, compensatory evolution ameliorating fitness cost can reduce plasmid burden 4 , 13 , 14 . Fig. 1 Conditions for plasmid persistence and elimination. a The concept of resistance reversal. A population initially consists of a mixture of sensitive (blue) and resistant (orange with plasmid) cells. In the presence of antibiotics (± indicates presence or absence of [A] antibiotic concentration), resistant cells are selected for. In the absence of antibiotics, as long as the plasmid imposes a fitness cost, then over a sufficiently long time the resistant cells will be presumably outcompeted, effectively reversing resistance. b Modeling plasmid dynamics in a single species ( S ). The plasmid-free population, S 0 , acquires the plasmid through conjugation at a rate constant \$\\eta _{\\mathrm{C}}\$ , becoming S 1 . S 1 reverts to S 0 through plasmid loss at a rate constant κ . S 0 grows at a rate proportional to S 1 ( μ 1 = μ , μ 0 = αμ ). The plasmid is costly when α > 1 and beneficial when α < 1. Both populations turnover at a constant dilution rate D . c Simulated fraction of S 1 as a function of α and \${\\eta _{\\rm C}}\$ after 5000 time units (~200 days). Fast conjugation can compensate for plasmid loss even if the plasmid carries a cost ( α > 1). A greater \${\\eta _{\\rm C}}\$ is required to maintain the plasmid population as α increases. d Criterion for plasmid persistence. If \${\\eta _{\\rm C}}\$ > \${\\eta _{\\rm Crit}} = \\alpha \\left( {\\kappa + D} \\right) - D\$ , the plasmid will dominate (Eq. ( 1 )) Full size image Horizontal gene transfer (HGT) of plasmids, primarily through conjugation, has also been proposed as a mechanism for plasmid persistence 6 , 10 , 15 . Theoretical analysis suggests that a sufficiently fast transfer rate can compensate for fitness cost and plasmid loss 16 , 17 , 18 , although the extent to which conjugation-mediated maintenance of costly plasmids occurs in nature has been debated 16 , 17 , 19 , 20 , 21 , 22 . For example, it has been suggested that transfer efficiencies required to overcome reasonable estimates of fitness cost and plasmid loss are too high to be biologically realistic 19 , 20 , 21 , 22 . Also, the persistence of purely parasitic genetic elements is evolutionarily paradoxical. Overall, conjugation alone is usually not considered to be a dominant mechanism for maintaining plasmids 23 , 24 , 25 , although this is not always the case 26 , 27 . The fate of a plasmid is largely driven by the relative magnitude of its fitness cost and segregation error rate compared with that of its conjugation efficiency. Indeed, studies investigating conjugal plasmid dynamics in the absence of selection attribute plasmid persistence to fast conjugation rate, low/no fitness cost, or both 22 , 28 , 29 , 30 , 31 . Similarly, plasmid elimination is attributed to slow conjugation and/or high growth burden 22 , 32 , 33 . Different outcomes likely depend on underlying parameter differences between experimental systems due to different plasmids, conjugation machinery, and mating procedures, among others. Accurate quantification of all three processes should provide a general framework to reconcile diverse outcomes and establish the role of conjugation in promoting plasmid persistence. However, confounding measurements of conjugation and growth dynamics have prevented general conclusions 34 , 35 . For instance, a high segregation error rate could be obscured by a fast conjugation efficiency 36 . Also, parameters depend on a range of variables including the host strain 37 and growth conditions 32 , which complicates data interpretation. Past studies did not provide precise estimates for all three processes. In some cases, this is because reasonable parameter estimates from available data appear sufficient 22 , which is appropriate so long as the estimates are obtained from a relevant experimental framework. In others, experimental complexities prevent accurate quantification within the relevant context (e.g., in vitro growth estimates to evaluate bacterial dynamics in the mouse gut) 29 , 32 . Even when all parameters are measured, confounding factors were often not accounted for in the data interpretation. For example, in some cases quantification of the conjugation efficiency was carried out without eliminating the contribution from selection dynamics 32 , 33 . As a result, the extent to which conjugation contributes to plasmid maintenance remains inconclusive 6 , 23 , 24 ,", "role": "user" }, { "content": "Researchers have discovered that reducing the use of antibiotics will not be enough to reverse the growing prevalence of antibiotic resistance for some types of bacteria. Besides passing along the genes bestowing antibiotic resistance to their offspring, many bacteria can also swap genes amongst themselves through a process called conjugation. There has long been a debate, however, as to whether this process occurs fast enough to spread through a population that is not under attack by antibiotics. In a new study, researchers from Duke University believe they have found a definitive answer to that question. Through a series of experiments with bacteria capable of conjugation, they show that all of the bacteria tested share genes fast enough to maintain resistance. They also show, however, that there are ways to disrupt the process and reverse antibiotic resistance. The results appear online on Nov. 22 in the journal Nature Communications. \"The results came as a surprise to me when I first saw the data,\" said Lingchong You, the Paul Ruffin Scarborough Associate Professor of Engineering at Duke University and corresponding author on the paper. \"For all of the bacteria we tested, their conjugation rate is sufficiently fast that, even if you don't use antibiotics, the resistance can be maintained —even if the genes carry a high cost.\" Most resistance to antibiotics arises and spreads through natural selection. If a few lucky bacteria have genes that help them survive a round of antibiotics, they quickly parent the next generation and pass on those genes. Many of these genes, however, come at a cost. For example, a mutation may allow a bacterium to build a thicker membrane to survive a particular antibiotic, but that mutation might also make it more difficult for the cell to reproduce. Without the selective pressure of antibiotics killing off the competition, bacteria with this mutation should disappear over time. But when the genes responsible for resistance can also be swapped between cells, the equation gets more complicated. In favor of maintaining the resistance is the rate at which the genes are shared. Working against it is the previously mentioned biological cost of the genes, and the natural error rate in genes when they are passed on. This movie depicts the basic process of antibiotic resistance spreading through horizontal gene transfer. Two strains of bacteria are grown together for four hours. One strain appears red and carries resistance to one type of antibiotic, while the other carries mobile genes that appear green and provide resistance to another antibiotic. After four hours, both antibiotics are applied, and the red bacteria that have received the green resistance genes through horizontal gene transfer appear yellow and take over the culture because they are resistant to both antibiotics. Credit: Allison Lopatkin, Duke University \"There have been some studies on how critical conjugation is to maintaining resistance despite its cost, but there has been a lack of careful and well-defined experiments to come to definitive conclusions,\" said You. \"That's where Allison has made a central contribution. Her incredibly thorough measurements allow us to draw our conclusions with high confidence.\" Allison Lopatkin, a doctoral student in You's laboratory and first author of the paper, carefully measured the rate of conjugation and antibiotic resistance in pathogens for more than a month. The strains were obtained through a parallel project with Duke Health, in which You is trying to determine just how common conjugation is amongst pathogens. So far, You has found that more than 30 percent of the bacterial pathogens he has tested spread resistance through conjugation. And of those, nine were further tested by Lopatkin to see how well they would maintain their resistance in the abscence of antibiotics. \"Every single clinical strain we tested maintained its resistance through conjugation even without the selective pressure of antibiotics,\" said Lopatkin. The results indicate that—at least for bacteria that swap resistance genes—simply managing the amount of antibiotics being used will not turn the tide on the growing problem of resistance. To make any headway, according to You and Lopatkin, drugs will also be needed that both stop the sharing of genes and decrease the rate at which they are passed on through reproduction. Luckily, such drugs already exist, and there may be many more out there waiting to be discovered. \"We did the same experiments with one drug that is known to inhibit conjugation and another that encourages resistance genes to be lost,\" Lopatkin said. \"We found that without the presence of antibiotics we could reverse the bacteria's resistance in four of the pathogens we tested and could stop it from spreading in the rest.\" One of the drugs is a benign natural product and the second is an FDA-approved antipsychotic. While the team has filed a provisional patent for the use of the combination to reverse antibiotic resistance, they hope future work will reveal even better options. \"As a next step, we're interested in identifying additional chemicals that can fill these roles more effectively,\" said You. \"Historically, when researchers screened huge libraries for medicines, they focused on drugs that can kill the bacteria. But what our studies suggest is that there is a whole new universe where you can now screen for other functions, like the ability to block conjugation or to induce the loss of resistance genes. These chemicals, once proven safe, can serve as adjuvants of the standard antibiotic treatment, or they can be applied in an environmental setting as a way of generally managing of the spread of antibiotic resistance.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In the absence of antibiotic-mediated selection, sensitive bacteria are expected to displace their resistant counterparts if resistance genes are costly. However, many resistance genes persist for long periods in the absence of antibiotics. Horizontal gene transfer (primarily conjugation) could explain this persistence, but it has been suggested that very high conjugation rates would be required. Here, we show that common conjugal plasmids, even when costly, are indeed transferred at sufficiently high rates to be maintained in the absence of antibiotics in Escherichia coli . The notion is applicable to nine plasmids from six major incompatibility groups and mixed populations carrying multiple plasmids. These results suggest that reducing antibiotic use alone is likely insufficient for reversing resistance. Therefore, combining conjugation inhibition and promoting plasmid loss would be an effective strategy to limit conjugation-assisted persistence of antibiotic resistance. Introduction Eliminating antibiotic use is an appealing strategy to promote resistance reversal, or the elimination of resistant bacteria by displacing them with their sensitive counterparts 1 , 2 , 3 (Fig. 1 a). Indeed, resistance genes often carry a fitness cost, giving the sensitive strains a growth advantage 4 , 5 , 6 . In the absence of selection for antibiotic resistance, competition between the two populations would presumably eliminate the resistant strain over time 5 , 7 . However, despite its conceptual simplicity, this approach has been largely unsuccessful 8 , 9 , 10 . Several factors can enable the persistence of resistance in the absence of selection. For instance, co-selection could propagate genetically linked resistance genes 11 , 12 . Also, compensatory evolution ameliorating fitness cost can reduce plasmid burden 4 , 13 , 14 . Fig. 1 Conditions for plasmid persistence and elimination. a The concept of resistance reversal. A population initially consists of a mixture of sensitive (blue) and resistant (orange with plasmid) cells. In the presence of antibiotics (± indicates presence or absence of [A] antibiotic concentration), resistant cells are selected for. In the absence of antibiotics, as long as the plasmid imposes a fitness cost, then over a sufficiently long time the resistant cells will be presumably outcompeted, effectively reversing resistance. b Modeling plasmid dynamics in a single species ( S ). The plasmid-free population, S 0 , acquires the plasmid through conjugation at a rate constant $\eta _{\mathrm{C}}$ , becoming S 1 . S 1 reverts to S 0 through plasmid loss at a rate constant κ . S 0 grows at a rate proportional to S 1 ( μ 1 = μ , μ 0 = αμ ). The plasmid is costly when α > 1 and beneficial when α < 1. Both populations turnover at a constant dilution rate D . c Simulated fraction of S 1 as a function of α and ${\eta _{\rm C}}$ after 5000 time units (~200 days). Fast conjugation can compensate for plasmid loss even if the plasmid carries a cost ( α > 1). A greater ${\eta _{\rm C}}$ is required to maintain the plasmid population as α increases. d Criterion for plasmid persistence. If ${\eta _{\rm C}}$ > ${\eta _{\rm Crit}} = \alpha \left( {\kappa + D} \right) - D$ , the plasmid will dominate (Eq. ( 1 )) Full size image Horizontal gene transfer (HGT) of plasmids, primarily through conjugation, has also been proposed as a mechanism for plasmid persistence 6 , 10 , 15 . Theoretical analysis suggests that a sufficiently fast transfer rate can compensate for fitness cost and plasmid loss 16 , 17 , 18 , although the extent to which conjugation-mediated maintenance of costly plasmids occurs in nature has been debated 16 , 17 , 19 , 20 , 21 , 22 . For example, it has been suggested that transfer efficiencies required to overcome reasonable estimates of fitness cost and plasmid loss are too high to be biologically realistic 19 , 20 , 21 , 22 . Also, the persistence of purely parasitic genetic elements is evolutionarily paradoxical. Overall, conjugation alone is usually not considered to be a dominant mechanism for maintaining plasmids 23 , 24 , 25 , although this is not always the case 26 , 27 . The fate of a plasmid is largely driven by the relative magnitude of its fitness cost and segregation error rate compared with that of its conjugation efficiency. Indeed, studies investigating conjugal plasmid dynamics in the absence of selection attribute plasmid persistence to fast conjugation rate, low/no fitness cost, or both 22 , 28 , 29 , 30 , 31 . Similarly, plasmid elimination is attributed to slow conjugation and/or high growth burden 22 , 32 , 33 . Different outcomes likely depend on underlying parameter differences between experimental systems due to different plasmids, conjugation machinery, and mating procedures, among others. Accurate quantification of all three processes should provide a general framework to reconcile diverse outcomes and establish the role of conjugation in promoting plasmid persistence. However, confounding measurements of conjugation and growth dynamics have prevented general conclusions 34 , 35 . For instance, a high segregation error rate could be obscured by a fast conjugation efficiency 36 . Also, parameters depend on a range of variables including the host strain 37 and growth conditions 32 , which complicates data interpretation. Past studies did not provide precise estimates for all three processes. In some cases, this is because reasonable parameter estimates from available data appear sufficient 22 , which is appropriate so long as the estimates are obtained from a relevant experimental framework. In others, experimental complexities prevent accurate quantification within the relevant context (e.g., in vitro growth estimates to evaluate bacterial dynamics in the mouse gut) 29 , 32 . Even when all parameters are measured, confounding factors were often not accounted for in the data interpretation. For example, in some cases quantification of the conjugation efficiency was carried out without eliminating the contribution from selection dynamics 32 , 33 . As a result, the extent to which conjugation contributes to plasmid maintenance remains inconclusive 6 , 23 , 24 ,<|im_end|> <|im_start|>assistant Researchers have discovered that reducing the use of antibiotics will not be enough to reverse the growing prevalence of antibiotic resistance for some types of bacteria. Besides passing along the genes bestowing antibiotic resistance to their offspring, many bacteria can also swap genes amongst themselves through a process called conjugation. There has long been a debate, however, as to whether this process occurs fast enough to spread through a population that is not under attack by antibiotics. In a new study, researchers from Duke University believe they have found a definitive answer to that question. Through a series of experiments with bacteria capable of conjugation, they show that all of the bacteria tested share genes fast enough to maintain resistance. They also show, however, that there are ways to disrupt the process and reverse antibiotic resistance. The results appear online on Nov. 22 in the journal Nature Communications. "The results came as a surprise to me when I first saw the data," said Lingchong You, the Paul Ruffin Scarborough Associate Professor of Engineering at Duke University and corresponding author on the paper. "For all of the bacteria we tested, their conjugation rate is sufficiently fast that, even if you don't use antibiotics, the resistance can be maintained —even if the genes carry a high cost." Most resistance to antibiotics arises and spreads through natural selection. If a few lucky bacteria have genes that help them survive a round of antibiotics, they quickly parent the next generation and pass on those genes. Many of these genes, however, come at a cost. For example, a mutation may allow a bacterium to build a thicker membrane to survive a particular antibiotic, but that mutation might also make it more difficult for the cell to reproduce. Without the selective pressure of antibiotics killing off the competition, bacteria with this mutation should disappear over time. But when the genes responsible for resistance can also be swapped between cells, the equation gets more complicated. In favor of maintaining the resistance is the rate at which the genes are shared. Working against it is the previously mentioned biological cost of the genes, and the natural error rate in genes when they are passed on. This movie depicts the basic process of antibiotic resistance spreading through horizontal gene transfer. Two strains of bacteria are grown together for four hours. One strain appears red and carries resistance to one type of antibiotic, while the other carries mobile genes that appear green and provide resistance to another antibiotic. After four hours, both antibiotics are applied, and the red bacteria that have received the green resistance genes through horizontal gene transfer appear yellow and take over the culture because they are resistant to both antibiotics. Credit: Allison Lopatkin, Duke University "There have been some studies on how critical conjugation is to maintaining resistance despite its cost, but there has been a lack of careful and well-defined experiments to come to definitive conclusions," said You. "That's where Allison has made a central contribution. Her incredibly thorough measurements allow us to draw our conclusions with high confidence." Allison Lopatkin, a doctoral student in You's laboratory and first author of the paper, carefully measured the rate of conjugation and antibiotic resistance in pathogens for more than a month. The strains were obtained through a parallel project with Duke Health, in which You is trying to determine just how common conjugation is amongst pathogens. So far, You has found that more than 30 percent of the bacterial pathogens he has tested spread resistance through conjugation. And of those, nine were further tested by Lopatkin to see how well they would maintain their resistance in the abscence of antibiotics. "Every single clinical strain we tested maintained its resistance through conjugation even without the selective pressure of antibiotics," said Lopatkin. The results indicate that—at least for bacteria that swap resistance genes—simply managing the amount of antibiotics being used will not turn the tide on the growing problem of resistance. To make any headway, according to You and Lopatkin, drugs will also be needed that both stop the sharing of genes and decrease the rate at which they are passed on through reproduction. Luckily, such drugs already exist, and there may be many more out there waiting to be discovered. "We did the same experiments with one drug that is known to inhibit conjugation and another that encourages resistance genes to be lost," Lopatkin said. "We found that without the presence of antibiotics we could reverse the bacteria's resistance in four of the pathogens we tested and could stop it from spreading in the rest." One of the drugs is a benign natural product and the second is an FDA-approved antipsychotic. While the team has filed a provisional patent for the use of the combination to reverse antibiotic resistance, they hope future work will reveal even better options. "As a next step, we're interested in identifying additional chemicals that can fill these roles more effectively," said You. "Historically, when researchers screened huge libraries for medicines, they focused on drugs that can kill the bacteria. But what our studies suggest is that there is a whole new universe where you can now screen for other functions, like the ability to block conjugation or to induce the loss of resistance genes. These chemicals, once proven safe, can serve as adjuvants of the standard antibiotic treatment, or they can be applied in an environmental setting as a way of generally managing of the spread of antibiotic resistance." <|im_end|>

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2,441

[ { "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 Improved, highly active cathode materials are needed to promote the commercialization of ceramic fuel cell technology. However, the conventional trial-and-error process of material design, characterization and testing can make for a long and complex research cycle. Here we demonstrate an experimentally validated machine-learning-driven approach to accelerate the discovery of efficient oxygen reduction electrodes, where the ionic Lewis acid strength (ISA) is introduced as an effective physical descriptor for the oxygen reduction reaction activity of perovskite oxides. Four oxides, screened from 6,871 distinct perovskite compositions, are successfully synthesized and confirmed to have superior activity metrics. Experimental characterization reveals that decreased A-site and increased B-site ISAs in perovskite oxides considerably improve the surface exchange kinetics. Theoretical calculations indicate such improved activity is mainly attributed to the shift of electron pairs caused by polarization distribution of ISAs at sites A and B, which greatly reduces oxygen vacancy formation energy and migration barrier. Main Functional materials play an important role in renewable, green energy technologies, which are of strategic importance to achieve carbon-neutrality. The solid oxide fuel cell (SOFC), as a representative of green electrochemical devices, has attracted great attention for its high energy efficiency, low emissions and fuel flexibility 1 , 2 , 3 , 4 , 5 . However, commercialization of the ceramic fuel cell technology has been largely hampered due to its high operating temperatures (800–1,000 °C), at which difficult sealing, high operational costs and accelerated material degradation are the main challenges 6 , 7 . Lowering the operation temperature while maintaining sufficient power output is a critical step towards its wider application and portability 8 . Over the years, numerous efforts have been devoted to explore functional materials to realize a reduction in SOFC operation temperatures 9 , 10 . However, the trial-and-error process for the material design, characterization and complicated test procedure could make for a long and tedious research cycle, especially considering the vast non-precious metal-based perovskite candidates 11 . Under this limitation, revealing the relationship between parameters and properties is of high merit in material design 12 . Multiple descriptors of the activity of perovskite oxide electrodes have previously been proposed to provide guidance for prediction of new materials in a more efficient way 13 . Theoretically, the bulk oxygen p -band centre 14 , the bulk vacancy formation energy 15 and the charge-transfer energy 16 were reported to be closely associated with the catalytic activities of the oxygen reduction/evolution reaction (ORR/OER) under various conditions. For instance, a huge number of perovskite compositions has been screened as SOFC cathode candidates with a high oxygen p -band centre value by employing high-throughput density functional theory (DFT) methods 17 . Unfortunately, such studies rely heavily on indispensable complex computational simulation methods that require time-consuming, costly simulation and calculation processes; thus, the key constraints affecting screening efficiency still exist. Physically, the A-site ionic electronegativity 18 , number of outer electrons 19 , σ *-orbital occupation 12 and nominal B-site oxidation state 20 were indexed as the intrinsic OER/ORR activity descriptors; however, most of these single physical descriptors are specific to a particular system, such as perovskite oxides with fixed B-site cations, which limits their wider applicability. A particular area of interest in recent studies is to acquire potential information hidden behind existing datasets and establish the trend of materials discovery through data-driven methods 21 . For instance, machine-learning techniques with powerful capabilities to reorganize information structure and support multidimensional features are broadly used in materials informatics 22 . The material information available in published experimental data and open-source databases such as the Inorganic Crystal Structure Database has substantially democratized access to high-quality datasets for scientific researchers. After decades of development, large amounts of published experimental data are available for SOFC cathodes, which are worth collecting, organizing and serving as a cornerstone for derivative new electrode candidates. To construct an accurate machine-learning model for rapid and efficient exploration of active electrode materials, high-quality datasets, appropriate descriptors for perovskite compositions and selection of suitable regression model are indispensable. However, we currently lack a representative physical descriptor that accurately reflects the mechanistic rationale of the ORR process at elevated temperatures. To bridge this gap, it is imperative to search for an effective physical descriptor, determine the control rule for the ORR kinetics and identify a reliable regression model for data mining and reconstruction. In this work we propose an experimentally validated machine-learning-driven approach to screen highly active cathodes for ceramic fuel cells from huge perovskite compositions via the Lewis acid strength (ISA) descriptor, which is strongly associated with the ORR kinetic rate at elevated temperatures. To verify the predictions, we synthesize four perovskite oxides screened from 6,871 distinct compositions and further conduct characterization and electrochemical tests. Sr 0.9 Cs 0.1 Co 0.9 Nb 0.1 O 3 (SCCN) in particular exhibits excellent ORR activity with an extremely low area-specific resistance (ASR). Owing to the regulation of ISA by increasing A-site and reducing B-site ISAs, increased surface exchange kinetics are achieved. Density functional theory calculations reveal that the polarization distribution of ISA is associated with an optimal structure with a reduced V O formation energy and migration barrier due to the shift of electron pairs. Workflow for discovery of oxygen reduction electrodes The overall workflow for the discovery of highly active oxygen reduction electrodes is shown in Fig. 1 , which includes three major parts: machine-learning model training and material screening, experimental verification and DFT analysis. We first collected the ASR values of the various materials as the activity indicators via electrochemical impedance spectroscopy (EIS) based on symmetrical cell tests as the initial dataset. Using rational descriptors to denote various compositions is of vital importance for eventually obtaining a valid prediction of activity. Here we chose nine ionic descriptors including A- and B-site: ISA values (AISA and BISA), ionic electronegativities (AIEN and BIEN), ionic radii ( R A and R B ) 23 and ionization energies (AIE and BIE) 24 , as well as the tolerance factor ( t ). The complete dataset—containing the", "role": "user" }, { "content": "Ceramic fuel cells, also known as solid oxide fuel cells, are promising green electrochemical devices offering high energy efficiency, low emissions and fuel flexibility. The development of high performance and durable cathode materials is key for efficient and durable ceramic fuel cells. However, previous cathode material development based on a trial-and-error approach is time-consuming, expensive and difficult to optimize. A new paper published in Nature Energy demonstrates an experimentally validated machine-learning-driven approach to accelerate the discovery of efficient oxygen reduction electrodes. Significantly, ionic Lewis acid strength (ISA) is introduced as an effective physical descriptor for the oxygen reduction reaction activity of perovskite oxides. Using an integrated approach combining machine-learning, density functional theory (DFT) computation and experimental testing, the team successfully identified potential cathode materials for ceramic fuel cell from over 6,000 possible material compositions. These new materials could enable ceramic fuel cells to achieve high performance and excellent durability. This research study demonstrates a new strategy to facilitate ceramic fuel cell development for clean power generation and carbon neutrality. ", "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 Improved, highly active cathode materials are needed to promote the commercialization of ceramic fuel cell technology. However, the conventional trial-and-error process of material design, characterization and testing can make for a long and complex research cycle. Here we demonstrate an experimentally validated machine-learning-driven approach to accelerate the discovery of efficient oxygen reduction electrodes, where the ionic Lewis acid strength (ISA) is introduced as an effective physical descriptor for the oxygen reduction reaction activity of perovskite oxides. Four oxides, screened from 6,871 distinct perovskite compositions, are successfully synthesized and confirmed to have superior activity metrics. Experimental characterization reveals that decreased A-site and increased B-site ISAs in perovskite oxides considerably improve the surface exchange kinetics. Theoretical calculations indicate such improved activity is mainly attributed to the shift of electron pairs caused by polarization distribution of ISAs at sites A and B, which greatly reduces oxygen vacancy formation energy and migration barrier. Main Functional materials play an important role in renewable, green energy technologies, which are of strategic importance to achieve carbon-neutrality. The solid oxide fuel cell (SOFC), as a representative of green electrochemical devices, has attracted great attention for its high energy efficiency, low emissions and fuel flexibility 1 , 2 , 3 , 4 , 5 . However, commercialization of the ceramic fuel cell technology has been largely hampered due to its high operating temperatures (800–1,000 °C), at which difficult sealing, high operational costs and accelerated material degradation are the main challenges 6 , 7 . Lowering the operation temperature while maintaining sufficient power output is a critical step towards its wider application and portability 8 . Over the years, numerous efforts have been devoted to explore functional materials to realize a reduction in SOFC operation temperatures 9 , 10 . However, the trial-and-error process for the material design, characterization and complicated test procedure could make for a long and tedious research cycle, especially considering the vast non-precious metal-based perovskite candidates 11 . Under this limitation, revealing the relationship between parameters and properties is of high merit in material design 12 . Multiple descriptors of the activity of perovskite oxide electrodes have previously been proposed to provide guidance for prediction of new materials in a more efficient way 13 . Theoretically, the bulk oxygen p -band centre 14 , the bulk vacancy formation energy 15 and the charge-transfer energy 16 were reported to be closely associated with the catalytic activities of the oxygen reduction/evolution reaction (ORR/OER) under various conditions. For instance, a huge number of perovskite compositions has been screened as SOFC cathode candidates with a high oxygen p -band centre value by employing high-throughput density functional theory (DFT) methods 17 . Unfortunately, such studies rely heavily on indispensable complex computational simulation methods that require time-consuming, costly simulation and calculation processes; thus, the key constraints affecting screening efficiency still exist. Physically, the A-site ionic electronegativity 18 , number of outer electrons 19 , σ *-orbital occupation 12 and nominal B-site oxidation state 20 were indexed as the intrinsic OER/ORR activity descriptors; however, most of these single physical descriptors are specific to a particular system, such as perovskite oxides with fixed B-site cations, which limits their wider applicability. A particular area of interest in recent studies is to acquire potential information hidden behind existing datasets and establish the trend of materials discovery through data-driven methods 21 . For instance, machine-learning techniques with powerful capabilities to reorganize information structure and support multidimensional features are broadly used in materials informatics 22 . The material information available in published experimental data and open-source databases such as the Inorganic Crystal Structure Database has substantially democratized access to high-quality datasets for scientific researchers. After decades of development, large amounts of published experimental data are available for SOFC cathodes, which are worth collecting, organizing and serving as a cornerstone for derivative new electrode candidates. To construct an accurate machine-learning model for rapid and efficient exploration of active electrode materials, high-quality datasets, appropriate descriptors for perovskite compositions and selection of suitable regression model are indispensable. However, we currently lack a representative physical descriptor that accurately reflects the mechanistic rationale of the ORR process at elevated temperatures. To bridge this gap, it is imperative to search for an effective physical descriptor, determine the control rule for the ORR kinetics and identify a reliable regression model for data mining and reconstruction. In this work we propose an experimentally validated machine-learning-driven approach to screen highly active cathodes for ceramic fuel cells from huge perovskite compositions via the Lewis acid strength (ISA) descriptor, which is strongly associated with the ORR kinetic rate at elevated temperatures. To verify the predictions, we synthesize four perovskite oxides screened from 6,871 distinct compositions and further conduct characterization and electrochemical tests. Sr 0.9 Cs 0.1 Co 0.9 Nb 0.1 O 3 (SCCN) in particular exhibits excellent ORR activity with an extremely low area-specific resistance (ASR). Owing to the regulation of ISA by increasing A-site and reducing B-site ISAs, increased surface exchange kinetics are achieved. Density functional theory calculations reveal that the polarization distribution of ISA is associated with an optimal structure with a reduced V O formation energy and migration barrier due to the shift of electron pairs. Workflow for discovery of oxygen reduction electrodes The overall workflow for the discovery of highly active oxygen reduction electrodes is shown in Fig. 1 , which includes three major parts: machine-learning model training and material screening, experimental verification and DFT analysis. We first collected the ASR values of the various materials as the activity indicators via electrochemical impedance spectroscopy (EIS) based on symmetrical cell tests as the initial dataset. Using rational descriptors to denote various compositions is of vital importance for eventually obtaining a valid prediction of activity. Here we chose nine ionic descriptors including A- and B-site: ISA values (AISA and BISA), ionic electronegativities (AIEN and BIEN), ionic radii ( R A and R B ) 23 and ionization energies (AIE and BIE) 24 , as well as the tolerance factor ( t ). The complete dataset—containing the<|im_end|> <|im_start|>assistant Ceramic fuel cells, also known as solid oxide fuel cells, are promising green electrochemical devices offering high energy efficiency, low emissions and fuel flexibility. The development of high performance and durable cathode materials is key for efficient and durable ceramic fuel cells. However, previous cathode material development based on a trial-and-error approach is time-consuming, expensive and difficult to optimize. A new paper published in Nature Energy demonstrates an experimentally validated machine-learning-driven approach to accelerate the discovery of efficient oxygen reduction electrodes. Significantly, ionic Lewis acid strength (ISA) is introduced as an effective physical descriptor for the oxygen reduction reaction activity of perovskite oxides. Using an integrated approach combining machine-learning, density functional theory (DFT) computation and experimental testing, the team successfully identified potential cathode materials for ceramic fuel cell from over 6,000 possible material compositions. These new materials could enable ceramic fuel cells to achieve high performance and excellent durability. This research study demonstrates a new strategy to facilitate ceramic fuel cell development for clean power generation and carbon neutrality. <|im_end|>

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1,551

[ { "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 COVID-19 can course with respiratory and extrapulmonary disease. SARS-CoV-2 RNA is detected in respiratory samples but also in blood, stool and urine. Severe COVID-19 is characterized by a dysregulated host response to this virus. We studied whether viral RNAemia or viral RNA load in plasma is associated with severe COVID-19 and also to this dysregulated response. Methods A total of 250 patients with COVID-19 were recruited (50 outpatients, 100 hospitalized ward patients and 100 critically ill). Viral RNA detection and quantification in plasma was performed using droplet digital PCR, targeting the N1 and N2 regions of the SARS-CoV-2 nucleoprotein gene. The association between SARS-CoV-2 RNAemia and viral RNA load in plasma with severity was evaluated by multivariate logistic regression. Correlations between viral RNA load and biomarkers evidencing dysregulation of host response were evaluated by calculating the Spearman correlation coefficients. Results The frequency of viral RNAemia was higher in the critically ill patients (78%) compared to ward patients (27%) and outpatients (2%) ( p < 0.001). Critical patients had higher viral RNA loads in plasma than non-critically ill patients, with non-survivors showing the highest values. When outpatients and ward patients were compared, viral RNAemia did not show significant associations in the multivariate analysis. In contrast, when ward patients were compared with ICU patients, both viral RNAemia and viral RNA load in plasma were associated with critical illness (OR [CI 95%], p ): RNAemia (3.92 [1.183–12.968], 0.025), viral RNA load (N1) (1.962 [1.244–3.096], 0.004); viral RNA load (N2) (2.229 [1.382–3.595], 0.001). Viral RNA load in plasma correlated with higher levels of chemokines (CXCL10, CCL2), biomarkers indicative of a systemic inflammatory response (IL-6, CRP, ferritin), activation of NK cells (IL-15), endothelial dysfunction (VCAM-1, angiopoietin-2, ICAM-1), coagulation activation (D-Dimer and INR), tissue damage (LDH, GPT), neutrophil response (neutrophils counts, myeloperoxidase, GM-CSF) and immunodepression (PD-L1, IL-10, lymphopenia and monocytopenia). Conclusions SARS-CoV-2 RNAemia and viral RNA load in plasma are associated with critical illness in COVID-19. Viral RNA load in plasma correlates with key signatures of dysregulated host responses, suggesting a major role of uncontrolled viral replication in the pathogenesis of this disease. Background With well over 43 million cases and 1.56212 deaths globally, Coronavirus disease 2019 (COVID-19) has become the top economic and health priority worldwide [ 1 ]. Among hospitalized patients, around 10–20% are admitted to the intensive care unit (ICU), 3–10% require intubation and 2–5% die [ 2 ]. SARS-CoV-2 RNA is commonly detected in nasopharyngeal swabs; however, viral RNA can be found in sputum, lung samples, peripheral blood, serum, stool samples and to a limited extent urine [ 3 , 4 , 5 , 6 ]. While the lungs are most often affected, severe COVID-19 also induces inflammatory cell infiltration, haemorrhage and degeneration or necrosis in extra-pulmonary organs (spleen, lymph nodes, kidney, liver, central nervous system) [ 7 , 8 ]. Patients with severe COVID-19 show signatures of dysregulated response to infection, with immunological alterations involving moderate elevation of some cytokines and chemokines such as IL-6, IL-10 or CXCL10, deep lymphopenia with neutrophilia, systemic inflammation (elevation of C-reactive protein, ferritin), endothelial dysfunction, coagulation hyper-activation (D-dimers) and tissue damage (LDH) [ 9 , 10 , 11 , 12 , 13 , 14 ]. Our hypothesis is that systemic distribution of the virus or viral components could be associated with the severity of COVID-19, and in turn to a number of parameters indicating the presence of a dysregulated response to the infection. While the SARS-CoV-2 virus has been reported to be difficult to culture from blood [ 4 ], PCR-based methods are able to detect and quantify the presence of genomic material of the virus in serum or plasma, representing an useful approach to evaluate the impact of the extrapulmonary dissemination of viral material on disease severity and also on the host response to the infection [ 5 , 15 ]. An excellent approach for achieving absolute quantification of viral RNA load is droplet digital PCR (ddPCR). ddPCR is a next-generation PCR method, which offers absolute quantification with no need of standard curve and greater precision and reproducibility than currently available qRT-PCR methods, as revised elsewhere [ 16 ]. We employed here ddPCR to detect and quantify viral RNA in plasma from COVID-19 patients discharged from the emergency room with mild severity, patients admitted to the ward with moderate severity and critically ill patients. Our objectives in this study were: (1) to evaluate if there is an association between SARS-CoV-2 RNAemia and viral RNA load with moderate disease; (2) to evaluate if there is an association between SARS-CoV-2 RNAemia and viral RNA load with critical illness; and (3) to evaluate the correlations between SARS-CoV-2 RNA load in plasma and parameters of dysregulated host responses against SARS-CoV-2. Methods Study design A total of 250 adult patients with a positive nasopharyngeal swab polymerase chain reaction (PCR) test for SARS-CoV-2 performed at participating hospitals were recruited during the first pandemic wave in Spain from March 16th to the 15th of April 2020. The patients recruited were of three different categories. The first corresponded to patients examined at an emergency room and discharged within the first 24 h (outpatients group, n = 50). The second group were patients hospitalized to pneumology, infectious diseases or internal medicine wards (wards group, n = 100). Patients who required critical care or died during hospitalization were excluded from this group, in order to have a group of clear moderate severity. The third group corresponded to patients admitted to the ICU (n = 100). Patient`s recruited by participating hospital are detailed in the Additional file 1 . Twenty healthy blood donors were included as controls. These controls were recruited during the pandemics, in parallel to the SARS-CoV-2 infected patients, and were negative for SARS-CoV-2 IgG. This study was registered at Clinicaltrials.gov with the identification NCT04457505. Blood samples Plasma from blood collected in EDTA tubes samples was obtained from the three groups of patients in the first 24 h following admission to the emergency room, to the ward, or to the ICU,", "role": "user" }, { "content": "An international team of researchers led by Dalhousie immunologists and critical care specialists in Spain has found key biomarkers in the plasma of COVID-19 patients, which will help predict the severity of illness and could lead to new treatments for the virus. The findings, published Tuesday in the journal Critical Care, involved 250 patients with COVID-19 whose plasma was tested in Spain for the presence of ribonucleic acid or RNA, the virus's genetic blueprint. Dr. David Kelvin, a professor and Canada Research Chair at the Dalhousie's Department of Microbiology and Immunology, collaborated with critical care scientists Dr. Jesus Bermejo-Martin of the Institute of Biomedical Investigation and Dr. Antoni Torres in Spain. More than 30 research hospitals in the country were involved in assessing the viral loads in the plasma of three groups of patients with varying degrees of illness during the first wave of the pandemic wave in Spain from March 16 to April 15, 2020. High levels of RNA The team found that 78 percent of patients who were severely ill had higher amounts of viral RNA than those with mild cases. Those who died had the highest concentrations of viral RNA in their plasma, leading the researchers to conclude that the presence of the RNA in a patient's blood is linked to critical illness. Dr. Kelvin (shown left) says the research could help in quickly identifying patients at crowded hospital emergency rooms who need immediate and intensive care, and those who may be able to go home. \"We now have an extremely reliable indicator for identifying severe COVID-19 patients who require critical care and should be admitted to the ICU, which will help intensive care unit doctors prioritize severely ill patients,\" says Dr. Kelvin. Dr. Kelvin says he and his colleagues are working with a large pharmaceutical company to develop a rapid test that could produce results in 15 minutes and indicate whether a positive patient has the viral RNA and what level of care they may need. Such a device could be a valuable asset as confirmed case counts and hospitalizations continue to surge, particularly in the U.S. Surging hospitalizations In Canada, Chief Public Health Officer Dr. Theresa Tam said Tuesday that the number of people reporting severe illness was rising steadily. She added that over the last week, \"there were an average of 3,020 individuals with COVID-19 being treated in Canadian hospitals, including over 600 in critical care.\" Several provinces, including Ontario and Quebec, have seen sharp increases in hospitalizations in recent weeks. \"The importance of this study is that it allows identification of those patients most in need of ICU admission—all of it done by a simple blood test for presence of viral RNA,\" Dr. Kelvin says. Importantly as well, the team also discovered that the presence of COVID-19 viral RNA was directly linked to a dysfunctional immune response. That may make severe patients unable to fend off the COVID-19 infection, due in part to elevated levels of certain proteins. The identification of these patients will also help identify those who could be treated with new therapeutics, such as antibody cocktails. New clues \"We are also trying to figure out the why viral components are in the blood and how this leads to immune dysfunction and severe disease. Several clues are now before us and we hope to develop novel therapeutics to aid in treating severe patients,\" he said. The team used a method called droplet digital PCR to quantify the virus's genomic material in plasma in the 50 outpatients, 100 hospitalized ward patients and 100 who were critically ill in what is believed to be the largest study of its kind using such methodology. Patients requiring hospitalization were older than those who were discharged from the ER. Critically ill patients were more frequently male, while obesity, hypertension and type 2 diabetes were more commonly found in patients requiring hospitalization. ", "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 COVID-19 can course with respiratory and extrapulmonary disease. SARS-CoV-2 RNA is detected in respiratory samples but also in blood, stool and urine. Severe COVID-19 is characterized by a dysregulated host response to this virus. We studied whether viral RNAemia or viral RNA load in plasma is associated with severe COVID-19 and also to this dysregulated response. Methods A total of 250 patients with COVID-19 were recruited (50 outpatients, 100 hospitalized ward patients and 100 critically ill). Viral RNA detection and quantification in plasma was performed using droplet digital PCR, targeting the N1 and N2 regions of the SARS-CoV-2 nucleoprotein gene. The association between SARS-CoV-2 RNAemia and viral RNA load in plasma with severity was evaluated by multivariate logistic regression. Correlations between viral RNA load and biomarkers evidencing dysregulation of host response were evaluated by calculating the Spearman correlation coefficients. Results The frequency of viral RNAemia was higher in the critically ill patients (78%) compared to ward patients (27%) and outpatients (2%) ( p < 0.001). Critical patients had higher viral RNA loads in plasma than non-critically ill patients, with non-survivors showing the highest values. When outpatients and ward patients were compared, viral RNAemia did not show significant associations in the multivariate analysis. In contrast, when ward patients were compared with ICU patients, both viral RNAemia and viral RNA load in plasma were associated with critical illness (OR [CI 95%], p ): RNAemia (3.92 [1.183–12.968], 0.025), viral RNA load (N1) (1.962 [1.244–3.096], 0.004); viral RNA load (N2) (2.229 [1.382–3.595], 0.001). Viral RNA load in plasma correlated with higher levels of chemokines (CXCL10, CCL2), biomarkers indicative of a systemic inflammatory response (IL-6, CRP, ferritin), activation of NK cells (IL-15), endothelial dysfunction (VCAM-1, angiopoietin-2, ICAM-1), coagulation activation (D-Dimer and INR), tissue damage (LDH, GPT), neutrophil response (neutrophils counts, myeloperoxidase, GM-CSF) and immunodepression (PD-L1, IL-10, lymphopenia and monocytopenia). Conclusions SARS-CoV-2 RNAemia and viral RNA load in plasma are associated with critical illness in COVID-19. Viral RNA load in plasma correlates with key signatures of dysregulated host responses, suggesting a major role of uncontrolled viral replication in the pathogenesis of this disease. Background With well over 43 million cases and 1.56212 deaths globally, Coronavirus disease 2019 (COVID-19) has become the top economic and health priority worldwide [ 1 ]. Among hospitalized patients, around 10–20% are admitted to the intensive care unit (ICU), 3–10% require intubation and 2–5% die [ 2 ]. SARS-CoV-2 RNA is commonly detected in nasopharyngeal swabs; however, viral RNA can be found in sputum, lung samples, peripheral blood, serum, stool samples and to a limited extent urine [ 3 , 4 , 5 , 6 ]. While the lungs are most often affected, severe COVID-19 also induces inflammatory cell infiltration, haemorrhage and degeneration or necrosis in extra-pulmonary organs (spleen, lymph nodes, kidney, liver, central nervous system) [ 7 , 8 ]. Patients with severe COVID-19 show signatures of dysregulated response to infection, with immunological alterations involving moderate elevation of some cytokines and chemokines such as IL-6, IL-10 or CXCL10, deep lymphopenia with neutrophilia, systemic inflammation (elevation of C-reactive protein, ferritin), endothelial dysfunction, coagulation hyper-activation (D-dimers) and tissue damage (LDH) [ 9 , 10 , 11 , 12 , 13 , 14 ]. Our hypothesis is that systemic distribution of the virus or viral components could be associated with the severity of COVID-19, and in turn to a number of parameters indicating the presence of a dysregulated response to the infection. While the SARS-CoV-2 virus has been reported to be difficult to culture from blood [ 4 ], PCR-based methods are able to detect and quantify the presence of genomic material of the virus in serum or plasma, representing an useful approach to evaluate the impact of the extrapulmonary dissemination of viral material on disease severity and also on the host response to the infection [ 5 , 15 ]. An excellent approach for achieving absolute quantification of viral RNA load is droplet digital PCR (ddPCR). ddPCR is a next-generation PCR method, which offers absolute quantification with no need of standard curve and greater precision and reproducibility than currently available qRT-PCR methods, as revised elsewhere [ 16 ]. We employed here ddPCR to detect and quantify viral RNA in plasma from COVID-19 patients discharged from the emergency room with mild severity, patients admitted to the ward with moderate severity and critically ill patients. Our objectives in this study were: (1) to evaluate if there is an association between SARS-CoV-2 RNAemia and viral RNA load with moderate disease; (2) to evaluate if there is an association between SARS-CoV-2 RNAemia and viral RNA load with critical illness; and (3) to evaluate the correlations between SARS-CoV-2 RNA load in plasma and parameters of dysregulated host responses against SARS-CoV-2. Methods Study design A total of 250 adult patients with a positive nasopharyngeal swab polymerase chain reaction (PCR) test for SARS-CoV-2 performed at participating hospitals were recruited during the first pandemic wave in Spain from March 16th to the 15th of April 2020. The patients recruited were of three different categories. The first corresponded to patients examined at an emergency room and discharged within the first 24 h (outpatients group, n = 50). The second group were patients hospitalized to pneumology, infectious diseases or internal medicine wards (wards group, n = 100). Patients who required critical care or died during hospitalization were excluded from this group, in order to have a group of clear moderate severity. The third group corresponded to patients admitted to the ICU (n = 100). Patient`s recruited by participating hospital are detailed in the Additional file 1 . Twenty healthy blood donors were included as controls. These controls were recruited during the pandemics, in parallel to the SARS-CoV-2 infected patients, and were negative for SARS-CoV-2 IgG. This study was registered at Clinicaltrials.gov with the identification NCT04457505. Blood samples Plasma from blood collected in EDTA tubes samples was obtained from the three groups of patients in the first 24 h following admission to the emergency room, to the ward, or to the ICU,<|im_end|> <|im_start|>assistant An international team of researchers led by Dalhousie immunologists and critical care specialists in Spain has found key biomarkers in the plasma of COVID-19 patients, which will help predict the severity of illness and could lead to new treatments for the virus. The findings, published Tuesday in the journal Critical Care, involved 250 patients with COVID-19 whose plasma was tested in Spain for the presence of ribonucleic acid or RNA, the virus's genetic blueprint. Dr. David Kelvin, a professor and Canada Research Chair at the Dalhousie's Department of Microbiology and Immunology, collaborated with critical care scientists Dr. Jesus Bermejo-Martin of the Institute of Biomedical Investigation and Dr. Antoni Torres in Spain. More than 30 research hospitals in the country were involved in assessing the viral loads in the plasma of three groups of patients with varying degrees of illness during the first wave of the pandemic wave in Spain from March 16 to April 15, 2020. High levels of RNA The team found that 78 percent of patients who were severely ill had higher amounts of viral RNA than those with mild cases. Those who died had the highest concentrations of viral RNA in their plasma, leading the researchers to conclude that the presence of the RNA in a patient's blood is linked to critical illness. Dr. Kelvin (shown left) says the research could help in quickly identifying patients at crowded hospital emergency rooms who need immediate and intensive care, and those who may be able to go home. "We now have an extremely reliable indicator for identifying severe COVID-19 patients who require critical care and should be admitted to the ICU, which will help intensive care unit doctors prioritize severely ill patients," says Dr. Kelvin. Dr. Kelvin says he and his colleagues are working with a large pharmaceutical company to develop a rapid test that could produce results in 15 minutes and indicate whether a positive patient has the viral RNA and what level of care they may need. Such a device could be a valuable asset as confirmed case counts and hospitalizations continue to surge, particularly in the U.S. Surging hospitalizations In Canada, Chief Public Health Officer Dr. Theresa Tam said Tuesday that the number of people reporting severe illness was rising steadily. She added that over the last week, "there were an average of 3,020 individuals with COVID-19 being treated in Canadian hospitals, including over 600 in critical care." Several provinces, including Ontario and Quebec, have seen sharp increases in hospitalizations in recent weeks. "The importance of this study is that it allows identification of those patients most in need of ICU admission—all of it done by a simple blood test for presence of viral RNA," Dr. Kelvin says. Importantly as well, the team also discovered that the presence of COVID-19 viral RNA was directly linked to a dysfunctional immune response. That may make severe patients unable to fend off the COVID-19 infection, due in part to elevated levels of certain proteins. The identification of these patients will also help identify those who could be treated with new therapeutics, such as antibody cocktails. New clues "We are also trying to figure out the why viral components are in the blood and how this leads to immune dysfunction and severe disease. Several clues are now before us and we hope to develop novel therapeutics to aid in treating severe patients," he said. The team used a method called droplet digital PCR to quantify the virus's genomic material in plasma in the 50 outpatients, 100 hospitalized ward patients and 100 who were critically ill in what is believed to be the largest study of its kind using such methodology. Patients requiring hospitalization were older than those who were discharged from the ER. Critically ill patients were more frequently male, while obesity, hypertension and type 2 diabetes were more commonly found in patients requiring hospitalization. <|im_end|>

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578, 4948, 1912, 8024, 291, 311, 6978, 16584, 311, 279, 85015, 320, 77, 284, 220, 1041, 570, 30024, 40929, 45425, 555, 24435, 8952, 527, 11944, 304, 279, 24086, 1052, 220, 16, 662, 44956, 9498, 6680, 33149, 1051, 5343, 439, 11835, 13, 4314, 11835, 1051, 45425, 2391, 279, 12495, 38305, 11, 304, 15638, 311, 279, 328, 17485, 87271, 53, 12, 17, 29374, 6978, 11, 323, 1051, 8389, 369, 328, 17485, 87271, 53, 12, 17, 39551, 38, 13, 1115, 4007, 574, 9879, 520, 33135, 376, 10522, 14489, 449, 279, 22654, 452, 1182, 20078, 21228, 2304, 13, 20671, 10688, 65632, 505, 6680, 14890, 304, 49023, 32, 34083, 10688, 574, 12457, 505, 279, 2380, 5315, 315, 6978, 304, 279, 1176, 220, 1187, 305, 2768, 26360, 311, 279, 13147, 3130, 11, 311, 279, 26741, 11, 477, 311, 279, 85015, 11, 128257, 198, 128256, 78191, 198, 2127, 6625, 2128, 315, 12074, 6197, 555, 29210, 71, 788, 648, 33119, 22012, 323, 9200, 2512, 35416, 304, 18157, 706, 1766, 1401, 39538, 91141, 304, 279, 32426, 315, 20562, 12, 777, 6978, 11, 902, 690, 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2495, 3346, 315, 6978, 889, 1051, 35906, 5986, 1047, 5190, 15055, 315, 29962, 41214, 1109, 1884, 449, 23900, 5157, 13, 13266, 889, 8636, 1047, 279, 8592, 32466, 315, 29962, 41214, 304, 872, 32426, 11, 6522, 279, 12074, 311, 32194, 430, 279, 9546, 315, 279, 41214, 304, 264, 8893, 596, 6680, 374, 10815, 311, 9200, 17563, 13, 2999, 13, 92073, 320, 70463, 2163, 8, 2795, 279, 3495, 1436, 1520, 304, 6288, 25607, 6978, 520, 39313, 8952, 13147, 12295, 889, 1205, 14247, 323, 37295, 2512, 11, 323, 1884, 889, 1253, 387, 3025, 311, 733, 2162, 13, 330, 1687, 1457, 617, 459, 9193, 15062, 21070, 369, 25607, 15748, 20562, 12, 777, 6978, 889, 1397, 9200, 2512, 323, 1288, 387, 16584, 311, 279, 85015, 11, 902, 690, 1520, 37295, 2512, 5089, 16410, 63652, 35906, 5986, 6978, 1359, 2795, 2999, 13, 92073, 13, 2999, 13, 92073, 2795, 568, 323, 813, 18105, 527, 3318, 449, 264, 3544, 35410, 2883, 311, 2274, 264, 11295, 1296, 430, 1436, 8356, 3135, 304, 220, 868, 4520, 323, 13519, 3508, 264, 6928, 8893, 706, 279, 29962, 41214, 323, 1148, 2237, 315, 2512, 814, 1253, 1205, 13, 15483, 264, 3756, 1436, 387, 264, 15525, 9513, 439, 11007, 1162, 14921, 323, 8952, 8200, 3136, 311, 22531, 11, 8104, 304, 279, 549, 815, 13, 8242, 3252, 8952, 8200, 763, 7008, 11, 14681, 3142, 6401, 20148, 2999, 13, 43812, 29988, 1071, 7742, 430, 279, 1396, 315, 1274, 13122, 15748, 17563, 574, 16448, 43071, 13, 3005, 3779, 430, 927, 279, 1566, 2046, 11, 330, 19041, 1051, 459, 5578, 315, 220, 18, 11, 11139, 7931, 449, 20562, 12, 777, 1694, 12020, 304, 12152, 24461, 11, 2737, 927, 220, 5067, 304, 9200, 2512, 1210, 26778, 41021, 11, 2737, 21193, 323, 35195, 11, 617, 3970, 17676, 12992, 304, 8952, 8200, 304, 3293, 5672, 13, 330, 791, 12939, 315, 420, 4007, 374, 430, 433, 6276, 22654, 315, 1884, 6978, 1455, 304, 1205, 315, 85015, 26360, 87247, 315, 433, 2884, 555, 264, 4382, 6680, 1296, 369, 9546, 315, 29962, 41214, 1359, 2999, 13, 92073, 2795, 13, 13516, 18007, 439, 1664, 11, 279, 2128, 1101, 11352, 430, 279, 9546, 315, 20562, 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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 Species radiations, despite immense phenotypic variation, can be difficult to resolve phylogenetically when genetic change poorly matches the rapidity of diversification. Genomic potential furnished by palaeopolyploidy, and relative roles for adaptation, random drift and hybridisation in the apportionment of genetic variation, remain poorly understood factors. Here, we study these aspects in a model radiation, Syzygium , the most species-rich tree genus worldwide. Genomes of 182 distinct species and 58 unidentified taxa are compared against a chromosome-level reference genome of the sea apple, Syzygium grande . We show that while Syzygium shares an ancient genome doubling event with other Myrtales, little evidence exists for recent polyploidy events. Phylogenomics confirms that Syzygium originated in Australia-New Guinea and diversified in multiple migrations, eastward to the Pacific and westward to India and Africa, in bursts of speciation visible as poorly resolved branches on phylogenies. Furthermore, some sublineages demonstrate genomic clines that recapitulate cladogenetic events, suggesting that stepwise geographic speciation, a neutral process, has been important in Syzygium diversification. Introduction Species radiations—wherein perplexing amounts of diversity appear to have formed extremely rapidly—have featured prominently in the history of evolutionary theory 1 . Various underlying mechanisms for their formation have been proposed 2 , including adaptation 2 , non-adaptive processes 3 , 4 , hybridisation 5 , 6 , and polyploidy 7 , 8 , but the relative importance of these drivers remains incompletely understood. Species radiations on islands have been among the most prominently studied systems 9 , 10 , 11 , 12 . For example, the Malesian archipelago in the tropical Far East 13 , consisting of thousands of islands and including New Guinea and Borneo, the second and third largest islands in the world, is a biodiversity hotspot containing many radiations of plant and animal species. Among forest trees, local tree species richness across Southeast Asian forests is largely driven by a small number of highly species-rich genera 14 . The clove genus, Syzygium , is one of the most important of these genera, and therefore understanding diversification and its underlying drivers within Syzygium may help explain large-scale patterns of diversity in the Palaeotropics. However, Syzygium , like many other species radiations that hold immense morphological and ecological variation, has so far been difficult to resolve phylogenetically 15 , 16 , 17 , 18 , leading to the impression that evolutionary change can be a swift process that may not require substantial underlying genetic change 9 . Here, we employ genome-scale approaches to investigate speciation patterns and their potential drivers in the most species-rich tree genus worldwide, Syzygium 19 . Syzygium , which includes 1193 species recognised worldwide 20 , is a genus in the myrtle family (Myrtaceae). Syzygium is restricted to tropical and subtropical regions of the Old World, where it is distributed from Africa through to India, across Southeast Asia and extending to Hawaii in the Pacific Ocean, with the centre of species diversity in Indomalesia 20 . The type species of Syzygium is S. caryophyllatum , a poorly known, small to medium-sized tree endemic to southern India and Sri Lanka 21 . The best-known species in the genus is the clove tree, Syzygium aromaticum , from which flower buds are gathered, dried, and used as a spice, a preservative and in pharmacology 22 . In addition, Syzygium aqueum , S. cumini , S. jambos , S. malaccense and S. samarangense are widely cultivated in the tropics for their large edible fruits 23 . Syzygium samarangense is cultivated commercially in Southeast Asia, where it is marketed as the wax apple, java apple, rose apple, or samarang rose apple. Apart from being used as cooking ingredients or cultivated for fruits, Syzygium species with dense and bushy crowns, such as S. antisepticum , S. australe , S. luehmannii , S. myrtifolium and S. zeylanicum , are used in the horticulture industry in Australia, Indonesia, Malaysia and Singapore for hedges, natural fences, natural sound barriers and privacy screens 24 . Syzygium species are generally medium-sized to large, characteristically sub-canopy trees that are sometimes emergent, while some also form shrubs, small forest understorey treelets, swamp and mangrove forest trees, and rheophytic vegetation 25 . As is true of many tropical trees, Syzygium flowers are visited by a large diversity of insects and vertebrates, and their fruits are typically eaten by a variety of flying and arboreal vertebrates and even terrestrial bird, mammal and reptile browsers 25 . Syzygium species also occur as dominant mid-level canopy trees, affecting the ecosystems of plants, animals, and fungi in lower forest layers 25 . Many species co-occur; for example, there exist ca. 50 taxa on a single 52-ha. ecological plot in the Lambir Hills National Park (Sarawak, East Malaysia, Borneo 26 ), where they display fine-scale differentiation in habitat occupancy and stature 14 . The genus is notorious as one of the most difficult to identify due to the paucity of clear, diagnostic morphological characters for distinguishing species; 25 , 27 , 28 morphological variation in the genus can appear as continua of traits rather than collections of discrete units. Given the immense number of species assigned to Syzygium , it contributes disproportionately to the diversity of Southeast Asian tropical forests. Therefore, understanding diversification and its underlying drivers within Syzygium may help explain large-scale patterns of diversity. Thus far, however, phylogenetic studies of Syzygium have involved only a few PCR-amplified plastid and nuclear marker genes 15 , 16 . An infrageneric classification proposed in 2010 was based on three plastid loci 17 , and although it resolved some major clades, interrelationships within the bulk of the genus, species of Syzygium subg. Syzygium , were left largely unresolved. Here, we sequence whole genomes to vastly increase the available data in an attempt to more fully resolve phylogenetic relationships among Syzygium species. We use Oxford Nanopore Technology (ONT) long-read sequencing 29 to assemble and annotate a chromosome-scale reference genome for the sea apple, Syzygium grande 23 . This species was selected as a representative because it is a well-known member", "role": "user" }, { "content": "An international study that analyzed the world's largest tree group has made breakthrough findings. The results are expected to guide future conservation of tropical and subtropical rain forests as well as help with predicting how certain plants will respond to climate change. More than 60 researchers explored the evolution and speciation patterns of the tree group Syzgium, which includes the trees that gives us the spice clove as well as numerous fruits. The study was led by the Singapore Botanic Gardens of Singapore's National Parks Board in collaboration with 26 international research institutions including the University of Aberdeen, Royal Botanic Gardens, Kew, Nanyang Technological University and the University of Buffalo. Published in Nature Communications the research is the most extensive study of any Syzgium group of trees to date and was carried out over two years using samples from some 300 species growing in Africa, Sri Lanka, Malaysia, Singapore, Indonesia, Japan, Australia and the Pacific Islands. Trees growing in tropical areas are understood to be some of the most valuable in the world in protecting biodiversity and global warming, but they are also among some of the most threatened because of commercial needs and use of the land for farming. Native and widespread in tropical and subtropical rain forests, studying the origins and drivers of the large hyperdiverse tree group Syzygium contributes to the understanding of how plant species have emerged in the past in response to environmental changes. This knowledge is valuable for predicting how plants might respond to ecological changes brought about by climate change and will guide conservation and management efforts for plant communities. The Syzygium species may be found growing together with other trees within the understory and canopy layers of forests. Because of its large diversity, they play an inordinate role in the functioning of forest ecosystems. Many Syzygium species are also cultivated in tropical countries for different types of spices as well as their large edible fruits. Understanding how Syzygium species have evolved will help to advance knowledge of the highly complex species-environment relationships in forest ecosystems and anticipate forest ecosystem changes in response to climate change. The University of Aberdeen's Interdisciplinary Director for Environment and Biodiversity Professor David Burslem says that \"tropical forests are under severe threat from conversion, industrial logging and climate change. The new results on the origins and biodiversity of Syzygium, an important group of tropical trees containing many species of commercial importance for timber and fruit production, provides the raw material for devising strategies for species conservation and restoration.\" \"This new paper will serve as a benchmark for future studies combining genomic analyses with extensive data-sets on species distributions and satellite-derived environmental sensing to finally understand the mechanisms that drive patterns of tropical forest biodiversity.\" \"It was a privilege for the University of Aberdeen to work closely with experts from Singapore Botanic Gardens as well as many other prestigious international organizations on this vitally important project which is one of the first genome-scale plant evolutionary studies on a single group to be published that was so widely-sampled.\" Dr. David Middleton, coordinating director at Singapore Botanic Gardens, says that \"Southeast Asia is a region of exceptionally rich species diversity. The Singapore Botanic Gardens has played a contributory role to the study of plant diversity in the region since its founding in 1859, as part of the Gardens' core roles in research, conservation and education.\" \"The enormous genus Syzygium, the species of which are mainly understory trees, has long been neglected in comparison to the iconic forest giants and plant groups of more immediate economic interest. However, their role in the diversity and functioning of our forests must be better understood if we are to succeed in our conservation goals.\" \"In partnership with our collaborators at home and abroad, we have begun to understand what drives such exceptional species diversity in tropical Southeast Asia and can make better informed decisions on how to conserve this diversity. This strengthens the science on conservation in the region and contributes towards Singapore's City in Nature vision.\" ", "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 Species radiations, despite immense phenotypic variation, can be difficult to resolve phylogenetically when genetic change poorly matches the rapidity of diversification. Genomic potential furnished by palaeopolyploidy, and relative roles for adaptation, random drift and hybridisation in the apportionment of genetic variation, remain poorly understood factors. Here, we study these aspects in a model radiation, Syzygium , the most species-rich tree genus worldwide. Genomes of 182 distinct species and 58 unidentified taxa are compared against a chromosome-level reference genome of the sea apple, Syzygium grande . We show that while Syzygium shares an ancient genome doubling event with other Myrtales, little evidence exists for recent polyploidy events. Phylogenomics confirms that Syzygium originated in Australia-New Guinea and diversified in multiple migrations, eastward to the Pacific and westward to India and Africa, in bursts of speciation visible as poorly resolved branches on phylogenies. Furthermore, some sublineages demonstrate genomic clines that recapitulate cladogenetic events, suggesting that stepwise geographic speciation, a neutral process, has been important in Syzygium diversification. Introduction Species radiations—wherein perplexing amounts of diversity appear to have formed extremely rapidly—have featured prominently in the history of evolutionary theory 1 . Various underlying mechanisms for their formation have been proposed 2 , including adaptation 2 , non-adaptive processes 3 , 4 , hybridisation 5 , 6 , and polyploidy 7 , 8 , but the relative importance of these drivers remains incompletely understood. Species radiations on islands have been among the most prominently studied systems 9 , 10 , 11 , 12 . For example, the Malesian archipelago in the tropical Far East 13 , consisting of thousands of islands and including New Guinea and Borneo, the second and third largest islands in the world, is a biodiversity hotspot containing many radiations of plant and animal species. Among forest trees, local tree species richness across Southeast Asian forests is largely driven by a small number of highly species-rich genera 14 . The clove genus, Syzygium , is one of the most important of these genera, and therefore understanding diversification and its underlying drivers within Syzygium may help explain large-scale patterns of diversity in the Palaeotropics. However, Syzygium , like many other species radiations that hold immense morphological and ecological variation, has so far been difficult to resolve phylogenetically 15 , 16 , 17 , 18 , leading to the impression that evolutionary change can be a swift process that may not require substantial underlying genetic change 9 . Here, we employ genome-scale approaches to investigate speciation patterns and their potential drivers in the most species-rich tree genus worldwide, Syzygium 19 . Syzygium , which includes 1193 species recognised worldwide 20 , is a genus in the myrtle family (Myrtaceae). Syzygium is restricted to tropical and subtropical regions of the Old World, where it is distributed from Africa through to India, across Southeast Asia and extending to Hawaii in the Pacific Ocean, with the centre of species diversity in Indomalesia 20 . The type species of Syzygium is S. caryophyllatum , a poorly known, small to medium-sized tree endemic to southern India and Sri Lanka 21 . The best-known species in the genus is the clove tree, Syzygium aromaticum , from which flower buds are gathered, dried, and used as a spice, a preservative and in pharmacology 22 . In addition, Syzygium aqueum , S. cumini , S. jambos , S. malaccense and S. samarangense are widely cultivated in the tropics for their large edible fruits 23 . Syzygium samarangense is cultivated commercially in Southeast Asia, where it is marketed as the wax apple, java apple, rose apple, or samarang rose apple. Apart from being used as cooking ingredients or cultivated for fruits, Syzygium species with dense and bushy crowns, such as S. antisepticum , S. australe , S. luehmannii , S. myrtifolium and S. zeylanicum , are used in the horticulture industry in Australia, Indonesia, Malaysia and Singapore for hedges, natural fences, natural sound barriers and privacy screens 24 . Syzygium species are generally medium-sized to large, characteristically sub-canopy trees that are sometimes emergent, while some also form shrubs, small forest understorey treelets, swamp and mangrove forest trees, and rheophytic vegetation 25 . As is true of many tropical trees, Syzygium flowers are visited by a large diversity of insects and vertebrates, and their fruits are typically eaten by a variety of flying and arboreal vertebrates and even terrestrial bird, mammal and reptile browsers 25 . Syzygium species also occur as dominant mid-level canopy trees, affecting the ecosystems of plants, animals, and fungi in lower forest layers 25 . Many species co-occur; for example, there exist ca. 50 taxa on a single 52-ha. ecological plot in the Lambir Hills National Park (Sarawak, East Malaysia, Borneo 26 ), where they display fine-scale differentiation in habitat occupancy and stature 14 . The genus is notorious as one of the most difficult to identify due to the paucity of clear, diagnostic morphological characters for distinguishing species; 25 , 27 , 28 morphological variation in the genus can appear as continua of traits rather than collections of discrete units. Given the immense number of species assigned to Syzygium , it contributes disproportionately to the diversity of Southeast Asian tropical forests. Therefore, understanding diversification and its underlying drivers within Syzygium may help explain large-scale patterns of diversity. Thus far, however, phylogenetic studies of Syzygium have involved only a few PCR-amplified plastid and nuclear marker genes 15 , 16 . An infrageneric classification proposed in 2010 was based on three plastid loci 17 , and although it resolved some major clades, interrelationships within the bulk of the genus, species of Syzygium subg. Syzygium , were left largely unresolved. Here, we sequence whole genomes to vastly increase the available data in an attempt to more fully resolve phylogenetic relationships among Syzygium species. We use Oxford Nanopore Technology (ONT) long-read sequencing 29 to assemble and annotate a chromosome-scale reference genome for the sea apple, Syzygium grande 23 . This species was selected as a representative because it is a well-known member<|im_end|> <|im_start|>assistant An international study that analyzed the world's largest tree group has made breakthrough findings. The results are expected to guide future conservation of tropical and subtropical rain forests as well as help with predicting how certain plants will respond to climate change. More than 60 researchers explored the evolution and speciation patterns of the tree group Syzgium, which includes the trees that gives us the spice clove as well as numerous fruits. The study was led by the Singapore Botanic Gardens of Singapore's National Parks Board in collaboration with 26 international research institutions including the University of Aberdeen, Royal Botanic Gardens, Kew, Nanyang Technological University and the University of Buffalo. Published in Nature Communications the research is the most extensive study of any Syzgium group of trees to date and was carried out over two years using samples from some 300 species growing in Africa, Sri Lanka, Malaysia, Singapore, Indonesia, Japan, Australia and the Pacific Islands. Trees growing in tropical areas are understood to be some of the most valuable in the world in protecting biodiversity and global warming, but they are also among some of the most threatened because of commercial needs and use of the land for farming. Native and widespread in tropical and subtropical rain forests, studying the origins and drivers of the large hyperdiverse tree group Syzygium contributes to the understanding of how plant species have emerged in the past in response to environmental changes. This knowledge is valuable for predicting how plants might respond to ecological changes brought about by climate change and will guide conservation and management efforts for plant communities. The Syzygium species may be found growing together with other trees within the understory and canopy layers of forests. Because of its large diversity, they play an inordinate role in the functioning of forest ecosystems. Many Syzygium species are also cultivated in tropical countries for different types of spices as well as their large edible fruits. Understanding how Syzygium species have evolved will help to advance knowledge of the highly complex species-environment relationships in forest ecosystems and anticipate forest ecosystem changes in response to climate change. The University of Aberdeen's Interdisciplinary Director for Environment and Biodiversity Professor David Burslem says that "tropical forests are under severe threat from conversion, industrial logging and climate change. The new results on the origins and biodiversity of Syzygium, an important group of tropical trees containing many species of commercial importance for timber and fruit production, provides the raw material for devising strategies for species conservation and restoration." "This new paper will serve as a benchmark for future studies combining genomic analyses with extensive data-sets on species distributions and satellite-derived environmental sensing to finally understand the mechanisms that drive patterns of tropical forest biodiversity." "It was a privilege for the University of Aberdeen to work closely with experts from Singapore Botanic Gardens as well as many other prestigious international organizations on this vitally important project which is one of the first genome-scale plant evolutionary studies on a single group to be published that was so widely-sampled." Dr. David Middleton, coordinating director at Singapore Botanic Gardens, says that "Southeast Asia is a region of exceptionally rich species diversity. The Singapore Botanic Gardens has played a contributory role to the study of plant diversity in the region since its founding in 1859, as part of the Gardens' core roles in research, conservation and education." "The enormous genus Syzygium, the species of which are mainly understory trees, has long been neglected in comparison to the iconic forest giants and plant groups of more immediate economic interest. However, their role in the diversity and functioning of our forests must be better understood if we are to succeed in our conservation goals." "In partnership with our collaborators at home and abroad, we have begun to understand what drives such exceptional species diversity in tropical Southeast Asia and can make better informed decisions on how to conserve this diversity. This strengthens the science on conservation in the region and contributes towards Singapore's City in Nature vision." <|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 ancient harbour of Pisa, Portus Pisanus , was one of Italy’s most influential seaports for many centuries. Nonetheless, very little is known about its oldest harbour and the relationships between environmental evolution and the main stages of harbour history. The port complex that ensured Pisa’s position as an economic and maritime power progressively shifted westwards by coastal progradation, before the maritime port of Livorno was built in the late 16 th century AD. The lost port is, however, described in the early 5 th century AD as being “a large, naturally sheltered embayment” that hosted merchant vessels, suggesting an important maritime structure with significant artificial infrastructure to reach the city. Despite its importance, the geographical location of the harbour complex remains controversial and its environmental evolution is unclear. To fill this knowledge gap and furnish accurate palaeoenvironmental information on Portus Pisanus , we used bio- and geosciences. Based on stratigraphic data, the area’s relative sea-level history, and long-term environmental dynamics, we established that at ~200 BC, a naturally protected lagoon developed and hosted Portus Pisanus until the 5 th century AD. The decline of the protected lagoon started at ~1350 AD and culminated ~1500 AD, after which time the basin was a coastal lake. Introduction While Italy’s rich maritime history has sharpened focus on ancient harbours and human impacts in port basins (e.g. Altinum -Venice, Portus Lunae -Luni, Portus -Rome, Ostia -Rome, Neapolis -Naples) 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , the evolution of Portus Pisanus , the powerful seaport of the city of Pisa (Italy, Tuscany), was, until recently, largely unknown 9 , 10 , 11 , 12 , 13 , 14 , 15 . The city is currently located ~10 km east of the Ligurian Sea coast but its long and complex history 16 , 17 is closely linked to its port, named Portus Pisanus by late Roman sources (Rutilius Namatianus descriptions in de reditu suo , Itinerarium Maritimum 501 ) 15 , 18 , 19 , 20 . Since the Imperial Roman period, most of the supplies imported from Mediterranean provinces reached the city of Pisa through a complex harbour system that included Portus Pisanus , the fluvial Ports San Piero a Grado and Isola di Migliarino, and other minor landings along the ancient coast, the Arno and Serchio rivers and canals including the site of Pisa-Stazione Ferroviaria San Rossore 21 , 22 , 23 , 24 , 25 , 26 . The heyday of the seaport played out from the Late Republican Roman period to the Middle Ages, when Pisa became an influential Commune and maritime power 16 , 18 , 27 . In the Middle Ages, Portus Pisanus was the main harbour of Pisa: the harbour system included Vada, the ports of the Piombino promontory, Castiglione della Pescaia and other minor landings 27 . During the 13 th century AD, it was one of the most important seaports in Italy, rivaling Genoa, Venice, and Amalfi 16 , 28 , 29 , 30 . The name Portus Pisanus , documented since the 5 th –6 th centuries AD, was probably in use earlier. In 56 BC, Cicero mentioned a harbour ( Ad Quintum fratrem 2, 5), Portus Labro , probably located in the same area. Is Portus Labro an earlier name for Portus Pisanus (as might be suggested by the current hydronym Calambrone, situated north of Livorno) or a different harbour? In the Middle Ages, the name Portus Pisanus was used to identify both the harbour and a large part of the Livorno hinterland. Between the second half of the 14 th century AD and the mid-15 th century AD, the names Portus Pisanus and Porto di Livorno coexisted. While the appellation Porto di Livorno became prevalent, part of the harbour basin was still named Portus Pisanus . The name Porto di Livorno has prevailed since the late 1500 s AD. The exact location of Portus Pisanus has long been discussed, despite several Roman literary sources (e.g. Itinerarium Maritimum , de reditu suo ) and studies 10 , 31 , 32 that placed the harbour ~10–13 km south of the city of Pisa, in an area which presently corresponds to the north-eastern edge of the port city Livorno, and despite an accurate description of the area (Santo Stefano ai Lupi) published by Targioni Tozzetti in 1775 33 with an associated map. Recent archaeological excavations at Santo Stefano ai Lupi corroborate both the classical sources and Targioni Tozzetti’s description with the discovery of portions of sea bed covered by fragments of ancient pottery (dated to the 6 th –5 th centuries B.C. and to a period between the 1 st century BC and the 6 th century AD), ballast stones, part of a small stone dock, some buildings including a warehouse, and a necropolis dated to the 4 th –5 th centuries AD 14 , 34 , 35 . These structures belong to Portus Pisanus’ harbour system, but just a small area of the ancient port city and the adjacent basin has been excavated. The pottery fragments found on the ancient sea bed prove that, in this part of what was called Portus Pisanus , boats and ships were loaded and unloaded. The associated harbour basin is believed to be a large, naturally sheltered embayment that accommodated ships from the Etruscan and Roman periods to the Late Medieval Ages, when Pisa grew into a very important commercial and naval center, controlling a significant merchant fleet and navy 35 . The existence of a highly protected natural basin would have been of great benefit to navigation and trade, facilitating the establishment of port complexes, through the use of the natural landscape. Historical sources or archaeological excavations have not unearthed any artificial moles at Portus Pisanus , suggesting a very confined harbour that was naturally protected by its geomorphological endowments 20 . Here, we use bio- and geosciences to probe the long maritime history of the seaport of", "role": "user" }, { "content": "New insights into the evolution and eventual disappearance of Portus Pisanus, the lost harbour of Pisa, have been revealed. Although it has been described as one of Italy's most influential seaports during the Middle Ages, little is known about the relationship between Portus Pisanus's environment and its history. To understand the role that long-term coastal dynamics, sea-level rise and a changing environment played in the harbour's evolution, researchers reconstructed relative sea levels for the eastern Ligurian Sea over a 10,500-year period. The research team, led by David Kaniewski, also coupled historical maps with geological data to reconstruct the morphology of the coast around the Pisa harbour basin. They analysed biological samples from sediment layers to investigate how seawater, freshwater or agricultural activities may have influenced the environment in the area, before comparing and contrasting their data with written sources and archaeological data. The findings suggest that at approximately 200 BC, a naturally protected lagoon with a good connection to the sea developed south of the city of Pisa that would have benefited navigation and trade and facilitated the establishment of port complexes. The lagoon hosted Portus Pisanus well beyond the 5th century AD but its degree of sea connection began to decline from around 1000-1250 AD, as coastlines shifted towards the sea. It was cut off from the sea and disappeared around 1500 AD when the basin developed into a coastal lake and Portus Pisanus was replaced by the maritime harbour of Livorno. \"This paper is the result of a very intense collaboration between geo-scientists and archaeologists in the Mediterranean Sea,\" said Dr. Matteo Vacchi, from the University of Exeter. \"Our results underline the importance of such approaches to understand the role of long-term coastal changes and their impacts on the societies living by the sea, notably in the last two millennia. \"The study of the evolution in the coastal zone in the past is a fundamental tool to predict future changes in the context of climatic change. \"Thanks to the huge amount of archaeological remains, the Mediterranean Sea offers the unique possibility to understand the ability of past societies to respond to such major coastal changes. \"I am working with colleagues on similar studies in other Mediterranean coastal areas, including Corsica and Sardinia. \"These Islands, placed in the middle of the Western Mediterranean, have a huge potential for this kind of investigations and represents a major focus of my current research activity.\" The paper, published in the journal Scientific Reports, is titled \"Holocene evolution of Portus Pisanus, the lost harbour of Pisa.\" ", "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 ancient harbour of Pisa, Portus Pisanus , was one of Italy’s most influential seaports for many centuries. Nonetheless, very little is known about its oldest harbour and the relationships between environmental evolution and the main stages of harbour history. The port complex that ensured Pisa’s position as an economic and maritime power progressively shifted westwards by coastal progradation, before the maritime port of Livorno was built in the late 16 th century AD. The lost port is, however, described in the early 5 th century AD as being “a large, naturally sheltered embayment” that hosted merchant vessels, suggesting an important maritime structure with significant artificial infrastructure to reach the city. Despite its importance, the geographical location of the harbour complex remains controversial and its environmental evolution is unclear. To fill this knowledge gap and furnish accurate palaeoenvironmental information on Portus Pisanus , we used bio- and geosciences. Based on stratigraphic data, the area’s relative sea-level history, and long-term environmental dynamics, we established that at ~200 BC, a naturally protected lagoon developed and hosted Portus Pisanus until the 5 th century AD. The decline of the protected lagoon started at ~1350 AD and culminated ~1500 AD, after which time the basin was a coastal lake. Introduction While Italy’s rich maritime history has sharpened focus on ancient harbours and human impacts in port basins (e.g. Altinum -Venice, Portus Lunae -Luni, Portus -Rome, Ostia -Rome, Neapolis -Naples) 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , the evolution of Portus Pisanus , the powerful seaport of the city of Pisa (Italy, Tuscany), was, until recently, largely unknown 9 , 10 , 11 , 12 , 13 , 14 , 15 . The city is currently located ~10 km east of the Ligurian Sea coast but its long and complex history 16 , 17 is closely linked to its port, named Portus Pisanus by late Roman sources (Rutilius Namatianus descriptions in de reditu suo , Itinerarium Maritimum 501 ) 15 , 18 , 19 , 20 . Since the Imperial Roman period, most of the supplies imported from Mediterranean provinces reached the city of Pisa through a complex harbour system that included Portus Pisanus , the fluvial Ports San Piero a Grado and Isola di Migliarino, and other minor landings along the ancient coast, the Arno and Serchio rivers and canals including the site of Pisa-Stazione Ferroviaria San Rossore 21 , 22 , 23 , 24 , 25 , 26 . The heyday of the seaport played out from the Late Republican Roman period to the Middle Ages, when Pisa became an influential Commune and maritime power 16 , 18 , 27 . In the Middle Ages, Portus Pisanus was the main harbour of Pisa: the harbour system included Vada, the ports of the Piombino promontory, Castiglione della Pescaia and other minor landings 27 . During the 13 th century AD, it was one of the most important seaports in Italy, rivaling Genoa, Venice, and Amalfi 16 , 28 , 29 , 30 . The name Portus Pisanus , documented since the 5 th –6 th centuries AD, was probably in use earlier. In 56 BC, Cicero mentioned a harbour ( Ad Quintum fratrem 2, 5), Portus Labro , probably located in the same area. Is Portus Labro an earlier name for Portus Pisanus (as might be suggested by the current hydronym Calambrone, situated north of Livorno) or a different harbour? In the Middle Ages, the name Portus Pisanus was used to identify both the harbour and a large part of the Livorno hinterland. Between the second half of the 14 th century AD and the mid-15 th century AD, the names Portus Pisanus and Porto di Livorno coexisted. While the appellation Porto di Livorno became prevalent, part of the harbour basin was still named Portus Pisanus . The name Porto di Livorno has prevailed since the late 1500 s AD. The exact location of Portus Pisanus has long been discussed, despite several Roman literary sources (e.g. Itinerarium Maritimum , de reditu suo ) and studies 10 , 31 , 32 that placed the harbour ~10–13 km south of the city of Pisa, in an area which presently corresponds to the north-eastern edge of the port city Livorno, and despite an accurate description of the area (Santo Stefano ai Lupi) published by Targioni Tozzetti in 1775 33 with an associated map. Recent archaeological excavations at Santo Stefano ai Lupi corroborate both the classical sources and Targioni Tozzetti’s description with the discovery of portions of sea bed covered by fragments of ancient pottery (dated to the 6 th –5 th centuries B.C. and to a period between the 1 st century BC and the 6 th century AD), ballast stones, part of a small stone dock, some buildings including a warehouse, and a necropolis dated to the 4 th –5 th centuries AD 14 , 34 , 35 . These structures belong to Portus Pisanus’ harbour system, but just a small area of the ancient port city and the adjacent basin has been excavated. The pottery fragments found on the ancient sea bed prove that, in this part of what was called Portus Pisanus , boats and ships were loaded and unloaded. The associated harbour basin is believed to be a large, naturally sheltered embayment that accommodated ships from the Etruscan and Roman periods to the Late Medieval Ages, when Pisa grew into a very important commercial and naval center, controlling a significant merchant fleet and navy 35 . The existence of a highly protected natural basin would have been of great benefit to navigation and trade, facilitating the establishment of port complexes, through the use of the natural landscape. Historical sources or archaeological excavations have not unearthed any artificial moles at Portus Pisanus , suggesting a very confined harbour that was naturally protected by its geomorphological endowments 20 . Here, we use bio- and geosciences to probe the long maritime history of the seaport of<|im_end|> <|im_start|>assistant New insights into the evolution and eventual disappearance of Portus Pisanus, the lost harbour of Pisa, have been revealed. Although it has been described as one of Italy's most influential seaports during the Middle Ages, little is known about the relationship between Portus Pisanus's environment and its history. To understand the role that long-term coastal dynamics, sea-level rise and a changing environment played in the harbour's evolution, researchers reconstructed relative sea levels for the eastern Ligurian Sea over a 10,500-year period. The research team, led by David Kaniewski, also coupled historical maps with geological data to reconstruct the morphology of the coast around the Pisa harbour basin. They analysed biological samples from sediment layers to investigate how seawater, freshwater or agricultural activities may have influenced the environment in the area, before comparing and contrasting their data with written sources and archaeological data. The findings suggest that at approximately 200 BC, a naturally protected lagoon with a good connection to the sea developed south of the city of Pisa that would have benefited navigation and trade and facilitated the establishment of port complexes. The lagoon hosted Portus Pisanus well beyond the 5th century AD but its degree of sea connection began to decline from around 1000-1250 AD, as coastlines shifted towards the sea. It was cut off from the sea and disappeared around 1500 AD when the basin developed into a coastal lake and Portus Pisanus was replaced by the maritime harbour of Livorno. "This paper is the result of a very intense collaboration between geo-scientists and archaeologists in the Mediterranean Sea," said Dr. Matteo Vacchi, from the University of Exeter. "Our results underline the importance of such approaches to understand the role of long-term coastal changes and their impacts on the societies living by the sea, notably in the last two millennia. "The study of the evolution in the coastal zone in the past is a fundamental tool to predict future changes in the context of climatic change. "Thanks to the huge amount of archaeological remains, the Mediterranean Sea offers the unique possibility to understand the ability of past societies to respond to such major coastal changes. "I am working with colleagues on similar studies in other Mediterranean coastal areas, including Corsica and Sardinia. "These Islands, placed in the middle of the Western Mediterranean, have a huge potential for this kind of investigations and represents a major focus of my current research activity." The paper, published in the journal Scientific Reports, is titled "Holocene evolution of Portus Pisanus, the lost harbour of Pisa." <|im_end|>

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1,964

[ { "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 Objective To assess the consistency of machine learning and statistical techniques in predicting individual level and population level risks of cardiovascular disease and the effects of censoring on risk predictions. Design Longitudinal cohort study from 1 January 1998 to 31 December 2018. Setting and participants 3.6 million patients from the Clinical Practice Research Datalink registered at 391 general practices in England with linked hospital admission and mortality records. Main outcome measures Model performance including discrimination, calibration, and consistency of individual risk prediction for the same patients among models with comparable model performance. 19 different prediction techniques were applied, including 12 families of machine learning models (grid searched for best models), three Cox proportional hazards models (local fitted, QRISK3, and Framingham), three parametric survival models, and one logistic model. Results The various models had similar population level performance (C statistics of about 0.87 and similar calibration). However, the predictions for individual risks of cardiovascular disease varied widely between and within different types of machine learning and statistical models, especially in patients with higher risks. A patient with a risk of 9.5-10.5% predicted by QRISK3 had a risk of 2.9-9.2% in a random forest and 2.4-7.2% in a neural network. The differences in predicted risks between QRISK3 and a neural network ranged between –23.2% and 0.1% (95% range). Models that ignored censoring (that is, assumed censored patients to be event free) substantially underestimated risk of cardiovascular disease. Of the 223 815 patients with a cardiovascular disease risk above 7.5% with QRISK3, 57.8% would be reclassified below 7.5% when using another model. Conclusions A variety of models predicted risks for the same patients very differently despite similar model performances. The logistic models and commonly used machine learning models should not be directly applied to the prediction of long term risks without considering censoring. Survival models that consider censoring and that are explainable, such as QRISK3, are preferable. The level of consistency within and between models should be routinely assessed before they are used for clinical decision making. Introduction Risk prediction models are used routinely in healthcare practice to identify patients at high risk and make treatment decisions, so that appropriate healthcare resources can be allocated to those patients who most need care. 1 These risk prediction models are usually built using statistical regression techniques. Examples include the Framingham risk score (developed from a US cohort with prospectively collected data) 2 and QRISK3 (developed from a large UK cohort using retrospective electronic health records). 3 Recently, machine learning models have gained considerable popularity. The English National Health Service has invested £250m ($323m; €275m) to further embed machine learning in healthcare. 4 A recent viewpoint article suggested that machine learning technology is about to start a revolution with the potential to transform the whole healthcare system. 5 Several studies suggested that machine learning models could outperform statistical models in terms of calibration and discrimination. 6 7 8 9 However, another viewpoint concerns the fact that these approaches cannot provide explainable reasons behind their predictions, potentially leading to inappropriate actions, 10 and a recent review found no evidence that machine learning models had better model performance than logistic models. 11 However, interpretation of this review is difficult, as it included models from mostly small sample sizes and with different outcomes and predictors. Machine learning has established strengths in image recognition that could help in diagnosing diseases in healthcare, 12 13 14 15 but censoring (patients lost to follow-up), which is common in risk prediction, does not exist in image recognition. Many commonly used machine learning models do not take into account censoring by default. 16 The objective of this study was to assess the robustness and consistency of a variety of machine learning and statistical models on individual risk prediction and the effects of censoring on risk predictions. We used cardiovascular disease as an exemplar. We defined robustness of individual risk prediction as the level of consistency in the prediction of risks for individual patients with models that have comparable population level performance metrics. 17 18 19 Methods Data source We derived the study cohort from Clinical Practice Research Datalink (CPRD GOLD), which includes data from about 6.9% of the population in England. 20 It also has been linked to Hospital Episode Statistics, Office for National Statistics mortality records, and Townsend deprivation scores, 3 to provide additional information about hospital admissions (including date and discharge diagnoses) and cause specific mortality. 20 CPRD includes patients’ electronic health records from general practice, capturing detailed information such as demographics (age, sex, and ethnicity), symptoms, tests, diagnoses, prescribed treatments, health related behaviours, and referrals to secondary care. 20 CPRD is a well established representative cohort of the UK population, and thousands of studies have used it, 21 22 including a validation of the QRISK2 model and an analysis of machine learning. 8 23 Study population This study used the same selection criteria for the study population, risk factors, and cardiovascular disease outcomes as were used for QRISK3. 3 18 Follow-up of patients started at the date of the patient’s registration with the practice, their 25th birthday, or 1 January 1998 (whichever was latest) and ended at the date of death, incident cardiovascular disease, date of leaving the practice, or last date of data collection (whichever was earliest). The index date for measurement of cardiovascular disease risk was randomly chosen from the follow-up period to capture time relevant practice variability with a better spread of calendar time and age. 24 This was different from QRISK3, for which a single calendar time date was mostly used. 18 The main inclusion criteria were age between 25 and 84 years, no history of cardiovascular disease, and no prescription for a statin before the index date. The outcome of interest was the 10 year risk of developing cardiovascular disease. The definition of the primary clinical outcome (cardiovascular disease) was the same as for QRISK3 (that is, coronary heart disease, ischaemic stroke, or transient ischaemic attack). 3 We extracted two main cohorts from the study", "role": "user" }, { "content": "Some claim that machine learning technology has the potential to transform healthcare systems, but a study published by The BMJ finds that machine learning models have similar performance to traditional statistical models and share similar uncertainty in making risk predictions for individual patients. The NHS has invested £250m ($323m; €275m) to embed machine learning in healthcare, but researchers say the level of consistency (stability) within and between models should be assessed before they are used to make treatment decisions for individual patients. Risk prediction models are widely used in clinical practice. They use statistical techniques alongside information about people, such as their age and ethnicity, to identify those at high risk of developing an illness and make decisions about their care. Previous research has found that a traditional risk prediction model such as QRISK3 has very good model performance at the population level, but has considerable uncertainty on individual risk prediction. Some studies claim that machine learning models can outperform traditional models, while others argue that they cannot provide explainable reasons behind their predictions, potentially leading to inappropriate actions. What's more, machine learning models often ignore censoring—when patients are lost (either by error or by being unreachable) during a study and the model assumes they are disease free, leading to biased predictions. To explore these issues further, researchers in the UK, China and the Netherlands set out to assess the consistency of machine learning and statistical techniques in predicting individual level and population level risks of cardiovascular disease and the effects of censoring on risk predictions. They assessed 19 different prediction techniques (12 machine learning models and seven statistical models) using data from 3.6 million patients registered at 391 general practices in England between 1998 and 2018. Data from general practices, hospital admission and mortality records were used to test each model's performance against actual events. All 19 models yielded similar population level performance. However, cardiovascular disease risk predictions for the same patients varied substantially between models, especially in patients with higher risks. For example, a patient with a cardiovascular disease risk of 9.5-10.5% predicted by the traditional QRISK3 model had a risk of 2.9-9.2% and 2.4-7.2% predicted by other models. Models that ignored censoring (including commonly used machine learning models) substantially underestimated risk of cardiovascular disease. Of the 223,815 patients with a cardiovascular disease risk above 7.5% with QRISK3 (a model that does consider censoring), 57.8% would be reclassified below 7.5% when using another type of model, explain the researchers. The researchers acknowledge some limitations in comparing the different models, such as the fact that more predictors could have been considered. However, they point out that their results remained similar after more detailed analyses, suggesting that they withstand scrutiny. \"A variety of models predicted risks for the same patients very differently despite similar model performances,\" they write. \"Consequently, different treatment decisions could be made by arbitrarily selecting another modelling technique.\" As such, they suggest these models \"should not be directly applied to the prediction of long term risks without considering censoring\" and that the level of consistency within and between models \"should be routinely assessed before they are used to inform clinical decision making.\" ", "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 Objective To assess the consistency of machine learning and statistical techniques in predicting individual level and population level risks of cardiovascular disease and the effects of censoring on risk predictions. Design Longitudinal cohort study from 1 January 1998 to 31 December 2018. Setting and participants 3.6 million patients from the Clinical Practice Research Datalink registered at 391 general practices in England with linked hospital admission and mortality records. Main outcome measures Model performance including discrimination, calibration, and consistency of individual risk prediction for the same patients among models with comparable model performance. 19 different prediction techniques were applied, including 12 families of machine learning models (grid searched for best models), three Cox proportional hazards models (local fitted, QRISK3, and Framingham), three parametric survival models, and one logistic model. Results The various models had similar population level performance (C statistics of about 0.87 and similar calibration). However, the predictions for individual risks of cardiovascular disease varied widely between and within different types of machine learning and statistical models, especially in patients with higher risks. A patient with a risk of 9.5-10.5% predicted by QRISK3 had a risk of 2.9-9.2% in a random forest and 2.4-7.2% in a neural network. The differences in predicted risks between QRISK3 and a neural network ranged between –23.2% and 0.1% (95% range). Models that ignored censoring (that is, assumed censored patients to be event free) substantially underestimated risk of cardiovascular disease. Of the 223 815 patients with a cardiovascular disease risk above 7.5% with QRISK3, 57.8% would be reclassified below 7.5% when using another model. Conclusions A variety of models predicted risks for the same patients very differently despite similar model performances. The logistic models and commonly used machine learning models should not be directly applied to the prediction of long term risks without considering censoring. Survival models that consider censoring and that are explainable, such as QRISK3, are preferable. The level of consistency within and between models should be routinely assessed before they are used for clinical decision making. Introduction Risk prediction models are used routinely in healthcare practice to identify patients at high risk and make treatment decisions, so that appropriate healthcare resources can be allocated to those patients who most need care. 1 These risk prediction models are usually built using statistical regression techniques. Examples include the Framingham risk score (developed from a US cohort with prospectively collected data) 2 and QRISK3 (developed from a large UK cohort using retrospective electronic health records). 3 Recently, machine learning models have gained considerable popularity. The English National Health Service has invested £250m ($323m; €275m) to further embed machine learning in healthcare. 4 A recent viewpoint article suggested that machine learning technology is about to start a revolution with the potential to transform the whole healthcare system. 5 Several studies suggested that machine learning models could outperform statistical models in terms of calibration and discrimination. 6 7 8 9 However, another viewpoint concerns the fact that these approaches cannot provide explainable reasons behind their predictions, potentially leading to inappropriate actions, 10 and a recent review found no evidence that machine learning models had better model performance than logistic models. 11 However, interpretation of this review is difficult, as it included models from mostly small sample sizes and with different outcomes and predictors. Machine learning has established strengths in image recognition that could help in diagnosing diseases in healthcare, 12 13 14 15 but censoring (patients lost to follow-up), which is common in risk prediction, does not exist in image recognition. Many commonly used machine learning models do not take into account censoring by default. 16 The objective of this study was to assess the robustness and consistency of a variety of machine learning and statistical models on individual risk prediction and the effects of censoring on risk predictions. We used cardiovascular disease as an exemplar. We defined robustness of individual risk prediction as the level of consistency in the prediction of risks for individual patients with models that have comparable population level performance metrics. 17 18 19 Methods Data source We derived the study cohort from Clinical Practice Research Datalink (CPRD GOLD), which includes data from about 6.9% of the population in England. 20 It also has been linked to Hospital Episode Statistics, Office for National Statistics mortality records, and Townsend deprivation scores, 3 to provide additional information about hospital admissions (including date and discharge diagnoses) and cause specific mortality. 20 CPRD includes patients’ electronic health records from general practice, capturing detailed information such as demographics (age, sex, and ethnicity), symptoms, tests, diagnoses, prescribed treatments, health related behaviours, and referrals to secondary care. 20 CPRD is a well established representative cohort of the UK population, and thousands of studies have used it, 21 22 including a validation of the QRISK2 model and an analysis of machine learning. 8 23 Study population This study used the same selection criteria for the study population, risk factors, and cardiovascular disease outcomes as were used for QRISK3. 3 18 Follow-up of patients started at the date of the patient’s registration with the practice, their 25th birthday, or 1 January 1998 (whichever was latest) and ended at the date of death, incident cardiovascular disease, date of leaving the practice, or last date of data collection (whichever was earliest). The index date for measurement of cardiovascular disease risk was randomly chosen from the follow-up period to capture time relevant practice variability with a better spread of calendar time and age. 24 This was different from QRISK3, for which a single calendar time date was mostly used. 18 The main inclusion criteria were age between 25 and 84 years, no history of cardiovascular disease, and no prescription for a statin before the index date. The outcome of interest was the 10 year risk of developing cardiovascular disease. The definition of the primary clinical outcome (cardiovascular disease) was the same as for QRISK3 (that is, coronary heart disease, ischaemic stroke, or transient ischaemic attack). 3 We extracted two main cohorts from the study<|im_end|> <|im_start|>assistant Some claim that machine learning technology has the potential to transform healthcare systems, but a study published by The BMJ finds that machine learning models have similar performance to traditional statistical models and share similar uncertainty in making risk predictions for individual patients. The NHS has invested £250m ($323m; €275m) to embed machine learning in healthcare, but researchers say the level of consistency (stability) within and between models should be assessed before they are used to make treatment decisions for individual patients. Risk prediction models are widely used in clinical practice. They use statistical techniques alongside information about people, such as their age and ethnicity, to identify those at high risk of developing an illness and make decisions about their care. Previous research has found that a traditional risk prediction model such as QRISK3 has very good model performance at the population level, but has considerable uncertainty on individual risk prediction. Some studies claim that machine learning models can outperform traditional models, while others argue that they cannot provide explainable reasons behind their predictions, potentially leading to inappropriate actions. What's more, machine learning models often ignore censoring—when patients are lost (either by error or by being unreachable) during a study and the model assumes they are disease free, leading to biased predictions. To explore these issues further, researchers in the UK, China and the Netherlands set out to assess the consistency of machine learning and statistical techniques in predicting individual level and population level risks of cardiovascular disease and the effects of censoring on risk predictions. They assessed 19 different prediction techniques (12 machine learning models and seven statistical models) using data from 3.6 million patients registered at 391 general practices in England between 1998 and 2018. Data from general practices, hospital admission and mortality records were used to test each model's performance against actual events. All 19 models yielded similar population level performance. However, cardiovascular disease risk predictions for the same patients varied substantially between models, especially in patients with higher risks. For example, a patient with a cardiovascular disease risk of 9.5-10.5% predicted by the traditional QRISK3 model had a risk of 2.9-9.2% and 2.4-7.2% predicted by other models. Models that ignored censoring (including commonly used machine learning models) substantially underestimated risk of cardiovascular disease. Of the 223,815 patients with a cardiovascular disease risk above 7.5% with QRISK3 (a model that does consider censoring), 57.8% would be reclassified below 7.5% when using another type of model, explain the researchers. The researchers acknowledge some limitations in comparing the different models, such as the fact that more predictors could have been considered. However, they point out that their results remained similar after more detailed analyses, suggesting that they withstand scrutiny. "A variety of models predicted risks for the same patients very differently despite similar model performances," they write. "Consequently, different treatment decisions could be made by arbitrarily selecting another modelling technique." As such, they suggest these models "should not be directly applied to the prediction of long term risks without considering censoring" and that the level of consistency within and between models "should be routinely assessed before they are used to inform clinical decision making." <|im_end|>

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1,994

[ { "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 Gene correction in human long-term hematopoietic stem cells (LT-HSCs) could be an effective therapy for monogenic diseases of the blood and immune system. Here we describe an approach for X-linked sSevere cCombined iImmunodeficiency (SCID-X1) using targeted integration of a cDNA into the endogenous start codon to functionally correct disease-causing mutations throughout the gene. Using a CRISPR-Cas9/AAV6 based strategy, we achieve up to 20% targeted integration frequencies in LT-HSCs. As measures of the lack of toxicity we observe no evidence of abnormal hematopoiesis following transplantation and no evidence of off-target mutations using a high-fidelity Cas9 as a ribonucleoprotein complex. We achieve high levels of targeting frequencies (median 45%) in CD34 + HSPCs from six SCID-X1 patients and demonstrate rescue of lymphopoietic defect in a patient derived HSPC population in vitro and in vivo. In sum, our study provides specificity, toxicity and efficacy data supportive of clinical development of genome editing to treat SCID-Xl. Introduction X-linked sSevere cCombined iImmunodeficiency (SCID-X1) is a primary immune deficiency disorder (PID) caused by mutations in the IL2RG gene on the X chromosome. The gene encodes a shared subunit of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Without early treatment, affected male infants die in the first year of life from infections. Although allogeneic hematopoietic cell transplant (allo-HCT) is considered the standard of care for SCID-X1, it holds significant risks due to potential incomplete immune reconstitution, graft versus host disease (GvHD) and a decreased survival rate in the absence of an human leukocyte antigen (HLA)-matched sibling donor 1 . Because of the selective advantage of lymphoid progenitors expressing normal IL2RG , however, only a small number of genetically corrected hematopoietic stem and progenitor cells (HSPCs) are needed to reconstitute T-cell immunity 2 , 3 . The importance of achieving gene correction in long-term hematopoietic stem cells (LT-HSCs) to achieve sustained clinical benefit is demonstrated by the waning of a functional immune system in patients who do not derive their immune system from LT-HSCs with a wild-type IL2RG gene. Gene therapy is an alternative therapy to allo-HSCT. Using integrating viral vectors, such as gamma-retroviral and lentiviral vectors, extra copies of a functional IL2RG gene are semi-randomly integrated into the genome of SCID-X1 patient-derived CD34 + HSPCs. This strategy has resulted in both successes and setbacks. While most patients treated with first generation of gene therapy survived and benefited from the therapy, a substantial fraction (>25%) of patients developed leukemia from insertional oncogenesis 4 , 5 , 6 . It is concerning that patients developed leukemia from insertional oncogenesis both early and late, 15 years after transplantation of retroviral-based engineered cells 7 . Constitutive activation of the transgene 8 , the choice of vectors 9 and specific details of the gene therapy procedure have all been proposed as factors contributing to the risk of leukemia and myelodysplastic syndrome that occurred in several trials for primary immunodeficiency disorders (PIDs) including SCID-X1 10 , 11 , chronic granulomatous disease (CGD) 12 , 13 and Wiskott–Aldrich Syndrome (WAS) 14 . With second-generation self-inactivating (SIN) vectors, multiple SCID-X1 patients have successfully reconstituted T-cell immunity in the absence of early leukemic events 15 , 16 , 17 with a follow-up of up to 7 years. However, the follow-up of these therapies remains too short to assess the long-term genotoxicity risk of the newer generation vectors, as transformation of T cells growth can take >10 years to manifest 7 . An alternative to the semi-random delivery of the complementary DNA (cDNA) is to use a targeted genome editing (GE) approach. GE is a means to alter the DNA sequence of a cell, including somatic stem cells, with nucleotide precision. Using homologous recombination-mediated GE (HR-GE), the approach can target a cDNA transgene into its endogenous locus, thereby preserving normal copy number and upstream and downstream non-coding elements that regulate expression 18 , 19 , 20 . The highest frequencies of GE are achieved using an engineered nuclease to create a site-specific double-strand break (DSB) in the cell’s genomic DNA 21 , 22 . When the DSB is repaired by non-homologous end joining (NHEJ), small insertions and deletions (INDELs) can be created at a specific genomic target site—an outcome that is not generally useful for correcting mutant genes 23 , 24 . In contrast, when the DSB is repaired by either HR (using a classic gene-targeting donor vector) or by single-stranded template repair (using a single-stranded oligonucleotide (ssODN)), precise sequence changes can be introduced, thereby providing a method to precisely revert disease-causing DNA variants 25 . Among the multiple GE platforms that use artificial nucleases to generate DSBs 18 , 26 , 27 , 28 , 29 , the CRISPR-Cas9 system has accelerated the field of GE because of its ease of use and high activity in a wide variety of cells. When CRISPR-Cas9 is delivered into primary human cells, including human CD34 + HSPCs as a ribonucleoprotein (RNP) complex using fully synthesized single-guide RNA molecules (sgRNAs) with end modifications to protect the guide from exonuclease degradation, high frequencies of INDELs are achieved 30 . Moreover, when the delivery of an RNP complex is combined with delivery of the gene-targeting donor molecule in a recombinant AAV6 (rAAV6) viral vector, high frequencies of homologous-mediated editing in human HSPCs are obtained 25 . The use of rAAV6 donor vectors have been successfully used with other nuclease systems as well, including zinc-finger nucleases (ZFNs) and in other cell types, such as primary human T cells 19 , 31 , 32 . Therefore, this HR-GE approach could transform the semi-random nature of viral-based gene therapy to a more controlled and precise strategy. By using AAV6 as a classic gene-targeting donor, in contrast to ssODNs, a full cDNA can be introduced at the endogenous target. The key challenges in translating GE into medical therapies is attaining clinically relevant targeted integration frequencies into LT-HSCs, attaining functional levels of protein expression, and establishing lack of toxicity derived from the GE approach. Here, we describe a clinically relevant, selection-free “universal”", "role": "user" }, { "content": "In preclinical trials, Stanford scientists and their collaborators harnessed the gene-editing system CRISPR-Cas9 to replace the mutated gene underpinning the devastating immune disease. Very rarely, a boy is born with a mutation that renders his immune system barren—devoid of any and all immune cells. The disease, X-linked severe combined immunodeficiency, or SCID-X1, often is referred to as the bubble boy disease. It affects only males and is lethal if not treated in the first year of life. Now, scientists at the School of Medicine and their collaborators have used the gene-editing system CRISPR-Cas9 to devise a new treatment to replenish immune cells in mouse models of SCID-X1. The results are promising, the scientists said, because they believe the treatment could potentially work in humans, as well. SCID-X1 affects about 1 in 50,000 male births. Those with the disease suffer from a debilitating mutation in a single gene, IL2R gamma. When this gene is defective, the immune system never develops. The standard treatment for patients with SCID-X1 is a bone marrow transplant, which supplies them with stem cells that will give rise to a working immune system. But the transfer process is tricky and not guaranteed to work. So, Matthew Porteus, MD, Ph.D., professor of pediatrics, came up with a new idea: correct the genes in the patients' own cells. Through CRISPR-Cas9, Porteus and his team have done just that. Using cell samples that came from people with SCID-X1, the researchers genetically altered the class of stem cells that give rise to blood and immune cells. Their approach got the gene working again. Each mouse that received the edited cells began generating new immune cells and displayed no detectable adverse side effects. \"To our knowledge, it's the first time that human SCID-X1 cells edited with CRISPR-Cas9 have been successfully used to make human immune cells in an animal model,\" said postdoctoral scholar Mara Pavel-Dinu, Ph.D. A paper describing the work was published online April 9 in Nature Communications. Porteus is the senior author, and Pavel-Dinu is the first author. Editing in a solution Gene-based therapy for SCID is not new. In the 1990s, scientists began to dabble in gene therapies that used a virus to deliver a new, functional IL2R gamma gene. \"It was very effective, but about 25 percent of the patients developed a leukemia because the virus integrated into an erroneous gene,\" Porteus said. \"It showed both the promise of what gene therapy could do and highlighted the area that needed to be improved.\" Porteus' approach uses CRISPR-Cas9 to create a double-stranded break in DNA to insert a healthy copy of the IL2R gamma gene in the stem cells that create immune cells. Using the gene-editing system, scientists tweaked cells from six people with SCID-X1 and then transplanted those cells into mouse models of SCID-X1. Those mice were then not only able to make their own immune cells, but many of the edited cells retained something called \"stemness,\" meaning that they maintained their ability to continually create new cells. \"The idea is that these modified stem cells will give rise to the blood system and the immune system for the entirety of the patient's life, which we hope is 90 or more years,\" Porteus said. \"And we see evidence for that in our study.\" Popping the bubble \"We've showed that this is a novel and effective strategy to potentially treat this disease, but the other big thing here is safety,\" Porteus said. \"We don't see any abnormalities in the mice that receive the treatment. More specifically, we also performed genetic analysis to see if the CRISPR-Cas9 system made DNA breaks at places that it's not supposed to, and we see no evidence of that.\" That's crucial, Porteus said, because it ensures that other healthy genes aren't being erroneously tampered with. Translating lab research to a patient population takes time, Porteus said, but he's optimistic that if larger mouse studies are successful, the CRISPR-Cas9 gene therapy could be piloted in human patients in the next year or two through the Stanford Center for Definitive and Curative 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 Gene correction in human long-term hematopoietic stem cells (LT-HSCs) could be an effective therapy for monogenic diseases of the blood and immune system. Here we describe an approach for X-linked sSevere cCombined iImmunodeficiency (SCID-X1) using targeted integration of a cDNA into the endogenous start codon to functionally correct disease-causing mutations throughout the gene. Using a CRISPR-Cas9/AAV6 based strategy, we achieve up to 20% targeted integration frequencies in LT-HSCs. As measures of the lack of toxicity we observe no evidence of abnormal hematopoiesis following transplantation and no evidence of off-target mutations using a high-fidelity Cas9 as a ribonucleoprotein complex. We achieve high levels of targeting frequencies (median 45%) in CD34 + HSPCs from six SCID-X1 patients and demonstrate rescue of lymphopoietic defect in a patient derived HSPC population in vitro and in vivo. In sum, our study provides specificity, toxicity and efficacy data supportive of clinical development of genome editing to treat SCID-Xl. Introduction X-linked sSevere cCombined iImmunodeficiency (SCID-X1) is a primary immune deficiency disorder (PID) caused by mutations in the IL2RG gene on the X chromosome. The gene encodes a shared subunit of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Without early treatment, affected male infants die in the first year of life from infections. Although allogeneic hematopoietic cell transplant (allo-HCT) is considered the standard of care for SCID-X1, it holds significant risks due to potential incomplete immune reconstitution, graft versus host disease (GvHD) and a decreased survival rate in the absence of an human leukocyte antigen (HLA)-matched sibling donor 1 . Because of the selective advantage of lymphoid progenitors expressing normal IL2RG , however, only a small number of genetically corrected hematopoietic stem and progenitor cells (HSPCs) are needed to reconstitute T-cell immunity 2 , 3 . The importance of achieving gene correction in long-term hematopoietic stem cells (LT-HSCs) to achieve sustained clinical benefit is demonstrated by the waning of a functional immune system in patients who do not derive their immune system from LT-HSCs with a wild-type IL2RG gene. Gene therapy is an alternative therapy to allo-HSCT. Using integrating viral vectors, such as gamma-retroviral and lentiviral vectors, extra copies of a functional IL2RG gene are semi-randomly integrated into the genome of SCID-X1 patient-derived CD34 + HSPCs. This strategy has resulted in both successes and setbacks. While most patients treated with first generation of gene therapy survived and benefited from the therapy, a substantial fraction (>25%) of patients developed leukemia from insertional oncogenesis 4 , 5 , 6 . It is concerning that patients developed leukemia from insertional oncogenesis both early and late, 15 years after transplantation of retroviral-based engineered cells 7 . Constitutive activation of the transgene 8 , the choice of vectors 9 and specific details of the gene therapy procedure have all been proposed as factors contributing to the risk of leukemia and myelodysplastic syndrome that occurred in several trials for primary immunodeficiency disorders (PIDs) including SCID-X1 10 , 11 , chronic granulomatous disease (CGD) 12 , 13 and Wiskott–Aldrich Syndrome (WAS) 14 . With second-generation self-inactivating (SIN) vectors, multiple SCID-X1 patients have successfully reconstituted T-cell immunity in the absence of early leukemic events 15 , 16 , 17 with a follow-up of up to 7 years. However, the follow-up of these therapies remains too short to assess the long-term genotoxicity risk of the newer generation vectors, as transformation of T cells growth can take >10 years to manifest 7 . An alternative to the semi-random delivery of the complementary DNA (cDNA) is to use a targeted genome editing (GE) approach. GE is a means to alter the DNA sequence of a cell, including somatic stem cells, with nucleotide precision. Using homologous recombination-mediated GE (HR-GE), the approach can target a cDNA transgene into its endogenous locus, thereby preserving normal copy number and upstream and downstream non-coding elements that regulate expression 18 , 19 , 20 . The highest frequencies of GE are achieved using an engineered nuclease to create a site-specific double-strand break (DSB) in the cell’s genomic DNA 21 , 22 . When the DSB is repaired by non-homologous end joining (NHEJ), small insertions and deletions (INDELs) can be created at a specific genomic target site—an outcome that is not generally useful for correcting mutant genes 23 , 24 . In contrast, when the DSB is repaired by either HR (using a classic gene-targeting donor vector) or by single-stranded template repair (using a single-stranded oligonucleotide (ssODN)), precise sequence changes can be introduced, thereby providing a method to precisely revert disease-causing DNA variants 25 . Among the multiple GE platforms that use artificial nucleases to generate DSBs 18 , 26 , 27 , 28 , 29 , the CRISPR-Cas9 system has accelerated the field of GE because of its ease of use and high activity in a wide variety of cells. When CRISPR-Cas9 is delivered into primary human cells, including human CD34 + HSPCs as a ribonucleoprotein (RNP) complex using fully synthesized single-guide RNA molecules (sgRNAs) with end modifications to protect the guide from exonuclease degradation, high frequencies of INDELs are achieved 30 . Moreover, when the delivery of an RNP complex is combined with delivery of the gene-targeting donor molecule in a recombinant AAV6 (rAAV6) viral vector, high frequencies of homologous-mediated editing in human HSPCs are obtained 25 . The use of rAAV6 donor vectors have been successfully used with other nuclease systems as well, including zinc-finger nucleases (ZFNs) and in other cell types, such as primary human T cells 19 , 31 , 32 . Therefore, this HR-GE approach could transform the semi-random nature of viral-based gene therapy to a more controlled and precise strategy. By using AAV6 as a classic gene-targeting donor, in contrast to ssODNs, a full cDNA can be introduced at the endogenous target. The key challenges in translating GE into medical therapies is attaining clinically relevant targeted integration frequencies into LT-HSCs, attaining functional levels of protein expression, and establishing lack of toxicity derived from the GE approach. Here, we describe a clinically relevant, selection-free “universal”<|im_end|> <|im_start|>assistant In preclinical trials, Stanford scientists and their collaborators harnessed the gene-editing system CRISPR-Cas9 to replace the mutated gene underpinning the devastating immune disease. Very rarely, a boy is born with a mutation that renders his immune system barren—devoid of any and all immune cells. The disease, X-linked severe combined immunodeficiency, or SCID-X1, often is referred to as the bubble boy disease. It affects only males and is lethal if not treated in the first year of life. Now, scientists at the School of Medicine and their collaborators have used the gene-editing system CRISPR-Cas9 to devise a new treatment to replenish immune cells in mouse models of SCID-X1. The results are promising, the scientists said, because they believe the treatment could potentially work in humans, as well. SCID-X1 affects about 1 in 50,000 male births. Those with the disease suffer from a debilitating mutation in a single gene, IL2R gamma. When this gene is defective, the immune system never develops. The standard treatment for patients with SCID-X1 is a bone marrow transplant, which supplies them with stem cells that will give rise to a working immune system. But the transfer process is tricky and not guaranteed to work. So, Matthew Porteus, MD, Ph.D., professor of pediatrics, came up with a new idea: correct the genes in the patients' own cells. Through CRISPR-Cas9, Porteus and his team have done just that. Using cell samples that came from people with SCID-X1, the researchers genetically altered the class of stem cells that give rise to blood and immune cells. Their approach got the gene working again. Each mouse that received the edited cells began generating new immune cells and displayed no detectable adverse side effects. "To our knowledge, it's the first time that human SCID-X1 cells edited with CRISPR-Cas9 have been successfully used to make human immune cells in an animal model," said postdoctoral scholar Mara Pavel-Dinu, Ph.D. A paper describing the work was published online April 9 in Nature Communications. Porteus is the senior author, and Pavel-Dinu is the first author. Editing in a solution Gene-based therapy for SCID is not new. In the 1990s, scientists began to dabble in gene therapies that used a virus to deliver a new, functional IL2R gamma gene. "It was very effective, but about 25 percent of the patients developed a leukemia because the virus integrated into an erroneous gene," Porteus said. "It showed both the promise of what gene therapy could do and highlighted the area that needed to be improved." Porteus' approach uses CRISPR-Cas9 to create a double-stranded break in DNA to insert a healthy copy of the IL2R gamma gene in the stem cells that create immune cells. Using the gene-editing system, scientists tweaked cells from six people with SCID-X1 and then transplanted those cells into mouse models of SCID-X1. Those mice were then not only able to make their own immune cells, but many of the edited cells retained something called "stemness," meaning that they maintained their ability to continually create new cells. "The idea is that these modified stem cells will give rise to the blood system and the immune system for the entirety of the patient's life, which we hope is 90 or more years," Porteus said. "And we see evidence for that in our study." Popping the bubble "We've showed that this is a novel and effective strategy to potentially treat this disease, but the other big thing here is safety," Porteus said. "We don't see any abnormalities in the mice that receive the treatment. More specifically, we also performed genetic analysis to see if the CRISPR-Cas9 system made DNA breaks at places that it's not supposed to, and we see no evidence of that." That's crucial, Porteus said, because it ensures that other healthy genes aren't being erroneously tampered with. Translating lab research to a patient population takes time, Porteus said, but he's optimistic that if larger mouse studies are successful, the CRISPR-Cas9 gene therapy could be piloted in human patients in the next year or two through the Stanford Center for Definitive and Curative Medicine. <|im_end|>

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926, 31650, 16, 374, 264, 17685, 83748, 43929, 11, 902, 17135, 1124, 449, 19646, 7917, 430, 690, 3041, 10205, 311, 264, 3318, 22852, 1887, 13, 2030, 279, 8481, 1920, 374, 34553, 323, 539, 19883, 311, 990, 13, 2100, 11, 19475, 5896, 90802, 11, 14306, 11, 2405, 920, 2637, 14561, 315, 10696, 71528, 11, 3782, 709, 449, 264, 502, 4623, 25, 4495, 279, 21389, 304, 279, 6978, 6, 1866, 7917, 13, 17331, 12904, 1669, 6616, 7813, 300, 24, 11, 5896, 90802, 323, 813, 2128, 617, 2884, 1120, 430, 13, 12362, 2849, 10688, 430, 3782, 505, 1274, 449, 7683, 926, 31650, 16, 11, 279, 12074, 52033, 29852, 279, 538, 315, 19646, 7917, 430, 3041, 10205, 311, 6680, 323, 22852, 7917, 13, 11205, 5603, 2751, 279, 15207, 3318, 1578, 13, 9062, 8814, 430, 4036, 279, 19685, 7917, 6137, 24038, 502, 22852, 7917, 323, 12882, 912, 11388, 481, 31959, 3185, 6372, 13, 330, 1271, 1057, 6677, 11, 433, 596, 279, 1176, 892, 430, 3823, 7683, 926, 31650, 16, 7917, 19685, 449, 12904, 1669, 6616, 7813, 300, 24, 617, 1027, 7946, 1511, 311, 1304, 3823, 22852, 7917, 304, 459, 10065, 1646, 1359, 1071, 1772, 38083, 278, 18640, 86604, 79369, 9607, 102437, 11, 2405, 920, 13, 362, 5684, 23524, 279, 990, 574, 4756, 2930, 5936, 220, 24, 304, 22037, 26545, 13, 5896, 90802, 374, 279, 10195, 3229, 11, 323, 79369, 9607, 102437, 374, 279, 1176, 3229, 13, 62153, 304, 264, 6425, 24983, 6108, 15419, 369, 7683, 926, 374, 539, 502, 13, 763, 279, 220, 2550, 15, 82, 11, 14248, 6137, 311, 294, 73291, 304, 15207, 52312, 430, 1511, 264, 17188, 311, 6493, 264, 502, 11, 16003, 11598, 17, 49, 22350, 15207, 13, 330, 2181, 574, 1633, 7524, 11, 719, 922, 220, 914, 3346, 315, 279, 6978, 8040, 264, 96306, 1606, 279, 17188, 18751, 1139, 459, 77772, 15207, 1359, 5896, 90802, 1071, 13, 330, 2181, 8710, 2225, 279, 11471, 315, 1148, 15207, 15419, 1436, 656, 323, 27463, 279, 3158, 430, 4460, 311, 387, 13241, 1210, 5896, 90802, 6, 5603, 5829, 12904, 1669, 6616, 7813, 300, 24, 311, 1893, 264, 2033, 42728, 6601, 1464, 304, 15922, 311, 5774, 264, 9498, 3048, 315, 279, 11598, 17, 49, 22350, 15207, 304, 279, 19646, 7917, 430, 1893, 22852, 7917, 13, 12362, 279, 15207, 22930, 287, 1887, 11, 14248, 89560, 7917, 505, 4848, 1274, 449, 7683, 926, 31650, 16, 323, 1243, 1380, 501, 7719, 1884, 7917, 1139, 8814, 4211, 315, 7683, 926, 31650, 16, 13, 13266, 24548, 1051, 1243, 539, 1193, 3025, 311, 1304, 872, 1866, 22852, 7917, 11, 719, 1690, 315, 279, 19685, 7917, 35363, 2555, 2663, 330, 65188, 2136, 1359, 7438, 430, 814, 18908, 872, 5845, 311, 35611, 1893, 502, 7917, 13, 330, 791, 4623, 374, 430, 1521, 11041, 19646, 7917, 690, 3041, 10205, 311, 279, 6680, 1887, 323, 279, 22852, 1887, 369, 279, 49017, 315, 279, 8893, 596, 2324, 11, 902, 584, 3987, 374, 220, 1954, 477, 810, 1667, 1359, 5896, 90802, 1071, 13, 330, 3112, 584, 1518, 6029, 369, 430, 304, 1057, 4007, 1210, 393, 7153, 279, 24529, 330, 1687, 3077, 8710, 430, 420, 374, 264, 11775, 323, 7524, 8446, 311, 13893, 4322, 420, 8624, 11, 719, 279, 1023, 2466, 3245, 1618, 374, 7296, 1359, 5896, 90802, 1071, 13, 330, 1687, 1541, 956, 1518, 904, 75815, 304, 279, 24548, 430, 5371, 279, 6514, 13, 4497, 11951, 11, 584, 1101, 10887, 19465, 6492, 311, 1518, 422, 279, 12904, 1669, 6616, 7813, 300, 24, 1887, 1903, 15922, 18808, 520, 7634, 430, 433, 596, 539, 10171, 311, 11, 323, 584, 1518, 912, 6029, 315, 430, 1210, 3011, 596, 16996, 11, 5896, 90802, 1071, 11, 1606, 433, 26420, 430, 1023, 9498, 21389, 7784, 956, 1694, 58889, 7162, 26555, 43868, 449, 13, 4149, 75, 1113, 10278, 3495, 311, 264, 8893, 7187, 5097, 892, 11, 5896, 90802, 1071, 11, 719, 568, 596, 37036, 430, 422, 8294, 8814, 7978, 527, 6992, 11, 279, 12904, 1669, 6616, 7813, 300, 24, 15207, 15419, 1436, 387, 11715, 9437, 304, 3823, 6978, 304, 279, 1828, 1060, 477, 1403, 1555, 279, 31788, 5955, 369, 3979, 2381, 535, 323, 13182, 1413, 19152, 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 Background Physical activity and sitting time independently contribute to chronic disease risk, though little work has focused on aspirational health outcomes. The purpose of this study was to examine associations between physical activity, sitting time, and excellent overall health (ExH) and quality of life (ExQoL) in Australian adults. Methods The 45 and Up Study is a large Australian prospective cohort study (n = 267,153). Present analyses are from 194,545 participants (48% male; mean age = 61.6 ± 10.7 yrs) with complete baseline questionnaire data on exposures, outcomes, and potential confounders (age, income, education, smoking, marital status, weight status, sex, residential remoteness and economic advantage, functional limitation and chronic disease). The Active Australia survey was used to assess walking, moderate, and vigorous physical activity. Sitting time was determined by asking participants to indicate number of hours per day usually spent sitting. Participants reported overall health and quality of life, using a five-point scale (excellent—poor). Binary logistic regression models were used to analyze associations, controlling for potential confounders. Results Approximately 16.5% of participants reported ExH, and 25.7% reported ExQoL. In fully adjusted models, physical activity was positively associated with ExH (AOR = adjusted odds ratio for most versus least active = 2.22, 95% CI = 2.20, 2.47; P trend < 0.001) and ExQoL (AOR for most versus least active = 2.30, 95% CI = 2.12, 2.49; P trend < 0.001). In fully adjusted models, sitting time was inversely associated with ExH (AOR for least versus most sitting group = 1.13, 95% CI = 1.09, 1.18; P trend < 0.001) and ExQoL (AOR for least versus most sitting group = 1.13, 95% CI = 1.10, 1.17; P trend < 0.001). In fully adjusted models, interactions between physical activity and sitting time were not significant for ExH ( P = 0.118) or ExQoL ( P = 0.296). Conclusions Physical activity and sitting time are independently associated with excellent health and quality of life in this large diverse sample of Australian middle-aged and older adults. These findings bolster evidence informing health promotion efforts to increase PA and decrease sitting time toward the achievement of better population health and the pursuit of successful aging. Peer Review reports Background Worldwide, nations are preparing for the demands of an aging population, and this entails dealing with challenges of maintaining health, functional capacity, and wellbeing [ 1 ]. Focusing on relevant lifestyle behaviors is an important consideration for preventing or delaying chronic disease and improving health [ 1 – 3 ]. An emerging body of literature indicates that the lifestyle behaviors of physical activity and time spent sitting independently contribute to health outcomes such as chronic disease morbidity and mortality risk [ 4 ]. Regularly engaging in moderate-to-vigorous physical activity has been shown to reduce the risk of all-cause mortality, cardiovascular mortality, cancer mortality, stroke, heart disease, breast cancer, colon cancer, and other undesirable health outcomes [ 5 ]. Over the past decade, however, research on the health impacts of sedentary behavior (time spent at low levels of energy expenditure while in a sitting posture) has expanded rapidly [ 4 ]. High volumes of time spent sitting are associated with an increased risk of all-cause mortality [ 6 – 10 ], cardiovascular disease mortality [ 8 ], type 2 diabetes mellitus [ 11 – 15 ], and other diseases or conditions [ 15 – 17 ] when adjusting for participation in moderate-to-vigorous intensity physical activity. Therefore, insufficient moderate-to-vigorous physical activity and sitting time may be distinct influences on poor health. Compared to abundant literature on risk factors for disease and poor health, research focusing on the influence of physical activity and sitting time on more aspirational health-related outcomes is much less common [ 5 , 18 – 20 ]. Successful aging has been described as a multidimensional intersection, where not only the avoidance of disease and disability are found, but also where high cognitive and physical function and engagement with life conjoin [ 21 ]. The focus on such aspirational outcomes represents a “salutogenic” approach to health promotion [ 22 ], rather than the traditional disease prevention approach. This salutogenic orientation is instructive for determining influences on aspirational levels of health and well-being. Aspirational positively framed messages may be more effective for motivating healthful behavior in some segments of the population, compared to focusing on the avoidance of chronic disease, which is often an abstract possibility many years away [ 23 ]. Despite the aging population and widespread problem of physical inactivity, there has been limited use of successful aging or salutogenic approaches to frame positive health messages toward motivating active lifestyles. This study examines both self-reported health and quality of life status as they are useful health outcomes and are predictive of more objective health indicators [ 24 ]. To investigate whether higher levels of physical activity and lower levels of sitting time were positively associated with excellent health and quality of life, we utilized self-reported data from a large sample of middle-aged and older Australian men and women, and we statistically adjusted for a range of associated covariates and potential confounding variables in the analyses. Methods The 45 and Up Study The 45 and Up Study is a large ongoing Australian prospective cohort study that began with a baseline sample of 267,153 men and women from New South Wales, the most populous state in Australia. A detailed description of The 45 and Up Study has been published previously [ 25 ]. The 45 and Up Study baseline [ 26 ] data provide information on a wide range of health-related variables. Participants were randomly sampled from the Medicare Australia (national health insurance) database between February 2006 and December 2008. All adults who were aged 45 years and over and who were currently residing in NSW at the time of recruitment were eligible for inclusion in the Study. Participants who completed a mailed baseline questionnaire and provided their signed consent for participation in the baseline questionnaire and long-term follow-up were included in the Study [ 25 ]. The", "role": "user" }, { "content": "People who decrease sitting time and increase physical activity have a lower risk of chronic disease, according to Kansas State University research. Even standing throughout the day—instead of sitting for hours at a time—can improve health and quality of life while reducing the risk for chronic diseases such as cardiovascular disease, diabetes, heart disease, stroke, breast cancer and colon cancer, among others. The researchers—Sara Rosenkranz and Richard Rosenkranz, both assistant professors of human nutrition—studied a sample of 194,545 men and women ages 45 to 106. The data was from the 45 and Up Study, which is a large Australian study of health and aging. \"Not only do people need to be more physically active by walking or doing moderate-to-vigorous physical activity, but they should also be looking at ways to reduce their sitting time,\" Richard Rosenkranz said. The twofold approach—sitting less and moving more—is key to improving health, the researchers said. People often spend the majority of the day being sedentary and might devote 30 to 60 minutes a day to exercise or physical activity, Sara Rosenkranz said. Taking breaks to stand up or move around can make a difference during long periods of sitting. Sitting for prolonged periods of time—with little muscular contraction occurring—shuts off a molecule called lipoprotein lipase, or LPL, Sara Rosenkranz said. Lipoprotein lipase helps to take in fat or triglycerides and use it for energy. Increasing physical activity and decreasing sitting time can reduce chronic disease and make aging easier, according to Kansas State University research. Credit: Kansas State University \"We're basically telling our bodies to shut down the processes that help to stimulate metabolism throughout the day and that is not good,\" Sara Rosenkranz said. \"Just by breaking up your sedentary time, we can actually upregulate that process in the body.\" In a previous study published in the International Journal of Behavioral Nutrition and Physical Activity, the researchers found that the more people sit, the greater their chances of obesity, diabetes, cardiovascular disease and overall mortality. For the more recent study, the researchers wanted to take a positive approach and see if increasing physical activity helped to increase health and quality of life. The researchers want to motivate people—especially younger people—to sit less and move more so they can age easier with less chronic disease. \"There is only so far that messages about avoiding diseases can go, especially when talking about chronic disease because it is so far removed and in the future,\" Richard Rosenkranz said. \"For young people, being motivated by avoiding diseases is probably not the most pressing matter in their lives. We wanted to look at excellent health and excellent quality of life as things to aspire to in health.\" To help office workers and employees who often sit for long periods of time, the researchers suggest trying a sit/stand desk as way to decrease sedentary time and add physical activity into the day. A sit/stand desk or workstation can adjust up and down so employees can add more standing time to their days. There are even sit/stand desks for children to stand and do homework or projects. The research appears in the journal BMC Public Health. Collaborators included Gregory Kolt of the School of Science and Health at the University of Western Sydney in Sydney, Australia, and Mitch Duncan of the Institute for Health and Social Science Research with the Centre for Physical Activity Studies at Central Queensland University in Rockhampton, Australia. While the researchers have used existing data for this latest study, the Rosenkranzes are now conducting experiments to manipulate sitting time in already active people. They want to understand how increased sitting time affects physiological risk factors such as blood pressure, body composition, triglyceride and cholesterol levels, inflammation and oxidative stress. ", "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 Physical activity and sitting time independently contribute to chronic disease risk, though little work has focused on aspirational health outcomes. The purpose of this study was to examine associations between physical activity, sitting time, and excellent overall health (ExH) and quality of life (ExQoL) in Australian adults. Methods The 45 and Up Study is a large Australian prospective cohort study (n = 267,153). Present analyses are from 194,545 participants (48% male; mean age = 61.6 ± 10.7 yrs) with complete baseline questionnaire data on exposures, outcomes, and potential confounders (age, income, education, smoking, marital status, weight status, sex, residential remoteness and economic advantage, functional limitation and chronic disease). The Active Australia survey was used to assess walking, moderate, and vigorous physical activity. Sitting time was determined by asking participants to indicate number of hours per day usually spent sitting. Participants reported overall health and quality of life, using a five-point scale (excellent—poor). Binary logistic regression models were used to analyze associations, controlling for potential confounders. Results Approximately 16.5% of participants reported ExH, and 25.7% reported ExQoL. In fully adjusted models, physical activity was positively associated with ExH (AOR = adjusted odds ratio for most versus least active = 2.22, 95% CI = 2.20, 2.47; P trend < 0.001) and ExQoL (AOR for most versus least active = 2.30, 95% CI = 2.12, 2.49; P trend < 0.001). In fully adjusted models, sitting time was inversely associated with ExH (AOR for least versus most sitting group = 1.13, 95% CI = 1.09, 1.18; P trend < 0.001) and ExQoL (AOR for least versus most sitting group = 1.13, 95% CI = 1.10, 1.17; P trend < 0.001). In fully adjusted models, interactions between physical activity and sitting time were not significant for ExH ( P = 0.118) or ExQoL ( P = 0.296). Conclusions Physical activity and sitting time are independently associated with excellent health and quality of life in this large diverse sample of Australian middle-aged and older adults. These findings bolster evidence informing health promotion efforts to increase PA and decrease sitting time toward the achievement of better population health and the pursuit of successful aging. Peer Review reports Background Worldwide, nations are preparing for the demands of an aging population, and this entails dealing with challenges of maintaining health, functional capacity, and wellbeing [ 1 ]. Focusing on relevant lifestyle behaviors is an important consideration for preventing or delaying chronic disease and improving health [ 1 – 3 ]. An emerging body of literature indicates that the lifestyle behaviors of physical activity and time spent sitting independently contribute to health outcomes such as chronic disease morbidity and mortality risk [ 4 ]. Regularly engaging in moderate-to-vigorous physical activity has been shown to reduce the risk of all-cause mortality, cardiovascular mortality, cancer mortality, stroke, heart disease, breast cancer, colon cancer, and other undesirable health outcomes [ 5 ]. Over the past decade, however, research on the health impacts of sedentary behavior (time spent at low levels of energy expenditure while in a sitting posture) has expanded rapidly [ 4 ]. High volumes of time spent sitting are associated with an increased risk of all-cause mortality [ 6 – 10 ], cardiovascular disease mortality [ 8 ], type 2 diabetes mellitus [ 11 – 15 ], and other diseases or conditions [ 15 – 17 ] when adjusting for participation in moderate-to-vigorous intensity physical activity. Therefore, insufficient moderate-to-vigorous physical activity and sitting time may be distinct influences on poor health. Compared to abundant literature on risk factors for disease and poor health, research focusing on the influence of physical activity and sitting time on more aspirational health-related outcomes is much less common [ 5 , 18 – 20 ]. Successful aging has been described as a multidimensional intersection, where not only the avoidance of disease and disability are found, but also where high cognitive and physical function and engagement with life conjoin [ 21 ]. The focus on such aspirational outcomes represents a “salutogenic” approach to health promotion [ 22 ], rather than the traditional disease prevention approach. This salutogenic orientation is instructive for determining influences on aspirational levels of health and well-being. Aspirational positively framed messages may be more effective for motivating healthful behavior in some segments of the population, compared to focusing on the avoidance of chronic disease, which is often an abstract possibility many years away [ 23 ]. Despite the aging population and widespread problem of physical inactivity, there has been limited use of successful aging or salutogenic approaches to frame positive health messages toward motivating active lifestyles. This study examines both self-reported health and quality of life status as they are useful health outcomes and are predictive of more objective health indicators [ 24 ]. To investigate whether higher levels of physical activity and lower levels of sitting time were positively associated with excellent health and quality of life, we utilized self-reported data from a large sample of middle-aged and older Australian men and women, and we statistically adjusted for a range of associated covariates and potential confounding variables in the analyses. Methods The 45 and Up Study The 45 and Up Study is a large ongoing Australian prospective cohort study that began with a baseline sample of 267,153 men and women from New South Wales, the most populous state in Australia. A detailed description of The 45 and Up Study has been published previously [ 25 ]. The 45 and Up Study baseline [ 26 ] data provide information on a wide range of health-related variables. Participants were randomly sampled from the Medicare Australia (national health insurance) database between February 2006 and December 2008. All adults who were aged 45 years and over and who were currently residing in NSW at the time of recruitment were eligible for inclusion in the Study. Participants who completed a mailed baseline questionnaire and provided their signed consent for participation in the baseline questionnaire and long-term follow-up were included in the Study [ 25 ]. The<|im_end|> <|im_start|>assistant People who decrease sitting time and increase physical activity have a lower risk of chronic disease, according to Kansas State University research. Even standing throughout the day—instead of sitting for hours at a time—can improve health and quality of life while reducing the risk for chronic diseases such as cardiovascular disease, diabetes, heart disease, stroke, breast cancer and colon cancer, among others. The researchers—Sara Rosenkranz and Richard Rosenkranz, both assistant professors of human nutrition—studied a sample of 194,545 men and women ages 45 to 106. The data was from the 45 and Up Study, which is a large Australian study of health and aging. "Not only do people need to be more physically active by walking or doing moderate-to-vigorous physical activity, but they should also be looking at ways to reduce their sitting time," Richard Rosenkranz said. The twofold approach—sitting less and moving more—is key to improving health, the researchers said. People often spend the majority of the day being sedentary and might devote 30 to 60 minutes a day to exercise or physical activity, Sara Rosenkranz said. Taking breaks to stand up or move around can make a difference during long periods of sitting. Sitting for prolonged periods of time—with little muscular contraction occurring—shuts off a molecule called lipoprotein lipase, or LPL, Sara Rosenkranz said. Lipoprotein lipase helps to take in fat or triglycerides and use it for energy. Increasing physical activity and decreasing sitting time can reduce chronic disease and make aging easier, according to Kansas State University research. Credit: Kansas State University "We're basically telling our bodies to shut down the processes that help to stimulate metabolism throughout the day and that is not good," Sara Rosenkranz said. "Just by breaking up your sedentary time, we can actually upregulate that process in the body." In a previous study published in the International Journal of Behavioral Nutrition and Physical Activity, the researchers found that the more people sit, the greater their chances of obesity, diabetes, cardiovascular disease and overall mortality. For the more recent study, the researchers wanted to take a positive approach and see if increasing physical activity helped to increase health and quality of life. The researchers want to motivate people—especially younger people—to sit less and move more so they can age easier with less chronic disease. "There is only so far that messages about avoiding diseases can go, especially when talking about chronic disease because it is so far removed and in the future," Richard Rosenkranz said. "For young people, being motivated by avoiding diseases is probably not the most pressing matter in their lives. We wanted to look at excellent health and excellent quality of life as things to aspire to in health." To help office workers and employees who often sit for long periods of time, the researchers suggest trying a sit/stand desk as way to decrease sedentary time and add physical activity into the day. A sit/stand desk or workstation can adjust up and down so employees can add more standing time to their days. There are even sit/stand desks for children to stand and do homework or projects. The research appears in the journal BMC Public Health. Collaborators included Gregory Kolt of the School of Science and Health at the University of Western Sydney in Sydney, Australia, and Mitch Duncan of the Institute for Health and Social Science Research with the Centre for Physical Activity Studies at Central Queensland University in Rockhampton, Australia. While the researchers have used existing data for this latest study, the Rosenkranzes are now conducting experiments to manipulate sitting time in already active people. They want to understand how increased sitting time affects physiological risk factors such as blood pressure, body composition, triglyceride and cholesterol levels, inflammation and oxidative stress. <|im_end|>

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2,128

[ { "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 significant risk of disease transmission has selected for effective immune-defense strategies in insect societies. Division of labour, with individuals specialized in immunity-related tasks, strongly contributes to prevent the spread of diseases. A trade-off, however, may exist between phenotypic specialization to increase task efficiency and maintenance of plasticity to cope with variable colony demands. We investigated the extent of phenotypic specialization associated with a specific task by using allogrooming in the honeybee, Apis mellifera , where worker behaviour might lower ectoparasites load. We adopted an integrated approach to characterize the behavioural and physiological phenotype of allogroomers, by analyzing their behavior (both at individual and social network level), their immunocompetence (bacterial clearance tests) and their chemosensory specialization (proteomics of olfactory organs). We found that allogroomers have higher immune capacity compared to control bees, while they do not differ in chemosensory proteomic profiles. Behaviourally, they do not show differences in the tasks performed (other than allogrooming), while they clearly differ in connectivity within the colonial social network, having a higher centrality than control bees. This demonstrates the presence of an immune-specific physiological and social behavioural specialization in individuals involved in a social immunity related task, thus linking individual to social immunity, and it shows how phenotypes may be specialized in the task performed while maintaining an overall plasticity. Introduction Division of labour is defined as the pattern of specialization by cooperative individuals of a social group, which perform different tasks or assume specific roles depending on their morphology (polyphenism) or behaviour (polyethism) 1 , 2 . These task specializations often occur with a suite of behavioural and physiological correlates, some of which are specific phenotypic specializations that increase the aptitude, the efficiency and/or decrease the costs of the task performed 3 , 4 , 5 , 6 . However, the phenotypic specialization associated with division of labour is expected to be under contrasting selective forces: a colony might benefit from having sets of workers with highly specialized phenotypes, highly efficient and apt to perform the appointed task; at the same time, specializing may limit task flexibility, therefore reducing performance of other tasks when needed 7 , 8 . Thus, division of labour should show an adequate degree of flexibility to allow the colony to rapidly reallocate its resources in response to the environmental demands 9 , 10 . Understanding the degree of phenotypic specialization in group of workers performing specific tasks has the potential to unravel the trade-off between phenotypic plasticity and specialization. Allogrooming 11 is a behaviour in which a worker uses its mouth parts to remove debris from the body of other colony members. This behaviour, observed in several species of eusocial insects, plays a role in defence against parasites and pathogens 12 , 13 , 14 , 15 . In honeybees, allogrooming represents an important resistance mechanism that seems to limit ectoparasites load, especially mites, within colonies 16 , 17 , 18 , 19 , 20 and its expression depends on genetic and environmental factors 21 , 22 . In Apis cerana , allogrooming is performed at a high rate and appears to be a particularly effective counter-adaptation against the major worldwide threat for honey bee colonies and apiculture, the parasitic mites Varroa destructor 16 , 17 , 20 , 23 . The relatively recent spread of this parasite in many countries heavily impacted on Apis mellifera colonies 23 but effective strategies to deal with this emergency are still lacking 23 , 24 , 25 . Being allogrooming expressed with efficacy against V. destructor in A. cerana , its characterization in A. mellifera may clarify its possible effectiveness to control parasite load at colony level. Despite the potential value that allogrooming could have in maximizing colony resistance to parasites and disease transmission, very scarce attention has been given to the behavioural and physiological specializations of allogrooming at the individual level. Thus, the degree of specialization of individuals performing this task is still unclear and behavioural and physiological correlates of allogroomers are largely unknown. Here, we investigated the degree of phenotypic specialization of allogroomers in the honeybee A. mellifera . Empirical evidence reported in literature about the temporal expression of allogrooming and the degree of behavioural specialization in individuals performing this task is contrasting. According to some authors, in A. mellifera this behaviour is temporally restricted from the 1 st to the 20 th day post-emergence 26 while other researchers observed workers performing allogrooming during their entire life 27 , 28 . We thus characterized the temporal and spatial dynamics of allogrooming occurrence. To assess the timing of allogrooming expression, we performed detailed behavioural observations on a large cohort of workers along their lifespan inside the hive (until the onset of foraging activities). We then characterized the spatial occurrence of allogrooming events on the comb surface, in order to test whether they are randomly distributed or clustered in specific areas. Moreover, we investigated the degree of behavioural specialization of allogroomers, focusing on their individual behavioural profile (i.e. the array of tasks performed) and on the role they play in the colony social network. Indeed, it is not clear to what extent specialization in allogrooming implies a different behavioural repertoire in allogroomers compared to same age range non-grooming nestmates. Previous studies showed that allogroomers are specialized individuals performing the behaviour at a consistently higher frequency compared to other tasks typical of same age range workers 29 , while others reported that this behaviour is unfrequently expressed also by the few individuals performing it, which also carry out all the tasks typical of their age 30 . We thus compared the behavioural repertoire of allogroomers with that of same age range non-grooming bees, predicting that, in case of specialization, allogroomer workers would show a reduced performance of the other in-hive tasks ( prediction 1 ). In A. mellifera colonies, individuals have been shown to occupy different positions (more or less central, i.e. more or less connected) within the colony social network, according to their caste, age and task 31 , producing", "role": "user" }, { "content": "Honeybees that specialize in grooming their nestmates (allogroomers) to ward off pests play a central role in the colony, finds a new UCL and University of Florence study. Allogroomer bees also appear to have stronger immune systems, possibly enabling them to withstand their higher risk of infection, according to the findings published in Scientific Reports. Ectoparasites (parasites that live on the outside of a host's body, such as mites) are a growing threat to honeybees worldwide, so the researchers say that supporting allogrooming behavior might be an effective pest control strategy. Lead author Dr. Alessandro Cini, who began the project at the University of Florence before moving over to UCL Centre for Biodiversity & Environment Research, said: \"An ectoparasitic mite, Varroa destructor, represents a major global threat to bee colonies. By understanding how allogrooming practices are used to ward off parasites, we may be able to develop strategies to promote allogrooming behavior and increase resilience to the parasites. \"Here, we found worker bees that specialize in allogrooming are highly connected within their colonies, and have developed stronger immune systems. \"We suspect that if more bees engaged in these allogrooming behaviors that ward off parasites, the colony as a whole could have greater immunity.\" Honeybees that specialise in grooming their nestmates (allogroomers) to ward off pests play a central role in the colony, finds a new UCL and University of Florence study published in Scientific Reports. Credit: Dr Alessandro Cini, UCL Among bees, allogrooming consists of a worker using its mouth to remove debris, which may include parasites and other pathogens, from the body of another member of its colony. In bee colonies, different groups of worker bees conduct different activities—one such specialization is allogrooming, although it was not previously known how specialized the groomer bees are, and how their physiology may be different. The current study focused on Apis mellifera, commonly known as the western honeybee, which is the most common species of honeybee and also the world's most-used bee for both honey production and pollination in agriculture. As allogrooming would likely put the grooming bees at an elevated risk of contracting pathogens and parasites, the researchers tested their immune systems, and found that their hemolymph (like blood, but for insects) could more effectively clear out potentially harmful bacteria than the immune systems of other bees in the colony. Co-author Dr. Rita Cervo from the University of Florence said: \"By identifying a striking difference in the immune systems of the allogrooming bees, which are involved in tasks important to colony-wide immunity from pathogens, we have found a link between individual and social immunity.\" Honeybees engaging in allogrooming behavior. Credit: Dr Adele Bordoni, University of Florence The researchers found that allogroomer bees occupy a central position in the colony's social network, as they are more connected to bees across the colony than the average bee, enabling their grooming habits to benefit a large number of bees and keep the colony as pest-free as possible. The researchers found that allogrooming is a relatively weak, transient specialty, as the groomer bees still devoted a similar amount of time to other tasks as the rest of the colony's worker bees. The researchers say this shows that bees can develop physiological differences narrowly tailored to specific tasks, while still maintaining a degree of plasticity enabling them to switch to other tasks as needed. The researchers did not detect any differences in how well the allogroomer bees could detect when other bees needed grooming, as their antennae were not more finely-tuned to relevant odors. It is possible they can detect who needs grooming in other ways, such as by noticing the 'grooming invitation dance' whereby bees shake their whole body from side-to-side. ", "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 significant risk of disease transmission has selected for effective immune-defense strategies in insect societies. Division of labour, with individuals specialized in immunity-related tasks, strongly contributes to prevent the spread of diseases. A trade-off, however, may exist between phenotypic specialization to increase task efficiency and maintenance of plasticity to cope with variable colony demands. We investigated the extent of phenotypic specialization associated with a specific task by using allogrooming in the honeybee, Apis mellifera , where worker behaviour might lower ectoparasites load. We adopted an integrated approach to characterize the behavioural and physiological phenotype of allogroomers, by analyzing their behavior (both at individual and social network level), their immunocompetence (bacterial clearance tests) and their chemosensory specialization (proteomics of olfactory organs). We found that allogroomers have higher immune capacity compared to control bees, while they do not differ in chemosensory proteomic profiles. Behaviourally, they do not show differences in the tasks performed (other than allogrooming), while they clearly differ in connectivity within the colonial social network, having a higher centrality than control bees. This demonstrates the presence of an immune-specific physiological and social behavioural specialization in individuals involved in a social immunity related task, thus linking individual to social immunity, and it shows how phenotypes may be specialized in the task performed while maintaining an overall plasticity. Introduction Division of labour is defined as the pattern of specialization by cooperative individuals of a social group, which perform different tasks or assume specific roles depending on their morphology (polyphenism) or behaviour (polyethism) 1 , 2 . These task specializations often occur with a suite of behavioural and physiological correlates, some of which are specific phenotypic specializations that increase the aptitude, the efficiency and/or decrease the costs of the task performed 3 , 4 , 5 , 6 . However, the phenotypic specialization associated with division of labour is expected to be under contrasting selective forces: a colony might benefit from having sets of workers with highly specialized phenotypes, highly efficient and apt to perform the appointed task; at the same time, specializing may limit task flexibility, therefore reducing performance of other tasks when needed 7 , 8 . Thus, division of labour should show an adequate degree of flexibility to allow the colony to rapidly reallocate its resources in response to the environmental demands 9 , 10 . Understanding the degree of phenotypic specialization in group of workers performing specific tasks has the potential to unravel the trade-off between phenotypic plasticity and specialization. Allogrooming 11 is a behaviour in which a worker uses its mouth parts to remove debris from the body of other colony members. This behaviour, observed in several species of eusocial insects, plays a role in defence against parasites and pathogens 12 , 13 , 14 , 15 . In honeybees, allogrooming represents an important resistance mechanism that seems to limit ectoparasites load, especially mites, within colonies 16 , 17 , 18 , 19 , 20 and its expression depends on genetic and environmental factors 21 , 22 . In Apis cerana , allogrooming is performed at a high rate and appears to be a particularly effective counter-adaptation against the major worldwide threat for honey bee colonies and apiculture, the parasitic mites Varroa destructor 16 , 17 , 20 , 23 . The relatively recent spread of this parasite in many countries heavily impacted on Apis mellifera colonies 23 but effective strategies to deal with this emergency are still lacking 23 , 24 , 25 . Being allogrooming expressed with efficacy against V. destructor in A. cerana , its characterization in A. mellifera may clarify its possible effectiveness to control parasite load at colony level. Despite the potential value that allogrooming could have in maximizing colony resistance to parasites and disease transmission, very scarce attention has been given to the behavioural and physiological specializations of allogrooming at the individual level. Thus, the degree of specialization of individuals performing this task is still unclear and behavioural and physiological correlates of allogroomers are largely unknown. Here, we investigated the degree of phenotypic specialization of allogroomers in the honeybee A. mellifera . Empirical evidence reported in literature about the temporal expression of allogrooming and the degree of behavioural specialization in individuals performing this task is contrasting. According to some authors, in A. mellifera this behaviour is temporally restricted from the 1 st to the 20 th day post-emergence 26 while other researchers observed workers performing allogrooming during their entire life 27 , 28 . We thus characterized the temporal and spatial dynamics of allogrooming occurrence. To assess the timing of allogrooming expression, we performed detailed behavioural observations on a large cohort of workers along their lifespan inside the hive (until the onset of foraging activities). We then characterized the spatial occurrence of allogrooming events on the comb surface, in order to test whether they are randomly distributed or clustered in specific areas. Moreover, we investigated the degree of behavioural specialization of allogroomers, focusing on their individual behavioural profile (i.e. the array of tasks performed) and on the role they play in the colony social network. Indeed, it is not clear to what extent specialization in allogrooming implies a different behavioural repertoire in allogroomers compared to same age range non-grooming nestmates. Previous studies showed that allogroomers are specialized individuals performing the behaviour at a consistently higher frequency compared to other tasks typical of same age range workers 29 , while others reported that this behaviour is unfrequently expressed also by the few individuals performing it, which also carry out all the tasks typical of their age 30 . We thus compared the behavioural repertoire of allogroomers with that of same age range non-grooming bees, predicting that, in case of specialization, allogroomer workers would show a reduced performance of the other in-hive tasks ( prediction 1 ). In A. mellifera colonies, individuals have been shown to occupy different positions (more or less central, i.e. more or less connected) within the colony social network, according to their caste, age and task 31 , producing<|im_end|> <|im_start|>assistant Honeybees that specialize in grooming their nestmates (allogroomers) to ward off pests play a central role in the colony, finds a new UCL and University of Florence study. Allogroomer bees also appear to have stronger immune systems, possibly enabling them to withstand their higher risk of infection, according to the findings published in Scientific Reports. Ectoparasites (parasites that live on the outside of a host's body, such as mites) are a growing threat to honeybees worldwide, so the researchers say that supporting allogrooming behavior might be an effective pest control strategy. Lead author Dr. Alessandro Cini, who began the project at the University of Florence before moving over to UCL Centre for Biodiversity & Environment Research, said: "An ectoparasitic mite, Varroa destructor, represents a major global threat to bee colonies. By understanding how allogrooming practices are used to ward off parasites, we may be able to develop strategies to promote allogrooming behavior and increase resilience to the parasites. "Here, we found worker bees that specialize in allogrooming are highly connected within their colonies, and have developed stronger immune systems. "We suspect that if more bees engaged in these allogrooming behaviors that ward off parasites, the colony as a whole could have greater immunity." Honeybees that specialise in grooming their nestmates (allogroomers) to ward off pests play a central role in the colony, finds a new UCL and University of Florence study published in Scientific Reports. Credit: Dr Alessandro Cini, UCL Among bees, allogrooming consists of a worker using its mouth to remove debris, which may include parasites and other pathogens, from the body of another member of its colony. In bee colonies, different groups of worker bees conduct different activities—one such specialization is allogrooming, although it was not previously known how specialized the groomer bees are, and how their physiology may be different. The current study focused on Apis mellifera, commonly known as the western honeybee, which is the most common species of honeybee and also the world's most-used bee for both honey production and pollination in agriculture. As allogrooming would likely put the grooming bees at an elevated risk of contracting pathogens and parasites, the researchers tested their immune systems, and found that their hemolymph (like blood, but for insects) could more effectively clear out potentially harmful bacteria than the immune systems of other bees in the colony. Co-author Dr. Rita Cervo from the University of Florence said: "By identifying a striking difference in the immune systems of the allogrooming bees, which are involved in tasks important to colony-wide immunity from pathogens, we have found a link between individual and social immunity." Honeybees engaging in allogrooming behavior. Credit: Dr Adele Bordoni, University of Florence The researchers found that allogroomer bees occupy a central position in the colony's social network, as they are more connected to bees across the colony than the average bee, enabling their grooming habits to benefit a large number of bees and keep the colony as pest-free as possible. The researchers found that allogrooming is a relatively weak, transient specialty, as the groomer bees still devoted a similar amount of time to other tasks as the rest of the colony's worker bees. The researchers say this shows that bees can develop physiological differences narrowly tailored to specific tasks, while still maintaining a degree of plasticity enabling them to switch to other tasks as needed. The researchers did not detect any differences in how well the allogroomer bees could detect when other bees needed grooming, as their antennae were not more finely-tuned to relevant odors. It is possible they can detect who needs grooming in other ways, such as by noticing the 'grooming invitation dance' whereby bees shake their whole body from side-to-side. <|im_end|>

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4184, 311, 279, 14955, 4756, 304, 38130, 29140, 13, 469, 302, 454, 73942, 3695, 320, 1768, 300, 3695, 430, 3974, 389, 279, 4994, 315, 264, 3552, 596, 2547, 11, 1778, 439, 296, 3695, 8, 527, 264, 7982, 6023, 311, 26828, 1395, 288, 15603, 11, 779, 279, 12074, 2019, 430, 12899, 453, 848, 3039, 287, 7865, 2643, 387, 459, 7524, 44885, 2585, 8446, 13, 30982, 3229, 2999, 13, 70885, 42824, 356, 6729, 11, 889, 6137, 279, 2447, 520, 279, 3907, 315, 48606, 1603, 7366, 927, 311, 549, 3218, 14821, 369, 426, 3205, 3050, 612, 11847, 8483, 11, 1071, 25, 330, 2127, 77594, 454, 73942, 49086, 296, 635, 11, 8909, 299, 64, 47099, 11, 11105, 264, 3682, 3728, 6023, 311, 38328, 49028, 13, 3296, 8830, 1268, 453, 848, 3039, 287, 12659, 527, 1511, 311, 26741, 1022, 79383, 11, 584, 1253, 387, 3025, 311, 2274, 15174, 311, 12192, 453, 848, 3039, 287, 7865, 323, 5376, 56062, 311, 279, 79383, 13, 330, 8586, 11, 584, 1766, 12128, 40558, 430, 48444, 304, 453, 848, 3039, 287, 527, 7701, 8599, 2949, 872, 49028, 11, 323, 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98985, 21446, 11, 3907, 315, 48606, 578, 12074, 1766, 430, 453, 848, 3039, 261, 40558, 48678, 264, 8792, 2361, 304, 279, 42036, 596, 3674, 4009, 11, 439, 814, 527, 810, 8599, 311, 40558, 4028, 279, 42036, 1109, 279, 5578, 38328, 11, 28462, 872, 75161, 26870, 311, 8935, 264, 3544, 1396, 315, 40558, 323, 2567, 279, 42036, 439, 44885, 12862, 439, 3284, 13, 578, 12074, 1766, 430, 453, 848, 3039, 287, 374, 264, 12309, 7621, 11, 41658, 36974, 11, 439, 279, 40941, 261, 40558, 2103, 29329, 264, 4528, 3392, 315, 892, 311, 1023, 9256, 439, 279, 2800, 315, 279, 42036, 596, 12128, 40558, 13, 578, 12074, 2019, 420, 5039, 430, 40558, 649, 2274, 53194, 12062, 65047, 41891, 311, 3230, 9256, 11, 1418, 2103, 20958, 264, 8547, 315, 12466, 488, 28462, 1124, 311, 3480, 311, 1023, 9256, 439, 4460, 13, 578, 12074, 1550, 539, 11388, 904, 12062, 304, 1268, 1664, 279, 453, 848, 3039, 261, 40558, 1436, 11388, 994, 1023, 40558, 4460, 75161, 11, 439, 872, 72577, 6043, 1051, 539, 810, 61802, 2442, 49983, 311, 9959, 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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 Marseilleviridae is a family of giant viruses, showing a characteristic internal membrane with extrusions underneath the icosahedral vertices. However, such large objects, with a maximum diameter of 250 nm are technically difficult to examine at sub-nanometre resolution by cryo-electron microscopy. Here, we tested the utility of 1 MV high-voltage cryo-EM (cryo-HVEM) for single particle structural analysis (SPA) of giant viruses using tokyovirus, a species of Marseilleviridae , and revealed the capsid structure at 7.7 Å resolution. The capsid enclosing the viral DNA consisted primarily of four layers: (1) major capsid proteins (MCPs) and penton proteins, (2) minor capsid proteins (mCPs), (3) scaffold protein components (ScPCs), and (4) internal membrane. The mCPs showed a novel capsid lattice consisting of eight protein components. ScPCs connecting the icosahedral vertices supported the formation of the membrane extrusions, and possibly act like tape measure proteins reported in other giant viruses. The density on top of the MCP trimer was suggested to include glycoproteins. This is the first attempt at cryo-HVEM SPA. We found the primary limitations to be the lack of automated data acquisition and software support for collection and processing and thus achievable resolution. However, the results pave the way for using cryo-HVEM for structural analysis of larger biological specimens. Introduction The “giant viruses” are exceptionally large physical size viruses, larger than small bacteria 1 . They also have a much larger genome (> 100 kilobases (kb)) than other viruses and contain many genes (> 50 genes) not found in other viruses 2 . One of the characteristics of these viruses is that they possess double-stranded DNA encapsulated in a lipid bilayer 3 . These large DNA viruses are now taxonomically classified into the phylum Nucleocytoviricota 4 , but have historically been referred to be nucleo-cytoplasmic large DNA virus (NCLDV). NCLDVs are an expansive clade of large viruses that possess double-stranded DNA and target varying host eukaryotes 5 . NCLDVs are composed of several families, including the Asfarviridae , Ascoviridae , Iridoviridae , Marseilleviridae , Mimiviridae , Phycodnaviridae , and Poxviridae , and unclassified viruses such as cedratviruses, faustoviruses, medusaviruses, Mininucleoviridae , molliviruses, orpheoviruses, pacmanviruses, pandoraviruses, and pithoviruses 6 . Even now, a variety of NCLDVs are isolated and studied from around the world. A new order, Megavirales , has been proposed based on the shared characteristics of these viruses 7 . NCLDVs exhibit several types of shapes depend on the species 2 . Asfarviridae , Ascoviridae , Iridoviridae , Marseilleviridae , Mimiviridae , Phycodnaviridae , faustoviruses, medusaviruses, pacmanviruses, and Mininucleoviridae exhibit an icosahedral shape. Poxviridae exhibits a brick shape. Cedratviruses, molliviruses, orpheoviruses, pandoraviruses, and pithoviruses exhibits an amphora shape. Sizes vary also; the amphora-shaped pithoviruses are the largest of the giant viruses, exceeding 2 μm in size, but there is a significant variation in the actual dimensions 8 . On the other hand, the icosahedral-shaped mimivirus is ~ 500 nm in diameter (not including fibrous filaments extending from the capsid) 9 , and its closest known relative cafeteriavirus is ~ 300 nm 10 . The brick-shaped poxviruses are approximately 350 × 270 nm, although precise dimensions are variable 11 . Other icosahedral viruses are ~ 260 nm for medusavirus 12 , 13 , ~ 180 nm for iridovirus 14 , ~ 190 nm for PBCV-1 15 . ASFV is ~ 250 nm, but is complicated because it has an external membrane 16 . Marseilleviridae is a family of the new order of NCLDVs 17 , which have a highly complex ~ 360 kb genome and a particle size of ~ 250 nm. The first member, Marseillevirus, was isolated in 2007 by culturing a water sample from a cooling tower in Paris, France 18 . Currently, Cannes 8 virus, Melbournevirus, Marseillevirus, Tokyovirus, Port-Miou virus, Lausannevirus, Noumeavirus, Insectminevirus, Tunisvirus, Brazilian marseillevirus, Golden mussel marseillevirus, and more species belong to this family, and these are classified into five lineages, A to E 19 , 20 . Several studies have also reported the presence of Marseilleviridae in humans 21 , 22 , 23 , 24 . However, there is controversy surrounding marseillevirus infections of humans as other studies have shown no evidence 25 , 26 . Melbournevirus, one of the Marseilleviridae belonging to lineage A 27 , has previously been analysed by cryo-electron microscopy (cryo-EM) single particle analysis (SPA) at 26 Å resolution 28 . It shows the icosahedral capsid with a triangulation number of T = 309, shows the characteristic internal membrane inside the capsid that extrudes just underneath the vertices, and the unique large density body inside the nucleoid. Tokyovirus is the first Marseilleviridae isolated in Asia in 2016 and is classified in lineage A 29 . Tokyovirus was utilised to investigate the characteristic capsid structure of the icosahedral Marseilleviridae in this study. Few studies have revealed the capsid structure of large icosahedral viruses in detail. An electron microscopy study half a century ago showed that the large icosahedral virus capsid is composed of 20 and 12 sets of trisymmetron and pentasymmetron, respectively 30 , 31 , although these viruses are not classified as NCLDVs. Each of these is a cluster of capsomers formed by pseudo-hexamer. In recent years, the structures of many viruses have been revealed with high resolution by using cryo-EM SPA for determination of overall structure 32 , dynamics 33 , 34 , and assembly 35 . However, the large icosahedral viruses present special challenges for high resolution cryo-EM simply from their size, which imposes hard limits on sample preparation, data acquisition and image reconstruction techniques. A hard limit is one which cannot be overcome using the same conditions, e.g.: particle count per micrograph, or the resolution limit imposed by the Nyquist frequency. A soft limit can be overcome, e.g., by collecting more micrographs, but a hard limit cannot. Therefore, several different methods including cryo-electron tomography, scanning electron microscopy, and atomic force microscopy, were initially combined with cryo-EM and investigated the structure of giant viruses 9 , 36 . The different methods which have been used to investigate giant viruses have", "role": "user" }, { "content": "Despite their name, giant viruses are difficult to visualize in detail. They are too big for conventional electron microscopy, yet too small for optical microscopy used to study larger specimens. Now, for the first time, an international collaboration has revealed the structure of tokyovirus, a giant virus named for the city in which it was discovered in 2016, with the help of cryo-high-voltage electron microscopy. They published their results on Dec. 11 in Scientific Reports. \"'Giant viruses' are exceptionally large physical size viruses, larger than small bacteria, with a much larger genome than other viruses,\" said co-corresponding author Kazuyoshi Murata, project professor, Exploratory Research Center on Life and Living Systems (ExCELLS) and National Institute for Physiological Sciences, the National Institutes of Natural Sciences in Japan. \"Few studies have revealed the capsid—the protein shell encapsulating the double-stranded viral DNA—structure of large icosahedral, or 20-sided, viruses in detail. They present special challenges for high-resolution cryo-electron microscopy from their size, which imposes hard limits on data acquisition.\" To overcome the challenge, the researchers used one of the few high-voltage electron microscopy (HVEM) facilities in the world that is equipped to image biological specimens. This type of electron microscope accelerates voltage to theoretically increase the power of the microscope, which allows for thicker samples to be imaged at higher resolutions. A) Particle structure of tokyovirus. From the outside, MCP: major capsid protein (light blue), mCP: minor capsid protein (blue), ScP: scaffold protein (yellow), IM: internal membrane (gray), covering the viral DNA inside. * is the protruding structure on the internal membrane. B) A novel network structure of mCP and ScP (yellow) in which 7 types of mCP structures are combined in a complex manner. mCPs are ScP are viewed from inside the shell. A triangular mCP network extends between the 5-fold vertices (bottom left and right). Credit: Scientific Reports (2022). DOI: 10.1038/s41598-022-24651-2 At the Research Center for Ultra-High Voltage Electron Microscopy at Osaka University, the team imaged flash-frozen tokyovirus particles, with the goal of reconstructing a single particle in full detail for the first time. \"Cryo-HVEM on biological samples has not been previously reported for single particle analysis,\" Murata said. \"For thick samples, such as tokyovirus with a maximum diameter for 250 nanometers, the influence of the depth of field causes an internal focus shift, imposing a hard limit on attainable resolution. Accelerating the voltage, or shortening the wavelength of the emitted electrons, can increase the depth of field and improve the optical conditions in thick samples.\" Prepared with these adjustments, the researchers imaged tokyovirus in detail to clarify the structure of the full virus particle. They achieved a 3D reconstruction at a resolution of 7.7 angstroms, a resolution just a bit lower than the technology could theoretically attain. Murata said that the result of the resolution was limited by the amount of data they could collect. \"Cryo-HVEM currently requires the manual collection of micrographs taken with the microscope,\" Murata said. Micrographs are photographs taken with the microscope. \"We identified 1,182 particles from 160 micrographs, which is an extremely small number compared to reports of other giant viruses imaged with less powerful microscopes.\" According to Murata, a lower magnification increases the number of particles included in each micrograph, but the magnification must be high enough to image the particles in detail. While the automated acquisition of micrographs—routinely used in standard cryo-electron microscopy—has facilitated a significant increase in the number of images captured at high magnification, but the manual mode allowed researchers to maintain a better particle count per micrograph while also maintaining a higher sampling frequency. A) The MCP structural model of another virus is fitted to the MCP density. The presence of unknown proteins other than MCP was recognized in the upper part (white area to which the structural model is not fitted). B) The unknown protein portion is shown in red. Credit: Scientific Reports (2022). DOI: 10.1038/s41598-022-24651-2 Even with limited samples and slightly lower resolution, Murata said, the researchers gathered enough information to better understand the giant virus particles structure with more clarity than ever before. \"The cryo-HVEM map revealed a novel capsid protein network, which included a scaffold protein component network,\" Murata said, noting that this scaffolding network's connection between vertices in the icosahedral particle may determine the particle size. \"Icosahedral giant viruses, including tokyovirus, have large, uniform sized functional cages created with limited components to protect the viral genome and infect the host cell. We are beginning to learn how this works, including the advanced functions of the structures and how we might be able to apply this understanding.\" The researchers plan to implement automated acquisition software capable of maintaining their desired parameters to image more giant virus structures and discover common architecture to better understand how the limited structures can be used for multifunctional organisms, Murata 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 Marseilleviridae is a family of giant viruses, showing a characteristic internal membrane with extrusions underneath the icosahedral vertices. However, such large objects, with a maximum diameter of 250 nm are technically difficult to examine at sub-nanometre resolution by cryo-electron microscopy. Here, we tested the utility of 1 MV high-voltage cryo-EM (cryo-HVEM) for single particle structural analysis (SPA) of giant viruses using tokyovirus, a species of Marseilleviridae , and revealed the capsid structure at 7.7 Å resolution. The capsid enclosing the viral DNA consisted primarily of four layers: (1) major capsid proteins (MCPs) and penton proteins, (2) minor capsid proteins (mCPs), (3) scaffold protein components (ScPCs), and (4) internal membrane. The mCPs showed a novel capsid lattice consisting of eight protein components. ScPCs connecting the icosahedral vertices supported the formation of the membrane extrusions, and possibly act like tape measure proteins reported in other giant viruses. The density on top of the MCP trimer was suggested to include glycoproteins. This is the first attempt at cryo-HVEM SPA. We found the primary limitations to be the lack of automated data acquisition and software support for collection and processing and thus achievable resolution. However, the results pave the way for using cryo-HVEM for structural analysis of larger biological specimens. Introduction The “giant viruses” are exceptionally large physical size viruses, larger than small bacteria 1 . They also have a much larger genome (> 100 kilobases (kb)) than other viruses and contain many genes (> 50 genes) not found in other viruses 2 . One of the characteristics of these viruses is that they possess double-stranded DNA encapsulated in a lipid bilayer 3 . These large DNA viruses are now taxonomically classified into the phylum Nucleocytoviricota 4 , but have historically been referred to be nucleo-cytoplasmic large DNA virus (NCLDV). NCLDVs are an expansive clade of large viruses that possess double-stranded DNA and target varying host eukaryotes 5 . NCLDVs are composed of several families, including the Asfarviridae , Ascoviridae , Iridoviridae , Marseilleviridae , Mimiviridae , Phycodnaviridae , and Poxviridae , and unclassified viruses such as cedratviruses, faustoviruses, medusaviruses, Mininucleoviridae , molliviruses, orpheoviruses, pacmanviruses, pandoraviruses, and pithoviruses 6 . Even now, a variety of NCLDVs are isolated and studied from around the world. A new order, Megavirales , has been proposed based on the shared characteristics of these viruses 7 . NCLDVs exhibit several types of shapes depend on the species 2 . Asfarviridae , Ascoviridae , Iridoviridae , Marseilleviridae , Mimiviridae , Phycodnaviridae , faustoviruses, medusaviruses, pacmanviruses, and Mininucleoviridae exhibit an icosahedral shape. Poxviridae exhibits a brick shape. Cedratviruses, molliviruses, orpheoviruses, pandoraviruses, and pithoviruses exhibits an amphora shape. Sizes vary also; the amphora-shaped pithoviruses are the largest of the giant viruses, exceeding 2 μm in size, but there is a significant variation in the actual dimensions 8 . On the other hand, the icosahedral-shaped mimivirus is ~ 500 nm in diameter (not including fibrous filaments extending from the capsid) 9 , and its closest known relative cafeteriavirus is ~ 300 nm 10 . The brick-shaped poxviruses are approximately 350 × 270 nm, although precise dimensions are variable 11 . Other icosahedral viruses are ~ 260 nm for medusavirus 12 , 13 , ~ 180 nm for iridovirus 14 , ~ 190 nm for PBCV-1 15 . ASFV is ~ 250 nm, but is complicated because it has an external membrane 16 . Marseilleviridae is a family of the new order of NCLDVs 17 , which have a highly complex ~ 360 kb genome and a particle size of ~ 250 nm. The first member, Marseillevirus, was isolated in 2007 by culturing a water sample from a cooling tower in Paris, France 18 . Currently, Cannes 8 virus, Melbournevirus, Marseillevirus, Tokyovirus, Port-Miou virus, Lausannevirus, Noumeavirus, Insectminevirus, Tunisvirus, Brazilian marseillevirus, Golden mussel marseillevirus, and more species belong to this family, and these are classified into five lineages, A to E 19 , 20 . Several studies have also reported the presence of Marseilleviridae in humans 21 , 22 , 23 , 24 . However, there is controversy surrounding marseillevirus infections of humans as other studies have shown no evidence 25 , 26 . Melbournevirus, one of the Marseilleviridae belonging to lineage A 27 , has previously been analysed by cryo-electron microscopy (cryo-EM) single particle analysis (SPA) at 26 Å resolution 28 . It shows the icosahedral capsid with a triangulation number of T = 309, shows the characteristic internal membrane inside the capsid that extrudes just underneath the vertices, and the unique large density body inside the nucleoid. Tokyovirus is the first Marseilleviridae isolated in Asia in 2016 and is classified in lineage A 29 . Tokyovirus was utilised to investigate the characteristic capsid structure of the icosahedral Marseilleviridae in this study. Few studies have revealed the capsid structure of large icosahedral viruses in detail. An electron microscopy study half a century ago showed that the large icosahedral virus capsid is composed of 20 and 12 sets of trisymmetron and pentasymmetron, respectively 30 , 31 , although these viruses are not classified as NCLDVs. Each of these is a cluster of capsomers formed by pseudo-hexamer. In recent years, the structures of many viruses have been revealed with high resolution by using cryo-EM SPA for determination of overall structure 32 , dynamics 33 , 34 , and assembly 35 . However, the large icosahedral viruses present special challenges for high resolution cryo-EM simply from their size, which imposes hard limits on sample preparation, data acquisition and image reconstruction techniques. A hard limit is one which cannot be overcome using the same conditions, e.g.: particle count per micrograph, or the resolution limit imposed by the Nyquist frequency. A soft limit can be overcome, e.g., by collecting more micrographs, but a hard limit cannot. Therefore, several different methods including cryo-electron tomography, scanning electron microscopy, and atomic force microscopy, were initially combined with cryo-EM and investigated the structure of giant viruses 9 , 36 . The different methods which have been used to investigate giant viruses have<|im_end|> <|im_start|>assistant Despite their name, giant viruses are difficult to visualize in detail. They are too big for conventional electron microscopy, yet too small for optical microscopy used to study larger specimens. Now, for the first time, an international collaboration has revealed the structure of tokyovirus, a giant virus named for the city in which it was discovered in 2016, with the help of cryo-high-voltage electron microscopy. They published their results on Dec. 11 in Scientific Reports. "'Giant viruses' are exceptionally large physical size viruses, larger than small bacteria, with a much larger genome than other viruses," said co-corresponding author Kazuyoshi Murata, project professor, Exploratory Research Center on Life and Living Systems (ExCELLS) and National Institute for Physiological Sciences, the National Institutes of Natural Sciences in Japan. "Few studies have revealed the capsid—the protein shell encapsulating the double-stranded viral DNA—structure of large icosahedral, or 20-sided, viruses in detail. They present special challenges for high-resolution cryo-electron microscopy from their size, which imposes hard limits on data acquisition." To overcome the challenge, the researchers used one of the few high-voltage electron microscopy (HVEM) facilities in the world that is equipped to image biological specimens. This type of electron microscope accelerates voltage to theoretically increase the power of the microscope, which allows for thicker samples to be imaged at higher resolutions. A) Particle structure of tokyovirus. From the outside, MCP: major capsid protein (light blue), mCP: minor capsid protein (blue), ScP: scaffold protein (yellow), IM: internal membrane (gray), covering the viral DNA inside. * is the protruding structure on the internal membrane. B) A novel network structure of mCP and ScP (yellow) in which 7 types of mCP structures are combined in a complex manner. mCPs are ScP are viewed from inside the shell. A triangular mCP network extends between the 5-fold vertices (bottom left and right). Credit: Scientific Reports (2022). DOI: 10.1038/s41598-022-24651-2 At the Research Center for Ultra-High Voltage Electron Microscopy at Osaka University, the team imaged flash-frozen tokyovirus particles, with the goal of reconstructing a single particle in full detail for the first time. "Cryo-HVEM on biological samples has not been previously reported for single particle analysis," Murata said. "For thick samples, such as tokyovirus with a maximum diameter for 250 nanometers, the influence of the depth of field causes an internal focus shift, imposing a hard limit on attainable resolution. Accelerating the voltage, or shortening the wavelength of the emitted electrons, can increase the depth of field and improve the optical conditions in thick samples." Prepared with these adjustments, the researchers imaged tokyovirus in detail to clarify the structure of the full virus particle. They achieved a 3D reconstruction at a resolution of 7.7 angstroms, a resolution just a bit lower than the technology could theoretically attain. Murata said that the result of the resolution was limited by the amount of data they could collect. "Cryo-HVEM currently requires the manual collection of micrographs taken with the microscope," Murata said. Micrographs are photographs taken with the microscope. "We identified 1,182 particles from 160 micrographs, which is an extremely small number compared to reports of other giant viruses imaged with less powerful microscopes." According to Murata, a lower magnification increases the number of particles included in each micrograph, but the magnification must be high enough to image the particles in detail. While the automated acquisition of micrographs—routinely used in standard cryo-electron microscopy—has facilitated a significant increase in the number of images captured at high magnification, but the manual mode allowed researchers to maintain a better particle count per micrograph while also maintaining a higher sampling frequency. A) The MCP structural model of another virus is fitted to the MCP density. The presence of unknown proteins other than MCP was recognized in the upper part (white area to which the structural model is not fitted). B) The unknown protein portion is shown in red. Credit: Scientific Reports (2022). DOI: 10.1038/s41598-022-24651-2 Even with limited samples and slightly lower resolution, Murata said, the researchers gathered enough information to better understand the giant virus particles structure with more clarity than ever before. "The cryo-HVEM map revealed a novel capsid protein network, which included a scaffold protein component network," Murata said, noting that this scaffolding network's connection between vertices in the icosahedral particle may determine the particle size. "Icosahedral giant viruses, including tokyovirus, have large, uniform sized functional cages created with limited components to protect the viral genome and infect the host cell. We are beginning to learn how this works, including the advanced functions of the structures and how we might be able to apply this understanding." The researchers plan to implement automated acquisition software capable of maintaining their desired parameters to image more giant virus structures and discover common architecture to better understand how the limited structures can be used for multifunctional organisms, Murata said. <|im_end|>

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2,730