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 Honey bees ( Apis mellifera) host a wide range of parasites, some being known contributors towards dramatic colony losses as reported over recent years. To counter parasitic threats, honey bees possess effective immune systems. Because immune responses are predicted to cause substantial physiological costs for infected individuals, they are expected to trade off with other life history traits that ultimately affect the performance and fitness of the entire colony. Here, we tested whether the initial onset of an infection negatively impacts the flight behaviour of honey bee workers, which is an energetically demanding behaviour and a key component of foraging activities. To do this, we infected workers with the widespread fungal pathogen Nosema apis , which is recognised and killed by the honey bee immune system. We compared their survival and flight behaviour with non-infected individuals from the same cohort and colony using radio frequency identification tags (RFID). We found that over a time frame of four days post infection, Nosema did not increase mortality but workers quickly altered their flight behaviour and performed more flights of shorter duration. We conclude that parasitic infections influence foraging activities, which could reduce foraging ranges of colonies and impact their ability to provide pollination services. Introduction The lifestyle of social hymenopteran insects, as found in all ants and some bees and wasps, results in related individuals living in close proximity to each other inside the colony, which offers parasites highly favourable conditions to spread and multiply 1 . Social insects are indeed known to host a wide range of different parasites such as viruses 2 , 3 , bacteria 1 , 4 fungi 5 , 6 , protozoa 7 , 8 , as well as arachnids 9 , 10 or other insects 11 , 12 that can pose substantial threats to these societies. In the case of the honey bee ( Apis mellifera ), their impact has been identified as a main contributing factor towards the massive losses as observed in some managed and wild honey bee populations 10 , 12 . Social insects are not defenceless however, and their immune systems consist of several adaptations to detect and combat pathogens 1 , 13 such as social immunity, which includes a number of behaviours that reduce the spread of pathogens including grooming of infected relatives, or hygienic behaviour to remove parasitised brood from the colony 13 , 14 , 15 . Parasitised honey bee workers are known to start foraging at a younger age to reduce the risk of spreading disease to their nestmates 16 , 17 , 18 . Social insects also possess individual-based innate immune systems, and the individual’s ability to combat parasites is of central importance for colony fitness 19 . These consist of a cellular response to combat large parasites (through processes such as encapsulation and melanisation), as well as a humoral response mediated by antimicrobial peptides, proteins and other cytotoxic compounds 20 , 21 , 22 . The activation and use of such defence mechanisms is complex 23 and assumed to be costly and to trade-off with other life history traits 24 . For example, immune activation reduces the survival of infected workers in the bumblebee Bombus terrestris 25 and affects reproduction in honey bees by diverting their energy stores towards immunity 26 , 27 . Trade-offs between immunity and other life history traits seem also present in queens of the leaf cutting ant Atta colombica , where the capacity to activate the immune system during colony foundation is inversely proportional to the number of sperm stored during matings 28 . If parasitic infections spread to an increasing number of colony members and impact their task performance such as brood care, grooming or foraging, their effects eventually become visible at the colony level 1 , 20 . In the most extreme case, they can result in the collapse and death of the entire colony, a phenomenon that has been frequently reported in honey bees and therefore received growing interest over recent years 19 . However, how parasite-driven stress acting at the individual level eventually translates into the collapse of an entire colony remains to be studied in detail. Here, we quantified the initial impact of an infection on cellular immune response and flight behaviour of a cohort of same-aged honey bee workers. Our experimental setup covered the time frame of establishment of a primary infection and the consequent physiological and behavioural responses of the host. We predicted that the response of the immune system to infection is costly, which bees compensate for by reducing the duration or frequency of their foraging trips. To do this we took workers with an age of 18–19 days, which coincides with the start of their foraging activities 29 and infected them with the widespread fungal pathogen Nosema apis . Infections of this obligate parasite occur when spores are ingested and multiply in the epithelial cells of the mid gut. The pathogen can eventually be transmitted to other bees through faecal contaminations 30 , 31 or during mating from males to queens 32 . N. apis infections are often phenotypically expressed by dysentery 30 , 33 , 34 and increased hunger levels of workers 35 , 36 resulting in elevated sugar consumption 37 , 38 . N. apis is typically referred to as a parasite with low virulence 10 , 37 , and parasite spores are indeed recognised and killed by the immune system of honey bee males 39 . Furthermore, infections result in a complex but very specific response of the innate immune system, but also induce substantial changes in the expression of core metabolic pathways that are similar to those observed during energetic stress 34 . In some cases, N. apis infections can spread and cause colony death, although this seems driven by the co-occurrence of additional stress factors such as unfavourable climatic conditions, pesticide exposure or the presence of additional infections with other pathogens 40 , 41 , 42 . We used flight behaviour of worker bees as a", "role": "user" }, { "content": "Scientists from The University of Western Australia's Centre for Integrative Bee Research (CIBER) tagged 200 honey bee workers to find out how a highly-contagious fungal parasite (Nosema apis) impacts their ability to pollinate crops. N. apis is a uni-cellular fungus that lives in the gut cells of honey bees and causes dysentery. Especially in combination with other parasites or additional environmental stressors, it is an important contributor to the bee declines observed worldwide. The CIBER team found that infected worker bees performed more flights, but of shorter duration than uninfected ones. To establish this they fed 100 newly hatched workers with sugar water or sugar water with N. apis spores, and glued tiny 1.5 millimetre computer tags to their backs, tracking the bees' time outside their hive. UWA Research Associate Dr Ryan Dosselli from CIBER said the research team had expected the parasite to drain energy of worker bees, and knew that flying was an energetically highly demanding task. \"However, it took us by surprise that the fungus would impair the workers' flight duration as early as two days after being infected,\" he said. \"That a highly contagious parasite is impacting honey bee workers so quickly, is concerning. \"If parasites reduce foraging ranges of honey bee colonies, they ultimately impact the bees' ability to pollinate agricultural crops. \"Bees are important for humans, the environment and agriculture, as they pollinate one sixth of all flowering plants world-wide, and help to produce a third of everything we eat.\" Dr Dosselli said it was interesting to see that workers from one colony seemed to cope much better with the parasite than workers of the other two colonies in the experiment. Their flight times were by far the longest, and their immune activity in response to the parasite the strongest of all three colonies investigated. The researchers are planning to unravel the sophisticated molecular interactions between the parasite N. apis and its host the bee, with the ultimate goal of being able to breed disease tolerant bees. The research has been published in the online journal 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 Honey bees ( Apis mellifera) host a wide range of parasites, some being known contributors towards dramatic colony losses as reported over recent years. To counter parasitic threats, honey bees possess effective immune systems. Because immune responses are predicted to cause substantial physiological costs for infected individuals, they are expected to trade off with other life history traits that ultimately affect the performance and fitness of the entire colony. Here, we tested whether the initial onset of an infection negatively impacts the flight behaviour of honey bee workers, which is an energetically demanding behaviour and a key component of foraging activities. To do this, we infected workers with the widespread fungal pathogen Nosema apis , which is recognised and killed by the honey bee immune system. We compared their survival and flight behaviour with non-infected individuals from the same cohort and colony using radio frequency identification tags (RFID). We found that over a time frame of four days post infection, Nosema did not increase mortality but workers quickly altered their flight behaviour and performed more flights of shorter duration. We conclude that parasitic infections influence foraging activities, which could reduce foraging ranges of colonies and impact their ability to provide pollination services. Introduction The lifestyle of social hymenopteran insects, as found in all ants and some bees and wasps, results in related individuals living in close proximity to each other inside the colony, which offers parasites highly favourable conditions to spread and multiply 1 . Social insects are indeed known to host a wide range of different parasites such as viruses 2 , 3 , bacteria 1 , 4 fungi 5 , 6 , protozoa 7 , 8 , as well as arachnids 9 , 10 or other insects 11 , 12 that can pose substantial threats to these societies. In the case of the honey bee ( Apis mellifera ), their impact has been identified as a main contributing factor towards the massive losses as observed in some managed and wild honey bee populations 10 , 12 . Social insects are not defenceless however, and their immune systems consist of several adaptations to detect and combat pathogens 1 , 13 such as social immunity, which includes a number of behaviours that reduce the spread of pathogens including grooming of infected relatives, or hygienic behaviour to remove parasitised brood from the colony 13 , 14 , 15 . Parasitised honey bee workers are known to start foraging at a younger age to reduce the risk of spreading disease to their nestmates 16 , 17 , 18 . Social insects also possess individual-based innate immune systems, and the individual’s ability to combat parasites is of central importance for colony fitness 19 . These consist of a cellular response to combat large parasites (through processes such as encapsulation and melanisation), as well as a humoral response mediated by antimicrobial peptides, proteins and other cytotoxic compounds 20 , 21 , 22 . The activation and use of such defence mechanisms is complex 23 and assumed to be costly and to trade-off with other life history traits 24 . For example, immune activation reduces the survival of infected workers in the bumblebee Bombus terrestris 25 and affects reproduction in honey bees by diverting their energy stores towards immunity 26 , 27 . Trade-offs between immunity and other life history traits seem also present in queens of the leaf cutting ant Atta colombica , where the capacity to activate the immune system during colony foundation is inversely proportional to the number of sperm stored during matings 28 . If parasitic infections spread to an increasing number of colony members and impact their task performance such as brood care, grooming or foraging, their effects eventually become visible at the colony level 1 , 20 . In the most extreme case, they can result in the collapse and death of the entire colony, a phenomenon that has been frequently reported in honey bees and therefore received growing interest over recent years 19 . However, how parasite-driven stress acting at the individual level eventually translates into the collapse of an entire colony remains to be studied in detail. Here, we quantified the initial impact of an infection on cellular immune response and flight behaviour of a cohort of same-aged honey bee workers. Our experimental setup covered the time frame of establishment of a primary infection and the consequent physiological and behavioural responses of the host. We predicted that the response of the immune system to infection is costly, which bees compensate for by reducing the duration or frequency of their foraging trips. To do this we took workers with an age of 18–19 days, which coincides with the start of their foraging activities 29 and infected them with the widespread fungal pathogen Nosema apis . Infections of this obligate parasite occur when spores are ingested and multiply in the epithelial cells of the mid gut. The pathogen can eventually be transmitted to other bees through faecal contaminations 30 , 31 or during mating from males to queens 32 . N. apis infections are often phenotypically expressed by dysentery 30 , 33 , 34 and increased hunger levels of workers 35 , 36 resulting in elevated sugar consumption 37 , 38 . N. apis is typically referred to as a parasite with low virulence 10 , 37 , and parasite spores are indeed recognised and killed by the immune system of honey bee males 39 . Furthermore, infections result in a complex but very specific response of the innate immune system, but also induce substantial changes in the expression of core metabolic pathways that are similar to those observed during energetic stress 34 . In some cases, N. apis infections can spread and cause colony death, although this seems driven by the co-occurrence of additional stress factors such as unfavourable climatic conditions, pesticide exposure or the presence of additional infections with other pathogens 40 , 41 , 42 . We used flight behaviour of worker bees as a<|im_end|> <|im_start|>assistant Scientists from The University of Western Australia's Centre for Integrative Bee Research (CIBER) tagged 200 honey bee workers to find out how a highly-contagious fungal parasite (Nosema apis) impacts their ability to pollinate crops. N. apis is a uni-cellular fungus that lives in the gut cells of honey bees and causes dysentery. Especially in combination with other parasites or additional environmental stressors, it is an important contributor to the bee declines observed worldwide. The CIBER team found that infected worker bees performed more flights, but of shorter duration than uninfected ones. To establish this they fed 100 newly hatched workers with sugar water or sugar water with N. apis spores, and glued tiny 1.5 millimetre computer tags to their backs, tracking the bees' time outside their hive. UWA Research Associate Dr Ryan Dosselli from CIBER said the research team had expected the parasite to drain energy of worker bees, and knew that flying was an energetically highly demanding task. "However, it took us by surprise that the fungus would impair the workers' flight duration as early as two days after being infected," he said. "That a highly contagious parasite is impacting honey bee workers so quickly, is concerning. "If parasites reduce foraging ranges of honey bee colonies, they ultimately impact the bees' ability to pollinate agricultural crops. "Bees are important for humans, the environment and agriculture, as they pollinate one sixth of all flowering plants world-wide, and help to produce a third of everything we eat." Dr Dosselli said it was interesting to see that workers from one colony seemed to cope much better with the parasite than workers of the other two colonies in the experiment. Their flight times were by far the longest, and their immune activity in response to the parasite the strongest of all three colonies investigated. The researchers are planning to unravel the sophisticated molecular interactions between the parasite N. apis and its host the bee, with the ultimate goal of being able to breed disease tolerant bees. The research has been published in the online journal Scientific Reports. <|im_end|>

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1,668

[ { "content": "You are a great 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 amygdala is importantly involved in stress and obesity, but its role on weight change and diet-related stress remains unexplored among adolescents with excess weight. We aimed to examine the functional connectivity of the Central and Basolateral amygdala nuclei (CeA and BLA) among adolescents, and to explore the longitudinal association between brain connectivity measures and diet-related cortisol and weight loss in adolescents with excess weight. Methods We compared resting-state functional connectivity between adolescents with excess (EW, N = 34; Age = 16.44 ± 1.66) and normal weight (NW, N = 36; Age = 16.50 ± 1.40) using a seed-based (CeA and BLA) whole-brain approach. Then, in a subset of 30 adolescents with EW, followed-up after 3-months of dietary/lifestyle intervention, we explored for interactions between connectivity in the CeA/BLA networks and weight loss. Regression analyses were performed to explore the relationship between accumulated cortisol and weight loss, and to test the potential effect of the amygdala networks on such association. Results In EW compared with NW, the CeA regions showed higher functional connectivity with anterior portions, and lower connectivity with posterior portions of the cingulate cortex, while the left BLA regions showed lower connectivity with the dorsal caudate and angular gyrus. In addition, higher connectivity between the left CeA-midbrain network was negatively associated with weight loss. Hair cortisol significantly predicted weight change ( p = 0.012). However, this association was no longer significant ( p = 0.164) when considering the CeA-midbrain network in the model as an additional predictor. Conclusions Adolescents with EW showed functional connectivity alterations within the BLA/CeA networks. The CeA-midbrain network might constitute an important brain pathway regulating weight change. Introduction The prevalence of adolescent obesity has exponentially increased in the last three decades [ 1 ]. Heightened stress reactivity during adolescence is a risk factor for the development of obesity [ 2 ]. The emergence of excessive weight in this stage may lead to structural and functional neuroadaptations which may alter the balance between homeostatic and hedonic brain regions [ 3 , 4 , 5 ], thus compromising the ability to lose weight. One of the most common ways of losing weight is dieting, but this process increases psychological stress and cortisol production [ 6 , 7 ]. Evidence indicates that restrictive diets induce biological stress linked to cortisol alterations [ 8 ] which, in turn, contributes to an inappropriate weight regulation, diet failure and, consequently, unsuccessful weight loss [ 6 , 7 , 8 ]. This vicious circle between stress-related cortisol and weight change is not entirely novel, but the role of hedonic brain regions as predictors of failed weight loss is [ 6 , 8 , 9 ]. Particularly, functional magnetic resonance imaging (fMRI) studies indicate that main hedonic brain hotspots (i.e., ventral striatum, ventral tegmental area, and amygdala) could be early predictive markers of weight loss outcomes after a diet intervention [ 9 , 10 ] because of their crucial role on eating behavior [ 11 , 12 ]. Among these areas, the amygdala stands out as a critical region in emotion processing [ 13 , 14 ] and the stress response linked to a dietary process [ 6 , 7 , 8 ]. Under stressful conditions, the amygdala shows greater functional connectivity with several regions of the default mode network (DMN) [ 13 , 15 , 16 ] and with the anterior insula and pontine areas [ 15 ], regions previously involved in food reward/motivation [ 9 , 17 , 18 ]. Further research about the amygdala found that, under an overnight fasting, obese individuals showed a higher resting-state functional connectivity (rsFC) between the amygdala and the brain areas processing food motivation (e.g., the insula) and a weaker connectivity with the inferior frontal gyrus [ 19 ], commonly implicated in attentional control and inhibition. Similarly, another study [ 20 ] showed that participants with obesity who lost weight after a 3-week total meal replacement showed a negative functional connectivity between the dorsolateral prefrontal cortex and the amygdala during a food-cue reactivity task. Despite the well-established role of the amygdala in stress response [ 3 , 5 ], and the impact of stress on feeding and weight regulation [ 6 , 7 , 8 ], no studies have examined the functional connectivity of the amygdala networks in adolescents, and no study has investigated their association with longitudinal assessments of weight loss and its related cortisol accumulation in adolescents with excess weight. This is especially concerning as, compared with adults, adolescents show hyperactivity of the amygdala under negative affect and stressful situations [ 21 , 22 ]. According to previous research [ 5 ], this hyperactivity could become an indicator of weight dysregulation related to non-homeostatic eating. Two main interconnected networks have been defined within the amygdala [ 23 ]. The Basolateral Amygdala (BLA) is the sensory input nucleus and it is involved in the high-level processing of sensory and emotional input. This nucleus has predominant connections with associative cortical and striatal areas [ 24 ] and directly project to the Central Amygdala (CeA). The CeA is the major output nucleus in the amygdala. Due to its principal connections with prefrontal, autonomic and limbic areas [ 25 ], the CeA has been implicated in the behavioral and physiological responses to stress [ 26 ], and in reward motivation [ 27 ]. For these reasons, it has been suggested the importance of the CeA in the “comfort food eating” phenomenon, stimulating eating behavior during the presence of chronic stressors [ 28 ]. In the present study, we aimed to compare the functional connectivity of the CeA and BLA networks between adolescents with excess and normal weight. We hypothesized that CeA and BLA regions will show higher functional connectivity with areas related to motivational drives to eat and emotional valuation of food, but lower functional connectivity with areas related to internal awareness and eating behavior inhibition [ 5 , 25 , 27 , 29 , 30 ]. In addition, we sought to examine the longitudinal", "role": "user" }, { "content": "A research group from Mind, Brain and Behaviour Research Centre (CIMCYC) of the University of Granada (UGR) has been studying the issue of excess weight from a neuroscientific perspective for many years, to determine the precise role played by the brain. In a study recently published in the International Journal of Obesity—based on the doctoral thesis of Cristina Martín, which dealt with overweight adolescents—researchers from the UGR have found that that inferior weight loss among adolescents following a diet is linked to a stronger connection between the areas of the brain associated with the motivation to eat and the rewarding effect of food. This finding adds to those previously obtained by the UGR's Applied Neuropsychology and Psychoneuroimmunology Research Group in its work devoted to studying adolescents and adults, which shows how the brains of overweight people work differently from those of people of a healthy weight in all matters related to food. \"When faced with a decision about what best to eat and when presented with highly appetizing food, in terms of brain response we observed that the 'impulsive' circuits are more highly activated than the 'reflective' circuits,\" explains Raquel Vilar López, a researcher at the UGR's Department of Personality, Evaluation and Psychological Treatment and one of the authors of this work. Different thickness in the cerebral cortex In addition to these differences in brain activation, various areas of the brain in overweight people were found to differ in terms of how they connect and in the thickness of the cerebral cortex. There is also a link between these differences (which could be related to a diet high in fat) and the difficulty experienced by some people in following a diet and exercising, and therefore weight loss. Based on these findings, researchers Raquel Vilar and Alfonso Caracuel of the UGR's Department of Developmental and Educational Psychology, in collaboration with two international research groups, have recently started a project to combat the phenomenon of excess weight. This involves a combination of training approaches that, individually, have proven effective in modifying imbalanced aspects in the functioning of the brain circuits involved in being overweight or obese. These approaches can be delivered online or in person. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 amygdala is importantly involved in stress and obesity, but its role on weight change and diet-related stress remains unexplored among adolescents with excess weight. We aimed to examine the functional connectivity of the Central and Basolateral amygdala nuclei (CeA and BLA) among adolescents, and to explore the longitudinal association between brain connectivity measures and diet-related cortisol and weight loss in adolescents with excess weight. Methods We compared resting-state functional connectivity between adolescents with excess (EW, N = 34; Age = 16.44 ± 1.66) and normal weight (NW, N = 36; Age = 16.50 ± 1.40) using a seed-based (CeA and BLA) whole-brain approach. Then, in a subset of 30 adolescents with EW, followed-up after 3-months of dietary/lifestyle intervention, we explored for interactions between connectivity in the CeA/BLA networks and weight loss. Regression analyses were performed to explore the relationship between accumulated cortisol and weight loss, and to test the potential effect of the amygdala networks on such association. Results In EW compared with NW, the CeA regions showed higher functional connectivity with anterior portions, and lower connectivity with posterior portions of the cingulate cortex, while the left BLA regions showed lower connectivity with the dorsal caudate and angular gyrus. In addition, higher connectivity between the left CeA-midbrain network was negatively associated with weight loss. Hair cortisol significantly predicted weight change ( p = 0.012). However, this association was no longer significant ( p = 0.164) when considering the CeA-midbrain network in the model as an additional predictor. Conclusions Adolescents with EW showed functional connectivity alterations within the BLA/CeA networks. The CeA-midbrain network might constitute an important brain pathway regulating weight change. Introduction The prevalence of adolescent obesity has exponentially increased in the last three decades [ 1 ]. Heightened stress reactivity during adolescence is a risk factor for the development of obesity [ 2 ]. The emergence of excessive weight in this stage may lead to structural and functional neuroadaptations which may alter the balance between homeostatic and hedonic brain regions [ 3 , 4 , 5 ], thus compromising the ability to lose weight. One of the most common ways of losing weight is dieting, but this process increases psychological stress and cortisol production [ 6 , 7 ]. Evidence indicates that restrictive diets induce biological stress linked to cortisol alterations [ 8 ] which, in turn, contributes to an inappropriate weight regulation, diet failure and, consequently, unsuccessful weight loss [ 6 , 7 , 8 ]. This vicious circle between stress-related cortisol and weight change is not entirely novel, but the role of hedonic brain regions as predictors of failed weight loss is [ 6 , 8 , 9 ]. Particularly, functional magnetic resonance imaging (fMRI) studies indicate that main hedonic brain hotspots (i.e., ventral striatum, ventral tegmental area, and amygdala) could be early predictive markers of weight loss outcomes after a diet intervention [ 9 , 10 ] because of their crucial role on eating behavior [ 11 , 12 ]. Among these areas, the amygdala stands out as a critical region in emotion processing [ 13 , 14 ] and the stress response linked to a dietary process [ 6 , 7 , 8 ]. Under stressful conditions, the amygdala shows greater functional connectivity with several regions of the default mode network (DMN) [ 13 , 15 , 16 ] and with the anterior insula and pontine areas [ 15 ], regions previously involved in food reward/motivation [ 9 , 17 , 18 ]. Further research about the amygdala found that, under an overnight fasting, obese individuals showed a higher resting-state functional connectivity (rsFC) between the amygdala and the brain areas processing food motivation (e.g., the insula) and a weaker connectivity with the inferior frontal gyrus [ 19 ], commonly implicated in attentional control and inhibition. Similarly, another study [ 20 ] showed that participants with obesity who lost weight after a 3-week total meal replacement showed a negative functional connectivity between the dorsolateral prefrontal cortex and the amygdala during a food-cue reactivity task. Despite the well-established role of the amygdala in stress response [ 3 , 5 ], and the impact of stress on feeding and weight regulation [ 6 , 7 , 8 ], no studies have examined the functional connectivity of the amygdala networks in adolescents, and no study has investigated their association with longitudinal assessments of weight loss and its related cortisol accumulation in adolescents with excess weight. This is especially concerning as, compared with adults, adolescents show hyperactivity of the amygdala under negative affect and stressful situations [ 21 , 22 ]. According to previous research [ 5 ], this hyperactivity could become an indicator of weight dysregulation related to non-homeostatic eating. Two main interconnected networks have been defined within the amygdala [ 23 ]. The Basolateral Amygdala (BLA) is the sensory input nucleus and it is involved in the high-level processing of sensory and emotional input. This nucleus has predominant connections with associative cortical and striatal areas [ 24 ] and directly project to the Central Amygdala (CeA). The CeA is the major output nucleus in the amygdala. Due to its principal connections with prefrontal, autonomic and limbic areas [ 25 ], the CeA has been implicated in the behavioral and physiological responses to stress [ 26 ], and in reward motivation [ 27 ]. For these reasons, it has been suggested the importance of the CeA in the “comfort food eating” phenomenon, stimulating eating behavior during the presence of chronic stressors [ 28 ]. In the present study, we aimed to compare the functional connectivity of the CeA and BLA networks between adolescents with excess and normal weight. We hypothesized that CeA and BLA regions will show higher functional connectivity with areas related to motivational drives to eat and emotional valuation of food, but lower functional connectivity with areas related to internal awareness and eating behavior inhibition [ 5 , 25 , 27 , 29 , 30 ]. In addition, we sought to examine the longitudinal<|im_end|> <|im_start|>assistant A research group from Mind, Brain and Behaviour Research Centre (CIMCYC) of the University of Granada (UGR) has been studying the issue of excess weight from a neuroscientific perspective for many years, to determine the precise role played by the brain. In a study recently published in the International Journal of Obesity—based on the doctoral thesis of Cristina Martín, which dealt with overweight adolescents—researchers from the UGR have found that that inferior weight loss among adolescents following a diet is linked to a stronger connection between the areas of the brain associated with the motivation to eat and the rewarding effect of food. This finding adds to those previously obtained by the UGR's Applied Neuropsychology and Psychoneuroimmunology Research Group in its work devoted to studying adolescents and adults, which shows how the brains of overweight people work differently from those of people of a healthy weight in all matters related to food. "When faced with a decision about what best to eat and when presented with highly appetizing food, in terms of brain response we observed that the 'impulsive' circuits are more highly activated than the 'reflective' circuits," explains Raquel Vilar López, a researcher at the UGR's Department of Personality, Evaluation and Psychological Treatment and one of the authors of this work. Different thickness in the cerebral cortex In addition to these differences in brain activation, various areas of the brain in overweight people were found to differ in terms of how they connect and in the thickness of the cerebral cortex. There is also a link between these differences (which could be related to a diet high in fat) and the difficulty experienced by some people in following a diet and exercising, and therefore weight loss. Based on these findings, researchers Raquel Vilar and Alfonso Caracuel of the UGR's Department of Developmental and Educational Psychology, in collaboration with two international research groups, have recently started a project to combat the phenomenon of excess weight. This involves a combination of training approaches that, individually, have proven effective in modifying imbalanced aspects in the functioning of the brain circuits involved in being overweight or obese. These approaches can be delivered online or in person. <|im_end|>

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1,782

[ { "content": "You are a great 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 studies of the effects on cognition of selective serotonin reuptake inhibitors (SSRI), administered either acutely or sub-chronically in healthy volunteers, have found changes in learning and reinforcement outcomes. In contrast, to our knowledge, there have been no studies of chronic effects of escitalopram on cognition in healthy volunteers. This is important in view of its clinical use in major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). Consequently, we aimed to investigate the chronic effect of the SSRI, escitalopram, on measures of ‘cold’ cognition (including inhibition, cognitive flexibility, memory) and ‘hot cognition’ including decision-making and particularly reinforcement learning. The study, conducted at the University of Copenhagen between May 2020 and October 2021, used a double-blind placebo-controlled design with 66 healthy volunteers, semi-randomised to receive either 20 mg of escitalopram ( n = 32) or placebo ( n = 34), balanced for age, sex and intelligence quotient (IQ) for at least 21 days. Questionnaires, neuropsychological tests and serum escitalopram measures were taken. We analysed group differences on the cognitive measures using linear regression models as well as innovative hierarchical Bayesian modelling of the Probabilistic Reversal Learning (PRL) task. The novel and important finding was that escitalopram reduced reinforcement sensitivity compared to placebo on both the Sequential Model-Based/Model-Free task and the PRL task. We found no other significant group differences on ‘cold’ or ‘hot’ cognition. These findings demonstrate that serotonin reuptake inhibition is involved in reinforcement learning in healthy individuals. Lower reinforcement sensitivity in response to chronic SSRI administration may reflect the ‘blunting’ effect often reported by patients with MDD treated with SSRIs. Trial Registration: NCT04239339 . Introduction Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter implicated in several cognitive and affective brain functions [ 1 ]. Drugs that target serotonin transmission, such as selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatments for many neuropsychiatric disorders such as major depressive disorder (MDD), obsessive-compulsive disorder (OCD) and anxiety [ 2 ]. Understanding the modulatory role of serotonin on cognition and reinforcement learning is particularly important [ 3 ]. Many studies examining the modulatory effects of serotonin on cognition have been conducted in experimental animals [ 4 , 5 , 6 ]. In rats, impairing serotonin function disrupted reversal learning, whereas enhancing serotonin function improved reversal learning [ 4 ]. In marmoset monkeys, targeted neurotoxic serotonin depletion of the orbito-frontal cortex, but not of the caudate nucleus, consistently produced reversal deficits [ 5 , 6 ]. Marmosets have also shown reduced reinforcement sensitivity following serotonin depletion [ 7 ]. In humans, the modulatory effects of serotonin on cognition have largely been examined through acute dietary tryptophan depletion (ATD) [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ], or through acute SSRI administration [ 19 , 20 , 21 , 22 , 23 ]. ATD has been shown to affect measures of both ‘cold’ (rational and non-emotional), and ‘hot’ (social and emotional) cognition [ 13 , 14 , 15 , 16 , 17 , 18 ]. Specifically, ATD induces ‘waiting’ impulsivity and impulsive behaviours, impairs goal-directed behaviour and shifts behavioural control toward habitual responding in appetitive conditions, but goal-directed in aversive conditions [ 10 , 11 , 12 ]. Effects of ATD have also been seen on reinforcement behaviour [ 13 ], reversal learning [ 9 , 14 ], learning and memory [ 15 ], affective and social cognition [ 9 , 16 , 17 ] and moral judgement [ 18 ]. Studies examining the acute administration of SSRIs have shown impaired probabilistic learning [ 19 , 20 ], and impaired cognitive flexibility [ 20 ], but increased long-term memory recall [ 21 ], emotion recognition [ 22 ], and harm aversion for moral judgements [ 23 ]. One study showed that response inhibition improved with SSRI administration [ 20 ], whereas another showed no effect [ 19 ]. Taken together, a wide range of cognitive functions is affected by serotonin modulation in healthy volunteers. Given that SSRIs are administered chronically in the treatment of neuropsychiatric disorders, it is particularly important to understand the long-term effects of SSRI administration on cognition. Currently, only a few studies have examined SSRIs administered sub-chronically, over approximately 7 days [ 24 , 25 ]. Short-term administration of antidepressants may ameliorate the negative biases in information processing that are often present in mood and anxiety disorders [ 24 ]. A recent study examined both the acute and short-term effects of SSRIs. The results showed that acute administration did not affect reinforcement learning, but short-term administration resulted in increased learning from punishment, with reduced learning from reward [ 25 ]. However, there was no statistical difference in performance between the acute and short-term administration, and therefore these results must be interpreted with caution. In addition, studies with patients with MDD have shown that SSRIs impair learning from negative feedback, while having negligible effect on learning from positive feedback [ 26 ]. These findings demonstrate the difficulty in understanding the modulatory role of SSRI on various cognitive and motivational processes. One study gave a tryptophan-rich diet to middle-aged healthy volunteers for 19 days and showed that emotional bias to negative stimuli was reduced [ 27 ]. Understanding the acute effects of SSRIs on cognitive processes in healthy volunteers and patients with MDD is complex. This may be due to the differing possible pre- and post-synaptic actions [ 28 ]. In addition, there is some evidence that the neuroplasticity effects of SSRIs emerge only after more chronic administration (14–21 days) [ 29 , 30 ]. As such, the chronic administration of SSRI may provide more robust results. Importantly, chronic SSRI administration is an experimental model that better mimics a treatment model of MDD. In addition, to our knowledge, no studies have examined the more chronic effects of SSRIs on a wide range of cognitive measures. Escitalopram is the active S-enantiomer of the racemic SSRI citalopram (RS-citalopram) [ 31 ]. By removing the R enantiomer and only", "role": "user" }, { "content": "Scientists have worked out why common anti-depressants cause around half of users to feel emotionally \"blunted.\" In a study published today in Neuropsychopharmacology, they show that the drugs affect reinforcement learning, an important behavioral process that allows people to learn from their environment. According to the NHS, more than 8.3 million patients in England received an antidepressant drug in 2021/22. A widely used class of antidepressants, particularly for persistent or severe cases, is selective serotonin reuptake inhibitors (SSRIs). These drugs target serotonin, a chemical that carries messages between nerve cells in the brain and has been dubbed the \"pleasure chemical.\" One of the widely reported side effects of SSRIs is \"blunting,\" where patients report feeling emotionally dull and no longer finding things as pleasurable as they used to. Between 40% and 60% of patients taking SSRIs are believed to experience this side effect. To date, most studies of SSRIs have only examined their short term use, but, for clinical use in depression these drugs are taken chronically, over a longer period of time. A team led by researchers at the University of Cambridge, in collaboration with the University of Copenhagen, sought to address this by recruiting healthy volunteers and administering escitalopram, an SSRI known to be one of the best-tolerated, over several weeks and assessing the impact the drug had on their performance on a suite of cognitive tests. In total, 66 volunteers took part in the experiment, 32 of whom were given escitalopram while the other 34 were given a placebo. Volunteers took the drug or placebo for at least 21 days and completed a comprehensive set of self-report questionnaires and were given a series of tests to assess cognitive functions including learning, inhibition, executive function, reinforcement behavior, and decision-making. The team found no significant group differences when it came to \"cold\" cognition—such as attention and memory. There were no differences in most tests of \"hot\" cognition—cognitive functions that involve our emotions. However, the key novel finding was that there was reduced reinforcement sensitivity on two tasks for the escitalopram group compared to those on placebo. Reinforcement learning is how we learn from feedback from our actions and environment. In order to assess reinforcement sensitivity, the researchers used a \"probabilistic reversal test.\" In this task, a participant would typically be shown two stimuli, A and B. If they chose A, then four out of five times, they would receive a reward; if they chose B, they would only receive a reward one time out of five. Volunteers would not be told this rule, but would have to learn it themselves, and at some point in the experiment, the probabilities would switch and participants would need to learn the new rule. The team found that participants taking escitalopram were less likely to use the positive and negative feedback to guide their learning of the task compared with participants on placebo. This suggests that the drug affected their sensitivity to the rewards and their ability to respond accordingly. The finding may also explain the one difference the team found in the self-reported questionnaires, that volunteers taking escitalopram had more trouble reaching orgasm when having sex, a side effect often reported by patients. Professor Barbara Sahakian, senior author, from the Department of Psychiatry at the University of Cambridge and a Fellow at Clare Hall, said, \"Emotional blunting is a common side effect of SSRI antidepressants. In a way, this may be in part how they work—they take away some of the emotional pain that people who experience depression feel, but, unfortunately, it seems that they also take away some of the enjoyment. From our study, we can now see that this is because they become less sensitive to rewards, which provide important feedback.\" Dr. Christelle Langley, joint first author also from the Department of Psychiatry, added, \"Our findings provide important evidence for the role of serotonin in reinforcement learning. We are following this work up with a study examining neuroimaging data to understand how escitalopram affects the brain during reward learning.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 studies of the effects on cognition of selective serotonin reuptake inhibitors (SSRI), administered either acutely or sub-chronically in healthy volunteers, have found changes in learning and reinforcement outcomes. In contrast, to our knowledge, there have been no studies of chronic effects of escitalopram on cognition in healthy volunteers. This is important in view of its clinical use in major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). Consequently, we aimed to investigate the chronic effect of the SSRI, escitalopram, on measures of ‘cold’ cognition (including inhibition, cognitive flexibility, memory) and ‘hot cognition’ including decision-making and particularly reinforcement learning. The study, conducted at the University of Copenhagen between May 2020 and October 2021, used a double-blind placebo-controlled design with 66 healthy volunteers, semi-randomised to receive either 20 mg of escitalopram ( n = 32) or placebo ( n = 34), balanced for age, sex and intelligence quotient (IQ) for at least 21 days. Questionnaires, neuropsychological tests and serum escitalopram measures were taken. We analysed group differences on the cognitive measures using linear regression models as well as innovative hierarchical Bayesian modelling of the Probabilistic Reversal Learning (PRL) task. The novel and important finding was that escitalopram reduced reinforcement sensitivity compared to placebo on both the Sequential Model-Based/Model-Free task and the PRL task. We found no other significant group differences on ‘cold’ or ‘hot’ cognition. These findings demonstrate that serotonin reuptake inhibition is involved in reinforcement learning in healthy individuals. Lower reinforcement sensitivity in response to chronic SSRI administration may reflect the ‘blunting’ effect often reported by patients with MDD treated with SSRIs. Trial Registration: NCT04239339 . Introduction Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter implicated in several cognitive and affective brain functions [ 1 ]. Drugs that target serotonin transmission, such as selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatments for many neuropsychiatric disorders such as major depressive disorder (MDD), obsessive-compulsive disorder (OCD) and anxiety [ 2 ]. Understanding the modulatory role of serotonin on cognition and reinforcement learning is particularly important [ 3 ]. Many studies examining the modulatory effects of serotonin on cognition have been conducted in experimental animals [ 4 , 5 , 6 ]. In rats, impairing serotonin function disrupted reversal learning, whereas enhancing serotonin function improved reversal learning [ 4 ]. In marmoset monkeys, targeted neurotoxic serotonin depletion of the orbito-frontal cortex, but not of the caudate nucleus, consistently produced reversal deficits [ 5 , 6 ]. Marmosets have also shown reduced reinforcement sensitivity following serotonin depletion [ 7 ]. In humans, the modulatory effects of serotonin on cognition have largely been examined through acute dietary tryptophan depletion (ATD) [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ], or through acute SSRI administration [ 19 , 20 , 21 , 22 , 23 ]. ATD has been shown to affect measures of both ‘cold’ (rational and non-emotional), and ‘hot’ (social and emotional) cognition [ 13 , 14 , 15 , 16 , 17 , 18 ]. Specifically, ATD induces ‘waiting’ impulsivity and impulsive behaviours, impairs goal-directed behaviour and shifts behavioural control toward habitual responding in appetitive conditions, but goal-directed in aversive conditions [ 10 , 11 , 12 ]. Effects of ATD have also been seen on reinforcement behaviour [ 13 ], reversal learning [ 9 , 14 ], learning and memory [ 15 ], affective and social cognition [ 9 , 16 , 17 ] and moral judgement [ 18 ]. Studies examining the acute administration of SSRIs have shown impaired probabilistic learning [ 19 , 20 ], and impaired cognitive flexibility [ 20 ], but increased long-term memory recall [ 21 ], emotion recognition [ 22 ], and harm aversion for moral judgements [ 23 ]. One study showed that response inhibition improved with SSRI administration [ 20 ], whereas another showed no effect [ 19 ]. Taken together, a wide range of cognitive functions is affected by serotonin modulation in healthy volunteers. Given that SSRIs are administered chronically in the treatment of neuropsychiatric disorders, it is particularly important to understand the long-term effects of SSRI administration on cognition. Currently, only a few studies have examined SSRIs administered sub-chronically, over approximately 7 days [ 24 , 25 ]. Short-term administration of antidepressants may ameliorate the negative biases in information processing that are often present in mood and anxiety disorders [ 24 ]. A recent study examined both the acute and short-term effects of SSRIs. The results showed that acute administration did not affect reinforcement learning, but short-term administration resulted in increased learning from punishment, with reduced learning from reward [ 25 ]. However, there was no statistical difference in performance between the acute and short-term administration, and therefore these results must be interpreted with caution. In addition, studies with patients with MDD have shown that SSRIs impair learning from negative feedback, while having negligible effect on learning from positive feedback [ 26 ]. These findings demonstrate the difficulty in understanding the modulatory role of SSRI on various cognitive and motivational processes. One study gave a tryptophan-rich diet to middle-aged healthy volunteers for 19 days and showed that emotional bias to negative stimuli was reduced [ 27 ]. Understanding the acute effects of SSRIs on cognitive processes in healthy volunteers and patients with MDD is complex. This may be due to the differing possible pre- and post-synaptic actions [ 28 ]. In addition, there is some evidence that the neuroplasticity effects of SSRIs emerge only after more chronic administration (14–21 days) [ 29 , 30 ]. As such, the chronic administration of SSRI may provide more robust results. Importantly, chronic SSRI administration is an experimental model that better mimics a treatment model of MDD. In addition, to our knowledge, no studies have examined the more chronic effects of SSRIs on a wide range of cognitive measures. Escitalopram is the active S-enantiomer of the racemic SSRI citalopram (RS-citalopram) [ 31 ]. By removing the R enantiomer and only<|im_end|> <|im_start|>assistant Scientists have worked out why common anti-depressants cause around half of users to feel emotionally "blunted." In a study published today in Neuropsychopharmacology, they show that the drugs affect reinforcement learning, an important behavioral process that allows people to learn from their environment. According to the NHS, more than 8.3 million patients in England received an antidepressant drug in 2021/22. A widely used class of antidepressants, particularly for persistent or severe cases, is selective serotonin reuptake inhibitors (SSRIs). These drugs target serotonin, a chemical that carries messages between nerve cells in the brain and has been dubbed the "pleasure chemical." One of the widely reported side effects of SSRIs is "blunting," where patients report feeling emotionally dull and no longer finding things as pleasurable as they used to. Between 40% and 60% of patients taking SSRIs are believed to experience this side effect. To date, most studies of SSRIs have only examined their short term use, but, for clinical use in depression these drugs are taken chronically, over a longer period of time. A team led by researchers at the University of Cambridge, in collaboration with the University of Copenhagen, sought to address this by recruiting healthy volunteers and administering escitalopram, an SSRI known to be one of the best-tolerated, over several weeks and assessing the impact the drug had on their performance on a suite of cognitive tests. In total, 66 volunteers took part in the experiment, 32 of whom were given escitalopram while the other 34 were given a placebo. Volunteers took the drug or placebo for at least 21 days and completed a comprehensive set of self-report questionnaires and were given a series of tests to assess cognitive functions including learning, inhibition, executive function, reinforcement behavior, and decision-making. The team found no significant group differences when it came to "cold" cognition—such as attention and memory. There were no differences in most tests of "hot" cognition—cognitive functions that involve our emotions. However, the key novel finding was that there was reduced reinforcement sensitivity on two tasks for the escitalopram group compared to those on placebo. Reinforcement learning is how we learn from feedback from our actions and environment. In order to assess reinforcement sensitivity, the researchers used a "probabilistic reversal test." In this task, a participant would typically be shown two stimuli, A and B. If they chose A, then four out of five times, they would receive a reward; if they chose B, they would only receive a reward one time out of five. Volunteers would not be told this rule, but would have to learn it themselves, and at some point in the experiment, the probabilities would switch and participants would need to learn the new rule. The team found that participants taking escitalopram were less likely to use the positive and negative feedback to guide their learning of the task compared with participants on placebo. This suggests that the drug affected their sensitivity to the rewards and their ability to respond accordingly. The finding may also explain the one difference the team found in the self-reported questionnaires, that volunteers taking escitalopram had more trouble reaching orgasm when having sex, a side effect often reported by patients. Professor Barbara Sahakian, senior author, from the Department of Psychiatry at the University of Cambridge and a Fellow at Clare Hall, said, "Emotional blunting is a common side effect of SSRI antidepressants. In a way, this may be in part how they work—they take away some of the emotional pain that people who experience depression feel, but, unfortunately, it seems that they also take away some of the enjoyment. From our study, we can now see that this is because they become less sensitive to rewards, which provide important feedback." Dr. Christelle Langley, joint first author also from the Department of Psychiatry, added, "Our findings provide important evidence for the role of serotonin in reinforcement learning. We are following this work up with a study examining neuroimaging data to understand how escitalopram affects the brain during reward learning." <|im_end|>

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2,239

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Many fruitful analogies have emerged between the theories of quantum entanglement and thermodynamics, motivating the pursuit of an axiomatic description of entanglement akin to the laws of thermodynamics. A long-standing open problem has been to establish a true second law of entanglement, and in particular a unique function that governs all transformations between entangled systems, mirroring the role of entropy in thermodynamics. Contrary to previous promising evidence, here we show that this is impossible and that no direct counterpart to the second law of thermodynamics can be established. This is accomplished by demonstrating the irreversibility of entanglement theory from first principles. Assuming only the most general microscopic physical constraints of entanglement manipulation, we show that entanglement theory is irreversible under all non-entangling transformations. We furthermore rule out reversibility without significant entanglement expenditure, showing that reversible entanglement transformations require the generation of macroscopically large amounts of entanglement according to certain measures. Our results not only reveal fundamental differences between quantum entanglement transformations and thermodynamic processes, but also showcase a unique property of entanglement that distinguishes it from other known quantum resources. Main Thermodynamics is perhaps the only physical theory that has withstood the several revolutions that have overturned the scientific paradigm since its inception. It started as a phenomenological theory of heat engines, in which context the first and second laws were first formulated, and has since evolved to encompass general relativity and quantum mechanics. Arguably, its special status stems from its meta-theoretic character: at its root, thermodynamics is a framework to decide which transformations a closed system can or cannot undergo, independently of the underlying physics. In accordance with this view, axiomatic approaches have played an important role in the development of thermodynamics, from the formulations of Clausius 1 and Kelvin 2 of the second law to the ground-breaking work of Carathéodory 3 , Giles 4 and recently Lieb and Yngvason 5 . A key feature and strength of these approaches is that only generic assumptions are made regarding the physical laws that govern the systems under consideration. Early statements of the second law posited the absolute physical impossibility of realising certain transformations, and already in the minds of Carnot, Clausius and Kelvin were intended to hold equally well, for example, for mechanical and electromagnetic processes 2 , 6 . A remarkable success of the axiomatic approach is to arrive at an abstract construction of the entropy as the unique function S that encodes all transformations between comparable equilibrium states: given two such states X and Y , X can be transformed into Y adiabatically if and only if S ( X ) ≤ S ( Y ) (refs. 4 , 5 ). A logical consequence is that comparable states with the same entropy must be connected by reversible transformations, for example, Carnot cycles 6 . With the advent of quantum information science, the phenomenon of quantum entanglement emerged as a physical resource in its own right 7 , enabling remarkable advantages in tasks such as communication 8 , 9 , 10 , computation 11 and cryptography 12 . The parallel with thermodynamics prompted a debate concerning the axiomatisation of entanglement theory 13 , 14 , 15 , 16 and the possible emergence of a single entanglement measure, akin to entropy, which would govern all entanglement transformations and establish the reversibility of this resource 13 , 16 , 17 , 18 . Although later results suggested that entanglement may often be quite different from thermodynamics, even exhibiting irreversibility in some of the most practically relevant settings 19 , 20 , hope persisted for an axiomatic framework for entanglement manipulation that would exactly mirror thermodynamic properties. Notably, identifying a unique entropic measure of entanglement was long known to be possible for the special case of pure states 13 , 21 , and several proposals for general reversible frameworks have been formulated 16 , 22 , 23 . The seminal work of Brandão and Plenio 23 , 24 then provided further evidence in this direction by showing that reversible manipulation may 25 be possible when the physical restrictions governing entanglement transformations are suitably relaxed. These findings strengthened the belief that a fully reversible and physically consistent theory of entanglement could be established. Here, however, we prove a general no-go result showing that entanglement theory is fundamentally irreversible. Equivalently, we show from first principles that entanglement transformations cannot be governed by a single measure, and that an axiomatic second law of entanglement manipulation cannot be established. Our sole assumption is that entanglement manipulation by separated parties should be accomplished by means of operations that make the theory fully consistent, that is, that never transform an unentangled system into an entangled one. This can be thought of as the analogue in the entanglement setting of the Kelvin–Planck statement of the second law, which in classical thermodynamics forbids the creation of resources (work) from objects that are not resourceful themselves (a single heat bath) 2 , 26 . By imposing only this requirement, we dispense with the need to make any assumptions about the structure of the considered processes. For example, we do not even posit that all intermediate transformations obey the laws of standard quantum mechanics, as previous works implicitly did. Instead, we only look at the initial and final states of the system, and demand that no resource, in this case entanglement, is generated in the overall transformation. This philosophy, hereafter termed ‘axiomatic’, is analogous to that followed by the pioneers of thermodynamics (and more recently by Lieb and Yngvason 5 ) to establish truly universal versions of the second law. Such a general approach allows us to preclude the reversibility of entanglement under all physically motivated manipulation protocols. Importantly, however, our conclusions remain unaffected even when the above assumptions are substantially relaxed. It is intuitive to ask whether irreversibility could be avoided with just a small amount of generated entanglement, restoring the hope for reversible transformations in practice. We disprove such a possibility by strengthening our result to show that, with", "role": "user" }, { "content": "The second law of thermodynamics is often considered to be one of only a few physical laws that is absolutely and unquestionably true. The law states that the amount of 'entropy'—a physical property—of any closed system can never decrease. It adds an 'arrow of time' to everyday occurrences, determining which processes are reversible and which are not. It explains why an ice cube placed on a hot stove will always melt, and why compressed gas will always fly out of its container (and never back in) when a valve is opened to the atmosphere. Only states of equal entropy and energy can be reversibly converted from one to the other. This reversibility condition led to the discovery of thermodynamic processes such as the (idealized) Carnot cycle, which poses an upper limit to how efficiently one can convert heat into work, or the other way around, by cycling a closed system through different temperatures and pressures. Our understanding of this process underpinned the rapid economic development during the Western Industrial Revolution. Quantum entropy The beauty of the second law of thermodynamics is its applicability to any macroscopic system, regardless of the microscopic details. In quantum systems, one of these details may be entanglement: a quantum connection that makes separated components of the system share properties. Intriguingly, quantum entanglement shares many profound similarities with thermodynamics, even though quantum systems are mostly studied in the microscopic regime. Scientists have uncovered a notion of 'entanglement entropy' that precisely mimics the role of the thermodynamical entropy, at least for idealized quantum systems that are perfectly isolated from their surroundings. \"Quantum entanglement is a key resource that underlies much of the power of future quantum computers. To make effective use of it, we need to learn how to manipulate it,\" says quantum information researcher Ludovico Lami. A fundamental question became whether entanglement can always be reversibly manipulated, in direct analogy to the Carnot cycle. Crucially, this reversibility would need to hold, at least in theory, even for noisy ('mixed') quantum systems that have not been kept perfectly isolated from their environment. It was conjectured that a 'second law of entanglement' could be established, embodied in a single function that would generalize the entanglement entropy and govern all entanglement manipulation protocols. This conjecture featured in a famous list of open problems in quantum information theory. No second law of entanglement Resolving this long-standing open question, research carried out by Lami (previously at University of Ulm and currently at QuSoft and the University of Amsterdam) and Bartosz Regula (University of Tokyo) demonstrates that manipulation of entanglement is fundamentally irreversible, putting to rest any hopes of establishing a second law of entanglement. This new result relies on the construction of a particular quantum state which is very 'expensive' to create using pure entanglement. Creating this state will always result in a loss of some of this entanglement, as the invested entanglement cannot be fully recovered. As a result, it is inherently impossible to transform this state into another and back again. The existence of such states was previously unknown. Because the approach used here does not presuppose what exact transformation protocols are used, it rules out the reversibility of entanglement in all possible settings. It applies to all protocols, assuming they don't generate new entanglement themselves. Lami explains, \"Using entangling operations would be like running a distillery in which alcohol from elsewhere is secretly added to the beverage.\" Lami says, \"We can conclude that no single quantity, such as the entanglement entropy, can tell us everything there is to know about the allowed transformations of entangled physical systems. The theory of entanglement and thermodynamics are thus governed by fundamentally different and incompatible sets of laws.\" This may mean that describing quantum entanglement is not as simple as scientists had hoped. Rather than being a drawback, however, the vastly greater complexity of the theory of entanglement compared to the classical laws of thermodynamics may allow us to use entanglement to achieve feats that would otherwise be completely inconceivable. \"For now, what we know for certain is that entanglement hides an even richer and more complicated structure that we had given it credit for,\" concludes Lami. The paper is published in the journal Nature Physics. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Many fruitful analogies have emerged between the theories of quantum entanglement and thermodynamics, motivating the pursuit of an axiomatic description of entanglement akin to the laws of thermodynamics. A long-standing open problem has been to establish a true second law of entanglement, and in particular a unique function that governs all transformations between entangled systems, mirroring the role of entropy in thermodynamics. Contrary to previous promising evidence, here we show that this is impossible and that no direct counterpart to the second law of thermodynamics can be established. This is accomplished by demonstrating the irreversibility of entanglement theory from first principles. Assuming only the most general microscopic physical constraints of entanglement manipulation, we show that entanglement theory is irreversible under all non-entangling transformations. We furthermore rule out reversibility without significant entanglement expenditure, showing that reversible entanglement transformations require the generation of macroscopically large amounts of entanglement according to certain measures. Our results not only reveal fundamental differences between quantum entanglement transformations and thermodynamic processes, but also showcase a unique property of entanglement that distinguishes it from other known quantum resources. Main Thermodynamics is perhaps the only physical theory that has withstood the several revolutions that have overturned the scientific paradigm since its inception. It started as a phenomenological theory of heat engines, in which context the first and second laws were first formulated, and has since evolved to encompass general relativity and quantum mechanics. Arguably, its special status stems from its meta-theoretic character: at its root, thermodynamics is a framework to decide which transformations a closed system can or cannot undergo, independently of the underlying physics. In accordance with this view, axiomatic approaches have played an important role in the development of thermodynamics, from the formulations of Clausius 1 and Kelvin 2 of the second law to the ground-breaking work of Carathéodory 3 , Giles 4 and recently Lieb and Yngvason 5 . A key feature and strength of these approaches is that only generic assumptions are made regarding the physical laws that govern the systems under consideration. Early statements of the second law posited the absolute physical impossibility of realising certain transformations, and already in the minds of Carnot, Clausius and Kelvin were intended to hold equally well, for example, for mechanical and electromagnetic processes 2 , 6 . A remarkable success of the axiomatic approach is to arrive at an abstract construction of the entropy as the unique function S that encodes all transformations between comparable equilibrium states: given two such states X and Y , X can be transformed into Y adiabatically if and only if S ( X ) ≤ S ( Y ) (refs. 4 , 5 ). A logical consequence is that comparable states with the same entropy must be connected by reversible transformations, for example, Carnot cycles 6 . With the advent of quantum information science, the phenomenon of quantum entanglement emerged as a physical resource in its own right 7 , enabling remarkable advantages in tasks such as communication 8 , 9 , 10 , computation 11 and cryptography 12 . The parallel with thermodynamics prompted a debate concerning the axiomatisation of entanglement theory 13 , 14 , 15 , 16 and the possible emergence of a single entanglement measure, akin to entropy, which would govern all entanglement transformations and establish the reversibility of this resource 13 , 16 , 17 , 18 . Although later results suggested that entanglement may often be quite different from thermodynamics, even exhibiting irreversibility in some of the most practically relevant settings 19 , 20 , hope persisted for an axiomatic framework for entanglement manipulation that would exactly mirror thermodynamic properties. Notably, identifying a unique entropic measure of entanglement was long known to be possible for the special case of pure states 13 , 21 , and several proposals for general reversible frameworks have been formulated 16 , 22 , 23 . The seminal work of Brandão and Plenio 23 , 24 then provided further evidence in this direction by showing that reversible manipulation may 25 be possible when the physical restrictions governing entanglement transformations are suitably relaxed. These findings strengthened the belief that a fully reversible and physically consistent theory of entanglement could be established. Here, however, we prove a general no-go result showing that entanglement theory is fundamentally irreversible. Equivalently, we show from first principles that entanglement transformations cannot be governed by a single measure, and that an axiomatic second law of entanglement manipulation cannot be established. Our sole assumption is that entanglement manipulation by separated parties should be accomplished by means of operations that make the theory fully consistent, that is, that never transform an unentangled system into an entangled one. This can be thought of as the analogue in the entanglement setting of the Kelvin–Planck statement of the second law, which in classical thermodynamics forbids the creation of resources (work) from objects that are not resourceful themselves (a single heat bath) 2 , 26 . By imposing only this requirement, we dispense with the need to make any assumptions about the structure of the considered processes. For example, we do not even posit that all intermediate transformations obey the laws of standard quantum mechanics, as previous works implicitly did. Instead, we only look at the initial and final states of the system, and demand that no resource, in this case entanglement, is generated in the overall transformation. This philosophy, hereafter termed ‘axiomatic’, is analogous to that followed by the pioneers of thermodynamics (and more recently by Lieb and Yngvason 5 ) to establish truly universal versions of the second law. Such a general approach allows us to preclude the reversibility of entanglement under all physically motivated manipulation protocols. Importantly, however, our conclusions remain unaffected even when the above assumptions are substantially relaxed. It is intuitive to ask whether irreversibility could be avoided with just a small amount of generated entanglement, restoring the hope for reversible transformations in practice. We disprove such a possibility by strengthening our result to show that, with<|im_end|> <|im_start|>assistant The second law of thermodynamics is often considered to be one of only a few physical laws that is absolutely and unquestionably true. The law states that the amount of 'entropy'—a physical property—of any closed system can never decrease. It adds an 'arrow of time' to everyday occurrences, determining which processes are reversible and which are not. It explains why an ice cube placed on a hot stove will always melt, and why compressed gas will always fly out of its container (and never back in) when a valve is opened to the atmosphere. Only states of equal entropy and energy can be reversibly converted from one to the other. This reversibility condition led to the discovery of thermodynamic processes such as the (idealized) Carnot cycle, which poses an upper limit to how efficiently one can convert heat into work, or the other way around, by cycling a closed system through different temperatures and pressures. Our understanding of this process underpinned the rapid economic development during the Western Industrial Revolution. Quantum entropy The beauty of the second law of thermodynamics is its applicability to any macroscopic system, regardless of the microscopic details. In quantum systems, one of these details may be entanglement: a quantum connection that makes separated components of the system share properties. Intriguingly, quantum entanglement shares many profound similarities with thermodynamics, even though quantum systems are mostly studied in the microscopic regime. Scientists have uncovered a notion of 'entanglement entropy' that precisely mimics the role of the thermodynamical entropy, at least for idealized quantum systems that are perfectly isolated from their surroundings. "Quantum entanglement is a key resource that underlies much of the power of future quantum computers. To make effective use of it, we need to learn how to manipulate it," says quantum information researcher Ludovico Lami. A fundamental question became whether entanglement can always be reversibly manipulated, in direct analogy to the Carnot cycle. Crucially, this reversibility would need to hold, at least in theory, even for noisy ('mixed') quantum systems that have not been kept perfectly isolated from their environment. It was conjectured that a 'second law of entanglement' could be established, embodied in a single function that would generalize the entanglement entropy and govern all entanglement manipulation protocols. This conjecture featured in a famous list of open problems in quantum information theory. No second law of entanglement Resolving this long-standing open question, research carried out by Lami (previously at University of Ulm and currently at QuSoft and the University of Amsterdam) and Bartosz Regula (University of Tokyo) demonstrates that manipulation of entanglement is fundamentally irreversible, putting to rest any hopes of establishing a second law of entanglement. This new result relies on the construction of a particular quantum state which is very 'expensive' to create using pure entanglement. Creating this state will always result in a loss of some of this entanglement, as the invested entanglement cannot be fully recovered. As a result, it is inherently impossible to transform this state into another and back again. The existence of such states was previously unknown. Because the approach used here does not presuppose what exact transformation protocols are used, it rules out the reversibility of entanglement in all possible settings. It applies to all protocols, assuming they don't generate new entanglement themselves. Lami explains, "Using entangling operations would be like running a distillery in which alcohol from elsewhere is secretly added to the beverage." Lami says, "We can conclude that no single quantity, such as the entanglement entropy, can tell us everything there is to know about the allowed transformations of entangled physical systems. The theory of entanglement and thermodynamics are thus governed by fundamentally different and incompatible sets of laws." This may mean that describing quantum entanglement is not as simple as scientists had hoped. Rather than being a drawback, however, the vastly greater complexity of the theory of entanglement compared to the classical laws of thermodynamics may allow us to use entanglement to achieve feats that would otherwise be completely inconceivable. "For now, what we know for certain is that entanglement hides an even richer and more complicated structure that we had given it credit for," concludes Lami. The paper is published in the journal Nature Physics. <|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 Mirrored carbon-spirals have been produced from pressured ferrocene via the bilateral extrusion of the spiral pairs from an iron core. A parametric plot of the surface geometry displays the fractal growth of the conical helix made with the logarithmic spiral. Electron microscopy studies show the core is a crystalline cementite which grows and transforms its shape from spherical to biconical as it extrudes two spiralling carbon arms. In a cross section along the arms we observe graphitic flakes arranged in a herringbone structure, normal to which defects propagate. Local-wave-pattern analysis reveals nanoscale defect patterns of two-fold symmetry around the core. The data suggest that the bilateral growth originates from a globular cementite crystal with molten surfaces and the nano-defects shape emerging hexagonal carbon into a fractal structure. Understanding and knowledge obtained provide a basis for the controlled production of advanced carbon materials with designed geometries. Introduction The discovery of new forms of inorganic nanomaterials with advanced properties has opened exciting possibilities in nanosciences. A large variety of nanomaterials were synthesised via methods from colloidal synthesis of quantum dots and metal clusters 1 to physical synthesis of molecular nanostructures 2 , 3 , 4 . The unique physical and chemical properties of nanomaterials stem from their nanoscale structures which allow quantum effects to emerge. The synthesis of predefined structural dimensions and geometries is of great importance and hence, understanding and control of nanoscale shape formation are major focuses in materials science. On one hand, complex inorganic nanostructures such as polyhedral metals 5 , helical oxides 6 , 7 and semiconductors 8 and helical carbon nanotubes 9 can be formed as a result of crystallographic and defect arrangements. On the other hand, the size and shape of nuclei, seeds or catalysts play important roles in promoting chemical processes in the production of low dimensional nanostructures, such as semiconducting nanowires 10 , carbon nanotubes (CNTs) 3 and graphene 4 . When nanowires or nanotubes grow via the vapour-liquid-solid mechanism 11 , catalyst nanoparticles nucleate and extrude a 1D structure from one side of the particle 12 . The epitaxial growth of graphene via the chemical vapour deposition (CVD) method generally requires an atomically flat metal surface to catalyse and support the self-organisation of carbon atoms in a hexagonal form with one atom thick. As such, the way atoms and molecules are assembled into nanostructures depends critically on the shape of the catalysts prepared in advance or formed in the course of the synthesis 13 . In this paper, we study the formation mechanism for bilateral carbon spirals, with special emphasis on the role of metal catalysts and defects. The spiral samples are grown by the pyrolysis of pure ferrocene vapour at high pressure in a sealed volume 14 . At effective ferrocene pressures greater than 5 MPa, the catalytic activity on the created metal particle is polarized bilaterally so that it forms a pair of carbon arms out of an almost spherical metal surface. This stands in stark contrast to the cases for CNTs and graphene where sp 2 carbon layers grow unilaterally from one side of the catalyst only. The novelty of this bilateral carbon formation is manifested by the unique morphology that is transposed on the fully symmetric structures from nanoscale to microscale. Scanning electron microscopy (SEM) observations show that the symmetric objects are produced in large yield and high purity (see the SEM micrograph provided in the supplementary material ). Most of the objects observed exhibit a similar morphological identity whilst there are variations in size and shape. The fact that the arms are conical and each arm is a mirrored shape of the other, can be explained by our growth model 14 ; two carbon arms are extruded bilaterally from the opposite side of the symmetric core, resulting in its mirrored shape. The cone shape of the arms occurs as a result of the core growing simultaneously as the arms grow out of the core. A fascinating feature of this novel nanostructure is its spiralling arms. Its high reflectional symmetry ensures that the helicity of one arm is mirrored to the other in an opposite orientation. Although some of the key features of the mirrored objects were highlighted in our previous paper 14 , microscopic details of the bilateral growth is yet to be explained and the growth mechanism elucidated for the complex spiralling shapes. Knowing microscopic details of the interior structures of the micro objects will allow us to understand the cause of the symmetric growth, hence provide a deeper insight into the origin of the emergence of complex shape symmetry that spontaneously occurs at the nanoscale. We show from SEM observations of different samples that the iron core transforms its shape from a original sphere to a bicone as the carbon arms end spiralling. The spiralling morphologies are reproduced by a parametric plot that exhibits the fractal growth of the bilateral conical helix made with the logarithmic spirals. Microscopic insight into the symmetric growth is sought via cross-sectional transmission electron microscopy (TEM) studies of spiral samples. Selected area electron diffraction (SAED) patterns acquired across the cross-section of a spiral show graphite [002] diffractions whose orientations are found to be consistent with the reflectional symmetry of the surface morphology and constitute herringbone structures within the arm's cross section. Nanometer-scale patterns of defects are observed by TEM in the same cross-section. Long-range properties of the defect patterns are exploited via mapping of the local wave orientation 15 , 16 . The image obtained exhibits two-fold symmetry around the core, ascertaining the herringbone arrangement of nano-defects roughly normal to the layer of graphite flakes. This provides us an important insight that the defects propagate normal to the graphite layers as the arms grow. Such defect arrangements could be created as a result of temporal anomalies or instabilities in growth reaction on the core surface which must be molten at a high temperature. The defects are then arranged at the nanoscale to form complex shapes of micro-objects from hexagonal carbon.", "role": "user" }, { "content": "Nanotechnology draws on the fabrication of nanostructures. Scientists have now succeeded in growing a unique carbon structure at the nanoscale that resembles a tiny twirled mustache. Their method might lead the way to the formation of more complex nano-networks. Researchers of the Electronic Properties of Materials Group at the Faculty of Physics (University of Vienna) and their international collaborators have published their results in the new open-access journal of the Nature Publishing group, Scientific Reports. Nanomaterials exhibit unique properties that can only unfold when the structures of the material are very small – that is, at the nanoscale. In order to exploit these special properties such as, for example, specific quantum effects it is very important to produce predefined nanostructures in a controlled way and interpret the formation of their shape. Scientists try to understand how to initiate and control the growth of nanomaterials and are exploring different ways to design and build up nanostructures with fine control over shapes. In nature, many organic forms grow bilaterally, that is, symmetrically in two distinct directions. An international team of researchers from the University of Vienna (Austria), the University of Surrey (UK) and the IFW Dresden (Germany) have now achieved such a bilateral formation of inorganic nanomaterials in a controlled environment by implementing a new method. How to grow a nanomoustache The scientists pressurized a gas consisting of carbon and iron atoms at an elevated temperature until they observed two arms of carbon atoms spontaneously started growing out of an iron core. When the iron core was small enough, the two carbon arms started spiraling at their ends so that the whole nanostructure bore a striking resemblance with a twirled moustache. \"The encouraging insights we gained from our experiments provide a very good starting point for the controlled production of extraordinary new materials with designed nanostructures\", expects Dr. Hidetsugu Shiozawa, leading author of the scientific publication and researcher at the Faculty of Physics at the University of Vienna. Useful imperfections In order to find out more about the internal architecture of the nanomoustaches, the researchers cut their nanomaterial into extremely thin slices and used a special microscopy technique – the transmission electron microscopy – to have a closer look at the slices. When nanostructures grow, structural imperfections of the material emerge that are characteristic for the way the material was formed. In the observed herringbone pattern of the sliced nanomoustache, the distribution of the structural imperfections allowed the scientists to look back in time and extract further information about the formation of the nanomaterial. For future applications it will be fundamental to apply their knowledge to the growth of nanostructures in 2 or 3 dimensions in order to build regular patterns and networks at the nanoscale. Therefore, the scientists strive to understand even more about the mechanism behind the formation pattern of the nanomoustaches and are aiming at growing more dimensional and more complex nanostructures in future research projects. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Mirrored carbon-spirals have been produced from pressured ferrocene via the bilateral extrusion of the spiral pairs from an iron core. A parametric plot of the surface geometry displays the fractal growth of the conical helix made with the logarithmic spiral. Electron microscopy studies show the core is a crystalline cementite which grows and transforms its shape from spherical to biconical as it extrudes two spiralling carbon arms. In a cross section along the arms we observe graphitic flakes arranged in a herringbone structure, normal to which defects propagate. Local-wave-pattern analysis reveals nanoscale defect patterns of two-fold symmetry around the core. The data suggest that the bilateral growth originates from a globular cementite crystal with molten surfaces and the nano-defects shape emerging hexagonal carbon into a fractal structure. Understanding and knowledge obtained provide a basis for the controlled production of advanced carbon materials with designed geometries. Introduction The discovery of new forms of inorganic nanomaterials with advanced properties has opened exciting possibilities in nanosciences. A large variety of nanomaterials were synthesised via methods from colloidal synthesis of quantum dots and metal clusters 1 to physical synthesis of molecular nanostructures 2 , 3 , 4 . The unique physical and chemical properties of nanomaterials stem from their nanoscale structures which allow quantum effects to emerge. The synthesis of predefined structural dimensions and geometries is of great importance and hence, understanding and control of nanoscale shape formation are major focuses in materials science. On one hand, complex inorganic nanostructures such as polyhedral metals 5 , helical oxides 6 , 7 and semiconductors 8 and helical carbon nanotubes 9 can be formed as a result of crystallographic and defect arrangements. On the other hand, the size and shape of nuclei, seeds or catalysts play important roles in promoting chemical processes in the production of low dimensional nanostructures, such as semiconducting nanowires 10 , carbon nanotubes (CNTs) 3 and graphene 4 . When nanowires or nanotubes grow via the vapour-liquid-solid mechanism 11 , catalyst nanoparticles nucleate and extrude a 1D structure from one side of the particle 12 . The epitaxial growth of graphene via the chemical vapour deposition (CVD) method generally requires an atomically flat metal surface to catalyse and support the self-organisation of carbon atoms in a hexagonal form with one atom thick. As such, the way atoms and molecules are assembled into nanostructures depends critically on the shape of the catalysts prepared in advance or formed in the course of the synthesis 13 . In this paper, we study the formation mechanism for bilateral carbon spirals, with special emphasis on the role of metal catalysts and defects. The spiral samples are grown by the pyrolysis of pure ferrocene vapour at high pressure in a sealed volume 14 . At effective ferrocene pressures greater than 5 MPa, the catalytic activity on the created metal particle is polarized bilaterally so that it forms a pair of carbon arms out of an almost spherical metal surface. This stands in stark contrast to the cases for CNTs and graphene where sp 2 carbon layers grow unilaterally from one side of the catalyst only. The novelty of this bilateral carbon formation is manifested by the unique morphology that is transposed on the fully symmetric structures from nanoscale to microscale. Scanning electron microscopy (SEM) observations show that the symmetric objects are produced in large yield and high purity (see the SEM micrograph provided in the supplementary material ). Most of the objects observed exhibit a similar morphological identity whilst there are variations in size and shape. The fact that the arms are conical and each arm is a mirrored shape of the other, can be explained by our growth model 14 ; two carbon arms are extruded bilaterally from the opposite side of the symmetric core, resulting in its mirrored shape. The cone shape of the arms occurs as a result of the core growing simultaneously as the arms grow out of the core. A fascinating feature of this novel nanostructure is its spiralling arms. Its high reflectional symmetry ensures that the helicity of one arm is mirrored to the other in an opposite orientation. Although some of the key features of the mirrored objects were highlighted in our previous paper 14 , microscopic details of the bilateral growth is yet to be explained and the growth mechanism elucidated for the complex spiralling shapes. Knowing microscopic details of the interior structures of the micro objects will allow us to understand the cause of the symmetric growth, hence provide a deeper insight into the origin of the emergence of complex shape symmetry that spontaneously occurs at the nanoscale. We show from SEM observations of different samples that the iron core transforms its shape from a original sphere to a bicone as the carbon arms end spiralling. The spiralling morphologies are reproduced by a parametric plot that exhibits the fractal growth of the bilateral conical helix made with the logarithmic spirals. Microscopic insight into the symmetric growth is sought via cross-sectional transmission electron microscopy (TEM) studies of spiral samples. Selected area electron diffraction (SAED) patterns acquired across the cross-section of a spiral show graphite [002] diffractions whose orientations are found to be consistent with the reflectional symmetry of the surface morphology and constitute herringbone structures within the arm's cross section. Nanometer-scale patterns of defects are observed by TEM in the same cross-section. Long-range properties of the defect patterns are exploited via mapping of the local wave orientation 15 , 16 . The image obtained exhibits two-fold symmetry around the core, ascertaining the herringbone arrangement of nano-defects roughly normal to the layer of graphite flakes. This provides us an important insight that the defects propagate normal to the graphite layers as the arms grow. Such defect arrangements could be created as a result of temporal anomalies or instabilities in growth reaction on the core surface which must be molten at a high temperature. The defects are then arranged at the nanoscale to form complex shapes of micro-objects from hexagonal carbon.<|im_end|> <|im_start|>assistant Nanotechnology draws on the fabrication of nanostructures. Scientists have now succeeded in growing a unique carbon structure at the nanoscale that resembles a tiny twirled mustache. Their method might lead the way to the formation of more complex nano-networks. Researchers of the Electronic Properties of Materials Group at the Faculty of Physics (University of Vienna) and their international collaborators have published their results in the new open-access journal of the Nature Publishing group, Scientific Reports. Nanomaterials exhibit unique properties that can only unfold when the structures of the material are very small – that is, at the nanoscale. In order to exploit these special properties such as, for example, specific quantum effects it is very important to produce predefined nanostructures in a controlled way and interpret the formation of their shape. Scientists try to understand how to initiate and control the growth of nanomaterials and are exploring different ways to design and build up nanostructures with fine control over shapes. In nature, many organic forms grow bilaterally, that is, symmetrically in two distinct directions. An international team of researchers from the University of Vienna (Austria), the University of Surrey (UK) and the IFW Dresden (Germany) have now achieved such a bilateral formation of inorganic nanomaterials in a controlled environment by implementing a new method. How to grow a nanomoustache The scientists pressurized a gas consisting of carbon and iron atoms at an elevated temperature until they observed two arms of carbon atoms spontaneously started growing out of an iron core. When the iron core was small enough, the two carbon arms started spiraling at their ends so that the whole nanostructure bore a striking resemblance with a twirled moustache. "The encouraging insights we gained from our experiments provide a very good starting point for the controlled production of extraordinary new materials with designed nanostructures", expects Dr. Hidetsugu Shiozawa, leading author of the scientific publication and researcher at the Faculty of Physics at the University of Vienna. Useful imperfections In order to find out more about the internal architecture of the nanomoustaches, the researchers cut their nanomaterial into extremely thin slices and used a special microscopy technique – the transmission electron microscopy – to have a closer look at the slices. When nanostructures grow, structural imperfections of the material emerge that are characteristic for the way the material was formed. In the observed herringbone pattern of the sliced nanomoustache, the distribution of the structural imperfections allowed the scientists to look back in time and extract further information about the formation of the nanomaterial. For future applications it will be fundamental to apply their knowledge to the growth of nanostructures in 2 or 3 dimensions in order to build regular patterns and networks at the nanoscale. Therefore, the scientists strive to understand even more about the mechanism behind the formation pattern of the nanomoustaches and are aiming at growing more dimensional and more complex nanostructures in future research projects. <|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 present work gives a proof-of-concept for the complex factors that affect radon-in-water measurements through its progeny activities. Mathematical model was formulated, and an experiment was performed on a solution containing thorium and uranium series to identify the conditions for radon-in-water transfer. The experiment was performed on a solution containing thorium and uranium series at pH 5.5, isolated for 2 y, just measured before and repeatedly after exposing its surface to the ambient atmosphere. The measurement setup was carefully designed to avoid turbulence in consequence to rise velocity of these gaseous bubbles. During isolation time, radon found to accumulate in voids within the soft medium of water, and radon progeny may be re-dissolved in the medium in a non-homogenous manner that depends on the properties and geometry of the soft solution and existence of carrier gases such as emanating helium and water vapor. The rate of radon exhalation from the surface of the liquid was determined. The present results threw doubt on the activities measured assuming equilibrium between radon concentration and its progeny due to its dependence on geometry and ambient conditions. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes 1 Introduction Radioactivity from the excavating, refining, extraction, and processing of ore (cf. Ref. [ 1 ]), as well as transport of radium and thorium through aquifers, arises from the decay chains of naturally occurring radioactive materials (NORMs) (cf. Ref. [ 2 ]). All NORM series contains, at least, one of the radon isotopes. There are three different terms that govern radon transfer in media; emanation is associated with the escape of radon atoms, formed from the radium decay, escape from the medium into the voids, and air pocket within the medium. Diffusion deals with the movement of the emanated radon atoms through the medium to the surface. Exhalation combines both emanation and diffusion to account for the rate of radon transfer from the medium to the ambient atmosphere. The predictions of radon exhalation into the atmosphere provide input parameters for assessment of radiological impact [ 3 ], trace and earthquake precursory [ 4 ], flow prediction [ 5 ], etc. Natural radioactivity is an excellent tracer, e.g., for water infiltration rate in the environment and soil [ 6 , 7 ]. Radon tracers require the steady state of radon concentration in order to attain saturation required between that all sources and sinks, which is often a difficult task. In liquid media, radon may migrate to voids and/or make bubbles of radon and helium (a decay chain product), while in the case of a granular medium, the diverse shapes and geometries of the surfaces of these grains may control the adsorption of radon atoms and contribute to the chance for radon to be accumulated within the voids among grains. Whatever the medium of such voids, it contributes to the disturbance in radon decay equilibrium. For granular medium, immobilization of radon may be attained by mixing the dry powder with liquid tar, which is not possible for an aqueous medium. The Rn activities of water are usually measured by means of radon-in-air collection methods [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ] or radon-in-water techniques [ 11 , 13 , 16 , 17 , 18 , 19 ]. In any case, the radon concentration in water can be measured using different techniques, from alpha detectors, and liquid scintillation techniques to gamma-ray spectroscopy. All methods, however, need to be inter-compared with a reference standard with a creditable reference value of radon concentration. Based on previous studies on radioactive ions in solution, there is a chance for uncontrolled disturbance in radon concentration and its progeny due to atom–atom adsorption in the solution, progeny ions diffusion under different concentration gradients, and the possible formation of radon-containing voids in the solution, cf. Refs. [ 10 , 20 , 21 , 22 , 23 ]. In the present work, we measured the time evolution of radon exhalation from an aqueous medium with a method for measurement and analysis which allows time-based analysis for activities and follow-up the progeny measurements for radon-in-water. Our intention is to exemplify the misstated detection efficiencies and activities of radioactive isotopes in aqueous, in the general sense. 2 Experimental 2.1 Preparation of the radon source Amount of 5 grams of natural monazite mineral (fortuitously contained high concentration of both thorium and uranium progeny isotopes) was grind into fine powder and then packed in a plastic cylindrical having diameter of 1.12 cm and height of 1 cm. The \$^{226}\\hbox {Ra}\$ and \$^{228}\\hbox {Ac}\$ activity in the grind sample was determined using gamma ray spectrometry to be \$221\\pm 5\$ Bq for \$^{226}\\hbox {Ra}\$ and \$200\\pm \$ 2 Bq for \$^{228}\\,\\hbox {Ac}\$ . This amount was digested in an acidic medium as follows: 10 ml of hydrofluoric acid was used initially to dissolve as much as possible of the mineral contents at room temperature and then 25 ml of concentrated sulfuric acid was applied to the sample for 24 h under heating to about \$60\\,^{\\circ }\\hbox {C}\$ . Amount of 25 ml of 35% nitric acid was added to the solution and kept in \$60\\,^{\\circ }\\hbox {C}\$ for another 24 h. The solution was filtered using filter paper in which the residue in the filter itself was washed by concentrated nitric acid solution to dissolve any radioactive material absorbed in it in order to ensure that the whole amount of radioactive material was obtained; check had been made by counting the filter after filtration process. Ammonium hydroxide and hydrochloric acid were used to adjust the pH of the solution to 5.5. After 48 h, the solution was filtered again to remove any precipitates and the residue was washed by deionized water to recover any radioactivity in the filter paper. The final volume of the filtrate solution was 100 ml. The solution was stored in a conical-shaped flask having an effective conical volume of 100", "role": "user" }, { "content": "State-level environmental justice screening tools are being supported by environmental justice advocacy groups in Michigan and across the country, according to a new study from the University of Michigan. These screening tools document the communities that are hardest hit by environmental injustices. In the new study, published online Feb. 1 in the journal Environmental Law Reporter, U-M researchers reviewed state-level environmental justice screening tools and conducted in-depth interviews with nearly 30 stakeholders across the United States to determine their views about the utility of employing such tools to advance environmental justice goals. The researchers identified states that have developed state-specific environmental justice screening tools, analyzed existing state-specific screening tools and how they informed their respective states' environmental justice policies and programs, and identified the benefits of screening tools. They also identified the reasons for possible resistance to the use of environmental justice screening tools and strategies to overcome that resistance. The researchers interviewed stakeholders from California, Minnesota, Washington, New Jersey, Maryland and Michigan, where the state's official environmental justice screening tool, MiEJSCREEN, is expected to be released in 2022. Several benefits of screening tools were identified by stakeholders, including their ability to share information, aid in community advocacy-based actions, and influence regulatory or policy-based decision-making. \"Many frontline community members across the United States have shared their experiences of pollution and its impacts on public health. However, these testimonies are rarely incorporated into decision-making processes by polluting industries, or state and local authorities,\" said Molly Blondell, one of the study's co-authors and a graduate of the U-M School for Environment and Sustainability. \"By combining socioeconomic data with health data, these EJ screening tools can visualize areas with the greatest environmental injustices and support community testimony. Our interviewees spoke of the versatility that these tools have to aid in the development of EJ policy and community-oriented decision-making processes.\" The study was conducted in partnership with the Michigan Environmental Justice Coalition, which has been actively involved in advancing the use of a Michigan-based environmental justice screening tool to establish environmental justice policies and ensure justice-based community actions in the state of Michigan. This study is timely, given the \"considerable interest around the country in developing state-specific EJ screening tools that can help locate and document where disproportionate cumulative environmental burdens occur,\" said Paul Mohai, a professor at the U-M School for Environment and Sustainability and one of the study's other co-authors. Mohai noted that the state of Michigan used previous environmental justice research conducted by former U-M graduate students—which identified \"hot spots\" of environmental injustice across the state—as a guide when creating the Michigan-specific screening tool. While there are many takeaways about the benefits of screening tools, researchers found that there may also be stakeholder resistance to the development of screening tools, which can occur both internally (within state governments and agencies) and externally (from outside industries, groups and organizations). For instance, screening tools may be met with resistance by industry, state officials or community members who question the tools' relative scope, data accuracy and capacity for implementation, the study shows. \"We found that, while each state had their own socio-political concerns, there were common groups that our interviewees thought were resistant,\" said Arianna Zrzavy, the study's lead author, who also is a graduate of the U-M School for Environment and Sustainability. \"Some groups were already familiar to us, as they have appeared in environmental justice literature. However, the ways that state governments or agencies would be resistant to a screening tool—by impacting their resources or internal processes, for example—was surprising for us to learn.\" The researchers sought suggestions from stakeholders on how to overcome that resistance through framing and messaging. \"Many of our interviewees noted that resistance to EJ screening tools came from a lack of understanding of how these tools can be used for decision-making,\" Blondell said. \"In response to this, our interviewees discussed how EJ screening tools could be framed as information-gathering and educational resources. They also noted how these tools are adaptable, as they can capture state-level and local-level matters.\" While environmental justice screening tools are \"crucial for promoting EJ policies,\" Zrzavy noted, a key takeaway is that \"these tools are only impactful insofar as they are used to correct environmental injustices. State decision-makers in Michigan and across the U.S. must work to improve the health and well-being of communities experiencing cumulative impacts by using these tools together with community testimony.\" Over the years, several definitions of environmental justice have been advanced, including one from the U.S. Environmental Protection Agency. Environmental justice is the fair treatment and meaningful involvement of all people regardless of race, color, national origin or income with respect to the development, implementation and enforcement of environmental laws, regulations and policies, according to the EPA definition. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 present work gives a proof-of-concept for the complex factors that affect radon-in-water measurements through its progeny activities. Mathematical model was formulated, and an experiment was performed on a solution containing thorium and uranium series to identify the conditions for radon-in-water transfer. The experiment was performed on a solution containing thorium and uranium series at pH 5.5, isolated for 2 y, just measured before and repeatedly after exposing its surface to the ambient atmosphere. The measurement setup was carefully designed to avoid turbulence in consequence to rise velocity of these gaseous bubbles. During isolation time, radon found to accumulate in voids within the soft medium of water, and radon progeny may be re-dissolved in the medium in a non-homogenous manner that depends on the properties and geometry of the soft solution and existence of carrier gases such as emanating helium and water vapor. The rate of radon exhalation from the surface of the liquid was determined. The present results threw doubt on the activities measured assuming equilibrium between radon concentration and its progeny due to its dependence on geometry and ambient conditions. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes 1 Introduction Radioactivity from the excavating, refining, extraction, and processing of ore (cf. Ref. [ 1 ]), as well as transport of radium and thorium through aquifers, arises from the decay chains of naturally occurring radioactive materials (NORMs) (cf. Ref. [ 2 ]). All NORM series contains, at least, one of the radon isotopes. There are three different terms that govern radon transfer in media; emanation is associated with the escape of radon atoms, formed from the radium decay, escape from the medium into the voids, and air pocket within the medium. Diffusion deals with the movement of the emanated radon atoms through the medium to the surface. Exhalation combines both emanation and diffusion to account for the rate of radon transfer from the medium to the ambient atmosphere. The predictions of radon exhalation into the atmosphere provide input parameters for assessment of radiological impact [ 3 ], trace and earthquake precursory [ 4 ], flow prediction [ 5 ], etc. Natural radioactivity is an excellent tracer, e.g., for water infiltration rate in the environment and soil [ 6 , 7 ]. Radon tracers require the steady state of radon concentration in order to attain saturation required between that all sources and sinks, which is often a difficult task. In liquid media, radon may migrate to voids and/or make bubbles of radon and helium (a decay chain product), while in the case of a granular medium, the diverse shapes and geometries of the surfaces of these grains may control the adsorption of radon atoms and contribute to the chance for radon to be accumulated within the voids among grains. Whatever the medium of such voids, it contributes to the disturbance in radon decay equilibrium. For granular medium, immobilization of radon may be attained by mixing the dry powder with liquid tar, which is not possible for an aqueous medium. The Rn activities of water are usually measured by means of radon-in-air collection methods [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ] or radon-in-water techniques [ 11 , 13 , 16 , 17 , 18 , 19 ]. In any case, the radon concentration in water can be measured using different techniques, from alpha detectors, and liquid scintillation techniques to gamma-ray spectroscopy. All methods, however, need to be inter-compared with a reference standard with a creditable reference value of radon concentration. Based on previous studies on radioactive ions in solution, there is a chance for uncontrolled disturbance in radon concentration and its progeny due to atom–atom adsorption in the solution, progeny ions diffusion under different concentration gradients, and the possible formation of radon-containing voids in the solution, cf. Refs. [ 10 , 20 , 21 , 22 , 23 ]. In the present work, we measured the time evolution of radon exhalation from an aqueous medium with a method for measurement and analysis which allows time-based analysis for activities and follow-up the progeny measurements for radon-in-water. Our intention is to exemplify the misstated detection efficiencies and activities of radioactive isotopes in aqueous, in the general sense. 2 Experimental 2.1 Preparation of the radon source Amount of 5 grams of natural monazite mineral (fortuitously contained high concentration of both thorium and uranium progeny isotopes) was grind into fine powder and then packed in a plastic cylindrical having diameter of 1.12 cm and height of 1 cm. The $^{226}\hbox {Ra}$ and $^{228}\hbox {Ac}$ activity in the grind sample was determined using gamma ray spectrometry to be $221\pm 5$ Bq for $^{226}\hbox {Ra}$ and $200\pm $ 2 Bq for $^{228}\,\hbox {Ac}$ . This amount was digested in an acidic medium as follows: 10 ml of hydrofluoric acid was used initially to dissolve as much as possible of the mineral contents at room temperature and then 25 ml of concentrated sulfuric acid was applied to the sample for 24 h under heating to about $60\,^{\circ }\hbox {C}$ . Amount of 25 ml of 35% nitric acid was added to the solution and kept in $60\,^{\circ }\hbox {C}$ for another 24 h. The solution was filtered using filter paper in which the residue in the filter itself was washed by concentrated nitric acid solution to dissolve any radioactive material absorbed in it in order to ensure that the whole amount of radioactive material was obtained; check had been made by counting the filter after filtration process. Ammonium hydroxide and hydrochloric acid were used to adjust the pH of the solution to 5.5. After 48 h, the solution was filtered again to remove any precipitates and the residue was washed by deionized water to recover any radioactivity in the filter paper. The final volume of the filtrate solution was 100 ml. The solution was stored in a conical-shaped flask having an effective conical volume of 100<|im_end|> <|im_start|>assistant State-level environmental justice screening tools are being supported by environmental justice advocacy groups in Michigan and across the country, according to a new study from the University of Michigan. These screening tools document the communities that are hardest hit by environmental injustices. In the new study, published online Feb. 1 in the journal Environmental Law Reporter, U-M researchers reviewed state-level environmental justice screening tools and conducted in-depth interviews with nearly 30 stakeholders across the United States to determine their views about the utility of employing such tools to advance environmental justice goals. The researchers identified states that have developed state-specific environmental justice screening tools, analyzed existing state-specific screening tools and how they informed their respective states' environmental justice policies and programs, and identified the benefits of screening tools. They also identified the reasons for possible resistance to the use of environmental justice screening tools and strategies to overcome that resistance. The researchers interviewed stakeholders from California, Minnesota, Washington, New Jersey, Maryland and Michigan, where the state's official environmental justice screening tool, MiEJSCREEN, is expected to be released in 2022. Several benefits of screening tools were identified by stakeholders, including their ability to share information, aid in community advocacy-based actions, and influence regulatory or policy-based decision-making. "Many frontline community members across the United States have shared their experiences of pollution and its impacts on public health. However, these testimonies are rarely incorporated into decision-making processes by polluting industries, or state and local authorities," said Molly Blondell, one of the study's co-authors and a graduate of the U-M School for Environment and Sustainability. "By combining socioeconomic data with health data, these EJ screening tools can visualize areas with the greatest environmental injustices and support community testimony. Our interviewees spoke of the versatility that these tools have to aid in the development of EJ policy and community-oriented decision-making processes." The study was conducted in partnership with the Michigan Environmental Justice Coalition, which has been actively involved in advancing the use of a Michigan-based environmental justice screening tool to establish environmental justice policies and ensure justice-based community actions in the state of Michigan. This study is timely, given the "considerable interest around the country in developing state-specific EJ screening tools that can help locate and document where disproportionate cumulative environmental burdens occur," said Paul Mohai, a professor at the U-M School for Environment and Sustainability and one of the study's other co-authors. Mohai noted that the state of Michigan used previous environmental justice research conducted by former U-M graduate students—which identified "hot spots" of environmental injustice across the state—as a guide when creating the Michigan-specific screening tool. While there are many takeaways about the benefits of screening tools, researchers found that there may also be stakeholder resistance to the development of screening tools, which can occur both internally (within state governments and agencies) and externally (from outside industries, groups and organizations). For instance, screening tools may be met with resistance by industry, state officials or community members who question the tools' relative scope, data accuracy and capacity for implementation, the study shows. "We found that, while each state had their own socio-political concerns, there were common groups that our interviewees thought were resistant," said Arianna Zrzavy, the study's lead author, who also is a graduate of the U-M School for Environment and Sustainability. "Some groups were already familiar to us, as they have appeared in environmental justice literature. However, the ways that state governments or agencies would be resistant to a screening tool—by impacting their resources or internal processes, for example—was surprising for us to learn." The researchers sought suggestions from stakeholders on how to overcome that resistance through framing and messaging. "Many of our interviewees noted that resistance to EJ screening tools came from a lack of understanding of how these tools can be used for decision-making," Blondell said. "In response to this, our interviewees discussed how EJ screening tools could be framed as information-gathering and educational resources. They also noted how these tools are adaptable, as they can capture state-level and local-level matters." While environmental justice screening tools are "crucial for promoting EJ policies," Zrzavy noted, a key takeaway is that "these tools are only impactful insofar as they are used to correct environmental injustices. State decision-makers in Michigan and across the U.S. must work to improve the health and well-being of communities experiencing cumulative impacts by using these tools together with community testimony." Over the years, several definitions of environmental justice have been advanced, including one from the U.S. Environmental Protection Agency. Environmental justice is the fair treatment and meaningful involvement of all people regardless of race, color, national origin or income with respect to the development, implementation and enforcement of environmental laws, regulations and policies, according to the EPA definition. <|im_end|>

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2,365

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Local delivery of therapeutics for the treatment of inflammatory arthritis (IA) is limited by short intra-articular half-lives. Since IA severity often fluctuates over time, a local drug delivery method that titrates drug release to arthritis activity would represent an attractive paradigm in IA therapy. Here we report the development of a hydrogel platform that exhibits disassembly and drug release controlled by the concentration of enzymes expressed during arthritis flares. In vitro, hydrogel loaded with triamcinolone acetonide (TA) releases drug on-demand upon exposure to enzymes or synovial fluid from patients with rheumatoid arthritis. In arthritic mice, hydrogel loaded with a fluorescent dye demonstrates flare-dependent disassembly measured as loss of fluorescence. Moreover, a single dose of TA-loaded hydrogel but not the equivalent dose of locally injected free TA reduces arthritis activity in the injected paw. Together, our data suggest flare-responsive hydrogel as a promising next-generation drug delivery approach for the treatment of IA. Introduction Inflammatory arthritis (IA) encompasses a spectrum of inflammatory arthropathies affecting individual joints (monoarthritis), a few joints (oligoarthritis), or many joints (polyarthritis). In polyarthritides-like rheumatoid arthritis, systemic therapy is generally indicated and appropriate. However, in situations where only one or a few joints are involved, local therapy with intra-articular injections may offer distinct advantages over systemic therapy by increasing the drug bioavailability locally and reducing the potential for drug-induced systemic toxicity. Unfortunately, drugs injected into joints are often cleared very rapidly ( t 1/2 ∼ 0.1–6 h) 1 , 2 , which severely limits the feasibility of this approach. Multiple platforms have been developed to increase the joint residence time of drugs after intra-articular injection, including liposomes 3 , 4 , solid lipid nanoparticles 5 , micelles 6 , polymeric microparticles/nanoparticles 7 , 8 , 9 , and hydrogels 10 , 11 . Such systems have been shown to increase intra-articular drug half-lives by at least 10–30-fold in preclinical models 2 . However, none of the formulations have advanced past clinical trials for IA. IA often exhibits variable disease activity over time with exacerbations (flares) and periods of low disease activity. Previously described intra-articular drug delivery systems provide sustained drug release irrespective of disease activity. This likely results in sub- or supra-therapeutic drug levels locally during periods of high or low disease activity, respectively. A flare-responsive drug delivery system would titrate drug release to match the disease activity, resulting in optimal therapeutic efficacy. It would also minimize unnecessary drug release during periods of low disease activity, thereby prolonging the joint residence time of the injected drug depot and hence the duration of the therapeutic effect. We have developed an arthritis flare-responsive hydrogel platform by self-assembling a small-molecule amphiphile, triglycerol monostearate (TG-18). This compound was identified in a screen of the Food and Drug Administration’s (FDA’s) list of generally recognized as safe (GRAS) compounds looking for hydrogelators that can encapsulate a wide range of therapeutic agents and have an enzyme-labile ester linkage to facilitate hydrogel disassembly and drug release in response to enzymatic activities present in inflammatory milieus 12 . As a GRAS agent, TG-18 is relatively inexpensive and commercially available in large quantities at high purity (Good Manufacturing Practice Grade or Food Grade). In this study, we loaded TG-18 hydrogel with the corticosteroid triamcinolone acetonide (TA) as a model drug and demonstrated drug release in response to arthritis-related enzyme activities in vitro. Using the K/BxN mouse model of IA 13 , 14 we showed that TG-18 hydrogel disassembly and hence the release of an encapsulated dye correlate with the severity of the arthritis flare in vivo. A single dose of TA-loaded hydrogel but not the equivalent dose of locally injected free TA reduced arthritis activity in the injected paw. Our study provides proof of concept for TG-18 hydrogel as a potential next-generation drug delivery platform for the treatment of IA. We demonstrate that flare-responsive intra-articular drug release, i.e. the matching of drug release to current disease activity, is feasible and deserves further exploration. Results TG-18 self-assembly to hydrogel and encapsulation of TA TG-18 comprises a polyhydroxyl hydrophilic head group and a polymethylene hydrophobic tail (Fig. 1a ), and has a Krafft point of approximately 55–60 °C in a dimethyl sulfoxide (DMSO)/water mixture. Therefore, TG-18 heated in DMSO/water to 55–60 °C dissolves due to micelle formation, resulting in a clear solution. Upon cooling, the solution forms a solid hydrogel comprising self-assembled fibrous structures with interdigitated bilayers and extended micelles 15 (Fig. 1a ). During self-assembly, hydrophobic drugs can be encapsulated into the hydrophobic core of the lamellar fibers of the hydrogel (Fig. 1a ). The drug-loaded bulk hydrogel is injectable and can be administered as an intra-articular injection. Within joints, enzymes overexpressed during arthritis flare can disassemble the hydrogel, resulting in flare-responsive drug release (Fig. 1c ). Fig. 1 Triglycerol monostearate (TG-18) self-assembles to form arthritis flare-responsive hydrogel. a Schematic showing self-assembly of TG-18 to form hydrogel and encapsulation of triamcinolone acetonide (TA). TG-18 dissolves by heating in DMSO/water and self-assembles into lamellar structures upon cooling. Drugs like triamcinolone acetonide (TA) can be encapsulated within the hydrophobic core of the lamellae. b High-resolution scanning electron microscopy (HR-SEM) of TA-loaded TG-18 hydrogels. TG-18 lamellar structures extend to form higher order fibrous assemblies. The entangled fibers form the bulk injectable hydrogel that can be administered via intra-articular injection. c Disassembly of TG-18 hydrogel in response to flare-associated enzymes, including MMPs that are present in the inflamed joint Full size image We encapsulated TA into TG-18 hydrogel (10% w/v) and were able to achieve loading efficiency as high as 40% (w/w). Higher order fibrous assemblies of TA-loaded hydrogel were observed with high-resolution scanning electron microscopy (HR-SEM) (Fig. 1b ). To determine the stability of TA encapsulation into TG-18 hydrogel, we evaluated the in vitro release of TA in phosphate-buffered saline (PBS, pH 7.4) at 37 °C comparing hydrogel formulations generated with the same amount of TG-18 (10% w/v), but loaded with different concentrations of TA. We observed a dose–response relationship between the TA concentration and its encapsulation stability in the hydrogel (Supplementary", "role": "user" }, { "content": "Arthritis flares - the unpredictable and often sudden worsening of arthritis symptoms—can be debilitating. These episodes can make the management of inflammatory arthritis, which includes rheumatoid arthritis and psoriatic arthritis, challenging for patients and physicians. But investigators at Brigham and Women's Hospital have found that flares may also represent an important opportunity for improving treatment options for patients. In experiments carried out in the lab, BWH bioengineers have developed a hydrogel—a soft, flexible material that can be loaded with arthritis drugs and injected locally into an inflamed joint. Instead of delivering the drug continuously at a steady rate, the hydrogel is designed to respond to increased disease activity during flares, releasing the drug when symptoms worsen. The team's laboratory-based findings are published this week in Nature Communications and investigators are working on next steps to bring their technology closer to the clinic. \"Arthritis represents a huge unmet clinical need,\" said co-senior author Jeff Karp, PhD, a bioengineer and principal investigator at BWH. \"Although new therapeutics have been developed, many have had systemic, toxic effects. We wanted to design a delivery system that could be efficient, deliver drugs locally and release drugs in response to inflammation.\" The newly created flare-responsive hydrogel is made from triglycerol monostearate (TG-18), a compound from the Food and Drug Administration's list of \"generally recognized as safe\" compounds. TG-18 is a molecule capable of self-assembling, meaning that it can form a gel-like structure comprising fibers. This structure can be easily injected as a suspension In this study, the TG-18 hydrogel was loaded with triamcinolone acetonide (TA) used here as a model drug, but could potentially be loaded with many other kinds of anti-inflammatory compounds. \"The hydrogel is designed so that drug release is triggered by the activity of specific, arthritis-related enzymes that are increased during flares. To test the TG-18 hydrogel, we exposed the gel to several different kinds of environments mimicking conditions in arthritic joints,\" said Nitin Joshi, co-first author on the work an Instructor of Medicine at BWH. When the gel was incubated in synovial fluid from a healthy human joint, drug release was minimal, but when incubated in synovial fluid from a patient with rheumatoid arthritis, the drug was readily released from the hydrogel. Importantly, the drug supply was not exhausted in one spike of synovial fluid—instead, it could be released in response to multiple spikes over time. The team also tested hydrogel's effects on cells from cartilage and joints, finding that it appeared to be safe. The team further tested the clinical efficacy of the TG-18 hydrogel in a mouse model of inflammatory arthritis. They choose a model, the K/BxN serum transfer model, in which disease severity can be precisely controlled, which allowed them to test the hydrogel in animals with different degrees of arthritis severity. They found that when arthritis was more severe, the locally injected hydrogel degraded more rapidly corresponding to increased drug release. Swelling and severity of arthritis diminished in response to the drug-loaded hydrogel. One of the advantages of the hydrogel is that it offers the promise of treating arthritis specifically in the joints where the disease is flaring, rather than delivering a drug throughout the body. \"Local therapy could be a viable treatment option for patients with only one or a few inflamed joints, said co-corresponding author Joerg Ermann, MD, a rheumatologist in the BWH Division of Rheumatology, Immunology and Allergy. \"Moreover, if a patient is already on a systemic drug but is experiencing a flare in a limited number of joints, we could specifically treat these joints rather than switching systemic therapy or adding another systemic drug. Having this option would substantially increase our ability to successfully manage arthritis flares in the clinic.\" The team will continue testing the hydrogel in preclinical models to further validate it, and continue to advance toward human clinical trials. The technology has been licensed by Alivio Therapeutics, which is developing therapies to treat inflammatory disorders via targeted disease immunomodulation. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Local delivery of therapeutics for the treatment of inflammatory arthritis (IA) is limited by short intra-articular half-lives. Since IA severity often fluctuates over time, a local drug delivery method that titrates drug release to arthritis activity would represent an attractive paradigm in IA therapy. Here we report the development of a hydrogel platform that exhibits disassembly and drug release controlled by the concentration of enzymes expressed during arthritis flares. In vitro, hydrogel loaded with triamcinolone acetonide (TA) releases drug on-demand upon exposure to enzymes or synovial fluid from patients with rheumatoid arthritis. In arthritic mice, hydrogel loaded with a fluorescent dye demonstrates flare-dependent disassembly measured as loss of fluorescence. Moreover, a single dose of TA-loaded hydrogel but not the equivalent dose of locally injected free TA reduces arthritis activity in the injected paw. Together, our data suggest flare-responsive hydrogel as a promising next-generation drug delivery approach for the treatment of IA. Introduction Inflammatory arthritis (IA) encompasses a spectrum of inflammatory arthropathies affecting individual joints (monoarthritis), a few joints (oligoarthritis), or many joints (polyarthritis). In polyarthritides-like rheumatoid arthritis, systemic therapy is generally indicated and appropriate. However, in situations where only one or a few joints are involved, local therapy with intra-articular injections may offer distinct advantages over systemic therapy by increasing the drug bioavailability locally and reducing the potential for drug-induced systemic toxicity. Unfortunately, drugs injected into joints are often cleared very rapidly ( t 1/2 ∼ 0.1–6 h) 1 , 2 , which severely limits the feasibility of this approach. Multiple platforms have been developed to increase the joint residence time of drugs after intra-articular injection, including liposomes 3 , 4 , solid lipid nanoparticles 5 , micelles 6 , polymeric microparticles/nanoparticles 7 , 8 , 9 , and hydrogels 10 , 11 . Such systems have been shown to increase intra-articular drug half-lives by at least 10–30-fold in preclinical models 2 . However, none of the formulations have advanced past clinical trials for IA. IA often exhibits variable disease activity over time with exacerbations (flares) and periods of low disease activity. Previously described intra-articular drug delivery systems provide sustained drug release irrespective of disease activity. This likely results in sub- or supra-therapeutic drug levels locally during periods of high or low disease activity, respectively. A flare-responsive drug delivery system would titrate drug release to match the disease activity, resulting in optimal therapeutic efficacy. It would also minimize unnecessary drug release during periods of low disease activity, thereby prolonging the joint residence time of the injected drug depot and hence the duration of the therapeutic effect. We have developed an arthritis flare-responsive hydrogel platform by self-assembling a small-molecule amphiphile, triglycerol monostearate (TG-18). This compound was identified in a screen of the Food and Drug Administration’s (FDA’s) list of generally recognized as safe (GRAS) compounds looking for hydrogelators that can encapsulate a wide range of therapeutic agents and have an enzyme-labile ester linkage to facilitate hydrogel disassembly and drug release in response to enzymatic activities present in inflammatory milieus 12 . As a GRAS agent, TG-18 is relatively inexpensive and commercially available in large quantities at high purity (Good Manufacturing Practice Grade or Food Grade). In this study, we loaded TG-18 hydrogel with the corticosteroid triamcinolone acetonide (TA) as a model drug and demonstrated drug release in response to arthritis-related enzyme activities in vitro. Using the K/BxN mouse model of IA 13 , 14 we showed that TG-18 hydrogel disassembly and hence the release of an encapsulated dye correlate with the severity of the arthritis flare in vivo. A single dose of TA-loaded hydrogel but not the equivalent dose of locally injected free TA reduced arthritis activity in the injected paw. Our study provides proof of concept for TG-18 hydrogel as a potential next-generation drug delivery platform for the treatment of IA. We demonstrate that flare-responsive intra-articular drug release, i.e. the matching of drug release to current disease activity, is feasible and deserves further exploration. Results TG-18 self-assembly to hydrogel and encapsulation of TA TG-18 comprises a polyhydroxyl hydrophilic head group and a polymethylene hydrophobic tail (Fig. 1a ), and has a Krafft point of approximately 55–60 °C in a dimethyl sulfoxide (DMSO)/water mixture. Therefore, TG-18 heated in DMSO/water to 55–60 °C dissolves due to micelle formation, resulting in a clear solution. Upon cooling, the solution forms a solid hydrogel comprising self-assembled fibrous structures with interdigitated bilayers and extended micelles 15 (Fig. 1a ). During self-assembly, hydrophobic drugs can be encapsulated into the hydrophobic core of the lamellar fibers of the hydrogel (Fig. 1a ). The drug-loaded bulk hydrogel is injectable and can be administered as an intra-articular injection. Within joints, enzymes overexpressed during arthritis flare can disassemble the hydrogel, resulting in flare-responsive drug release (Fig. 1c ). Fig. 1 Triglycerol monostearate (TG-18) self-assembles to form arthritis flare-responsive hydrogel. a Schematic showing self-assembly of TG-18 to form hydrogel and encapsulation of triamcinolone acetonide (TA). TG-18 dissolves by heating in DMSO/water and self-assembles into lamellar structures upon cooling. Drugs like triamcinolone acetonide (TA) can be encapsulated within the hydrophobic core of the lamellae. b High-resolution scanning electron microscopy (HR-SEM) of TA-loaded TG-18 hydrogels. TG-18 lamellar structures extend to form higher order fibrous assemblies. The entangled fibers form the bulk injectable hydrogel that can be administered via intra-articular injection. c Disassembly of TG-18 hydrogel in response to flare-associated enzymes, including MMPs that are present in the inflamed joint Full size image We encapsulated TA into TG-18 hydrogel (10% w/v) and were able to achieve loading efficiency as high as 40% (w/w). Higher order fibrous assemblies of TA-loaded hydrogel were observed with high-resolution scanning electron microscopy (HR-SEM) (Fig. 1b ). To determine the stability of TA encapsulation into TG-18 hydrogel, we evaluated the in vitro release of TA in phosphate-buffered saline (PBS, pH 7.4) at 37 °C comparing hydrogel formulations generated with the same amount of TG-18 (10% w/v), but loaded with different concentrations of TA. We observed a dose–response relationship between the TA concentration and its encapsulation stability in the hydrogel (Supplementary<|im_end|> <|im_start|>assistant Arthritis flares - the unpredictable and often sudden worsening of arthritis symptoms—can be debilitating. These episodes can make the management of inflammatory arthritis, which includes rheumatoid arthritis and psoriatic arthritis, challenging for patients and physicians. But investigators at Brigham and Women's Hospital have found that flares may also represent an important opportunity for improving treatment options for patients. In experiments carried out in the lab, BWH bioengineers have developed a hydrogel—a soft, flexible material that can be loaded with arthritis drugs and injected locally into an inflamed joint. Instead of delivering the drug continuously at a steady rate, the hydrogel is designed to respond to increased disease activity during flares, releasing the drug when symptoms worsen. The team's laboratory-based findings are published this week in Nature Communications and investigators are working on next steps to bring their technology closer to the clinic. "Arthritis represents a huge unmet clinical need," said co-senior author Jeff Karp, PhD, a bioengineer and principal investigator at BWH. "Although new therapeutics have been developed, many have had systemic, toxic effects. We wanted to design a delivery system that could be efficient, deliver drugs locally and release drugs in response to inflammation." The newly created flare-responsive hydrogel is made from triglycerol monostearate (TG-18), a compound from the Food and Drug Administration's list of "generally recognized as safe" compounds. TG-18 is a molecule capable of self-assembling, meaning that it can form a gel-like structure comprising fibers. This structure can be easily injected as a suspension In this study, the TG-18 hydrogel was loaded with triamcinolone acetonide (TA) used here as a model drug, but could potentially be loaded with many other kinds of anti-inflammatory compounds. "The hydrogel is designed so that drug release is triggered by the activity of specific, arthritis-related enzymes that are increased during flares. To test the TG-18 hydrogel, we exposed the gel to several different kinds of environments mimicking conditions in arthritic joints," said Nitin Joshi, co-first author on the work an Instructor of Medicine at BWH. When the gel was incubated in synovial fluid from a healthy human joint, drug release was minimal, but when incubated in synovial fluid from a patient with rheumatoid arthritis, the drug was readily released from the hydrogel. Importantly, the drug supply was not exhausted in one spike of synovial fluid—instead, it could be released in response to multiple spikes over time. The team also tested hydrogel's effects on cells from cartilage and joints, finding that it appeared to be safe. The team further tested the clinical efficacy of the TG-18 hydrogel in a mouse model of inflammatory arthritis. They choose a model, the K/BxN serum transfer model, in which disease severity can be precisely controlled, which allowed them to test the hydrogel in animals with different degrees of arthritis severity. They found that when arthritis was more severe, the locally injected hydrogel degraded more rapidly corresponding to increased drug release. Swelling and severity of arthritis diminished in response to the drug-loaded hydrogel. One of the advantages of the hydrogel is that it offers the promise of treating arthritis specifically in the joints where the disease is flaring, rather than delivering a drug throughout the body. "Local therapy could be a viable treatment option for patients with only one or a few inflamed joints, said co-corresponding author Joerg Ermann, MD, a rheumatologist in the BWH Division of Rheumatology, Immunology and Allergy. "Moreover, if a patient is already on a systemic drug but is experiencing a flare in a limited number of joints, we could specifically treat these joints rather than switching systemic therapy or adding another systemic drug. Having this option would substantially increase our ability to successfully manage arthritis flares in the clinic." The team will continue testing the hydrogel in preclinical models to further validate it, and continue to advance toward human clinical trials. The technology has been licensed by Alivio Therapeutics, which is developing therapies to treat inflammatory disorders via targeted disease immunomodulation. <|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 Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions 1 . Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role 2 . However, it has been uncertain whether the observed amnesia in the early stages of AD is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early AD, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent 3 , 4 , 5 , which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in the early stages of AD. Main AD is the most common cause of brain degeneration, and typically begins with impairments in cognitive functions 1 . Most research has focused on understanding the relationship between memory impairments and the formation of two pathological hallmarks seen in the late stages of AD: extracellular amyloid plaques and intracellular aggregates of tau protein 1 , 2 . The early phases of AD have received relatively less attention, although synaptic phenotypes have been identified as major correlates of cognitive impairments in both human patients and mouse models 3 , 6 . Several studies have suggested that the episodic memory deficit of AD patients is due to ineffective encoding of new information 7 , 8 , 9 . However, since the cognitive measures used in these studies rely on memory retrieval, it is not possible to discriminate rigorously between impairments in information storage and disrupted retrieval of stored information. This issue has an important clinical implication: if the amnesia is due to retrieval impairments, memory could be restored by technologies involving targeted brain stimulation. A mouse model of AD (hereafter referred to as ‘AD mice’) 10 overexpresses the delta exon 9 variant of presenilin 1 (PS1; also known as PSEN1), in combination with the Swedish mutation of β-amyloid precursor (APP). Consistent with previous reports 3 , 4 , 5 , 9-month-old AD mice showed severe plaque deposition across multiple brain regions ( Fig. 1a ), specifically in the dentate gyrus (DG) ( Fig. 1b ) and medial entorhinal cortex (EC) ( Fig. 1c ); in contrast, 7-month-old AD mice lacked amyloid plaques ( Fig. 1d and Extended Data Fig. 1a–d ). Focusing on these two age groups of AD mice, we quantified short-term (1 h; STM) and long-term (24 h; LTM) memory formation using contextual fear conditioning (CFC) ( Fig. 1e ). Nine-month-old AD mice were impaired in both STM and LTM, which suggested a deficit in memory encoding ( Fig. 1k–o ). By contrast, 7-month-old AD mice showed normal levels of training-induced freezing ( Fig. 1f ) and normal STM ( Fig. 1g ), but were impaired in LTM ( Fig. 1h ). Neither control nor 7-month-old AD mice displayed freezing behaviour in a neutral context ( Fig. 1i ). In the DG of 7-month-old AD mice, the levels of cells that were immediate early gene c-Fos-positive after CFC training were normal, but were lower compared with control mice after LTM tests ( Fig. 1j ). Motor behaviours and the density of DG granule cells were normal in these mice ( Extended Data Fig. 1e–k ). Thus, these behavioural- and cellular-level observations confirmed that 7-month-old AD mice serve as a mouse model of early AD regarding memory impairments. Figure 1: Optogenetic activation of memory engrams restores fear memory in early AD mice. a – c , Amyloid-β (Aβ) plaques in 9-month-old AD mice ( a ), in the DG ( b ), and in the EC ( c ). d , Plaque counts in HPC sections ( n = 4 mice per group). ND, not detected. e , CFC behavioural schedule ( n = 10 mice per group). f – i , Freezing levels of 7-month-old AD groups during training ( f ), STM test ( g ), LTM test ( h ) or exposure to neutral context ( i ). j , c-Fos + cell counts in the DG of 7-month-old mice after CFC training or LTM test, represented in f , h ( n = 4 mice per group). DAPI, 4′,6-diamidino-2-phenylindole. k – n , Freezing levels of 9-month-old AD mice during training ( k ), STM test ( l ), LTM test ( m ) or exposure to neutral context ( n ). o , c-Fos + cell counts in the DG of 9-month-old mice ( n = 3 mice per group) after CFC training represented in k . p , Virus-mediated engram labelling strategy using a cocktail of AAV 9 -c-Fos-tTA and AAV 9 -TRE-ChR2-eYFP. q , AD mice were injected with the two viruses bilaterally and implanted with an optic fibre bilaterally into the DG. r , Behavioural schedule and DG engram cell labelling (see Methods). s , ChR2–eYFP + cell counts from DG sections shown in r ( n = 3 mice per group). t , Behavioural schedule for optogenetic activation of DG engram cells. u , ChR2–eYFP + cell counts from 7-month-old mice ( n = 5 mice per group). v , Memory recall in context A 1 day after training (test 1, n = 9 mice per group). w , Freezing by blue light stimulation (left). Average freezing for two", "role": "user" }, { "content": "In the early stages of Alzheimer's disease, patients are often unable to remember recent experiences. However, a new study from MIT suggests that those memories are still stored in the brain—they just can't be easily accessed. The MIT neuroscientists report in Nature that mice in the early stages of Alzheimer's can form new memories just as well as normal mice but cannot recall them a few days later. Furthermore, the researchers were able to artificially stimulate those memories using a technique known as optogenetics, suggesting that those memories can still be retrieved with a little help. Although optogenetics cannot currently be used in humans, the findings raise the possibility of developing future treatments that might reverse some of the memory loss seen in early-stage Alzheimer's, the researchers say. \"The important point is, this a proof of concept. That is, even if a memory seems to be gone, it is still there. It's a matter of how to retrieve it,\" says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience and director of the RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory. Tonegawa is the senior author of the study, which appears in the March 16 online edition of Nature. Dheeraj Roy, an MIT graduate student, is the paper's lead author. A single memory engram cell in the hippocampal dentate gyrus region of a mouse model of early Alzheimer's disease. To optically manipulate specific connections to these engram cells, a blue light-sensitive protein oChIEF was expressed in an upstream brain region, i.e., medial entorhinal cortical inputs (red) to the DG. The majority of DG granule cells were not active during engram labeling (blue, non-engram cells). Credit: RIKEN Lost memories In recent years, Tonegawa's lab has identified cells in the brain's hippocampus that store specific memories. The researchers have also shown that they can manipulate these memory traces, or engrams, to plant false memories, activate existing memories, or alter a memory's emotional associations. Last year, Tonegawa, Roy, and colleagues found that mice with retrograde amnesia, which follows traumatic injury or stress, had impaired memory recall but could still form new memories. That led the team to wonder whether this might also be true for the memory loss seen in the early stages of Alzheimer's disease, which occurs before characteristic amyloid plaques appear in patients' brains. To investigate that possibility, the researchers studied two different strains of mice genetically engineered to develop Alzheimer's symptoms, plus a group of healthy mice. All of these mice, when exposed to a chamber where they received a foot shock, showed fear when placed in the same chamber an hour later. However, when placed in the chamber again several days later, only the normal mice still showed fear. The Alzheimer's mice did not appear to remember the foot shock. \"Short-term memory seems to be normal, on the order of hours. But for long-term memory, these early Alzheimer's mice seem to be impaired,\" Roy says. A coronal section of hippocampal dentate gyrus from a mouse model of early Alzheimer's disease. These AD mice lack β-amyloid plaques at 7-months of age. Using these mice combined with a novel viral strategy, memory engram cells (green) for a contextual fear memory were labeled with a light-sensitive protein ChR2. Credit: RIKEN \"An access problem\" The researchers then showed that while the mice cannot recall their experiences when prompted by natural cues, those memories are still there. To demonstrate this, they first tagged the engram cells associated with the fearful experience with a light-sensitive protein called channelrhodopsin, using a technique they developed in 2012. Whenever these tagged engram cells are activated by light, normal mice recall the memory encoded by that group of cells. Likewise, when the researchers placed the Alzheimer's mice in a chamber they had never seen before and shined light on the engram cells encoding the fearful experience, the mice immediately showed fear. \"Directly activating the cells that we believe are holding the memory gets them to retrieve it,\" Roy says. \"This suggests that it is indeed an access problem to the information, not that they're unable to learn or store this memory.\" The researchers also showed that the engram cells of Alzheimer's mice had fewer dendritic spines, which are small buds that allow neurons to receive incoming signals from other neurons. Normally, when a new memory is generated, the engram cells corresponding to that memory grow new dendritic spines, but this did not happen in the Alzheimer's mice. This suggests that the engram cells are not receiving sensory input from another part of the brain called the entorhinal cortex. The natural cue that should reactivate the memory—being in the chamber again—has no effect because the sensory information doesn't get into the engram cells. \"If we want to recall a memory, the memory-holding cells have to be reactivated by the correct cue. If the spine density does not go up during learning process, then later, if you give a natural recall cue, it may not be able to reach the nucleus of the engram cells,\" Tonegawa says. Long-term connection The researchers were also able to induce a longer-term reactivation of the \"lost\" memories by stimulating new connections between the entorhinal cortex and the hippocampus. To achieve this, they used light to optogenetically stimulate entorhinal cortex cells that feed into the hippocampal engram cells encoding the fearful memory. After three hours of this treatment, the researchers waited a week and tested the mice again. This time, the mice could retrieve the memory on their own when placed in the original chamber, and they had many more dendritic spines on their engram cells. However, this approach does not work if too large a section of the entorhinal cortex is stimulated, suggesting that any potential treatments for human patients would have to be very targeted. Optogenetics is very precise but too invasive to use in humans, and existing methods for deep brain stimulation—a form of electrical stimulation sometimes used to treat Parkinson's and other diseases—affect too much of the brain. \"It's possible that in the future some technology will be developed to activate or inactivate cells deep inside the brain, like the hippocampus or entorhinal cortex, with more precision,\" Tonegawa says. \"Basic research as conducted in this study provides information on cell populations to be targeted, which is critical for future treatments and technologies.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions 1 . Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role 2 . However, it has been uncertain whether the observed amnesia in the early stages of AD is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early AD, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent 3 , 4 , 5 , which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in the early stages of AD. Main AD is the most common cause of brain degeneration, and typically begins with impairments in cognitive functions 1 . Most research has focused on understanding the relationship between memory impairments and the formation of two pathological hallmarks seen in the late stages of AD: extracellular amyloid plaques and intracellular aggregates of tau protein 1 , 2 . The early phases of AD have received relatively less attention, although synaptic phenotypes have been identified as major correlates of cognitive impairments in both human patients and mouse models 3 , 6 . Several studies have suggested that the episodic memory deficit of AD patients is due to ineffective encoding of new information 7 , 8 , 9 . However, since the cognitive measures used in these studies rely on memory retrieval, it is not possible to discriminate rigorously between impairments in information storage and disrupted retrieval of stored information. This issue has an important clinical implication: if the amnesia is due to retrieval impairments, memory could be restored by technologies involving targeted brain stimulation. A mouse model of AD (hereafter referred to as ‘AD mice’) 10 overexpresses the delta exon 9 variant of presenilin 1 (PS1; also known as PSEN1), in combination with the Swedish mutation of β-amyloid precursor (APP). Consistent with previous reports 3 , 4 , 5 , 9-month-old AD mice showed severe plaque deposition across multiple brain regions ( Fig. 1a ), specifically in the dentate gyrus (DG) ( Fig. 1b ) and medial entorhinal cortex (EC) ( Fig. 1c ); in contrast, 7-month-old AD mice lacked amyloid plaques ( Fig. 1d and Extended Data Fig. 1a–d ). Focusing on these two age groups of AD mice, we quantified short-term (1 h; STM) and long-term (24 h; LTM) memory formation using contextual fear conditioning (CFC) ( Fig. 1e ). Nine-month-old AD mice were impaired in both STM and LTM, which suggested a deficit in memory encoding ( Fig. 1k–o ). By contrast, 7-month-old AD mice showed normal levels of training-induced freezing ( Fig. 1f ) and normal STM ( Fig. 1g ), but were impaired in LTM ( Fig. 1h ). Neither control nor 7-month-old AD mice displayed freezing behaviour in a neutral context ( Fig. 1i ). In the DG of 7-month-old AD mice, the levels of cells that were immediate early gene c-Fos-positive after CFC training were normal, but were lower compared with control mice after LTM tests ( Fig. 1j ). Motor behaviours and the density of DG granule cells were normal in these mice ( Extended Data Fig. 1e–k ). Thus, these behavioural- and cellular-level observations confirmed that 7-month-old AD mice serve as a mouse model of early AD regarding memory impairments. Figure 1: Optogenetic activation of memory engrams restores fear memory in early AD mice. a – c , Amyloid-β (Aβ) plaques in 9-month-old AD mice ( a ), in the DG ( b ), and in the EC ( c ). d , Plaque counts in HPC sections ( n = 4 mice per group). ND, not detected. e , CFC behavioural schedule ( n = 10 mice per group). f – i , Freezing levels of 7-month-old AD groups during training ( f ), STM test ( g ), LTM test ( h ) or exposure to neutral context ( i ). j , c-Fos + cell counts in the DG of 7-month-old mice after CFC training or LTM test, represented in f , h ( n = 4 mice per group). DAPI, 4′,6-diamidino-2-phenylindole. k – n , Freezing levels of 9-month-old AD mice during training ( k ), STM test ( l ), LTM test ( m ) or exposure to neutral context ( n ). o , c-Fos + cell counts in the DG of 9-month-old mice ( n = 3 mice per group) after CFC training represented in k . p , Virus-mediated engram labelling strategy using a cocktail of AAV 9 -c-Fos-tTA and AAV 9 -TRE-ChR2-eYFP. q , AD mice were injected with the two viruses bilaterally and implanted with an optic fibre bilaterally into the DG. r , Behavioural schedule and DG engram cell labelling (see Methods). s , ChR2–eYFP + cell counts from DG sections shown in r ( n = 3 mice per group). t , Behavioural schedule for optogenetic activation of DG engram cells. u , ChR2–eYFP + cell counts from 7-month-old mice ( n = 5 mice per group). v , Memory recall in context A 1 day after training (test 1, n = 9 mice per group). w , Freezing by blue light stimulation (left). Average freezing for two<|im_end|> <|im_start|>assistant In the early stages of Alzheimer's disease, patients are often unable to remember recent experiences. However, a new study from MIT suggests that those memories are still stored in the brain—they just can't be easily accessed. The MIT neuroscientists report in Nature that mice in the early stages of Alzheimer's can form new memories just as well as normal mice but cannot recall them a few days later. Furthermore, the researchers were able to artificially stimulate those memories using a technique known as optogenetics, suggesting that those memories can still be retrieved with a little help. Although optogenetics cannot currently be used in humans, the findings raise the possibility of developing future treatments that might reverse some of the memory loss seen in early-stage Alzheimer's, the researchers say. "The important point is, this a proof of concept. That is, even if a memory seems to be gone, it is still there. It's a matter of how to retrieve it," says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience and director of the RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory. Tonegawa is the senior author of the study, which appears in the March 16 online edition of Nature. Dheeraj Roy, an MIT graduate student, is the paper's lead author. A single memory engram cell in the hippocampal dentate gyrus region of a mouse model of early Alzheimer's disease. To optically manipulate specific connections to these engram cells, a blue light-sensitive protein oChIEF was expressed in an upstream brain region, i.e., medial entorhinal cortical inputs (red) to the DG. The majority of DG granule cells were not active during engram labeling (blue, non-engram cells). Credit: RIKEN Lost memories In recent years, Tonegawa's lab has identified cells in the brain's hippocampus that store specific memories. The researchers have also shown that they can manipulate these memory traces, or engrams, to plant false memories, activate existing memories, or alter a memory's emotional associations. Last year, Tonegawa, Roy, and colleagues found that mice with retrograde amnesia, which follows traumatic injury or stress, had impaired memory recall but could still form new memories. That led the team to wonder whether this might also be true for the memory loss seen in the early stages of Alzheimer's disease, which occurs before characteristic amyloid plaques appear in patients' brains. To investigate that possibility, the researchers studied two different strains of mice genetically engineered to develop Alzheimer's symptoms, plus a group of healthy mice. All of these mice, when exposed to a chamber where they received a foot shock, showed fear when placed in the same chamber an hour later. However, when placed in the chamber again several days later, only the normal mice still showed fear. The Alzheimer's mice did not appear to remember the foot shock. "Short-term memory seems to be normal, on the order of hours. But for long-term memory, these early Alzheimer's mice seem to be impaired," Roy says. A coronal section of hippocampal dentate gyrus from a mouse model of early Alzheimer's disease. These AD mice lack β-amyloid plaques at 7-months of age. Using these mice combined with a novel viral strategy, memory engram cells (green) for a contextual fear memory were labeled with a light-sensitive protein ChR2. Credit: RIKEN "An access problem" The researchers then showed that while the mice cannot recall their experiences when prompted by natural cues, those memories are still there. To demonstrate this, they first tagged the engram cells associated with the fearful experience with a light-sensitive protein called channelrhodopsin, using a technique they developed in 2012. Whenever these tagged engram cells are activated by light, normal mice recall the memory encoded by that group of cells. Likewise, when the researchers placed the Alzheimer's mice in a chamber they had never seen before and shined light on the engram cells encoding the fearful experience, the mice immediately showed fear. "Directly activating the cells that we believe are holding the memory gets them to retrieve it," Roy says. "This suggests that it is indeed an access problem to the information, not that they're unable to learn or store this memory." The researchers also showed that the engram cells of Alzheimer's mice had fewer dendritic spines, which are small buds that allow neurons to receive incoming signals from other neurons. Normally, when a new memory is generated, the engram cells corresponding to that memory grow new dendritic spines, but this did not happen in the Alzheimer's mice. This suggests that the engram cells are not receiving sensory input from another part of the brain called the entorhinal cortex. The natural cue that should reactivate the memory—being in the chamber again—has no effect because the sensory information doesn't get into the engram cells. "If we want to recall a memory, the memory-holding cells have to be reactivated by the correct cue. If the spine density does not go up during learning process, then later, if you give a natural recall cue, it may not be able to reach the nucleus of the engram cells," Tonegawa says. Long-term connection The researchers were also able to induce a longer-term reactivation of the "lost" memories by stimulating new connections between the entorhinal cortex and the hippocampus. To achieve this, they used light to optogenetically stimulate entorhinal cortex cells that feed into the hippocampal engram cells encoding the fearful memory. After three hours of this treatment, the researchers waited a week and tested the mice again. This time, the mice could retrieve the memory on their own when placed in the original chamber, and they had many more dendritic spines on their engram cells. However, this approach does not work if too large a section of the entorhinal cortex is stimulated, suggesting that any potential treatments for human patients would have to be very targeted. Optogenetics is very precise but too invasive to use in humans, and existing methods for deep brain stimulation—a form of electrical stimulation sometimes used to treat Parkinson's and other diseases—affect too much of the brain. "It's possible that in the future some technology will be developed to activate or inactivate cells deep inside the brain, like the hippocampus or entorhinal cortex, with more precision," Tonegawa says. "Basic research as conducted in this study provides information on cell populations to be targeted, which is critical for future treatments and technologies." <|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 All text AUTHORS • Use these formats for best results: Smith or J Smith • Use a comma to separate multiple people: J Smith, RL Jones, Macarthur Any : All : ? Tips for preparing a search: Keep it simple - don't use too many different parameters. Separate search groups with parentheses and Booleans. Note the Boolean sign must be in upper-case. Example: (diode OR solid-state) AND laser [search contains \"diode\" or \"solid-state\" and laser] Example: (photons AND downconversion) - pump [search contains both \"photons\" and \"downconversion\" but not \"pump\"] Improve efficiency in your search by using wildcards. Asterisk ( * ) -- Example: \"elect*\" retrieves documents containing \"electron,\" \"electronic,\" and \"electricity\" Question mark (?) -- Example: \"gr?y\" retrieves documents containing \"grey\" or \"gray\" Use quotation marks \" \" around specific phrases where you want the entire phrase only. For best results, use the separate Authors field to search for author names. Author name searching: Use these formats for best results: Smith or J Smith Use a comma to separate multiple people: J Smith, RL Jones, Macarthur Note: Author names will be searched in the keywords field, also, but that may find papers where the person is mentioned, rather than papers they authored. SEARCH IN Journals Vol. Issue Page Conferences Year Paper # Industry Reports Report Year PUBLICATION YEARS From To Enter only one date to search After (\"From\") or Before (\"To\") OPTICS & PHOTONICS TOPICS Browse All Topics Selected topics Find articles with any selected topics Find articles with all selected topics Browse All Topics Click the to reveal subtopics. Use the checkbox to select a topic to filter your search. Amorphous materials Analog to digital converters Analytical techniques Application specific integrated circuits Artificially engineered materials Astrophotonics Autostereoscopic displays Binary optics Biodefense Biology Biophotonics Biosensors Cathode ray tubes Ceramics Chemical elements Chemistry CMOS technology Color Complex dielectric constant Composite materials Crystalline materials Damage Defect center materials Detector materials Dielectric boundaries Dielectric microcavities Diode lasers Electrical breakdown Electrodes Electromagnetic concentrators Electronics Electrooptical materials Environmental optics Equipment Ferroelectrics Fiber optics Field programmable gate arrays Flat panel displays Flexible circuits Flexible displays Fluorescence Fundamental processes Geometric optical design Head mounted displays Heads up displays Holographic displays Hybrid circuits Imaging Information theoretical analysis Integral imaging Integrated circuit design Integrated optics Integrated optoelectronics Laser displays Laser materials LED displays Light emitting diodes Light matter interactions Liquid crystal displays Low light level techniques Machine vision Magnetic fluids Magnetooptics Material properties Material storage Materials processing Mathematics Medical imaging Medicine Metrology Microchips Microfluidics Microoptics Microscopy Microstructures Microwave photonics Mixed signal circuits Modulators Nanomaterials Nanometer integrated circuits Nanophotonics Nonimaging optics Nonlinear optics On screen displays Optical amplification Optical circuits Optical communications Optical computing Optical design Optical fields Optical manipulation Optical materials Optical recording Optical safety Optical standards Optical systems Optical testing Optofluidics Optomechanics Organic materials Parametric processes Pattern recognition Phase Photochemistry Photographic emulsion Photographic film Photon correlations Photon echoes Photon localization Photon migration Photonic bandgap structure Photonic detection Photonic devices Photonic integrated circuits Photonic metamaterials Photonics applications Photovoltaics Physical optics Physics Piezoelectric drives Plasma displays Plasmonics Polarization control Polymers Printed circuit boards Process monitoring Psychophysics Quantum efficiency Quantum electronics Quantum well materials Quantum wires Radio frequency circuits Radio frequency photonics Rare earth doped materials Readout integrated circuits Reflective displays Semiconductors Silicon photonics Slow light applications Solar fuels Solgel Stretchable circuits Superconductors Surfaces Switching Terahertz wave photonics Thermodynamics Thin films Three dimensional displays Tissue optics Transient phenomena Transition metal doped materials Ultrafast information processing Ultrafast optics Viewing angles Vision Visual optics Visual system ? About Optics & Photonics Topics Optica Publishing Group developed the Optics and Photonics Topics to help organize its diverse content more accurately by topic area. This topic browser contains over 2400 terms and is organized in a three-level hierarchy. Read more. Topics can be refined further in the search results. The Topic facet will reveal the high-level topics associated with the articles returned in the search results. SPECIAL COLLECTIONS Energy and Environmental Optics Express Engineering and Laboratory Notes Memoranda Opinions Reviews Spotlight on Optics Tutorials Clear my choices above Search Journals Journals Advances in Optics and Photonics Applied Optics Applied Spectroscopy Biomedical Optics Express Chinese Optics Letters Current Optics and Photonics Journal of Lightwave Technology Journal of Near Infrared Spectroscopy Journal of Optical Technology Journal of Optical Communications and Networking Journal of the Optical Society of America A Journal of the Optical Society of America B Optica Optical Materials Express Optics Continuum Optics Express Optics Letters Photonics Research Legacy Journals Journal of Display Technology (2005-2016) Journal of the Optical Society of Korea (1997-2016) Journal of Optical Networking (2002-2009) Journal of the Optical Society of America (1917-1983) Optics News (1975-1989) OSA Continuum (2018-2021) Advances in Optics and Photonics Applied Optics Applied Spectroscopy Biomedical Optics Express Chinese Optics Letters Current Optics and Photonics Journal of Lightwave Technology Journal of Near Infrared Spectroscopy Journal of Optical Technology Journal of Optical Communications and Networking Journal of the Optical Society of America A Journal of the Optical Society of America B Optica Optica Quantum Optical Materials Express Optics and Photonics News Optics Continuum Optics Express Optics Letters Photonics Research Legacy Journals Journal of Display Technology (2005-2016) Journal of the Optical Society of Korea (1997-2016) Journal of Optical Networking (2002-2009) Journal of the Optical Society of America (1917-1983) Optics News (1975-1989) OSA Continuum (2018-2021) Conferences Find Conferences By Year By Name Featured Optical Fiber Communication (OFC) Conference on Lasers and Electro-Optics (CLEO) Frontiers in Optics (FiO) Newly Published Bio-Optics: Design and Application Novel Techniques in Microscopy Optical Manipulation and Its Applications Optical Molecular Probes, Imaging and Drug Delivery Optics and the Brain Preprints Optica Open View preprints Submit preprint Author instructions About FAQ Other Resources Information For Authors Reviewers Librarians Products and Services Digital Archive Interactive Science Publishing (ISP) Optica Open Optics ImageBank Optics and Photonics Topics Spotlight on Optics Publications Bookshelf \"INDUSTRY REPORTS\" LINK TEMPORARILY DISABLED ON 3/3/2023 UNTIL FURTHER NOTICE FROM CORP DEPT. li><a href=\"/industryreports.cfm\">Industry Reports</a></li Special Collections Regional Content On The Cover: Photonics Research Spotlight: Chinese Optics", "role": "user" }, { "content": "The color of a material can often tell you something about how it handles heat. Think of wearing a black shirt on a sweltering summer's day—the darker the pigment, the warmer you're likely to feel. Likewise, the more transparent a glass window, the more heat it can let through. A material's responses to visible and infrared radiation are often naturally linked. Now MIT engineers have made samples of strong, tissue-like polymer material, the color and heat properties of which they can tailor independently of the other. For instance, they have fabricated samples of very thin black film designed to reflect heat and stay cool. They've also made films exhibiting a rainbow of other colors, each made to reflect or absorb infrared radiation regardless of the way they respond to visible light. The researchers can specifically tune the color and heat properties of this new material to fit the requirements for a host of wide-ranging applications, including colorful, heat-reflecting building facades, windows, and roofs; light-absorbing, heat-dissipating covers for solar panels; and lightweight fabric for clothing, outerwear, tents, and backpacks—all designed to either trap or reflect heat, depending on the environments in which they would be used. \"With this material, everything could look more colorful, because then you wouldn't be concerned with what color does to the thermal balance of, say, a building, or a window, or your clothing,\" says Svetlana Boriskina, a research scientist in MIT's Department of Mechanical Engineering. Boriskina is author of a study that appears today in the journal Optical Materials Express, outlining the new material-engineering technique. Her MIT co-authors are Luis Marcelo Lozano, Seongdon Hong, Yi Huang, Hadi Zandavi, Yoichiro Tsurimaki, Jiawei Zhou, Yanfei Xu, and Gang Chen, the Carl Richard Soderberg Professor of Power Engineering, along with Yassine Ait El Aoud and Richard Osgood III, both of the Combat Capabilities Development Command Soldier Center, in Natick, Massachusetts. Polymer conductors For this work, Boriskina was inspired by the vibrant colors in stained-glass windows, which for centuries have been made by adding particles of metals and other natural pigments to glass. \"However, despite providing excellent visual transparency, glass has many limitations as a material,\" Boriskina notes. \"It is bulky, inflexible, fragile, does not spread heat well, and is obviously not suitable for wearable applications.\" She says that while it's relatively simple to tailor the color of glass, the material's response to heat is difficult to tune. For instance, glass panels reflect room-temperature heat and trap it inside the room. Furthermore, if colored glass is exposed to incoming sunlight from a particular direction, the heat from the sun can create a hotspot, which is difficult to dissipate in glass. If a material like glass can't conduct or dissipate heat well, that heat could damage the material. The same can be said for most plastics, which can be engineered in any color but for the most part are thermal absorbers and insulators, concentrating and trapping heat rather than reflecting it away. For the past several years, Chen's lab has been looking into ways to manipulate flexible, lightweight polymer materials to conduct, rather than insulate, heat, mostly for applications in electronics. In previous work, the researchers found that by carefully stretching polymers like polyethylene, they could change the material's internal structure in a way that also changed its heat-conducting properties. Boriskina thought this technique might be useful not just for fabricating polymer-based electronics, but also in architecture and apparel. She adapted this polymer-fabrication technique, adding a twist of color. \"It's very hard to develop a new material with all these different properties in it,\" she says. \"Usually if you tune one property, the other gets destroyed. Here, we started with one property that was discovered in this group, and then we added a new property creatively. All together it works as a multifunctional material.\" Hotspots stretched away To fabricate the colorful films, the team started with a mixture of polyethylene powder and a chemical solvent, to which they added certain nanoparticles to give the film a desired color. For instance, to make black film, they added particles of silicon; other red, blue, green, and yellow films were made with the addition of various commercial dyes. The team then attached each nanoparticle-embedded film onto a roll-to-roll apparatus, which they heated up to soften the film, making it more pliable as the researchers carefully stretched the material. As they stretched each film, they found, unsurprisingly, that the material became more transparent. They also observed that polyethylene's microscopic structure changed as it stretched. Where normally the material's polymer chains resemble a disorganized tangle, similar to cooked spaghetti, when stretched these chains straighten out, forming parallel fibers. When the researchers placed each sample under a solar simulator—a lamp that mimics the visible and thermal radiation of the sun—they found the more stretched out a film, the more heat it was able to dissipate. The long, parallel polymer chains essentially provided a direct route along which heat could travel. Along these chains, heat, in the form of phonons, could then shoot away from its source, in a \"ballistic\" fashion, avoiding the formation of hotspots. The researchers also found that the less they stretched the material, the more insulating it was, trapping heat, and forming hotspots within polymer tangles. By controlling the degree to which the material is stretched, Boriskina could control polyethylene's heat-conducting properties, regardless of the material's color. She also carefully chose the nanoparticles, not just by their visual color, but also by their interactions with invisible radiative heat. She says researchers can potentially use this technique to produce thin, flexible, colorful polymer films, that can conduct or insulate heat, depending on the application. Going forward, she plans to launch a website that offers algorithms to calculate a material's color and thermal properties, based on its dimensions and internal structure. In addition to films, her group is now working on fabricating nanoparticle-embedded polyethylene thread, which can be stitched together to form lightweight apparel, designed to be either insulating, or cooling. \"This is in film factor now, but we're working it into fibers and fabrics,\" Boriskina says. \"Polyethylene is produced by the billions of tons and could be recycled, too. I don't see any significant impediments to large-scale production.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract All text AUTHORS • Use these formats for best results: Smith or J Smith • Use a comma to separate multiple people: J Smith, RL Jones, Macarthur Any : All : ? Tips for preparing a search: Keep it simple - don't use too many different parameters. Separate search groups with parentheses and Booleans. Note the Boolean sign must be in upper-case. Example: (diode OR solid-state) AND laser [search contains "diode" or "solid-state" and laser] Example: (photons AND downconversion) - pump [search contains both "photons" and "downconversion" but not "pump"] Improve efficiency in your search by using wildcards. 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Think of wearing a black shirt on a sweltering summer's day—the darker the pigment, the warmer you're likely to feel. Likewise, the more transparent a glass window, the more heat it can let through. A material's responses to visible and infrared radiation are often naturally linked. Now MIT engineers have made samples of strong, tissue-like polymer material, the color and heat properties of which they can tailor independently of the other. For instance, they have fabricated samples of very thin black film designed to reflect heat and stay cool. They've also made films exhibiting a rainbow of other colors, each made to reflect or absorb infrared radiation regardless of the way they respond to visible light. The researchers can specifically tune the color and heat properties of this new material to fit the requirements for a host of wide-ranging applications, including colorful, heat-reflecting building facades, windows, and roofs; light-absorbing, heat-dissipating covers for solar panels; and lightweight fabric for clothing, outerwear, tents, and backpacks—all designed to either trap or reflect heat, depending on the environments in which they would be used. "With this material, everything could look more colorful, because then you wouldn't be concerned with what color does to the thermal balance of, say, a building, or a window, or your clothing," says Svetlana Boriskina, a research scientist in MIT's Department of Mechanical Engineering. Boriskina is author of a study that appears today in the journal Optical Materials Express, outlining the new material-engineering technique. Her MIT co-authors are Luis Marcelo Lozano, Seongdon Hong, Yi Huang, Hadi Zandavi, Yoichiro Tsurimaki, Jiawei Zhou, Yanfei Xu, and Gang Chen, the Carl Richard Soderberg Professor of Power Engineering, along with Yassine Ait El Aoud and Richard Osgood III, both of the Combat Capabilities Development Command Soldier Center, in Natick, Massachusetts. Polymer conductors For this work, Boriskina was inspired by the vibrant colors in stained-glass windows, which for centuries have been made by adding particles of metals and other natural pigments to glass. "However, despite providing excellent visual transparency, glass has many limitations as a material," Boriskina notes. "It is bulky, inflexible, fragile, does not spread heat well, and is obviously not suitable for wearable applications." She says that while it's relatively simple to tailor the color of glass, the material's response to heat is difficult to tune. For instance, glass panels reflect room-temperature heat and trap it inside the room. Furthermore, if colored glass is exposed to incoming sunlight from a particular direction, the heat from the sun can create a hotspot, which is difficult to dissipate in glass. If a material like glass can't conduct or dissipate heat well, that heat could damage the material. The same can be said for most plastics, which can be engineered in any color but for the most part are thermal absorbers and insulators, concentrating and trapping heat rather than reflecting it away. For the past several years, Chen's lab has been looking into ways to manipulate flexible, lightweight polymer materials to conduct, rather than insulate, heat, mostly for applications in electronics. In previous work, the researchers found that by carefully stretching polymers like polyethylene, they could change the material's internal structure in a way that also changed its heat-conducting properties. Boriskina thought this technique might be useful not just for fabricating polymer-based electronics, but also in architecture and apparel. She adapted this polymer-fabrication technique, adding a twist of color. "It's very hard to develop a new material with all these different properties in it," she says. "Usually if you tune one property, the other gets destroyed. Here, we started with one property that was discovered in this group, and then we added a new property creatively. All together it works as a multifunctional material." Hotspots stretched away To fabricate the colorful films, the team started with a mixture of polyethylene powder and a chemical solvent, to which they added certain nanoparticles to give the film a desired color. For instance, to make black film, they added particles of silicon; other red, blue, green, and yellow films were made with the addition of various commercial dyes. The team then attached each nanoparticle-embedded film onto a roll-to-roll apparatus, which they heated up to soften the film, making it more pliable as the researchers carefully stretched the material. As they stretched each film, they found, unsurprisingly, that the material became more transparent. They also observed that polyethylene's microscopic structure changed as it stretched. Where normally the material's polymer chains resemble a disorganized tangle, similar to cooked spaghetti, when stretched these chains straighten out, forming parallel fibers. When the researchers placed each sample under a solar simulator—a lamp that mimics the visible and thermal radiation of the sun—they found the more stretched out a film, the more heat it was able to dissipate. The long, parallel polymer chains essentially provided a direct route along which heat could travel. Along these chains, heat, in the form of phonons, could then shoot away from its source, in a "ballistic" fashion, avoiding the formation of hotspots. The researchers also found that the less they stretched the material, the more insulating it was, trapping heat, and forming hotspots within polymer tangles. By controlling the degree to which the material is stretched, Boriskina could control polyethylene's heat-conducting properties, regardless of the material's color. She also carefully chose the nanoparticles, not just by their visual color, but also by their interactions with invisible radiative heat. She says researchers can potentially use this technique to produce thin, flexible, colorful polymer films, that can conduct or insulate heat, depending on the application. Going forward, she plans to launch a website that offers algorithms to calculate a material's color and thermal properties, based on its dimensions and internal structure. In addition to films, her group is now working on fabricating nanoparticle-embedded polyethylene thread, which can be stitched together to form lightweight apparel, designed to be either insulating, or cooling. "This is in film factor now, but we're working it into fibers and fabrics," Boriskina says. "Polyethylene is produced by the billions of tons and could be recycled, too. I don't see any significant impediments to large-scale production." <|im_end|>

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48934, 59509, 11, 473, 2836, 1901, 438, 6321, 11, 44188, 718, 8869, 350, 20370, 318, 14966, 11, 55551, 38685, 67927, 11, 25191, 1897, 72, 57514, 11, 323, 35517, 25507, 11, 279, 22770, 12131, 328, 4414, 7881, 17054, 315, 7572, 17005, 11, 3235, 449, 816, 395, 483, 362, 275, 4072, 362, 3023, 323, 12131, 507, 2034, 1411, 14767, 11, 2225, 315, 279, 37082, 8171, 8623, 11050, 7498, 53529, 5955, 11, 304, 452, 780, 74, 11, 22108, 13, 97770, 6929, 1105, 1789, 420, 990, 11, 23768, 3267, 2259, 574, 14948, 555, 279, 34076, 8146, 304, 61152, 2427, 448, 11276, 11, 902, 369, 24552, 617, 1027, 1903, 555, 7999, 19252, 315, 37182, 323, 1023, 5933, 24623, 1392, 311, 9168, 13, 330, 11458, 11, 8994, 8405, 9250, 9302, 28330, 11, 9168, 706, 1690, 9669, 439, 264, 3769, 1359, 23768, 3267, 2259, 8554, 13, 330, 2181, 374, 78921, 11, 4225, 95644, 11, 45350, 11, 1587, 539, 9041, 8798, 1664, 11, 323, 374, 14224, 539, 14791, 369, 78348, 8522, 1210, 3005, 2795, 430, 1418, 433, 596, 12309, 4382, 311, 52056, 279, 1933, 315, 9168, 11, 279, 3769, 596, 2077, 311, 8798, 374, 5107, 311, 26306, 13, 1789, 2937, 11, 9168, 21988, 8881, 3130, 12, 35658, 8798, 323, 23709, 433, 4871, 279, 3130, 13, 24296, 11, 422, 28296, 9168, 374, 15246, 311, 19957, 40120, 505, 264, 4040, 5216, 11, 279, 8798, 505, 279, 7160, 649, 1893, 264, 80310, 11, 902, 374, 5107, 311, 93522, 349, 304, 9168, 13, 1442, 264, 3769, 1093, 9168, 649, 956, 6929, 477, 93522, 349, 8798, 1664, 11, 430, 8798, 1436, 5674, 279, 3769, 13, 578, 1890, 649, 387, 1071, 369, 1455, 68386, 11, 902, 649, 387, 46036, 304, 904, 1933, 719, 369, 279, 1455, 961, 527, 29487, 15938, 1941, 323, 1672, 42391, 11, 76387, 323, 93669, 8798, 4856, 1109, 42852, 433, 3201, 13, 1789, 279, 3347, 3892, 1667, 11, 25507, 596, 10278, 706, 1027, 3411, 1139, 5627, 311, 37735, 19303, 11, 30244, 47393, 7384, 311, 6929, 11, 4856, 1109, 1672, 6468, 11, 8798, 11, 10213, 369, 8522, 304, 31591, 13, 763, 3766, 990, 11, 279, 12074, 1766, 430, 555, 15884, 42949, 46033, 388, 1093, 10062, 88640, 11, 814, 1436, 2349, 279, 3769, 596, 5419, 6070, 304, 264, 1648, 430, 1101, 5614, 1202, 8798, 15204, 1076, 287, 6012, 13, 23768, 3267, 2259, 3463, 420, 15105, 2643, 387, 5505, 539, 1120, 369, 13354, 1113, 47393, 6108, 31591, 11, 719, 1101, 304, 18112, 323, 55425, 13, 3005, 30464, 420, 47393, 2269, 29997, 367, 15105, 11, 7999, 264, 27744, 315, 1933, 13, 330, 2181, 596, 1633, 2653, 311, 2274, 264, 502, 3769, 449, 682, 1521, 2204, 6012, 304, 433, 1359, 1364, 2795, 13, 330, 71744, 422, 499, 26306, 832, 3424, 11, 279, 1023, 5334, 14763, 13, 5810, 11, 584, 3940, 449, 832, 3424, 430, 574, 11352, 304, 420, 1912, 11, 323, 1243, 584, 3779, 264, 502, 3424, 93396, 13, 2052, 3871, 433, 4375, 439, 264, 62387, 600, 278, 3769, 1210, 8166, 68110, 41398, 3201, 2057, 13354, 349, 279, 34966, 12631, 11, 279, 2128, 3940, 449, 264, 21655, 315, 10062, 88640, 17138, 323, 264, 11742, 69996, 11, 311, 902, 814, 3779, 3738, 94753, 311, 3041, 279, 4632, 264, 12974, 1933, 13, 1789, 2937, 11, 311, 1304, 3776, 4632, 11, 814, 3779, 19252, 315, 51692, 26, 1023, 2579, 11, 6437, 11, 6307, 11, 323, 14071, 12631, 1051, 1903, 449, 279, 5369, 315, 5370, 8518, 294, 9891, 13, 578, 2128, 1243, 12673, 1855, 76307, 7203, 12, 70964, 4632, 8800, 264, 6638, 4791, 87860, 41705, 11, 902, 814, 32813, 709, 311, 81045, 279, 4632, 11, 3339, 433, 810, 628, 2205, 439, 279, 12074, 15884, 41398, 279, 3769, 13, 1666, 814, 41398, 1855, 4632, 11, 814, 1766, 11, 69217, 49264, 11, 430, 279, 3769, 6244, 810, 18300, 13, 2435, 1101, 13468, 430, 10062, 88640, 596, 90090, 6070, 5614, 439, 433, 41398, 13, 11208, 14614, 279, 3769, 596, 47393, 27271, 52280, 264, 834, 63316, 259, 4134, 11, 4528, 311, 30205, 88010, 11, 994, 41398, 1521, 27271, 7833, 268, 704, 11, 30164, 15638, 49774, 13, 3277, 279, 12074, 9277, 1855, 6205, 1234, 264, 13238, 42991, 29096, 29062, 430, 28003, 1233, 279, 9621, 323, 29487, 25407, 315, 279, 7160, 71201, 1766, 279, 810, 41398, 704, 264, 4632, 11, 279, 810, 8798, 433, 574, 3025, 311, 93522, 349, 13, 578, 1317, 11, 15638, 47393, 27271, 16168, 3984, 264, 2167, 6149, 3235, 902, 8798, 1436, 5944, 13, 32944, 1521, 27271, 11, 8798, 11, 304, 279, 1376, 315, 51923, 2439, 11, 1436, 1243, 6230, 3201, 505, 1202, 2592, 11, 304, 264, 330, 4047, 4633, 1, 11401, 11, 31526, 279, 18488, 315, 4106, 68110, 13, 578, 12074, 1101, 1766, 430, 279, 2753, 814, 41398, 279, 3769, 11, 279, 810, 1672, 15853, 433, 574, 11, 93669, 8798, 11, 323, 30164, 4106, 68110, 2949, 47393, 259, 17694, 13, 3296, 26991, 279, 8547, 311, 902, 279, 3769, 374, 41398, 11, 23768, 3267, 2259, 1436, 2585, 10062, 88640, 596, 8798, 15204, 1076, 287, 6012, 11, 15851, 315, 279, 3769, 596, 1933, 13, 3005, 1101, 15884, 14896, 279, 94753, 11, 539, 1120, 555, 872, 9302, 1933, 11, 719, 1101, 555, 872, 22639, 449, 30547, 12164, 1413, 8798, 13, 3005, 2795, 12074, 649, 13893, 1005, 420, 15105, 311, 8356, 15792, 11, 19303, 11, 34966, 47393, 12631, 11, 430, 649, 6929, 477, 1672, 6468, 8798, 11, 11911, 389, 279, 3851, 13, 35971, 4741, 11, 1364, 6787, 311, 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2,843

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Unlike other malignancies, therapeutic options in pancreatic ductal adenocarcinoma (PDAC) are largely limited to cytotoxic chemotherapy without the benefit of molecular markers predicting response. Here we report tumor-cell-intrinsic chromatin accessibility patterns of treatment-naïve surgically resected PDAC tumors that were subsequently treated with (Gem)/Abraxane adjuvant chemotherapy. By ATAC-seq analyses of EpCAM + PDAC malignant epithelial cells sorted from 54 freshly resected human tumors, we show here the discovery of a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identify two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further develop a chromatin accessibility microarray methodology termed “ ATAC-array”, an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validate ATAC-array technology in both the original ATAC-seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a low-cost, clinically feasible technology for assessing chromatin accessibility profiles. Introduction Prognostic precision is pivotal to therapeutic decision making. Pancreatic ductal adenocarcinoma (PDAC) patients with the limited local disease and with no detectable metastasis typically have their primary tumor surgically resected and subsequently receive adjuvant chemotherapy. Approximately 50% of these resected PDAC patients have a poor prognosis, with disease recurring within 1 year of surgery in spite of apparently complete tumor removal (R0 margin-negative resection) and adjuvant chemotherapy. An additional 30-35% of patients recur within 2-5 years, but a small subset (14%), is characterized by prolonged disease-free survival (DFS) of 5–10 years 1 , 2 , 3 . Recurrence in spite of adjuvant chemotherapy may be due to the presence of undetected chemotherapy-refractory micro-metastatic lesions, while non-recurrence may mean that the tumor never metastasized or that micro-metastatic lesions responded well to the adjuvant chemotherapy. Previous literature including large-scale efforts from both the TCGA and the ICGC have reported genomic and transcriptomic analyses on resected PDAC bulk tumors 4 , 5 , 6 , 7 , with follow-up studies ongoing to derive clinically actionable leads 8 . Complementing these large-scale studies of differential gene expression in PDAC, we sought to map in parallel the epigenetic heterogeneity of this disease. Considering the variable epithelial cellularity of PDAC tumor microenvironment 9 , rather than relying on bulk tumor material, we decided to investigate the tumor-cell-intrinsic epigenetic profile of resected PDAC. By analyzing genome-wide chromatin accessibility patterns by Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) 10 of EpCAM-sorted PDAC malignant epithelial cells from 54 surgically resected PDAC tumors we identified 121,697 open chromatin peaks and discovered 1092 regions that are differentially represented between patients with DFS < 1 year and patients with DFS > 1 year. We further identified and validated two transcription factors (TFs) HNF1b and ZKSCAN1, with differential nuclear localization between poor and good prognosis tumors. We also developed “ ATAC-array ” technology—the only microarray that reads chromatin accessibility patterns—as a potential diagnostic tool that may be utilized in PDAC clinic. Combining ATAC-array and HNF1b together we segregate resected PDAC patients into good, intermediate, and poor prognosis groups with greater than 7-fold differences in DFS. Results PDAC malignant epithelial cellularity is variable We hypothesized that epigenetic differences at the level of chromatin accessibility, potentially linked to distinct differentiation states, might distinguish rapidly recurrent from non-recurrent tumors. To test our hypothesis, we sought to characterize tumor-cell intrinsic chromatin accessibility patterns from a prospective cohort of treatment-naïve, surgically resected tumors from 54 PDAC patients at Memorial Sloan Kettering Cancer Center. Consistent with the known issue of variable neoplastic cellularity in PDAC, an initial histopathological survey of frozen archival tissues in our repository ( n = 120) found variable epithelial contents ranging from 0 to 90%, with median cellularity of 40% (Supplementary Fig. 1a ). To overcome this variability, we optimized the sorting of PDAC malignant cells from freshly resected tumors using EpCAM antibody-conjugated magnetic beads (Supplementary Fig. 1b ). We collected both EpCAM + and EpCAM - cells from each of the tumors and confirmed effective enrichment of malignant epithelial cells by comparing 15 variant allele frequencies (VAFs) of canonical pancreatic cancer driver genes, including six variant alleles for KRAS and nine variant alleles for TP53 (Supplementary Fig. 1c ), where each of the variant alleles is denoted by different colored lines comparing EpCAM + and EpCAM − subpopulations of the same tumor collected from each patient. We observed that the VAFs of KRAS and TP53 were both dramatically higher in the EpCAM + cells than in the EpCAM - cells ( P < 0.001, t-test), confirming effective enrichment of malignant epithelial cells in the EpCAM + subpopulation. This enrichment was further confirmed by transcriptome analysis using Quant-Seq 11 , which demonstrated high-level expression of epithelial genes in the EpCAM + subpopulation, with the corresponding expression of immune cell and collagen genes in the EpCAM − subpopulation (Supplementary Fig. 2 and Supplementary Data 1 ). ATAC-seq analysis on sorted PDAC malignant cells We then performed Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) analysis 10 on the EpCAM + cells to interrogate genome-wide chromatin accessibility and associated differentially accessible TF-binding sites. After initial quality control (described in Methods and in Supplementary Fig. 3 ), we assembled a global atlas of 121,697 chromatin peaks, where each peak was reproducible in replicate ATAC-seq libraries for at least two patients. We performed saturation analysis to estimate incremental new peak discovery associated with stepwise increases in sample size and confirmed that a sample size of n = 40 approached saturating coverage (Supplementary Fig. 4a ). Discovery of 1092-peak chromatin accessibility signature Follow-up clinical data were available for 36 out of 40 patients included in the atlas (see remarks in Supplementary Data 2 and Supplementary Fig. 4b ). 19 out of 36 patients were at least 365 days post-treatment, among", "role": "user" }, { "content": "By 2030, pancreatic ductal adenocarcinoma (PDAC), the most lethal form of pancreatic cancer, is projected to become the second leading cause of cancer-related deaths in the United States. Not only are therapeutic options limited, but nearly half of all PDAC patients who have their tumors removed surgically experience disease recurrence within a year, despite receiving additional chemotherapy. For more advanced stages, only about one-third of patients have a limited response to approved chemotherapy. A team of researchers led by Dartmouth and Dartmouth-Hitchcock's Norris Cotton Cancer Center (NCCC) Director Steven D. Leach, MD, and Surajit Dhara, Ph.D., Senior Research Scientist in the Leach laboratory, in collaboration with colleagues at Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, are developing the first prognostic and therapeutic epigenetic biomarker for PDAC patients. Their discoveries will help predict which patients are likely or not likely to benefit from traditional chemotherapy. The likely \"responder\" patients can be confidently treated with traditional chemotherapy regimens, while the likely \"non-responder\" patients can be given an alternate regimen—potentially a combination of epigenetic therapy. The technology addresses a pressing clinical need by introducing the first ever epigenetic precision medicine approach to pancreatic cancer, as a means toward better outcomes and quality of life for all patients. Epigenetic therapy can reactivate expression of the regulatory genes that have been silenced in chemo-resistant tumors and therefore make the tumors responsive to chemotherapy. The team's work, entitled \"Pancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility,\" is newly published in Nature Communications. \"We have a discovery and an invention emanating from this work,\" says Dhara. \"By investigating all epigenetic elements that regulate genes in PDAC, we discovered that only about 1,092 elements are associated with chemotherapy resistance and early recurrence of this disease. Of those, 723 elements are silenced in chemo-resistant tumors, and are optimally predictive.\" To translate this knowledge into the clinic, Leach and Dhara invented a novel technology platform called \"ATAC-array\" that assesses gene regulatory elements as a means to predict chemotherapy response and the potential benefit of epigenetic therapy in patients with PDAC. The technology is DNA-based and can potentially be performed on fine-needle aspiration specimens collected from tumors at the time of diagnosis. Although there are nine FDA-approved epigenetic drugs, and more in the pharma pipeline, a fundamental means of distinguishing tumors that would benefit from epigenetic reprogramming therapy is still lacking. \"We currently appear to be at the dawn of a new era in which epigenetic reprogramming is poised to become increasingly relied upon to optimize therapeutic effectiveness in multiple tumor types,\" says Leach. \"With this work, we have pioneered a precision epigenetic approach in PDAC, a treatment approach that is now ready to be translated into the clinic.\" Leach and Dhara have co-founded Episteme Prognostics, Inc.— a precision medicine company developing therapeutic biomarkers for pancreatic cancer—in order to translate this work directly to the clinic as rapidly as possible. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Unlike other malignancies, therapeutic options in pancreatic ductal adenocarcinoma (PDAC) are largely limited to cytotoxic chemotherapy without the benefit of molecular markers predicting response. Here we report tumor-cell-intrinsic chromatin accessibility patterns of treatment-naïve surgically resected PDAC tumors that were subsequently treated with (Gem)/Abraxane adjuvant chemotherapy. By ATAC-seq analyses of EpCAM + PDAC malignant epithelial cells sorted from 54 freshly resected human tumors, we show here the discovery of a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identify two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further develop a chromatin accessibility microarray methodology termed “ ATAC-array”, an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validate ATAC-array technology in both the original ATAC-seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a low-cost, clinically feasible technology for assessing chromatin accessibility profiles. Introduction Prognostic precision is pivotal to therapeutic decision making. Pancreatic ductal adenocarcinoma (PDAC) patients with the limited local disease and with no detectable metastasis typically have their primary tumor surgically resected and subsequently receive adjuvant chemotherapy. Approximately 50% of these resected PDAC patients have a poor prognosis, with disease recurring within 1 year of surgery in spite of apparently complete tumor removal (R0 margin-negative resection) and adjuvant chemotherapy. An additional 30-35% of patients recur within 2-5 years, but a small subset (14%), is characterized by prolonged disease-free survival (DFS) of 5–10 years 1 , 2 , 3 . Recurrence in spite of adjuvant chemotherapy may be due to the presence of undetected chemotherapy-refractory micro-metastatic lesions, while non-recurrence may mean that the tumor never metastasized or that micro-metastatic lesions responded well to the adjuvant chemotherapy. Previous literature including large-scale efforts from both the TCGA and the ICGC have reported genomic and transcriptomic analyses on resected PDAC bulk tumors 4 , 5 , 6 , 7 , with follow-up studies ongoing to derive clinically actionable leads 8 . Complementing these large-scale studies of differential gene expression in PDAC, we sought to map in parallel the epigenetic heterogeneity of this disease. Considering the variable epithelial cellularity of PDAC tumor microenvironment 9 , rather than relying on bulk tumor material, we decided to investigate the tumor-cell-intrinsic epigenetic profile of resected PDAC. By analyzing genome-wide chromatin accessibility patterns by Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) 10 of EpCAM-sorted PDAC malignant epithelial cells from 54 surgically resected PDAC tumors we identified 121,697 open chromatin peaks and discovered 1092 regions that are differentially represented between patients with DFS < 1 year and patients with DFS > 1 year. We further identified and validated two transcription factors (TFs) HNF1b and ZKSCAN1, with differential nuclear localization between poor and good prognosis tumors. We also developed “ ATAC-array ” technology—the only microarray that reads chromatin accessibility patterns—as a potential diagnostic tool that may be utilized in PDAC clinic. Combining ATAC-array and HNF1b together we segregate resected PDAC patients into good, intermediate, and poor prognosis groups with greater than 7-fold differences in DFS. Results PDAC malignant epithelial cellularity is variable We hypothesized that epigenetic differences at the level of chromatin accessibility, potentially linked to distinct differentiation states, might distinguish rapidly recurrent from non-recurrent tumors. To test our hypothesis, we sought to characterize tumor-cell intrinsic chromatin accessibility patterns from a prospective cohort of treatment-naïve, surgically resected tumors from 54 PDAC patients at Memorial Sloan Kettering Cancer Center. Consistent with the known issue of variable neoplastic cellularity in PDAC, an initial histopathological survey of frozen archival tissues in our repository ( n = 120) found variable epithelial contents ranging from 0 to 90%, with median cellularity of 40% (Supplementary Fig. 1a ). To overcome this variability, we optimized the sorting of PDAC malignant cells from freshly resected tumors using EpCAM antibody-conjugated magnetic beads (Supplementary Fig. 1b ). We collected both EpCAM + and EpCAM - cells from each of the tumors and confirmed effective enrichment of malignant epithelial cells by comparing 15 variant allele frequencies (VAFs) of canonical pancreatic cancer driver genes, including six variant alleles for KRAS and nine variant alleles for TP53 (Supplementary Fig. 1c ), where each of the variant alleles is denoted by different colored lines comparing EpCAM + and EpCAM − subpopulations of the same tumor collected from each patient. We observed that the VAFs of KRAS and TP53 were both dramatically higher in the EpCAM + cells than in the EpCAM - cells ( P < 0.001, t-test), confirming effective enrichment of malignant epithelial cells in the EpCAM + subpopulation. This enrichment was further confirmed by transcriptome analysis using Quant-Seq 11 , which demonstrated high-level expression of epithelial genes in the EpCAM + subpopulation, with the corresponding expression of immune cell and collagen genes in the EpCAM − subpopulation (Supplementary Fig. 2 and Supplementary Data 1 ). ATAC-seq analysis on sorted PDAC malignant cells We then performed Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) analysis 10 on the EpCAM + cells to interrogate genome-wide chromatin accessibility and associated differentially accessible TF-binding sites. After initial quality control (described in Methods and in Supplementary Fig. 3 ), we assembled a global atlas of 121,697 chromatin peaks, where each peak was reproducible in replicate ATAC-seq libraries for at least two patients. We performed saturation analysis to estimate incremental new peak discovery associated with stepwise increases in sample size and confirmed that a sample size of n = 40 approached saturating coverage (Supplementary Fig. 4a ). Discovery of 1092-peak chromatin accessibility signature Follow-up clinical data were available for 36 out of 40 patients included in the atlas (see remarks in Supplementary Data 2 and Supplementary Fig. 4b ). 19 out of 36 patients were at least 365 days post-treatment, among<|im_end|> <|im_start|>assistant By 2030, pancreatic ductal adenocarcinoma (PDAC), the most lethal form of pancreatic cancer, is projected to become the second leading cause of cancer-related deaths in the United States. Not only are therapeutic options limited, but nearly half of all PDAC patients who have their tumors removed surgically experience disease recurrence within a year, despite receiving additional chemotherapy. For more advanced stages, only about one-third of patients have a limited response to approved chemotherapy. A team of researchers led by Dartmouth and Dartmouth-Hitchcock's Norris Cotton Cancer Center (NCCC) Director Steven D. Leach, MD, and Surajit Dhara, Ph.D., Senior Research Scientist in the Leach laboratory, in collaboration with colleagues at Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, are developing the first prognostic and therapeutic epigenetic biomarker for PDAC patients. Their discoveries will help predict which patients are likely or not likely to benefit from traditional chemotherapy. The likely "responder" patients can be confidently treated with traditional chemotherapy regimens, while the likely "non-responder" patients can be given an alternate regimen—potentially a combination of epigenetic therapy. The technology addresses a pressing clinical need by introducing the first ever epigenetic precision medicine approach to pancreatic cancer, as a means toward better outcomes and quality of life for all patients. Epigenetic therapy can reactivate expression of the regulatory genes that have been silenced in chemo-resistant tumors and therefore make the tumors responsive to chemotherapy. The team's work, entitled "Pancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility," is newly published in Nature Communications. "We have a discovery and an invention emanating from this work," says Dhara. "By investigating all epigenetic elements that regulate genes in PDAC, we discovered that only about 1,092 elements are associated with chemotherapy resistance and early recurrence of this disease. Of those, 723 elements are silenced in chemo-resistant tumors, and are optimally predictive." To translate this knowledge into the clinic, Leach and Dhara invented a novel technology platform called "ATAC-array" that assesses gene regulatory elements as a means to predict chemotherapy response and the potential benefit of epigenetic therapy in patients with PDAC. The technology is DNA-based and can potentially be performed on fine-needle aspiration specimens collected from tumors at the time of diagnosis. Although there are nine FDA-approved epigenetic drugs, and more in the pharma pipeline, a fundamental means of distinguishing tumors that would benefit from epigenetic reprogramming therapy is still lacking. "We currently appear to be at the dawn of a new era in which epigenetic reprogramming is poised to become increasingly relied upon to optimize therapeutic effectiveness in multiple tumor types," says Leach. "With this work, we have pioneered a precision epigenetic approach in PDAC, a treatment approach that is now ready to be translated into the clinic." Leach and Dhara have co-founded Episteme Prognostics, Inc.— a precision medicine company developing therapeutic biomarkers for pancreatic cancer—in order to translate this work directly to the clinic as rapidly as possible. <|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 initiation of an intestinal tumour is a probabilistic process that depends on the competition between mutant and normal epithelial stem cells in crypts 1 . Intestinal stem cells are closely associated with a diverse but poorly characterized network of mesenchymal cell types 2 , 3 . However, whether the physiological mesenchymal microenvironment of mutant stem cells affects tumour initiation remains unknown. Here we provide in vivo evidence that the mesenchymal niche controls tumour initiation in trans . By characterizing the heterogeneity of the intestinal mesenchyme using single-cell RNA-sequencing analysis, we identified a population of rare pericryptal Ptgs2 -expressing fibroblasts that constitutively process arachidonic acid into highly labile prostaglandin E 2 (PGE 2 ). Specific ablation of Ptgs2 in fibroblasts was sufficient to prevent tumour initiation in two different models of sporadic, autochthonous tumorigenesis. Mechanistically, single-cell RNA-sequencing analyses of a mesenchymal niche model showed that fibroblast-derived PGE 2 drives the expansion οf a population of Sca-1 + reserve-like stem cells. These express a strong regenerative/tumorigenic program, driven by the Hippo pathway effector Yap. In vivo, Yap is indispensable for Sca-1 + cell expansion and early tumour initiation and displays a nuclear localization in both mouse and human adenomas. Using organoid experiments, we identified a molecular mechanism whereby PGE 2 promotes Yap dephosphorylation, nuclear translocation and transcriptional activity by signalling through the receptor Ptger4. Epithelial-specific ablation of Ptger4 misdirected the regenerative reprogramming of stem cells and prevented Sca-1 + cell expansion and sporadic tumour initiation in mutant mice, thereby demonstrating the robust paracrine control of tumour-initiating stem cells by PGE 2 –Ptger4. Analyses of patient-derived organoids established that PGE 2 –PTGER4 also regulates stem-cell function in humans. Our study demonstrates that initiation of colorectal cancer is orchestrated by the mesenchymal niche and reveals a mechanism by which rare pericryptal Ptgs2 -expressing fibroblasts exert paracrine control over tumour-initiating stem cells via the druggable PGE 2 –Ptger4–Yap signalling axis. Main Mesenchymal cells are localized in tight association with stem cells in crypts, separated from them by a layer of extracellular matrix less than a 1 μm in thickness (Extended Data Fig. 1a, b ). To investigate the heterogeneity of intestinal mesenchymal cells and identify specific pathways that could control stem-cell dynamics, we performed single-cell RNA-sequencing (RNA-seq) analysis in the mouse intestinal mesenchyme. By sequencing 3,179 non-epithelial, non-immune cells we identified all major mesenchymal cell types of the lamina propria, including vascular and lymphatic endothelial cells, pericytes, smooth muscle cells and glial cells (Fig. 1a ). Our analyses also revealed the existence of four different fibroblast populations—which we designate F1 to F4—all characterized by expression of Pdgfra (Fig. 1b ); F1 and F2 cells are Pdgfra low , whereas F3 and F4 cells are Pdgfra high (Fig. 1b ). A similar division of fibroblasts into PDGFRA high and low populations was found in a single-cell dataset 3 of the human colonic mesenchyme (Extended Data Fig. 1h ). Confocal and two-photon imaging in Pdgfra eGFP/+ -knockin mice 4 confirmed the presence of Pdgfra high and Pdgfra low fibroblasts and revealed a distinct localization of these two populations in the adult intestine (Extended Data Fig. 2a, b ). A dichotomous and compartmentalized expression of Pdgfra was observed in the intestinal mesenchyme throughout postnatal development and on embryonic day 15, when Pdgfra high cells are associated with early villus formation, whereas Pdgfra low cells occupy the rest of the mesenchyme (Extended Data Fig. 2c ). Among Pdgfra low cells, F1 fibroblasts comprise two subsets (F1a and F1b), both marked by expression of Cd34 and Has1 (Fig. 1b ). Population F2 expresses Cd34 and Fgfr2 and comprises four subsets (F2a–F2d) occupying diverse niches in the intestine, as shown in Fgfr2 mCherry -knockin mice 5 (Fig. 1b , Extended Data Fig. 2d ). Among Pdgfra high cells, F3 cells express the Cajal-cell marker Ano2 whereas F4 cells express Acta2 , consistent with a myofibroblast phenotype (Fig. 1b ). To understand the potential functions of these uncharacterized populations we performed pathway analyses. We observed a robust enrichment of arachidonic acid metabolism genes in F3 (Cajal) cells and in the small population of F2d fibroblasts (Extended Data Fig. 1g , Supplementary Table 1 ), a pathway strongly associated with colorectal cancer 6 . Arachidonic acid is processed by cyclooxygenases to prostanoids, highly bioactive lipid mediators with a very short half-life and an autocrine or paracrine function in tissues 6 . In humans, pharmacological inhibition of cyclooxygenase-2 (Cox-2, also known as Ptgs2) prevents both hereditary and sporadic forms of colorectal cancer through an unknown cellular mechanism, but adverse cardiovascular effects currently impede its clinical application 7 . By fractionating normal human colonic tissues we found that expression of the Cox-2-encoding gene PTGS2 is nearly undetectable in the epithelium but occurs predominantly in stromal cells; the same pattern as observed in the mouse intestine (Extended Data Fig. 1c, d ). Our single-cell analyses showed that in the steady-state, mouse intestine Ptgs2 is predominantly expressed in F3 (Cajal) cells and in the Pdgfra low Fgfr2 + Vcam1 high F2d fibroblasts (cluster 13) (Fig. 1c , Extended Data Fig. 1f ). In humans, PTGS2 is mainly expressed in PDGFRA low FGFR2 + VCAM1 + fibroblasts (cluster 8) and, to a lesser extent, in other fibroblast populations (Extended Data Fig. 1h ). Immunostaining of Cox-2 protein in the mouse intestine verified the presence of a Cox-2-expressing fibroblast population in the muscular layer, a location consistent with that of Cajal cells, and a second rare Cox-2-expressing fibroblast population located around part of the crypts, in close proximity to the stem-cell zone, suggestive of the F2d fibroblast cluster (Fig. 1d ). We named these cells rare pericryptal Ptgs2-expressing fibroblasts (RPPFs). In agreement with their pericryptal location, RPPFs are marked by expression of the laminin subunit A1 (encoded by Lama1 ), a basement membrane protein detected specifically at the mesenchymal–epithelial interface, and also by expression of R-spondin 1 (encoded by Rspo1 ), a stem-cell niche factor detected mainly at the crypt base (Fig. 1b , Extended Data Fig.", "role": "user" }, { "content": "Colorectal cancer kills more than 50,000 people a year in the United States alone, but scientists have struggled to find the exact mechanisms that trigger the growth of tumors in the intestine. Cancer researchers have zeroed in on a tightly sequestered group of stem cells within the intestine as suspects in the development of colon cancer but have been unable to explain exactly how genetic mutations within those stem cells can cause tumors of the digestive track. Now scientists at Yale and collaborators in Greece have found that some unprepossessing neighbors of those stem cells actually harbor a molecular villain that can jump-start cancers of the colon, they report in the journal Nature. The tightly packed group of stem cells within the intestine are surrounded by fibroblasts, which help form connective tissue and are one of the most common cell types in the body. Yale's Manolis Roulis, associate research scientist in the lab of Richard Flavell, Sterling Professor of Immunobiology, found that a rare form of fibroblast expressing Cox-2 enzymes directs communication with intestinal stem cells. When they blocked signals from this fibroblast to intestinal stem cells in mice with colorectal cancer, tumors were reduced by 50%, they report. Intriguingly, the authors said, this same communication is also blocked by aspirin and other anti-inflammatory drugs, which have previously been shown to have a protective effect against development of colorectal cancers. \"We also found that blocking this same cellular communication has a dramatic effect on the interactions of fibroblasts and stem cells in human systems we studied in the lab,\" Roulis said. Roulis said the findings could help researchers develop new specific drugs to prevent colon cancer in those at risk without the side effects of aspirin and other inhibitors of this pathway currently used as anti-inflammatory drugs. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 initiation of an intestinal tumour is a probabilistic process that depends on the competition between mutant and normal epithelial stem cells in crypts 1 . Intestinal stem cells are closely associated with a diverse but poorly characterized network of mesenchymal cell types 2 , 3 . However, whether the physiological mesenchymal microenvironment of mutant stem cells affects tumour initiation remains unknown. Here we provide in vivo evidence that the mesenchymal niche controls tumour initiation in trans . By characterizing the heterogeneity of the intestinal mesenchyme using single-cell RNA-sequencing analysis, we identified a population of rare pericryptal Ptgs2 -expressing fibroblasts that constitutively process arachidonic acid into highly labile prostaglandin E 2 (PGE 2 ). Specific ablation of Ptgs2 in fibroblasts was sufficient to prevent tumour initiation in two different models of sporadic, autochthonous tumorigenesis. Mechanistically, single-cell RNA-sequencing analyses of a mesenchymal niche model showed that fibroblast-derived PGE 2 drives the expansion οf a population of Sca-1 + reserve-like stem cells. These express a strong regenerative/tumorigenic program, driven by the Hippo pathway effector Yap. In vivo, Yap is indispensable for Sca-1 + cell expansion and early tumour initiation and displays a nuclear localization in both mouse and human adenomas. Using organoid experiments, we identified a molecular mechanism whereby PGE 2 promotes Yap dephosphorylation, nuclear translocation and transcriptional activity by signalling through the receptor Ptger4. Epithelial-specific ablation of Ptger4 misdirected the regenerative reprogramming of stem cells and prevented Sca-1 + cell expansion and sporadic tumour initiation in mutant mice, thereby demonstrating the robust paracrine control of tumour-initiating stem cells by PGE 2 –Ptger4. Analyses of patient-derived organoids established that PGE 2 –PTGER4 also regulates stem-cell function in humans. Our study demonstrates that initiation of colorectal cancer is orchestrated by the mesenchymal niche and reveals a mechanism by which rare pericryptal Ptgs2 -expressing fibroblasts exert paracrine control over tumour-initiating stem cells via the druggable PGE 2 –Ptger4–Yap signalling axis. Main Mesenchymal cells are localized in tight association with stem cells in crypts, separated from them by a layer of extracellular matrix less than a 1 μm in thickness (Extended Data Fig. 1a, b ). To investigate the heterogeneity of intestinal mesenchymal cells and identify specific pathways that could control stem-cell dynamics, we performed single-cell RNA-sequencing (RNA-seq) analysis in the mouse intestinal mesenchyme. By sequencing 3,179 non-epithelial, non-immune cells we identified all major mesenchymal cell types of the lamina propria, including vascular and lymphatic endothelial cells, pericytes, smooth muscle cells and glial cells (Fig. 1a ). Our analyses also revealed the existence of four different fibroblast populations—which we designate F1 to F4—all characterized by expression of Pdgfra (Fig. 1b ); F1 and F2 cells are Pdgfra low , whereas F3 and F4 cells are Pdgfra high (Fig. 1b ). A similar division of fibroblasts into PDGFRA high and low populations was found in a single-cell dataset 3 of the human colonic mesenchyme (Extended Data Fig. 1h ). Confocal and two-photon imaging in Pdgfra eGFP/+ -knockin mice 4 confirmed the presence of Pdgfra high and Pdgfra low fibroblasts and revealed a distinct localization of these two populations in the adult intestine (Extended Data Fig. 2a, b ). A dichotomous and compartmentalized expression of Pdgfra was observed in the intestinal mesenchyme throughout postnatal development and on embryonic day 15, when Pdgfra high cells are associated with early villus formation, whereas Pdgfra low cells occupy the rest of the mesenchyme (Extended Data Fig. 2c ). Among Pdgfra low cells, F1 fibroblasts comprise two subsets (F1a and F1b), both marked by expression of Cd34 and Has1 (Fig. 1b ). Population F2 expresses Cd34 and Fgfr2 and comprises four subsets (F2a–F2d) occupying diverse niches in the intestine, as shown in Fgfr2 mCherry -knockin mice 5 (Fig. 1b , Extended Data Fig. 2d ). Among Pdgfra high cells, F3 cells express the Cajal-cell marker Ano2 whereas F4 cells express Acta2 , consistent with a myofibroblast phenotype (Fig. 1b ). To understand the potential functions of these uncharacterized populations we performed pathway analyses. We observed a robust enrichment of arachidonic acid metabolism genes in F3 (Cajal) cells and in the small population of F2d fibroblasts (Extended Data Fig. 1g , Supplementary Table 1 ), a pathway strongly associated with colorectal cancer 6 . Arachidonic acid is processed by cyclooxygenases to prostanoids, highly bioactive lipid mediators with a very short half-life and an autocrine or paracrine function in tissues 6 . In humans, pharmacological inhibition of cyclooxygenase-2 (Cox-2, also known as Ptgs2) prevents both hereditary and sporadic forms of colorectal cancer through an unknown cellular mechanism, but adverse cardiovascular effects currently impede its clinical application 7 . By fractionating normal human colonic tissues we found that expression of the Cox-2-encoding gene PTGS2 is nearly undetectable in the epithelium but occurs predominantly in stromal cells; the same pattern as observed in the mouse intestine (Extended Data Fig. 1c, d ). Our single-cell analyses showed that in the steady-state, mouse intestine Ptgs2 is predominantly expressed in F3 (Cajal) cells and in the Pdgfra low Fgfr2 + Vcam1 high F2d fibroblasts (cluster 13) (Fig. 1c , Extended Data Fig. 1f ). In humans, PTGS2 is mainly expressed in PDGFRA low FGFR2 + VCAM1 + fibroblasts (cluster 8) and, to a lesser extent, in other fibroblast populations (Extended Data Fig. 1h ). Immunostaining of Cox-2 protein in the mouse intestine verified the presence of a Cox-2-expressing fibroblast population in the muscular layer, a location consistent with that of Cajal cells, and a second rare Cox-2-expressing fibroblast population located around part of the crypts, in close proximity to the stem-cell zone, suggestive of the F2d fibroblast cluster (Fig. 1d ). We named these cells rare pericryptal Ptgs2-expressing fibroblasts (RPPFs). In agreement with their pericryptal location, RPPFs are marked by expression of the laminin subunit A1 (encoded by Lama1 ), a basement membrane protein detected specifically at the mesenchymal–epithelial interface, and also by expression of R-spondin 1 (encoded by Rspo1 ), a stem-cell niche factor detected mainly at the crypt base (Fig. 1b , Extended Data Fig.<|im_end|> <|im_start|>assistant Colorectal cancer kills more than 50,000 people a year in the United States alone, but scientists have struggled to find the exact mechanisms that trigger the growth of tumors in the intestine. Cancer researchers have zeroed in on a tightly sequestered group of stem cells within the intestine as suspects in the development of colon cancer but have been unable to explain exactly how genetic mutations within those stem cells can cause tumors of the digestive track. Now scientists at Yale and collaborators in Greece have found that some unprepossessing neighbors of those stem cells actually harbor a molecular villain that can jump-start cancers of the colon, they report in the journal Nature. The tightly packed group of stem cells within the intestine are surrounded by fibroblasts, which help form connective tissue and are one of the most common cell types in the body. Yale's Manolis Roulis, associate research scientist in the lab of Richard Flavell, Sterling Professor of Immunobiology, found that a rare form of fibroblast expressing Cox-2 enzymes directs communication with intestinal stem cells. When they blocked signals from this fibroblast to intestinal stem cells in mice with colorectal cancer, tumors were reduced by 50%, they report. Intriguingly, the authors said, this same communication is also blocked by aspirin and other anti-inflammatory drugs, which have previously been shown to have a protective effect against development of colorectal cancers. "We also found that blocking this same cellular communication has a dramatic effect on the interactions of fibroblasts and stem cells in human systems we studied in the lab," Roulis said. Roulis said the findings could help researchers develop new specific drugs to prevent colon cancer in those at risk without the side effects of aspirin and other inhibitors of this pathway currently used as anti-inflammatory drugs. <|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 Intensive fisheries have reduced fish biodiversity and abundance in aquatic ecosystems worldwide 1 , 2 , 3 . ‘No-take’ marine reserves have become a cornerstone of marine ecosystem-based fisheries management 4 , 5 , 6 , and their benefits for adjacent fisheries are maximized when reserve design fosters synergies among nearby reserves 7 , 8 . The applicability of this marine reserve network paradigm to riverine biodiversity and inland fisheries remains largely untested. Here we show that reserves created by 23 separate communities in Thailand’s Salween basin have markedly increased fish richness, density, and biomass relative to adjacent areas. Moreover, key correlates of the success of protected areas in marine ecosystems—particularly reserve size and enforcement—predict differences in ecological benefits among riverine reserves. Occupying a central position in the network confers additional gains, underscoring the importance of connectivity within dendritic river systems. The emergence of network-based benefits is remarkable given that these reserves are young (less than 25 years old) and arose without formal coordination. Freshwater ecosystems are under-represented among the world’s protected areas 9 , and our findings suggest that networks of small, community-based reserves offer a generalizable model for protecting biodiversity and augmenting fisheries as the world’s rivers face unprecedented pressures 10 , 11 . Main Overharvesting of fisheries threatens thousands of species and the food and nutrition security of hundreds of millions of people around the world 12 , 13 , 14 . Over the past several decades, no-take marine reserves have become central management tools for conserving marine ecosystems and sustaining local fisheries 5 , 7 . The widespread success of marine reserves in enhancing the abundance, size, and biomass of fishes 4 has guided the distillation of design principles that maximize both conservation efficacy within reserves 8 , 15 and the export of harvestable biomass across their boundaries 7 , 16 , 17 . The success of individual marine reserves in providing ecological benefits varies widely 18 , but typically increases with vigorous enforcement, complete bans on harvest, time since establishment, large size, and high degree of isolation 8 , 15 . As catchable fish disperse across reserve borders, they can augment nearby fisheries and local livelihoods, thereby providing an incentive to respect reserve boundaries 16 . Furthermore, gains in diversity and biomass within a reserve can be amplified by exchange among nearby reserves 7 , 16 , which has motivated the expansion of reserve networks worldwide. To date, the reserve network paradigm remains untested for halting high rates of biodiversity loss 11 and bolstering human food supplies from the world’s freshwater ecosystems. Despite holding roughly half of all fish species and providing accessible sources of animal protein and critical micronutrients to many poor and undernourished populations 12 , 13 , 14 , freshwater ecosystems are not well represented by existing protected areas 9 . Indeed, formal protection of rivers and lakes has been largely limited to their incidental inclusion within terrestrial reserves 19 , 20 . Although terrestrial reserves can provide watershed-level benefits, they often inadequately represent freshwater biodiversity 21 and rarely address overfishing 3 . By contrast, recent marine reserve paradigms have explicitly aimed to balance protection of biodiversity inside reserve boundaries with sustainable harvests beyond them 7 . Although the effectiveness of reserves as a large-scale management strategy continues to be debated 18 , 22 , there is widespread evidence that small, community-based reserves can improve the sustainability of coastal fisheries 23 , particularly for nations with limited fisheries management capacity 24 . Such an approach offers great potential to address human and ecosystem needs in low-income countries where biodiverse rivers contribute disproportionately to inland fisheries 12 , 13 , frequently suffer from overharvesting 3 , and defy efforts to apply traditional fisheries management strategies 12 . Southeast Asia is the only region of the world where riverine reserves are commonplace; hundreds of communities have designated no-fishing zones that together form de facto reserve networks in rivers throughout the region 25 , 26 . Here, we use one such network of small, community-based reserves located within the Salween River basin in northern Thailand (Fig. 1 ) to test how fish communities respond to protection. We studied 23 reserves that, despite a common cultural context (see Supplementary Information ), represent gradients in age, size, enforcement, isolation, and network connectivity. Each of these factors contributes to the success of marine reserves 7 , 8 , 17 , so we tested their influence on the responses of fish species richness, density, and biomass to protection from fishing in rivers. These reserves are surrounded by reaches in which intensive harvests discriminate little among fish species, sizes, or trophic positions 27 , providing a strong test of the overall effectiveness of community-based reserves as well as the design principles that can maximize their ecological benefits. Fig. 1: Riverine reserve network within the Mae Ngao basin. Network of 52 community-based reserves documented in 2018 within the 1,000-km 2 Mae Ngao River, a tributary of the Salween River in northern Thailand (inset). Reserves are depicted by circles scaled according to reserve length. Purple denotes the 23 reserves where fish communities were profiled for this study, which represent a stratified subset of all known reserves. River basin and stream delineation are detailed in the Methods. Full size image Despite their small size, grassroots reserves enhanced the species richness, density, and biomass of protected fish communities enormously (Fig. 2 ). Relative to adjacent fished areas with comparable water depth and substrate composition (see Methods ), reserves held an average of 27% more fish species (95% confidence interval (CI), 9–47%), 124% higher fish density (118–130%), and 2,247% higher biomass (1,460–3,433%). Whereas richness and density responses at our study sites were similar to those reported for marine reserves, mean biomass differences were six times higher than those typically observed in marine protected areas 4 . These large biomass responses reflect defaunation of the majority of the river by fishers, which creates such stark disparities that unmarked reserve boundaries can be readily discerned by", "role": "user" }, { "content": "Freshwater fish reserves are extraordinarily successful at protecting multiple species of fish, a new study of a network of community-based reserves in Thailand has found. Aaron Koning, a postdoctoral research fellow at the University of Nevada, Reno's Global Water Center, spent seven years studying a network of freshwater protected areas (fish reserves) that communities established in one branch of the Salween River Basin in northern Thailand. He mapped more than 50 reserves, all community organized and managed independently of government support, throughout the river and its branches. The area supports more than 40 species of fish, ranging from large minnows to catfish to needlefish. The results are published today in the scientific journal Nature in the article \"A network of grassroots reserves protects tropical river fish diversity.\" \"The conservation benefits of each reserve established independently by local Pgagayaw, or Karen, indigenous communities are remarkable, and the collective benefits for fish within the entire network of reserves are even greater,\" Koning said. \"Twenty-seven years ago, one community created a reserve in an effort to protect their fish, and since then reserves have spread among communities throughout the valley. It's a great story of effective community-based resource management.\" Koning worked with a team of scientists who he had known from his work at the University of Wisconsin-Madison: Martin Perales from the University of Wisconsin-Madison; Etienne Fluet-Chouinard, now from Stanford University, and aquatic conservation ecologist and Associate Professor Peter McIntyre of Cornell University. \"During six weeks of fieldwork related to this study, Martin and I lived with friends in riverside villages, but made the 90 minute drive to Mae Sarieng for internet access on a couple of weekends.\" They bounced around the study area of the 50-mile-long Mae Ngao River in a 1999 Toyota Hilux 4X4 truck, through the various regions and communities, including teak forests and upland agricultural areas with rice paddies and soybean crops. \"When I initially started documenting the locations of reserves several years ago, I tried to find the locations of as many reserves within the basin as I could by exploring every road and trail on the map, and many that weren't on any map,\" he said. \"For our fish surveys, we selected a set of 23 reserves distributed throughout the river basin that broadly represented all of the reserves. While there are probably 40 species within this river valley, in this study we regularly observed 33 species of fish.\" Fieldwork in communities often results in curious onlookers, presenting a great opportunity for inclusion and awareness raising. Here two regular observers help Aaron Koning release a radio-tagged mahseer as part of his research on fish movement in Mae Ngao, Mae Hong Son, Thailand. His new study describes the successful use of freshwater fish reserves. Credit: University of Nevada, Reno. Intensive fisheries have reduced fish biodiversity and abundance in aquatic ecosystems worldwide. No-take reserves have become a cornerstone of marine ecosystem-based fisheries management. The team used the knowledge gained from decades of study on marine reserves to test if the same principles of success might apply to this network of riverine reserves, where one might not think reserves would work. \"The applicability of this marine reserve network paradigm to riverine biodiversity and inland fisheries remains largely untested,\" Koning said. \"Our research shows that freshwater reserves created by 23 separate communities in Thailand's Salween basin have dramatically increased fish richness, density and biomass when compared to adjacent areas. One river reserve is 1,000 feet long and just 12 feet wide in dry season, but you can see fish everywhere.\" Underwater fish surveys were done using masks and snorkels with lots of crawling over and around rocks underwater. In many reserves, the abundance and size of fish seeking protection was evident by eye from the river bank in the dry season. McIntyre, now Koning's colleague in this research, was once his doctoral advisor at the University of Wisconsin, and co-advisor for his postdoctoral work at Cornell. McIntyre said he was shocked that the reserves worked so well. \"When you see piles of fish in each of these reserves, it is clear that something big is happening,\" he said. \"Questions remain about whether the fish populations are viable in the long run, and how durable the governance approach will prove, but this unique experiment in conservation still has much to teach us.\" Despite their small size, grassroots reserves enhanced the species richness, density and biomass of protected fish communities enormously. Relative to adjacent fished areas with comparable water depth and substrate composition, reserves held 27% more fish species; 124% higher fish density and an astounding 2,247% higher biomass on average. \"Our results demonstrate that small reserves have great benefits for intensively harvested fishes in this tropical river, even though their collective area encompasses only 2% of the channel in our study catchment,\" Koning said. \"The area of individual reserves ranged from just a half acre up to six acres.\" \"One of the most important findings is that the network of reserves adds benefits beyond those arising from any single reserve,\" McIntyre said. \"Another key lesson is that communities have the power to protect the resource themselves, in a way that doesn't prevent them from using it intensively outside of the reserve boundary.\" This study demonstrates that fish reserves can work well in subsistence fisheries targeting rivers, thereby offering a model for protecting fish biodiversity and offsetting overfishing in rivers worldwide. The study is especially timely given that overharvest of fisheries threatens thousands of species and the food security of hundreds of millions of people around the world. \"Freshwaters are under-represented among the world's protected areas, and our findings suggest that networks of small, community-based reserves offer a generalizable model for protecting biodiversity and augmenting fisheries as the world's rivers face unprecedented pressures,\" Koning said. In Southeast Asia, riverine reserves are commonplace; hundreds of communities have designated no-fishing zones that together form de facto reserve networks in rivers throughout the region. The idea has the potential to be a big step forward in terms of freshwater biodiversity protection, not just in Thailand but worldwide. These results and the model could be applied in freshwater ecosystems worldwide—including highly diverse and highly threatened tropical rivers such as the Amazon, Congo and Mekong Rivers. McIntyre echoed Koning's take on the potential for worldwide implementation. \"Aaron's findings offer a great model for other parts of the world, \"he said. \"The role of cultural traditions and governance structure can't be overstated, so we do not expect simplistic transferability. However, many of the principles identified could be applicable to subsistence fisheries elsewhere.\" Koning is currently a postdoctoral researcher working with Zeb Hogan and based at the University of Nevada, Reno's Global Water Center in the College of Science. Koning and Hogan, an aquatic conservation ecologist, along with Sudeep Chandra, the Director of the Global Water Center at the University of Nevada, Reno will be replicating the Thailand study on Cambodian rivers as part of their Wonders of the Mekong project, a comprehensive approach to fish conservation, economics and cultural values. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Intensive fisheries have reduced fish biodiversity and abundance in aquatic ecosystems worldwide 1 , 2 , 3 . ‘No-take’ marine reserves have become a cornerstone of marine ecosystem-based fisheries management 4 , 5 , 6 , and their benefits for adjacent fisheries are maximized when reserve design fosters synergies among nearby reserves 7 , 8 . The applicability of this marine reserve network paradigm to riverine biodiversity and inland fisheries remains largely untested. Here we show that reserves created by 23 separate communities in Thailand’s Salween basin have markedly increased fish richness, density, and biomass relative to adjacent areas. Moreover, key correlates of the success of protected areas in marine ecosystems—particularly reserve size and enforcement—predict differences in ecological benefits among riverine reserves. Occupying a central position in the network confers additional gains, underscoring the importance of connectivity within dendritic river systems. The emergence of network-based benefits is remarkable given that these reserves are young (less than 25 years old) and arose without formal coordination. Freshwater ecosystems are under-represented among the world’s protected areas 9 , and our findings suggest that networks of small, community-based reserves offer a generalizable model for protecting biodiversity and augmenting fisheries as the world’s rivers face unprecedented pressures 10 , 11 . Main Overharvesting of fisheries threatens thousands of species and the food and nutrition security of hundreds of millions of people around the world 12 , 13 , 14 . Over the past several decades, no-take marine reserves have become central management tools for conserving marine ecosystems and sustaining local fisheries 5 , 7 . The widespread success of marine reserves in enhancing the abundance, size, and biomass of fishes 4 has guided the distillation of design principles that maximize both conservation efficacy within reserves 8 , 15 and the export of harvestable biomass across their boundaries 7 , 16 , 17 . The success of individual marine reserves in providing ecological benefits varies widely 18 , but typically increases with vigorous enforcement, complete bans on harvest, time since establishment, large size, and high degree of isolation 8 , 15 . As catchable fish disperse across reserve borders, they can augment nearby fisheries and local livelihoods, thereby providing an incentive to respect reserve boundaries 16 . Furthermore, gains in diversity and biomass within a reserve can be amplified by exchange among nearby reserves 7 , 16 , which has motivated the expansion of reserve networks worldwide. To date, the reserve network paradigm remains untested for halting high rates of biodiversity loss 11 and bolstering human food supplies from the world’s freshwater ecosystems. Despite holding roughly half of all fish species and providing accessible sources of animal protein and critical micronutrients to many poor and undernourished populations 12 , 13 , 14 , freshwater ecosystems are not well represented by existing protected areas 9 . Indeed, formal protection of rivers and lakes has been largely limited to their incidental inclusion within terrestrial reserves 19 , 20 . Although terrestrial reserves can provide watershed-level benefits, they often inadequately represent freshwater biodiversity 21 and rarely address overfishing 3 . By contrast, recent marine reserve paradigms have explicitly aimed to balance protection of biodiversity inside reserve boundaries with sustainable harvests beyond them 7 . Although the effectiveness of reserves as a large-scale management strategy continues to be debated 18 , 22 , there is widespread evidence that small, community-based reserves can improve the sustainability of coastal fisheries 23 , particularly for nations with limited fisheries management capacity 24 . Such an approach offers great potential to address human and ecosystem needs in low-income countries where biodiverse rivers contribute disproportionately to inland fisheries 12 , 13 , frequently suffer from overharvesting 3 , and defy efforts to apply traditional fisheries management strategies 12 . Southeast Asia is the only region of the world where riverine reserves are commonplace; hundreds of communities have designated no-fishing zones that together form de facto reserve networks in rivers throughout the region 25 , 26 . Here, we use one such network of small, community-based reserves located within the Salween River basin in northern Thailand (Fig. 1 ) to test how fish communities respond to protection. We studied 23 reserves that, despite a common cultural context (see Supplementary Information ), represent gradients in age, size, enforcement, isolation, and network connectivity. Each of these factors contributes to the success of marine reserves 7 , 8 , 17 , so we tested their influence on the responses of fish species richness, density, and biomass to protection from fishing in rivers. These reserves are surrounded by reaches in which intensive harvests discriminate little among fish species, sizes, or trophic positions 27 , providing a strong test of the overall effectiveness of community-based reserves as well as the design principles that can maximize their ecological benefits. Fig. 1: Riverine reserve network within the Mae Ngao basin. Network of 52 community-based reserves documented in 2018 within the 1,000-km 2 Mae Ngao River, a tributary of the Salween River in northern Thailand (inset). Reserves are depicted by circles scaled according to reserve length. Purple denotes the 23 reserves where fish communities were profiled for this study, which represent a stratified subset of all known reserves. River basin and stream delineation are detailed in the Methods. Full size image Despite their small size, grassroots reserves enhanced the species richness, density, and biomass of protected fish communities enormously (Fig. 2 ). Relative to adjacent fished areas with comparable water depth and substrate composition (see Methods ), reserves held an average of 27% more fish species (95% confidence interval (CI), 9–47%), 124% higher fish density (118–130%), and 2,247% higher biomass (1,460–3,433%). Whereas richness and density responses at our study sites were similar to those reported for marine reserves, mean biomass differences were six times higher than those typically observed in marine protected areas 4 . These large biomass responses reflect defaunation of the majority of the river by fishers, which creates such stark disparities that unmarked reserve boundaries can be readily discerned by<|im_end|> <|im_start|>assistant Freshwater fish reserves are extraordinarily successful at protecting multiple species of fish, a new study of a network of community-based reserves in Thailand has found. Aaron Koning, a postdoctoral research fellow at the University of Nevada, Reno's Global Water Center, spent seven years studying a network of freshwater protected areas (fish reserves) that communities established in one branch of the Salween River Basin in northern Thailand. He mapped more than 50 reserves, all community organized and managed independently of government support, throughout the river and its branches. The area supports more than 40 species of fish, ranging from large minnows to catfish to needlefish. The results are published today in the scientific journal Nature in the article "A network of grassroots reserves protects tropical river fish diversity." "The conservation benefits of each reserve established independently by local Pgagayaw, or Karen, indigenous communities are remarkable, and the collective benefits for fish within the entire network of reserves are even greater," Koning said. "Twenty-seven years ago, one community created a reserve in an effort to protect their fish, and since then reserves have spread among communities throughout the valley. It's a great story of effective community-based resource management." Koning worked with a team of scientists who he had known from his work at the University of Wisconsin-Madison: Martin Perales from the University of Wisconsin-Madison; Etienne Fluet-Chouinard, now from Stanford University, and aquatic conservation ecologist and Associate Professor Peter McIntyre of Cornell University. "During six weeks of fieldwork related to this study, Martin and I lived with friends in riverside villages, but made the 90 minute drive to Mae Sarieng for internet access on a couple of weekends." They bounced around the study area of the 50-mile-long Mae Ngao River in a 1999 Toyota Hilux 4X4 truck, through the various regions and communities, including teak forests and upland agricultural areas with rice paddies and soybean crops. "When I initially started documenting the locations of reserves several years ago, I tried to find the locations of as many reserves within the basin as I could by exploring every road and trail on the map, and many that weren't on any map," he said. "For our fish surveys, we selected a set of 23 reserves distributed throughout the river basin that broadly represented all of the reserves. While there are probably 40 species within this river valley, in this study we regularly observed 33 species of fish." Fieldwork in communities often results in curious onlookers, presenting a great opportunity for inclusion and awareness raising. Here two regular observers help Aaron Koning release a radio-tagged mahseer as part of his research on fish movement in Mae Ngao, Mae Hong Son, Thailand. His new study describes the successful use of freshwater fish reserves. Credit: University of Nevada, Reno. Intensive fisheries have reduced fish biodiversity and abundance in aquatic ecosystems worldwide. No-take reserves have become a cornerstone of marine ecosystem-based fisheries management. The team used the knowledge gained from decades of study on marine reserves to test if the same principles of success might apply to this network of riverine reserves, where one might not think reserves would work. "The applicability of this marine reserve network paradigm to riverine biodiversity and inland fisheries remains largely untested," Koning said. "Our research shows that freshwater reserves created by 23 separate communities in Thailand's Salween basin have dramatically increased fish richness, density and biomass when compared to adjacent areas. One river reserve is 1,000 feet long and just 12 feet wide in dry season, but you can see fish everywhere." Underwater fish surveys were done using masks and snorkels with lots of crawling over and around rocks underwater. In many reserves, the abundance and size of fish seeking protection was evident by eye from the river bank in the dry season. McIntyre, now Koning's colleague in this research, was once his doctoral advisor at the University of Wisconsin, and co-advisor for his postdoctoral work at Cornell. McIntyre said he was shocked that the reserves worked so well. "When you see piles of fish in each of these reserves, it is clear that something big is happening," he said. "Questions remain about whether the fish populations are viable in the long run, and how durable the governance approach will prove, but this unique experiment in conservation still has much to teach us." Despite their small size, grassroots reserves enhanced the species richness, density and biomass of protected fish communities enormously. Relative to adjacent fished areas with comparable water depth and substrate composition, reserves held 27% more fish species; 124% higher fish density and an astounding 2,247% higher biomass on average. "Our results demonstrate that small reserves have great benefits for intensively harvested fishes in this tropical river, even though their collective area encompasses only 2% of the channel in our study catchment," Koning said. "The area of individual reserves ranged from just a half acre up to six acres." "One of the most important findings is that the network of reserves adds benefits beyond those arising from any single reserve," McIntyre said. "Another key lesson is that communities have the power to protect the resource themselves, in a way that doesn't prevent them from using it intensively outside of the reserve boundary." This study demonstrates that fish reserves can work well in subsistence fisheries targeting rivers, thereby offering a model for protecting fish biodiversity and offsetting overfishing in rivers worldwide. The study is especially timely given that overharvest of fisheries threatens thousands of species and the food security of hundreds of millions of people around the world. "Freshwaters are under-represented among the world's protected areas, and our findings suggest that networks of small, community-based reserves offer a generalizable model for protecting biodiversity and augmenting fisheries as the world's rivers face unprecedented pressures," Koning said. In Southeast Asia, riverine reserves are commonplace; hundreds of communities have designated no-fishing zones that together form de facto reserve networks in rivers throughout the region. The idea has the potential to be a big step forward in terms of freshwater biodiversity protection, not just in Thailand but worldwide. These results and the model could be applied in freshwater ecosystems worldwide—including highly diverse and highly threatened tropical rivers such as the Amazon, Congo and Mekong Rivers. McIntyre echoed Koning's take on the potential for worldwide implementation. "Aaron's findings offer a great model for other parts of the world, "he said. "The role of cultural traditions and governance structure can't be overstated, so we do not expect simplistic transferability. However, many of the principles identified could be applicable to subsistence fisheries elsewhere." Koning is currently a postdoctoral researcher working with Zeb Hogan and based at the University of Nevada, Reno's Global Water Center in the College of Science. Koning and Hogan, an aquatic conservation ecologist, along with Sudeep Chandra, the Director of the Global Water Center at the University of Nevada, Reno will be replicating the Thailand study on Cambodian rivers as part of their Wonders of the Mekong project, a comprehensive approach to fish conservation, economics and cultural values. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Objectives Determine the effect of the catheter to vein ratio (CVR) on rates of symptomatic thrombosis in individuals with a peripherally inserted central catheter (PICC) and identify the optimal CVR cut-off point according to diagnostic group. Design Retrospective cohort study. Setting 4 tertiary hospitals in Australia and New Zealand. Participants Adults who had undergone PICC insertion. Primary outcome measure Symptomatic thrombus of the limb in which the PICC was inserted. Results 2438 PICC insertions were included with 39 cases of thrombosis (1.6%; 95% CI 1.14% to 2.19%). Receiver operator characteristic analysis was unable to be performed to determine the optimal CVR overall or according to diagnosis. The association between risk of thrombosis and CVR cut-offs commonly used in clinical practice were analysed. A 45% cut-off (≤45% versus ≥46%) was predictive of thrombosis, with those with a higher ratio having more than twice the risk (relative risk 2.30; 95% CI 1.202 to 4.383; p=0.01). This pattern continued when only those with malignancy were included in the analysis, those with cancer had twice the risk of thrombosis with a CVR greater than 45%. Whereas the 33% CVR cut-off was not associated with statistically significant results overall or in those with malignancy. Neither the 33% or 45% CVR cut-off produced statistically significant results in those with infection or other non-malignant conditions. Conclusions Adherence to CVR cut-offs are an important component of PICC insertion clinical decision making to reduce the risk of thrombosis. These results suggest that in individuals with cancer, the use of a CVR ≤45% should be considered to minimise risk of thrombosis. Further research is needed to determine the risk of thrombosis according to malignancy type and the optimal CVR for those with a non-malignant diagnosis. radiology & imaging interventional radiology adult oncology Data availability statement Data are available on reasonable request from the corresponding author. 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 10 news outlets Blogged by 1 Tweeted by 16 51 readers on Mendeley 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 radiology & imaging interventional radiology adult oncology Strengths and limitations of this study Large, multisite study with 2438 peripherally inserted central catheters (PICCs). First study to analyse risk of thrombosis associated with the 33% and 45% catheter to vein ratio (CVR) cut-off recommendations commonly used in clinical practice for PICC insertion. Analysed risk of thrombosis associated with CVRs according to diagnostic group. Unable to perform planned analysis (receiver operator characteristic analysis) to determine the optimal CVR to prevent thrombosis in individuals with a PICC. The use of a tapered PICC impacted the accuracy of the PICC diameter and hence CVR for those participants that had the tapered portion inserted. Introduction Peripherally inserted central catheter (PICC)-associated thrombosis is often uncomfortable, may result in loss of intravenous access for treatment and damage to the vasculature limiting further PICC insertions. In some cases, PICC associated thrombosis precipitates pulmonary embolism and post-thrombotic syndrome. 1 2 Approximately 2% of individuals receiving antimicrobials as part of outpatient parenteral therapy develop thrombosis. 3 4 While those receiving cancer treatment suffer much higher rates, with 4%–6% of consumers with a haematological malignancy and 2%–5% of those with a solid tumour developing PICC associated thrombosis. 3 5–7 This adverse event can be explained using mechanisms related to Virchow’s triad (stasis, endothelial damage and hypercoagulable state of the patient). PICCs may have a large impact on the interruption of blood flow (stasis). In a mechanical model, Nifong and McDevitt 8 demonstrated that blood flow was dependant on the size of the catheter and cylinder (or vein) size and PICCs commonly used in clinical practice may impede blood flow up to 80%. 8 PICC insertion decisions such as the use of an appropriate catheter to vein ratio (CVR) affect PICC-associated thrombosis rates. 3 Contemporary insertion approaches include measurement of the target vein diameter using ultrasound and limiting the CVR to reduce the risk of thrombosis. 9 Different CVR cut-offs are used in clinical practice, many sites use a 33% CVR limit, that is only one-third of the vein should be occupied by the catheter. 7 10–13 Other sites use a 45% CVR limit as advocated by the Infusion Therapy Standards of Practice (Infusion Nurses Society 2021). 14 However, there is a lack of research investigating safe CVRs to use for PICC insertion. Previous research in an adult population that used receiver operator characteristic (ROC) analysis found that a 45% CVR was the optimal cut-off to reduce the risk of thrombus. 15 Participants with a CVR of more than 45% were 13 times more likely to suffer from thrombosis. Yet these findings were based on just four cases and all participants with this adverse event had a haematological malignancy. Most of the research investigating thrombosis rates associated with CVR cut-offs focus on individuals with cancer. 5 7 11 13 This is problematic as many consumers with an infection (without an underlying malignancy diagnosis) receive a PICC for antimicrobial treatment and it is unknown whether the CVR cut-off may differ according to diagnosis. There is a need to investigate the association between the CVR and PICC-associated thrombosis in a larger sample and to determine a safe CVR cut-off in individuals with both malignant and non-malignant health conditions. This study aimed to determine the effect of the CVR on rates of symptomatic thrombosis in individuals", "role": "user" }, { "content": "A world-first study led by the University of South Australia has found that cancer patients receiving chemotherapy intravenously have more than double the risk of developing a blood clot or thrombosis if the vein is too small and the catheter occupies more than 45 percent of the vein. The finding, published in the British Medical Journal Open, is the first time that catheter-vein ratios (CVRs) have been studied in different patient groups to determine the risk of thrombosis depending on how much the catheter obstructs blood flow. Cancer itself (especially leukemia and other blood cancers) and the chemotherapy used to treat it both increase thrombosis risk, and the catheters increase this risk even further if blood flow is restricted, according to Dr. Rebecca Sharp, a UniSA vascular access device researcher who led the study. \"Catheters are commonly used to infuse medications or liquid nutrition, but they come with risks, particularly if the catheter is too big for the vein. Previous research has shown they can impede blood flow by up to 80 percent,\" Dr. Sharp says. Data from 2438 patients with a peripherally inserted central catheter (PICC) was analyzed from four hospitals across Australia and New Zealand, identifying 39 cases of thrombosis. \"Many clinicians use a CVR of less than 33 percent, where the catheter occupies only one third of the vein. Others adhere to a 45 percent limit. However, there is a lack of evidence showing which CVRs are safe for individual patients. Some clinicians don't measure veins at all.\" Credit: University of South Australia PICCs are commonly used internationally. They are convenient, easy to insert and cheaper than other devices such as a port (a flexible tube placed into a vein in the chest), which is invasive and requires surgery. However, PICCs are riskier, researchers say. \"We have identified how to reduce some of these risks, by recommending specific limits on catheter-to-vein ratios for individual patients. These results will help nurses and doctors to provide safe care and reduce harm for people with cancer,\" Dr. Sharp says. The analysis did not find any increased risk of blood clots for non-cancer patients treated for infections via catheters. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 Determine the effect of the catheter to vein ratio (CVR) on rates of symptomatic thrombosis in individuals with a peripherally inserted central catheter (PICC) and identify the optimal CVR cut-off point according to diagnostic group. Design Retrospective cohort study. Setting 4 tertiary hospitals in Australia and New Zealand. Participants Adults who had undergone PICC insertion. Primary outcome measure Symptomatic thrombus of the limb in which the PICC was inserted. Results 2438 PICC insertions were included with 39 cases of thrombosis (1.6%; 95% CI 1.14% to 2.19%). Receiver operator characteristic analysis was unable to be performed to determine the optimal CVR overall or according to diagnosis. The association between risk of thrombosis and CVR cut-offs commonly used in clinical practice were analysed. A 45% cut-off (≤45% versus ≥46%) was predictive of thrombosis, with those with a higher ratio having more than twice the risk (relative risk 2.30; 95% CI 1.202 to 4.383; p=0.01). This pattern continued when only those with malignancy were included in the analysis, those with cancer had twice the risk of thrombosis with a CVR greater than 45%. Whereas the 33% CVR cut-off was not associated with statistically significant results overall or in those with malignancy. Neither the 33% or 45% CVR cut-off produced statistically significant results in those with infection or other non-malignant conditions. Conclusions Adherence to CVR cut-offs are an important component of PICC insertion clinical decision making to reduce the risk of thrombosis. These results suggest that in individuals with cancer, the use of a CVR ≤45% should be considered to minimise risk of thrombosis. Further research is needed to determine the risk of thrombosis according to malignancy type and the optimal CVR for those with a non-malignant diagnosis. radiology & imaging interventional radiology adult oncology Data availability statement Data are available on reasonable request from the corresponding author. 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 10 news outlets Blogged by 1 Tweeted by 16 51 readers on Mendeley 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 radiology & imaging interventional radiology adult oncology Strengths and limitations of this study Large, multisite study with 2438 peripherally inserted central catheters (PICCs). First study to analyse risk of thrombosis associated with the 33% and 45% catheter to vein ratio (CVR) cut-off recommendations commonly used in clinical practice for PICC insertion. Analysed risk of thrombosis associated with CVRs according to diagnostic group. Unable to perform planned analysis (receiver operator characteristic analysis) to determine the optimal CVR to prevent thrombosis in individuals with a PICC. The use of a tapered PICC impacted the accuracy of the PICC diameter and hence CVR for those participants that had the tapered portion inserted. Introduction Peripherally inserted central catheter (PICC)-associated thrombosis is often uncomfortable, may result in loss of intravenous access for treatment and damage to the vasculature limiting further PICC insertions. In some cases, PICC associated thrombosis precipitates pulmonary embolism and post-thrombotic syndrome. 1 2 Approximately 2% of individuals receiving antimicrobials as part of outpatient parenteral therapy develop thrombosis. 3 4 While those receiving cancer treatment suffer much higher rates, with 4%–6% of consumers with a haematological malignancy and 2%–5% of those with a solid tumour developing PICC associated thrombosis. 3 5–7 This adverse event can be explained using mechanisms related to Virchow’s triad (stasis, endothelial damage and hypercoagulable state of the patient). PICCs may have a large impact on the interruption of blood flow (stasis). In a mechanical model, Nifong and McDevitt 8 demonstrated that blood flow was dependant on the size of the catheter and cylinder (or vein) size and PICCs commonly used in clinical practice may impede blood flow up to 80%. 8 PICC insertion decisions such as the use of an appropriate catheter to vein ratio (CVR) affect PICC-associated thrombosis rates. 3 Contemporary insertion approaches include measurement of the target vein diameter using ultrasound and limiting the CVR to reduce the risk of thrombosis. 9 Different CVR cut-offs are used in clinical practice, many sites use a 33% CVR limit, that is only one-third of the vein should be occupied by the catheter. 7 10–13 Other sites use a 45% CVR limit as advocated by the Infusion Therapy Standards of Practice (Infusion Nurses Society 2021). 14 However, there is a lack of research investigating safe CVRs to use for PICC insertion. Previous research in an adult population that used receiver operator characteristic (ROC) analysis found that a 45% CVR was the optimal cut-off to reduce the risk of thrombus. 15 Participants with a CVR of more than 45% were 13 times more likely to suffer from thrombosis. Yet these findings were based on just four cases and all participants with this adverse event had a haematological malignancy. Most of the research investigating thrombosis rates associated with CVR cut-offs focus on individuals with cancer. 5 7 11 13 This is problematic as many consumers with an infection (without an underlying malignancy diagnosis) receive a PICC for antimicrobial treatment and it is unknown whether the CVR cut-off may differ according to diagnosis. There is a need to investigate the association between the CVR and PICC-associated thrombosis in a larger sample and to determine a safe CVR cut-off in individuals with both malignant and non-malignant health conditions. This study aimed to determine the effect of the CVR on rates of symptomatic thrombosis in individuals<|im_end|> <|im_start|>assistant A world-first study led by the University of South Australia has found that cancer patients receiving chemotherapy intravenously have more than double the risk of developing a blood clot or thrombosis if the vein is too small and the catheter occupies more than 45 percent of the vein. The finding, published in the British Medical Journal Open, is the first time that catheter-vein ratios (CVRs) have been studied in different patient groups to determine the risk of thrombosis depending on how much the catheter obstructs blood flow. Cancer itself (especially leukemia and other blood cancers) and the chemotherapy used to treat it both increase thrombosis risk, and the catheters increase this risk even further if blood flow is restricted, according to Dr. Rebecca Sharp, a UniSA vascular access device researcher who led the study. "Catheters are commonly used to infuse medications or liquid nutrition, but they come with risks, particularly if the catheter is too big for the vein. Previous research has shown they can impede blood flow by up to 80 percent," Dr. Sharp says. Data from 2438 patients with a peripherally inserted central catheter (PICC) was analyzed from four hospitals across Australia and New Zealand, identifying 39 cases of thrombosis. "Many clinicians use a CVR of less than 33 percent, where the catheter occupies only one third of the vein. Others adhere to a 45 percent limit. However, there is a lack of evidence showing which CVRs are safe for individual patients. Some clinicians don't measure veins at all." Credit: University of South Australia PICCs are commonly used internationally. They are convenient, easy to insert and cheaper than other devices such as a port (a flexible tube placed into a vein in the chest), which is invasive and requires surgery. However, PICCs are riskier, researchers say. "We have identified how to reduce some of these risks, by recommending specific limits on catheter-to-vein ratios for individual patients. These results will help nurses and doctors to provide safe care and reduce harm for people with cancer," Dr. Sharp says. The analysis did not find any increased risk of blood clots for non-cancer patients treated for infections via catheters. <|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 Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways. Although ATP-competitive, first-generation RAF inhibitors (vemurafenib/PLX4720, RAFi) cause paradoxical activation of the MAPK pathway in BRAF-fusion tumors, inhibition can be achieved with ‘paradox breaker’ RAFi, such as PLX8394. Here we report that, unlike BRAF fusions, CRAF fusions are unresponsive to both generations of RAFi, vemurafenib and PLX8394, highlighting a distinct responsiveness of CRAF fusions to clinically relevant RAFi. Whereas PLX8394 decreased BRAF-fusion dimerization, CRAF-fusion dimerization is unaffected primarily because of robust protein–protein interactions mediated by the N-terminal non-kinase fusion partner, such as QKI. The pan-RAF dimer inhibitor, LY3009120, could suppress CRAF-fusion oncogenicity by inhibiting dimer-mediated signaling. In addition, as CRAF fusions activate both the MAPK and PI3K/mTOR signaling pathways, we identify combinatorial inhibition of the MAPK/mTOR pathway as a potential therapeutic strategy for CRAF-fusion-driven tumors. Overall, we define a mechanistic distinction between PLGG-associated BRAF- and CRAF/RAF1 fusions in response to RAFi, highlighting the importance of molecularly classifying PLGG patients for targeted therapy. Furthermore, our study uncovers an important contribution of the non-kinase fusion partner to oncogenesis and potential therapeutic strategies against PLGG-associated CRAF fusions and possibly pan-cancer CRAF fusions. Introduction Pediatric low-grade gliomas (PLGGs) represent a heterogeneous group of commonly diagnosed brain tumors in children, 1 with histologies ranging from pilocytic astrocytomas (PAs; WHO grade I) to diffuse fibrillary astrocytomas (WHO grade II). Alterations in the mitogen-associated protein kinase (MAPK) pathway are frequent in PLGGs, specifically KIAA1549-BRAF gene fusion in PAs 2 , 3 and BRAF-V600E mutation mostly in Pleomorphic Xanthoastrocytomas. 4 Comprehensive whole-genome sequencing studies have discovered a diversity of novel RAF-fusion gene combinations. In particular, multiple gene fusions harboring CRAF (or RAF1 ), a serine/threonine kinase first discovered as the v-raf oncogene in transforming mouse sarcoma virus, 5 have been reported in PLGGs. QKI-RAF1 and FYCO-RAF1 have been identified as rare alterations in PAs using whole-genome sequencing, 6 whereas SRGAP3-RAF1 was first reported as a tandem duplication event. 7 , 8 Recently, ATG7-RAF1 fusions were reported in anaplastic Pleomorphic Xanthoastrocytomas without BRAF-V600E. 9 Although SRGAP3-RAF1 was shown to activate the MAPK pathway, no further studies with RAF1 fusions have been reported. Interestingly, several adult cancers such as prostate cancer, 10 , 11 breast cancer, 12 pancreatic cancer 13 and thyroid cancer 12 also harbor CRAF fusions. However, the true prevalence, oncogenic mechanism and sensitivity of pan-cancer CRAF fusions to targeted therapeutics remain unknown. The prevalence of RAF fusions in PLGGs led to studies examining the therapeutic efficacy of RAF inhibitors (RAFi). ATP-competitive, first-generation RAFi, such as vemurafenib (research analog PLX4720), have been FDA-approved for BRAF-V600E malignant melanoma 14 but were found to be ineffective in targeting BRAF fusions because of paradoxical activation of the MAPK pathway. 3 Interestingly, second-generation RAFi PLX8394 could successfully target BRAF fusions, hence termed 'paradox breaker'. 3 , 15 These studies highlight the differential sensitivity of RAF mutations. While ATP-competitive RAFi inhibits wild-type BRAF and CRAF kinase activity at similar IC 50 in vitro , 15 the effect of RAFi on CRAF fusions versus BRAF fusions is yet to be clinically defined. Despite recent focus on the kinase fusion partner in fusion-driven cancers, the non-kinase partner is increasingly recognized as important to oncogenesis. The N-terminal fusion partners of CRAF fusions, such as in QKI (QKI-RAF1) and SRGAP3 (SRGAP3-RAF1), have been previously implicated in cancers. QKI is an RNA-binding protein that regulates glial development and central nervous system myelination. 16 , 17 We previously identified QKI’s contribution as a fusion partner in MYB-QKI fusion in angiocentric gliomas, 18 corroborating previous findings that QKI deletions are oncogenic in cancers such as glioblastomas, 19 , 20 prostate cancer, 21 lung cancer 22 and gastric cancer. 23 SRGAP3, which is a member of the SLIT-ROBO Rho-GTPase-activating protein (srGAP) family regulating actin cytoskeleton dynamics, 24 has been reported as a tumor suppressor-like gene in breast cancer. 25 These studies suggest the potential involvement of QKI and SRGAP3 in CRAF-fusion-driven tumors. To address these questions, we performed cellular, molecular and in vivo assays to test oncogenic mechanisms and therapeutic response of two PLGG-associated CRAF fusions, QKI-RAF1 and SRGAP3-RAF1 . We found that CRAF fusions activated both the MAPK and the phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) pathways and were unresponsive to 'paradox-breaker' RAFi. We identified robust, RAFi-resistant dimerization mediated by the non-kinase fusion partner in CRAF fusions. To overcome this RAF-directed therapeutic challenge, we characterize other potential targeting approaches for CRAF-fusion-driven tumors including the pan-RAFi LY3009120 and combinatorial targeting of the MAPK and PI3K/mTOR pathways. Results QKI-RAF1 and SRGAP3-RAF1 are oncogenic fusions that activate the MAPK and PI3K signaling pathways Similar to most BRAF fusions, QKI-RAF1 and SRGAP3-RAF1 lack the N-terminal non-catalytic, inhibitory domain of RAF but retain the functional kinase domain ( Figure 1a ). Loss of N-terminal domains of CRAF can activate oncogenic properties, 26 , 27 but such studies on PLGG CRAF fusions are limited to a single report on SRGAP3-RAF1. 8 QKI-RAF1 contains QKI exons 1–3 encoding QKI homodimerization domain and part of its RNA-binding domain ( Figure 1a ). In SRGAP3-RAF1 , SRGAP3 exons 1–10 encode the Fes-CIP4-homology domain and a coiled-coil domain (together called F-BAR domain) with dimerization properties, 28 but the central Rho-GAP and C-terminal SH3 domains are lost ( Figure 1a ). Figure 1 QKI-RAF1 and SRGAP3-RAF1 are oncogenic via activation of MAPK and PI3K pathways. ( a ) Structure of CRAF fusions in PLGGs. QKI-RAF1: QKI exons 1–3 encode QUA1 dimerization domain and a truncated K-homology domain (KH-Tr), and CRAF/RAF1 exons 8–17 encode the protein kinase domain. SRGAP3-RAF1: SRGAP3 exons 1–10 encode the Fes/CIP4-Homology (FCH) domain and,", "role": "user" }, { "content": "Researchers investigating pediatric low-grade gliomas (PLGG), the most common type of brain tumor in children, have discovered key biological differences in how mutated genes combine with other genes to drive this childhood cancer. By shedding light on subtle distinctions in tumor biology, these findings offer clues to designing more effective anticancer treatments to precisely target tumors in individual patients. \"Carefully defining the molecular landscape of these tumor subtypes may guide us in pediatric precision medicine, to better treat children with brain tumors,\" said Payal Jain, PhD, a postdoctoral researcher at Children's Hospital of Philadelphia (CHOP). Jain, a former graduate student in the Perelman School of Medicine at the University of Pennsylvania, is the first author of two recent PLGG studies, with colleagues from CHOP, Penn and other institutions. The first study, published Aug. 14 in Oncogene, was co-led by Adam C. Resnick, PhD, co-director of the CHOP's Center for Data Driven Discovery in Biomedicine (D3b), and Angela J. Waanders, MD, MPH, director of clinical research for D3b along with senior author Phillip B. Storm, MD, Division Chief of Neurosurgery at CHOP and co-director of D3b. Neuro-oncology researchers Resnick and Waanders also were co-senior authors of a second study, published Sept. 15 in Oncotarget. Both papers analyzed members of the RAF gene family that play key roles in driving cancer. Two related genes, CRAF and BRAF, express their respective proteins, CRAF and BRAF, which are signaling proteins called kinases. A mutation in either gene causes it to combine with a partner gene to express an abnormal fusion protein that acts along a cellular growth pathway to result in cancer. In the Oncogene study, the research team found key distinctions in how these mutated genes give rise to PLGGs, a varied group of cancers that collectively account for the most common brain tumor in children. Although PLGGs are often slow-growing, they may disrupt hormones and lead to blindness or coma, and can occur in locations where they can't be surgically removed. Although BRAF gene fusions were well known to be involved in PLGGs, the study team found important differences in a related gene, CRAF, in which mutations can also lead to this type of glioma. One crucial distinction is that CRAF-fusions may not respond as well as BRAF-fusions to anticancer drugs called RAF inhibitors. Part of the reason for the difference in drug response, say the authors, is that the fusion partner—the non-kinase gene that BRAF or CRAF combines with—alters the tumor's response. \"We showed for the first time that the non-kinase fusion partner has functional significance—affecting how the gene fusion-driven tumor responds to therapy,\" said Waanders, who added, \"This means that we need to carefully classify these tumors to better predict whether a patient is likely to respond to RAF-inhibitor therapy.\" The study in Oncotarget, by revealing biological mechanisms by which RAF-fusion tumors develop drug resistance, suggests a possible solution: using a combination of drugs to inhibit downstream signals along two cancer-driving pathways, thus bypassing the difference in how RAF inhibitors succeed against CRAF-fusions compared to BRAF-fusions. \"Parsing the molecular details of tumor subtypes and resistance mechanism allows us to better define the therapeutic landscape as we pursue translational research,\" said Resnick. \"Large-scale clinical sequencing and molecular profiling can better inform collaborative programs such as the National Cancer Institute-Children's Oncology Group Pediatric MATCH clinical trials and the Pacific Neuro-Oncology Consortium. Our findings in these new studies will advance our clinical efforts to develop more effective, personalized treatments for children.\" Storm, who performs surgery on children with brain tumors, added that, \"Better understanding of tumor characteristics, as we found in this research, will help guide our surgical planning and clinical decisions for patients with PLGGs in this current era of target-centric clinical trials and personalized 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 Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways. Although ATP-competitive, first-generation RAF inhibitors (vemurafenib/PLX4720, RAFi) cause paradoxical activation of the MAPK pathway in BRAF-fusion tumors, inhibition can be achieved with ‘paradox breaker’ RAFi, such as PLX8394. Here we report that, unlike BRAF fusions, CRAF fusions are unresponsive to both generations of RAFi, vemurafenib and PLX8394, highlighting a distinct responsiveness of CRAF fusions to clinically relevant RAFi. Whereas PLX8394 decreased BRAF-fusion dimerization, CRAF-fusion dimerization is unaffected primarily because of robust protein–protein interactions mediated by the N-terminal non-kinase fusion partner, such as QKI. The pan-RAF dimer inhibitor, LY3009120, could suppress CRAF-fusion oncogenicity by inhibiting dimer-mediated signaling. In addition, as CRAF fusions activate both the MAPK and PI3K/mTOR signaling pathways, we identify combinatorial inhibition of the MAPK/mTOR pathway as a potential therapeutic strategy for CRAF-fusion-driven tumors. Overall, we define a mechanistic distinction between PLGG-associated BRAF- and CRAF/RAF1 fusions in response to RAFi, highlighting the importance of molecularly classifying PLGG patients for targeted therapy. Furthermore, our study uncovers an important contribution of the non-kinase fusion partner to oncogenesis and potential therapeutic strategies against PLGG-associated CRAF fusions and possibly pan-cancer CRAF fusions. Introduction Pediatric low-grade gliomas (PLGGs) represent a heterogeneous group of commonly diagnosed brain tumors in children, 1 with histologies ranging from pilocytic astrocytomas (PAs; WHO grade I) to diffuse fibrillary astrocytomas (WHO grade II). Alterations in the mitogen-associated protein kinase (MAPK) pathway are frequent in PLGGs, specifically KIAA1549-BRAF gene fusion in PAs 2 , 3 and BRAF-V600E mutation mostly in Pleomorphic Xanthoastrocytomas. 4 Comprehensive whole-genome sequencing studies have discovered a diversity of novel RAF-fusion gene combinations. In particular, multiple gene fusions harboring CRAF (or RAF1 ), a serine/threonine kinase first discovered as the v-raf oncogene in transforming mouse sarcoma virus, 5 have been reported in PLGGs. QKI-RAF1 and FYCO-RAF1 have been identified as rare alterations in PAs using whole-genome sequencing, 6 whereas SRGAP3-RAF1 was first reported as a tandem duplication event. 7 , 8 Recently, ATG7-RAF1 fusions were reported in anaplastic Pleomorphic Xanthoastrocytomas without BRAF-V600E. 9 Although SRGAP3-RAF1 was shown to activate the MAPK pathway, no further studies with RAF1 fusions have been reported. Interestingly, several adult cancers such as prostate cancer, 10 , 11 breast cancer, 12 pancreatic cancer 13 and thyroid cancer 12 also harbor CRAF fusions. However, the true prevalence, oncogenic mechanism and sensitivity of pan-cancer CRAF fusions to targeted therapeutics remain unknown. The prevalence of RAF fusions in PLGGs led to studies examining the therapeutic efficacy of RAF inhibitors (RAFi). ATP-competitive, first-generation RAFi, such as vemurafenib (research analog PLX4720), have been FDA-approved for BRAF-V600E malignant melanoma 14 but were found to be ineffective in targeting BRAF fusions because of paradoxical activation of the MAPK pathway. 3 Interestingly, second-generation RAFi PLX8394 could successfully target BRAF fusions, hence termed 'paradox breaker'. 3 , 15 These studies highlight the differential sensitivity of RAF mutations. While ATP-competitive RAFi inhibits wild-type BRAF and CRAF kinase activity at similar IC 50 in vitro , 15 the effect of RAFi on CRAF fusions versus BRAF fusions is yet to be clinically defined. Despite recent focus on the kinase fusion partner in fusion-driven cancers, the non-kinase partner is increasingly recognized as important to oncogenesis. The N-terminal fusion partners of CRAF fusions, such as in QKI (QKI-RAF1) and SRGAP3 (SRGAP3-RAF1), have been previously implicated in cancers. QKI is an RNA-binding protein that regulates glial development and central nervous system myelination. 16 , 17 We previously identified QKI’s contribution as a fusion partner in MYB-QKI fusion in angiocentric gliomas, 18 corroborating previous findings that QKI deletions are oncogenic in cancers such as glioblastomas, 19 , 20 prostate cancer, 21 lung cancer 22 and gastric cancer. 23 SRGAP3, which is a member of the SLIT-ROBO Rho-GTPase-activating protein (srGAP) family regulating actin cytoskeleton dynamics, 24 has been reported as a tumor suppressor-like gene in breast cancer. 25 These studies suggest the potential involvement of QKI and SRGAP3 in CRAF-fusion-driven tumors. To address these questions, we performed cellular, molecular and in vivo assays to test oncogenic mechanisms and therapeutic response of two PLGG-associated CRAF fusions, QKI-RAF1 and SRGAP3-RAF1 . We found that CRAF fusions activated both the MAPK and the phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) pathways and were unresponsive to 'paradox-breaker' RAFi. We identified robust, RAFi-resistant dimerization mediated by the non-kinase fusion partner in CRAF fusions. To overcome this RAF-directed therapeutic challenge, we characterize other potential targeting approaches for CRAF-fusion-driven tumors including the pan-RAFi LY3009120 and combinatorial targeting of the MAPK and PI3K/mTOR pathways. Results QKI-RAF1 and SRGAP3-RAF1 are oncogenic fusions that activate the MAPK and PI3K signaling pathways Similar to most BRAF fusions, QKI-RAF1 and SRGAP3-RAF1 lack the N-terminal non-catalytic, inhibitory domain of RAF but retain the functional kinase domain ( Figure 1a ). Loss of N-terminal domains of CRAF can activate oncogenic properties, 26 , 27 but such studies on PLGG CRAF fusions are limited to a single report on SRGAP3-RAF1. 8 QKI-RAF1 contains QKI exons 1–3 encoding QKI homodimerization domain and part of its RNA-binding domain ( Figure 1a ). In SRGAP3-RAF1 , SRGAP3 exons 1–10 encode the Fes-CIP4-homology domain and a coiled-coil domain (together called F-BAR domain) with dimerization properties, 28 but the central Rho-GAP and C-terminal SH3 domains are lost ( Figure 1a ). Figure 1 QKI-RAF1 and SRGAP3-RAF1 are oncogenic via activation of MAPK and PI3K pathways. ( a ) Structure of CRAF fusions in PLGGs. QKI-RAF1: QKI exons 1–3 encode QUA1 dimerization domain and a truncated K-homology domain (KH-Tr), and CRAF/RAF1 exons 8–17 encode the protein kinase domain. SRGAP3-RAF1: SRGAP3 exons 1–10 encode the Fes/CIP4-Homology (FCH) domain and,<|im_end|> <|im_start|>assistant Researchers investigating pediatric low-grade gliomas (PLGG), the most common type of brain tumor in children, have discovered key biological differences in how mutated genes combine with other genes to drive this childhood cancer. By shedding light on subtle distinctions in tumor biology, these findings offer clues to designing more effective anticancer treatments to precisely target tumors in individual patients. "Carefully defining the molecular landscape of these tumor subtypes may guide us in pediatric precision medicine, to better treat children with brain tumors," said Payal Jain, PhD, a postdoctoral researcher at Children's Hospital of Philadelphia (CHOP). Jain, a former graduate student in the Perelman School of Medicine at the University of Pennsylvania, is the first author of two recent PLGG studies, with colleagues from CHOP, Penn and other institutions. The first study, published Aug. 14 in Oncogene, was co-led by Adam C. Resnick, PhD, co-director of the CHOP's Center for Data Driven Discovery in Biomedicine (D3b), and Angela J. Waanders, MD, MPH, director of clinical research for D3b along with senior author Phillip B. Storm, MD, Division Chief of Neurosurgery at CHOP and co-director of D3b. Neuro-oncology researchers Resnick and Waanders also were co-senior authors of a second study, published Sept. 15 in Oncotarget. Both papers analyzed members of the RAF gene family that play key roles in driving cancer. Two related genes, CRAF and BRAF, express their respective proteins, CRAF and BRAF, which are signaling proteins called kinases. A mutation in either gene causes it to combine with a partner gene to express an abnormal fusion protein that acts along a cellular growth pathway to result in cancer. In the Oncogene study, the research team found key distinctions in how these mutated genes give rise to PLGGs, a varied group of cancers that collectively account for the most common brain tumor in children. Although PLGGs are often slow-growing, they may disrupt hormones and lead to blindness or coma, and can occur in locations where they can't be surgically removed. Although BRAF gene fusions were well known to be involved in PLGGs, the study team found important differences in a related gene, CRAF, in which mutations can also lead to this type of glioma. One crucial distinction is that CRAF-fusions may not respond as well as BRAF-fusions to anticancer drugs called RAF inhibitors. Part of the reason for the difference in drug response, say the authors, is that the fusion partner—the non-kinase gene that BRAF or CRAF combines with—alters the tumor's response. "We showed for the first time that the non-kinase fusion partner has functional significance—affecting how the gene fusion-driven tumor responds to therapy," said Waanders, who added, "This means that we need to carefully classify these tumors to better predict whether a patient is likely to respond to RAF-inhibitor therapy." The study in Oncotarget, by revealing biological mechanisms by which RAF-fusion tumors develop drug resistance, suggests a possible solution: using a combination of drugs to inhibit downstream signals along two cancer-driving pathways, thus bypassing the difference in how RAF inhibitors succeed against CRAF-fusions compared to BRAF-fusions. "Parsing the molecular details of tumor subtypes and resistance mechanism allows us to better define the therapeutic landscape as we pursue translational research," said Resnick. "Large-scale clinical sequencing and molecular profiling can better inform collaborative programs such as the National Cancer Institute-Children's Oncology Group Pediatric MATCH clinical trials and the Pacific Neuro-Oncology Consortium. Our findings in these new studies will advance our clinical efforts to develop more effective, personalized treatments for children." Storm, who performs surgery on children with brain tumors, added that, "Better understanding of tumor characteristics, as we found in this research, will help guide our surgical planning and clinical decisions for patients with PLGGs in this current era of target-centric clinical trials and personalized medicine." <|im_end|>

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2,690

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Human gut microbiome composition is shaped by multiple factors but the relative contribution of host genetics remains elusive. Here we examine genotype and microbiome data from 1,046 healthy individuals with several distinct ancestral origins who share a relatively common environment, and demonstrate that the gut microbiome is not significantly associated with genetic ancestry, and that host genetics have a minor role in determining microbiome composition. We show that, by contrast, there are significant similarities in the compositions of the microbiomes of genetically unrelated individuals who share a household, and that over 20% of the inter-person microbiome variability is associated with factors related to diet, drugs and anthropometric measurements. We further demonstrate that microbiome data significantly improve the prediction accuracy for many human traits, such as glucose and obesity measures, compared to models that use only host genetic and environmental data. These results suggest that microbiome alterations aimed at improving clinical outcomes may be carried out across diverse genetic backgrounds. Main The gut microbiome is increasingly recognized as having fundamental roles in human physiology and health 1 , 2 . A central question is the extent to which microbiome composition is determined by host genetics. Previous studies have identified several heritable bacterial taxa 3 , 4 , 5 , 6 , 7 but the combined bacterial abundance accounted for by them has not yet been quantified. Other studies have found associations between host single nucleotide polymorphisms (SNPs) and individual bacterial taxa or pathways 5 , 8 , 9 , 10 , 11 . However, most previously reported associations are not statistically significant after multiple testing correction 3 . A recent study identified 42 SNPs that together explained 10% of the variance of microbiome β-diversity 9 . However, the statistical significance of this result has not yet been evaluated. Thus, the extent to which human genetics shape microbiome composition remains unclear. Here we studied microbial–genetic associations using a cohort of 1,046 healthy Israeli individuals with metagenome-sequenced and 16S rRNA gene-sequenced gut microbiomes, genotypes, anthropometric and blood measurements, and dietary habits 12 . Individuals in our cohort are of several different ancestral origins but we assume, owing to their broadly similar lifestyles, that they share a relatively homogeneous environment. Our results demonstrate that gut microbiome composition is shaped predominantly by environmental factors. Specifically, we show that the microbiome is not significantly associated with genetic ancestry or with individual SNPs, and that previously reported associations are not replicated across different studies. We further estimate that the average heritability of gut microbiome taxa is only 1.9%, by analysing data from 2,252 twins from the TwinsUK cohort 6 . However, further and larger-scale studies are required to accurately quantify gut microbiome heritability. To provide direct evidence that the microbiome is shaped largely by environmental factors, we show that there is significant similarity among the microbiomes of genetically unrelated individuals who share a household, but no significant microbiome similarity among relatives who do not have a history of household sharing. We further demonstrate that over 20% of the variance in microbiome β-diversity can be inferred from environmental factors associated with diet and lifestyle, consistent with previous studies 13 , 14 . Because our findings suggest that gut microbiome and host genetics are largely independent, we compare the power of the gut microbiome and of host genetics to predict host phenotypes. We define the term ‘microbiome-association index’ ( b 2 ) that—by analogy with genetic heritability, which is typically termed h 2 —quantifies the overall association between the microbiome and a host phenotype after accounting for host genetics. We find significant b 2 levels of 22–36% for body mass index (BMI; 25%), fasting glucose levels (22%), glycaemic status (25%), levels of high-density lipoprotein (HDL) cholesterol (36%), waist circumference (29%), hip circumference (27%), waist–hip ratio (WHR; 24%) and lactose consumption (36%). We note that b 2 should be interpreted with caution, because it is a correlative measure that does not necessarily indicate causality and it may be confounded by environmental factors. We additionally demonstrate that using microbiome data together with human genetic data substantially improves the accuracy with which human phenotypes can be predicted, consistent with a previous smaller-scale study 15 . Finally, we successfully replicate our results in 836 Dutch individuals, with genotypes and metagenomic data, from the LifeLines DEEP (LLD) cohort 8 . Taken together, our results demonstrate that the gut microbiome is predominantly shaped by environmental factors, and is strongly correlated with many human phenotypes after accounting for host genetics. Results We studied a cohort of 1,046 healthy Israeli adults from whom we collected blood for genotyping and phenotyping, stools for metagenome sequencing and 16S rRNA gene sequencing, anthropometric measurements, and answers to food frequency and lifestyle questionnaires 12 ( Extended Data Table 1 and Supplementary Table 1 ). We performed genotyping at 712,540 SNPs and imputed them to 5,567,647 SNPs (Methods). Stool samples were profiled using both metagenome sequencing and 16S rRNA gene sequencing, and then analysed at multiple taxonomic levels; the results presented here are based on metagenome species analysis (results at metagenome phylum, class, order, family, genus or bacterial gene levels, and for 16S genus and operational taxonomic unit levels, are provided in Supplementary Tables where appropriate). We included covariates for age, gender, stool collection method, and self-reported daily median caloric, fat, protein and carbohydrate consumption (Methods). Limited evidence of microbiome–genetic associations Our sample consists of self-reported Ashkenazi ( n = 508), North African ( n = 64), Middle Eastern ( n = 34), Sephardi ( n = 19), Yemenite ( n = 13) and ‘admixed/other’ ( n = 408) ancestries 16 ( Supplementary Table 2 ). We first successfully verified that the top two host genetic principal components are strongly associated with self-reported ancestry ( P < 10 −32 for both principal component 1 and principal component 2, Kruskal–Wallis test; Fig. 1a , Extended Data Table 2 and Supplementary Table 3 ). By contrast, we found no significant association between ancestry and microbiome composition. Specifically, there was no significant correlation between", "role": "user" }, { "content": "The question of nature vs nurture extends to our microbiome - the personal complement of mostly-friendly bacteria we carry around with us. Study after study has found that our microbiome affects nearly every aspect of our health; and its microbial composition, which varies from individual to individual, may hold the key to everything from weight gain to moods. Some microbiome researchers had suggested that this variation begins with differences in our genes; but a large-scale study conducted at the Weizmann Institute of Science challenges this idea and provides evidence that the connection between microbiome and health may be even more important than we thought. Indeed, the working hypothesis has been that genetics plays a major role in determining microbiome variation among people. According to this view, our genes determine the environment our microbiome occupies, and each particular environment allows certain bacterial strains to thrive. However, the Weizmann researchers were surprised to discover that the host's genetics play a very minor role in determining microbiome composition - only accounting for about 2% of the variation between populations. The research was led by research students Daphna Rothschild, Dr. Omer Weissbrod and Dr. Elad Barkan from the lab of Prof. Eran Segal of the Computer Science and Applied Mathematics Department, together with members of Prof. Eran Elinav's group of the Immunology Department, all at the Weizmann Institute of Science. Their findings, which were recently published in Nature, were based on a unique database of around 1,000 Israelis who had participated in a longitudinal study of personalized nutrition. Israel has a highly diverse population, which presents an ideal experimental setting for investigating the effects of genetic differences. In addition to genetic data and microbiome composition, the information collected for each study participant included dietary habits, lifestyle, medications and additional measurements. The scientists analyzing this data concluded that diet and lifestyle are by far the most dominant factors shaping our microbiome composition. If microbiome populations are not shaped by our genetics, how do they nonetheless interact with our genes to modify our health? The scientists investigated the connections between microbiome and the measurements in the database of cholesterol, weight, blood glucose levels, and other clinical parameters. The study results were very surprising: For most of these clinical measures, the association with bacterial genomes was at least as strong, and in some cases stronger, than the association with the host's human genome. According to the scientists, these findings provide solid evidence that understanding the factors that shape our microbiome may be key to understanding and treating many common health problems. Segal: \"We cannot change our genes, but we now know that we can affect - and even reshape - the composition of the different kinds of bacteria we host in our bodies. So the findings of our research are quite hopeful; they suggest that our microbiome could be a powerful means for improving our health.\" The field of microbiome research is relatively young; the database of 1,000 individuals collected at the Weizmann institute is one of the most extensive in the world. Segal and Elinav believe that over time, with the further addition of data to their study and those of others, these recent findings may be further validated, and the connection between our microbiome, our genetics and our health will become clearer. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Human gut microbiome composition is shaped by multiple factors but the relative contribution of host genetics remains elusive. Here we examine genotype and microbiome data from 1,046 healthy individuals with several distinct ancestral origins who share a relatively common environment, and demonstrate that the gut microbiome is not significantly associated with genetic ancestry, and that host genetics have a minor role in determining microbiome composition. We show that, by contrast, there are significant similarities in the compositions of the microbiomes of genetically unrelated individuals who share a household, and that over 20% of the inter-person microbiome variability is associated with factors related to diet, drugs and anthropometric measurements. We further demonstrate that microbiome data significantly improve the prediction accuracy for many human traits, such as glucose and obesity measures, compared to models that use only host genetic and environmental data. These results suggest that microbiome alterations aimed at improving clinical outcomes may be carried out across diverse genetic backgrounds. Main The gut microbiome is increasingly recognized as having fundamental roles in human physiology and health 1 , 2 . A central question is the extent to which microbiome composition is determined by host genetics. Previous studies have identified several heritable bacterial taxa 3 , 4 , 5 , 6 , 7 but the combined bacterial abundance accounted for by them has not yet been quantified. Other studies have found associations between host single nucleotide polymorphisms (SNPs) and individual bacterial taxa or pathways 5 , 8 , 9 , 10 , 11 . However, most previously reported associations are not statistically significant after multiple testing correction 3 . A recent study identified 42 SNPs that together explained 10% of the variance of microbiome β-diversity 9 . However, the statistical significance of this result has not yet been evaluated. Thus, the extent to which human genetics shape microbiome composition remains unclear. Here we studied microbial–genetic associations using a cohort of 1,046 healthy Israeli individuals with metagenome-sequenced and 16S rRNA gene-sequenced gut microbiomes, genotypes, anthropometric and blood measurements, and dietary habits 12 . Individuals in our cohort are of several different ancestral origins but we assume, owing to their broadly similar lifestyles, that they share a relatively homogeneous environment. Our results demonstrate that gut microbiome composition is shaped predominantly by environmental factors. Specifically, we show that the microbiome is not significantly associated with genetic ancestry or with individual SNPs, and that previously reported associations are not replicated across different studies. We further estimate that the average heritability of gut microbiome taxa is only 1.9%, by analysing data from 2,252 twins from the TwinsUK cohort 6 . However, further and larger-scale studies are required to accurately quantify gut microbiome heritability. To provide direct evidence that the microbiome is shaped largely by environmental factors, we show that there is significant similarity among the microbiomes of genetically unrelated individuals who share a household, but no significant microbiome similarity among relatives who do not have a history of household sharing. We further demonstrate that over 20% of the variance in microbiome β-diversity can be inferred from environmental factors associated with diet and lifestyle, consistent with previous studies 13 , 14 . Because our findings suggest that gut microbiome and host genetics are largely independent, we compare the power of the gut microbiome and of host genetics to predict host phenotypes. We define the term ‘microbiome-association index’ ( b 2 ) that—by analogy with genetic heritability, which is typically termed h 2 —quantifies the overall association between the microbiome and a host phenotype after accounting for host genetics. We find significant b 2 levels of 22–36% for body mass index (BMI; 25%), fasting glucose levels (22%), glycaemic status (25%), levels of high-density lipoprotein (HDL) cholesterol (36%), waist circumference (29%), hip circumference (27%), waist–hip ratio (WHR; 24%) and lactose consumption (36%). We note that b 2 should be interpreted with caution, because it is a correlative measure that does not necessarily indicate causality and it may be confounded by environmental factors. We additionally demonstrate that using microbiome data together with human genetic data substantially improves the accuracy with which human phenotypes can be predicted, consistent with a previous smaller-scale study 15 . Finally, we successfully replicate our results in 836 Dutch individuals, with genotypes and metagenomic data, from the LifeLines DEEP (LLD) cohort 8 . Taken together, our results demonstrate that the gut microbiome is predominantly shaped by environmental factors, and is strongly correlated with many human phenotypes after accounting for host genetics. Results We studied a cohort of 1,046 healthy Israeli adults from whom we collected blood for genotyping and phenotyping, stools for metagenome sequencing and 16S rRNA gene sequencing, anthropometric measurements, and answers to food frequency and lifestyle questionnaires 12 ( Extended Data Table 1 and Supplementary Table 1 ). We performed genotyping at 712,540 SNPs and imputed them to 5,567,647 SNPs (Methods). Stool samples were profiled using both metagenome sequencing and 16S rRNA gene sequencing, and then analysed at multiple taxonomic levels; the results presented here are based on metagenome species analysis (results at metagenome phylum, class, order, family, genus or bacterial gene levels, and for 16S genus and operational taxonomic unit levels, are provided in Supplementary Tables where appropriate). We included covariates for age, gender, stool collection method, and self-reported daily median caloric, fat, protein and carbohydrate consumption (Methods). Limited evidence of microbiome–genetic associations Our sample consists of self-reported Ashkenazi ( n = 508), North African ( n = 64), Middle Eastern ( n = 34), Sephardi ( n = 19), Yemenite ( n = 13) and ‘admixed/other’ ( n = 408) ancestries 16 ( Supplementary Table 2 ). We first successfully verified that the top two host genetic principal components are strongly associated with self-reported ancestry ( P < 10 −32 for both principal component 1 and principal component 2, Kruskal–Wallis test; Fig. 1a , Extended Data Table 2 and Supplementary Table 3 ). By contrast, we found no significant association between ancestry and microbiome composition. Specifically, there was no significant correlation between<|im_end|> <|im_start|>assistant The question of nature vs nurture extends to our microbiome - the personal complement of mostly-friendly bacteria we carry around with us. Study after study has found that our microbiome affects nearly every aspect of our health; and its microbial composition, which varies from individual to individual, may hold the key to everything from weight gain to moods. Some microbiome researchers had suggested that this variation begins with differences in our genes; but a large-scale study conducted at the Weizmann Institute of Science challenges this idea and provides evidence that the connection between microbiome and health may be even more important than we thought. Indeed, the working hypothesis has been that genetics plays a major role in determining microbiome variation among people. According to this view, our genes determine the environment our microbiome occupies, and each particular environment allows certain bacterial strains to thrive. However, the Weizmann researchers were surprised to discover that the host's genetics play a very minor role in determining microbiome composition - only accounting for about 2% of the variation between populations. The research was led by research students Daphna Rothschild, Dr. Omer Weissbrod and Dr. Elad Barkan from the lab of Prof. Eran Segal of the Computer Science and Applied Mathematics Department, together with members of Prof. Eran Elinav's group of the Immunology Department, all at the Weizmann Institute of Science. Their findings, which were recently published in Nature, were based on a unique database of around 1,000 Israelis who had participated in a longitudinal study of personalized nutrition. Israel has a highly diverse population, which presents an ideal experimental setting for investigating the effects of genetic differences. In addition to genetic data and microbiome composition, the information collected for each study participant included dietary habits, lifestyle, medications and additional measurements. The scientists analyzing this data concluded that diet and lifestyle are by far the most dominant factors shaping our microbiome composition. If microbiome populations are not shaped by our genetics, how do they nonetheless interact with our genes to modify our health? The scientists investigated the connections between microbiome and the measurements in the database of cholesterol, weight, blood glucose levels, and other clinical parameters. The study results were very surprising: For most of these clinical measures, the association with bacterial genomes was at least as strong, and in some cases stronger, than the association with the host's human genome. According to the scientists, these findings provide solid evidence that understanding the factors that shape our microbiome may be key to understanding and treating many common health problems. Segal: "We cannot change our genes, but we now know that we can affect - and even reshape - the composition of the different kinds of bacteria we host in our bodies. So the findings of our research are quite hopeful; they suggest that our microbiome could be a powerful means for improving our health." The field of microbiome research is relatively young; the database of 1,000 individuals collected at the Weizmann institute is one of the most extensive in the world. Segal and Elinav believe that over time, with the further addition of data to their study and those of others, these recent findings may be further validated, and the connection between our microbiome, our genetics and our health will become clearer. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract We report a van der Waals heterostructure formed by monolayers of MoS 2 and ReS 2 with a type-I band alignment. First-principle calculations show that in this heterostructure, both the conduction band minimum and the valence band maximum are located in the ReS 2 layer. This configuration is different from previously accomplished type-II van der Waals heterostructures where electrons and holes reside in different layers. The type-I nature of this heterostructure is evident by photocarrier dynamics observed by transient absorption measurements. We found that carriers injected in MoS 2 transfer to ReS 2 in about 1 ps, while no charge transfer was observed when carriers are injected in ReS 2 . The carrier lifetime in the heterostructure is similar to that in monolayer ReS 2 , further confirming the lack of charge separation. We attribute the slower transfer time to the incoherent nature of the charge transfer due to the different crystal structures of the two materials forming the heterostructure. The demonstrated type-I semiconducting van der Waals heterostructure provides new ways to utilize two-dimensional materials for light emission applications, and a new platform to study light–matter interaction in atomically thin materials with strong confinement of electrons and holes. This article is part of the themed collection: National Nanotechnology Day Conceptual insights A type-I van der Waals heterostructure is demonstrated. Existing research on vertical van der Waals heterostructures formed by semiconducting two-dimensional materials have focused on structures showing type-II band alignments, where electrons and holes reside in different atomic layers. In the type-I heterostructure formed here, by stacking monolayers of MoS 2 and ReS 2 , both electrons and holes are confined in ReS 2 . Traditional semiconducting heterostructures based on ionic and covalent compounds are important artificial materials for electronic and optoelectronic technologies. Type-I band alignment has been widely achieved in such materials, in the form of semiconducting quantum wells. Due to the enhanced light-matter interaction by confining electrons and holes in the same region, these heterostructures are widely used in light emitting diodes and semiconductor lasers. However, the lattice-matching requirement severely limits the selection of partner materials. The van der Waals materials have the potential to unleash this constrain on achieving “on-demand” properties, and therefore transform the research on semiconductor heterostructures. The demonstration of the type-I band alignment diversifies the current research on van der Waals heterostructures, enables design and fabrication of complex band landscapes, and facilitates application of van der Waals heterostructures in light emitting devices. 1 Introduction Forming heterostructures by combining two materials is one of the key approaches to control electrons in semiconductors, which has led to discoveries such as integer, 1 fractional, 2 and quantum spin Hall effects, 3,4 as well as exciton-polariton condensations. 5 Functional materials based on heterostructures are the cornerstone of many applications including semiconductor lasers and light emitting diodes. Depending on the work functions of the involved materials, two types of band alignments can be formed in heterostructures. A type-I alignment refers to the case where both the conduction band minimum (CBM) and the valence band maximum (VBM) are located in the material with the narrower bandgap, as shown in Fig. 1(a) and (b) . Electrons and holes excited in the wide-gap material transfer to the narrow-gap material, as indicated by the arrows. The quantum confinement of electrons and holes in the same region facilitates their radiative recombination, which is desirable in light-emitting applications. 6 Carriers excited in the narrow-gap material are prohibited from interlayer transfer due to their lower energies. When the CBM and VBM are located in different materials, the alignment is called type-II. Fig. 1(c) and (d) show the situation where the CBM and VBM are located in the narrow-gap and wide-gap materials, respectively. In this case, excitation of the wide-gap material is followed by the transfer of electrons, but not the holes, while opposite charge transfer occurs when the narrow-gap material is excited. The separation of the electrons and holes to different layers can increase their lifetime, and is desired for applications in photovoltaics and photodetection. 7–10 Fig. 1 Schematic of the band alignment between two semiconductors, showing type-I (a and b) and type-II (c and d) alignments. The newly developed two-dimensional materials brought the semiconductor heterostructures to a new regime exhibiting an ultimate thinness, atomically sharp and near-defect-free interfaces, exceptional mechanical flexibility, and chemical stability. 11,12 More importantly, van der Waals interlayer coupling imposes almost no restrictions on the selection of component materials, opening up a huge number of combinations to explore and utilize. So far, most semiconducting van der Waals heterostructures are composed of monolayers (MLs) of different materials in the family of transition metal dichalcogenides (TMDs). Using the four most extensively studied TMDs, namely MoS 2 , MoSe 2 , WS 2 , and WSe 2 , 6 combinations exist, and have all been studied: MoS 2 –MoSe 2 , 13 MoS 2 –WS 2 , 14–18 MoS 2 –WSe 2 , 19–25 MoSe 2 –WSe 2 , 26 MoSe 2 –WSe 2 , 27 and WS 2 –WSe 2 . 28 These heterostructures were all found to be type-II, with qualitatively similar electronic and optical properties. Hence, demonstration of a semiconducting van der Waals heterostructure with type-I band alignment is of fundamental importance for control of electrons in atomically thin materials. Such a structure can facilitate applications of van der Waals heterostructures for light emitting devices and enable designs of sophisticated bandgap landscaping in functional materials. It will also provide a platform to study light–matter interaction in atomically thin systems with adjustable confinement energy, and to study the transport of electron–hole pairs and excitons across van der Waals interfaces. Here we demonstrate the first type-I semiconducting van der Waals heterostructure, MoS 2 –ReS 2 . 2 Results and discussion Our first-principle computation results of the electronic structures of ReS 2 and MoS 2 MLs, as well as the MoS 2 –ReS 2 heterostructure, are shown in Fig. 2(a) and (b) . Details of the first-principle computation are given in the ESI. †", "role": "user" }, { "content": "A cover story appearing in the peer-reviewed journal Nanoscale Horizons reports a new bilayer material, with each layer measuring less than one nanometer in thickness, that someday could lead to more efficient and versatile light emission. Researchers working at the Ultrafast Laser Lab at the University of Kansas successfully created the material by combining atomically thin layers of molybdenum disulfide and rhenium disulfide. \"Both absorb light very well as semiconductors, and they're both very flexible can be stretched or compressed,\" said Hui Zhao, associate professor of physics and astronomy at KU, who co-authored the paper. \"The goal of this whole direction of research is to produce light-emitting devices, such as LEDs that are ultrathin—just a few nanometers thick—and flexible enough that you can bend it. We showed through this bilayer material, it can be achieved.\" To explain the breakthrough, Zhao likens the behavior of electrons in the new material to a classroom. \"One can think of a material as a classroom full of students—which are the electrons—one on each seat,\" he said. \"Sitting on a seat, a student—or electron—can't move freely to conduct electricity. Light can provide enough energy to stand up some of the students, who can now move freely and, as electrons, to conduct electricity. This process is the foundation for photovoltaic devices, where the energy of sunlight is captured and converted to electricity.\" The KU researcher said that emission of light involves the inverse process, in which a standing electron sits down in a seat, releasing its kinetic energy in the form of light. \"To make a good material for light emission devices, one needs not only the electrons that carry energy, but also the 'seats'—called holes—for the electrons to sit down,\" he said. Previous studies by several groups, including Zhao's, have produced various bilayer materials by stacking different types of atomic sheets. However, in these materials, the electrons and the \"seats\" exist in different atomic layers. \"Because electrons cannot easily find seats, light emission efficiency of these bilayer materials is very low – more than 100 times lower than in one atomic layer,\" he said. But in the new material announced by Zhao and his co-authors, \"All the electrons and their seats will be in their original layer, instead of separate. The light emission will be a lot stronger.\" Zhao and fellow researchers Matthew Bellus, Samuel Lane, Frank Ceballos and Qiannan Cui, all KU physics graduate students, and Ming Li and Xiao Cheng Zeng of the University of Nebraska-Lincoln created the new material using the same low-tech \"Scotch tape\" method pioneered in creating graphene, the single-atomic-layer material that won its creators the Nobel Prize for physics in 2010. \"There's a trick,\" Zhao said. \"You use Scotch tape to peel off a layer from the crystal and then you fold the tape a few times, so when you push the tape against a substrate and quickly peel it off, some of the material will be left on the substrate. Under a microscope, single-atom layer sections will have a different color because of their thickness—very much like a thin film of oil on water.\" The researchers at KU's Ultrafast Laser Lab, led by Bellus, the first author of the paper, then accomplished the most challenging step: stacking the MoS2 layer on top of ReS2, with a precision better than one micrometer. The atomically thin sheets were connected by the so-called van der Waals force, the same force which allows a gecko to scale a smooth window pane. \"The van der Waals force isn't very sensitive to the atomic arrangement,\" said Zhao. \"So, one can use these atomic sheets to form multilayer materials, in a fashion like atomic Legos.\" After the samples were made, team members used ultrafast lasers to observe motion of electrons and seats between the two atomic layers, and they saw clear evidence that both electrons and the seats can move from MoS2 to ReS2, but not along the opposite direction. In doing so, the team confirmed theoretical calculations performed by Li and Zeng, who previously had analyzed related properties of about a dozen atomic sheets, and predicted that bilayers formed by MoS2 and ReS2 would have promise as the basis for LED technology. According to Zhao, the ultimate goal is to develop a method that allows precise control of the location of electrons and seats among different atomic layers so that the electronic and optical properties of the material can be controlled and optimized. \"We'd someday like to see LEDs that are thinner, more energy efficient and bendable,\" he said. \"Think about a computer or phone screen if you could fold it a few times or and put it in your pocket.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract We report a van der Waals heterostructure formed by monolayers of MoS 2 and ReS 2 with a type-I band alignment. First-principle calculations show that in this heterostructure, both the conduction band minimum and the valence band maximum are located in the ReS 2 layer. This configuration is different from previously accomplished type-II van der Waals heterostructures where electrons and holes reside in different layers. The type-I nature of this heterostructure is evident by photocarrier dynamics observed by transient absorption measurements. We found that carriers injected in MoS 2 transfer to ReS 2 in about 1 ps, while no charge transfer was observed when carriers are injected in ReS 2 . The carrier lifetime in the heterostructure is similar to that in monolayer ReS 2 , further confirming the lack of charge separation. We attribute the slower transfer time to the incoherent nature of the charge transfer due to the different crystal structures of the two materials forming the heterostructure. The demonstrated type-I semiconducting van der Waals heterostructure provides new ways to utilize two-dimensional materials for light emission applications, and a new platform to study light–matter interaction in atomically thin materials with strong confinement of electrons and holes. This article is part of the themed collection: National Nanotechnology Day Conceptual insights A type-I van der Waals heterostructure is demonstrated. Existing research on vertical van der Waals heterostructures formed by semiconducting two-dimensional materials have focused on structures showing type-II band alignments, where electrons and holes reside in different atomic layers. In the type-I heterostructure formed here, by stacking monolayers of MoS 2 and ReS 2 , both electrons and holes are confined in ReS 2 . Traditional semiconducting heterostructures based on ionic and covalent compounds are important artificial materials for electronic and optoelectronic technologies. Type-I band alignment has been widely achieved in such materials, in the form of semiconducting quantum wells. Due to the enhanced light-matter interaction by confining electrons and holes in the same region, these heterostructures are widely used in light emitting diodes and semiconductor lasers. However, the lattice-matching requirement severely limits the selection of partner materials. The van der Waals materials have the potential to unleash this constrain on achieving “on-demand” properties, and therefore transform the research on semiconductor heterostructures. The demonstration of the type-I band alignment diversifies the current research on van der Waals heterostructures, enables design and fabrication of complex band landscapes, and facilitates application of van der Waals heterostructures in light emitting devices. 1 Introduction Forming heterostructures by combining two materials is one of the key approaches to control electrons in semiconductors, which has led to discoveries such as integer, 1 fractional, 2 and quantum spin Hall effects, 3,4 as well as exciton-polariton condensations. 5 Functional materials based on heterostructures are the cornerstone of many applications including semiconductor lasers and light emitting diodes. Depending on the work functions of the involved materials, two types of band alignments can be formed in heterostructures. A type-I alignment refers to the case where both the conduction band minimum (CBM) and the valence band maximum (VBM) are located in the material with the narrower bandgap, as shown in Fig. 1(a) and (b) . Electrons and holes excited in the wide-gap material transfer to the narrow-gap material, as indicated by the arrows. The quantum confinement of electrons and holes in the same region facilitates their radiative recombination, which is desirable in light-emitting applications. 6 Carriers excited in the narrow-gap material are prohibited from interlayer transfer due to their lower energies. When the CBM and VBM are located in different materials, the alignment is called type-II. Fig. 1(c) and (d) show the situation where the CBM and VBM are located in the narrow-gap and wide-gap materials, respectively. In this case, excitation of the wide-gap material is followed by the transfer of electrons, but not the holes, while opposite charge transfer occurs when the narrow-gap material is excited. The separation of the electrons and holes to different layers can increase their lifetime, and is desired for applications in photovoltaics and photodetection. 7–10 Fig. 1 Schematic of the band alignment between two semiconductors, showing type-I (a and b) and type-II (c and d) alignments. The newly developed two-dimensional materials brought the semiconductor heterostructures to a new regime exhibiting an ultimate thinness, atomically sharp and near-defect-free interfaces, exceptional mechanical flexibility, and chemical stability. 11,12 More importantly, van der Waals interlayer coupling imposes almost no restrictions on the selection of component materials, opening up a huge number of combinations to explore and utilize. So far, most semiconducting van der Waals heterostructures are composed of monolayers (MLs) of different materials in the family of transition metal dichalcogenides (TMDs). Using the four most extensively studied TMDs, namely MoS 2 , MoSe 2 , WS 2 , and WSe 2 , 6 combinations exist, and have all been studied: MoS 2 –MoSe 2 , 13 MoS 2 –WS 2 , 14–18 MoS 2 –WSe 2 , 19–25 MoSe 2 –WSe 2 , 26 MoSe 2 –WSe 2 , 27 and WS 2 –WSe 2 . 28 These heterostructures were all found to be type-II, with qualitatively similar electronic and optical properties. Hence, demonstration of a semiconducting van der Waals heterostructure with type-I band alignment is of fundamental importance for control of electrons in atomically thin materials. Such a structure can facilitate applications of van der Waals heterostructures for light emitting devices and enable designs of sophisticated bandgap landscaping in functional materials. It will also provide a platform to study light–matter interaction in atomically thin systems with adjustable confinement energy, and to study the transport of electron–hole pairs and excitons across van der Waals interfaces. Here we demonstrate the first type-I semiconducting van der Waals heterostructure, MoS 2 –ReS 2 . 2 Results and discussion Our first-principle computation results of the electronic structures of ReS 2 and MoS 2 MLs, as well as the MoS 2 –ReS 2 heterostructure, are shown in Fig. 2(a) and (b) . Details of the first-principle computation are given in the ESI. †<|im_end|> <|im_start|>assistant A cover story appearing in the peer-reviewed journal Nanoscale Horizons reports a new bilayer material, with each layer measuring less than one nanometer in thickness, that someday could lead to more efficient and versatile light emission. Researchers working at the Ultrafast Laser Lab at the University of Kansas successfully created the material by combining atomically thin layers of molybdenum disulfide and rhenium disulfide. "Both absorb light very well as semiconductors, and they're both very flexible can be stretched or compressed," said Hui Zhao, associate professor of physics and astronomy at KU, who co-authored the paper. "The goal of this whole direction of research is to produce light-emitting devices, such as LEDs that are ultrathin—just a few nanometers thick—and flexible enough that you can bend it. We showed through this bilayer material, it can be achieved." To explain the breakthrough, Zhao likens the behavior of electrons in the new material to a classroom. "One can think of a material as a classroom full of students—which are the electrons—one on each seat," he said. "Sitting on a seat, a student—or electron—can't move freely to conduct electricity. Light can provide enough energy to stand up some of the students, who can now move freely and, as electrons, to conduct electricity. This process is the foundation for photovoltaic devices, where the energy of sunlight is captured and converted to electricity." The KU researcher said that emission of light involves the inverse process, in which a standing electron sits down in a seat, releasing its kinetic energy in the form of light. "To make a good material for light emission devices, one needs not only the electrons that carry energy, but also the 'seats'—called holes—for the electrons to sit down," he said. Previous studies by several groups, including Zhao's, have produced various bilayer materials by stacking different types of atomic sheets. However, in these materials, the electrons and the "seats" exist in different atomic layers. "Because electrons cannot easily find seats, light emission efficiency of these bilayer materials is very low – more than 100 times lower than in one atomic layer," he said. But in the new material announced by Zhao and his co-authors, "All the electrons and their seats will be in their original layer, instead of separate. The light emission will be a lot stronger." Zhao and fellow researchers Matthew Bellus, Samuel Lane, Frank Ceballos and Qiannan Cui, all KU physics graduate students, and Ming Li and Xiao Cheng Zeng of the University of Nebraska-Lincoln created the new material using the same low-tech "Scotch tape" method pioneered in creating graphene, the single-atomic-layer material that won its creators the Nobel Prize for physics in 2010. "There's a trick," Zhao said. "You use Scotch tape to peel off a layer from the crystal and then you fold the tape a few times, so when you push the tape against a substrate and quickly peel it off, some of the material will be left on the substrate. Under a microscope, single-atom layer sections will have a different color because of their thickness—very much like a thin film of oil on water." The researchers at KU's Ultrafast Laser Lab, led by Bellus, the first author of the paper, then accomplished the most challenging step: stacking the MoS2 layer on top of ReS2, with a precision better than one micrometer. The atomically thin sheets were connected by the so-called van der Waals force, the same force which allows a gecko to scale a smooth window pane. "The van der Waals force isn't very sensitive to the atomic arrangement," said Zhao. "So, one can use these atomic sheets to form multilayer materials, in a fashion like atomic Legos." After the samples were made, team members used ultrafast lasers to observe motion of electrons and seats between the two atomic layers, and they saw clear evidence that both electrons and the seats can move from MoS2 to ReS2, but not along the opposite direction. In doing so, the team confirmed theoretical calculations performed by Li and Zeng, who previously had analyzed related properties of about a dozen atomic sheets, and predicted that bilayers formed by MoS2 and ReS2 would have promise as the basis for LED technology. According to Zhao, the ultimate goal is to develop a method that allows precise control of the location of electrons and seats among different atomic layers so that the electronic and optical properties of the material can be controlled and optimized. "We'd someday like to see LEDs that are thinner, more energy efficient and bendable," he said. "Think about a computer or phone screen if you could fold it a few times or and put it in your pocket." <|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 African lions ( Panthera leo ) and African savanna ( Loxodonta africana ) and forest ( L. cyclotis ) elephants pose threats to people, crops, and livestock, and are themselves threatened with extinction. Here, we map these human-wildlife conflicts across Africa. Eighty-two percent of sites containing lions and elephants are adjacent to areas with considerable human pressure. Areas at severe risk of conflict (defined as high densities of humans, crops, and cattle) comprise 9% of the perimeter of these species’ ranges and are found in 18 countries hosting, respectively, ~ 74% and 41% of African lion and elephant populations. Although a variety of alternative conflict-mitigation strategies could be deployed, we focus on assessing the potential of high-quality mitigation fences. Our spatial and economic assessments suggest that investments in the construction and maintenance of strategically located mitigation fences would be a cost-effective strategy to support local communities, protect people from dangerous wildlife, and prevent further declines in lion and elephant populations. Introduction Current rates of species extinction are unprecedented 1 and are destined to increase without adequate conservation actions 2 . Large-bodied mammals have suffered significant population declines over the past century and are further threatened by continued habitat loss, unsustainable use, and human–wildlife conflict 3 . The transformation of natural habitat to agriculture and intensive livestock husbandry has not only contracted these species’ ranges and largely restricted their distribution to the confines of protected areas 4 , 5 , 6 , but the closer proximity of human activity to wildlife has also increased the dangers posed to people, livestock, and crops 7 . Human–wildlife conflict involves the tangible and/or perceived impacts of wildlife on people 8 , including human injury and death 9 , direct and indirect economic damage to crops, livestock, and property 10 , food insecurity 11 , and diminished psychological wellbeing 12 . Unmitigated conflict decreases local support for biodiversity conservation 13 and frequently escalates into retaliatory killing of wildlife 14 , 15 . Implementing effective human–wildlife conflict-mitigation strategies has, therefore, become a growing priority for engaging rural communities and preventing localized wildlife extinctions. Mitigation efforts can be broadly classified into tactics that directly or indirectly target wildlife (e.g., culling or translocating problem animals vs. noxious stimuli to deter crop-raiding elephants 16 , or improved livestock husbandry to reduce lion predation 17 ), whereas other approaches attempt to increase tolerance to economic losses inflicted by wildlife (e.g., compensation schemes 18 , performance–payment schemes, and increased benefits to local communities from wildlife-based tourism; see ref. 8 for a review), although the large-scale effectiveness of most of these efforts remains equivocal 8 , 19 , 20 . Africa is one of the last global strongholds for the conservation of large carnivores and herbivores 5 , 7 . However, Africa’s human population is projected to grow from the current 1.2 billion people to nearly two billion by the end of the century 21 and Africa is also the centre of large-scale agricultural investments for the purposes of food and biofuel production 22 . Unsurprisingly, numerous parts of Africa have been identified as major hotspots of human pressure on biodiversity 23 , 24 and pressures will likely intensify further as a result of future pandemics, political instability, or armed conflicts that hinder wildlife-based tourism, reduce effective conservation funding, and undermine national economies 25 . The continent-wide conservation challenges of human–wildlife conflict are encapsulated by the iconic African lion and the African savanna and forest elephants (hereafter referred to as elephants), which have all experienced extensive range contractions 4 , 5 and suffered local extinctions and significant population declines throughout their ranges 26 , 27 , largely owing to (i) habitat loss 28 , (ii) unsustainable hunting 26 , 29 , (iii) retaliatory and preemptive killing to protect humans, livestock, and crops 8 , and (iv) extensive prey depletion (for lions) 30 . Recent evidence suggests that African lion and elephant populations are persisting, or even increasing, in areas where conservation budgets are adequate and/or mitigation fences successfully prevent conflict with humans 19 , 27 , 31 , 32 . According to protected area managers, mitigation fences are essential along boundaries with the highest human, crop, and livestock densities, as alternative mitigation strategies are often ineffective 33 (but see ref. 20 on the lack of quantitative comparisons about the utility of the alternatives) and mitigation fences are currently found in at least ten African countries, despite the costs of attaining the necessary standards 19 , 33 . However, a number of conservationists have expressed opposition to fencing on the grounds that large-scale barriers have often disrupted wildlife movements and decreased landscape connectivity in the past, and that these impacts will be likely to intensify as species respond to climate change 34 . However, these concerns were largely inspired by the widespread deployment of veterinary fences in southern Africa, where barriers were erected to prevent disease transmission from wildlife to livestock with little regard for their ecological impacts on migratory wildlife species 35 . Thus, the ongoing debate on the costs and benefits of fencing for both people and wildlife should turn its focus to identifying boundaries where fencing can be a financially sustainable strategy for preventing human–wildlife conflict, while minimizing any negative conservation impacts 36 . Here we identify the areas that are most at risk for conflicts and estimate the associated return on investment of building and maintaining mitigation fences. Our analysis combines the most up-to-date information on the distribution of lions and elephants with spatial information on human population density, cropland, and cattle density, as these are considered to be the major drivers of human–wildlife conflict in Africa 4 , 8 . Conflict decreases with distance from protected areas 37 , 38 ; thus, we identify areas on the perimeter of the ranges of lions and elephants that are within 10 km of the highest densities of humans, cattle, and crops. To avoid interrupting ecological processes such as migrations and/or causing unintended consequences to other biodiversity (e.g., habitat fragmentation),", "role": "user" }, { "content": "Elephants and lions are iconic species that help raise substantial funds for conservation. However, they also pose significant threats to people, crops, and livestock, and are themselves threatened with extinction. Areas at severe risk are identified In a new article published in the journal Nature Communications, scientists have identified the areas that are most at risk for conflicts between humans and elephants and lions in Africa. They also estimated the associated return on investment of building and maintaining high-quality fences, which are used to reduce conflict between humans and wildlife. Associate Professor Enrico Di Minin, who is the lead author of this article and leads the Helsinki Lab of Interdisciplinary Conservation Science at the University of Helsinki, highlights that human pressure on elephants and lions is extremely high. \"We found that 82% of sites containing lions and elephants in Africa are adjacent to areas with considerable human pressure,\" says Di Minin. Distribution of African lions (Panthera leo) and African elephants (Loxodonta africana and Loxodonta cyclotis), and regional contribution to their conservation. Credit: Di Minin et al. \"Areas at severe risk of conflict (defined as areas with high densities of humans, crops, and cattle) comprise 9% of the perimeter of these species' ranges and are found in 18 countries hosting, respectively, ~ 74% and 41% of African lion and elephant populations,\" he continues. African forest and savanna elephants have recently been classified as Critically Endangered and Endangered in the IUCN Red List of species, while African lions are classified as Vulnerable. Human activities pose the greatest threats to these species, particularly retaliatory killings of lions in response to livestock losses and of elephants in response to crop damage. Elephants and lions also kill dozens to hundreds of people each year. Areas at risk of conflict on the extended ranges of African lions (Panthera leo) and African elephants (Loxodonta africana and Loxodonta cyclotis). Credit: Di Minin et al. \"We found that elephants and lions are now most abundant at localities where human population density is lowest. At a national scale, lion populations are higher in countries where funding for conservation is higher and elephant numbers are higher in countries with higher gross domestic product per capita,\" states Professor Rob Slotow from the University of KwaZulu-Natal in South Africa \"We also found that areas at high risk of conflict are especially found in East and West Africa,\" he continuous. Benefits of mitigation fences Although a variety of conflict mitigation strategies could be deployed to address human-wildlife conflict, the team has assessed the return on investment of deploying high-quality mitigation fences, which have been found to be effective in reducing human-wildlife but are very expensive to build and maintain. \"Our results show how mitigation fences would provide considerable return on investment via reduced cattle loss and crop damage, especially in Tanzania, Ethiopia, and Kenya,\" says Professor Craig Packer from the University of Minnesota in the US. \"Our analysis reveals the location of about 10,000 kms of protected-area boundaries immediately adjacent to landscapes with such high densities of people, farmland and cattle pastures that wildlife movements have already been largely blocked. Mitigation fencing would merely reflect the reality of conserving large, dangerous, wildlife species in the Anthropocene. More and more African countries are starting to rely on mitigation fencing to better protect their citizens from the most dangerous wildlife species.\", he continues. The authors highlight how attention should be paid to prevent further habitat fragmentation for any migratory species that still manage to traverse the worst affected areas and to carefully consider the values, preferences, and motivations of local people before building mitigation fences. \"However, areas of intensive human pressure already produce hard boundaries around remaining areas of natural habitat and bold strategies to conserve these species are immediately needed, especially as human pressure will increase in the future with Africa experiencing very high human population growth by the end of the century,\" concludes Associate Professor Enrico Di Minin. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract African lions ( Panthera leo ) and African savanna ( Loxodonta africana ) and forest ( L. cyclotis ) elephants pose threats to people, crops, and livestock, and are themselves threatened with extinction. Here, we map these human-wildlife conflicts across Africa. Eighty-two percent of sites containing lions and elephants are adjacent to areas with considerable human pressure. Areas at severe risk of conflict (defined as high densities of humans, crops, and cattle) comprise 9% of the perimeter of these species’ ranges and are found in 18 countries hosting, respectively, ~ 74% and 41% of African lion and elephant populations. Although a variety of alternative conflict-mitigation strategies could be deployed, we focus on assessing the potential of high-quality mitigation fences. Our spatial and economic assessments suggest that investments in the construction and maintenance of strategically located mitigation fences would be a cost-effective strategy to support local communities, protect people from dangerous wildlife, and prevent further declines in lion and elephant populations. Introduction Current rates of species extinction are unprecedented 1 and are destined to increase without adequate conservation actions 2 . Large-bodied mammals have suffered significant population declines over the past century and are further threatened by continued habitat loss, unsustainable use, and human–wildlife conflict 3 . The transformation of natural habitat to agriculture and intensive livestock husbandry has not only contracted these species’ ranges and largely restricted their distribution to the confines of protected areas 4 , 5 , 6 , but the closer proximity of human activity to wildlife has also increased the dangers posed to people, livestock, and crops 7 . Human–wildlife conflict involves the tangible and/or perceived impacts of wildlife on people 8 , including human injury and death 9 , direct and indirect economic damage to crops, livestock, and property 10 , food insecurity 11 , and diminished psychological wellbeing 12 . Unmitigated conflict decreases local support for biodiversity conservation 13 and frequently escalates into retaliatory killing of wildlife 14 , 15 . Implementing effective human–wildlife conflict-mitigation strategies has, therefore, become a growing priority for engaging rural communities and preventing localized wildlife extinctions. Mitigation efforts can be broadly classified into tactics that directly or indirectly target wildlife (e.g., culling or translocating problem animals vs. noxious stimuli to deter crop-raiding elephants 16 , or improved livestock husbandry to reduce lion predation 17 ), whereas other approaches attempt to increase tolerance to economic losses inflicted by wildlife (e.g., compensation schemes 18 , performance–payment schemes, and increased benefits to local communities from wildlife-based tourism; see ref. 8 for a review), although the large-scale effectiveness of most of these efforts remains equivocal 8 , 19 , 20 . Africa is one of the last global strongholds for the conservation of large carnivores and herbivores 5 , 7 . However, Africa’s human population is projected to grow from the current 1.2 billion people to nearly two billion by the end of the century 21 and Africa is also the centre of large-scale agricultural investments for the purposes of food and biofuel production 22 . Unsurprisingly, numerous parts of Africa have been identified as major hotspots of human pressure on biodiversity 23 , 24 and pressures will likely intensify further as a result of future pandemics, political instability, or armed conflicts that hinder wildlife-based tourism, reduce effective conservation funding, and undermine national economies 25 . The continent-wide conservation challenges of human–wildlife conflict are encapsulated by the iconic African lion and the African savanna and forest elephants (hereafter referred to as elephants), which have all experienced extensive range contractions 4 , 5 and suffered local extinctions and significant population declines throughout their ranges 26 , 27 , largely owing to (i) habitat loss 28 , (ii) unsustainable hunting 26 , 29 , (iii) retaliatory and preemptive killing to protect humans, livestock, and crops 8 , and (iv) extensive prey depletion (for lions) 30 . Recent evidence suggests that African lion and elephant populations are persisting, or even increasing, in areas where conservation budgets are adequate and/or mitigation fences successfully prevent conflict with humans 19 , 27 , 31 , 32 . According to protected area managers, mitigation fences are essential along boundaries with the highest human, crop, and livestock densities, as alternative mitigation strategies are often ineffective 33 (but see ref. 20 on the lack of quantitative comparisons about the utility of the alternatives) and mitigation fences are currently found in at least ten African countries, despite the costs of attaining the necessary standards 19 , 33 . However, a number of conservationists have expressed opposition to fencing on the grounds that large-scale barriers have often disrupted wildlife movements and decreased landscape connectivity in the past, and that these impacts will be likely to intensify as species respond to climate change 34 . However, these concerns were largely inspired by the widespread deployment of veterinary fences in southern Africa, where barriers were erected to prevent disease transmission from wildlife to livestock with little regard for their ecological impacts on migratory wildlife species 35 . Thus, the ongoing debate on the costs and benefits of fencing for both people and wildlife should turn its focus to identifying boundaries where fencing can be a financially sustainable strategy for preventing human–wildlife conflict, while minimizing any negative conservation impacts 36 . Here we identify the areas that are most at risk for conflicts and estimate the associated return on investment of building and maintaining mitigation fences. Our analysis combines the most up-to-date information on the distribution of lions and elephants with spatial information on human population density, cropland, and cattle density, as these are considered to be the major drivers of human–wildlife conflict in Africa 4 , 8 . Conflict decreases with distance from protected areas 37 , 38 ; thus, we identify areas on the perimeter of the ranges of lions and elephants that are within 10 km of the highest densities of humans, cattle, and crops. To avoid interrupting ecological processes such as migrations and/or causing unintended consequences to other biodiversity (e.g., habitat fragmentation),<|im_end|> <|im_start|>assistant Elephants and lions are iconic species that help raise substantial funds for conservation. However, they also pose significant threats to people, crops, and livestock, and are themselves threatened with extinction. Areas at severe risk are identified In a new article published in the journal Nature Communications, scientists have identified the areas that are most at risk for conflicts between humans and elephants and lions in Africa. They also estimated the associated return on investment of building and maintaining high-quality fences, which are used to reduce conflict between humans and wildlife. Associate Professor Enrico Di Minin, who is the lead author of this article and leads the Helsinki Lab of Interdisciplinary Conservation Science at the University of Helsinki, highlights that human pressure on elephants and lions is extremely high. "We found that 82% of sites containing lions and elephants in Africa are adjacent to areas with considerable human pressure," says Di Minin. Distribution of African lions (Panthera leo) and African elephants (Loxodonta africana and Loxodonta cyclotis), and regional contribution to their conservation. Credit: Di Minin et al. "Areas at severe risk of conflict (defined as areas with high densities of humans, crops, and cattle) comprise 9% of the perimeter of these species' ranges and are found in 18 countries hosting, respectively, ~ 74% and 41% of African lion and elephant populations," he continues. African forest and savanna elephants have recently been classified as Critically Endangered and Endangered in the IUCN Red List of species, while African lions are classified as Vulnerable. Human activities pose the greatest threats to these species, particularly retaliatory killings of lions in response to livestock losses and of elephants in response to crop damage. Elephants and lions also kill dozens to hundreds of people each year. Areas at risk of conflict on the extended ranges of African lions (Panthera leo) and African elephants (Loxodonta africana and Loxodonta cyclotis). Credit: Di Minin et al. "We found that elephants and lions are now most abundant at localities where human population density is lowest. At a national scale, lion populations are higher in countries where funding for conservation is higher and elephant numbers are higher in countries with higher gross domestic product per capita," states Professor Rob Slotow from the University of KwaZulu-Natal in South Africa "We also found that areas at high risk of conflict are especially found in East and West Africa," he continuous. Benefits of mitigation fences Although a variety of conflict mitigation strategies could be deployed to address human-wildlife conflict, the team has assessed the return on investment of deploying high-quality mitigation fences, which have been found to be effective in reducing human-wildlife but are very expensive to build and maintain. "Our results show how mitigation fences would provide considerable return on investment via reduced cattle loss and crop damage, especially in Tanzania, Ethiopia, and Kenya," says Professor Craig Packer from the University of Minnesota in the US. "Our analysis reveals the location of about 10,000 kms of protected-area boundaries immediately adjacent to landscapes with such high densities of people, farmland and cattle pastures that wildlife movements have already been largely blocked. Mitigation fencing would merely reflect the reality of conserving large, dangerous, wildlife species in the Anthropocene. More and more African countries are starting to rely on mitigation fencing to better protect their citizens from the most dangerous wildlife species.", he continues. The authors highlight how attention should be paid to prevent further habitat fragmentation for any migratory species that still manage to traverse the worst affected areas and to carefully consider the values, preferences, and motivations of local people before building mitigation fences. "However, areas of intensive human pressure already produce hard boundaries around remaining areas of natural habitat and bold strategies to conserve these species are immediately needed, especially as human pressure will increase in the future with Africa experiencing very high human population growth by the end of the century," concludes Associate Professor Enrico Di Minin. <|im_end|>

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2,096

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Anisotropic exchange splitting in semiconductor quantum dots results in bright-exciton fine-structure splitting important for quantum information processing. Direct measurement of fine-structure splitting usually requires single/few quantum dots at liquid-helium temperature because of its sensitivity to quantum dot size and shape, whereas measuring and controlling fine-structure splitting at an ensemble level seem to be impossible unless all the dots are made to be nearly identical. Here we report strong bright-exciton fine-structure splitting up to 1.6 meV in solution-processed CsPbI 3 perovskite quantum dots, manifested as quantum beats in ensemble-level transient absorption at liquid-nitrogen to room temperature. The splitting is robust to quantum dot size and shape heterogeneity, and increases with decreasing temperature, pointing towards a mechanism associated with orthorhombic distortion of the perovskite lattice. Effective-mass-approximation calculations reveal an intrinsic ‘fine-structure gap’ that agrees well with the observed fine-structure splitting. This gap stems from an avoided crossing of bright excitons confined in orthorhombically distorted quantum dots that are bounded by the pseudocubic {100} family of planes. Main Semiconductor quantum dots (QDs) constitute an important material platform for quantum information science (QIS) 1 . While earlier efforts on QD-related QIS focus on epitaxially grown QDs, more recent attention has been paid to low-cost, solution-processable counterparts called colloidal QDs or nanocrystals 2 . Colloidal QDs have achieved great success in applications such as light-emitting diodes, lasers and photodetectors and in solar energy conversion 3 , 4 . Their implementation into QIS, however, has remained challenging due to the intrinsic ‘lossy’ nature of these materials (such as defects, dangling bonds and surface ligands). For example, photon emission from colloidal QDs is often unstable (due to ‘blinking’ phenomena) 5 , 6 and incoherent. Consequently they have not previously been comparable with epitaxial QDs for application as single-photon sources 7 , 8 . Nevertheless, recent studies suggest that a unique combination of fast radiative emission and long optical coherence in solution-grown lead halide perovskite QDs did give rise to highly coherent single-photon emission 9 , 10 , heralding perovskite colloidal QDs as candidates for quantum emitters. In addition to single-photon emission, another property closely connected to QIS applications is the exciton fine-structure splitting (FSS) induced by the electron–hole exchange interaction. In perovskite QDs, the major effect of this interaction is to split the exciton into a dark (optically inactive) singlet level and a bright (optically active) triplet 11 , 12 , 13 . In addition, anisotropy due to QD shape or orthorhombic lattice symmetry causes a further splitting of the bright triplet into three levels whose transition dipoles are oriented along the symmetry axes of the QD (Fig. 1a ), with splitting typically ranging from a few to 100 s of microelectronvolts 11 , 12 , 13 , 14 , 15 , 16 . The resulting bright FFS states can be exploited for coherent control of quantum states for quantum computing 17 , 18 or for polarization-entangled photon pairs in quantum optics 11 , although for the latter it is important to suppress the magnitude of the FSS in order to increase photon indistinguishability in energy 19 , 20 . Thus, exchange-split bright excitons are closely relevant to the quantum coherence and entanglement that are essential for quantum information technologies. Fig. 1: Principle of FSS and sample information. a , The bright triplet |1,±1〉 exciton states in cubic symmetry transform into two new eigenstates | X 〉 and | Y 〉 in orthorhombic QDs. The splitting between | X 〉 and | Y 〉 is Δ FSS . | G 〉 is the crystal ground state while | Z 〉 = |1,0〉 is the exciton state with its transition dipole oriented along the Z axis. For illustration, we consider excitation using a circularly polarized pulse directed along the Z axis with bandwidth larger than Δ FSS , which can create a coherent superposition of | X 〉 and | Y 〉. b , A representative TEM image of 7.9 nm QDs. Inset is a high-resolution dark-field image of a typical QD. c , d , Absorption ( c ) and photoluminescence ( d ) spectra of varying-size QDs dispersed in hexane. Source data Full size image Bright-exciton FSS in epitaxial QDs can be observed using polarization-resolved micro-photoluminescence of single/few QDs at a temperature of a few kelvins 21 , but there have been only limited reports of such experiments for colloidal CdSe QDs due to the slow emission in these systems 22 . By contrast, the fast, efficient emission in perovskite QDs has enabled multiple reports of bright-exciton FSS using single-QD micro-photoluminescence, which typically exhibits substantial dispersity due to the sensitivity of FSS to size and shape non-uniformity 11 , 12 , 13 , 14 , 15 , 16 . Therefore, ensemble-level measurements of FSS in perovskite QDs seem to be impractical. Here we report strong bright-exciton FSS up to 1.6 meV in CsPbI 3 QDs measured with ensemble-level circularly polarized transient absorption (TA) performed in the regime of liquid-nitrogen temperature to room temperature. The FSS is manifested as time-domain coherent exciton quantum beats that are surprisingly robust to QD size and shape non-uniformity, and can be readily modulated through temperature. Effective-mass model calculations, in conjunction with temperature-dependent X-ray diffraction measurements, indicate that the observed FSS originates from an avoided crossing fine-structure gap between bright excitons. The excitons are confined in orthorhombic-phase QDs, but these QDs are bounded by the pseudocubic {100} family of planes instead of the low index orthorhombic crystal planes, as revealed here by transmission electron microscope (TEM) imaging. This salient feature results in the gap that can be detected in spite of QD size and shape heterogeneity across an ensemble sample. Quantum beats in ensemble QDs CsPbI 3 QDs of varying sizes were synthesized using a hot-injection method developed in prior studies 23 , 24 , 25 ; details can be found in the Methods . Their TEM images are shown in Supplementary Fig. 1 , exhibiting cuboid nanocrystals with average edge lengths ranging from 4.9 to 17.3 nm. A typical TEM", "role": "user" }, { "content": "A research group led by Prof. Wu Kaifeng from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences (CAS), in collaboration with Dr. Peter C. Sercel from the Center for Hybrid Organic Inorganic Semiconductors for Energy, recently reported the utilization of lattice distortion in lead halide perovskite quantum dots (QDs) to control their exciton fine structure. The study was published in Nature Materials on Sept. 8. It is well known that shape or crystal anisotropy in QDs, which are tiny semiconductor nanoparticles, results in energy splitting of their optically bright excitons (bound electron-hole pairs), known as fine structure splitting (FSS). These excitons form an important playground for quantum information science. For example, the excitons' FSS can be exploited for coherent control of quantum states for quantum computing, or for polarization-entangled photon-pairs in quantum optics, although for the latter it is important to suppress the magnitude of splitting. Traditionally, studying FSS usually requires single or just a few QDs at liquid-helium temperature, because of its sensitivity to QD size and shape. Measuring FSS at an ensemble-level, let alone controlling it, seems impossible unless all the dots are made to be nearly identical. In this study, by using ensemble-level femtosecond polarized transient absorption, the researchers observed clear bright-exciton FSS in solution-processed CsPbI3 perovskite QDs, which is manifested as exciton quantum beats (periodic oscillations of kinetic traces). \"Even more amazingly, the beat frequency, as determined by the FSS energy, of a given sample can be continuously controlled by changing the temperature. This is an unprecedented result, meaning that now scientists can facilely control FSS through temperature,\" said Prof. Wu. The researchers also found that the temperature-dependent FSS was related to the interesting, highly-dynamic lattice of lead halide perovskites. Lowering the temperature led to a more distorted lead-iodide octahedral framework. Calculations indicated that, because these orthorhombic-phase QDs were actually still bounded by the pseudocubic family of crystal planes, the lattice distortion results in an avoided crossing fine-structure gap between bright exciton. This gap was responsible for the observed FSS, and it could be detected in spite of QD size and shape heterogeneity across an ensemble sample. \"Lattice distortion in CsPbI3 perovskites is well known in the photovoltaic community, as it is connected to the issue of phase stability of perovskite solar cells, but nobody has previously connected it experimentally to the exciton fine structure\" said Prof. Wu. \"Our study demonstrates that this material property can actually be harnessed to control the bright-exciton splitting in quantum dots for quantum information technologies.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Anisotropic exchange splitting in semiconductor quantum dots results in bright-exciton fine-structure splitting important for quantum information processing. Direct measurement of fine-structure splitting usually requires single/few quantum dots at liquid-helium temperature because of its sensitivity to quantum dot size and shape, whereas measuring and controlling fine-structure splitting at an ensemble level seem to be impossible unless all the dots are made to be nearly identical. Here we report strong bright-exciton fine-structure splitting up to 1.6 meV in solution-processed CsPbI 3 perovskite quantum dots, manifested as quantum beats in ensemble-level transient absorption at liquid-nitrogen to room temperature. The splitting is robust to quantum dot size and shape heterogeneity, and increases with decreasing temperature, pointing towards a mechanism associated with orthorhombic distortion of the perovskite lattice. Effective-mass-approximation calculations reveal an intrinsic ‘fine-structure gap’ that agrees well with the observed fine-structure splitting. This gap stems from an avoided crossing of bright excitons confined in orthorhombically distorted quantum dots that are bounded by the pseudocubic {100} family of planes. Main Semiconductor quantum dots (QDs) constitute an important material platform for quantum information science (QIS) 1 . While earlier efforts on QD-related QIS focus on epitaxially grown QDs, more recent attention has been paid to low-cost, solution-processable counterparts called colloidal QDs or nanocrystals 2 . Colloidal QDs have achieved great success in applications such as light-emitting diodes, lasers and photodetectors and in solar energy conversion 3 , 4 . Their implementation into QIS, however, has remained challenging due to the intrinsic ‘lossy’ nature of these materials (such as defects, dangling bonds and surface ligands). For example, photon emission from colloidal QDs is often unstable (due to ‘blinking’ phenomena) 5 , 6 and incoherent. Consequently they have not previously been comparable with epitaxial QDs for application as single-photon sources 7 , 8 . Nevertheless, recent studies suggest that a unique combination of fast radiative emission and long optical coherence in solution-grown lead halide perovskite QDs did give rise to highly coherent single-photon emission 9 , 10 , heralding perovskite colloidal QDs as candidates for quantum emitters. In addition to single-photon emission, another property closely connected to QIS applications is the exciton fine-structure splitting (FSS) induced by the electron–hole exchange interaction. In perovskite QDs, the major effect of this interaction is to split the exciton into a dark (optically inactive) singlet level and a bright (optically active) triplet 11 , 12 , 13 . In addition, anisotropy due to QD shape or orthorhombic lattice symmetry causes a further splitting of the bright triplet into three levels whose transition dipoles are oriented along the symmetry axes of the QD (Fig. 1a ), with splitting typically ranging from a few to 100 s of microelectronvolts 11 , 12 , 13 , 14 , 15 , 16 . The resulting bright FFS states can be exploited for coherent control of quantum states for quantum computing 17 , 18 or for polarization-entangled photon pairs in quantum optics 11 , although for the latter it is important to suppress the magnitude of the FSS in order to increase photon indistinguishability in energy 19 , 20 . Thus, exchange-split bright excitons are closely relevant to the quantum coherence and entanglement that are essential for quantum information technologies. Fig. 1: Principle of FSS and sample information. a , The bright triplet |1,±1〉 exciton states in cubic symmetry transform into two new eigenstates | X 〉 and | Y 〉 in orthorhombic QDs. The splitting between | X 〉 and | Y 〉 is Δ FSS . | G 〉 is the crystal ground state while | Z 〉 = |1,0〉 is the exciton state with its transition dipole oriented along the Z axis. For illustration, we consider excitation using a circularly polarized pulse directed along the Z axis with bandwidth larger than Δ FSS , which can create a coherent superposition of | X 〉 and | Y 〉. b , A representative TEM image of 7.9 nm QDs. Inset is a high-resolution dark-field image of a typical QD. c , d , Absorption ( c ) and photoluminescence ( d ) spectra of varying-size QDs dispersed in hexane. Source data Full size image Bright-exciton FSS in epitaxial QDs can be observed using polarization-resolved micro-photoluminescence of single/few QDs at a temperature of a few kelvins 21 , but there have been only limited reports of such experiments for colloidal CdSe QDs due to the slow emission in these systems 22 . By contrast, the fast, efficient emission in perovskite QDs has enabled multiple reports of bright-exciton FSS using single-QD micro-photoluminescence, which typically exhibits substantial dispersity due to the sensitivity of FSS to size and shape non-uniformity 11 , 12 , 13 , 14 , 15 , 16 . Therefore, ensemble-level measurements of FSS in perovskite QDs seem to be impractical. Here we report strong bright-exciton FSS up to 1.6 meV in CsPbI 3 QDs measured with ensemble-level circularly polarized transient absorption (TA) performed in the regime of liquid-nitrogen temperature to room temperature. The FSS is manifested as time-domain coherent exciton quantum beats that are surprisingly robust to QD size and shape non-uniformity, and can be readily modulated through temperature. Effective-mass model calculations, in conjunction with temperature-dependent X-ray diffraction measurements, indicate that the observed FSS originates from an avoided crossing fine-structure gap between bright excitons. The excitons are confined in orthorhombic-phase QDs, but these QDs are bounded by the pseudocubic {100} family of planes instead of the low index orthorhombic crystal planes, as revealed here by transmission electron microscope (TEM) imaging. This salient feature results in the gap that can be detected in spite of QD size and shape heterogeneity across an ensemble sample. Quantum beats in ensemble QDs CsPbI 3 QDs of varying sizes were synthesized using a hot-injection method developed in prior studies 23 , 24 , 25 ; details can be found in the Methods . Their TEM images are shown in Supplementary Fig. 1 , exhibiting cuboid nanocrystals with average edge lengths ranging from 4.9 to 17.3 nm. A typical TEM<|im_end|> <|im_start|>assistant A research group led by Prof. Wu Kaifeng from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences (CAS), in collaboration with Dr. Peter C. Sercel from the Center for Hybrid Organic Inorganic Semiconductors for Energy, recently reported the utilization of lattice distortion in lead halide perovskite quantum dots (QDs) to control their exciton fine structure. The study was published in Nature Materials on Sept. 8. It is well known that shape or crystal anisotropy in QDs, which are tiny semiconductor nanoparticles, results in energy splitting of their optically bright excitons (bound electron-hole pairs), known as fine structure splitting (FSS). These excitons form an important playground for quantum information science. For example, the excitons' FSS can be exploited for coherent control of quantum states for quantum computing, or for polarization-entangled photon-pairs in quantum optics, although for the latter it is important to suppress the magnitude of splitting. Traditionally, studying FSS usually requires single or just a few QDs at liquid-helium temperature, because of its sensitivity to QD size and shape. Measuring FSS at an ensemble-level, let alone controlling it, seems impossible unless all the dots are made to be nearly identical. In this study, by using ensemble-level femtosecond polarized transient absorption, the researchers observed clear bright-exciton FSS in solution-processed CsPbI3 perovskite QDs, which is manifested as exciton quantum beats (periodic oscillations of kinetic traces). "Even more amazingly, the beat frequency, as determined by the FSS energy, of a given sample can be continuously controlled by changing the temperature. This is an unprecedented result, meaning that now scientists can facilely control FSS through temperature," said Prof. Wu. The researchers also found that the temperature-dependent FSS was related to the interesting, highly-dynamic lattice of lead halide perovskites. Lowering the temperature led to a more distorted lead-iodide octahedral framework. Calculations indicated that, because these orthorhombic-phase QDs were actually still bounded by the pseudocubic family of crystal planes, the lattice distortion results in an avoided crossing fine-structure gap between bright exciton. This gap was responsible for the observed FSS, and it could be detected in spite of QD size and shape heterogeneity across an ensemble sample. "Lattice distortion in CsPbI3 perovskites is well known in the photovoltaic community, as it is connected to the issue of phase stability of perovskite solar cells, but nobody has previously connected it experimentally to the exciton fine structure" said Prof. Wu. "Our study demonstrates that this material property can actually be harnessed to control the bright-exciton splitting in quantum dots for quantum information technologies." <|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 Mitochondria are essential organelles, found within eukaryotic cells, which contain their own DNA. Mitochondrial DNA (mtDNA) has traditionally been used in population genetic and biogeographic studies as a maternally-inherited and evolutionary-neutral genetic marker. However, it is now clear that polymorphisms within the mtDNA sequence are routinely non-neutral, and furthermore several studies have suggested that such mtDNA polymorphisms are also sensitive to thermal selection. These observations led to the formulation of the “mitochondrial climatic adaptation” hypothesis, for which all published evidence to date is correlational. Here, we use laboratory-based experimental evolution in the fruit fly, Drosophila melanogaster , to test whether thermal selection can shift population frequencies of two mtDNA haplogroups whose natural frequencies exhibit clinal associations with latitude along the Australian east-coast. We present experimental evidence that the thermal regime in which the laboratory populations were maintained drove changes in haplogroup frequencies across generations. Our results strengthen the emerging view that intra-specific mtDNA variants are sensitive to selection, and suggest spatial distributions of mtDNA variants in natural populations of metazoans might reflect adaptation to climatic environments rather than within-population coalescence and diffusion of selectively-neutral haplotypes across populations. Introduction Mitochondrial DNA (mtDNA) is usually maternally inherited 1 , and was long considered a neutral evolutionary marker 2 . Accordingly, the mtDNA has been routinely harnessed as a quintessential tool in phylogenetics, population genetic studies, and especially in phylogeographic reconstructions seeking to understand demographic responses to postglacial climate change 3 . Nevertheless, non-neutral evolution of DNA can compromise historical inferences in population and evolutionary biology 4 . Selection on standing genetic variation plays an important role in facilitating rapid adaptation to novel environments 5 , 6 , and evidence published over the past two decades has suggested that a sizeable amount of genetic variation within the mitochondrial genome is sensitive to natural selection, and exerts strong effects on the phenotype 7 , 8 , 9 , 10 , 11 . Previously, it has been suggested that the thermal environment is likely to impose particularly strong selection on the mtDNA sequence 9 , 12 . The underpinning logic is that mitochondrial genes encode multiple subunits in four of the five enzyme complexes that drive mitochondrial respiration, and these enzymatic processes are highly temperature sensitive. The mitochondria of poikilotherms will, for example, presumably be constantly exposed to the prevailing environmental temperature. On the other hand, the mitochondria of homeotherms are not just involved in the production of ATP, but also the production of heat via the uncoupling of mitochondrial respiration 13 , 14 . Thus, particular mitochondrial polymorphisms might accumulate that confer highly efficient ATP production, but at the expense of heat production, or vice versa . Thus, adaptation to novel environments might routinely involve selection of mitochondrial polymorphisms that optimize thermal performance in those environments, and this process might be relevant to all metazoans, both poikilothermic or homeothermic, and indeed to all eukaryote life. In support of this contention, emerging data indicate that not all mitochondrial haplotypes perform equally well under the same thermal conditions – some perform best when it is warmer, others when it is colder 15 , 16 , 17 , 18 , 19 . Correlative molecular data in humans are also consistent with the idea that certain mitochondrial mutations might represent adaptations to cold climates 20 , 21 , 22 , 23 , and thus support is growing for a hypothesis, which suggests that polymorphisms that accumulate across mtDNA haplotypes found in different spatial locations have been shaped by selection to the prevailing climate. This hypothesis was termed the “mitochondrial climatic adaptation” hypothesis in 2017 24 . Currently, this hypothesis remains contentious, primarily because the conclusions of previous studies have, by and large, been based on correlations between mutational patterns in the mtDNA sequence and climatic regions, many of which have proven difficult to replicate in other or larger datasets 25 , 26 . We therefore decided to apply experimental evolution to test the mitochondrial climatic adaptation hypothesis, by determining whether multigenerational exposure of replicated populations of fruit flies to different thermal conditions leads to consistent changes in the population frequencies of naturally-occurring mtDNA haplotypes. In the wild, different locally-adapted populations routinely come into secondary contact and hybridize, which enables selection of novel mito-nuclear genotypes that might be better suited to a new or changing environment 27 . Such an evolutionary scenario is likely to have become increasingly common in the Anthropocene, wherein humans have rapidly altered both climatic conditions and levels of habitat connectivity 28 . We reproduced such a hybridization event under controlled laboratory conditions by interbreeding two subpopulations of D. melanogaster , each adapted to thermal environments at a different end of an established and well-studied latitudinal cline 29 , 30 . It is thought that the species was introduced into Australia during the past one to two hundred years, probably via recurrent introductions of flies from both African and European origins 30 , 31 . The species has been studied extensively in the context of thermal adaptation along latitudinal clines, both within Australia, and other replicated clines in other continents 29 , 30 , 32 . This research has shown that numerous phenotypes related to thermal tolerance exhibit linear associations with latitude, and that these patterns are underscored by linear associations of key candidate nuclear genes 29 . Yet, no research had focused on the quantitative spatial distribution of mtDNA variants 32 , until Camus et al . 24 reported that similar clinal patterns are found for two phylogenetic groups of mtDNA haplotypes (haplogroups) along the eastern coast of Australia. Furthermore, Camus et al . 24 were able to map these clinal patterns of mtDNA variation to the phenotype, showing that the mtDNA haplotype that predominates at subtropical latitudes confers superior resistance to extreme heat exposure, but inferior resistance to cold exposure than its temperate-predominant counterparts. To characterize our model system in detail, we designed a study based on experimental evolution, in which we submitted replicated laboratory populations of D. melanogaster to one of", "role": "user" }, { "content": "A new study by researchers at Okinawa Institute of Science and Technology Graduate University (OIST), provides evidence towards selection in mtDNA due to variations in temperature. In multicellular organisms, including humans, most DNA is coiled up within the cell's nucleus. A small part, however, is tucked away within the mitochondria— organelles that produce energy and regulate many metabolic processes within the cell. Unlike nuclear DNA, which is inherited from both parents, mitochondrial DNA (mtDNA) is usually passed down from one generation to the next only through the mother. Researchers have long assumed that variations in the nucleotide sequence of the small mtDNA neither affects cell functioning nor undergoes natural selection. For these reasons, it has been considered a quintessential tool in many fields of science, from genetics to climate change, to examine evolutionary history and relationships among individuals or groups of organisms. However, there is growing evidence that some mtDNA variants can get selected over the others under certain circumstances. A new study by researchers at Okinawa Institute of Science and Technology Graduate University (OIST), in collaboration with Monash University in Australia and University College London in the UK, has found that mtDNA can be even more subjected to selection than currently believed. Dr. Zdenek Lajbner and his colleagues from the OIST Physics and Biology Unit, led by Professor Jonathan Miller, conducted experiments with fruit flies (Drosophila melanogaster) to demonstrate how differences in environmental temperature can influence the selection of one mtDNA variant over another. \"Our design is the first of its kind when it comes to inferring the role of thermal selection in shaping mtDNA frequencies in nature,\" says Dr. Lajbner, lead author of the study, which was published in Scientific Reports. Fruit flies were collected from two sites in Australia: a northern site that had a warm sub-tropical climate, and a southern site that had a cold temperate climate. The flies from the two sites were then interbred in the laboratory. The initial stage, called admixture, took place at 25ºC, and the later generations were reared in bottles maintained at different temperatures ranging from warm to cold. While two bottles were maintained in constant 19ºC and 25ºC, the temperature in the other two bottles simulated the thermal conditions of the two sites from where the flies were collected (fluctuating cold and warm). Credit: Dr. Zdenek Lajbner Dr. Lajbner and his colleagues studied two naturally occurring mtDNA variants that are carried by fruit flies inhabiting the east coast of Australia. One of these variants is more common in the sub-tropical, northern part of the country, where temperatures run warm, and the other is more common in the temperate, southern part, which tends to be colder. The researchers collected flies from the two sites and then interbred them to get a series of populations with equally mixed genes. They then divided each mixed population into four subpopulations. Each of the four subpopulations was maintained at different temperatures. The temperature in two of the subpopulations was kept at constants of 19ºC and 25ºC respectively. The temperature in the other two subpopulations fluctuated to simulate the thermal conditions of the two sites from where the flies were collected. After three months, the researchers sequenced the mtDNA of fruit flies from all these subpopulations. The team also examined how the presence of bacteria such as Wolbachia, which commonly infect fruit flies, affects mtDNA selection. To distinguish their effect, the team treated some of the fly populations with antibiotics to kill off any Wolbachia infections that they might be harboring. The researchers found that in flies reared under warm laboratory conditions, one of the two mtDNA variants became more common than the other. The same mtDNA variant was also found to be widely prevalent in flies from the warmer northern parts of Australia. A similar pattern was observed with the other mtDNA variant in flies reared under cold laboratory conditions. However, researchers only observed this effect in populations where Wolbachia infections had been wiped out. Moreover, the variation patterns they observed in males didn't always match up with the ones in females. The results show that temperature shapes how mtDNA varies in nature. They also suggest that additional factors, such as sex and infection with microbes, might also influence how the mitochondrial genome evolves in the wild. \"Further studies are needed to identify the parts of the mitochondrial genomes that are sensitive to environmental temperature and to understand the mechanisms behind it,\" says Dr. Lajbner. He also notes that researchers using mtDNA as a genetic tool should keep in mind that it evolves in response to thermal environment. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Mitochondria are essential organelles, found within eukaryotic cells, which contain their own DNA. Mitochondrial DNA (mtDNA) has traditionally been used in population genetic and biogeographic studies as a maternally-inherited and evolutionary-neutral genetic marker. However, it is now clear that polymorphisms within the mtDNA sequence are routinely non-neutral, and furthermore several studies have suggested that such mtDNA polymorphisms are also sensitive to thermal selection. These observations led to the formulation of the “mitochondrial climatic adaptation” hypothesis, for which all published evidence to date is correlational. Here, we use laboratory-based experimental evolution in the fruit fly, Drosophila melanogaster , to test whether thermal selection can shift population frequencies of two mtDNA haplogroups whose natural frequencies exhibit clinal associations with latitude along the Australian east-coast. We present experimental evidence that the thermal regime in which the laboratory populations were maintained drove changes in haplogroup frequencies across generations. Our results strengthen the emerging view that intra-specific mtDNA variants are sensitive to selection, and suggest spatial distributions of mtDNA variants in natural populations of metazoans might reflect adaptation to climatic environments rather than within-population coalescence and diffusion of selectively-neutral haplotypes across populations. Introduction Mitochondrial DNA (mtDNA) is usually maternally inherited 1 , and was long considered a neutral evolutionary marker 2 . Accordingly, the mtDNA has been routinely harnessed as a quintessential tool in phylogenetics, population genetic studies, and especially in phylogeographic reconstructions seeking to understand demographic responses to postglacial climate change 3 . Nevertheless, non-neutral evolution of DNA can compromise historical inferences in population and evolutionary biology 4 . Selection on standing genetic variation plays an important role in facilitating rapid adaptation to novel environments 5 , 6 , and evidence published over the past two decades has suggested that a sizeable amount of genetic variation within the mitochondrial genome is sensitive to natural selection, and exerts strong effects on the phenotype 7 , 8 , 9 , 10 , 11 . Previously, it has been suggested that the thermal environment is likely to impose particularly strong selection on the mtDNA sequence 9 , 12 . The underpinning logic is that mitochondrial genes encode multiple subunits in four of the five enzyme complexes that drive mitochondrial respiration, and these enzymatic processes are highly temperature sensitive. The mitochondria of poikilotherms will, for example, presumably be constantly exposed to the prevailing environmental temperature. On the other hand, the mitochondria of homeotherms are not just involved in the production of ATP, but also the production of heat via the uncoupling of mitochondrial respiration 13 , 14 . Thus, particular mitochondrial polymorphisms might accumulate that confer highly efficient ATP production, but at the expense of heat production, or vice versa . Thus, adaptation to novel environments might routinely involve selection of mitochondrial polymorphisms that optimize thermal performance in those environments, and this process might be relevant to all metazoans, both poikilothermic or homeothermic, and indeed to all eukaryote life. In support of this contention, emerging data indicate that not all mitochondrial haplotypes perform equally well under the same thermal conditions – some perform best when it is warmer, others when it is colder 15 , 16 , 17 , 18 , 19 . Correlative molecular data in humans are also consistent with the idea that certain mitochondrial mutations might represent adaptations to cold climates 20 , 21 , 22 , 23 , and thus support is growing for a hypothesis, which suggests that polymorphisms that accumulate across mtDNA haplotypes found in different spatial locations have been shaped by selection to the prevailing climate. This hypothesis was termed the “mitochondrial climatic adaptation” hypothesis in 2017 24 . Currently, this hypothesis remains contentious, primarily because the conclusions of previous studies have, by and large, been based on correlations between mutational patterns in the mtDNA sequence and climatic regions, many of which have proven difficult to replicate in other or larger datasets 25 , 26 . We therefore decided to apply experimental evolution to test the mitochondrial climatic adaptation hypothesis, by determining whether multigenerational exposure of replicated populations of fruit flies to different thermal conditions leads to consistent changes in the population frequencies of naturally-occurring mtDNA haplotypes. In the wild, different locally-adapted populations routinely come into secondary contact and hybridize, which enables selection of novel mito-nuclear genotypes that might be better suited to a new or changing environment 27 . Such an evolutionary scenario is likely to have become increasingly common in the Anthropocene, wherein humans have rapidly altered both climatic conditions and levels of habitat connectivity 28 . We reproduced such a hybridization event under controlled laboratory conditions by interbreeding two subpopulations of D. melanogaster , each adapted to thermal environments at a different end of an established and well-studied latitudinal cline 29 , 30 . It is thought that the species was introduced into Australia during the past one to two hundred years, probably via recurrent introductions of flies from both African and European origins 30 , 31 . The species has been studied extensively in the context of thermal adaptation along latitudinal clines, both within Australia, and other replicated clines in other continents 29 , 30 , 32 . This research has shown that numerous phenotypes related to thermal tolerance exhibit linear associations with latitude, and that these patterns are underscored by linear associations of key candidate nuclear genes 29 . Yet, no research had focused on the quantitative spatial distribution of mtDNA variants 32 , until Camus et al . 24 reported that similar clinal patterns are found for two phylogenetic groups of mtDNA haplotypes (haplogroups) along the eastern coast of Australia. Furthermore, Camus et al . 24 were able to map these clinal patterns of mtDNA variation to the phenotype, showing that the mtDNA haplotype that predominates at subtropical latitudes confers superior resistance to extreme heat exposure, but inferior resistance to cold exposure than its temperate-predominant counterparts. To characterize our model system in detail, we designed a study based on experimental evolution, in which we submitted replicated laboratory populations of D. melanogaster to one of<|im_end|> <|im_start|>assistant A new study by researchers at Okinawa Institute of Science and Technology Graduate University (OIST), provides evidence towards selection in mtDNA due to variations in temperature. In multicellular organisms, including humans, most DNA is coiled up within the cell's nucleus. A small part, however, is tucked away within the mitochondria— organelles that produce energy and regulate many metabolic processes within the cell. Unlike nuclear DNA, which is inherited from both parents, mitochondrial DNA (mtDNA) is usually passed down from one generation to the next only through the mother. Researchers have long assumed that variations in the nucleotide sequence of the small mtDNA neither affects cell functioning nor undergoes natural selection. For these reasons, it has been considered a quintessential tool in many fields of science, from genetics to climate change, to examine evolutionary history and relationships among individuals or groups of organisms. However, there is growing evidence that some mtDNA variants can get selected over the others under certain circumstances. A new study by researchers at Okinawa Institute of Science and Technology Graduate University (OIST), in collaboration with Monash University in Australia and University College London in the UK, has found that mtDNA can be even more subjected to selection than currently believed. Dr. Zdenek Lajbner and his colleagues from the OIST Physics and Biology Unit, led by Professor Jonathan Miller, conducted experiments with fruit flies (Drosophila melanogaster) to demonstrate how differences in environmental temperature can influence the selection of one mtDNA variant over another. "Our design is the first of its kind when it comes to inferring the role of thermal selection in shaping mtDNA frequencies in nature," says Dr. Lajbner, lead author of the study, which was published in Scientific Reports. Fruit flies were collected from two sites in Australia: a northern site that had a warm sub-tropical climate, and a southern site that had a cold temperate climate. The flies from the two sites were then interbred in the laboratory. The initial stage, called admixture, took place at 25ºC, and the later generations were reared in bottles maintained at different temperatures ranging from warm to cold. While two bottles were maintained in constant 19ºC and 25ºC, the temperature in the other two bottles simulated the thermal conditions of the two sites from where the flies were collected (fluctuating cold and warm). Credit: Dr. Zdenek Lajbner Dr. Lajbner and his colleagues studied two naturally occurring mtDNA variants that are carried by fruit flies inhabiting the east coast of Australia. One of these variants is more common in the sub-tropical, northern part of the country, where temperatures run warm, and the other is more common in the temperate, southern part, which tends to be colder. The researchers collected flies from the two sites and then interbred them to get a series of populations with equally mixed genes. They then divided each mixed population into four subpopulations. Each of the four subpopulations was maintained at different temperatures. The temperature in two of the subpopulations was kept at constants of 19ºC and 25ºC respectively. The temperature in the other two subpopulations fluctuated to simulate the thermal conditions of the two sites from where the flies were collected. After three months, the researchers sequenced the mtDNA of fruit flies from all these subpopulations. The team also examined how the presence of bacteria such as Wolbachia, which commonly infect fruit flies, affects mtDNA selection. To distinguish their effect, the team treated some of the fly populations with antibiotics to kill off any Wolbachia infections that they might be harboring. The researchers found that in flies reared under warm laboratory conditions, one of the two mtDNA variants became more common than the other. The same mtDNA variant was also found to be widely prevalent in flies from the warmer northern parts of Australia. A similar pattern was observed with the other mtDNA variant in flies reared under cold laboratory conditions. However, researchers only observed this effect in populations where Wolbachia infections had been wiped out. Moreover, the variation patterns they observed in males didn't always match up with the ones in females. The results show that temperature shapes how mtDNA varies in nature. They also suggest that additional factors, such as sex and infection with microbes, might also influence how the mitochondrial genome evolves in the wild. "Further studies are needed to identify the parts of the mitochondrial genomes that are sensitive to environmental temperature and to understand the mechanisms behind it," says Dr. Lajbner. He also notes that researchers using mtDNA as a genetic tool should keep in mind that it evolves in response to thermal environment. <|im_end|>

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2,305

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Trillions of plastic debris fragments are floating at sea, presenting a substantial surface area for microbial colonization. Numerous cultivation-independent surveys have characterized plastic-associated microbial biofilms, however, quantitative studies addressing microbial carbon biomass are lacking. Our confocal laser scanning microscopy data show that early biofilm development on polyethylene, polypropylene, polystyrene, and glass substrates displayed variable cell size, abundance, and carbon biomass, whereas these parameters stabilized in mature biofilms. Unexpectedly, plastic substrates presented lower volume proportions of photosynthetic cells after 8 weeks, compared to glass. Early biofilms displayed the highest proportions of diatoms, which could influence the vertical transport of plastic debris. In total, conservative estimates suggest 2.1 × 10 21 to 3.4 × 10 21 cells, corresponding to about 1% of the microbial cells in the ocean surface microlayer (1.5 × 10 3 to 1.1 × 10 4 tons of carbon biomass), inhabit plastic debris globally. As an unnatural addition to sea surface waters, the large quantity of cells and biomass carried by plastic debris has the potential to impact biodiversity, autochthonous ecological functions, and biogeochemical cycles within the ocean. Introduction Trillions of plastic particles are floating at sea [ 1 ] and provide a substantial surface area for microbial colonization [ 2 ]. Plastic marine debris (PMD) microbial biomass has been hypothesized to range from 860 to 16,000 metric tons [ 3 , 4 ] compared to the total mass of PMD (~268,940 tons) in the global ocean [ 5 ]. With the potential to be transported across marine ecosystem boundaries, microbial biomass on PMD represents an emerging perturbation to the fragile oligotrophic ocean habitats with unknown biogeochemical and ecological consequences. Although poorly understood, the quantification of cell numbers and microbial biomass on PMD (referenced herein as microbial carrying capacity) is crucial for understanding the implications of PMD on oceanic ecosystems. Employing culture-independent approaches and scanning electron microscopy (SEM), Zettler et al. [ 6 ] described the microbial communities on microplastic litter from the North Atlantic, which were distinct from ambient seawater communities. This plastic-associated biofilm, coined the “plastisphere”, consists of a complex community comprised of bacterial, archaeal, and eukaryotic microorganisms, and microscopic animals. Since then, plastisphere research has largely employed molecular ecology methods focused on characterization of these microbial biofilm communities, their correlation to environmental and geographical factors, and variation between plastic substrates [ 7 , 8 ]. In these field studies, the unknown origin and age of field-collected plastic debris have impeded the determination of substrate-specific biofilm composition. A growing number of experimental studies have directly compared different synthetic polymer-associated biofilm assemblages and nonplastic substrates exposed to the identical environments (Table S1 ). But few studies, summarized in the Table S1 , have incorporated a time-course element to their incubation schemes. SEM and DNA sequence-based microbial survey techniques, methods widely used in plastisphere research, each have advantages and limitations when quantifying diverse microbial biofilm assemblages. The well-established microscopic technique of SEM fails to detect cells embedded within a biofilm in three dimensions [ 9 ], but provides information on spatial structure at the surface. Sequencing provides detailed information on taxonomy of the whole community, but multiple copies of SSU rRNA genes per cell, ranging 1–17 for bacteria and in up to 10 4 for protists, provide an innate bias for quantitative estimates [ 10 ]. Quantitative real-time PCR (Q-PCR) allows estimates of target gene sequence concentrations in environmental samples, and taxon-specific Q-PCR primer sets can provide cell numbers for a single taxon [ 11 ], but a posteriori knowledge of target groups present is crucial. In addition, sets of degenerate oligonucleotide primers designed for different targets have various reaction kinetics leading to inaccuracies during Q-PCR, and other errors such as DNA extraction efficiency, PCR template properties, and data analysis can lead to several orders of magnitude bias [ 11 ]. Confocal laser scanning microscopy (CLSM) has been used extensively to nondestructively study biofilm structure [ 12 ]. Recording the signal of different fluorochromes together with natural pigment fluorescence (such as the phytopigment chlorophyll a ( Chl-a )), CLSM has been employed to differentiate between phototrophs, heterotrophs, bacteria, archaea, and eukaryotes [ 12 ]. Furthermore, analysis of CLSM images with computer software can directly obtain data ranging from cell counts, size and the characterization of microbial morphotypes, to complete three-dimensional constructs [ 13 ]. More recently, CLASI-FISH or Combinatorial Labeling and Spectral Imaging Fluorescence In Situ Hybridization visualized plastisphere membership of multiple taxa on polyethylene (PE) via custom group specific rRNA-based phylogenetic probes and CLSM [ 14 ]. This study compared relative bacterial counts via CLSM to those derived from amplicon sequencing in a time-series study taken from the same incubation experiment as described in this report. Here we employed CLSM in combination with digital image analysis to directly count cells in order to determine biomass contribution of the whole microbial community (bacteria, archaea, and eukaryotes) and ascertain the carrying capacity of the plastisphere. We chose two fluorophores: Hoechst 33342, capable of penetrating diverse cell membranes and intercalating double stranded DNA; and FM 1–43, a lipophilic styryl dye used to stain membranes of diverse cell types. This combination allowed us to determine cell abundances and morphologies on a range of chemically distinct substrates (PE; polypropylene, PP; polystyrene, PS; Glass). The selection of these test substrates was dependent on the varying index of their previously reported hydrophobicity [ 15 , 16 ], which allowed testing whether this physicochemical surface property can influence the microbial assemblages on the substratum surfaces. In addition, we used Chl-a autofluorescence as a proxy for quantifying cells capable of photosynthesis. All substrate samples were simultaneously incubated at the Marine Biological Laboratory dock (Woods Hole, Massachusetts, USA) from July to October 2013. Cell volume measurements allowed an estimation of carbon biomass to be calculated based on previously published “carbon/volume ( C / vol )” relationships and measurements of carbon per cell for various microbial taxa [ 17 , 18 ]. Our approach allowed us to address the following questions: (1) how do cell abundances, size, cellular", "role": "user" }, { "content": "Trillions of plastic debris fragments are afloat at sea, creating the 'perfect storm' for microbial colonization. Introduced more than 50 years ago, plastic substrates are a novel microbial habitat in the world's oceans. This 'plastisphere' consists of a complex community comprised of bacterial, archaeal, and eukaryotic microorganisms and microscopic animals. These unnatural additions to sea surface waters and the large quantity of cells and biomass carried by plastic debris has the potential to impact biodiversity, ecological functions and biogeochemical cycles within the ocean. Biofilm formation in the marine environment—a collective of one or more types of microorganisms that can grow on many different surfaces—is a complex process, involving many variables. While several studies have surveyed microbial diversity and quantified specific members of these biofilm habitats, a new study is the first to holistically quantify total cell inventories under in situ conditions. This study is fundamentally different from others due to the relatively non-biased visualization methods used to arrive at a quantitative number for biomass, which is the first estimate of its kind. Researchers from Florida Atlantic University's Harbor Branch Oceanographic Institute and Harriet L. Wilkes Honors College, in collaboration with Utrecht University, Netherlands, the University of Amsterdam, and The Royal Netherlands Institute for Sea Research (NIOZ), examined cell abundances, size, cellular carbon mass, and how photosynthetic cells differ on polymeric and glass substrates over time. They investigated nanoparticle generation from plastic such as polystyrene, which is known to disintegrate into nanoparticles in sunlight and ultraviolet radiation, and how this might disrupt microalgae. Results of the study, published in the ISME Journal, a monthly publication of the International Society for Microbial Ecology, reveal that by measuring the average microbial biomass carrying capacity of different plastic polymers and, by extension, plastic marine debris in the global ocean, conservative estimates suggest that about 1 percent of microbial cells in the ocean surface microlayer inhabit plastic debris globally. This mass of cells would not exist if plastic debris was not in the ocean, and therefore, represents a disruption of the proportions of native flora in that habitat. \"In the open ocean, nutrients are limiting. Just like we need to put fertilizer on a garden, microorganisms in the ocean are limited by nitrogen, iron or phosphorous depending upon where they are—except in the open ocean, there is typically no fertilizer, so something has to die for another organism to live,\" said Tracy Mincer, Ph.D., lead author and an assistant professor of biology/bio-geochemistry at FAU's Harbor Branch and Wilkes Honors College. \"With the advantage of a surface, which concentrates nutrients, organisms colonizing plastics in the ocean are taking up those limiting nutrients that normally would have been consumed or out-competed by free-living microbes. So essentially, these microbes on plastics are taking habitat space away and represent the beginning of a regime shift for these habitats.\" Using confocal laser scanning microscopy with sophisticated imaging software, researchers directly obtained data ranging from cell counts, size and the characterization of microbial morphotypes to complete three-dimensional constructs. They tested a range of chemically distinct substrates that included polypropylene, polystyrene, polyethylene and glass. Polypropylene is used by the automotive industry, for consumer goods such as packaging, industrial applications and the furniture market; polystyrene is used to make clear products like food packing or laboratory equipment; and polyethylene is the most widely used plastic in the world ranging from products such as clear food wrap to shopping bags to detergent bottles. Data from the confocal laser scanning microscopy showed that early biofilms displayed a high proportion of diatoms (unicellular eukaryotic microalgae that have cell walls made of glass). These diatoms could play a key role in the sinking of plastic debris. Unexpectedly, plastic substrates appeared to reduce the growth of photosynthetic cells after eight weeks compared to glass. \"The quantification of cell numbers and microbial biomass on plastic marine debris is crucial for understanding the implications of plastic marine debris on oceanic ecosystems,\" said Shiye Zhao, Ph.D., first author and a post-doctoral fellow at FAU's Harbor Branch. \"Future efforts should focus on how this biomass fluctuates with season and latitude and its potential to perturb the flux of nutrients in the upper layers of the ocean.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Trillions of plastic debris fragments are floating at sea, presenting a substantial surface area for microbial colonization. Numerous cultivation-independent surveys have characterized plastic-associated microbial biofilms, however, quantitative studies addressing microbial carbon biomass are lacking. Our confocal laser scanning microscopy data show that early biofilm development on polyethylene, polypropylene, polystyrene, and glass substrates displayed variable cell size, abundance, and carbon biomass, whereas these parameters stabilized in mature biofilms. Unexpectedly, plastic substrates presented lower volume proportions of photosynthetic cells after 8 weeks, compared to glass. Early biofilms displayed the highest proportions of diatoms, which could influence the vertical transport of plastic debris. In total, conservative estimates suggest 2.1 × 10 21 to 3.4 × 10 21 cells, corresponding to about 1% of the microbial cells in the ocean surface microlayer (1.5 × 10 3 to 1.1 × 10 4 tons of carbon biomass), inhabit plastic debris globally. As an unnatural addition to sea surface waters, the large quantity of cells and biomass carried by plastic debris has the potential to impact biodiversity, autochthonous ecological functions, and biogeochemical cycles within the ocean. Introduction Trillions of plastic particles are floating at sea [ 1 ] and provide a substantial surface area for microbial colonization [ 2 ]. Plastic marine debris (PMD) microbial biomass has been hypothesized to range from 860 to 16,000 metric tons [ 3 , 4 ] compared to the total mass of PMD (~268,940 tons) in the global ocean [ 5 ]. With the potential to be transported across marine ecosystem boundaries, microbial biomass on PMD represents an emerging perturbation to the fragile oligotrophic ocean habitats with unknown biogeochemical and ecological consequences. Although poorly understood, the quantification of cell numbers and microbial biomass on PMD (referenced herein as microbial carrying capacity) is crucial for understanding the implications of PMD on oceanic ecosystems. Employing culture-independent approaches and scanning electron microscopy (SEM), Zettler et al. [ 6 ] described the microbial communities on microplastic litter from the North Atlantic, which were distinct from ambient seawater communities. This plastic-associated biofilm, coined the “plastisphere”, consists of a complex community comprised of bacterial, archaeal, and eukaryotic microorganisms, and microscopic animals. Since then, plastisphere research has largely employed molecular ecology methods focused on characterization of these microbial biofilm communities, their correlation to environmental and geographical factors, and variation between plastic substrates [ 7 , 8 ]. In these field studies, the unknown origin and age of field-collected plastic debris have impeded the determination of substrate-specific biofilm composition. A growing number of experimental studies have directly compared different synthetic polymer-associated biofilm assemblages and nonplastic substrates exposed to the identical environments (Table S1 ). But few studies, summarized in the Table S1 , have incorporated a time-course element to their incubation schemes. SEM and DNA sequence-based microbial survey techniques, methods widely used in plastisphere research, each have advantages and limitations when quantifying diverse microbial biofilm assemblages. The well-established microscopic technique of SEM fails to detect cells embedded within a biofilm in three dimensions [ 9 ], but provides information on spatial structure at the surface. Sequencing provides detailed information on taxonomy of the whole community, but multiple copies of SSU rRNA genes per cell, ranging 1–17 for bacteria and in up to 10 4 for protists, provide an innate bias for quantitative estimates [ 10 ]. Quantitative real-time PCR (Q-PCR) allows estimates of target gene sequence concentrations in environmental samples, and taxon-specific Q-PCR primer sets can provide cell numbers for a single taxon [ 11 ], but a posteriori knowledge of target groups present is crucial. In addition, sets of degenerate oligonucleotide primers designed for different targets have various reaction kinetics leading to inaccuracies during Q-PCR, and other errors such as DNA extraction efficiency, PCR template properties, and data analysis can lead to several orders of magnitude bias [ 11 ]. Confocal laser scanning microscopy (CLSM) has been used extensively to nondestructively study biofilm structure [ 12 ]. Recording the signal of different fluorochromes together with natural pigment fluorescence (such as the phytopigment chlorophyll a ( Chl-a )), CLSM has been employed to differentiate between phototrophs, heterotrophs, bacteria, archaea, and eukaryotes [ 12 ]. Furthermore, analysis of CLSM images with computer software can directly obtain data ranging from cell counts, size and the characterization of microbial morphotypes, to complete three-dimensional constructs [ 13 ]. More recently, CLASI-FISH or Combinatorial Labeling and Spectral Imaging Fluorescence In Situ Hybridization visualized plastisphere membership of multiple taxa on polyethylene (PE) via custom group specific rRNA-based phylogenetic probes and CLSM [ 14 ]. This study compared relative bacterial counts via CLSM to those derived from amplicon sequencing in a time-series study taken from the same incubation experiment as described in this report. Here we employed CLSM in combination with digital image analysis to directly count cells in order to determine biomass contribution of the whole microbial community (bacteria, archaea, and eukaryotes) and ascertain the carrying capacity of the plastisphere. We chose two fluorophores: Hoechst 33342, capable of penetrating diverse cell membranes and intercalating double stranded DNA; and FM 1–43, a lipophilic styryl dye used to stain membranes of diverse cell types. This combination allowed us to determine cell abundances and morphologies on a range of chemically distinct substrates (PE; polypropylene, PP; polystyrene, PS; Glass). The selection of these test substrates was dependent on the varying index of their previously reported hydrophobicity [ 15 , 16 ], which allowed testing whether this physicochemical surface property can influence the microbial assemblages on the substratum surfaces. In addition, we used Chl-a autofluorescence as a proxy for quantifying cells capable of photosynthesis. All substrate samples were simultaneously incubated at the Marine Biological Laboratory dock (Woods Hole, Massachusetts, USA) from July to October 2013. Cell volume measurements allowed an estimation of carbon biomass to be calculated based on previously published “carbon/volume ( C / vol )” relationships and measurements of carbon per cell for various microbial taxa [ 17 , 18 ]. Our approach allowed us to address the following questions: (1) how do cell abundances, size, cellular<|im_end|> <|im_start|>assistant Trillions of plastic debris fragments are afloat at sea, creating the 'perfect storm' for microbial colonization. Introduced more than 50 years ago, plastic substrates are a novel microbial habitat in the world's oceans. This 'plastisphere' consists of a complex community comprised of bacterial, archaeal, and eukaryotic microorganisms and microscopic animals. These unnatural additions to sea surface waters and the large quantity of cells and biomass carried by plastic debris has the potential to impact biodiversity, ecological functions and biogeochemical cycles within the ocean. Biofilm formation in the marine environment—a collective of one or more types of microorganisms that can grow on many different surfaces—is a complex process, involving many variables. While several studies have surveyed microbial diversity and quantified specific members of these biofilm habitats, a new study is the first to holistically quantify total cell inventories under in situ conditions. This study is fundamentally different from others due to the relatively non-biased visualization methods used to arrive at a quantitative number for biomass, which is the first estimate of its kind. Researchers from Florida Atlantic University's Harbor Branch Oceanographic Institute and Harriet L. Wilkes Honors College, in collaboration with Utrecht University, Netherlands, the University of Amsterdam, and The Royal Netherlands Institute for Sea Research (NIOZ), examined cell abundances, size, cellular carbon mass, and how photosynthetic cells differ on polymeric and glass substrates over time. They investigated nanoparticle generation from plastic such as polystyrene, which is known to disintegrate into nanoparticles in sunlight and ultraviolet radiation, and how this might disrupt microalgae. Results of the study, published in the ISME Journal, a monthly publication of the International Society for Microbial Ecology, reveal that by measuring the average microbial biomass carrying capacity of different plastic polymers and, by extension, plastic marine debris in the global ocean, conservative estimates suggest that about 1 percent of microbial cells in the ocean surface microlayer inhabit plastic debris globally. This mass of cells would not exist if plastic debris was not in the ocean, and therefore, represents a disruption of the proportions of native flora in that habitat. "In the open ocean, nutrients are limiting. Just like we need to put fertilizer on a garden, microorganisms in the ocean are limited by nitrogen, iron or phosphorous depending upon where they are—except in the open ocean, there is typically no fertilizer, so something has to die for another organism to live," said Tracy Mincer, Ph.D., lead author and an assistant professor of biology/bio-geochemistry at FAU's Harbor Branch and Wilkes Honors College. "With the advantage of a surface, which concentrates nutrients, organisms colonizing plastics in the ocean are taking up those limiting nutrients that normally would have been consumed or out-competed by free-living microbes. So essentially, these microbes on plastics are taking habitat space away and represent the beginning of a regime shift for these habitats." Using confocal laser scanning microscopy with sophisticated imaging software, researchers directly obtained data ranging from cell counts, size and the characterization of microbial morphotypes to complete three-dimensional constructs. They tested a range of chemically distinct substrates that included polypropylene, polystyrene, polyethylene and glass. Polypropylene is used by the automotive industry, for consumer goods such as packaging, industrial applications and the furniture market; polystyrene is used to make clear products like food packing or laboratory equipment; and polyethylene is the most widely used plastic in the world ranging from products such as clear food wrap to shopping bags to detergent bottles. Data from the confocal laser scanning microscopy showed that early biofilms displayed a high proportion of diatoms (unicellular eukaryotic microalgae that have cell walls made of glass). These diatoms could play a key role in the sinking of plastic debris. Unexpectedly, plastic substrates appeared to reduce the growth of photosynthetic cells after eight weeks compared to glass. "The quantification of cell numbers and microbial biomass on plastic marine debris is crucial for understanding the implications of plastic marine debris on oceanic ecosystems," said Shiye Zhao, Ph.D., first author and a post-doctoral fellow at FAU's Harbor Branch. "Future efforts should focus on how this biomass fluctuates with season and latitude and its potential to perturb the flux of nutrients in the upper layers of the ocean." <|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 Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes 1 , 2 , 3 , 4 . Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases 3 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 . GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference 5 , 6 , 14 , 15 , 16 . Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents. Main To investigate the role of GPR120 in metabolism, we examined GPR120-deficient mice ( Supplementary Fig. 1 ) with respect to lipogenesis, glucose and energy homeostasis. On a normal diet containing 13% fat, the body weight was similar in both GPR120-deficient and wild-type mice. However, when 5-week-old GPR120-deficient mice were fed a high-fat diet (HFD) containing 60% fat, their body weight increase was ∼ 10% higher than that of wild-type mice on a HFD ( Fig. 1a ). The difference in HFD-induced body weight gain between wild-type and GPR120-deficient mice was marked at ∼ 8–10 weeks old and reached a plateau at 13 weeks old. To assess energy expenditure and substrate utilization, we next performed indirect calorimetry on wild-type and mutant mice on a HFD at 9–10 weeks old ( Fig. 1b ) and 15–16 weeks old ( Supplementary Fig. 2a ). The young GPR120-deficient mice showed decreased energy expenditure compared with the young wild-type mice, particularly during the light/inactive phase ( Fig. 1b , left), whereas older mutant and wild-type mice showed no such a difference ( Supplementary Fig. 2a, left ). The difference in energy expenditure between GPR120-deficient and wild-type mice was observed only in the light phase, indicating that the lack of the GPR120 receptor primarily affects basal metabolism, especially in young mice. The decreased energy expenditure might explain the difference we found in body weight gain between HFD-fed wild-type and mutant young mice. The lower values of respiratory quotient in mutant mice could be due to insufficient glucose utility, probably as a result of the decreased insulin sensitivity. In all experiments, both groups of mice showed similar levels of locomotor activity (data not shown). Figure 1: Obesity, hypertrophic adipocytes, accumulation of pro-inflammatory macrophages and hepatic steatosis in HFD-fed GPR120-deficient mice. a , Body weight changes of wild-type (WT) and GPR120-deficient mice fed a normal diet (ND) or a HFD ( n = 36–47). b , Indirect calorimetry in HFD-fed mice. Energy expenditure and respiratory quotient ( n = 4, 5). c , Representative cross-sectional images of wild-type and GPR120-deficient mice subjected to microcomputed tomography analysis of the in situ accumulation of fat. Fat depots are demarcated (green) for illustration. d , Haematoxylin and eosin (H&E)-stained epididymal WAT and mean area of adipocytes ( n = 6). Scale bar, 100 μm. e , Relative expression of Cd11b , Cd68 and F4/80 messenger RNA in WAT ( n = 6). a.u., arbitrary units. f , Representative images of epididymal WAT stained with anti-F4/80 antibody (arrows, F4/80-positive cells) and the number of F4/80 cells ( n = 6). Scale bar, 100 μm. g , Oil Red O-stained liver and hepatic triglyceride content after 24hr fasting ( n = 13). Scale bar, 50 μm. All data represent mean ± s.e.m. * P < 0.05 and ** P < 0.01 versus the corresponding wild-type value. PowerPoint slide Full size image White adipose tissue (WAT) and liver were substantially heavier in HFD-fed GPR120-deficient mice ( Supplementary Fig. 2b ). Plasma low- and high-density lipoprotein cholesterol levels were significantly higher in HFD-fed GPR120-deficient mice, and serum alanine aminotransferase levels were substantially increased, indicating abnormal cholesterol metabolism and liver function ( Supplementary Table 1 ). Microcomputed tomography scanning revealed that 16-week-old GPR120-deficient mice stored much more fat than did wild type ( Fig. 1c ). A significant increase in adipocyte size in both epididymal ( Fig. 1d ) and subcutaneous ( Supplementary Fig. 2c ) fat was observed in GPR120-deficient mice. Furthermore, the expression of macrophage marker genes ( Cd11b ( Itgam ), Cd68 and F4/80 ( Emr1 )) and the number of F4/80-positive cells were markedly enhanced in epididymal tissue from HFD-fed GPR120-deficient mice ( Fig. 1e, f ). Moreover, these mice showed liver steatosis and hepatic triglyceride content was markedly increased ( Fig. 1g ). Overall, HFD-induced obesity and liver fattiness were more severe in GPR120-deficient mice than in wild type. Obesity-associated insulin resistance was also more severe in GPR120--fed GPR120-deficient mice showed higher levels of fasting plasma glucose and insulin than did wild type, although these parameters were similar between the two groups on a normal diet ( Fig. 2a ). HFD-induced insulin resistance, as determined by an insulin tolerance test, was more prominent in GPR120-deficient mice than in wild type ( Fig. 2b , left, and Supplementary Fig. 3a, b ). A glucose tolerance test further revealed that these mice suffered from impaired glucose metabolism ( Fig. 2b , right, and Supplementary Fig. 3a, b ). The level of plasma leptin was significantly higher in HFD-fed GPR120-deficient mice than in wild type ( Supplementary Fig. 3c ).", "role": "user" }, { "content": "Defects in a protein that functions as a dietary fat sensor may be a cause of obesity and liver disease, according to a study published in the journal Nature, led by researchers at Imperial College London. The findings highlight a promising target for new drugs to treat obesity and metabolic disorders. The protein GPR120 is found on the surface of cells in the gut, liver and fat tissue and allows cells to detect and respond to unsaturated fatty acids from the diet, especially the omega-3 fatty acids which are believed to have a beneficial impact on health. Scientists found that mice deficient in GPR120 were more prone to developing obesity and liver disease when fed a high-fat diet. They also found that people with a certain mutation in the gene encoding GPR120, which stops the protein from responding to omega-3 fatty acids, were significantly more likely to be obese. In the gut, when unsaturated fatty acids from food bind to GPR120, this stimulates the release of hormones that suppress appetite and stimulate the pancreas to secrete insulin. When fat cells sense high levels of fat in the blood through GPR120, it stimulates them to divide to produce more fat cells to store all the fat, reducing the risk of fatty liver and furring of the arteries. This mechanism could be an important pathway for bringing about some of the healthy effects of omega-3s. When they were fed on a high-fat diet, mice that lacked GPR120 not only became obese but also had fatty livers, lower numbers of fat cells, and poor control of blood glucose. The researchers believe that mice that are deficient in GPR120 have difficulty storing excess fat in fat tissue. Instead, their bodies store fat in areas where it can cause health problems, like the liver, the muscles and in the walls of arteries. In humans, this pattern of obesity is associated with type 2 diabetes and heart disease. The study involved scientists in the UK, France and Japan. It was led by Professor Philippe Froguel, from the School of Public Health at Imperial College London. \"Being overweight is not always unhealthy if you can make more fat cells to store fat,\" said Professor Froguel. \"Some people seem to be unable to do this, and instead they deposit fat around their internal organs, which is very unhealthy. Our study suggests that in both mice and humans, defects in GPR120 combined with a high-fat diet greatly increase the risk of this unhealthy pattern of obesity. We think GPR120 could be a useful target for new drugs to treat obesity and liver diseases.\" The researchers analysed the gene for GPR120 in 6,942 obese people and 7,654 controls to test whether differences in the code that carries instructions for making the protein contribute to obesity in humans. They found that one mutation that renders the protein dysfunctional increases a person's risk of obesity by 60 per cent. The researchers think this mutation mimics the effect of a bad diet lacking in unsaturated omega-3 fat. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes 1 , 2 , 3 , 4 . Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases 3 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 . GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference 5 , 6 , 14 , 15 , 16 . Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents. Main To investigate the role of GPR120 in metabolism, we examined GPR120-deficient mice ( Supplementary Fig. 1 ) with respect to lipogenesis, glucose and energy homeostasis. On a normal diet containing 13% fat, the body weight was similar in both GPR120-deficient and wild-type mice. However, when 5-week-old GPR120-deficient mice were fed a high-fat diet (HFD) containing 60% fat, their body weight increase was ∼ 10% higher than that of wild-type mice on a HFD ( Fig. 1a ). The difference in HFD-induced body weight gain between wild-type and GPR120-deficient mice was marked at ∼ 8–10 weeks old and reached a plateau at 13 weeks old. To assess energy expenditure and substrate utilization, we next performed indirect calorimetry on wild-type and mutant mice on a HFD at 9–10 weeks old ( Fig. 1b ) and 15–16 weeks old ( Supplementary Fig. 2a ). The young GPR120-deficient mice showed decreased energy expenditure compared with the young wild-type mice, particularly during the light/inactive phase ( Fig. 1b , left), whereas older mutant and wild-type mice showed no such a difference ( Supplementary Fig. 2a, left ). The difference in energy expenditure between GPR120-deficient and wild-type mice was observed only in the light phase, indicating that the lack of the GPR120 receptor primarily affects basal metabolism, especially in young mice. The decreased energy expenditure might explain the difference we found in body weight gain between HFD-fed wild-type and mutant young mice. The lower values of respiratory quotient in mutant mice could be due to insufficient glucose utility, probably as a result of the decreased insulin sensitivity. In all experiments, both groups of mice showed similar levels of locomotor activity (data not shown). Figure 1: Obesity, hypertrophic adipocytes, accumulation of pro-inflammatory macrophages and hepatic steatosis in HFD-fed GPR120-deficient mice. a , Body weight changes of wild-type (WT) and GPR120-deficient mice fed a normal diet (ND) or a HFD ( n = 36–47). b , Indirect calorimetry in HFD-fed mice. Energy expenditure and respiratory quotient ( n = 4, 5). c , Representative cross-sectional images of wild-type and GPR120-deficient mice subjected to microcomputed tomography analysis of the in situ accumulation of fat. Fat depots are demarcated (green) for illustration. d , Haematoxylin and eosin (H&E)-stained epididymal WAT and mean area of adipocytes ( n = 6). Scale bar, 100 μm. e , Relative expression of Cd11b , Cd68 and F4/80 messenger RNA in WAT ( n = 6). a.u., arbitrary units. f , Representative images of epididymal WAT stained with anti-F4/80 antibody (arrows, F4/80-positive cells) and the number of F4/80 cells ( n = 6). Scale bar, 100 μm. g , Oil Red O-stained liver and hepatic triglyceride content after 24hr fasting ( n = 13). Scale bar, 50 μm. All data represent mean ± s.e.m. * P < 0.05 and ** P < 0.01 versus the corresponding wild-type value. PowerPoint slide Full size image White adipose tissue (WAT) and liver were substantially heavier in HFD-fed GPR120-deficient mice ( Supplementary Fig. 2b ). Plasma low- and high-density lipoprotein cholesterol levels were significantly higher in HFD-fed GPR120-deficient mice, and serum alanine aminotransferase levels were substantially increased, indicating abnormal cholesterol metabolism and liver function ( Supplementary Table 1 ). Microcomputed tomography scanning revealed that 16-week-old GPR120-deficient mice stored much more fat than did wild type ( Fig. 1c ). A significant increase in adipocyte size in both epididymal ( Fig. 1d ) and subcutaneous ( Supplementary Fig. 2c ) fat was observed in GPR120-deficient mice. Furthermore, the expression of macrophage marker genes ( Cd11b ( Itgam ), Cd68 and F4/80 ( Emr1 )) and the number of F4/80-positive cells were markedly enhanced in epididymal tissue from HFD-fed GPR120-deficient mice ( Fig. 1e, f ). Moreover, these mice showed liver steatosis and hepatic triglyceride content was markedly increased ( Fig. 1g ). Overall, HFD-induced obesity and liver fattiness were more severe in GPR120-deficient mice than in wild type. Obesity-associated insulin resistance was also more severe in GPR120--fed GPR120-deficient mice showed higher levels of fasting plasma glucose and insulin than did wild type, although these parameters were similar between the two groups on a normal diet ( Fig. 2a ). HFD-induced insulin resistance, as determined by an insulin tolerance test, was more prominent in GPR120-deficient mice than in wild type ( Fig. 2b , left, and Supplementary Fig. 3a, b ). A glucose tolerance test further revealed that these mice suffered from impaired glucose metabolism ( Fig. 2b , right, and Supplementary Fig. 3a, b ). The level of plasma leptin was significantly higher in HFD-fed GPR120-deficient mice than in wild type ( Supplementary Fig. 3c ).<|im_end|> <|im_start|>assistant Defects in a protein that functions as a dietary fat sensor may be a cause of obesity and liver disease, according to a study published in the journal Nature, led by researchers at Imperial College London. The findings highlight a promising target for new drugs to treat obesity and metabolic disorders. The protein GPR120 is found on the surface of cells in the gut, liver and fat tissue and allows cells to detect and respond to unsaturated fatty acids from the diet, especially the omega-3 fatty acids which are believed to have a beneficial impact on health. Scientists found that mice deficient in GPR120 were more prone to developing obesity and liver disease when fed a high-fat diet. They also found that people with a certain mutation in the gene encoding GPR120, which stops the protein from responding to omega-3 fatty acids, were significantly more likely to be obese. In the gut, when unsaturated fatty acids from food bind to GPR120, this stimulates the release of hormones that suppress appetite and stimulate the pancreas to secrete insulin. When fat cells sense high levels of fat in the blood through GPR120, it stimulates them to divide to produce more fat cells to store all the fat, reducing the risk of fatty liver and furring of the arteries. This mechanism could be an important pathway for bringing about some of the healthy effects of omega-3s. When they were fed on a high-fat diet, mice that lacked GPR120 not only became obese but also had fatty livers, lower numbers of fat cells, and poor control of blood glucose. The researchers believe that mice that are deficient in GPR120 have difficulty storing excess fat in fat tissue. Instead, their bodies store fat in areas where it can cause health problems, like the liver, the muscles and in the walls of arteries. In humans, this pattern of obesity is associated with type 2 diabetes and heart disease. The study involved scientists in the UK, France and Japan. It was led by Professor Philippe Froguel, from the School of Public Health at Imperial College London. "Being overweight is not always unhealthy if you can make more fat cells to store fat," said Professor Froguel. "Some people seem to be unable to do this, and instead they deposit fat around their internal organs, which is very unhealthy. Our study suggests that in both mice and humans, defects in GPR120 combined with a high-fat diet greatly increase the risk of this unhealthy pattern of obesity. We think GPR120 could be a useful target for new drugs to treat obesity and liver diseases." The researchers analysed the gene for GPR120 in 6,942 obese people and 7,654 controls to test whether differences in the code that carries instructions for making the protein contribute to obesity in humans. They found that one mutation that renders the protein dysfunctional increases a person's risk of obesity by 60 per cent. The researchers think this mutation mimics the effect of a bad diet lacking in unsaturated omega-3 fat. <|im_end|>

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2,140

[ { "content": "You are a great 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 quantum optical Enhancement of Index of Refraction (EIR), coherence and quantum interference render the atomic systems to exhibit orders of magnitude higher susceptibilities with vanishing or even negative absorption at their resonances. Here we show the plasmonic analogue of the quantum optical EIR effect in an optical system and further implement this in a linear all-optical switching mechanism. We realize plasmon-induced EIR using a particular plasmonic metasurface consisting of a square array of L-shaped meta-molecules. In contrast to the conventional methods, this approach provides a scheme to modulate the amplitude of incident signals by coherent control of absorption without implementing gain materials or nonlinear processes. Therefore, light is controlled by applying ultra-low intensity at the extreme levels of spatiotemporal localization. In the pursuit of potential applications of linear all-optical switching devices, this scheme may introduce an effective tool for improving the modulation strength of optical modulators and switches through the amplification of input signals at ultra-low power. Introduction Ultra-compact optical switches and modulators with ultrashort response time and minimal energy consumption are highly desirable in nanophotonics for the development of efficient all-optical computing, photonic information processing, and networking 1 . Conventional all-optical nanoswitches are mainly based on nonlinear effects, such as Kerr 2 , Raman 3 , two-photon absorption 4 and frequency mixing 5 . To improve the performance of nonlinear optical switches, they are usually equipped with plasmonic or resonant nanostructures to exploit their field enhancement and confinement features 6 , 7 , 8 , 9 . Other switching schemes involve the hybridization of metamaterials by functional components such as semiconductors, carbon nanotubes, graphene, liquid crystals, and phase-change materials 10 , 11 , 12 , 13 , 14 , 15 and a metamaterial of plasmonic circuits 16 . However, the aforementioned switching mechanisms generally suffer from unsatisfactory response time and/or high power requirements. Linear interference phenomena are introduced as a promising approach to achieving ultrafast all-optical switching 16 , 17 , 18 requiring arbitrarily low-intensity optical beams down to the level of single-photon regime 19 . The realization of this approach is based on the interference of two collinear, counter-propagating and phase-controlled coherent beams interacting with a plasmonic metasurface of subwavelength dimensions. The absorption of standing wave light is modulated by controlling the phase or amplitude of one of the counter-propagating light waves and consequently tuning the position of the nodes and antinodes on the metasurface 20 , 21 . As another more efficient approach, a class of linear optical nanoswitches and modulators are specifically designed to meet the requirements of the coherent perfect absorption (CPA) phenomenon 22 , 23 , which is a time-reversed counterpart to laser emission and a generalization of the concept of critical coupling to an optical cavity 24 . In a CPA system, complete absorption of electromagnetic radiation is achieved by controlling the interference of multiple incident waves. It can be realized in a variety of photonic structures, including planar and guided-mode structures, graphene-based systems, parity- and time-symmetric structures, epsilon-near-zero multi-layer films, quantum-mechanical systems and chiral metamaterials 25 , 26 , 27 . In a plasmonic nanostructure, CPA occurs when coherent light is completely absorbed and transferred to surface plasmons by exciting the nanostructure with the time-reversed mode of the corresponding surface plasmon laser or the so-called SPASER 23 . In experimental realizations of the effect, usually two symmetric plane waves incident on opposite sides of the system are completely absorbed, as a result of critical coupling into the dissipative degrees of freedom of the system. The plasmonic counterparts of some quantum optical effects have also been widely implemented to develop the functionality of optical systems, metamaterials and switching devices 24 , 28 , 29 including the Fano resonance effect and electromagnetically induced transparency (EIT). In plasmonic systems, the plasmon-induced transparency (PIT) creates a narrow transparent window within a broader absorption band of the system due to destructive interference of super-radiant (radiative) and subradiant (dark) resonance modes of the plasmonic nanostructures. This effect is not only limited by the narrow band but also by its weak response. Typically, in an optical switch based on PIT, the transparency window of the medium is reversibly shifted in a wavelength range to provide the ON and OFF states of the switch by applying a light-induced change in the refractive index of a nonlinear material integrated with plasmonic constituents 15 , 17 . Furthermore, a large resonant index of refraction with vanishing absorption has also been reported in quantum optics. This fascinating phenomenon arises when coherence takes place between an excited state and coherently prepared ground state doublet of atomic gas and is known as an enhancement of index of refraction (EIR) 30 . Recently, plasmonic analogue of this quantum optical EIR is theoretically reported in coupled plasmonic resonators, enabling the maximum susceptibility (strong electromagnetic response) with zero optical losses at resonance frequencies via coherent control of surface plasmons 31 . Thus, apart from some newly proposed potential applications 32 , 33 , this approach has suggested a unique path to realize loss-compensated plasmonic devices operating at resonance frequencies through extraordinary enhancement of refractive index without using any gain media 34 , 35 , 36 , 37 or nonlinear processes 28 , 38 . In this work, we introduce and experimentally realize an ultrafast all-optical switching mechanism based on the plasmonic analogue of the EIR effect by designing and fabricating a particular plasmonic metasurface consisting of a square array of L-shaped meta-molecules. In contrast to the conventional methods of optical switching between zero and complete absorption limits of the system, our scheme is based on a linear phenomenon that enables the switching of system absorption between positive and negative values at low exciting power levels. This is achieved through coherent control of polarizability of nanoantennas by controlling the phase and amplitude of a control beam with a polarization perpendicular to the signal beam resulting in unprecedented control of modulation strength of optical switches. Therefore, the scheme is not restricted to counter-propagating light waves and the system", "role": "user" }, { "content": "A group of photonics researchers at Tampere University have introduced a novel method to control a light beam with another beam through a unique plasmonic metasurface in a linear medium at ultra-low power. This simple linear switching method makes nanophotonic devices such as optical computing and communication systems more sustainable, requiring low intensity of light. All-optical switching is the modulation of signal light due to control light in such a way that it possesses the on/off conversion function. In general, a light beam can be modulated with another intense laser beam in the presence of a nonlinear medium. The switching method developed by the researchers is fundamentally based on the quantum optical phenomenon known as Enhancement of Index of Refraction (EIR). \"Our work is the first experimental demonstration of this effect on the optical system and its utilization for linear all-optical switching. The research also enlightens the scientific community to achieve loss-compensated plasmonic devices operating at resonance frequencies through extraordinary enhancement of refractive index without using any gain media or nonlinear processes,\" says Humeyra Caglayan, Associate Professor (tenure track) in Photonics at Tampere University. Optical switching enabled with ultrafast speed High-speed switching and low-loss medium to avoid the strong dissipation of signal during propagation are the basis to develop integrated photonic technology where photons are utilized as information carriers instead of electrons. To realize on-chip ultrafast all-optical switch networks and photonic central processing units, all-optical switching must have ultrafast switching time, ultralow threshold control power, ultrahigh switching efficiency, and nanoscale feature size. \"Switching between signal values of 0 and 1 is fundamental in all digital electronic devices including computers and communication systems. Over the past decades, these electronic elements have gradually become smaller and faster. For example, the ordinary calculations done with our computers on the order of seconds could not be done with old room-sized computers, even in several days,\" Caglayan remarks. In conventional electronics, switching relies on controlling the flow of electrons on the time scale of a microsecond (10-6 sec) or nanosecond (10-9 sec) range by connecting or disconnecting electrical voltage. \"However, the switching speed can be raised to an ultrafast time scale (femtosecond 10-15 sec) by replacing the electrons with plasmons. Plasmons are a combination of photons and a collection of electrons on the surface of metals. This enables optical switching with our device with femtosecond (10-15 sec) speeds,\" she states. \"Our plasmonic nano-switch consists of an L-shaped combination of metallic nanorods. One of the nanorods receives a linearly polarized signal and the other receives another linearly polarized 'control' beam perpendicular to the first beam,\" says Postdoctoral Research Fellow Rakesh Dhama, the first author of the article published in Nature Communications. Polarization means the direction in which the electric field of the beam is oscillating. The control beam can attenuate or amplify the signal depending on the phase difference between the beams. The phase difference refers to the time difference when each beam reaches its maximum intensity. The signal amplification occurs due to the transfer of some optical energy from the control beam to the signal through a constructive superposition with a carefully engineered phase difference. Enhancing the performance of plasmonic devices Similarly, the attenuation of the signal is achieved by destructive superposition when the beams have the opposite phase difference. This finding makes nanophotonic devices such as optical computing and communication systems more sustainable requiring low intensity of light. This simple linear switching method can replace the current methods of optical processing, computing, or communication by accelerating the development and realization of nanoscale plasmonic systems. \"We expect to see further studies of plasmonic structures utilizing our improved switching method and possibly the use of our method in plasmonic circuits in the future. Additionally, the L-shaped metasurface could be further studied to reveal ultrahigh-speed switching under the illumination of femtosecond laser pulses and to investigate the nonlinear enhancement and control of plasmonic nanoparticles,\" Humeyra Caglayan notes. Controlling the nonlinear response of nanostructures provides even more interesting applications and functionalities to nanophotonic devices such as optical computing and communication systems. \"This approach has also the potential to enhance the performance of plasmonic devices by creating broadband transparency for a signal beam without any gain medium. It can open up several ways to design smart photonic elements for integrated photonics,\" Cagalayan 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 In quantum optical Enhancement of Index of Refraction (EIR), coherence and quantum interference render the atomic systems to exhibit orders of magnitude higher susceptibilities with vanishing or even negative absorption at their resonances. Here we show the plasmonic analogue of the quantum optical EIR effect in an optical system and further implement this in a linear all-optical switching mechanism. We realize plasmon-induced EIR using a particular plasmonic metasurface consisting of a square array of L-shaped meta-molecules. In contrast to the conventional methods, this approach provides a scheme to modulate the amplitude of incident signals by coherent control of absorption without implementing gain materials or nonlinear processes. Therefore, light is controlled by applying ultra-low intensity at the extreme levels of spatiotemporal localization. In the pursuit of potential applications of linear all-optical switching devices, this scheme may introduce an effective tool for improving the modulation strength of optical modulators and switches through the amplification of input signals at ultra-low power. Introduction Ultra-compact optical switches and modulators with ultrashort response time and minimal energy consumption are highly desirable in nanophotonics for the development of efficient all-optical computing, photonic information processing, and networking 1 . Conventional all-optical nanoswitches are mainly based on nonlinear effects, such as Kerr 2 , Raman 3 , two-photon absorption 4 and frequency mixing 5 . To improve the performance of nonlinear optical switches, they are usually equipped with plasmonic or resonant nanostructures to exploit their field enhancement and confinement features 6 , 7 , 8 , 9 . Other switching schemes involve the hybridization of metamaterials by functional components such as semiconductors, carbon nanotubes, graphene, liquid crystals, and phase-change materials 10 , 11 , 12 , 13 , 14 , 15 and a metamaterial of plasmonic circuits 16 . However, the aforementioned switching mechanisms generally suffer from unsatisfactory response time and/or high power requirements. Linear interference phenomena are introduced as a promising approach to achieving ultrafast all-optical switching 16 , 17 , 18 requiring arbitrarily low-intensity optical beams down to the level of single-photon regime 19 . The realization of this approach is based on the interference of two collinear, counter-propagating and phase-controlled coherent beams interacting with a plasmonic metasurface of subwavelength dimensions. The absorption of standing wave light is modulated by controlling the phase or amplitude of one of the counter-propagating light waves and consequently tuning the position of the nodes and antinodes on the metasurface 20 , 21 . As another more efficient approach, a class of linear optical nanoswitches and modulators are specifically designed to meet the requirements of the coherent perfect absorption (CPA) phenomenon 22 , 23 , which is a time-reversed counterpart to laser emission and a generalization of the concept of critical coupling to an optical cavity 24 . In a CPA system, complete absorption of electromagnetic radiation is achieved by controlling the interference of multiple incident waves. It can be realized in a variety of photonic structures, including planar and guided-mode structures, graphene-based systems, parity- and time-symmetric structures, epsilon-near-zero multi-layer films, quantum-mechanical systems and chiral metamaterials 25 , 26 , 27 . In a plasmonic nanostructure, CPA occurs when coherent light is completely absorbed and transferred to surface plasmons by exciting the nanostructure with the time-reversed mode of the corresponding surface plasmon laser or the so-called SPASER 23 . In experimental realizations of the effect, usually two symmetric plane waves incident on opposite sides of the system are completely absorbed, as a result of critical coupling into the dissipative degrees of freedom of the system. The plasmonic counterparts of some quantum optical effects have also been widely implemented to develop the functionality of optical systems, metamaterials and switching devices 24 , 28 , 29 including the Fano resonance effect and electromagnetically induced transparency (EIT). In plasmonic systems, the plasmon-induced transparency (PIT) creates a narrow transparent window within a broader absorption band of the system due to destructive interference of super-radiant (radiative) and subradiant (dark) resonance modes of the plasmonic nanostructures. This effect is not only limited by the narrow band but also by its weak response. Typically, in an optical switch based on PIT, the transparency window of the medium is reversibly shifted in a wavelength range to provide the ON and OFF states of the switch by applying a light-induced change in the refractive index of a nonlinear material integrated with plasmonic constituents 15 , 17 . Furthermore, a large resonant index of refraction with vanishing absorption has also been reported in quantum optics. This fascinating phenomenon arises when coherence takes place between an excited state and coherently prepared ground state doublet of atomic gas and is known as an enhancement of index of refraction (EIR) 30 . Recently, plasmonic analogue of this quantum optical EIR is theoretically reported in coupled plasmonic resonators, enabling the maximum susceptibility (strong electromagnetic response) with zero optical losses at resonance frequencies via coherent control of surface plasmons 31 . Thus, apart from some newly proposed potential applications 32 , 33 , this approach has suggested a unique path to realize loss-compensated plasmonic devices operating at resonance frequencies through extraordinary enhancement of refractive index without using any gain media 34 , 35 , 36 , 37 or nonlinear processes 28 , 38 . In this work, we introduce and experimentally realize an ultrafast all-optical switching mechanism based on the plasmonic analogue of the EIR effect by designing and fabricating a particular plasmonic metasurface consisting of a square array of L-shaped meta-molecules. In contrast to the conventional methods of optical switching between zero and complete absorption limits of the system, our scheme is based on a linear phenomenon that enables the switching of system absorption between positive and negative values at low exciting power levels. This is achieved through coherent control of polarizability of nanoantennas by controlling the phase and amplitude of a control beam with a polarization perpendicular to the signal beam resulting in unprecedented control of modulation strength of optical switches. Therefore, the scheme is not restricted to counter-propagating light waves and the system<|im_end|> <|im_start|>assistant A group of photonics researchers at Tampere University have introduced a novel method to control a light beam with another beam through a unique plasmonic metasurface in a linear medium at ultra-low power. This simple linear switching method makes nanophotonic devices such as optical computing and communication systems more sustainable, requiring low intensity of light. All-optical switching is the modulation of signal light due to control light in such a way that it possesses the on/off conversion function. In general, a light beam can be modulated with another intense laser beam in the presence of a nonlinear medium. The switching method developed by the researchers is fundamentally based on the quantum optical phenomenon known as Enhancement of Index of Refraction (EIR). "Our work is the first experimental demonstration of this effect on the optical system and its utilization for linear all-optical switching. The research also enlightens the scientific community to achieve loss-compensated plasmonic devices operating at resonance frequencies through extraordinary enhancement of refractive index without using any gain media or nonlinear processes," says Humeyra Caglayan, Associate Professor (tenure track) in Photonics at Tampere University. Optical switching enabled with ultrafast speed High-speed switching and low-loss medium to avoid the strong dissipation of signal during propagation are the basis to develop integrated photonic technology where photons are utilized as information carriers instead of electrons. To realize on-chip ultrafast all-optical switch networks and photonic central processing units, all-optical switching must have ultrafast switching time, ultralow threshold control power, ultrahigh switching efficiency, and nanoscale feature size. "Switching between signal values of 0 and 1 is fundamental in all digital electronic devices including computers and communication systems. Over the past decades, these electronic elements have gradually become smaller and faster. For example, the ordinary calculations done with our computers on the order of seconds could not be done with old room-sized computers, even in several days," Caglayan remarks. In conventional electronics, switching relies on controlling the flow of electrons on the time scale of a microsecond (10-6 sec) or nanosecond (10-9 sec) range by connecting or disconnecting electrical voltage. "However, the switching speed can be raised to an ultrafast time scale (femtosecond 10-15 sec) by replacing the electrons with plasmons. Plasmons are a combination of photons and a collection of electrons on the surface of metals. This enables optical switching with our device with femtosecond (10-15 sec) speeds," she states. "Our plasmonic nano-switch consists of an L-shaped combination of metallic nanorods. One of the nanorods receives a linearly polarized signal and the other receives another linearly polarized 'control' beam perpendicular to the first beam," says Postdoctoral Research Fellow Rakesh Dhama, the first author of the article published in Nature Communications. Polarization means the direction in which the electric field of the beam is oscillating. The control beam can attenuate or amplify the signal depending on the phase difference between the beams. The phase difference refers to the time difference when each beam reaches its maximum intensity. The signal amplification occurs due to the transfer of some optical energy from the control beam to the signal through a constructive superposition with a carefully engineered phase difference. Enhancing the performance of plasmonic devices Similarly, the attenuation of the signal is achieved by destructive superposition when the beams have the opposite phase difference. This finding makes nanophotonic devices such as optical computing and communication systems more sustainable requiring low intensity of light. This simple linear switching method can replace the current methods of optical processing, computing, or communication by accelerating the development and realization of nanoscale plasmonic systems. "We expect to see further studies of plasmonic structures utilizing our improved switching method and possibly the use of our method in plasmonic circuits in the future. Additionally, the L-shaped metasurface could be further studied to reveal ultrahigh-speed switching under the illumination of femtosecond laser pulses and to investigate the nonlinear enhancement and control of plasmonic nanoparticles," Humeyra Caglayan notes. Controlling the nonlinear response of nanostructures provides even more interesting applications and functionalities to nanophotonic devices such as optical computing and communication systems. "This approach has also the potential to enhance the performance of plasmonic devices by creating broadband transparency for a signal beam without any gain medium. It can open up several ways to design smart photonic elements for integrated photonics," Cagalayan says. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The astrophysical sources of the extraterrestrial, very high-energy neutrinos detected by the IceCube collaboration remain to be identified. Gamma-ray (γ-ray) blazars have been predicted to yield a cumulative neutrino signal exceeding the atmospheric background above energies of 100 TeV, assuming that both the neutrinos and the γ-ray photons are produced by accelerated protons in relativistic jets. As the background spectrum falls steeply with increasing energy, the individual events with the clearest signature of being of extraterrestrial origin are those at petaelectronvolt energies. Inside the large positional-uncertainty fields of the first two petaelectronvolt neutrinos detected by IceCube, the integrated emission of the blazar population has a sufficiently high electromagnetic flux to explain the detected IceCube events, but fluences of individual objects are too low to make an unambiguous source association. Here, we report that a major outburst of the blazar PKS B1424–418 occurred in temporal and positional coincidence with a third petaelectronvolt-energy neutrino event (HESE-35) detected by IceCube. On the basis of an analysis of the full sample of γ-ray blazars in the HESE-35 field, we show that the long-term average γ-ray emission of blazars as a class is in agreement with both the measured all-sky flux of petaelectronvolt neutrinos and the spectral slope of the IceCube signal. The outburst of PKS B1424–418 provides an energy output high enough to explain the observed petaelectronvolt event, suggestive of a direct physical association. Main The neutrino excess detected by IceCube comprises 37 events (from May 2010 to May 2013) with energies between 30 TeV and 2 PeV, rejecting a purely atmospheric origin at a significance of 5.7 standard deviations 1 , 2 , 3 . These events show a broad distribution across both hemispheres of the sky consistent with an extragalactic source population. Owing to the very steep background of atmospheric neutrinos, events at petaelectronvolt energies are best suited for attempting to establish associations with individual blazars. In the first two years of observations, IceCube detected two events with about 1 PeV of deposited energy 1 , 2 (HESE-14 and HESE-20; dubbed ‘Bert’ and ‘Ernie’). A third event at 2 PeV (HESE-35; dubbed ‘BigBird’) was recorded in the third year of IceCube data 3 on 4 December 2012. The IceCube analysis concentrated on very high-energy events with interaction signatures that were fully contained within the detector (high-energy starting events; HESEs). In combination with an equal-neutrino-flavour flux at Earth 4 , this resulted in most of the detected events being cascade-like, with relatively large median positional uncertainties ( R 50 ) of typically 10° to 20° so that the field of interest ( Ω v R 50 ) of a given HESE event typically covers more than 300 square degrees. Although a number of different source classes have been discussed as a possible origin of a diffuse neutrino flux 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , no individual astrophysical object has been identified so far from which a neutrino flux with a substantial Poisson probability for a detection by IceCube is expected. Owing to the Earth’s opacity, the IceCube HESE analysis detects events at petaelectronvolt energies mainly from the southern sky 3 . Thus, contemporaneous astronomical data to probe the various source hypotheses can best be obtained via Southern Hemisphere monitoring programmes. TANAMI is a multiwavelength programme 16 , 17 that monitors the brightest γ-ray-loud active galactic nuclei (AGN) located at declinations below − 30°. It comprises the ideal database to estimate the diffuse neutrino flux owing to the integrated emission of AGN in a given large field at a given time, as well as the maximal-possible neutrino flux associated with an individual object of the sample. Blazars are radio-loud AGN with jets oriented close to the line of sight. This substantially increases the apparent brightness of these objects owing to the Doppler boosting of the emission from the relativistically moving emission zones. A direct association of a petaelectronvolt neutrino with an individual γ-ray blazar would have the important implication that a sizeable fraction of their observed γ-ray emission must be due to hadronic decays, and suggests that some blazar jets are also sources of ultrahigh-energy cosmic rays 18 . The X-ray and γ-ray emission of blazars may originate from the photoproduction of pions by accelerated protons 19 . Protons that are accelerated in the jet (for example, through shock acceleration) could interact with ‘seed’ photons (for example, ultraviolet photons from the accretion disk surrounding the central supermassive black hole). The resulting cascades produce charged and neutral pions, which decay and produce neutrinos and high-energy photons. Simple estimates and detailed Monte Carlo simulations show 5 , 20 that in this scenario F γ ≲ F ν , where the X-ray to γ-ray energy flux F γ (formatted as in Table 1 with a subscript γ) is integrated over the high-energy spectral energy distribution (SED). If the seed photons are provided by a blue/ultraviolet bump component, as is typical in the blazar subclass of flat-spectrum radio quasars (FSRQs), and if the proton spectra steepen owing to energy losses, the neutrino spectrum is expected to peak at petaelectronvolt energies 5 . Attributing the high-energy electromagnetic emission to these photohadronic processes, the maximal-possible neutrino petaelectronvolt emission can be estimated from the measured integrated flux of high-energy photons. Table 1 Maximum-possible number of petaelectronvolt-neutrino events in 36 months (988 days live-time) of IceCube data for the 17 2LAC γ-ray blazars in the field of the 2 PeV IceCube event based on 2LAC catalogue γ-ray spectra and contemporaneous X-ray data. Full size table Using TANAMI multiwavelength data, we previously compiled and discussed the multiwavelength properties of the six radio- and γ-ray-brightest blazars located inside the Ω v R 50 fields of the two ∼ 1 PeV events HESE-14 and HESE-20 from the first two years of IceCube data 5 . We found relatively low maximal neutrino fluxes of these six individual blazars owing to their low fluence over two years, but the diffuse", "role": "user" }, { "content": "Nearly 10 billion years ago, the black hole at the center of a galaxy known as PKS B1424-418 produced a powerful outburst. Light from this blast began arriving at Earth in 2012. Now astronomers using data from NASA's Fermi Gamma-ray Space Telescope and other space- and ground-based observatories have shown that a record-breaking neutrino seen around the same time likely was born in the same event. \"Neutrinos are the fastest, lightest, most unsociable and least understood fundamental particles, and we are just now capable of detecting high-energy ones arriving from beyond our galaxy,\" said Roopesh Ojha, a Fermi team member at NASA's Goddard Space Flight Center in Greenbelt, Maryland, and a coauthor of the study. \"Our work provides the first plausible association between a single extragalactic object and one of these cosmic neutrinos.\" Although neutrinos far outnumber all the atoms in the universe, they rarely interact with matter, which makes detecting them quite a challenge. But this same property lets neutrinos make a fast exit from places where light cannot easily escape—such as the core of a collapsing star—and zip across the universe almost completely unimpeded. Neutrinos can provide information about processes and environments that simply aren't available through a study of light alone. The IceCube Neutrino Observatory, built into a cubic kilometer of clear glacial ice at the South Pole, detects neutrinos when they interact with atoms in the ice. This triggers a cascade of fast-moving charged particles that emit a faint glow, called Cerenkov light, as they travel, which is picked up by thousands of optical sensors strung throughout IceCube. Scientists determine the energy of an incoming neutrino by the amount of light its particle cascade emits. NASA Goddard scientist Roopesh Ojha explains how Fermi and TANAMI uncovered the first plausible link between a blazar eruption and a neutrino from deep space. Credit: NASA’s Goddard Space Flight Center To date, the IceCube science team has detected about a hundred very high-energy neutrinos and nicknamed some of the most extreme events after characters on the children's TV series \"Sesame Street.\" On Dec. 4, 2012, IceCube detected an event known as Big Bird, a neutrino with an energy exceeding 2 quadrillion electron volts (PeV). To put that in perspective, it's more than a million million times greater than the energy of a dental X-ray packed into a single particle thought to possess less than a millionth the mass of an electron. Big Bird was the highest-energy neutrino ever detected at the time and still ranks second. Where did it come from? The best IceCube position only narrowed the source to a patch of the southern sky about 32 degrees across, equivalent to the apparent size of 64 full moons. Enter Fermi. Starting in the summer of 2012, the satellite's Large Area Telescope (LAT) witnessed a dramatic brightening of PKS B1424-418, an active galaxy classified as a gamma-ray blazar. An active galaxy is an otherwise typical galaxy with a compact and unusually bright core. The excess luminosity of the central region is produced by matter falling toward a supermassive black hole weighing millions of times the mass of our sun. As it approaches the black hole, some of the material becomes channeled into particle jets moving outward in opposite directions at nearly the speed of light. In blazars, one of these jets happens to point almost directly toward Earth. During the year-long outburst, PKS B1424-418 shone between 15 and 30 times brighter in gamma rays than its average before the eruption. The blazar is located within the Big Bird source region, but then so are many other active galaxies detected by Fermi. Radio images from the TANAMI project reveal the 2012-2013 eruption of PKS B1424-418 at a wavelength of 8.4 GHz. The core of the blazar’s jet brightened by four times, producing the most dramatic blazar outburst TANAMI has observed to date. Credit: TANAMI The scientists searching for the neutrino source then turned to data from a long-term observing program named TANAMI. Since 2007, TANAMI has routinely monitored nearly 100 active galaxies in the southern sky, including many flaring sources detected by Fermi. The program includes regular radio observations using the Australian Long Baseline Array (LBA) and associated telescopes in Chile, South Africa, New Zealand and Antarctica. When networked together, they operate as a single radio telescope more than 6,000 miles across and provide a unique high-resolution look into the jets of active galaxies. Three radio observations of PKS B1424-418 between 2011 and 2013 cover the period of the Fermi outburst. They reveal that the core of the galaxy's jet had brightened by about four times. No other galaxy observed by TANAMI over the life of the program has exhibited such a dramatic change. \"We combed through the field where Big Bird must have originated looking for astrophysical objects capable of producing high-energy particles and light,\" said coauthor Felicia Krauss, a doctoral student at the University of Erlangen-Nuremberg in Germany. \"There was a moment of wonder and awe when we realized that the most dramatic outburst we had ever seen in a blazar happened in just the right place at just the right time.\" In a paper published Monday, April 18, in Nature Physics, the team suggests the PKS B1424-418 outburst and Big Bird are linked, calculating only a 5-percent probability the two events occurred by chance alone. Using data from Fermi, NASA's Swift and WISE satellites, the LBA and other facilities, the researchers determined how the energy of the eruption was distributed across the electromagnetic spectrum and showed that it was sufficiently powerful to produce a neutrino at PeV energies. \"Taking into account all of the observations, the blazar seems to have had means, motive and opportunity to fire off the Big Bird neutrino, which makes it our prime suspect,\" said lead author Matthias Kadler, a professor of astrophysics at the University of Wuerzburg in Germany. Francis Halzen, the principal investigator of IceCube at the University of Wisconsin–Madison, and not involved in this study, thinks the result is an exciting hint of things to come. \"IceCube is about to send out real-time alerts when it records a neutrino that can be localized to an area a little more than half a degree across, or slightly larger than the apparent size of a full moon,\" he said. \"We're slowly opening a neutrino window onto the cosmos.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 astrophysical sources of the extraterrestrial, very high-energy neutrinos detected by the IceCube collaboration remain to be identified. Gamma-ray (γ-ray) blazars have been predicted to yield a cumulative neutrino signal exceeding the atmospheric background above energies of 100 TeV, assuming that both the neutrinos and the γ-ray photons are produced by accelerated protons in relativistic jets. As the background spectrum falls steeply with increasing energy, the individual events with the clearest signature of being of extraterrestrial origin are those at petaelectronvolt energies. Inside the large positional-uncertainty fields of the first two petaelectronvolt neutrinos detected by IceCube, the integrated emission of the blazar population has a sufficiently high electromagnetic flux to explain the detected IceCube events, but fluences of individual objects are too low to make an unambiguous source association. Here, we report that a major outburst of the blazar PKS B1424–418 occurred in temporal and positional coincidence with a third petaelectronvolt-energy neutrino event (HESE-35) detected by IceCube. On the basis of an analysis of the full sample of γ-ray blazars in the HESE-35 field, we show that the long-term average γ-ray emission of blazars as a class is in agreement with both the measured all-sky flux of petaelectronvolt neutrinos and the spectral slope of the IceCube signal. The outburst of PKS B1424–418 provides an energy output high enough to explain the observed petaelectronvolt event, suggestive of a direct physical association. Main The neutrino excess detected by IceCube comprises 37 events (from May 2010 to May 2013) with energies between 30 TeV and 2 PeV, rejecting a purely atmospheric origin at a significance of 5.7 standard deviations 1 , 2 , 3 . These events show a broad distribution across both hemispheres of the sky consistent with an extragalactic source population. Owing to the very steep background of atmospheric neutrinos, events at petaelectronvolt energies are best suited for attempting to establish associations with individual blazars. In the first two years of observations, IceCube detected two events with about 1 PeV of deposited energy 1 , 2 (HESE-14 and HESE-20; dubbed ‘Bert’ and ‘Ernie’). A third event at 2 PeV (HESE-35; dubbed ‘BigBird’) was recorded in the third year of IceCube data 3 on 4 December 2012. The IceCube analysis concentrated on very high-energy events with interaction signatures that were fully contained within the detector (high-energy starting events; HESEs). In combination with an equal-neutrino-flavour flux at Earth 4 , this resulted in most of the detected events being cascade-like, with relatively large median positional uncertainties ( R 50 ) of typically 10° to 20° so that the field of interest ( Ω v R 50 ) of a given HESE event typically covers more than 300 square degrees. Although a number of different source classes have been discussed as a possible origin of a diffuse neutrino flux 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , no individual astrophysical object has been identified so far from which a neutrino flux with a substantial Poisson probability for a detection by IceCube is expected. Owing to the Earth’s opacity, the IceCube HESE analysis detects events at petaelectronvolt energies mainly from the southern sky 3 . Thus, contemporaneous astronomical data to probe the various source hypotheses can best be obtained via Southern Hemisphere monitoring programmes. TANAMI is a multiwavelength programme 16 , 17 that monitors the brightest γ-ray-loud active galactic nuclei (AGN) located at declinations below − 30°. It comprises the ideal database to estimate the diffuse neutrino flux owing to the integrated emission of AGN in a given large field at a given time, as well as the maximal-possible neutrino flux associated with an individual object of the sample. Blazars are radio-loud AGN with jets oriented close to the line of sight. This substantially increases the apparent brightness of these objects owing to the Doppler boosting of the emission from the relativistically moving emission zones. A direct association of a petaelectronvolt neutrino with an individual γ-ray blazar would have the important implication that a sizeable fraction of their observed γ-ray emission must be due to hadronic decays, and suggests that some blazar jets are also sources of ultrahigh-energy cosmic rays 18 . The X-ray and γ-ray emission of blazars may originate from the photoproduction of pions by accelerated protons 19 . Protons that are accelerated in the jet (for example, through shock acceleration) could interact with ‘seed’ photons (for example, ultraviolet photons from the accretion disk surrounding the central supermassive black hole). The resulting cascades produce charged and neutral pions, which decay and produce neutrinos and high-energy photons. Simple estimates and detailed Monte Carlo simulations show 5 , 20 that in this scenario F γ ≲ F ν , where the X-ray to γ-ray energy flux F γ (formatted as in Table 1 with a subscript γ) is integrated over the high-energy spectral energy distribution (SED). If the seed photons are provided by a blue/ultraviolet bump component, as is typical in the blazar subclass of flat-spectrum radio quasars (FSRQs), and if the proton spectra steepen owing to energy losses, the neutrino spectrum is expected to peak at petaelectronvolt energies 5 . Attributing the high-energy electromagnetic emission to these photohadronic processes, the maximal-possible neutrino petaelectronvolt emission can be estimated from the measured integrated flux of high-energy photons. Table 1 Maximum-possible number of petaelectronvolt-neutrino events in 36 months (988 days live-time) of IceCube data for the 17 2LAC γ-ray blazars in the field of the 2 PeV IceCube event based on 2LAC catalogue γ-ray spectra and contemporaneous X-ray data. Full size table Using TANAMI multiwavelength data, we previously compiled and discussed the multiwavelength properties of the six radio- and γ-ray-brightest blazars located inside the Ω v R 50 fields of the two ∼ 1 PeV events HESE-14 and HESE-20 from the first two years of IceCube data 5 . We found relatively low maximal neutrino fluxes of these six individual blazars owing to their low fluence over two years, but the diffuse<|im_end|> <|im_start|>assistant Nearly 10 billion years ago, the black hole at the center of a galaxy known as PKS B1424-418 produced a powerful outburst. Light from this blast began arriving at Earth in 2012. Now astronomers using data from NASA's Fermi Gamma-ray Space Telescope and other space- and ground-based observatories have shown that a record-breaking neutrino seen around the same time likely was born in the same event. "Neutrinos are the fastest, lightest, most unsociable and least understood fundamental particles, and we are just now capable of detecting high-energy ones arriving from beyond our galaxy," said Roopesh Ojha, a Fermi team member at NASA's Goddard Space Flight Center in Greenbelt, Maryland, and a coauthor of the study. "Our work provides the first plausible association between a single extragalactic object and one of these cosmic neutrinos." Although neutrinos far outnumber all the atoms in the universe, they rarely interact with matter, which makes detecting them quite a challenge. But this same property lets neutrinos make a fast exit from places where light cannot easily escape—such as the core of a collapsing star—and zip across the universe almost completely unimpeded. Neutrinos can provide information about processes and environments that simply aren't available through a study of light alone. The IceCube Neutrino Observatory, built into a cubic kilometer of clear glacial ice at the South Pole, detects neutrinos when they interact with atoms in the ice. This triggers a cascade of fast-moving charged particles that emit a faint glow, called Cerenkov light, as they travel, which is picked up by thousands of optical sensors strung throughout IceCube. Scientists determine the energy of an incoming neutrino by the amount of light its particle cascade emits. NASA Goddard scientist Roopesh Ojha explains how Fermi and TANAMI uncovered the first plausible link between a blazar eruption and a neutrino from deep space. Credit: NASA’s Goddard Space Flight Center To date, the IceCube science team has detected about a hundred very high-energy neutrinos and nicknamed some of the most extreme events after characters on the children's TV series "Sesame Street." On Dec. 4, 2012, IceCube detected an event known as Big Bird, a neutrino with an energy exceeding 2 quadrillion electron volts (PeV). To put that in perspective, it's more than a million million times greater than the energy of a dental X-ray packed into a single particle thought to possess less than a millionth the mass of an electron. Big Bird was the highest-energy neutrino ever detected at the time and still ranks second. Where did it come from? The best IceCube position only narrowed the source to a patch of the southern sky about 32 degrees across, equivalent to the apparent size of 64 full moons. Enter Fermi. Starting in the summer of 2012, the satellite's Large Area Telescope (LAT) witnessed a dramatic brightening of PKS B1424-418, an active galaxy classified as a gamma-ray blazar. An active galaxy is an otherwise typical galaxy with a compact and unusually bright core. The excess luminosity of the central region is produced by matter falling toward a supermassive black hole weighing millions of times the mass of our sun. As it approaches the black hole, some of the material becomes channeled into particle jets moving outward in opposite directions at nearly the speed of light. In blazars, one of these jets happens to point almost directly toward Earth. During the year-long outburst, PKS B1424-418 shone between 15 and 30 times brighter in gamma rays than its average before the eruption. The blazar is located within the Big Bird source region, but then so are many other active galaxies detected by Fermi. Radio images from the TANAMI project reveal the 2012-2013 eruption of PKS B1424-418 at a wavelength of 8.4 GHz. The core of the blazar’s jet brightened by four times, producing the most dramatic blazar outburst TANAMI has observed to date. Credit: TANAMI The scientists searching for the neutrino source then turned to data from a long-term observing program named TANAMI. Since 2007, TANAMI has routinely monitored nearly 100 active galaxies in the southern sky, including many flaring sources detected by Fermi. The program includes regular radio observations using the Australian Long Baseline Array (LBA) and associated telescopes in Chile, South Africa, New Zealand and Antarctica. When networked together, they operate as a single radio telescope more than 6,000 miles across and provide a unique high-resolution look into the jets of active galaxies. Three radio observations of PKS B1424-418 between 2011 and 2013 cover the period of the Fermi outburst. They reveal that the core of the galaxy's jet had brightened by about four times. No other galaxy observed by TANAMI over the life of the program has exhibited such a dramatic change. "We combed through the field where Big Bird must have originated looking for astrophysical objects capable of producing high-energy particles and light," said coauthor Felicia Krauss, a doctoral student at the University of Erlangen-Nuremberg in Germany. "There was a moment of wonder and awe when we realized that the most dramatic outburst we had ever seen in a blazar happened in just the right place at just the right time." In a paper published Monday, April 18, in Nature Physics, the team suggests the PKS B1424-418 outburst and Big Bird are linked, calculating only a 5-percent probability the two events occurred by chance alone. Using data from Fermi, NASA's Swift and WISE satellites, the LBA and other facilities, the researchers determined how the energy of the eruption was distributed across the electromagnetic spectrum and showed that it was sufficiently powerful to produce a neutrino at PeV energies. "Taking into account all of the observations, the blazar seems to have had means, motive and opportunity to fire off the Big Bird neutrino, which makes it our prime suspect," said lead author Matthias Kadler, a professor of astrophysics at the University of Wuerzburg in Germany. Francis Halzen, the principal investigator of IceCube at the University of Wisconsin–Madison, and not involved in this study, thinks the result is an exciting hint of things to come. "IceCube is about to send out real-time alerts when it records a neutrino that can be localized to an area a little more than half a degree across, or slightly larger than the apparent size of a full moon," he said. "We're slowly opening a neutrino window onto the cosmos." <|im_end|>

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373, 6825, 1210, 1952, 3799, 13, 220, 19, 11, 220, 679, 17, 11, 20534, 44429, 16914, 459, 1567, 3967, 439, 6295, 24214, 11, 264, 42699, 3394, 449, 459, 4907, 49005, 220, 17, 30236, 15068, 17130, 87167, 320, 10407, 53, 570, 2057, 2231, 430, 304, 13356, 11, 433, 596, 810, 1109, 264, 3610, 3610, 3115, 7191, 1109, 279, 4907, 315, 264, 29106, 1630, 30630, 19937, 1139, 264, 3254, 19320, 3463, 311, 15575, 2753, 1109, 264, 3610, 339, 279, 3148, 315, 459, 17130, 13, 6295, 24214, 574, 279, 8592, 65487, 42699, 3394, 3596, 16914, 520, 279, 892, 323, 2103, 21467, 2132, 13, 11208, 1550, 433, 2586, 505, 30, 578, 1888, 20534, 44429, 2361, 1193, 74035, 279, 2592, 311, 264, 11140, 315, 279, 18561, 13180, 922, 220, 843, 12628, 4028, 11, 13890, 311, 279, 10186, 1404, 315, 220, 1227, 2539, 81260, 13, 11502, 99362, 72, 13, 28757, 304, 279, 7474, 315, 220, 679, 17, 11, 279, 24088, 596, 20902, 12299, 87062, 320, 79998, 8, 32126, 264, 22520, 10107, 6147, 315, 25864, 50, 426, 10239, 19, 12, 19770, 11, 459, 4642, 34261, 21771, 439, 264, 22350, 30630, 1529, 34144, 13, 1556, 4642, 34261, 374, 459, 6062, 14595, 34261, 449, 264, 17251, 323, 57899, 10107, 6332, 13, 578, 13937, 46058, 22828, 315, 279, 8792, 5654, 374, 9124, 555, 5030, 16054, 9017, 264, 2307, 27428, 535, 3776, 14512, 47826, 11990, 315, 3115, 279, 3148, 315, 1057, 7160, 13, 1666, 433, 20414, 279, 3776, 14512, 11, 1063, 315, 279, 3769, 9221, 523, 20991, 839, 1139, 19320, 44305, 7366, 52046, 304, 14329, 18445, 520, 7154, 279, 4732, 315, 3177, 13, 763, 1529, 1394, 1590, 11, 832, 315, 1521, 44305, 8741, 311, 1486, 4661, 6089, 9017, 9420, 13, 12220, 279, 1060, 24725, 704, 58838, 11, 25864, 50, 426, 10239, 19, 12, 19770, 559, 606, 1990, 220, 868, 323, 220, 966, 3115, 53657, 304, 22350, 45220, 1109, 1202, 5578, 1603, 279, 80502, 13, 578, 1529, 34144, 374, 7559, 2949, 279, 6295, 24214, 2592, 5654, 11, 719, 1243, 779, 527, 1690, 1023, 4642, 66017, 16914, 555, 99362, 72, 13, 13792, 5448, 505, 279, 350, 1111, 67668, 2447, 16805, 279, 220, 679, 17, 12, 679, 18, 80502, 315, 25864, 50, 426, 10239, 19, 12, 19770, 520, 264, 46406, 315, 220, 23, 13, 19, 52405, 13, 578, 6332, 315, 279, 1529, 34144, 753, 17004, 10107, 6901, 555, 3116, 3115, 11, 17843, 279, 1455, 22520, 1529, 34144, 704, 58838, 350, 1111, 67668, 706, 13468, 311, 2457, 13, 16666, 25, 350, 1111, 67668, 578, 14248, 15389, 369, 279, 42699, 3394, 2592, 1243, 6656, 311, 828, 505, 264, 1317, 9860, 46071, 2068, 7086, 350, 1111, 67668, 13, 8876, 220, 1049, 22, 11, 350, 1111, 67668, 706, 40076, 41223, 7154, 220, 1041, 4642, 66017, 304, 279, 18561, 13180, 11, 2737, 1690, 1344, 3329, 8336, 16914, 555, 99362, 72, 13, 578, 2068, 5764, 5912, 9063, 24654, 1701, 279, 13673, 5843, 15004, 4939, 2982, 320, 43, 7209, 8, 323, 5938, 78513, 19031, 304, 34100, 11, 4987, 10384, 11, 1561, 17340, 323, 72787, 13, 3277, 4009, 291, 3871, 11, 814, 14816, 439, 264, 3254, 9063, 56925, 810, 1109, 220, 21, 11, 931, 8931, 4028, 323, 3493, 264, 5016, 1579, 64036, 1427, 1139, 279, 44305, 315, 4642, 66017, 13, 14853, 9063, 24654, 315, 25864, 50, 426, 10239, 19, 12, 19770, 1990, 220, 679, 16, 323, 220, 679, 18, 3504, 279, 4261, 315, 279, 99362, 72, 704, 58838, 13, 2435, 16805, 430, 279, 6332, 315, 279, 34261, 596, 17004, 1047, 10107, 6901, 555, 922, 3116, 3115, 13, 2360, 1023, 34261, 13468, 555, 350, 1111, 67668, 927, 279, 2324, 315, 279, 2068, 706, 51713, 1778, 264, 22520, 2349, 13, 330, 1687, 470, 2788, 1555, 279, 2115, 1405, 6295, 24214, 2011, 617, 44853, 3411, 369, 12025, 22761, 19506, 6302, 13171, 315, 17843, 1579, 65487, 19252, 323, 3177, 1359, 1071, 1080, 3170, 27246, 24985, 62167, 1892, 11, 264, 74657, 5575, 520, 279, 3907, 315, 81934, 60241, 11500, 554, 76, 7881, 304, 10057, 13, 330, 3947, 574, 264, 4545, 315, 5895, 323, 51517, 994, 584, 15393, 430, 279, 1455, 22520, 704, 58838, 584, 1047, 3596, 3970, 304, 264, 1529, 34144, 7077, 304, 1120, 279, 1314, 2035, 520, 1120, 279, 1314, 892, 1210, 763, 264, 5684, 4756, 7159, 11, 5936, 220, 972, 11, 304, 22037, 28415, 11, 279, 2128, 13533, 279, 25864, 50, 426, 10239, 19, 12, 19770, 704, 58838, 323, 6295, 24214, 527, 10815, 11, 38714, 1193, 264, 220, 20, 71724, 19463, 279, 1403, 4455, 10222, 555, 6140, 7636, 13, 12362, 828, 505, 99362, 72, 11, 22146, 596, 24594, 323, 468, 9311, 47710, 11, 279, 445, 7209, 323, 1023, 13077, 11, 279, 12074, 11075, 1268, 279, 4907, 315, 279, 80502, 574, 4332, 4028, 279, 66669, 20326, 323, 8710, 430, 433, 574, 40044, 8147, 311, 8356, 264, 42699, 3394, 520, 5250, 53, 49969, 13, 330, 51197, 1139, 2759, 682, 315, 279, 24654, 11, 279, 1529, 34144, 5084, 311, 617, 1047, 3445, 11, 47094, 323, 6776, 311, 4027, 1022, 279, 6295, 24214, 42699, 3394, 11, 902, 3727, 433, 1057, 10461, 15562, 1359, 1071, 3063, 3229, 90587, 74776, 1565, 11, 264, 14561, 315, 12025, 22761, 17688, 520, 279, 3907, 315, 468, 8977, 79302, 304, 10057, 13, 26184, 20442, 5797, 11, 279, 12717, 49581, 315, 20534, 44429, 520, 279, 3907, 315, 21073, 4235, 38136, 3416, 11, 323, 539, 6532, 304, 420, 4007, 11, 15849, 279, 1121, 374, 459, 13548, 13310, 315, 2574, 311, 2586, 13, 330, 52430, 44429, 374, 922, 311, 3708, 704, 1972, 7394, 30350, 994, 433, 7576, 264, 42699, 3394, 430, 649, 387, 44589, 311, 459, 3158, 264, 2697, 810, 1109, 4376, 264, 8547, 4028, 11, 477, 10284, 8294, 1109, 279, 10186, 1404, 315, 264, 2539, 18266, 1359, 568, 1071, 13, 330, 1687, 2351, 14297, 8736, 264, 42699, 3394, 3321, 8800, 279, 83645, 1210, 220, 128257, 198 ]

2,848

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Natural space is associated with reduced risk of, and narrower socioeconomic inequalities in, diseases that affect older populations, and some contributors to premature mortality in younger individuals. Burden of disease measures such as years of life lost (YLL) are influenced by premature poor health and death. We hypothesised some association between natural space and both rates of and inequalities in YLL might be present. Methods The outcome data were the YLL component from Scottish Burden of Disease 2016, provided at small-area level (datazone) for males and females under 65 years of age in Scotland, UK. Exposure variables were the percentages of land cover within each datazone defined as ‘natural space’ (NS), and ‘natural space and private gardens’ (NSG). Together with a measure of area income deprivation, these were fitted in a multilevel Poisson model accounting for intra-datazone level variation, and spatial autocorrelation between datazones. Results An increased percentage cover of NSG was associated with lower YLL in males (incident rate ratio (IRR) 0.993, 95% credible interval (CrI) 0.989 to 0.997) and females (IRR 0.993, CrI 0.987 to 0.998); each 10% increase of natural space cover was associated with a 7% decrease in the incidence rate. An increased amount of natural space within local areas was associated with reduced disparity in YLL between the most and least income deprived areas. Conclusions The health benefits of natural space also apply when indicators sensitive to health events at younger ages are used. An increased amount of natural space within local areas has the potential to reduce the disparity in YLL between the most and least income deprived areas—the ‘equigenic’ effect. spatial analysis health inequalities geography Data availability statement Data are available upon reasonable request. The data used are available from Ordinance Survey and Scottish Public Health Observatory/Public Health Scotland upon request; data from the latter two are subject to protocol to prevent disclosure of person details. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: . googletag.cmd.push(function() { googletag.display(\"dfp-ad-mpu\"); }); Statistics from Altmetric.com See more details Picked up by 24 news outlets Blogged by 3 Tweeted by 43 On 1 Facebook pages 10 readers on Mendeley Linked Articles Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. ?xml version=\"1.0\" encoding=\"UTF-8\" ? Request permissions spatial analysis health inequalities geography WHAT IS ALREADY KNOWN ON THIS TOPIC Greater access and exposure to natural space has been shown to have a direct impact on health. Measures such as years of life lost (YLL) are particularly effective at detecting the impacts of premature poor health and death. The association between natural space and YLL in Scotland, after accounting for deprivation, has not been explored. WHAT THIS STUDY ADDS These results indicate that, using a measure (YLL) that should not be impacted much by the presence of natural space, some association is still there—further reinforcing how important natural space is to public health. An increased amount of natural space within local areas was associated with lower disparity in YLL between the most and least income deprived areas. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY This study reinforces the evidence that local natural space, and in particular private gardens, has a positive impact on health, and the potential for reducing health inequalities; thus natural spaces and private gardens should be an important feature in any building/development planning. Introduction Many studies have assessed the apparent health benefits to individuals and populations of exposure to natural spaces. There is strong evidence that spending more time in ‘green’ areas is associated with many positive health outcomes, including lower heart rate, improved birth weights and lower mortality rates. 1–4 However, associations are not consistently positive, which may be due to inconsistency in how ‘greenness’ is measured. 1 3 5 Further, emerging evidence suggests that ‘blue’ spaces provide health benefits, such as lower prescribing of antidepressant medication among older people. 6 A potential way to advance is therefore to capture the whole natural environment , or ‘natural space’, by including both green and blue spaces measured with landcover data. When epidemiologists assess associations between exposures and health, they often use direct measures of illness or function such as mortality rates or prevalence of poor mental health, and the overwhelming majority of epidemiological studies of natural space take this approach (see, for example, Steel et al , Labib et al , Richardson et al , and Olsen et al 7–10 ). However, there are also indirect measures of health, such as those that measure the gap between an individual or population’s current health status and ideal health status (living to old age, free from disease and disability), or ‘health lost’ through premature death. Such measures give a different perspective on population health and, in particular, can alter the ways in which we assess and prioritise the importance of pathogenic risk factors or salutogenic characteristics. Total burden of disease is one such indirect measure of health. In 2018, Scotland published its first estimate of the Scottish Burden of Disease (SBoD), based on a 3 year average of mortality and morbidity from 2013 to 2016. 11 SBoD is measured in disability adjusted life years (DALYs)—the sum of years of life lost (YLL) and years lived with disability (YLD)—to indicate the burden of disease for an area. 12 DALYs have been linked to various pathogenic environmental exposures such as air pollution and noise. 13 The YLL component of the SBoD estimate is the disparity between the actual age at death, and the age to which", "role": "user" }, { "content": "Increasing the amount of natural (green and blue) space and private gardens has the potential to narrow the lifespan gap between those living in the most and least deprived areas, suggests research published online in the Journal of Epidemiology of Community Health. Each 10% increase in natural space is linked to a 7% fall in the incidence of early death among the under 65s, the findings indicate. The idea that the natural environment provides health benefits isn't new: there's strong evidence that greater access and exposure to natural space has a direct positive impact on health. But it's not clear if access to natural space might also be associated with differences in lifespan and protection against an earlier than expected death, so the researchers used the measure of \"years of life lost,\" or YLL for short, to try and find out. They drew on YLL data from the 2016 Scottish Burden of Disease, reflecting the gap between expected and actual lifespan for men and women under 65 who were resident in Scotland, U.K., at time of death. The YLL data were divided up by \"datazone\"—defined as a geographical unit of approximately 500–1,000 household residents that aligns with physical boundaries and natural communities, has a regular shape, and contains households with broadly similar social characteristics. The Ordnance Survey Mastermap was used to track areas of natural space or private gardens in square meters. Natural space was defined as: woodland; scattered trees; scrub; marsh; heath; open water (inland or tidal); semi natural grassland; general natural areas, such as grass on sports pitches, roadside verges, and farmland; agriculture; hard bare ground, such as rocks, boulders, and cliffs; and soft bare ground, such as sand, soil, and foreshore. Areas with the highest income deprivation had the lowest average percentage cover of natural space and gardens (58.5%, 49–65%). People living in these areas had the highest levels of ill health. The study found that every 10% increase in natural space cover was associated with a 7% fall in the incidence of premature death. Increased availability of natural space within local areas was also associated with a reduction in the disparity in YLL between the most and least deprived areas. Even moderate levels of natural space seemed to make a difference. \"In practice, not everyone can live in an area with a high percentage of green or natural space; however, this does not mean that even small amounts of such areas are not beneficial,\" point out the researchers. This is an observational study, and as such, can't establish cause and effect. And the researchers acknowledge that they didn't have information on individual lifestyle behavior and personal economic circumstances, or how much people used their local natural space or its quality, all of which may have influenced their findings. But their findings echo those of other studies, they point out. And they conclude that \"an increased amount of natural/green spaces within local areas has the potential to reduce the disparity in YLL between the most and least income deprived areas—the 'equigenic' effect.\" They add that \"natural spaces and private gardens should be an important feature in any building/ development planning.\" A linked editorial cautions that the researchers weren't able to differentiate between type and level of exposure to natural space in urban and rural areas, or important factors such as air pollution and access to health care. But the editorialists from Massey University, Wellington, New Zealand, USDA Forest Service, Portland, Oregon, and the US Fred Hutchinson Cancer Center, Seattle, point out that if the link between natural space and a reduction in health inequity turns out to be true, then this \"could provide an additional public-health tool to reduce the large health inequities that exist for deprived populations, indigenous peoples, and other ethnic minorities.\" The natural environment may exert its beneficial effects because it has driven human evolution, facilitates physical activity, absorbs air pollutants, and may also boost the diversity of helpful microbes, they suggest. But they caution that \"substantial knowledge gaps remain, including limited understanding of what aspects of the natural environment are protective, which biological mechanisms are involved and how we can most effectively apply this knowledge to reduce the increasing burden of [non-communicable 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 Background Natural space is associated with reduced risk of, and narrower socioeconomic inequalities in, diseases that affect older populations, and some contributors to premature mortality in younger individuals. Burden of disease measures such as years of life lost (YLL) are influenced by premature poor health and death. We hypothesised some association between natural space and both rates of and inequalities in YLL might be present. Methods The outcome data were the YLL component from Scottish Burden of Disease 2016, provided at small-area level (datazone) for males and females under 65 years of age in Scotland, UK. Exposure variables were the percentages of land cover within each datazone defined as ‘natural space’ (NS), and ‘natural space and private gardens’ (NSG). Together with a measure of area income deprivation, these were fitted in a multilevel Poisson model accounting for intra-datazone level variation, and spatial autocorrelation between datazones. Results An increased percentage cover of NSG was associated with lower YLL in males (incident rate ratio (IRR) 0.993, 95% credible interval (CrI) 0.989 to 0.997) and females (IRR 0.993, CrI 0.987 to 0.998); each 10% increase of natural space cover was associated with a 7% decrease in the incidence rate. An increased amount of natural space within local areas was associated with reduced disparity in YLL between the most and least income deprived areas. Conclusions The health benefits of natural space also apply when indicators sensitive to health events at younger ages are used. An increased amount of natural space within local areas has the potential to reduce the disparity in YLL between the most and least income deprived areas—the ‘equigenic’ effect. spatial analysis health inequalities geography Data availability statement Data are available upon reasonable request. The data used are available from Ordinance Survey and Scottish Public Health Observatory/Public Health Scotland upon request; data from the latter two are subject to protocol to prevent disclosure of person details. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: . googletag.cmd.push(function() { googletag.display("dfp-ad-mpu"); }); Statistics from Altmetric.com See more details Picked up by 24 news outlets Blogged by 3 Tweeted by 43 On 1 Facebook pages 10 readers on Mendeley Linked Articles Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. ?xml version="1.0" encoding="UTF-8" ? Request permissions spatial analysis health inequalities geography WHAT IS ALREADY KNOWN ON THIS TOPIC Greater access and exposure to natural space has been shown to have a direct impact on health. Measures such as years of life lost (YLL) are particularly effective at detecting the impacts of premature poor health and death. The association between natural space and YLL in Scotland, after accounting for deprivation, has not been explored. WHAT THIS STUDY ADDS These results indicate that, using a measure (YLL) that should not be impacted much by the presence of natural space, some association is still there—further reinforcing how important natural space is to public health. An increased amount of natural space within local areas was associated with lower disparity in YLL between the most and least income deprived areas. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY This study reinforces the evidence that local natural space, and in particular private gardens, has a positive impact on health, and the potential for reducing health inequalities; thus natural spaces and private gardens should be an important feature in any building/development planning. Introduction Many studies have assessed the apparent health benefits to individuals and populations of exposure to natural spaces. There is strong evidence that spending more time in ‘green’ areas is associated with many positive health outcomes, including lower heart rate, improved birth weights and lower mortality rates. 1–4 However, associations are not consistently positive, which may be due to inconsistency in how ‘greenness’ is measured. 1 3 5 Further, emerging evidence suggests that ‘blue’ spaces provide health benefits, such as lower prescribing of antidepressant medication among older people. 6 A potential way to advance is therefore to capture the whole natural environment , or ‘natural space’, by including both green and blue spaces measured with landcover data. When epidemiologists assess associations between exposures and health, they often use direct measures of illness or function such as mortality rates or prevalence of poor mental health, and the overwhelming majority of epidemiological studies of natural space take this approach (see, for example, Steel et al , Labib et al , Richardson et al , and Olsen et al 7–10 ). However, there are also indirect measures of health, such as those that measure the gap between an individual or population’s current health status and ideal health status (living to old age, free from disease and disability), or ‘health lost’ through premature death. Such measures give a different perspective on population health and, in particular, can alter the ways in which we assess and prioritise the importance of pathogenic risk factors or salutogenic characteristics. Total burden of disease is one such indirect measure of health. In 2018, Scotland published its first estimate of the Scottish Burden of Disease (SBoD), based on a 3 year average of mortality and morbidity from 2013 to 2016. 11 SBoD is measured in disability adjusted life years (DALYs)—the sum of years of life lost (YLL) and years lived with disability (YLD)—to indicate the burden of disease for an area. 12 DALYs have been linked to various pathogenic environmental exposures such as air pollution and noise. 13 The YLL component of the SBoD estimate is the disparity between the actual age at death, and the age to which<|im_end|> <|im_start|>assistant Increasing the amount of natural (green and blue) space and private gardens has the potential to narrow the lifespan gap between those living in the most and least deprived areas, suggests research published online in the Journal of Epidemiology of Community Health. Each 10% increase in natural space is linked to a 7% fall in the incidence of early death among the under 65s, the findings indicate. The idea that the natural environment provides health benefits isn't new: there's strong evidence that greater access and exposure to natural space has a direct positive impact on health. But it's not clear if access to natural space might also be associated with differences in lifespan and protection against an earlier than expected death, so the researchers used the measure of "years of life lost," or YLL for short, to try and find out. They drew on YLL data from the 2016 Scottish Burden of Disease, reflecting the gap between expected and actual lifespan for men and women under 65 who were resident in Scotland, U.K., at time of death. The YLL data were divided up by "datazone"—defined as a geographical unit of approximately 500–1,000 household residents that aligns with physical boundaries and natural communities, has a regular shape, and contains households with broadly similar social characteristics. The Ordnance Survey Mastermap was used to track areas of natural space or private gardens in square meters. Natural space was defined as: woodland; scattered trees; scrub; marsh; heath; open water (inland or tidal); semi natural grassland; general natural areas, such as grass on sports pitches, roadside verges, and farmland; agriculture; hard bare ground, such as rocks, boulders, and cliffs; and soft bare ground, such as sand, soil, and foreshore. Areas with the highest income deprivation had the lowest average percentage cover of natural space and gardens (58.5%, 49–65%). People living in these areas had the highest levels of ill health. The study found that every 10% increase in natural space cover was associated with a 7% fall in the incidence of premature death. Increased availability of natural space within local areas was also associated with a reduction in the disparity in YLL between the most and least deprived areas. Even moderate levels of natural space seemed to make a difference. "In practice, not everyone can live in an area with a high percentage of green or natural space; however, this does not mean that even small amounts of such areas are not beneficial," point out the researchers. This is an observational study, and as such, can't establish cause and effect. And the researchers acknowledge that they didn't have information on individual lifestyle behavior and personal economic circumstances, or how much people used their local natural space or its quality, all of which may have influenced their findings. But their findings echo those of other studies, they point out. And they conclude that "an increased amount of natural/green spaces within local areas has the potential to reduce the disparity in YLL between the most and least income deprived areas—the 'equigenic' effect." They add that "natural spaces and private gardens should be an important feature in any building/ development planning." A linked editorial cautions that the researchers weren't able to differentiate between type and level of exposure to natural space in urban and rural areas, or important factors such as air pollution and access to health care. But the editorialists from Massey University, Wellington, New Zealand, USDA Forest Service, Portland, Oregon, and the US Fred Hutchinson Cancer Center, Seattle, point out that if the link between natural space and a reduction in health inequity turns out to be true, then this "could provide an additional public-health tool to reduce the large health inequities that exist for deprived populations, indigenous peoples, and other ethnic minorities." The natural environment may exert its beneficial effects because it has driven human evolution, facilitates physical activity, absorbs air pollutants, and may also boost the diversity of helpful microbes, they suggest. But they caution that "substantial knowledge gaps remain, including limited understanding of what aspects of the natural environment are protective, which biological mechanisms are involved and how we can most effectively apply this knowledge to reduce the increasing burden of [non-communicable 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 The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development. Main High-throughput sequencing approaches can generate detailed catalogues of genetic variation in both disease patients and the general population. However, for these technologies to have the greatest medical impact we must be able to separate genuine disease-causing or disease-associated genetic variants reliably from the broader background of variants present in all human genomes that are rare, potentially functional, but not actually pathogenic ( Box 1 ) for the disease or phenotype under investigation. Many, but unfortunately not all, variants that have been causally associated with rare and common genetic disorders represent robust and correct conclusions. False assignments of pathogenicity can have severe consequences for patients, resulting in incorrect prognostic, therapeutic or reproductive advice, and for the research enterprise, resulting in misallocation of resources for basic and therapeutic research. Unfortunately, although the vast majority of genes reported as causally linked to monogenic diseases are true positives, false assignments of causality at the variant level are a substantial issue. One recent analysis of 406 published severe disease mutations observed in 104 newly sequenced individuals reported that 122 (27%) of these were either common polymorphisms or lacked direct evidence for pathogenicity 1 . Other studies have identified numerous alleged severe-disease-causing variants in the genomes of population controls 2 , 3 . In other cases, well-powered follow-up studies of high-profile reported mutations have cast serious doubts on initial reports assigning disease causality to sequence variants 4 , 5 , but the vast majority of false-positive findings probably remain undetected. As the volume of patient sequencing data increases it is critical that candidate variants are subjected to rigorous evaluation to prevent further misannotation of the pathogenicity of variants in public databases. This paper describes the challenges in reliably investigating the role of sequence variants in human disease, and approaches to evaluate the evidence supporting variant causality. It represents the conclusions of a working group of experts in genomic research, analysis and clinical diagnostic sequencing convened by the US National Human Genome Research Institute. We focus on the application of genome-scale approaches to investigating rare germline variants, defined here as variants with a minor allele frequency of <1%. Our recommendations are most relevant for variants with relatively large effects on disease risk. Our intended scope encompasses the vast majority of variants implicated in severe monogenic diseases as well as rare, large-effect risk variants in complex disease 6 , but excludes the common, small-effect variants typically identified by genome-wide association studies of complex traits 7 . Unambiguous assignment of disease causality for sequence variants is often impossible, particularly for the very low-frequency variants underlying many cases of rare, severe diseases. Consequently, we refer in this manuscript to the concept of implicating a gene or sequence variant: that is, the process of integrating and assessing the evidence supporting a role for that gene or variant in pathogenesis. We emphasize the primacy of strong genetic support for causation for any new gene, which may then be supplemented and extended with ancillary support from functional and informatic studies. Our recommendations centre on five key areas: study design; gene-level implication; variant-level implication; publication and databases; and implications for clinical diagnosis. Core guidelines for researchers are summarized in Box 2 . We also provide a list of factors to consider in the analyses of candidate variants in presumed monogenic diseases ( Supplementary Information ) and a list of resources for assessing pathogenicity ( Supplementary Table 1 ). Box 1: Terms used to describe sequence variants Lack of clarity in the terms used to describe sequence variants is a major source of confusion in human genetics. We have adopted the following definitions for terms used throughout this manuscript. Pathogenic: contributes mechanistically to disease, but is not necessarily fully penetrant (i.e., may not be sufficient in isolation to cause disease). Implicated: possesses evidence consistent with a pathogenic role, with a defined level of confidence. Associated: significantly enriched in disease cases compared to matched controls. Damaging: alters the normal levels or biochemical function of a gene or gene product. Deleterious: reduces the reproductive fitness of carriers, and would thus be targeted by purifying natural selection. Show more Box 2: Guidelines for implicating sequence variants in human disease General guidelines • Provide complete positive and negative evidence associated with the gene or variant implication, not just the results that are consistent with pathogenicity. • In all cases in which it is possible, place genetic, informatic and experimental results within a quantitative framework: determine the probability of observing this result by chance with a randomly selected variant or gene. • Take advantage of public data sets of genomic variation, functional genomic data and model-organism phenotypes. • Do not regard prior reports of gene or variant implication as definitive: to the degree that supporting data are available, reassess them as rigorously as your own data. • Describe and assess clearly the available evidence supporting prior reports of gene or variant implication. Assessment of evidence for candidate disease genes • In presumed monogenic-disease cases, evaluate genes previously implicated in similar phenotypes before exploring potential new genes. • Report a new gene as confidently implicated only when variants in the same gene and similar clinical presentations have been confidently implicated in multiple unrelated individuals. • In all cases in which it is possible, apply statistical methods to compare the distribution of variants in patients with large matched control cohorts or well-calibrated null models. Assessment of evidence for candidate", "role": "user" }, { "content": "Sequencing an entire human genome is faster and cheaper than ever before, leading to an explosion of studies comparing the genomes of people with and without a given disease. Often clinicians and researchers studying genetic contributions to a certain disease encounter variations that appear to be responsible, only to find other people with the same mutation who don't have the disease or who are affected to a lesser degree. How do doctors pinpoint the genetic changes that really cause disease? An open-access policy paper to be published Wednesday in Nature proposes guidelines for researchers studying the effects of rare genetic variants. The recommendations focus on several key areas, such as study design, gene- and variant-level implication, databases and implications for diagnosis. Co-author Chris Gunter, PhD, associate director of research at Marcus Autism Center and associate professor of pediatrics at Emory, is one of the organizers of the 2012 workshop of leading genomics researchers, sponsored by the National Human Genome Research Institute, that led to the paper. \"Several of us had noticed that studies were coming out with wrong conclusions about the relationship between a specific sequence and disease, and we were extremely concerned that this would translate into inappropriate clinical decisions,\" she says. Potentially, based on flawed results, physicians could order additional testing or treatments that are not truly supported by a link between a genetic variant and disease, and this paper could help prevent such inappropriate decisions, Gunter says. The group of 27 researchers proposes two steps for claiming that a genetic variation causes disease: detailed statistical analysis followed by an assessment of evidence from all sources supporting a role for the variant in that specific disease or condition. In addition, they highlight priorities for research and infrastructure development, including added incentives for researchers to share genetic and clinical data. One case cited in the paper relates to autism. Researchers found four independent variations in a gene called TTN when they compared genomes between individuals with and without autism. However, the TTN gene encodes a muscle protein (titin) that is the largest known; variations are simply more likely to be found within its boundaries compared to those of other genes. Without applying the proper statistical corrections, researchers may have falsely concluded that TTN was worthy of further investigation in autism studies. The authors note that many DNA variants \"may suggest a potentially convincing story about how the variant may influence the trait,\" but few will actually have causal effects. Thus, using evidence-based guidelines such as the ones in the Nature paper will be crucial. \"We believe that these guidelines will be particularly useful to scientists and clinicians in other areas who want to do human genomic studies, and need a defined starting point for investigating genetic effects, \" Gunter says. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development. Main High-throughput sequencing approaches can generate detailed catalogues of genetic variation in both disease patients and the general population. However, for these technologies to have the greatest medical impact we must be able to separate genuine disease-causing or disease-associated genetic variants reliably from the broader background of variants present in all human genomes that are rare, potentially functional, but not actually pathogenic ( Box 1 ) for the disease or phenotype under investigation. Many, but unfortunately not all, variants that have been causally associated with rare and common genetic disorders represent robust and correct conclusions. False assignments of pathogenicity can have severe consequences for patients, resulting in incorrect prognostic, therapeutic or reproductive advice, and for the research enterprise, resulting in misallocation of resources for basic and therapeutic research. Unfortunately, although the vast majority of genes reported as causally linked to monogenic diseases are true positives, false assignments of causality at the variant level are a substantial issue. One recent analysis of 406 published severe disease mutations observed in 104 newly sequenced individuals reported that 122 (27%) of these were either common polymorphisms or lacked direct evidence for pathogenicity 1 . Other studies have identified numerous alleged severe-disease-causing variants in the genomes of population controls 2 , 3 . In other cases, well-powered follow-up studies of high-profile reported mutations have cast serious doubts on initial reports assigning disease causality to sequence variants 4 , 5 , but the vast majority of false-positive findings probably remain undetected. As the volume of patient sequencing data increases it is critical that candidate variants are subjected to rigorous evaluation to prevent further misannotation of the pathogenicity of variants in public databases. This paper describes the challenges in reliably investigating the role of sequence variants in human disease, and approaches to evaluate the evidence supporting variant causality. It represents the conclusions of a working group of experts in genomic research, analysis and clinical diagnostic sequencing convened by the US National Human Genome Research Institute. We focus on the application of genome-scale approaches to investigating rare germline variants, defined here as variants with a minor allele frequency of <1%. Our recommendations are most relevant for variants with relatively large effects on disease risk. Our intended scope encompasses the vast majority of variants implicated in severe monogenic diseases as well as rare, large-effect risk variants in complex disease 6 , but excludes the common, small-effect variants typically identified by genome-wide association studies of complex traits 7 . Unambiguous assignment of disease causality for sequence variants is often impossible, particularly for the very low-frequency variants underlying many cases of rare, severe diseases. Consequently, we refer in this manuscript to the concept of implicating a gene or sequence variant: that is, the process of integrating and assessing the evidence supporting a role for that gene or variant in pathogenesis. We emphasize the primacy of strong genetic support for causation for any new gene, which may then be supplemented and extended with ancillary support from functional and informatic studies. Our recommendations centre on five key areas: study design; gene-level implication; variant-level implication; publication and databases; and implications for clinical diagnosis. Core guidelines for researchers are summarized in Box 2 . We also provide a list of factors to consider in the analyses of candidate variants in presumed monogenic diseases ( Supplementary Information ) and a list of resources for assessing pathogenicity ( Supplementary Table 1 ). Box 1: Terms used to describe sequence variants Lack of clarity in the terms used to describe sequence variants is a major source of confusion in human genetics. We have adopted the following definitions for terms used throughout this manuscript. Pathogenic: contributes mechanistically to disease, but is not necessarily fully penetrant (i.e., may not be sufficient in isolation to cause disease). Implicated: possesses evidence consistent with a pathogenic role, with a defined level of confidence. Associated: significantly enriched in disease cases compared to matched controls. Damaging: alters the normal levels or biochemical function of a gene or gene product. Deleterious: reduces the reproductive fitness of carriers, and would thus be targeted by purifying natural selection. Show more Box 2: Guidelines for implicating sequence variants in human disease General guidelines • Provide complete positive and negative evidence associated with the gene or variant implication, not just the results that are consistent with pathogenicity. • In all cases in which it is possible, place genetic, informatic and experimental results within a quantitative framework: determine the probability of observing this result by chance with a randomly selected variant or gene. • Take advantage of public data sets of genomic variation, functional genomic data and model-organism phenotypes. • Do not regard prior reports of gene or variant implication as definitive: to the degree that supporting data are available, reassess them as rigorously as your own data. • Describe and assess clearly the available evidence supporting prior reports of gene or variant implication. Assessment of evidence for candidate disease genes • In presumed monogenic-disease cases, evaluate genes previously implicated in similar phenotypes before exploring potential new genes. • Report a new gene as confidently implicated only when variants in the same gene and similar clinical presentations have been confidently implicated in multiple unrelated individuals. • In all cases in which it is possible, apply statistical methods to compare the distribution of variants in patients with large matched control cohorts or well-calibrated null models. Assessment of evidence for candidate<|im_end|> <|im_start|>assistant Sequencing an entire human genome is faster and cheaper than ever before, leading to an explosion of studies comparing the genomes of people with and without a given disease. Often clinicians and researchers studying genetic contributions to a certain disease encounter variations that appear to be responsible, only to find other people with the same mutation who don't have the disease or who are affected to a lesser degree. How do doctors pinpoint the genetic changes that really cause disease? An open-access policy paper to be published Wednesday in Nature proposes guidelines for researchers studying the effects of rare genetic variants. The recommendations focus on several key areas, such as study design, gene- and variant-level implication, databases and implications for diagnosis. Co-author Chris Gunter, PhD, associate director of research at Marcus Autism Center and associate professor of pediatrics at Emory, is one of the organizers of the 2012 workshop of leading genomics researchers, sponsored by the National Human Genome Research Institute, that led to the paper. "Several of us had noticed that studies were coming out with wrong conclusions about the relationship between a specific sequence and disease, and we were extremely concerned that this would translate into inappropriate clinical decisions," she says. Potentially, based on flawed results, physicians could order additional testing or treatments that are not truly supported by a link between a genetic variant and disease, and this paper could help prevent such inappropriate decisions, Gunter says. The group of 27 researchers proposes two steps for claiming that a genetic variation causes disease: detailed statistical analysis followed by an assessment of evidence from all sources supporting a role for the variant in that specific disease or condition. In addition, they highlight priorities for research and infrastructure development, including added incentives for researchers to share genetic and clinical data. One case cited in the paper relates to autism. Researchers found four independent variations in a gene called TTN when they compared genomes between individuals with and without autism. However, the TTN gene encodes a muscle protein (titin) that is the largest known; variations are simply more likely to be found within its boundaries compared to those of other genes. Without applying the proper statistical corrections, researchers may have falsely concluded that TTN was worthy of further investigation in autism studies. The authors note that many DNA variants "may suggest a potentially convincing story about how the variant may influence the trait," but few will actually have causal effects. Thus, using evidence-based guidelines such as the ones in the Nature paper will be crucial. "We believe that these guidelines will be particularly useful to scientists and clinicians in other areas who want to do human genomic studies, and need a defined starting point for investigating genetic effects, " Gunter says. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Bacterial biofilms, especially those associated with implanted medical devices, are difficult to eradicate. Curli amyloid fibers are important components of the biofilms formed by the Enterobacteriaceae family. Here, we show that a human monoclonal antibody with pan-amyloid-binding activity (mAb 3H3) can disrupt biofilms formed by Salmonella enterica serovar Typhimurium in vitro and in vivo. The antibody disrupts the biofilm structure, enhancing biofilm eradication by antibiotics and immune cells. In mice, 3H3 injections allow antibiotic-mediated clearance of catheter-associated S . Typhimurium biofilms. Thus, monoclonal antibodies that bind a pan-amyloid epitope have potential to prevent or eradicate bacterial biofilms. Introduction Biofilms are three-dimensional multicellular communities that allow bacteria to irreversibly adhere to indwelling medical devices and provide resistance to antibiotics and prevent eradication by innate immune cells. Biofilm-associated infections of indwelling medical devices are refractory to antibiotic treatment and require surgical debridement and/or device removal 1 , 2 , 3 , 4 , 5 , 6 , 7 . Biofilm-producing enteric bacteria including Salmonella enterica and Escherichia coli remain to be the major cause of many bloodstream infections 8 , 9 , 10 , 11 . While biofilms of Salmonella play a critical role in persistent infections 11 , E. coli biofilms are important causes of prosthetic joint infections, recurrent urinary tract infections, and central line-associated blood infections (CLABSIs) 12 , 13 , 14 , 15 , 16 . Biofilms contribute to the development antibiotic tolerance and resistance 17 , 18 , 19 . Biofilms form a physical barrier to many antibiotics, restricting effective drug concentrations to sub-lethal levels and promoting the outgrowth of resistant strains 20 . They also block host immune responses, protecting cells from phagocytosis and complement mediated killing 21 , 22 , 23 . Lastly, biofilms enhance the ability of bacteria to generate “persister” sub-populations, which are multi-drug tolerant, essentially dormant cells with a characteristic gene expression signature 24 . Dispersal of a biofilm has the potential to seed a patient with drug-resistant bacteria 25 , 26 . Strategies are needed to break down biofilms associated with indwelling medical devices and chronic infections, in order to render bacteria sensitive to antibiotics and susceptible to immune clearance. Curli amyloid fibers are the major constituent (approximately 85%) of the extracellular matrix in biofilms formed by the members of Enterobacteriaceae family, e.g. E. coli and Salmonella ssp. 27 , 28 , 29 . Curli is a heteropolymeric amyloid fibril comprising two subunits, CsgA and CsgB, in a ~20:1 ratio. CsgB nucleates CsgA fibril formation in the biofilm and attaches the amyloid fibrils to the bacterial surface 30 , 31 , 32 , 33 , 34 . Curli also promotes adhesion among bacteria within the biofilm and aids in surface attachment 35 , 36 . Amyloids such as curli form insoluble protein polymers that are characterized by a repeated cross-beta-sheet structure that can display conformational antibody-binding epitopes shared by amyloids of completely unrelated protein sequences 37 . Monoclonal antibodies (mAbs) that bind these conformational epitopes can inhibit polymerization of amyloidogenic proteins and disperse aggregated amyloids under some conditions. 3H3 is a human mAb that preferentially binds amyloid beta protein (Aβ) oligomers and fibrils, relative to Aβ monomers, as well as many types of pathologic human amyloids, including immunoglobulin light chain and transthyretin amyloids 38 . 3H3 inhibits polymerization of Aβ and other amyloid precursors in vitro and reduces amyloid deposition in transgenic mouse models of AD and familial Danish dementia. In this study, we investigate whether the 3H3 mAb has analogous effects against curli amyloids, using S. Typhimurium biofilms as an experimental model. We show that 3H3 inhibits the polymerization of curli, leading to alteration of the biofilm architecture and rendering the biofilm bacteria more sensitive to antibiotic treatment and to macrophage uptake. In addition, 3H3 inhibits biofilm formation on a vascular catheter in vivo and collaborates with an antibiotic to clear an established, catheter-associated biofilm. Results Anti-Aβ mAb inhibits formation of S . Typhimurium biofilms We tested the 3H3 mAb for activity against S . Typhimurium biofilm formation in vitro. We compared its activity to the 6A isotype control IgG 39 and three additional human mAbs, 4A6, 4G1, and 2C10, which were obtained from an Alzheimer’s disease patient and preferentially bind to oligomeric Aβ forms (Supplementary Table 1 ). The 3H3 has been previously observed to bind a pan-amyloid epitope. Of the new mAbs, only 4G1 showed potential pan-amyloid binding, as it and the 3H3 mAb both also bind to tau-paired helical filaments (PHF) (Supplementary Fig. 1 ). 4G1 also inhibits Aβ fibril formation in vitro (Supplementary Fig. 2 ). As a negative control for biofilm formation, we used the isogenic S . Typhimurium mutant, csgBA , which does not express curli 40 . We cultured S . Typhimurium under biofilm-inducing conditions on glass coverslips at 28 °C for 72 h in the presence of 3H3, then rigorously washed the cultures and stained them with Syto9 green nucleic acid stain (bacteria) and Congo Red (CR) amyloid stain. We imaged the biofilms using confocal scanning laser microscopy. Three-dimensional reconstructions of the z-stacks showed that the untreated S . Typhimurium biofilm was highly structured and covered most of the surface with an average thickness of 20 µm (Fig. 1a ), in comparison to the csgBA strain, which had no biofilm. The biofilm exposed to the control 6A antibody was similar to the untreated control, 18.21 µm thick and essentially confluent, although the depth of CR staining was reduced. Biofilms formed in cultures containing the other mAbs were substantially thinner, approaching the value for the csgBA mutant (5.5 µm): 4A6, 10.9 µm; 4G1, 7.3 µm; 2C10, 9.5 µm; and 3H3, 7.5 µm (Fig. 1b ), with less surface coverage and CR staining (Fig. 1a ). We quantitated the CR mean relative fluorescent unit (RFU) values for the biofilms. Three of the four mAb-exposed samples had significantly reduced CR staining: 4G1 (23.9 RFU), 2C10 (22.1 RFU), and 3H3 (23.2 RFU), compared to the control and 6A samples (47.1 RFU and 48.1 RFU, respectively), although", "role": "user" }, { "content": "The same way baking soda breaks down grease and grime, making surfaces easier to clean, researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) now show that a new therapeutic molecule can break apart communities of harmful bacteria, opening the way for bacteria-killing antibiotics to more effectively clear out infections. Communities of bacteria known as biofilms are notorious for forming on implanted medical devices, such as catheters and prosthetics, and on tissues in the body, where they give rise to chronic and sometimes life-threatening infections in patients. Biofilms are extremely difficult to eradicate, because, united with an impermeable matrix, the microbes are able to resist antibiotics and other agents that would otherwise eliminate them. The new molecule, a type of monoclonal antibody, however, is able to open up these biofilms, causing their dissociation. It is the first agent of its kind to show promise as an immunotherapeutic strategy to fight off infectious biofilms. \"With this new antibody, we open the door for better treatment strategies for patients who suffer from chronic infections associated with implanted medical devices or who suffer from recurrent infections, such as repeated infections of the urinary tract,\" explained Cagla Tukel, Ph.D., Associate Professor in the Department of Microbiology and Immunology at LKSOM, and senior author on the new study. The study was published online in the journal Nature Communications. The new antibody, named 3H3, was isolated from a healthy human subject by Scott K. Dessain, MD, Ph.D., a professor at the Lankenau Institute for Medical Research and coauthor on the new study. Drs. Dessain and Tukel were intrigued by 3H3's ability to attach to beta-amyloid, a sticky protein that functions abnormally in Alzheimer's disease. A form of amyloid called curli is secreted by bacterial cells and is a major component of biofilms. Bacterial amyloid curli acts like glue, enabling bacterial cells to adhere to one another and form a continuous film over a surface. In experiments with biofilms of infectious Salmonella enterica serovar Typhimurium, which forms biofilms in the human intestinal tract and on medical devices, Dr. Tukel's team found that amyloid binding by 3H3 disrupted biofilm formation, causing the separation of bacterial cells within the biofilm. The researchers then tested the antibody in mice infected with catheter-associated S. Typhimurium biofilm. In these animals, 3H3 injections also led to biofilm dissociation and, when followed by antibiotic therapy, allowed for the swift eradication of individual bacterial cells from the animals. There are currently no existing therapies that are used clinically to break up biofilms. Here Dr. Tukel's team showed that while 3H3 breaks the biofilm, it also prevented the dissociating bacteria from entering the circulation, where they could cause sepsis. 3H3 was found to bind to individual bacterial cells facilitating their uptake by immune cells. Therefore, this novel approach has the potential to reduce the risk of sepsis. \"We are very excited about these findings,\" Dr. Tukel said. \"There is great need for an immunotherapy that can be used alongside lower dose antibiotics or other antimicrobials to safely and effectively eradicate biofilms in infectious settings.\" Dr. Tukel and colleagues plan next to test 3H3 on a wide variety of biofilms. As many important pathogenic bacteria produce curli or curli-like amyloids in their biofilms, such as Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa, this novel immunotherapy has the potential to be applied to a wide variety of infections. \"We also are developing a clinical approach,\" Dr. Tukel noted. \"Our preclinical findings in animals are promising, and we've identified a clear path to clinical 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 Bacterial biofilms, especially those associated with implanted medical devices, are difficult to eradicate. Curli amyloid fibers are important components of the biofilms formed by the Enterobacteriaceae family. Here, we show that a human monoclonal antibody with pan-amyloid-binding activity (mAb 3H3) can disrupt biofilms formed by Salmonella enterica serovar Typhimurium in vitro and in vivo. The antibody disrupts the biofilm structure, enhancing biofilm eradication by antibiotics and immune cells. In mice, 3H3 injections allow antibiotic-mediated clearance of catheter-associated S . Typhimurium biofilms. Thus, monoclonal antibodies that bind a pan-amyloid epitope have potential to prevent or eradicate bacterial biofilms. Introduction Biofilms are three-dimensional multicellular communities that allow bacteria to irreversibly adhere to indwelling medical devices and provide resistance to antibiotics and prevent eradication by innate immune cells. Biofilm-associated infections of indwelling medical devices are refractory to antibiotic treatment and require surgical debridement and/or device removal 1 , 2 , 3 , 4 , 5 , 6 , 7 . Biofilm-producing enteric bacteria including Salmonella enterica and Escherichia coli remain to be the major cause of many bloodstream infections 8 , 9 , 10 , 11 . While biofilms of Salmonella play a critical role in persistent infections 11 , E. coli biofilms are important causes of prosthetic joint infections, recurrent urinary tract infections, and central line-associated blood infections (CLABSIs) 12 , 13 , 14 , 15 , 16 . Biofilms contribute to the development antibiotic tolerance and resistance 17 , 18 , 19 . Biofilms form a physical barrier to many antibiotics, restricting effective drug concentrations to sub-lethal levels and promoting the outgrowth of resistant strains 20 . They also block host immune responses, protecting cells from phagocytosis and complement mediated killing 21 , 22 , 23 . Lastly, biofilms enhance the ability of bacteria to generate “persister” sub-populations, which are multi-drug tolerant, essentially dormant cells with a characteristic gene expression signature 24 . Dispersal of a biofilm has the potential to seed a patient with drug-resistant bacteria 25 , 26 . Strategies are needed to break down biofilms associated with indwelling medical devices and chronic infections, in order to render bacteria sensitive to antibiotics and susceptible to immune clearance. Curli amyloid fibers are the major constituent (approximately 85%) of the extracellular matrix in biofilms formed by the members of Enterobacteriaceae family, e.g. E. coli and Salmonella ssp. 27 , 28 , 29 . Curli is a heteropolymeric amyloid fibril comprising two subunits, CsgA and CsgB, in a ~20:1 ratio. CsgB nucleates CsgA fibril formation in the biofilm and attaches the amyloid fibrils to the bacterial surface 30 , 31 , 32 , 33 , 34 . Curli also promotes adhesion among bacteria within the biofilm and aids in surface attachment 35 , 36 . Amyloids such as curli form insoluble protein polymers that are characterized by a repeated cross-beta-sheet structure that can display conformational antibody-binding epitopes shared by amyloids of completely unrelated protein sequences 37 . Monoclonal antibodies (mAbs) that bind these conformational epitopes can inhibit polymerization of amyloidogenic proteins and disperse aggregated amyloids under some conditions. 3H3 is a human mAb that preferentially binds amyloid beta protein (Aβ) oligomers and fibrils, relative to Aβ monomers, as well as many types of pathologic human amyloids, including immunoglobulin light chain and transthyretin amyloids 38 . 3H3 inhibits polymerization of Aβ and other amyloid precursors in vitro and reduces amyloid deposition in transgenic mouse models of AD and familial Danish dementia. In this study, we investigate whether the 3H3 mAb has analogous effects against curli amyloids, using S. Typhimurium biofilms as an experimental model. We show that 3H3 inhibits the polymerization of curli, leading to alteration of the biofilm architecture and rendering the biofilm bacteria more sensitive to antibiotic treatment and to macrophage uptake. In addition, 3H3 inhibits biofilm formation on a vascular catheter in vivo and collaborates with an antibiotic to clear an established, catheter-associated biofilm. Results Anti-Aβ mAb inhibits formation of S . Typhimurium biofilms We tested the 3H3 mAb for activity against S . Typhimurium biofilm formation in vitro. We compared its activity to the 6A isotype control IgG 39 and three additional human mAbs, 4A6, 4G1, and 2C10, which were obtained from an Alzheimer’s disease patient and preferentially bind to oligomeric Aβ forms (Supplementary Table 1 ). The 3H3 has been previously observed to bind a pan-amyloid epitope. Of the new mAbs, only 4G1 showed potential pan-amyloid binding, as it and the 3H3 mAb both also bind to tau-paired helical filaments (PHF) (Supplementary Fig. 1 ). 4G1 also inhibits Aβ fibril formation in vitro (Supplementary Fig. 2 ). As a negative control for biofilm formation, we used the isogenic S . Typhimurium mutant, csgBA , which does not express curli 40 . We cultured S . Typhimurium under biofilm-inducing conditions on glass coverslips at 28 °C for 72 h in the presence of 3H3, then rigorously washed the cultures and stained them with Syto9 green nucleic acid stain (bacteria) and Congo Red (CR) amyloid stain. We imaged the biofilms using confocal scanning laser microscopy. Three-dimensional reconstructions of the z-stacks showed that the untreated S . Typhimurium biofilm was highly structured and covered most of the surface with an average thickness of 20 µm (Fig. 1a ), in comparison to the csgBA strain, which had no biofilm. The biofilm exposed to the control 6A antibody was similar to the untreated control, 18.21 µm thick and essentially confluent, although the depth of CR staining was reduced. Biofilms formed in cultures containing the other mAbs were substantially thinner, approaching the value for the csgBA mutant (5.5 µm): 4A6, 10.9 µm; 4G1, 7.3 µm; 2C10, 9.5 µm; and 3H3, 7.5 µm (Fig. 1b ), with less surface coverage and CR staining (Fig. 1a ). We quantitated the CR mean relative fluorescent unit (RFU) values for the biofilms. Three of the four mAb-exposed samples had significantly reduced CR staining: 4G1 (23.9 RFU), 2C10 (22.1 RFU), and 3H3 (23.2 RFU), compared to the control and 6A samples (47.1 RFU and 48.1 RFU, respectively), although<|im_end|> <|im_start|>assistant The same way baking soda breaks down grease and grime, making surfaces easier to clean, researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) now show that a new therapeutic molecule can break apart communities of harmful bacteria, opening the way for bacteria-killing antibiotics to more effectively clear out infections. Communities of bacteria known as biofilms are notorious for forming on implanted medical devices, such as catheters and prosthetics, and on tissues in the body, where they give rise to chronic and sometimes life-threatening infections in patients. Biofilms are extremely difficult to eradicate, because, united with an impermeable matrix, the microbes are able to resist antibiotics and other agents that would otherwise eliminate them. The new molecule, a type of monoclonal antibody, however, is able to open up these biofilms, causing their dissociation. It is the first agent of its kind to show promise as an immunotherapeutic strategy to fight off infectious biofilms. "With this new antibody, we open the door for better treatment strategies for patients who suffer from chronic infections associated with implanted medical devices or who suffer from recurrent infections, such as repeated infections of the urinary tract," explained Cagla Tukel, Ph.D., Associate Professor in the Department of Microbiology and Immunology at LKSOM, and senior author on the new study. The study was published online in the journal Nature Communications. The new antibody, named 3H3, was isolated from a healthy human subject by Scott K. Dessain, MD, Ph.D., a professor at the Lankenau Institute for Medical Research and coauthor on the new study. Drs. Dessain and Tukel were intrigued by 3H3's ability to attach to beta-amyloid, a sticky protein that functions abnormally in Alzheimer's disease. A form of amyloid called curli is secreted by bacterial cells and is a major component of biofilms. Bacterial amyloid curli acts like glue, enabling bacterial cells to adhere to one another and form a continuous film over a surface. In experiments with biofilms of infectious Salmonella enterica serovar Typhimurium, which forms biofilms in the human intestinal tract and on medical devices, Dr. Tukel's team found that amyloid binding by 3H3 disrupted biofilm formation, causing the separation of bacterial cells within the biofilm. The researchers then tested the antibody in mice infected with catheter-associated S. Typhimurium biofilm. In these animals, 3H3 injections also led to biofilm dissociation and, when followed by antibiotic therapy, allowed for the swift eradication of individual bacterial cells from the animals. There are currently no existing therapies that are used clinically to break up biofilms. Here Dr. Tukel's team showed that while 3H3 breaks the biofilm, it also prevented the dissociating bacteria from entering the circulation, where they could cause sepsis. 3H3 was found to bind to individual bacterial cells facilitating their uptake by immune cells. Therefore, this novel approach has the potential to reduce the risk of sepsis. "We are very excited about these findings," Dr. Tukel said. "There is great need for an immunotherapy that can be used alongside lower dose antibiotics or other antimicrobials to safely and effectively eradicate biofilms in infectious settings." Dr. Tukel and colleagues plan next to test 3H3 on a wide variety of biofilms. As many important pathogenic bacteria produce curli or curli-like amyloids in their biofilms, such as Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa, this novel immunotherapy has the potential to be applied to a wide variety of infections. "We also are developing a clinical approach," Dr. Tukel noted. "Our preclinical findings in animals are promising, and we've identified a clear path to clinical development." <|im_end|>

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2,438

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Although the first experiments on alpha-neurofeedback date back nearly six decades ago, when Joseph Kamiya reported successful operant conditioning of alpha-rhythm in humans, the effectiveness of this paradigm in various experimental and clinical settings is still a matter of debate. Here, we investigated the changes in EEG patterns during a continuously administered neurofeedback of P4 alpha activity. Two days of neurofeedback training were sufficient for a significant increase in the alpha power to occur. A detailed analysis of these EEG changes showed that the alpha power rose because of an increase in the incidence rate of alpha episodes, whereas the amplitude and the duration of alpha oscillations remained unchanged. These findings suggest that neurofeedback facilitates volitional control of alpha activity onset, but alpha episodes themselves appear to be maintained automatically with no volitional control – a property overlooked by previous studies that employed continuous alpha-power neurofeedback. We propose that future research on alpha neurofeedback should explore reinforcement schedules based on detection of onsets and offsets of alpha waves, and employ these statistics for exploration and quantification of neurofeedback induced effects. Introduction Neurofeedback is a form of biofeedback, which allows subjects to observe and ultimately gain volitional control over their own brain activity. Neurofeedback settings involve recording of neural activity, extraction of neural features of interest, transformation of these features, and feeding the resulting signal back to the subject via one of sensory modalities: visual, auditory or tactile. Under these conditions, subjects learn to volitionally modify their brain activity, which they are normally unaware of. One of the first neurofeedback experiments was conducted in the late 1960’s by Joe Kamiya 1 , 2 . His basic neurofeedback design consisted of two stages. During the first stage, called the training session, subjects appreciated their own mental state (high/low alpha) using the feedback. During the second stage, they trained to enter the target (high alpha) state upon an acoustic prompt. Kamiya reported that after the training session 80% of the subjects managed to successfully classify their mental state and initiate it upon the prompt 3 . After learning the task, subjects reported mental states reflecting relaxation, “letting go” and pleasant feelings associated with cortical alpha activity. A few years later, Barry Sterman demonstrated operant conditioning of cortical oscillations in cats. He studied the so-called sensorimotor (SMR) 12–15 Hz rhythm, which normally occurs in the motor cortex when an animal is in a state of alert immobility, often before attacking the prey. In Sterman’s study, cats learned to enter the SMR state following a conditioning stimulus. Additionally, the animals learned to produce the SMR even without any stimulus if food reinforcement was given each time they spontaneously entered the SMR state 4 . The same cats that underwent neurofeedback training were later used in an epilepsy study, and it was unexpectedly found that they were significantly less prone to seizures evoked by the epileptogenic fuel component than the cats that did not have the SMR training 5 . Thus, these experiments of Sterman and his colleagues revealed a potential of neurofeedback as a treatment for epilepsy 6 , 7 , 8 . Despite these spectacular early findings, the field of neurofeedback remained underestimated and barely alive until the mid 1990s, when technological advances, including reasonably priced and efficient computerized EEG diagnostic equipment, brought impetus to EEG research, in general, and EEG-based neurofeedback, in particular. Since then, the number of studies has been growing on various aspects of neurofeedback in both laboratory and clinical settings 9 . In addition to treatment of epilepsy, neurofeedback has been employed as a non-pharmacological therapy for a broad range of neurological conditions, such as ADHD 10 , 11 , 12 , 13 , depression 14 , 15 and autism spectrum disorder 16 , 17 . Furthermore, neurofeedback therapy has been shown to improve sleep quality 18 , 19 , mood 20 and cognitive function and even enhance performance of sports and arts professionals 21 , 22 , 23 . Finally, a new and increasingly popular line of research employed neurofeedback as a key component of brain-computer interfaces (BCIs), systems that connect the brain to computers in order to assist and rehabilitate communication and motor functions to patients suffering from different degrees of paralysis caused by injuries and diseases of the brain and the spinal cord 24 . Properly chosen neurofeedback improves and enriches BCI operations 25 , 26 . The rapid revival of neurofeedback research including the use of various recording 27 , 28 , 29 , 30 , 31 , 32 , 33 , signal processing and source-localization techniques 34 , 35 , 36 , however, came along with a number of skeptical concerns about the validity of this approach. Conflicting results on neurofeedback effectiveness, as well as the absence of standardized neurofeedback protocols 37 hinder our understanding of neurofeedback: what EEG features to use, where in the brain to record, and how to process EEG features in experimental studies and clinical applications. Several recent methodological papers 23 , 37 , 38 , 39 outline the requirements for any state-of-the-art neurofeedback experiment. The temporal specificity of the reinforcement is one of the major concerns raised in these studies. Since neurofeedback is a reinforcement learning process 40 , 41 , it is important that the reinforcement is delivered at the right time and that it triggers the desired brain adaptation. A reinforcement signal that arrives too late may not be properly matched with the desired activity pattern and, as a result, may impair or even prevent learning 42 . The choice of a relevant learning metrics for neurofeedback presentation has been a subject of long-lasting debate since the early experiments of Kamiya 43 , 44 , 45 . Typical neurofeedback protocols employ either discrete (percent-time) or continuous (integrated) schemes of reinforcement 38 . Another technique, called the Z-score neurofeedback, allows a generalized threshold-neurofeedback presentation based on a population distribution 46 of the EEG parameter used. Other common considerations include the choice of sensory modality 47 , 48 ,", "role": "user" }, { "content": "Researchers from the HSE Centre for Cognition & Decision Making and the (Institute of Problems of Mechanical Engineering, Russian Academy of Sciences, have conducted a series of experiments to determine what a person actually controls when tasked with independently affecting the activity of their own brain. This discovery may contribute to non-pharmacological methods for treating epilepsy, attention-deficit/hyperactivity disorder and depression. The research results were published in the journal Scientific Reports. The human brain is always electrically active. Neurons exchange information using very short electrical impulses. The aggregate of a large number of these impulses, which are distributed in time and appear in various parts of the brain, cause fluctuations in the electrical potential of the head's surface. Similar to a cardiogram, we can use methods such as electroencephalograms to register these fluctuations and judge brain activity. Further, several types of activity can be determined by the speed of the fluctuations: alpha, beta, gamma, theta, and delta waves. With electroencephalography, these waves can be registered, recoded into a perceivable form such as the brightness of a computer screen, and presented in real time. This serves as the basis for neurofeedback technology, which is one type of biofeedback. With the help of biofeedback, a person can learn to regulate the activity of his or her own brain. The first time neurofeedback was discussed as a method for teaching a person to regulate the electromagnetic activity of their brain was in research conducted by Joseph Kamiya of the University of Chicago in the 1960s. Kamiya showed that in receiving feedback on brain activity, a person learns to affect this activity while they learn to determine the current state of their brain activity and, for example, the prevalence of a particular kind of rhythm. In the experiment, the researchers used electroencephalography to assess the intensity of the brain's alpha wave activity. Alpha waves relate to a person's ability to relax, manage stress, and internalise new information. The research subjects saw information about their alpha wave activity in the form of red colour saturation on a monitor and tried to mentally make this colour more saturated. The study involved 18 people, nine of whom (the experimental group) received real feedback on their efforts, i.e., they saw the colour's saturation reflecting the current level of alpha wave activity. Conversely, the control group received false feedback, meaning changes in the intensity of the colour displayed on the screen were not connected with the research subjects' alpha wave activity. Over the course of two days, both groups carried out five two-minute sessions per day. The research subjects were not provided with a strategy that would produce the best results. At the end of the first day, the entire experimental group showed an increase in alpha wave activity, while alpha wave activity was slightly lower at the beginning of the second day than at the end of the first. But throughout the second day, activity continued to grow and exceeded the levels seen at the end of the first day. Two days of training in the neurofeedback paradigm were enough to significantly increase alpha wave capacity. This sort of increase was not seen in the control group. Alpha wave activity is non-stationary and occurs in the form of special bursts, each of which can be characterised by its duration and amplitude. Another important parameter is the number of such bursts per unit of time. \"We became interested in what exactly changes during feedback—the amplitude of each burst, its length, or how often these bursts occur,\" explains Professor Alexey Ossadtchi, who is a senior research fellow in the Centre for Cognition & Decision Making and one of the study's authors. \"These are three completely different metrics as far as neurophysiology is concerned. When amplitude increases, the size of the corresponding neuron population increases, and when the duration grows, short-term regulatory mechanisms with feedback are directly involved and allow the brain to maintain high alpha wave activity for a longer period of time. An increase in the frequency of bursts shows that under the influence of a person's intentional effort, the brain more easily enters a state in which the alpha rhythm dominates.\" After the experimenters compared how much the amplitude, duration, and frequency of bursts changed during the training process of all participants on different days, it was discovered that alpha wave bursts in particular undergo the most significant changes per unit of time. In other words, by training in the neurofeedback paradigm, a person learns to control entry into a completely alpha state. This is new information in the study of neurofeedback mechanisms. \"It turned out that the frequency of alpha wave bursts in particular is a coached metric that we can use to influence alpha wave activity as a whole, unlike amplitude and duration, which are likely coded at a lower level,\" Professor Ossadtchi adds. \"This means that in therapy and in training, we have to give people feedback specifically on the parameter that they are truly able to influence—in our case, for every entry into the [alpha] state and for every new burst. It's preferred that a person receive such reinforcement with as little delay as possible. That is what we are working on now.\" The researchers assume that the data they collected are valid not only for alpha waves, but for other types of electromagnetic frequencies, as well. A similar experiment will be conducted soon on different types of waves. The neurofeedback training paradigm lowers the likelihood of epileptic seizures, eliminates some manifestations of attention deficit/hyperactivity disorder, and provides relief to a person with depression. In addition, neurofeedback as a technology helps athletes control their psycho-emotional state, and it can also be used to master the art of meditation, improve memory, and increase a person's ability to concentrate. According to the researchers, knowing specifically which regulatory mechanisms are activated during a certain form of neurofeedback allows one to significantly increase the efficiency of this technology, while it also provides access to new resources in the human brain that have not yet been studied. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Although the first experiments on alpha-neurofeedback date back nearly six decades ago, when Joseph Kamiya reported successful operant conditioning of alpha-rhythm in humans, the effectiveness of this paradigm in various experimental and clinical settings is still a matter of debate. Here, we investigated the changes in EEG patterns during a continuously administered neurofeedback of P4 alpha activity. Two days of neurofeedback training were sufficient for a significant increase in the alpha power to occur. A detailed analysis of these EEG changes showed that the alpha power rose because of an increase in the incidence rate of alpha episodes, whereas the amplitude and the duration of alpha oscillations remained unchanged. These findings suggest that neurofeedback facilitates volitional control of alpha activity onset, but alpha episodes themselves appear to be maintained automatically with no volitional control – a property overlooked by previous studies that employed continuous alpha-power neurofeedback. We propose that future research on alpha neurofeedback should explore reinforcement schedules based on detection of onsets and offsets of alpha waves, and employ these statistics for exploration and quantification of neurofeedback induced effects. Introduction Neurofeedback is a form of biofeedback, which allows subjects to observe and ultimately gain volitional control over their own brain activity. Neurofeedback settings involve recording of neural activity, extraction of neural features of interest, transformation of these features, and feeding the resulting signal back to the subject via one of sensory modalities: visual, auditory or tactile. Under these conditions, subjects learn to volitionally modify their brain activity, which they are normally unaware of. One of the first neurofeedback experiments was conducted in the late 1960’s by Joe Kamiya 1 , 2 . His basic neurofeedback design consisted of two stages. During the first stage, called the training session, subjects appreciated their own mental state (high/low alpha) using the feedback. During the second stage, they trained to enter the target (high alpha) state upon an acoustic prompt. Kamiya reported that after the training session 80% of the subjects managed to successfully classify their mental state and initiate it upon the prompt 3 . After learning the task, subjects reported mental states reflecting relaxation, “letting go” and pleasant feelings associated with cortical alpha activity. A few years later, Barry Sterman demonstrated operant conditioning of cortical oscillations in cats. He studied the so-called sensorimotor (SMR) 12–15 Hz rhythm, which normally occurs in the motor cortex when an animal is in a state of alert immobility, often before attacking the prey. In Sterman’s study, cats learned to enter the SMR state following a conditioning stimulus. Additionally, the animals learned to produce the SMR even without any stimulus if food reinforcement was given each time they spontaneously entered the SMR state 4 . The same cats that underwent neurofeedback training were later used in an epilepsy study, and it was unexpectedly found that they were significantly less prone to seizures evoked by the epileptogenic fuel component than the cats that did not have the SMR training 5 . Thus, these experiments of Sterman and his colleagues revealed a potential of neurofeedback as a treatment for epilepsy 6 , 7 , 8 . Despite these spectacular early findings, the field of neurofeedback remained underestimated and barely alive until the mid 1990s, when technological advances, including reasonably priced and efficient computerized EEG diagnostic equipment, brought impetus to EEG research, in general, and EEG-based neurofeedback, in particular. Since then, the number of studies has been growing on various aspects of neurofeedback in both laboratory and clinical settings 9 . In addition to treatment of epilepsy, neurofeedback has been employed as a non-pharmacological therapy for a broad range of neurological conditions, such as ADHD 10 , 11 , 12 , 13 , depression 14 , 15 and autism spectrum disorder 16 , 17 . Furthermore, neurofeedback therapy has been shown to improve sleep quality 18 , 19 , mood 20 and cognitive function and even enhance performance of sports and arts professionals 21 , 22 , 23 . Finally, a new and increasingly popular line of research employed neurofeedback as a key component of brain-computer interfaces (BCIs), systems that connect the brain to computers in order to assist and rehabilitate communication and motor functions to patients suffering from different degrees of paralysis caused by injuries and diseases of the brain and the spinal cord 24 . Properly chosen neurofeedback improves and enriches BCI operations 25 , 26 . The rapid revival of neurofeedback research including the use of various recording 27 , 28 , 29 , 30 , 31 , 32 , 33 , signal processing and source-localization techniques 34 , 35 , 36 , however, came along with a number of skeptical concerns about the validity of this approach. Conflicting results on neurofeedback effectiveness, as well as the absence of standardized neurofeedback protocols 37 hinder our understanding of neurofeedback: what EEG features to use, where in the brain to record, and how to process EEG features in experimental studies and clinical applications. Several recent methodological papers 23 , 37 , 38 , 39 outline the requirements for any state-of-the-art neurofeedback experiment. The temporal specificity of the reinforcement is one of the major concerns raised in these studies. Since neurofeedback is a reinforcement learning process 40 , 41 , it is important that the reinforcement is delivered at the right time and that it triggers the desired brain adaptation. A reinforcement signal that arrives too late may not be properly matched with the desired activity pattern and, as a result, may impair or even prevent learning 42 . The choice of a relevant learning metrics for neurofeedback presentation has been a subject of long-lasting debate since the early experiments of Kamiya 43 , 44 , 45 . Typical neurofeedback protocols employ either discrete (percent-time) or continuous (integrated) schemes of reinforcement 38 . Another technique, called the Z-score neurofeedback, allows a generalized threshold-neurofeedback presentation based on a population distribution 46 of the EEG parameter used. Other common considerations include the choice of sensory modality 47 , 48 ,<|im_end|> <|im_start|>assistant Researchers from the HSE Centre for Cognition & Decision Making and the (Institute of Problems of Mechanical Engineering, Russian Academy of Sciences, have conducted a series of experiments to determine what a person actually controls when tasked with independently affecting the activity of their own brain. This discovery may contribute to non-pharmacological methods for treating epilepsy, attention-deficit/hyperactivity disorder and depression. The research results were published in the journal Scientific Reports. The human brain is always electrically active. Neurons exchange information using very short electrical impulses. The aggregate of a large number of these impulses, which are distributed in time and appear in various parts of the brain, cause fluctuations in the electrical potential of the head's surface. Similar to a cardiogram, we can use methods such as electroencephalograms to register these fluctuations and judge brain activity. Further, several types of activity can be determined by the speed of the fluctuations: alpha, beta, gamma, theta, and delta waves. With electroencephalography, these waves can be registered, recoded into a perceivable form such as the brightness of a computer screen, and presented in real time. This serves as the basis for neurofeedback technology, which is one type of biofeedback. With the help of biofeedback, a person can learn to regulate the activity of his or her own brain. The first time neurofeedback was discussed as a method for teaching a person to regulate the electromagnetic activity of their brain was in research conducted by Joseph Kamiya of the University of Chicago in the 1960s. Kamiya showed that in receiving feedback on brain activity, a person learns to affect this activity while they learn to determine the current state of their brain activity and, for example, the prevalence of a particular kind of rhythm. In the experiment, the researchers used electroencephalography to assess the intensity of the brain's alpha wave activity. Alpha waves relate to a person's ability to relax, manage stress, and internalise new information. The research subjects saw information about their alpha wave activity in the form of red colour saturation on a monitor and tried to mentally make this colour more saturated. The study involved 18 people, nine of whom (the experimental group) received real feedback on their efforts, i.e., they saw the colour's saturation reflecting the current level of alpha wave activity. Conversely, the control group received false feedback, meaning changes in the intensity of the colour displayed on the screen were not connected with the research subjects' alpha wave activity. Over the course of two days, both groups carried out five two-minute sessions per day. The research subjects were not provided with a strategy that would produce the best results. At the end of the first day, the entire experimental group showed an increase in alpha wave activity, while alpha wave activity was slightly lower at the beginning of the second day than at the end of the first. But throughout the second day, activity continued to grow and exceeded the levels seen at the end of the first day. Two days of training in the neurofeedback paradigm were enough to significantly increase alpha wave capacity. This sort of increase was not seen in the control group. Alpha wave activity is non-stationary and occurs in the form of special bursts, each of which can be characterised by its duration and amplitude. Another important parameter is the number of such bursts per unit of time. "We became interested in what exactly changes during feedback—the amplitude of each burst, its length, or how often these bursts occur," explains Professor Alexey Ossadtchi, who is a senior research fellow in the Centre for Cognition & Decision Making and one of the study's authors. "These are three completely different metrics as far as neurophysiology is concerned. When amplitude increases, the size of the corresponding neuron population increases, and when the duration grows, short-term regulatory mechanisms with feedback are directly involved and allow the brain to maintain high alpha wave activity for a longer period of time. An increase in the frequency of bursts shows that under the influence of a person's intentional effort, the brain more easily enters a state in which the alpha rhythm dominates." After the experimenters compared how much the amplitude, duration, and frequency of bursts changed during the training process of all participants on different days, it was discovered that alpha wave bursts in particular undergo the most significant changes per unit of time. In other words, by training in the neurofeedback paradigm, a person learns to control entry into a completely alpha state. This is new information in the study of neurofeedback mechanisms. "It turned out that the frequency of alpha wave bursts in particular is a coached metric that we can use to influence alpha wave activity as a whole, unlike amplitude and duration, which are likely coded at a lower level," Professor Ossadtchi adds. "This means that in therapy and in training, we have to give people feedback specifically on the parameter that they are truly able to influence—in our case, for every entry into the [alpha] state and for every new burst. It's preferred that a person receive such reinforcement with as little delay as possible. That is what we are working on now." The researchers assume that the data they collected are valid not only for alpha waves, but for other types of electromagnetic frequencies, as well. A similar experiment will be conducted soon on different types of waves. The neurofeedback training paradigm lowers the likelihood of epileptic seizures, eliminates some manifestations of attention deficit/hyperactivity disorder, and provides relief to a person with depression. In addition, neurofeedback as a technology helps athletes control their psycho-emotional state, and it can also be used to master the art of meditation, improve memory, and increase a person's ability to concentrate. According to the researchers, knowing specifically which regulatory mechanisms are activated during a certain form of neurofeedback allows one to significantly increase the efficiency of this technology, while it also provides access to new resources in the human brain that have not yet been studied. <|im_end|>

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2,485

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Over the last few decades, quantum chemistry has progressed through the development of computational methods based on modern digital computers. However, these methods can hardly fulfill the exponentially-growing resource requirements when applied to large quantum systems. As pointed out by Feynman, this restriction is intrinsic to all computational models based on classical physics. Recently, the rapid advancement of trapped-ion technologies has opened new possibilities for quantum control and quantum simulations. Here, we present an efficient toolkit that exploits both the internal and motional degrees of freedom of trapped ions for solving problems in quantum chemistry, including molecular electronic structure, molecular dynamics and vibronic coupling. We focus on applications that go beyond the capacity of classical computers, but may be realizable on state-of-the-art trapped-ion systems. These results allow us to envision a new paradigm of quantum chemistry that shifts from the current transistor to a near-future trapped-ion-based technology. Introduction Quantum chemistry represents one of the most successful applications of quantum mechanics. It provides an excellent platform for understanding matter from atomic to molecular scales and involves heavy interplay of experimental and theoretical methods. In 1929, shortly after the completion of the basic structure of the quantum theory, Dirac speculated 1 that the fundamental laws for chemistry were completely known, but the application of the fundamental laws led to equations that were too complex to be solved. About ninety years later, with the help of transistor-based digital computers, the development of quantum chemistry continues to flourish and many powerful methods, such as Hartree-Fock, configuration interaction, density functional theory, coupled-cluster and quantum Monte Carlo, have been developed to tackle the complex equations of quantum chemistry (see e.g. for a historical review 2 ). However, as the system size scales up, all of the methods known so far suffer from limitations that make them fail to maintain accuracy with a finite amount of resources 3 . In other words, quantum chemistry remains a hard problem to be solved by the current computer technology. As envisioned by Feynman 4 , one should be able to efficiently solve problems of quantum systems with a quantum computer. Instead of solving the complex equations, this approach, known as quantum simulation (see the recent reviews in Refs. 5 , 6 , 7 ), aims to solve the problems by simulating target systems with another controllable quantum system, or qubits. Indeed, simulating many-body systems beyond classical resources will be a cornerstone of quantum computers. Quantum simulation is a very active field of study and various methods have been developed. Quantum simulation methods have been proposed for preparing specific states such as ground 8 , 9 , 10 , 11 , 12 , 13 and thermal states 14 , 15 , 16 , 17 , 18 , 19 , 20 , simulating time evolution 21 , 22 , 23 , 24 , 25 , 26 , 27 and the measurement of physical observables 28 , 29 , 30 , 31 . Trapped-ion systems (see Fig. 1 ) are currently one of the most sophisticated technologies developed for quantum information processing 32 . These systems offer an unprecedented level of quantum control, which opens new possibilities for obtaining physico-chemical information about quantum chemical problems. The power of trapped ions for quantum simulation is manifested by the high-precision control over both the internal degrees of freedom of the individual ions and the phonon degrees of freedom of the collective motions of the trapped ions and the high-fidelity initialization and measurement 32 , 33 . Up to 100 quantum logic gates have been realized for six qubits with trapped ions 22 and quantum simulators involving 300 ions have been demonstrated 34 . Figure 1 Simulating quantum chemistry with trapped ions. (a) Scheme of a trapped-ion setup for quantum simulation, which contains a linear chain of trapped ions confined by a harmonic potential and external lasers that couple the motional and internal degrees of freedom. (b) Transitions between internal and motional degrees of freedom of the ions in the trap. (c) The normal modes of the trapped ions can simulate the vibrational degrees of freedom of molecules. (d) The internal states of two ions can simulate all four possible configurations of a molecular orbital. Full size image In this work, we present an efficient toolkit for solving quantum chemistry problems based on the state-of-the-art in trapped-ion technologies. The toolkit comprises two components i ) First, we present a hybrid quantum-classical variational optimization method, called quantum-assisted optimization, for approximating both ground-state energies and the ground-state eigenvectors for electronic problems. The optimized eigenvector can then be taken as an input for the phase estimation algorithm to project out the exact eigenstates and hence the potential-energy surfaces (see Fig. 2 ). Furthermore, we extend the application of the unitary coupled-cluster method 35 . This allows for the application of a method developed for classical numerical computations in the quantum domain. ii ) The second main component of our toolkit is the optimized use of trapped-ion phonon degrees of freedom not only for quantum-gate construction, but also for simulating molecular vibrations, representing a mixed digital-analog quantum simulation. The phonon degrees of freedom in trapped-ion systems provide a natural platform for addressing spin-boson or fermion-boson-type problems through quantum simulation 23 , 36 , 37 , 38 , 39 , 40 . It is noteworthy to mention that, contrary to the continuous of modes required for full-fledged quantum field theories, quantum simulations of quantum chemistry problems could reach realistic conditions for finite bosonic and fermionic mode numbers. Consequently, trapped ions can be exploited to solve dynamical problems involving linearly or non-linearly coupled oscillators, e.g., spin-boson models 41 , 42 , that are difficult to solve either analytically or numerically with a classical computer. Furthermore, we have also developed a novel protocol to measure correlation functions of observables in trapped ions that will be crucial for the quantum simulation of quantum chemistry. Figure 2 Outline of the quantum-assisted optimization method. (a) The key steps for quantum assisted optimization, which starts from", "role": "user" }, { "content": "Quantum simulators recreate the behaviour on a microscopic scale of biological and quantum systems and even of particles moving at the speed of light. The exact knowledge of these systems will lead to applications ranging from more efficient photovoltaic cells to more specific drugs. Researchers in the UPV/EHU's department of Physical Chemistry are working on the design of several of these quantum simulators so they can study the dynamics of complex physical systems. Quantum mechanics is the mathematical tool that enables us to describe the physical processes that take place on a microscopic level; it is capable of satisfactorily predicting the stability of atoms and molecules, the reactivity of different chemical compounds, or the result of the interaction between radiation and matter. They are all situations that constitute the basis of our physical world and for which there is no explanation within the framework of classical physics. \"The physical processes that take place on a quantum level obey such sophisticated mathematical models that they cannot be analysed by means of today's computers because of the computational limitations of these devices,\" explained Dr Jorge Casanova, researcher in the UPV/EHU's department of Physical Chemistry. One possible way of solving the problem of computational complexity of physical systems is to use a quantum platform or technology as a simulator. Quantum simulators are systems capable of reproducing the dynamics of a specific physical system, and overcoming the limitation of conventional computers. Among the various technologies that are studied with a view to developing efficient quantum simulators, this UPV/EHU research group has been focussing on the technology of trapped ions. \"Basically, these systems work by isolating individual atoms in a controlled environment so that there is no interference with the environment. They then undergo laser treatment, and after that, it is possible to conduct operations like exciting or de-exciting the electrons of these atoms. That way they are made to behave like the system we want to study,\" explained Casanova, the lead author of the work. Basing themselves on the technology of trapped ions, Casanova and his collaborators have designed various protocols for developing controlled quantum simulations. \"We are theoretical physicists; we work by designing the processes that will subsequently take place in a specific experiment. We base ourselves on the laws of quantum mechanics, the ones that govern these systems, and we put forward ideas that are then verified in the laboratories we are working in collaboration with,\" explained the researcher. Simulators for a range of physical situations In the course of this research the UPV/EHU group designed quantum simulation protocols for various physical situations. The first was a simulator of relativist systems, in other words, of particles that move at speeds close to that of light. \"This experiment is no trivial matter, because the ions used remain still, and yet we manage to get them to behave as if they were moving at the speed of light\". The experiment proposed by this group in the department of Physical Chemistry was carried out in Austria, \"and had quite an impact internationally, because until now this has been the experiment in which the highest level of quantum control has been achieved worldwide on ion movement states,\" remarked Casanova. Following the success achieved, they went on proposing quantum simulators for other types of systems, like those of interacting fermions and bosons. \"This is very important,\" pointed out Casanova, because in nature both types of particles basically exist: some are fermions (in atoms, for example, the electrons) and the others are bosons (photons or light particles or the Higgs boson).\"Our idea was to design the system under study artificially, so that we could gain access and extract information from it. The problem with these systems is that their dynamics are so complex that it is not possible to gain access to them by means of computations produced in classical computers, in other words, we are fully familiar with the equations that describe their dynamics, but we cannot resolve them,\" he remarked. They then went on to consider another two types of simulators. Firstly, they designed simulators for quantum field theory models. These theories \"are the ones that describe the most basic processes, like collisions between beams of particles that take place in accelerators, which are also very complex,\" explained Casanova. After that they focussed on the simulation of quantum chemistry models; \"this is a proposal that we have in collaboration with research personnel at Harvard University (USA), where we designed a specific protocol for quantum chemistry molecular models. \"They also proposed fusing a quantum simulator with a quantum computer, \"a new concept to increase the versatility of quantum simulations; what we did was to create a mathematical framework that provides the simulators with access to a larger number of tasks.\" Casanova explained the interest from the technological perspective of all these quantum simulators: \"The whole pharmaceutical industry, the chemical and materials industry, and even the energy industry are seeking to design molecules that are more efficient for a specific function. Photovoltaic cells, for example, which we use to capture solar energy, only trap 20% of the energy that reaches them. So a molecule model that is more efficient in capturing solar energy would increase the energy capture of these photovoltaic cells. To do this you need to be capable of designing molecules and knowing how they are going to behave. \"I reckon that within about 5 to 10 years we'll be able to design specific molecules for certain processes, like the capture of solar energy or even to design materials and drugs. Once we can understand complex systems, we will be able to predict their behaviour and design new technology based on that knowledge.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Over the last few decades, quantum chemistry has progressed through the development of computational methods based on modern digital computers. However, these methods can hardly fulfill the exponentially-growing resource requirements when applied to large quantum systems. As pointed out by Feynman, this restriction is intrinsic to all computational models based on classical physics. Recently, the rapid advancement of trapped-ion technologies has opened new possibilities for quantum control and quantum simulations. Here, we present an efficient toolkit that exploits both the internal and motional degrees of freedom of trapped ions for solving problems in quantum chemistry, including molecular electronic structure, molecular dynamics and vibronic coupling. We focus on applications that go beyond the capacity of classical computers, but may be realizable on state-of-the-art trapped-ion systems. These results allow us to envision a new paradigm of quantum chemistry that shifts from the current transistor to a near-future trapped-ion-based technology. Introduction Quantum chemistry represents one of the most successful applications of quantum mechanics. It provides an excellent platform for understanding matter from atomic to molecular scales and involves heavy interplay of experimental and theoretical methods. In 1929, shortly after the completion of the basic structure of the quantum theory, Dirac speculated 1 that the fundamental laws for chemistry were completely known, but the application of the fundamental laws led to equations that were too complex to be solved. About ninety years later, with the help of transistor-based digital computers, the development of quantum chemistry continues to flourish and many powerful methods, such as Hartree-Fock, configuration interaction, density functional theory, coupled-cluster and quantum Monte Carlo, have been developed to tackle the complex equations of quantum chemistry (see e.g. for a historical review 2 ). However, as the system size scales up, all of the methods known so far suffer from limitations that make them fail to maintain accuracy with a finite amount of resources 3 . In other words, quantum chemistry remains a hard problem to be solved by the current computer technology. As envisioned by Feynman 4 , one should be able to efficiently solve problems of quantum systems with a quantum computer. Instead of solving the complex equations, this approach, known as quantum simulation (see the recent reviews in Refs. 5 , 6 , 7 ), aims to solve the problems by simulating target systems with another controllable quantum system, or qubits. Indeed, simulating many-body systems beyond classical resources will be a cornerstone of quantum computers. Quantum simulation is a very active field of study and various methods have been developed. Quantum simulation methods have been proposed for preparing specific states such as ground 8 , 9 , 10 , 11 , 12 , 13 and thermal states 14 , 15 , 16 , 17 , 18 , 19 , 20 , simulating time evolution 21 , 22 , 23 , 24 , 25 , 26 , 27 and the measurement of physical observables 28 , 29 , 30 , 31 . Trapped-ion systems (see Fig. 1 ) are currently one of the most sophisticated technologies developed for quantum information processing 32 . These systems offer an unprecedented level of quantum control, which opens new possibilities for obtaining physico-chemical information about quantum chemical problems. The power of trapped ions for quantum simulation is manifested by the high-precision control over both the internal degrees of freedom of the individual ions and the phonon degrees of freedom of the collective motions of the trapped ions and the high-fidelity initialization and measurement 32 , 33 . Up to 100 quantum logic gates have been realized for six qubits with trapped ions 22 and quantum simulators involving 300 ions have been demonstrated 34 . Figure 1 Simulating quantum chemistry with trapped ions. (a) Scheme of a trapped-ion setup for quantum simulation, which contains a linear chain of trapped ions confined by a harmonic potential and external lasers that couple the motional and internal degrees of freedom. (b) Transitions between internal and motional degrees of freedom of the ions in the trap. (c) The normal modes of the trapped ions can simulate the vibrational degrees of freedom of molecules. (d) The internal states of two ions can simulate all four possible configurations of a molecular orbital. Full size image In this work, we present an efficient toolkit for solving quantum chemistry problems based on the state-of-the-art in trapped-ion technologies. The toolkit comprises two components i ) First, we present a hybrid quantum-classical variational optimization method, called quantum-assisted optimization, for approximating both ground-state energies and the ground-state eigenvectors for electronic problems. The optimized eigenvector can then be taken as an input for the phase estimation algorithm to project out the exact eigenstates and hence the potential-energy surfaces (see Fig. 2 ). Furthermore, we extend the application of the unitary coupled-cluster method 35 . This allows for the application of a method developed for classical numerical computations in the quantum domain. ii ) The second main component of our toolkit is the optimized use of trapped-ion phonon degrees of freedom not only for quantum-gate construction, but also for simulating molecular vibrations, representing a mixed digital-analog quantum simulation. The phonon degrees of freedom in trapped-ion systems provide a natural platform for addressing spin-boson or fermion-boson-type problems through quantum simulation 23 , 36 , 37 , 38 , 39 , 40 . It is noteworthy to mention that, contrary to the continuous of modes required for full-fledged quantum field theories, quantum simulations of quantum chemistry problems could reach realistic conditions for finite bosonic and fermionic mode numbers. Consequently, trapped ions can be exploited to solve dynamical problems involving linearly or non-linearly coupled oscillators, e.g., spin-boson models 41 , 42 , that are difficult to solve either analytically or numerically with a classical computer. Furthermore, we have also developed a novel protocol to measure correlation functions of observables in trapped ions that will be crucial for the quantum simulation of quantum chemistry. Figure 2 Outline of the quantum-assisted optimization method. (a) The key steps for quantum assisted optimization, which starts from<|im_end|> <|im_start|>assistant Quantum simulators recreate the behaviour on a microscopic scale of biological and quantum systems and even of particles moving at the speed of light. The exact knowledge of these systems will lead to applications ranging from more efficient photovoltaic cells to more specific drugs. Researchers in the UPV/EHU's department of Physical Chemistry are working on the design of several of these quantum simulators so they can study the dynamics of complex physical systems. Quantum mechanics is the mathematical tool that enables us to describe the physical processes that take place on a microscopic level; it is capable of satisfactorily predicting the stability of atoms and molecules, the reactivity of different chemical compounds, or the result of the interaction between radiation and matter. They are all situations that constitute the basis of our physical world and for which there is no explanation within the framework of classical physics. "The physical processes that take place on a quantum level obey such sophisticated mathematical models that they cannot be analysed by means of today's computers because of the computational limitations of these devices," explained Dr Jorge Casanova, researcher in the UPV/EHU's department of Physical Chemistry. One possible way of solving the problem of computational complexity of physical systems is to use a quantum platform or technology as a simulator. Quantum simulators are systems capable of reproducing the dynamics of a specific physical system, and overcoming the limitation of conventional computers. Among the various technologies that are studied with a view to developing efficient quantum simulators, this UPV/EHU research group has been focussing on the technology of trapped ions. "Basically, these systems work by isolating individual atoms in a controlled environment so that there is no interference with the environment. They then undergo laser treatment, and after that, it is possible to conduct operations like exciting or de-exciting the electrons of these atoms. That way they are made to behave like the system we want to study," explained Casanova, the lead author of the work. Basing themselves on the technology of trapped ions, Casanova and his collaborators have designed various protocols for developing controlled quantum simulations. "We are theoretical physicists; we work by designing the processes that will subsequently take place in a specific experiment. We base ourselves on the laws of quantum mechanics, the ones that govern these systems, and we put forward ideas that are then verified in the laboratories we are working in collaboration with," explained the researcher. Simulators for a range of physical situations In the course of this research the UPV/EHU group designed quantum simulation protocols for various physical situations. The first was a simulator of relativist systems, in other words, of particles that move at speeds close to that of light. "This experiment is no trivial matter, because the ions used remain still, and yet we manage to get them to behave as if they were moving at the speed of light". The experiment proposed by this group in the department of Physical Chemistry was carried out in Austria, "and had quite an impact internationally, because until now this has been the experiment in which the highest level of quantum control has been achieved worldwide on ion movement states," remarked Casanova. Following the success achieved, they went on proposing quantum simulators for other types of systems, like those of interacting fermions and bosons. "This is very important," pointed out Casanova, because in nature both types of particles basically exist: some are fermions (in atoms, for example, the electrons) and the others are bosons (photons or light particles or the Higgs boson)."Our idea was to design the system under study artificially, so that we could gain access and extract information from it. The problem with these systems is that their dynamics are so complex that it is not possible to gain access to them by means of computations produced in classical computers, in other words, we are fully familiar with the equations that describe their dynamics, but we cannot resolve them," he remarked. They then went on to consider another two types of simulators. Firstly, they designed simulators for quantum field theory models. These theories "are the ones that describe the most basic processes, like collisions between beams of particles that take place in accelerators, which are also very complex," explained Casanova. After that they focussed on the simulation of quantum chemistry models; "this is a proposal that we have in collaboration with research personnel at Harvard University (USA), where we designed a specific protocol for quantum chemistry molecular models. "They also proposed fusing a quantum simulator with a quantum computer, "a new concept to increase the versatility of quantum simulations; what we did was to create a mathematical framework that provides the simulators with access to a larger number of tasks." Casanova explained the interest from the technological perspective of all these quantum simulators: "The whole pharmaceutical industry, the chemical and materials industry, and even the energy industry are seeking to design molecules that are more efficient for a specific function. Photovoltaic cells, for example, which we use to capture solar energy, only trap 20% of the energy that reaches them. So a molecule model that is more efficient in capturing solar energy would increase the energy capture of these photovoltaic cells. To do this you need to be capable of designing molecules and knowing how they are going to behave. "I reckon that within about 5 to 10 years we'll be able to design specific molecules for certain processes, like the capture of solar energy or even to design materials and drugs. Once we can understand complex systems, we will be able to predict their behaviour and design new technology based on that knowledge." <|im_end|>

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11, 279, 6305, 430, 2633, 1521, 6067, 11, 323, 584, 2231, 4741, 6848, 430, 527, 1243, 24884, 304, 279, 70760, 584, 527, 3318, 304, 20632, 449, 1359, 11497, 279, 32185, 13, 4567, 42391, 369, 264, 2134, 315, 7106, 15082, 763, 279, 3388, 315, 420, 3495, 279, 12250, 53, 26729, 89114, 1912, 6319, 31228, 19576, 32885, 369, 5370, 7106, 15082, 13, 578, 1176, 574, 264, 42991, 315, 59425, 380, 6067, 11, 304, 1023, 4339, 11, 315, 19252, 430, 3351, 520, 25753, 3345, 311, 430, 315, 3177, 13, 330, 2028, 9526, 374, 912, 36747, 5030, 11, 1606, 279, 65125, 1511, 7293, 2103, 11, 323, 3686, 584, 10299, 311, 636, 1124, 311, 36792, 439, 422, 814, 1051, 7366, 520, 279, 4732, 315, 3177, 3343, 578, 9526, 11223, 555, 420, 1912, 304, 279, 9476, 315, 28479, 42846, 574, 11953, 704, 304, 35998, 11, 330, 438, 1047, 5115, 459, 5536, 37545, 11, 1606, 3156, 1457, 420, 706, 1027, 279, 9526, 304, 902, 279, 8592, 2237, 315, 31228, 2585, 706, 1027, 17427, 15603, 389, 28772, 7351, 5415, 1359, 61414, 11301, 86563, 13, 23548, 279, 2450, 17427, 11, 814, 4024, 389, 57515, 31228, 1675, 42391, 369, 1023, 4595, 315, 6067, 11, 1093, 1884, 315, 45830, 81682, 919, 323, 43746, 2439, 13, 330, 2028, 374, 1633, 3062, 1359, 14618, 704, 11301, 86563, 11, 1606, 304, 7138, 2225, 4595, 315, 19252, 13524, 3073, 25, 1063, 527, 81682, 919, 320, 258, 33299, 11, 369, 3187, 11, 279, 57678, 8, 323, 279, 3885, 527, 43746, 2439, 320, 52399, 2439, 477, 3177, 19252, 477, 279, 473, 62247, 43746, 263, 41418, 8140, 4623, 574, 311, 2955, 279, 1887, 1234, 4007, 78220, 11, 779, 430, 584, 1436, 8895, 2680, 323, 8819, 2038, 505, 433, 13, 578, 3575, 449, 1521, 6067, 374, 430, 872, 30295, 527, 779, 6485, 430, 433, 374, 539, 3284, 311, 8895, 2680, 311, 1124, 555, 3445, 315, 83699, 9124, 304, 29924, 19002, 11, 304, 1023, 4339, 11, 584, 527, 7373, 11537, 449, 279, 39006, 430, 7664, 872, 30295, 11, 719, 584, 4250, 9006, 1124, 1359, 568, 61414, 13, 2435, 1243, 4024, 389, 311, 2980, 2500, 1403, 4595, 315, 1675, 42391, 13, 77795, 11, 814, 6319, 1675, 42391, 369, 31228, 2115, 10334, 4211, 13, 4314, 26018, 330, 548, 279, 6305, 430, 7664, 279, 1455, 6913, 11618, 11, 1093, 48453, 1990, 51045, 315, 19252, 430, 1935, 2035, 304, 14511, 3046, 11, 902, 527, 1101, 1633, 6485, 1359, 11497, 11301, 86563, 13, 4740, 430, 814, 8413, 59942, 389, 279, 19576, 315, 31228, 30903, 4211, 26, 330, 576, 374, 264, 14050, 430, 584, 617, 304, 20632, 449, 3495, 17274, 520, 25996, 3907, 320, 25342, 705, 1405, 584, 6319, 264, 3230, 11766, 369, 31228, 30903, 31206, 4211, 13, 330, 7009, 1101, 11223, 282, 985, 264, 31228, 42991, 449, 264, 31228, 6500, 11, 330, 64, 502, 7434, 311, 5376, 279, 60112, 315, 31228, 47590, 26, 1148, 584, 1550, 574, 311, 1893, 264, 37072, 12914, 430, 5825, 279, 1675, 42391, 449, 2680, 311, 264, 8294, 1396, 315, 9256, 1210, 11301, 86563, 11497, 279, 2802, 505, 279, 30116, 13356, 315, 682, 1521, 31228, 1675, 42391, 25, 330, 791, 4459, 35410, 5064, 11, 279, 11742, 323, 7384, 5064, 11, 323, 1524, 279, 4907, 5064, 527, 11125, 311, 2955, 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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 Local electron triggered reactions of functional surface adsorbates were used as a maskless, dry, and minimally invasive nanolithography concept to stabilize the polarisation of individual vertical cavity surface emitting lasers (VCSELs) on a wafer in a post-processing step. Using a 30 keV focused electron beam of a scanning electron microscope and injecting volatile organo-metallic (CH 3 ) 2 Au(tfa) molecules, polarisation gratings were directly written on VCSELs by dissociating the surface adsorbed molecules. The electron triggered adsorbate dissociation resulted in electrically conductive Au-C nano-composite material, with gold nanocrystals embedded in a carbonaceous matrix. A resistivity of 2500 µΩcm was measured at a typical composition of 30 at.% Au. This material proved successful in suppressing polarisation switching when deposited as line gratings with a width of 200 nm, a thickness of 50 nm, and a pitch of 500 nm and 1µm. Refractive index measurements suggest that the optical attenuation by the deposited Au-C material is much lower than by pure Au thus giving a low emission power penalty while keeping the polarisation stable. This article is part of the themed collection: Lithography Introduction The possibility to deposit or remove very small amounts of material for trimming purposes on a fully processed micro/nanodevice at the right place at will without interference to surrounding sensitive areas can be very cost effective even if the speed of the deposition (or etching) is very low compared to standard photolithography. In this article, we describe an emerging lithography concept, based on gas-assisted focused electron beam induced deposition (FEBID), 1 which enables local deposition of conductive material for refining the performance of a micro-optical device, a vertical-cavity surface-emitting laser (VCSEL), see Fig. 1 . Long-wavelength emitting VCSELs in the 1310 nm range offer numerous advantages for applications in local and access networks and optical spectroscopy thanks to their low power consumption, high speed modulation, and ease of coupling to optical fibers. 2 However, due to the cylindrical symmetry of these devices typically made on standard (100) GaAs or InP substrates, they suffer from the lack of a stable polarisation state and hence the polarisation can flip along orthogonal 〈100〉 directions during operation, i.e. during current injection. Approaches for achieving polarisation control in VCSELs comprised non-isotropic gain using (311) substrates 3 and non-cylindrical resonators. 4 Classical, resist-based e-beam lithography approaches were also used to fabricate polarisation stabilizing line gratings on the VCSEL's distributed Bragg reflectors (DBRs) in combination with metal lift-off 5 or deep reactive ion etching. 6 However, using above methods, 100% yields were not achieved; moreover, a post-process method which could trim individual VCSEL devices to achieve standard emission output is preferable. Fig. 1 Gas-assisted focused electron beam induced deposition for laser refining. By scanning the focused electron beam, polarisation gratings can be deposited on top of individual VCSELs without the need for masks, lithography resist removal, or wet chemistry steps. We will demonstrate here that the FEBID lithography process illustrated in Fig. 1 is a viable method for depositing line gratings on top of individual VCSELs such that their polarisation state can be adjusted. The technique relies on the local dissociation of functional, volatile, surface physisorbed molecules by a focused electron beam. The volatile dissociation reaction products desorb into the vacuum chamber of the scanning electron microscope (SEM) and are removed by the vacuum system, while the non-volatile dissociation products form the deposit. Since the molecules are continuously supplied to the substrate surface via a gas injection system, the deposition can be continued to produce to (almost) any desired three-dimensional deposit shape by moving the focused electron beam or keeping it stationary. Once the desired structure is written, the gas injection system is closed and the non-dissociated molecules desorb, leaving the desired lithographic deposit pattern on the surface. This nanolithography concept is, by its nature, maskless and single step in contrast to standard resist based lithography and lift-off procedures. It does not require any wet chemical step, does not implant any material (which is the case when using focused Ga-ion beams) and thus is minimally invasive to sensitive underlying and surrounding structures and devices. While dissociation of molecules by electrons is a long studied subject extending several fundamental science fields, including DNA radiolysis and related genotoxic damage, 7 surface science, 8,9 auto-catalysis, 10 self-assembled monolayers, 11 and semiconductor process plasmas, 12 its potential for an electron-controlled chemical lithography concept was intensely studied only recently, both for nanoscale deposition and etching, see reviews. 13–17 Recent device prototypes demonstrate the flexibility in shape and material deposited by FEBID: magnetic sensors for bead detection, 18 nanopores for DNA sequencing, 19 plasmonic antennaes, 20,21 plasmonic-photonic nanodevices for label-free detection of molecules, 22 graphenoid membranes, 23 single-crystal nanowires, 24 and tunable strain sensors. 25 In semiconductor industry FEBID processes are used for in-line 45 nm node photomask repair. 26 Recent impressive progress in FEBID technology comprises the control over shape down to the nanometre scale using in situ detection schemes, 27 automation protocols for wafer processing, 28 and the control over material purity and nanocomposite composition via co-injection of reactive and organic gases. 29–32 Experimental The VCSELs in this study emitted at 1310 nm wavelength. They had an InAlGaAs/InP multi-quantum well active region and a p++/n++ InAlGaAs regrown tunnel junction for optical and electrical confinements. The non-doped AlGaAs DBRs were fused to the InP-based cavity using a localized double wafer fusion process. 33,34 These VCSELs have been demonstrated to be suitable for high speed telecommunication applications, with good performance obtained at 10 Gb s −1 modulation speeds up to 100 °C. 35 FEBID of polarisation stabilizing gratings on top of the VCSELs was carried out in a dual beam FIB/SEM (Lyra Tescan) with a tungsten filament operating at 30 kV for best lateral resolution. With a gas injection system (Alemnis) equipped with an internal reservoir, the vapour molecules of dimethyl-Au-trifluoroacetylacetonate, (CH 3 ) 2 -Au(O 2 C 5 H 4 F 3 ), (CAS 63470-53-1), were directed to the VCSEL. The impinging molecule flux was around 1 × 10", "role": "user" }, { "content": "A new laser procedure could boost optical fiber communications. This technique could become essential for the future expansion of the Internet. It also opens up new frontiers in basic research. Long-distance, high speed communications depend on lasers. But when information is transmitted down fiber optic cables, it's critical that the signal be clear enough to be decoded at the other end. Two factors are important in this respect: the color of the light, otherwise known as the wavelength, and the orientation of the light wave, known as polarization. A team from EPFL and the Swiss Federal Laboratories for Materials Science and Technology (EMPA) has developed a technique that improves control over these two parameters. \"All indications are that this technology could be useful at both industrial and scientific levels,\" explains Eli Kapon, head of EPFL's Laboratory of Physics of Nanostructures. More than fifteen years of research were required to arrive at this result, work that \"has caused many headaches and demanded significant investment.\" To obtain the right wavelength, the EPFL researchers adapted the lasers' size. In parallel, the EMPA scientists designed a nanometer-scale grating for the emitter in order to control the light's polarization. They were able to achieve this feat by vaporizing long molecules containing gold atoms with a straw-like tool operating above the lasers. Using an electron microscope, they were able to arrange and attach gold particles to the surface of each laser with extreme precision. Thus deposited, the grating serves as a filter for polarizing the light, much like the lenses of sunglasses are used to polarize sunlight. Industrial and scientific advantages This technique, developed in collaboration with EMPA, has many advantages. It allows a high-speed throughput of several gigabits a second with reduced transmission errors. The lasers involved are energy-efficient, consuming up to ten times less than their traditional counterparts, thanks to their small size. The technique is very precise and efficient, due to the use of the electron microscope. \"This progress is very satisfying,\" adds Kapon, who also outlines some possible applications. \"These kinds of lasers are also useful for studying and detecting gases using spectroscopic methods. We will thus make gains in precision by improving detector sensitivity.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Local electron triggered reactions of functional surface adsorbates were used as a maskless, dry, and minimally invasive nanolithography concept to stabilize the polarisation of individual vertical cavity surface emitting lasers (VCSELs) on a wafer in a post-processing step. Using a 30 keV focused electron beam of a scanning electron microscope and injecting volatile organo-metallic (CH 3 ) 2 Au(tfa) molecules, polarisation gratings were directly written on VCSELs by dissociating the surface adsorbed molecules. The electron triggered adsorbate dissociation resulted in electrically conductive Au-C nano-composite material, with gold nanocrystals embedded in a carbonaceous matrix. A resistivity of 2500 µΩcm was measured at a typical composition of 30 at.% Au. This material proved successful in suppressing polarisation switching when deposited as line gratings with a width of 200 nm, a thickness of 50 nm, and a pitch of 500 nm and 1µm. Refractive index measurements suggest that the optical attenuation by the deposited Au-C material is much lower than by pure Au thus giving a low emission power penalty while keeping the polarisation stable. This article is part of the themed collection: Lithography Introduction The possibility to deposit or remove very small amounts of material for trimming purposes on a fully processed micro/nanodevice at the right place at will without interference to surrounding sensitive areas can be very cost effective even if the speed of the deposition (or etching) is very low compared to standard photolithography. In this article, we describe an emerging lithography concept, based on gas-assisted focused electron beam induced deposition (FEBID), 1 which enables local deposition of conductive material for refining the performance of a micro-optical device, a vertical-cavity surface-emitting laser (VCSEL), see Fig. 1 . Long-wavelength emitting VCSELs in the 1310 nm range offer numerous advantages for applications in local and access networks and optical spectroscopy thanks to their low power consumption, high speed modulation, and ease of coupling to optical fibers. 2 However, due to the cylindrical symmetry of these devices typically made on standard (100) GaAs or InP substrates, they suffer from the lack of a stable polarisation state and hence the polarisation can flip along orthogonal 〈100〉 directions during operation, i.e. during current injection. Approaches for achieving polarisation control in VCSELs comprised non-isotropic gain using (311) substrates 3 and non-cylindrical resonators. 4 Classical, resist-based e-beam lithography approaches were also used to fabricate polarisation stabilizing line gratings on the VCSEL's distributed Bragg reflectors (DBRs) in combination with metal lift-off 5 or deep reactive ion etching. 6 However, using above methods, 100% yields were not achieved; moreover, a post-process method which could trim individual VCSEL devices to achieve standard emission output is preferable. Fig. 1 Gas-assisted focused electron beam induced deposition for laser refining. By scanning the focused electron beam, polarisation gratings can be deposited on top of individual VCSELs without the need for masks, lithography resist removal, or wet chemistry steps. We will demonstrate here that the FEBID lithography process illustrated in Fig. 1 is a viable method for depositing line gratings on top of individual VCSELs such that their polarisation state can be adjusted. The technique relies on the local dissociation of functional, volatile, surface physisorbed molecules by a focused electron beam. The volatile dissociation reaction products desorb into the vacuum chamber of the scanning electron microscope (SEM) and are removed by the vacuum system, while the non-volatile dissociation products form the deposit. Since the molecules are continuously supplied to the substrate surface via a gas injection system, the deposition can be continued to produce to (almost) any desired three-dimensional deposit shape by moving the focused electron beam or keeping it stationary. Once the desired structure is written, the gas injection system is closed and the non-dissociated molecules desorb, leaving the desired lithographic deposit pattern on the surface. This nanolithography concept is, by its nature, maskless and single step in contrast to standard resist based lithography and lift-off procedures. It does not require any wet chemical step, does not implant any material (which is the case when using focused Ga-ion beams) and thus is minimally invasive to sensitive underlying and surrounding structures and devices. While dissociation of molecules by electrons is a long studied subject extending several fundamental science fields, including DNA radiolysis and related genotoxic damage, 7 surface science, 8,9 auto-catalysis, 10 self-assembled monolayers, 11 and semiconductor process plasmas, 12 its potential for an electron-controlled chemical lithography concept was intensely studied only recently, both for nanoscale deposition and etching, see reviews. 13–17 Recent device prototypes demonstrate the flexibility in shape and material deposited by FEBID: magnetic sensors for bead detection, 18 nanopores for DNA sequencing, 19 plasmonic antennaes, 20,21 plasmonic-photonic nanodevices for label-free detection of molecules, 22 graphenoid membranes, 23 single-crystal nanowires, 24 and tunable strain sensors. 25 In semiconductor industry FEBID processes are used for in-line 45 nm node photomask repair. 26 Recent impressive progress in FEBID technology comprises the control over shape down to the nanometre scale using in situ detection schemes, 27 automation protocols for wafer processing, 28 and the control over material purity and nanocomposite composition via co-injection of reactive and organic gases. 29–32 Experimental The VCSELs in this study emitted at 1310 nm wavelength. They had an InAlGaAs/InP multi-quantum well active region and a p++/n++ InAlGaAs regrown tunnel junction for optical and electrical confinements. The non-doped AlGaAs DBRs were fused to the InP-based cavity using a localized double wafer fusion process. 33,34 These VCSELs have been demonstrated to be suitable for high speed telecommunication applications, with good performance obtained at 10 Gb s −1 modulation speeds up to 100 °C. 35 FEBID of polarisation stabilizing gratings on top of the VCSELs was carried out in a dual beam FIB/SEM (Lyra Tescan) with a tungsten filament operating at 30 kV for best lateral resolution. With a gas injection system (Alemnis) equipped with an internal reservoir, the vapour molecules of dimethyl-Au-trifluoroacetylacetonate, (CH 3 ) 2 -Au(O 2 C 5 H 4 F 3 ), (CAS 63470-53-1), were directed to the VCSEL. The impinging molecule flux was around 1 × 10<|im_end|> <|im_start|>assistant A new laser procedure could boost optical fiber communications. This technique could become essential for the future expansion of the Internet. It also opens up new frontiers in basic research. Long-distance, high speed communications depend on lasers. But when information is transmitted down fiber optic cables, it's critical that the signal be clear enough to be decoded at the other end. Two factors are important in this respect: the color of the light, otherwise known as the wavelength, and the orientation of the light wave, known as polarization. A team from EPFL and the Swiss Federal Laboratories for Materials Science and Technology (EMPA) has developed a technique that improves control over these two parameters. "All indications are that this technology could be useful at both industrial and scientific levels," explains Eli Kapon, head of EPFL's Laboratory of Physics of Nanostructures. More than fifteen years of research were required to arrive at this result, work that "has caused many headaches and demanded significant investment." To obtain the right wavelength, the EPFL researchers adapted the lasers' size. In parallel, the EMPA scientists designed a nanometer-scale grating for the emitter in order to control the light's polarization. They were able to achieve this feat by vaporizing long molecules containing gold atoms with a straw-like tool operating above the lasers. Using an electron microscope, they were able to arrange and attach gold particles to the surface of each laser with extreme precision. Thus deposited, the grating serves as a filter for polarizing the light, much like the lenses of sunglasses are used to polarize sunlight. Industrial and scientific advantages This technique, developed in collaboration with EMPA, has many advantages. It allows a high-speed throughput of several gigabits a second with reduced transmission errors. The lasers involved are energy-efficient, consuming up to ten times less than their traditional counterparts, thanks to their small size. The technique is very precise and efficient, due to the use of the electron microscope. "This progress is very satisfying," adds Kapon, who also outlines some possible applications. "These kinds of lasers are also useful for studying and detecting gases using spectroscopic methods. We will thus make gains in precision by improving detector sensitivity." <|im_end|>

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30465, 82, 2085, 279, 1205, 369, 27227, 11, 46282, 5814, 22884, 17065, 11, 477, 14739, 30903, 7504, 13, 1226, 690, 20461, 1618, 430, 279, 435, 8428, 926, 46282, 5814, 1920, 36762, 304, 23966, 13, 220, 16, 374, 264, 31528, 1749, 369, 16946, 287, 1584, 8902, 826, 389, 1948, 315, 3927, 44595, 30465, 82, 1778, 430, 872, 25685, 8082, 1614, 649, 387, 24257, 13, 578, 15105, 34744, 389, 279, 2254, 91342, 367, 315, 16003, 11, 17509, 11, 7479, 1343, 4548, 269, 2788, 35715, 555, 264, 10968, 17130, 24310, 13, 578, 17509, 91342, 367, 13010, 3956, 951, 30986, 1139, 279, 29302, 25199, 315, 279, 36201, 17130, 73757, 320, 84839, 8, 323, 527, 7108, 555, 279, 29302, 1887, 11, 1418, 279, 2536, 8437, 26598, 91342, 367, 3956, 1376, 279, 16946, 13, 8876, 279, 35715, 527, 31978, 17665, 311, 279, 54057, 7479, 4669, 264, 6962, 26127, 1887, 11, 279, 65374, 649, 387, 8738, 311, 8356, 311, 320, 60301, 8, 904, 12974, 2380, 33520, 16946, 6211, 555, 7366, 279, 10968, 17130, 24310, 477, 10494, 433, 53735, 13, 9843, 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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 There is concern that the body size of fashion store mannequins are too thin and promote unrealistic body ideals. To date there has been no systematic examination of the size of high street fashion store mannequins. Methods We surveyed national fashion retailers located on the high street of two English cities. The body size of ‘male’ and ‘female’ mannequins was assessed by two blinded research assistants using visual rating scales. Results The average female mannequin body size was representative of a very underweight woman and 100% of female mannequins represented an underweight body size. The average male mannequin body size was significantly larger than the average female mannequin body size. Only 8% of male mannequins represented an underweight body size. Conclusions The body size of mannequins used to advertise female fashion is unrealistic and would be considered medically unhealthy in humans. Plain english summary There is concern that the body size of fashion store mannequins are too thin and promote unrealistic body ideals. Although some retailers have reported that they now use more appropriate sized mannequins, the actual size of mannequins being used in high street fashion stores has not been formally examined. We surveyed national fashion retailers located on the high street of two English cities. The average female mannequin body size was representative of a very underweight woman and all mannequins rated represented an underweight body size. The average male mannequin body size was significantly larger than the average female mannequin body size. The body size of mannequins used to advertise female fashion is unrealistic and would be considered medically unhealthy in humans. Background It is well recognised that internalisation of ‘ultra-thin’ body ideals in women acts as risk factor the development of eating disorders and impaired psychological well-being [ 1 , 2 ]. However, in the modern developed world unrealistic body ideals are communicated both implicitly and explicitly to women [ 3 ]. For example, female models tend to have very thin body sizes that would be unattainable for most women [ 4 , 5 ]. The body size dimensions of the popular young girls toy doll ‘Barbie’ are also implausibly slim [ 6 ]. Similarly, catwalk fashion models often appear to be severely underweight [ 7 ] and public concern has resulted in recent legislation in European countries banning the use of very underweight catwalk models [ 8 ]. Likewise, the use of underweight models has recently been banned in Israel because of concerns that the use of such models communicates ultra-thin body ideals to young people. Thus, there is growing awareness that prevention efforts against body image problems need to address the wider environment and reduce communication of ultra-thin body ideals [ 9 , 10 ]. Rintala and Mustajoki [ 11 ] assessed six female mannequins made in Italy, Japan and Malaysia between the 1920s and 1960s. Based on the body dimensions of these mannequins, the authors concluded that if a human female had the same body dimensions, she would have such little body fat that she would be unable to menstruate. Of late, there has been public concern that the typical size of high street (the primary retail business street in a city or town) fashion store mannequins used in England represents an unrealistic body size for women [ 12 , 13 ] and this may communicate inappropriate body size ideals. In response to this there have been some news reports that nationwide fashion retailers in England have started to use larger more realistic mannequin sizes [ 14 ]. However, there has been no systematic examination of the size of high street fashion store mannequins. The body size of mannequins used to sell fashion may be relevant to the prevention of body image problems because slender mannequins may constitute an environmental factor that communicates and reinforces the ultra-thin ideal. The aim of the present research was to examine the size of male and female mannequins used in national high street fashion retailers in England. A secondary aim was to examine whether the size of mannequins used in stores differed dependent on the age of consumer a store targeted. We reasoned that stores targeting younger age ranges may be more likely to use slender mannequins because of the greater value attached to thinness in young people [ 15 ]. Methods Survey sites We surveyed national fashion retailers located on the high street of two large cities in the north (Liverpool) and centre (Coventry) of England. ‘High street’ stores were operationalised as stores located on the street that was home to the main shopping promenade area of that city. Stores were eligible to be sampled if they had at least one mannequin on display (male and/or female) and were part of a national chain (i.e. more than one store in the country). We opted to sample only national chains as we reasoned that this sampling approach would produce the most representative data for the size of mannequins widely used in high street fashion. The study procedures used were approved by the first author’s University Research Ethics Committee. Measurement of mannequin body size It was our original intention to collect anthropometric measurements of mannequins. However, we contacted all eligible retailers across both survey sites and no retailers gave permission to take anthropometric measurements. We therefore used visual rating scales to assess mannequin body size. Rating scales When rating mannequins each researcher completed two rating scales by selecting the figure on each scale that most closely resembled the size of mannequin being rated; a BMI-based body size guide rating scale [ 16 ] and the Contour Drawing Rating scale [ 17 ]. The BMI-based body size guide rating scale consists of ten standardised photographs of adults with known BMI values and is a validated body size perception tool [ 16 ]. The scale is gender specific and the photographs range in size from underweight (BMI < 18.5) to class III obesity (BMI ≥ 40), with approximately a 3-point BMI difference between scale figures. For the purpose", "role": "user" }, { "content": "New research from the University of Liverpool shows that the body size of mannequins used to advertise female fashion in the UK are too thin and may be promoting unrealistic body ideals. In the first study of its kind researchers, led by Dr Eric Robinson from the University's Institute of Psychology, Health and Society, surveyed national fashion retailers located on the high street of two cities in the UK. The body size of 'male' and 'female' mannequins was assessed by two research assistants using visual rating scales. Severely underweight The study, published in the Journal of Eating Disorders today, found that the average female mannequin body size was representative of a severely underweight woman. The average male mannequin body size was significantly larger than the average female mannequin body size and only a small proportion of male mannequins represented an underweight body size. Body image problems Dr Eric Robinson, said: \"We became interested in this topic after seeing some news report about members of the general public noticing that some mannequins in fashion stores were disturbingly thin. \"Around the same time we had also read news coverage that fashion retailers had responded to this concern and adopted more appropriate sized mannequins, so it felt like an interesting research question to examine. Our survey of these two high streets in the UK produced consistent results; the body size of female mannequins represented that of extremely underweight human women. \"Because ultra-thin ideals encourage the development of body image problems in young people, we need to change the environment to reduce emphasis on the value of extreme thinness. \"We of course are not saying that altering the size of high street fashion mannequins will on its own 'solve' body image problems. What we are instead saying is that presentation of ultra-thin female bodies is likely to reinforce inappropriate and unobtainable body ideals, so as a society we should be taking measures to stop this type of reinforcement. \"Given that the prevalence of body image problems and disordered eating in young people is worryingly high, positive action that challenges communication of ultra-thin ideal may be of particular benefit to children, adolescents and young adult females.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background There is concern that the body size of fashion store mannequins are too thin and promote unrealistic body ideals. To date there has been no systematic examination of the size of high street fashion store mannequins. Methods We surveyed national fashion retailers located on the high street of two English cities. The body size of ‘male’ and ‘female’ mannequins was assessed by two blinded research assistants using visual rating scales. Results The average female mannequin body size was representative of a very underweight woman and 100% of female mannequins represented an underweight body size. The average male mannequin body size was significantly larger than the average female mannequin body size. Only 8% of male mannequins represented an underweight body size. Conclusions The body size of mannequins used to advertise female fashion is unrealistic and would be considered medically unhealthy in humans. Plain english summary There is concern that the body size of fashion store mannequins are too thin and promote unrealistic body ideals. Although some retailers have reported that they now use more appropriate sized mannequins, the actual size of mannequins being used in high street fashion stores has not been formally examined. We surveyed national fashion retailers located on the high street of two English cities. The average female mannequin body size was representative of a very underweight woman and all mannequins rated represented an underweight body size. The average male mannequin body size was significantly larger than the average female mannequin body size. The body size of mannequins used to advertise female fashion is unrealistic and would be considered medically unhealthy in humans. Background It is well recognised that internalisation of ‘ultra-thin’ body ideals in women acts as risk factor the development of eating disorders and impaired psychological well-being [ 1 , 2 ]. However, in the modern developed world unrealistic body ideals are communicated both implicitly and explicitly to women [ 3 ]. For example, female models tend to have very thin body sizes that would be unattainable for most women [ 4 , 5 ]. The body size dimensions of the popular young girls toy doll ‘Barbie’ are also implausibly slim [ 6 ]. Similarly, catwalk fashion models often appear to be severely underweight [ 7 ] and public concern has resulted in recent legislation in European countries banning the use of very underweight catwalk models [ 8 ]. Likewise, the use of underweight models has recently been banned in Israel because of concerns that the use of such models communicates ultra-thin body ideals to young people. Thus, there is growing awareness that prevention efforts against body image problems need to address the wider environment and reduce communication of ultra-thin body ideals [ 9 , 10 ]. Rintala and Mustajoki [ 11 ] assessed six female mannequins made in Italy, Japan and Malaysia between the 1920s and 1960s. Based on the body dimensions of these mannequins, the authors concluded that if a human female had the same body dimensions, she would have such little body fat that she would be unable to menstruate. Of late, there has been public concern that the typical size of high street (the primary retail business street in a city or town) fashion store mannequins used in England represents an unrealistic body size for women [ 12 , 13 ] and this may communicate inappropriate body size ideals. In response to this there have been some news reports that nationwide fashion retailers in England have started to use larger more realistic mannequin sizes [ 14 ]. However, there has been no systematic examination of the size of high street fashion store mannequins. The body size of mannequins used to sell fashion may be relevant to the prevention of body image problems because slender mannequins may constitute an environmental factor that communicates and reinforces the ultra-thin ideal. The aim of the present research was to examine the size of male and female mannequins used in national high street fashion retailers in England. A secondary aim was to examine whether the size of mannequins used in stores differed dependent on the age of consumer a store targeted. We reasoned that stores targeting younger age ranges may be more likely to use slender mannequins because of the greater value attached to thinness in young people [ 15 ]. Methods Survey sites We surveyed national fashion retailers located on the high street of two large cities in the north (Liverpool) and centre (Coventry) of England. ‘High street’ stores were operationalised as stores located on the street that was home to the main shopping promenade area of that city. Stores were eligible to be sampled if they had at least one mannequin on display (male and/or female) and were part of a national chain (i.e. more than one store in the country). We opted to sample only national chains as we reasoned that this sampling approach would produce the most representative data for the size of mannequins widely used in high street fashion. The study procedures used were approved by the first author’s University Research Ethics Committee. Measurement of mannequin body size It was our original intention to collect anthropometric measurements of mannequins. However, we contacted all eligible retailers across both survey sites and no retailers gave permission to take anthropometric measurements. We therefore used visual rating scales to assess mannequin body size. Rating scales When rating mannequins each researcher completed two rating scales by selecting the figure on each scale that most closely resembled the size of mannequin being rated; a BMI-based body size guide rating scale [ 16 ] and the Contour Drawing Rating scale [ 17 ]. The BMI-based body size guide rating scale consists of ten standardised photographs of adults with known BMI values and is a validated body size perception tool [ 16 ]. The scale is gender specific and the photographs range in size from underweight (BMI < 18.5) to class III obesity (BMI ≥ 40), with approximately a 3-point BMI difference between scale figures. For the purpose<|im_end|> <|im_start|>assistant New research from the University of Liverpool shows that the body size of mannequins used to advertise female fashion in the UK are too thin and may be promoting unrealistic body ideals. In the first study of its kind researchers, led by Dr Eric Robinson from the University's Institute of Psychology, Health and Society, surveyed national fashion retailers located on the high street of two cities in the UK. The body size of 'male' and 'female' mannequins was assessed by two research assistants using visual rating scales. Severely underweight The study, published in the Journal of Eating Disorders today, found that the average female mannequin body size was representative of a severely underweight woman. The average male mannequin body size was significantly larger than the average female mannequin body size and only a small proportion of male mannequins represented an underweight body size. Body image problems Dr Eric Robinson, said: "We became interested in this topic after seeing some news report about members of the general public noticing that some mannequins in fashion stores were disturbingly thin. "Around the same time we had also read news coverage that fashion retailers had responded to this concern and adopted more appropriate sized mannequins, so it felt like an interesting research question to examine. Our survey of these two high streets in the UK produced consistent results; the body size of female mannequins represented that of extremely underweight human women. "Because ultra-thin ideals encourage the development of body image problems in young people, we need to change the environment to reduce emphasis on the value of extreme thinness. "We of course are not saying that altering the size of high street fashion mannequins will on its own 'solve' body image problems. What we are instead saying is that presentation of ultra-thin female bodies is likely to reinforce inappropriate and unobtainable body ideals, so as a society we should be taking measures to stop this type of reinforcement. "Given that the prevalence of body image problems and disordered eating in young people is worryingly high, positive action that challenges communication of ultra-thin ideal may be of particular benefit to children, adolescents and young adult females." <|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 Brown-headed cowbirds ( Molothrus ater ) deposit their eggs into the nests of other birds, which then raise the cowbird chick. Female cowbirds thus have limited options for impacting their offspring’s development via maternal effects compared to most other passerines. Cowbirds can impact their offspring’s phenotype by choosing among potential host nests, and by adjusting egg resources based on host characteristics. To examine whether cowbirds exhibit either or both of these strategies, we investigated rates of cowbird parasitism and egg investment (egg size, yolk-to-albumen ratio, and yolk testosterone and androstenedione) among and within host species in a shrubland bird community. We found that the probability of being parasitized by cowbirds, controlling for host status as a cowbird egg accepter or rejecter and ordinal date, varied significantly among host species, indicating an apparent preference for some hosts. Parasitism rates did not differ with host size, however, and despite variation in cowbird egg size among host species, this variation was not related to host size or cowbird preference. Among host species with eggs that are larger than those of the cowbird, cowbirds were significantly more likely to parasitize nests with relatively smaller eggs, whereas parasitism rates did not vary with relative egg size in host species with smaller eggs. There was no evidence for variation in cowbird egg components among or within host species. Our data indicate that cowbirds discriminate among host nests, but do not appear to adjust the composition of their eggs based on inter- or intraspecific host variation. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction The egg of an avian brood parasite faces long odds if it is to successfully fledge from the host nest. The female brood parasite can, in theory, impact those odds in two ways before laying the egg: she can be selective in choosing among host nests, and she can adjust the allocation of resources to the egg (Fig. 1 ). These strategies represent two different forms of maternal effects, which are any causal influences of the maternal genotype or phenotype on the offspring’s phenotype (Wolf and Wade 2009 ). Female brood parasites are limited in their capacity to impact the offspring’s phenotype after laying their eggs (but see Hoover and Robinson 2007 ), thus the relative importance of pre-laying maternal effects may be higher than that for non-parasitic species. Little work has focused on the maternal effects, per se, in brood parasites, but the potential to significantly affect the survival prospects of their offspring via investing time in selecting suitable hosts, and adjusting resources to their eggs based on host characteristics, is high. Fig. 1 Possible outcomes for variation in the rates of parasitism and egg investment for female brown-headed cowbirds based on whether cowbirds discriminate among and within accepter host species. Accepter hosts reject cowbird eggs at low rates (<20%). If cowbirds do discriminate, this can occur as variation in rates of parasitism and/or variation in resources allocated to their eggs. If they do not discriminate there should be no variation in rates of parasitism or egg resources Full size image In North America, the brown-headed cowbird ( Molothrus ater ; hereafter cowbird) is the most abundant brood parasite, and has been recorded parasitizing over 220 species (Friedmann and Kiff 1985 ). An individual female cowbird, however, typically parasitizes a small subset of those species, and some individuals may focus on one host species (Fleischer 1985 ; Alderson et al. 1999 ). Cowbirds are thought to have high reproductive capacity; some researchers have found cowbirds to be prolific layers, producing upwards of 40 eggs in a single season (Scott and Ankney 1980 ; Fleischer et al. 1987 ; Holford and Roby 1993 ), while others have estimated averages of just over 2 eggs per year (Woolfenden et al. 2003 ). Two hypotheses have been proposed to explain the extreme ends of female cowbird reproductive strategies. One is the “shotgun” hypothesis (Scott and Ankney 1983 ; Holford and Roby 1993 ; Rothstein and Robinson 1998 ) in which females produce many eggs and lay them indiscriminately across host species based on relative availability (Rothstein 1976 , 1990 ). The other is the “host selection” hypothesis (Kattan 1997 ; Rothstein and Robinson 1998 ; Grant and Sealy 2002 ), in which females discriminate among, and select, hosts that offer the best rearing environment for their chick, regardless of the host’s relative abundance (Mayfield 1977 ; Sealy and Bazin 1995 ). There is growing evidence in support of the “host selection” hypothesis (Hahn et al. 1999 ; Curson et al. 2010 ), indicating that cowbirds may frequently discriminate among potential hosts. Whether this discrimination occurs solely at the species level, or if cowbirds choose among nests within a species, remains unclear. There is ample evidence that cowbirds perform better in the nests of some host species compared to others due to differences among hosts in rates of cowbird egg acceptance (Rothstein 1975 ), host diet (Kozlovic et al. 1996 ), and cowbird chick competitive ability compared to host chicks (Rivers 2007 ). Detecting within-host variation in cowbird performance, however, is more challenging due to the smaller degree of trait variation within one host species. But there are some lines of evidence indicating that cowbirds are able to, and do, discriminate among host nests based on features of that particular nest. Female cowbirds prospect for host nests in advance of laying (Norman and Robertson 1975 ; Clotfelter 1998 ), and therefore may be able to acquire some information about the quality of a given nest. Moreover, they typically lay after the first host egg has been laid (Nolan 1978 ; Clotfelter 1998 ; Royle et al. 2011 ), which should enable them to discriminate among host nests within a species and select nests based on characteristics of the host eggs. The ability of cowbirds to discriminate among host nests is predicated on the availability of multiple nests during the time when the female is laying. This availability", "role": "user" }, { "content": "Brown-headed cowbirds are unconventional mothers. Rather than building nests and nurturing their chicks, they lay their eggs in the nests of other species, leaving their young ones to compete for resources with the foster parents' own hatchlings. Despite their reputation as uncaring, absentee moms, cowbird mothers are capable of making sophisticated choices among potential nests in order to give their offspring a better chance of thriving, a new study shows. Brown-headed cowbirds are known to lay their eggs in the nests of more than 200 other bird species of varying sizes, and typically do so after the host bird has laid her own eggs. The new study, led by a team at the University of Illinois, found that when cowbird mothers chose the nest of a larger host bird, they preferred those that held smaller-than-average eggs for that species. Smaller host eggs give the cowbird eggs a better chance of being successfully incubated; smaller host hatchlings mean the cowbird chicks face less competition for food and nest space. \"It implies a level of resolution in cowbird decision-making that people hadn't seen before,\" said Loren Merrill, a postdoctoral researcher at the Illinois Natural History Survey who conducted the study with INHS scientists Scott Chiavacci and Thomas Benson and Illinois State University researcher Ryan Paitz. \"Scientists originally saw cowbirds as egg dumpers that would put their eggs in any nest they found,\" Merrill said. \"And while that may be the case in some areas, or for some birds, it doesn't tell the whole story. In fact, the more people have looked at cowbird behavior, the more our understanding has evolved of exactly how discriminating cowbirds can be.\" The findings are reported in the journal Oecologia. From April through August for five seasons ending in 2015, the researchers hunted through 16 shrubland sites across Illinois, looking for cowbirds and nests in which cowbirds might place their eggs. \"Nest searching is really fun fieldwork, except when you're trekking through poison ivy- and hawthorn-infested lands,\" Merrill said. \"You either get really lucky and see nesting material in a bird's mouth, and you watch until they lead you to a nest, or you listen and watch for the vocalizations and behaviors the adults use when you are close to a nest.\" Cowbirds, top, lay their eggs in other birds' nests, including those of eastern towhees, yellow warblers and field sparrows. Credit: Loren Merrill Cowbirds use similar tactics to scout for host nests. \"They do a lot of skulking around the underbrush,\" Merrill said. \"They'll also perch in an inconspicuous place and just watch. They are cuing in on the behavior of hosts that are building their nests or taking food back to nests.\" The research team found nearly 3,000 nests of 34 bird species and checked each nest roughly every three days. Cowbirds placed eggs in more than 400 of these nests. In addition to weighing and measuring cowbird and host eggs in more than 180 nests, the researchers also tested the composition of some cowbird eggs to determine whether female cowbirds give some eggs an added boost, such as a greater proportion of yolk or higher levels of yolk hormones like testosterone. \"The cowbird could adjust allocation to the egg based on the perceived value of that egg. If she thinks the egg is in a good environment, she can invest more,\" Merrill said. \"Or, if the host isn't appropriate and she doesn't think the environment is favorable, she could invest less.\" The researchers found no variation in egg investment based on the differences among host species or size variations within a host species, however. \"We didn't see evidence that female cowbirds were adjusting resources in that respect, but that's not to say it isn't happening,\" Merrill said. Tracking individual female cowbirds would help scientists better understand how mother cowbirds try to help their offspring. \"It's really hard to do,\" he said. \"But being able to track the individual females over time and identify where they are depositing eggs would provide a lot of insight into how much of what we see is an adaptive allocation strategy, or whether the mother's health and other constraints are driving her behavior.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Brown-headed cowbirds ( Molothrus ater ) deposit their eggs into the nests of other birds, which then raise the cowbird chick. Female cowbirds thus have limited options for impacting their offspring’s development via maternal effects compared to most other passerines. Cowbirds can impact their offspring’s phenotype by choosing among potential host nests, and by adjusting egg resources based on host characteristics. To examine whether cowbirds exhibit either or both of these strategies, we investigated rates of cowbird parasitism and egg investment (egg size, yolk-to-albumen ratio, and yolk testosterone and androstenedione) among and within host species in a shrubland bird community. We found that the probability of being parasitized by cowbirds, controlling for host status as a cowbird egg accepter or rejecter and ordinal date, varied significantly among host species, indicating an apparent preference for some hosts. Parasitism rates did not differ with host size, however, and despite variation in cowbird egg size among host species, this variation was not related to host size or cowbird preference. Among host species with eggs that are larger than those of the cowbird, cowbirds were significantly more likely to parasitize nests with relatively smaller eggs, whereas parasitism rates did not vary with relative egg size in host species with smaller eggs. There was no evidence for variation in cowbird egg components among or within host species. Our data indicate that cowbirds discriminate among host nests, but do not appear to adjust the composition of their eggs based on inter- or intraspecific host variation. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction The egg of an avian brood parasite faces long odds if it is to successfully fledge from the host nest. The female brood parasite can, in theory, impact those odds in two ways before laying the egg: she can be selective in choosing among host nests, and she can adjust the allocation of resources to the egg (Fig. 1 ). These strategies represent two different forms of maternal effects, which are any causal influences of the maternal genotype or phenotype on the offspring’s phenotype (Wolf and Wade 2009 ). Female brood parasites are limited in their capacity to impact the offspring’s phenotype after laying their eggs (but see Hoover and Robinson 2007 ), thus the relative importance of pre-laying maternal effects may be higher than that for non-parasitic species. Little work has focused on the maternal effects, per se, in brood parasites, but the potential to significantly affect the survival prospects of their offspring via investing time in selecting suitable hosts, and adjusting resources to their eggs based on host characteristics, is high. Fig. 1 Possible outcomes for variation in the rates of parasitism and egg investment for female brown-headed cowbirds based on whether cowbirds discriminate among and within accepter host species. Accepter hosts reject cowbird eggs at low rates (<20%). If cowbirds do discriminate, this can occur as variation in rates of parasitism and/or variation in resources allocated to their eggs. If they do not discriminate there should be no variation in rates of parasitism or egg resources Full size image In North America, the brown-headed cowbird ( Molothrus ater ; hereafter cowbird) is the most abundant brood parasite, and has been recorded parasitizing over 220 species (Friedmann and Kiff 1985 ). An individual female cowbird, however, typically parasitizes a small subset of those species, and some individuals may focus on one host species (Fleischer 1985 ; Alderson et al. 1999 ). Cowbirds are thought to have high reproductive capacity; some researchers have found cowbirds to be prolific layers, producing upwards of 40 eggs in a single season (Scott and Ankney 1980 ; Fleischer et al. 1987 ; Holford and Roby 1993 ), while others have estimated averages of just over 2 eggs per year (Woolfenden et al. 2003 ). Two hypotheses have been proposed to explain the extreme ends of female cowbird reproductive strategies. One is the “shotgun” hypothesis (Scott and Ankney 1983 ; Holford and Roby 1993 ; Rothstein and Robinson 1998 ) in which females produce many eggs and lay them indiscriminately across host species based on relative availability (Rothstein 1976 , 1990 ). The other is the “host selection” hypothesis (Kattan 1997 ; Rothstein and Robinson 1998 ; Grant and Sealy 2002 ), in which females discriminate among, and select, hosts that offer the best rearing environment for their chick, regardless of the host’s relative abundance (Mayfield 1977 ; Sealy and Bazin 1995 ). There is growing evidence in support of the “host selection” hypothesis (Hahn et al. 1999 ; Curson et al. 2010 ), indicating that cowbirds may frequently discriminate among potential hosts. Whether this discrimination occurs solely at the species level, or if cowbirds choose among nests within a species, remains unclear. There is ample evidence that cowbirds perform better in the nests of some host species compared to others due to differences among hosts in rates of cowbird egg acceptance (Rothstein 1975 ), host diet (Kozlovic et al. 1996 ), and cowbird chick competitive ability compared to host chicks (Rivers 2007 ). Detecting within-host variation in cowbird performance, however, is more challenging due to the smaller degree of trait variation within one host species. But there are some lines of evidence indicating that cowbirds are able to, and do, discriminate among host nests based on features of that particular nest. Female cowbirds prospect for host nests in advance of laying (Norman and Robertson 1975 ; Clotfelter 1998 ), and therefore may be able to acquire some information about the quality of a given nest. Moreover, they typically lay after the first host egg has been laid (Nolan 1978 ; Clotfelter 1998 ; Royle et al. 2011 ), which should enable them to discriminate among host nests within a species and select nests based on characteristics of the host eggs. The ability of cowbirds to discriminate among host nests is predicated on the availability of multiple nests during the time when the female is laying. This availability<|im_end|> <|im_start|>assistant Brown-headed cowbirds are unconventional mothers. Rather than building nests and nurturing their chicks, they lay their eggs in the nests of other species, leaving their young ones to compete for resources with the foster parents' own hatchlings. Despite their reputation as uncaring, absentee moms, cowbird mothers are capable of making sophisticated choices among potential nests in order to give their offspring a better chance of thriving, a new study shows. Brown-headed cowbirds are known to lay their eggs in the nests of more than 200 other bird species of varying sizes, and typically do so after the host bird has laid her own eggs. The new study, led by a team at the University of Illinois, found that when cowbird mothers chose the nest of a larger host bird, they preferred those that held smaller-than-average eggs for that species. Smaller host eggs give the cowbird eggs a better chance of being successfully incubated; smaller host hatchlings mean the cowbird chicks face less competition for food and nest space. "It implies a level of resolution in cowbird decision-making that people hadn't seen before," said Loren Merrill, a postdoctoral researcher at the Illinois Natural History Survey who conducted the study with INHS scientists Scott Chiavacci and Thomas Benson and Illinois State University researcher Ryan Paitz. "Scientists originally saw cowbirds as egg dumpers that would put their eggs in any nest they found," Merrill said. "And while that may be the case in some areas, or for some birds, it doesn't tell the whole story. In fact, the more people have looked at cowbird behavior, the more our understanding has evolved of exactly how discriminating cowbirds can be." The findings are reported in the journal Oecologia. From April through August for five seasons ending in 2015, the researchers hunted through 16 shrubland sites across Illinois, looking for cowbirds and nests in which cowbirds might place their eggs. "Nest searching is really fun fieldwork, except when you're trekking through poison ivy- and hawthorn-infested lands," Merrill said. "You either get really lucky and see nesting material in a bird's mouth, and you watch until they lead you to a nest, or you listen and watch for the vocalizations and behaviors the adults use when you are close to a nest." Cowbirds, top, lay their eggs in other birds' nests, including those of eastern towhees, yellow warblers and field sparrows. Credit: Loren Merrill Cowbirds use similar tactics to scout for host nests. "They do a lot of skulking around the underbrush," Merrill said. "They'll also perch in an inconspicuous place and just watch. They are cuing in on the behavior of hosts that are building their nests or taking food back to nests." The research team found nearly 3,000 nests of 34 bird species and checked each nest roughly every three days. Cowbirds placed eggs in more than 400 of these nests. In addition to weighing and measuring cowbird and host eggs in more than 180 nests, the researchers also tested the composition of some cowbird eggs to determine whether female cowbirds give some eggs an added boost, such as a greater proportion of yolk or higher levels of yolk hormones like testosterone. "The cowbird could adjust allocation to the egg based on the perceived value of that egg. If she thinks the egg is in a good environment, she can invest more," Merrill said. "Or, if the host isn't appropriate and she doesn't think the environment is favorable, she could invest less." The researchers found no variation in egg investment based on the differences among host species or size variations within a host species, however. "We didn't see evidence that female cowbirds were adjusting resources in that respect, but that's not to say it isn't happening," Merrill said. Tracking individual female cowbirds would help scientists better understand how mother cowbirds try to help their offspring. "It's really hard to do," he said. "But being able to track the individual females over time and identify where they are depositing eggs would provide a lot of insight into how much of what we see is an adaptive allocation strategy, or whether the mother's health and other constraints are driving her behavior." <|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 Chimpanzees ( Pan troglodytes ), one of humankinds’ closest living relatives, are known to hunt and consume the meat of various animal taxa. Although some researchers have presented indirect evidence that chimpanzees may also prey on tortoises, until now, direct observations of this behaviour did not exist. Here, we provide systematic descriptions of the first observations of chimpanzee predation on tortoises ( Kinixys erosa ). We made these unprecedented observations on newly habituated chimpanzees ( Pan troglodytes troglodytes ) of the Rekambo community, living in the Loango National Park, Gabon. The behaviour qualified as customary, that is occurring in most or all adult males, involved a distinct smashing technique, and resulted frequently in food sharing with other group members. Our observations shed new light on the hitherto little understood percussive technology of chimpanzees, and expand our current knowledge on chimpanzees’ dietary and predatory repertoires with respect to reptiles. We also report a case of food storage and discuss it in the context of future-oriented cognition. Our findings suggest the need for more nuanced interpretations of chimpanzees’ cognitive skills in combination with an in-depth understanding of their unique socio-ecological niches. They further emphasize the importance of nonhuman primate field observations to inform theories of hominin evolution. Introduction The ability to use and manufacture tools, long thought to be uniquely human, has now been reported in a variety of species of birds (e.g., New Caledonian crows Corvus moneduloides ) 1 and mammals (e.g., sea otter Enhydra lutris 2 ; bottlenose dolphins Tursiops sp. 3 ). Scholars distinguish between tool-use and proto-tool use, although there is no evidence that proto-tool use is an evolutionary or ontogenetic precursor to tool use 4 . Tool use is defined as “the external employment of an unattached or manipulable attached environmental object to alter more efficiently the form, position, or condition of another object, another organism, or the user itself, when the user holds and directly manipulates the tool, during or prior to use, and is responsible for the proper and effective orientation of the tool” 4 , 5 (p. 5) (e.g., sea otter opening the shell of an abalone by pounding it on a stone that is balanced on the otter’s ventrum) 2 . Proto-tools, on the other hand, are functionally analogous to tools but are not held and directly manipulated during or prior to use (e.g., labrid fishes Cheilinus trilobatus and Coris angulata pound sea urchins on coral or stones to detach the spines and smash the exoskeletons). Compared to other nonhuman animals, chimpanzees ( Pan troglodytes ) have developed an exceptionally large and varied technological repertoire 6 , 7 . For instance, they deploy tools made from diverse plant sources to acquire social insects, and utilize spear-like tools to rouse prosimian prey from cavities 7 , 8 , 9 , 10 . In addition, they are known to use percussive technology, ranging from pounding open hard-shelled fruits ( Baobab sp. 11 , Strychnos sp. 12 ) and termite mounds 13 against substrates to pounding open nuts ( Coula edulis, Panda oleosa ) using hammers 14 , 15 . Some researchers have also suggested that chimpanzees employ percussive technology to prey on tortoises 16 , 17 , but direct evidence was, until now, non-existent. Concerning humans, the predation and consumption of tortoises has already been attributed to early hominins ( Homo erectus ; ≈ 1.9 mya ) 18 . Tortoises also represent an important food resource in the diet of present-day hunter-gatherer societies 19 , 20 . Here, we provide the first direct observations of tortoise predation in wild chimpanzees ( Pan troglodytes troglodytes ). The behaviour of individuals of the Rekambo community, Loango National Park (Gabon) was observed on a daily basis from July 2016 – May 2018. Tortoise predation events were, however, restricted to the dry season only. The behaviour is frequently shown by the majority of adult males of the Rekambo community, thereby qualifying as customary 7 . In addition, we report on a single case of food storage, in which an adult male tucked a half-eaten tortoise in a tree fork and retrieved it the next day to continue feeding. Our results shed new light on the percussive technology of chimpanzees. They also expand our current knowledge on the relatively broad dietary and predatory repertoires of these ecologically flexible omnivores to reptiles. Furthermore, although chimpanzees are renowned to frequently hunt and consume the meat of a variety of vertebrates (most heavily red colobus Piliocolobus spp., as well as black-and-white colobus monkeys Colobus spp., red-tailed guenons Cercopithecus ascanius , olive baboons Papio anubis , red duikers Cephalophus natalensis , and bushpigs Potomochoerus porcus ) 6 , 21 , 22 , food storage in primates has so far only been implicated for early hominins 16 . Results We observed 38 prey events (34 successful and four unsuccessful ones) on hinge-back tortoises ( Kinixys erosa ) by ten different chimpanzees (seven adult males, one adult female, one adolescent male, one adolescent female) of the Rekambo community in the Loango National Park, Gabon (see Table 1 , Figure 1 and video files in the Supplementary Material). Table 1 Tortoise predation events. Full size table Figure 1 Tortoise predation. Chimpanzee handling and consuming a predated tortoise ©Théleste. Full size image All predation events were observed in periods of high fruit availability and in the dry season 23 (July 2016, May to October 2017, May to June 2018). We were able to observe 13 prey events from the discovery of the tortoise until meat consumption. The most frequent behavioural sequence observed consisted of: (1) discovering and capturing the prey, (2) smashing the plastron with one hand repeatedly against a wooden anvil (trunk: N = 9; for other anvils used see Table S1 ), and (3) climbing into a tree to consume the meat (N = 9; see detailed information in Table S1 ). The smashing mainly occurred in a horizontal manner against the anvil (N = 22). In six cases, the chimpanzee first transported the tortoise", "role": "user" }, { "content": "Scientists have observed wild chimpanzees tucking into an unusual snack: tortoises, whose hard shells they crack against tree trunks before scooping out the meat. In a paper published Thursday by the journal Scientific Reports, researchers from Germany say the behavior they spotted dozens of times in a group of chimpanzees at Loango National Park in Gabon bolsters the notion that humankind's distant cousins develop their own distinct cultures. Tobias Deschner, one of the authors of the paper, said that while chimpanzees and tortoises coexist elsewhere—and other primates such as baboons and mandrills are known to feed on young, soft tortoises—scientists have never before spotted any that crack open and eat the reptiles. One explanation could be that the Loango park region also has abundant hard-shelled fruit, like that from the strychnos tree, that also needs to be whacked against trees to open, prompting some enterprising chimpanzees to try the same on passing tortoises, he said. \"They see this is a hard-shelled object with some interesting thing inside and I need to crack it open,\" said Deschner, a primate researcher at the Max Planck Institute for Evolutionary Anthropology in Leipzig. \"If I can do that with the fruit and have the same problem with a hard-shelled animal with something inside that I want to get access to, then I can say 'OK, why not do it in exactly the same way?'\" Some scientists dispute the idea that chimpanzees are capable of this kind of mental leap, much less of passing the trick on to others in such a way that it becomes an established 'cultural practice' among the whole population. But Deschner and colleagues from the University of Osnabrueck said their observations in Loango suggest that's what happened. \"They all use exactly the same way of doing it,\" he said. \"This suggests to me that they really look at how others are doing it and then copy the movements.\" Other researchers agreed. \"This fits into previous observations that are interpreted as traditional behavior, which some have broadly described as culture,\" said Dietmar Zinner, a zoologist at the German Primate Center in Goettingen who wasn't involved in the study. The authors also noted that weaker chimpanzees often pass their tortoises to stronger adults who are able to break them open and then share the meal among the whole group. In one case, a male was even spotted eating half a tortoise, then tucking the shell it into a tree fork and coming back the next day to finish the leftovers, suggesting chimpanzees are capable of planning ahead, the authors said. Deschner said such acquired practices may be lost if particularly groups of chimpanzees are wiped out, even if the area they inhabited is repopulated again later. \"We see chimpanzees disappearing all over Africa due to habitat destruction and poaching,\" he said. \"What disappears there is not only sheer numbers but with each population that goes there is a unique culture that is lost.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Chimpanzees ( Pan troglodytes ), one of humankinds’ closest living relatives, are known to hunt and consume the meat of various animal taxa. Although some researchers have presented indirect evidence that chimpanzees may also prey on tortoises, until now, direct observations of this behaviour did not exist. Here, we provide systematic descriptions of the first observations of chimpanzee predation on tortoises ( Kinixys erosa ). We made these unprecedented observations on newly habituated chimpanzees ( Pan troglodytes troglodytes ) of the Rekambo community, living in the Loango National Park, Gabon. The behaviour qualified as customary, that is occurring in most or all adult males, involved a distinct smashing technique, and resulted frequently in food sharing with other group members. Our observations shed new light on the hitherto little understood percussive technology of chimpanzees, and expand our current knowledge on chimpanzees’ dietary and predatory repertoires with respect to reptiles. We also report a case of food storage and discuss it in the context of future-oriented cognition. Our findings suggest the need for more nuanced interpretations of chimpanzees’ cognitive skills in combination with an in-depth understanding of their unique socio-ecological niches. They further emphasize the importance of nonhuman primate field observations to inform theories of hominin evolution. Introduction The ability to use and manufacture tools, long thought to be uniquely human, has now been reported in a variety of species of birds (e.g., New Caledonian crows Corvus moneduloides ) 1 and mammals (e.g., sea otter Enhydra lutris 2 ; bottlenose dolphins Tursiops sp. 3 ). Scholars distinguish between tool-use and proto-tool use, although there is no evidence that proto-tool use is an evolutionary or ontogenetic precursor to tool use 4 . Tool use is defined as “the external employment of an unattached or manipulable attached environmental object to alter more efficiently the form, position, or condition of another object, another organism, or the user itself, when the user holds and directly manipulates the tool, during or prior to use, and is responsible for the proper and effective orientation of the tool” 4 , 5 (p. 5) (e.g., sea otter opening the shell of an abalone by pounding it on a stone that is balanced on the otter’s ventrum) 2 . Proto-tools, on the other hand, are functionally analogous to tools but are not held and directly manipulated during or prior to use (e.g., labrid fishes Cheilinus trilobatus and Coris angulata pound sea urchins on coral or stones to detach the spines and smash the exoskeletons). Compared to other nonhuman animals, chimpanzees ( Pan troglodytes ) have developed an exceptionally large and varied technological repertoire 6 , 7 . For instance, they deploy tools made from diverse plant sources to acquire social insects, and utilize spear-like tools to rouse prosimian prey from cavities 7 , 8 , 9 , 10 . In addition, they are known to use percussive technology, ranging from pounding open hard-shelled fruits ( Baobab sp. 11 , Strychnos sp. 12 ) and termite mounds 13 against substrates to pounding open nuts ( Coula edulis, Panda oleosa ) using hammers 14 , 15 . Some researchers have also suggested that chimpanzees employ percussive technology to prey on tortoises 16 , 17 , but direct evidence was, until now, non-existent. Concerning humans, the predation and consumption of tortoises has already been attributed to early hominins ( Homo erectus ; ≈ 1.9 mya ) 18 . Tortoises also represent an important food resource in the diet of present-day hunter-gatherer societies 19 , 20 . Here, we provide the first direct observations of tortoise predation in wild chimpanzees ( Pan troglodytes troglodytes ). The behaviour of individuals of the Rekambo community, Loango National Park (Gabon) was observed on a daily basis from July 2016 – May 2018. Tortoise predation events were, however, restricted to the dry season only. The behaviour is frequently shown by the majority of adult males of the Rekambo community, thereby qualifying as customary 7 . In addition, we report on a single case of food storage, in which an adult male tucked a half-eaten tortoise in a tree fork and retrieved it the next day to continue feeding. Our results shed new light on the percussive technology of chimpanzees. They also expand our current knowledge on the relatively broad dietary and predatory repertoires of these ecologically flexible omnivores to reptiles. Furthermore, although chimpanzees are renowned to frequently hunt and consume the meat of a variety of vertebrates (most heavily red colobus Piliocolobus spp., as well as black-and-white colobus monkeys Colobus spp., red-tailed guenons Cercopithecus ascanius , olive baboons Papio anubis , red duikers Cephalophus natalensis , and bushpigs Potomochoerus porcus ) 6 , 21 , 22 , food storage in primates has so far only been implicated for early hominins 16 . Results We observed 38 prey events (34 successful and four unsuccessful ones) on hinge-back tortoises ( Kinixys erosa ) by ten different chimpanzees (seven adult males, one adult female, one adolescent male, one adolescent female) of the Rekambo community in the Loango National Park, Gabon (see Table 1 , Figure 1 and video files in the Supplementary Material). Table 1 Tortoise predation events. Full size table Figure 1 Tortoise predation. Chimpanzee handling and consuming a predated tortoise ©Théleste. Full size image All predation events were observed in periods of high fruit availability and in the dry season 23 (July 2016, May to October 2017, May to June 2018). We were able to observe 13 prey events from the discovery of the tortoise until meat consumption. The most frequent behavioural sequence observed consisted of: (1) discovering and capturing the prey, (2) smashing the plastron with one hand repeatedly against a wooden anvil (trunk: N = 9; for other anvils used see Table S1 ), and (3) climbing into a tree to consume the meat (N = 9; see detailed information in Table S1 ). The smashing mainly occurred in a horizontal manner against the anvil (N = 22). In six cases, the chimpanzee first transported the tortoise<|im_end|> <|im_start|>assistant Scientists have observed wild chimpanzees tucking into an unusual snack: tortoises, whose hard shells they crack against tree trunks before scooping out the meat. In a paper published Thursday by the journal Scientific Reports, researchers from Germany say the behavior they spotted dozens of times in a group of chimpanzees at Loango National Park in Gabon bolsters the notion that humankind's distant cousins develop their own distinct cultures. Tobias Deschner, one of the authors of the paper, said that while chimpanzees and tortoises coexist elsewhere—and other primates such as baboons and mandrills are known to feed on young, soft tortoises—scientists have never before spotted any that crack open and eat the reptiles. One explanation could be that the Loango park region also has abundant hard-shelled fruit, like that from the strychnos tree, that also needs to be whacked against trees to open, prompting some enterprising chimpanzees to try the same on passing tortoises, he said. "They see this is a hard-shelled object with some interesting thing inside and I need to crack it open," said Deschner, a primate researcher at the Max Planck Institute for Evolutionary Anthropology in Leipzig. "If I can do that with the fruit and have the same problem with a hard-shelled animal with something inside that I want to get access to, then I can say 'OK, why not do it in exactly the same way?'" Some scientists dispute the idea that chimpanzees are capable of this kind of mental leap, much less of passing the trick on to others in such a way that it becomes an established 'cultural practice' among the whole population. But Deschner and colleagues from the University of Osnabrueck said their observations in Loango suggest that's what happened. "They all use exactly the same way of doing it," he said. "This suggests to me that they really look at how others are doing it and then copy the movements." Other researchers agreed. "This fits into previous observations that are interpreted as traditional behavior, which some have broadly described as culture," said Dietmar Zinner, a zoologist at the German Primate Center in Goettingen who wasn't involved in the study. The authors also noted that weaker chimpanzees often pass their tortoises to stronger adults who are able to break them open and then share the meal among the whole group. In one case, a male was even spotted eating half a tortoise, then tucking the shell it into a tree fork and coming back the next day to finish the leftovers, suggesting chimpanzees are capable of planning ahead, the authors said. Deschner said such acquired practices may be lost if particularly groups of chimpanzees are wiped out, even if the area they inhabited is repopulated again later. "We see chimpanzees disappearing all over Africa due to habitat destruction and poaching," he said. "What disappears there is not only sheer numbers but with each population that goes there is a unique culture that is lost." <|im_end|>

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6200, 1094, 2392, 8348, 6200, 1094, 2392, 7609, 578, 17432, 315, 7931, 315, 279, 125709, 309, 754, 4029, 11, 6621, 5281, 5165, 5657, 320, 75739, 263, 8, 574, 13468, 389, 264, 7446, 8197, 505, 5887, 220, 679, 21, 1389, 3297, 220, 679, 23, 13, 56927, 69289, 4255, 367, 4455, 1051, 11, 4869, 11, 22486, 311, 279, 9235, 3280, 1193, 13, 578, 17432, 374, 14134, 6982, 555, 279, 8857, 315, 6822, 25000, 315, 279, 125709, 309, 754, 4029, 11, 28592, 37214, 439, 73348, 220, 22, 662, 763, 5369, 11, 584, 1934, 389, 264, 3254, 1162, 315, 3691, 5942, 11, 304, 902, 459, 6822, 8762, 61218, 264, 4376, 5773, 13827, 16831, 69289, 304, 264, 5021, 23243, 323, 31503, 433, 279, 1828, 1938, 311, 3136, 26040, 13, 5751, 3135, 25351, 502, 3177, 389, 279, 44563, 1892, 535, 5557, 315, 99425, 3059, 288, 13, 2435, 1101, 9407, 1057, 1510, 6677, 389, 279, 12309, 7353, 34625, 323, 88170, 2109, 14200, 3946, 315, 1521, 12208, 30450, 19303, 50197, 344, 4692, 311, 64873, 3742, 13, 24296, 11, 8051, 99425, 3059, 288, 527, 37048, 311, 14134, 19614, 323, 25024, 279, 13339, 315, 264, 8205, 315, 67861, 99868, 320, 3646, 17345, 2579, 1400, 126218, 393, 4008, 4650, 126218, 91799, 2637, 439, 1664, 439, 3776, 9976, 16237, 1400, 126218, 61820, 4349, 126218, 91799, 2637, 2579, 2442, 5805, 1709, 268, 2439, 356, 3035, 454, 275, 42750, 355, 439, 4919, 9334, 1174, 33213, 16993, 29639, 32743, 822, 459, 392, 285, 1174, 2579, 3930, 54213, 356, 752, 12130, 5237, 355, 308, 4306, 87778, 1174, 323, 30773, 79, 14801, 14020, 16279, 971, 46109, 4247, 57440, 883, 220, 21, 1174, 220, 1691, 1174, 220, 1313, 1174, 3691, 5942, 304, 9036, 988, 706, 779, 3117, 1193, 1027, 69702, 369, 4216, 5105, 258, 1354, 220, 845, 662, 18591, 1226, 13468, 220, 1987, 37693, 4455, 320, 1958, 6992, 323, 3116, 46025, 6305, 8, 389, 76693, 15825, 16831, 78, 5014, 320, 31991, 953, 1065, 2781, 12252, 883, 555, 5899, 2204, 99425, 3059, 288, 320, 81285, 6822, 25000, 11, 832, 6822, 8954, 11, 832, 36088, 8762, 11, 832, 36088, 8954, 8, 315, 279, 125709, 309, 754, 4029, 304, 279, 6621, 5281, 5165, 5657, 11, 24664, 263, 320, 4151, 6771, 220, 16, 1174, 19575, 220, 16, 323, 2835, 3626, 304, 279, 99371, 10441, 570, 6771, 220, 16, 56927, 69289, 4255, 367, 4455, 13, 8797, 1404, 2007, 19575, 220, 16, 56927, 69289, 4255, 367, 13, 82548, 857, 99066, 11850, 323, 35208, 264, 864, 3661, 16831, 69289, 7388, 1016, 978, 273, 5455, 13, 8797, 1404, 2217, 2052, 4255, 367, 4455, 1051, 13468, 304, 18852, 315, 1579, 14098, 18539, 323, 304, 279, 9235, 3280, 220, 1419, 320, 29527, 220, 679, 21, 11, 3297, 311, 6664, 220, 679, 22, 11, 3297, 311, 5651, 220, 679, 23, 570, 1226, 1051, 3025, 311, 23846, 220, 1032, 37693, 4455, 505, 279, 18841, 315, 279, 16831, 69289, 3156, 13339, 15652, 13, 578, 1455, 21420, 88979, 8668, 13468, 44660, 315, 25, 320, 16, 8, 42687, 323, 40880, 279, 37693, 11, 320, 17, 8, 83588, 279, 628, 21100, 263, 449, 832, 1450, 19352, 2403, 264, 23162, 459, 46352, 320, 376, 3200, 25, 452, 284, 220, 24, 26, 369, 1023, 60581, 8839, 1511, 1518, 6771, 328, 16, 7026, 323, 320, 18, 8, 30608, 1139, 264, 5021, 311, 25024, 279, 13339, 320, 45, 284, 220, 24, 26, 1518, 11944, 2038, 304, 6771, 328, 16, 7609, 578, 83588, 14918, 10222, 304, 264, 16600, 11827, 2403, 279, 459, 46352, 320, 45, 284, 220, 1313, 570, 763, 4848, 5157, 11, 279, 99425, 99066, 1176, 40460, 279, 16831, 69289, 128257, 198, 128256, 78191, 198, 72326, 617, 13468, 8545, 99425, 3059, 288, 259, 47270, 1139, 459, 19018, 40459, 25, 16831, 78, 5014, 11, 6832, 2653, 44054, 814, 17944, 2403, 5021, 490, 15655, 1603, 25661, 34807, 704, 279, 13339, 13, 763, 264, 5684, 4756, 7950, 555, 279, 8486, 38130, 29140, 11, 12074, 505, 10057, 2019, 279, 7865, 814, 30652, 22700, 315, 3115, 304, 264, 1912, 315, 99425, 3059, 288, 520, 6621, 5281, 5165, 5657, 304, 24664, 263, 21434, 12855, 279, 23035, 430, 2854, 70370, 596, 29827, 61007, 2274, 872, 1866, 12742, 27833, 13, 80102, 3959, 86677, 11, 832, 315, 279, 12283, 315, 279, 5684, 11, 1071, 430, 1418, 99425, 3059, 288, 323, 16831, 78, 5014, 1080, 29675, 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1243, 358, 649, 2019, 364, 4012, 11, 3249, 539, 656, 433, 304, 7041, 279, 1890, 1648, 30, 15260, 4427, 14248, 26086, 279, 4623, 430, 99425, 3059, 288, 527, 13171, 315, 420, 3169, 315, 10723, 32571, 11, 1790, 2753, 315, 12579, 279, 14397, 389, 311, 3885, 304, 1778, 264, 1648, 430, 433, 9221, 459, 9749, 364, 66, 44547, 6725, 6, 4315, 279, 4459, 7187, 13, 2030, 3959, 86677, 323, 18105, 505, 279, 3907, 315, 507, 9810, 78671, 361, 377, 1071, 872, 24654, 304, 6621, 5281, 4284, 430, 596, 1148, 7077, 13, 330, 7009, 682, 1005, 7041, 279, 1890, 1648, 315, 3815, 433, 1359, 568, 1071, 13, 330, 2028, 13533, 311, 757, 430, 814, 2216, 1427, 520, 1268, 3885, 527, 3815, 433, 323, 1243, 3048, 279, 19567, 1210, 7089, 12074, 7378, 13, 330, 2028, 18809, 1139, 3766, 24654, 430, 527, 33398, 439, 8776, 7865, 11, 902, 1063, 617, 44029, 7633, 439, 7829, 1359, 1071, 27304, 5730, 1901, 4481, 11, 264, 19263, 16549, 520, 279, 6063, 2394, 3509, 5955, 304, 6122, 52189, 268, 889, 5828, 956, 6532, 304, 279, 4007, 13, 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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 Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults ( N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort ( N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets. Main PVS are physiological spaces surrounding small vessel walls as they run from the subarachnoid space through the brain parenchyma 1 , 2 , 3 . Dilation of PVS observed on brain magnetic resonance imaging (MRI) is thought to be a marker of PVS dysfunction and, speculated from preclinical studies, to reflect impairment of brain fluid and waste clearance 2 , 4 . PVS increase in number with age and vascular risk factors, especially hypertension 2 . They are associated with white matter hyperintensities (WMH) of presumed vascular origin, lacunes and cerebral microbleeds 2 , all MRI features of cerebral small vessel disease (cSVD), a leading cause of stroke and dementia with no specific mechanistic treatment to date 5 , 6 . PVS are detected on brain MRI much earlier than WMH, lacunes or cerebral microbleeds 7 , and are described as the earliest stage of cSVD lesions on neuropathology 8 . Their pathophysiology is poorly understood 6 , 9 . In experimental models, PVS appear to be important conduits for substrate delivery, flushing interstitial fluid, clearing metabolic waste (for example, beta-amyloid peptide) and brain fluid regulation, as part of the ‘glymphatic system’ 4 , 7 . These processes were described to increase during sleep 2 , 4 , 7 . Mounting evidence suggests a major role of PVS in cerebral injury. Several studies suggested associations of PVS burden (number of visible PVS on brain MRI) with stroke 2 , 6 , 10 , Alzheimer’s disease pathology 2 and cerebral amyloid angiopathy (CAA) 11 , 12 , 13 . Post-stroke edema has been linked to post-stroke PVS enlargement 14 , and in amyotrophic lateral sclerosis PVS dilation was observed and perivascular fibroblast proteins were associated with survival 15 . PVS burden is highly heritable 16 . Identifying genetic risk variants for PVS could be a powerful tool to decipher underlying biological pathways. We conducted genome-wide association study (GWAS) meta-analyses and whole-exome/whole-genome sequencing (WES/WGS) studies of extensive PVS burden in up to 40,095 and 19,010 older community participants, respectively. Given differential associations with risk factors and neurological traits 2 , 10 , 17 and anatomical differences 18 , we ran analyses separately for white matter (WM)-PVS, basal ganglia (BG)-PVS and hippocampal (HIP)-PVS. We followed up identified risk loci in independent samples of young healthy adults and older Japanese community participants and examined shared genetic determinants with other vascular and neurological traits. Leveraging tissue and cell-specific gene expression databases and drug target libraries, we conducted extensive bioinformatics exploration of identified PVS risk loci. Results Genetic discovery Twenty-one population-based cohorts were included, of which 18 were for GWAS and 8 for whole-exome association studies (Supplementary Table 1 and Methods ). We tested associations of extensive PVS burden with ~8 million single-nucleotide polymorphisms (SNPs) (minor allele frequency (MAF) ≥ 1%) in GWAS meta-analyses, gathering up to 40,095 participants (66.3 ± 8.6 yr, 51.7% female, 66.7% with hypertension; Supplementary Tables 1 – 3 ). We dichotomized PVS burden based on cut-offs closest to the top quartile of PVS distribution to account for differences in PVS quantification methods, image acquisition and participant characteristics (Supplementary Tables 1 and 2 and Methods ). In total, 9,607 of 39,822, 9,189 of 40,000, and 9,339 of 40,095 participants had extensive PVS burden in WM, BG and hippocampus. The GWAS meta-analysis comprised 17 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium ( N ≤ 11,511) 19 , with PVS quantification primarily on visual rating scales, and UK Biobank (UKB, N ≤ 28,655), with computational PVS quantification ( Methods ). Participants were of European ( N = 38,871), Hispanic ( N = 717), East-Asian ( N = 339) and African-American ( N = 168) ancestry. We identified 22 independent genome-wide significant risk loci for extensive PVS burden (WM-PVS: 19; BG-PVS: 2; HIP-PVS: 3 (2 shared with WM-PVS)) and two additional risk loci for WM-PVS in Europeans only, leading to 24 independent signals (Table 1 , Fig. 1 , Extended Data Fig. 1 and Supplementary Fig. 1 ). There was no systematic inflation of association statistics (Supplementary Table 4 and Extended Data Fig. 1 ). Table 1 Genetic variants associated with high PVS burden Full size table Fig. 1: Illustration of extensive PVS burden and results of the cross-ancestry PVS GWAS meta-analysis, MTAG analysis and gene-based test. a , Extensive PVS burden (arrows) in WM (top, WM-PVS), BG (middle, BG-PVS) and hippocampus (bottom, HIP-PVS) on T1-weighted axial magnetic resonance images. b , Circular Manhattan plot. The inner circle corresponds to the cross-ancestry GWAS meta-analyses results, the middle circle to the results of the MTAG analysis and the outer circle to gene-based test results. Results for WM-PVS are in blue, for BG-PVS in purple and for HIP-PVS in green. The gray line corresponds to the genome-wide significance threshold ( P = 5 × 10 −8 , two-sided, correcting for multiple testing", "role": "user" }, { "content": "An international team of 79 researchers have collaborated on a study published in Nature Medicine to delve into perivascular spaces (PVS), a poorly understood artifact seen in magnetic resonance imaging of cerebral small vessel disease, a leading cause of stroke and dementia. In the study, \"Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease,\" researchers employed a genome-wide association study of 40,095 participants with brain imaging data in 18 population-based cohorts (66.3 ± 8.6 yr, 96.9% European ancestry). The analysis revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These loci were already associated with white matter PVS in young adults (N = 1,748; 22.1 ± 2.3 yr) and enriched in early-onset leukodystrophy (abnormal growth of white matter) genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. A Research Briefing discussing the findings has been published in the same journal issue. PVS are physiological spaces surrounding small vessel walls running from the subarachnoid space through the brain parenchyma. In experimental models, PVS appear to be important conduits for substrate delivery, flushing interstitial fluid, clearing metabolic waste like beta-amyloid peptide, and is involved in brain fluid regulation as part of the \"glymphatic system.\" Mounting evidence suggests a major role of PVS in cerebral injury, stroke, and dementia. Dilation of PVS observed on brain magnetic resonance imaging is thought to be a marker of dysfunction and is speculated to reflect impairment of brain fluid and waste clearance. The incidences of PVS increase with age and vascular risk factors like hypertension, and they are associated with a host of white matter and vascular-related brain diseases. Several studies have also suggested associations with the number of visible PVS on brain MRI with stroke, Alzheimer's disease and cerebral amyloid angiopathy. Post-stroke edema has been linked to post-stroke PVS enlargement. Researchers conducted a genome-wide association study (GWAS) meta-analyses with 40,095 participants and whole-exome/whole-genome sequencing (WES/WGS) of another 19,010. They ran analyses separately for white matter (WM)-PVS, basal ganglia (BG)-PVS and hippocampal (HIP)-PVS. With a decent data set collected, the bioinformatics exploration delved into tissue and cell-specific gene expression databases and drug target libraries of identified PVS risk loci. The study identified 24 independent genome-wide significant risk loci for extensive PVS burden. Two-thirds of PVS risk loci point to pathways not mediated by established risk factors and involve the extracellular matrix, the blood-brain barrier, membrane transport and vascular development. There was significant evidence for causal associations between high blood pressure and PVS and between PVS and stroke for BG. Significant enrichment of PVS loci in genes involved in early-onset leukodystrophies and expressed in fetal brain vascular endothelial cells suggests the involvement of developmental processes and in previously investigated targets of drugs for vascular and cognitive disorders. The researchers conclude that the study findings \"...provide insight into the biology of PVS across the adult lifespan and its contribution to cerebral small vessel disease pathophysiology, with potential for genetically informed prioritization of drug targets for prevention trials of cerebral small vessel disease, a major cause of stroke and dementia worldwide.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults ( N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort ( N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets. Main PVS are physiological spaces surrounding small vessel walls as they run from the subarachnoid space through the brain parenchyma 1 , 2 , 3 . Dilation of PVS observed on brain magnetic resonance imaging (MRI) is thought to be a marker of PVS dysfunction and, speculated from preclinical studies, to reflect impairment of brain fluid and waste clearance 2 , 4 . PVS increase in number with age and vascular risk factors, especially hypertension 2 . They are associated with white matter hyperintensities (WMH) of presumed vascular origin, lacunes and cerebral microbleeds 2 , all MRI features of cerebral small vessel disease (cSVD), a leading cause of stroke and dementia with no specific mechanistic treatment to date 5 , 6 . PVS are detected on brain MRI much earlier than WMH, lacunes or cerebral microbleeds 7 , and are described as the earliest stage of cSVD lesions on neuropathology 8 . Their pathophysiology is poorly understood 6 , 9 . In experimental models, PVS appear to be important conduits for substrate delivery, flushing interstitial fluid, clearing metabolic waste (for example, beta-amyloid peptide) and brain fluid regulation, as part of the ‘glymphatic system’ 4 , 7 . These processes were described to increase during sleep 2 , 4 , 7 . Mounting evidence suggests a major role of PVS in cerebral injury. Several studies suggested associations of PVS burden (number of visible PVS on brain MRI) with stroke 2 , 6 , 10 , Alzheimer’s disease pathology 2 and cerebral amyloid angiopathy (CAA) 11 , 12 , 13 . Post-stroke edema has been linked to post-stroke PVS enlargement 14 , and in amyotrophic lateral sclerosis PVS dilation was observed and perivascular fibroblast proteins were associated with survival 15 . PVS burden is highly heritable 16 . Identifying genetic risk variants for PVS could be a powerful tool to decipher underlying biological pathways. We conducted genome-wide association study (GWAS) meta-analyses and whole-exome/whole-genome sequencing (WES/WGS) studies of extensive PVS burden in up to 40,095 and 19,010 older community participants, respectively. Given differential associations with risk factors and neurological traits 2 , 10 , 17 and anatomical differences 18 , we ran analyses separately for white matter (WM)-PVS, basal ganglia (BG)-PVS and hippocampal (HIP)-PVS. We followed up identified risk loci in independent samples of young healthy adults and older Japanese community participants and examined shared genetic determinants with other vascular and neurological traits. Leveraging tissue and cell-specific gene expression databases and drug target libraries, we conducted extensive bioinformatics exploration of identified PVS risk loci. Results Genetic discovery Twenty-one population-based cohorts were included, of which 18 were for GWAS and 8 for whole-exome association studies (Supplementary Table 1 and Methods ). We tested associations of extensive PVS burden with ~8 million single-nucleotide polymorphisms (SNPs) (minor allele frequency (MAF) ≥ 1%) in GWAS meta-analyses, gathering up to 40,095 participants (66.3 ± 8.6 yr, 51.7% female, 66.7% with hypertension; Supplementary Tables 1 – 3 ). We dichotomized PVS burden based on cut-offs closest to the top quartile of PVS distribution to account for differences in PVS quantification methods, image acquisition and participant characteristics (Supplementary Tables 1 and 2 and Methods ). In total, 9,607 of 39,822, 9,189 of 40,000, and 9,339 of 40,095 participants had extensive PVS burden in WM, BG and hippocampus. The GWAS meta-analysis comprised 17 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium ( N ≤ 11,511) 19 , with PVS quantification primarily on visual rating scales, and UK Biobank (UKB, N ≤ 28,655), with computational PVS quantification ( Methods ). Participants were of European ( N = 38,871), Hispanic ( N = 717), East-Asian ( N = 339) and African-American ( N = 168) ancestry. We identified 22 independent genome-wide significant risk loci for extensive PVS burden (WM-PVS: 19; BG-PVS: 2; HIP-PVS: 3 (2 shared with WM-PVS)) and two additional risk loci for WM-PVS in Europeans only, leading to 24 independent signals (Table 1 , Fig. 1 , Extended Data Fig. 1 and Supplementary Fig. 1 ). There was no systematic inflation of association statistics (Supplementary Table 4 and Extended Data Fig. 1 ). Table 1 Genetic variants associated with high PVS burden Full size table Fig. 1: Illustration of extensive PVS burden and results of the cross-ancestry PVS GWAS meta-analysis, MTAG analysis and gene-based test. a , Extensive PVS burden (arrows) in WM (top, WM-PVS), BG (middle, BG-PVS) and hippocampus (bottom, HIP-PVS) on T1-weighted axial magnetic resonance images. b , Circular Manhattan plot. The inner circle corresponds to the cross-ancestry GWAS meta-analyses results, the middle circle to the results of the MTAG analysis and the outer circle to gene-based test results. Results for WM-PVS are in blue, for BG-PVS in purple and for HIP-PVS in green. The gray line corresponds to the genome-wide significance threshold ( P = 5 × 10 −8 , two-sided, correcting for multiple testing<|im_end|> <|im_start|>assistant An international team of 79 researchers have collaborated on a study published in Nature Medicine to delve into perivascular spaces (PVS), a poorly understood artifact seen in magnetic resonance imaging of cerebral small vessel disease, a leading cause of stroke and dementia. In the study, "Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease," researchers employed a genome-wide association study of 40,095 participants with brain imaging data in 18 population-based cohorts (66.3 ± 8.6 yr, 96.9% European ancestry). The analysis revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These loci were already associated with white matter PVS in young adults (N = 1,748; 22.1 ± 2.3 yr) and enriched in early-onset leukodystrophy (abnormal growth of white matter) genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. A Research Briefing discussing the findings has been published in the same journal issue. PVS are physiological spaces surrounding small vessel walls running from the subarachnoid space through the brain parenchyma. In experimental models, PVS appear to be important conduits for substrate delivery, flushing interstitial fluid, clearing metabolic waste like beta-amyloid peptide, and is involved in brain fluid regulation as part of the "glymphatic system." Mounting evidence suggests a major role of PVS in cerebral injury, stroke, and dementia. Dilation of PVS observed on brain magnetic resonance imaging is thought to be a marker of dysfunction and is speculated to reflect impairment of brain fluid and waste clearance. The incidences of PVS increase with age and vascular risk factors like hypertension, and they are associated with a host of white matter and vascular-related brain diseases. Several studies have also suggested associations with the number of visible PVS on brain MRI with stroke, Alzheimer's disease and cerebral amyloid angiopathy. Post-stroke edema has been linked to post-stroke PVS enlargement. Researchers conducted a genome-wide association study (GWAS) meta-analyses with 40,095 participants and whole-exome/whole-genome sequencing (WES/WGS) of another 19,010. They ran analyses separately for white matter (WM)-PVS, basal ganglia (BG)-PVS and hippocampal (HIP)-PVS. With a decent data set collected, the bioinformatics exploration delved into tissue and cell-specific gene expression databases and drug target libraries of identified PVS risk loci. The study identified 24 independent genome-wide significant risk loci for extensive PVS burden. Two-thirds of PVS risk loci point to pathways not mediated by established risk factors and involve the extracellular matrix, the blood-brain barrier, membrane transport and vascular development. There was significant evidence for causal associations between high blood pressure and PVS and between PVS and stroke for BG. Significant enrichment of PVS loci in genes involved in early-onset leukodystrophies and expressed in fetal brain vascular endothelial cells suggests the involvement of developmental processes and in previously investigated targets of drugs for vascular and cognitive disorders. The researchers conclude that the study findings "...provide insight into the biology of PVS across the adult lifespan and its contribution to cerebral small vessel disease pathophysiology, with potential for genetically informed prioritization of drug targets for prevention trials of cerebral small vessel disease, a major cause of stroke and dementia worldwide." <|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 Fossil amber offers the opportunity to investigate the dynamics of glass-forming materials far below the nominal glass transition temperature. This is important in the context of classical theory, as well as some new theories that challenge the idea of an ‘ideal’ glass transition. Here we report results from calorimetric and stress relaxation experiments using a 20-million-year-old Dominican amber. By performing the stress relaxation experiments in a step-wise fashion, we measured the relaxation time at each temperature and, above the fictive temperature of this 20-million-year-old glass, this is an upper bound to the equilibrium relaxation time. The results deviate dramatically from the expectation of classical theory and are consistent with some modern ideas, in which the diverging timescale signature of complex fluids disappears below the glass transition temperature. Introduction P.W. Anderson said in 1995 ‘The deepest and most interesting unsolved problem in solid state theory is probably the theory of the nature of glass and the glass transition. 1 ’ This remains to be true and in the present work, we use measurements of the calorimetric and dynamic properties of an extremely stable fossil amber glass to provide new insights into the fundamentals of the nature of glass-forming materials. Vogel–Fulcher–Tammann (VFT) 2 , 3 , 4 behaviour is a classic signature of glass-forming or complex systems, and describes their equilibrium dynamics as following a super-Arrhenius behaviour that diverges at a finite temperature 5 , 6 . However, classic models 7 , 8 and some modern models 9 that predict such VFT-like behaviour have been challenged by new evidence from both theoretical 10 , 11 , 12 , 13 , 14 and experimental 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 works, which contradict such a finite temperature divergence. The difficulty of directly addressing the VFT behaviour experimentally arises owing to the ‘geological’ ages 23 required to attain equilibrium far below the glass transition temperature T g . Prior direct 15 , 16 , 17 , 18 interrogation of the equilibrium dynamics was limited to <16 °C below the T g . The VFT function describes the temperature dependence of material viscosity η or relaxation time τ : where η 0 , τ 0 , B and T ∞ are material-dependent constants. T ∞ defines the divergent point for the viscosity or relaxation time and is often related to the Kauzmann temperature 24 , which is thought to be related to the ‘ideal’ glass temperature 25 . Determining the equilibrium behaviour of a glass-forming system far below the conventional glass transition temperature has been a problem that dates at least since the time of Kauzmann 24 owing to the fact that the relaxation times grow extremely rapidly as the temperature is lowered—the previously referred to ‘geologic’ age problem 23 . While there has been some work to try to investigate the thermodynamics via extrapolation methods 26 , the dynamics remain elusive. The traditional method of addressing the sub- T g dynamics is to quench a sample from above T g to the temperature of interest and age it isothermally until it reaches equilibrium. 15 , 16 , 17 , 18 Then the equilibrium relaxation time can be determined as a function of temperature. However, this kind of measurement cannot obtain data far below T g owing to the (apparently) super-Arrhenius increase in times for the non-equilibrium glass to age into equilibrium, for example, 12 days for the mechanical response 8 K below the T g 16 . In the present work, an extremely stable (20 million year) Dominican fossil amber 27 is used to establish upper bounds on the equilibrium dynamics of a glass-forming material at temperatures to 43.6 °C below the conventional T g —sufficient to discriminate between the VFT function and the upper bounds to the equilibrium dynamics and even among non-diverging models 10 , 11 , 12 , 13 . The findings that these upper bounds deviate strongly from the ‘classical’ Vogel–Fulcher behaviour challenge classic theories 2 , 3 , 4 , 7 , 8 , some modern theories 9 and are consistent with the non-diverging models 10 , 11 , 12 , 13 . Results Amber sample In this work, a 20 million year (Ma) old fossil resin 27 from the Dominican Republic ( Fig. 1a ) was used to study the diverging (or not) dynamics, and the torsion rectangular mode was used to determine the stress relaxation response using a rheometer. Figure 1b shows an amber sample in the testing fixtures. Figure 1: Images of old amber. ( a ) As-received Dominican amber before machining. ( b ) Rectangular amber sample in rheometer fixtures. Full size image The advantage of this Miocene amber compared with a normal glass-forming substance is that it has a very long-aging history at ambient conditions. This long-aging history, regardless of the full details, leads to a highly densified material 28 , which can be used to test the diverging (or not) dynamics described above. Hydrostatic weighing was used here to measure the density difference at room temperature for the 20-Ma-old amber and the same amber after thermal rejuvenation by heating to above T g followed by cooling to room temperature at 10 K min −1 . The 20-Ma-old amber has 2.1% higher density than the latter. Figure 2 shows a schematic of the amber volume or enthalpy beginning with ambient temperature. Importantly, even after 20 Ma, the material has not aged into equilibrium. However, as shown in the figure, as temperature is increased the volume (or enthalpy H) increases and eventually intersects with the equilibrium liquid-state extrapolated parameter. At temperatures below this intersection ( H > H eq ), the relaxation times measured should be shorter than the equilibrium times owing to the excess of volume or enthalpy relative to the equilibrium state 29 . Once the equilibrium line is crossed, as temperature increases further, the glass is in a state of lower volume or enthalpy than the equilibrium value ( H < H", "role": "user" }, { "content": "(Phys.org) —Fact or fiction? Stained glass found in medieval cathedrals becomes thicker at the bottom because glass moves over time. For years researchers have had their doubts, now a team at Texas Tech University has further evidence that the glass is not going anywhere. \"Glass transition is related to the performance of materials, whether it is inorganic glass or organic polymers,\" said Gregory McKenna, professor of chemical engineering at Texas Tech. \"For example, this would be important to people who own a boat made of fiberglass, or fly in an airplane made with epoxy-based composites. Information like that can help predict if that jet will still be flying in 30 years.\" The idea for this research came from a doctoral student's qualifying exam, McKenna said. He gave Jing Zhao a problem relating to diverging time-scales using polyvinyl acetate, a substance often found in adhesives. Her results were consistent with a lack of divergence – contrary to received thought. So they decided to up the ante by performing similar experiments on a much older, ultra-stable glass. They chose 20-million-year-old Dominican amber, and together with Whitacre Department Chair and Horn Professor Sindee Simon, Zhao performed calorimetric and stress relaxation experiments on the samples. \"What we found is that the amber relaxation times did not diverge,\" McKenna said. \"This result challenges all the classic theories of glass transition behavior.\" This research is supported by the National Science Foundation under a grant from the Division of Materials Research, Polymers Program. The process and results were recently published in Nature Communications. Meanwhile, McKenna has recently acquired additional samples from around the world, including 220-million-year-old Triassic amber from Eugenio Ragazzi, a pharmacology professor at the University of Padova in Italy. The team now has plans to perform similar experiments on the new samples. \"We are in the very early stages,\" McKenna said. \"However, our research definitely is 'to be continued.'\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Fossil amber offers the opportunity to investigate the dynamics of glass-forming materials far below the nominal glass transition temperature. This is important in the context of classical theory, as well as some new theories that challenge the idea of an ‘ideal’ glass transition. Here we report results from calorimetric and stress relaxation experiments using a 20-million-year-old Dominican amber. By performing the stress relaxation experiments in a step-wise fashion, we measured the relaxation time at each temperature and, above the fictive temperature of this 20-million-year-old glass, this is an upper bound to the equilibrium relaxation time. The results deviate dramatically from the expectation of classical theory and are consistent with some modern ideas, in which the diverging timescale signature of complex fluids disappears below the glass transition temperature. Introduction P.W. Anderson said in 1995 ‘The deepest and most interesting unsolved problem in solid state theory is probably the theory of the nature of glass and the glass transition. 1 ’ This remains to be true and in the present work, we use measurements of the calorimetric and dynamic properties of an extremely stable fossil amber glass to provide new insights into the fundamentals of the nature of glass-forming materials. Vogel–Fulcher–Tammann (VFT) 2 , 3 , 4 behaviour is a classic signature of glass-forming or complex systems, and describes their equilibrium dynamics as following a super-Arrhenius behaviour that diverges at a finite temperature 5 , 6 . However, classic models 7 , 8 and some modern models 9 that predict such VFT-like behaviour have been challenged by new evidence from both theoretical 10 , 11 , 12 , 13 , 14 and experimental 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 works, which contradict such a finite temperature divergence. The difficulty of directly addressing the VFT behaviour experimentally arises owing to the ‘geological’ ages 23 required to attain equilibrium far below the glass transition temperature T g . Prior direct 15 , 16 , 17 , 18 interrogation of the equilibrium dynamics was limited to <16 °C below the T g . The VFT function describes the temperature dependence of material viscosity η or relaxation time τ : where η 0 , τ 0 , B and T ∞ are material-dependent constants. T ∞ defines the divergent point for the viscosity or relaxation time and is often related to the Kauzmann temperature 24 , which is thought to be related to the ‘ideal’ glass temperature 25 . Determining the equilibrium behaviour of a glass-forming system far below the conventional glass transition temperature has been a problem that dates at least since the time of Kauzmann 24 owing to the fact that the relaxation times grow extremely rapidly as the temperature is lowered—the previously referred to ‘geologic’ age problem 23 . While there has been some work to try to investigate the thermodynamics via extrapolation methods 26 , the dynamics remain elusive. The traditional method of addressing the sub- T g dynamics is to quench a sample from above T g to the temperature of interest and age it isothermally until it reaches equilibrium. 15 , 16 , 17 , 18 Then the equilibrium relaxation time can be determined as a function of temperature. However, this kind of measurement cannot obtain data far below T g owing to the (apparently) super-Arrhenius increase in times for the non-equilibrium glass to age into equilibrium, for example, 12 days for the mechanical response 8 K below the T g 16 . In the present work, an extremely stable (20 million year) Dominican fossil amber 27 is used to establish upper bounds on the equilibrium dynamics of a glass-forming material at temperatures to 43.6 °C below the conventional T g —sufficient to discriminate between the VFT function and the upper bounds to the equilibrium dynamics and even among non-diverging models 10 , 11 , 12 , 13 . The findings that these upper bounds deviate strongly from the ‘classical’ Vogel–Fulcher behaviour challenge classic theories 2 , 3 , 4 , 7 , 8 , some modern theories 9 and are consistent with the non-diverging models 10 , 11 , 12 , 13 . Results Amber sample In this work, a 20 million year (Ma) old fossil resin 27 from the Dominican Republic ( Fig. 1a ) was used to study the diverging (or not) dynamics, and the torsion rectangular mode was used to determine the stress relaxation response using a rheometer. Figure 1b shows an amber sample in the testing fixtures. Figure 1: Images of old amber. ( a ) As-received Dominican amber before machining. ( b ) Rectangular amber sample in rheometer fixtures. Full size image The advantage of this Miocene amber compared with a normal glass-forming substance is that it has a very long-aging history at ambient conditions. This long-aging history, regardless of the full details, leads to a highly densified material 28 , which can be used to test the diverging (or not) dynamics described above. Hydrostatic weighing was used here to measure the density difference at room temperature for the 20-Ma-old amber and the same amber after thermal rejuvenation by heating to above T g followed by cooling to room temperature at 10 K min −1 . The 20-Ma-old amber has 2.1% higher density than the latter. Figure 2 shows a schematic of the amber volume or enthalpy beginning with ambient temperature. Importantly, even after 20 Ma, the material has not aged into equilibrium. However, as shown in the figure, as temperature is increased the volume (or enthalpy H) increases and eventually intersects with the equilibrium liquid-state extrapolated parameter. At temperatures below this intersection ( H > H eq ), the relaxation times measured should be shorter than the equilibrium times owing to the excess of volume or enthalpy relative to the equilibrium state 29 . Once the equilibrium line is crossed, as temperature increases further, the glass is in a state of lower volume or enthalpy than the equilibrium value ( H < H<|im_end|> <|im_start|>assistant (Phys.org) —Fact or fiction? Stained glass found in medieval cathedrals becomes thicker at the bottom because glass moves over time. For years researchers have had their doubts, now a team at Texas Tech University has further evidence that the glass is not going anywhere. "Glass transition is related to the performance of materials, whether it is inorganic glass or organic polymers," said Gregory McKenna, professor of chemical engineering at Texas Tech. "For example, this would be important to people who own a boat made of fiberglass, or fly in an airplane made with epoxy-based composites. Information like that can help predict if that jet will still be flying in 30 years." The idea for this research came from a doctoral student's qualifying exam, McKenna said. He gave Jing Zhao a problem relating to diverging time-scales using polyvinyl acetate, a substance often found in adhesives. Her results were consistent with a lack of divergence – contrary to received thought. So they decided to up the ante by performing similar experiments on a much older, ultra-stable glass. They chose 20-million-year-old Dominican amber, and together with Whitacre Department Chair and Horn Professor Sindee Simon, Zhao performed calorimetric and stress relaxation experiments on the samples. "What we found is that the amber relaxation times did not diverge," McKenna said. "This result challenges all the classic theories of glass transition behavior." This research is supported by the National Science Foundation under a grant from the Division of Materials Research, Polymers Program. The process and results were recently published in Nature Communications. Meanwhile, McKenna has recently acquired additional samples from around the world, including 220-million-year-old Triassic amber from Eugenio Ragazzi, a pharmacology professor at the University of Padova in Italy. The team now has plans to perform similar experiments on the new samples. "We are in the very early stages," McKenna said. "However, our research definitely is 'to be continued.'" <|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 One of the grand challenges in chemistry is the construction of functional out-of-equilibrium networks, which are typical of living cells. Building such a system from molecular components requires control over the formation and degradation of the interacting chemicals and homeostasis of the internal physical-chemical conditions. The provision and consumption of ATP lies at the heart of this challenge. Here we report the in vitro construction of a pathway in vesicles for sustained ATP production that is maintained away from equilibrium by control of energy dissipation. We maintain a constant level of ATP with varying load on the system. The pathway enables us to control the transmembrane fluxes of osmolytes and to demonstrate basic physicochemical homeostasis. Our work demonstrates metabolic energy conservation and cell volume regulatory mechanisms in a cell-like system at a level of complexity minimally needed for life. Introduction The generation and consumption of ATP lies at the heart of life. Complex networks of proteins, nucleic acids and small molecules sustain the essential processes of gene expression and cell division that characterize living cells, but without ATP they are non-functional. Herein lies one of the major challenges in the construction of synthetic cell-like systems. Other processes, such as achieving tunable DNA replication, efficient transcription and translation, and vesicle division 1 , 2 are essentially secondary to the solution of a controlled energy supply. Metabolic energy conservation is a prerequisite for synthetic systems no matter how complex. Energy is critical not just for (macro)molecular syntheses but also for maintaining the cytoplasm in a state compatible with metabolism through control over pH, ionic strength and solute composition. Here we have addressed that issue and show that we can control ATP production and ionic homeostasis in synthetic vesicles. The bottom-up construction of synthetic cells from molecular components 3 differs in concept and strategy from the top–down approach to engineer minimal cells, pioneered by the J. Craig Venter institute 4 . Yet, both approaches address what tasks a living cell should minimally perform and how this can be accomplished with a minimal set of components. New biochemical functions and regulatory principles will be discovered as we make progress toward constructing a minimal cell. In the field of bottom-up synthetic biology (perhaps better called synthetic biochemistry), work is progressing toward establishing new information storage systems 5 , replication of DNA by self-encoded proteins 6 , the engineering of gene and protein networks 7 , 8 , formation of skeletal-like networks 9 , biosynthesis of lipids 10 , 11 , 12 , division of vesicles 13 , 14 , development of non-lipid compartment systems 15 , 16 and chemical homeostasis through self-replication 17 , 18 . Protein synthesis has been realized using recombinant elements 19 , which have been incorporated into vesicles 20 , 21 or water-in-oil droplets 16 . However, long-term sustained synthesis of chemicals is a bottleneck in the development and application of synthetic cell-like systems 22 , 23 . At the root of the poor performance of reconstituted systems are challenges that relate to sustained production of nucleotides, import of substrate(s) and export of waste product(s), control of the internal physicochemical conditions (pH, ionic strength, crowding) and stability of the lipid-bounded compartment, all of which require constant energy dissipation. Inspired by the challenges of the bottom-up construction of a living cell, we focus on the development of new open vesicle systems that sustain nucleotide levels and electrochemical gradients to allow further functionalities to be integrated. ATP is especially crucial, not only as a source of metabolic energy for most biological processes, but also as a hydrotrope, influencing the viscosity and possibly the structure of the cytosol 24 . Energy consumption in a growing cell is dominated by polymerization reactions and maintenance processes 25 , so regeneration of ATP is required to keep the cell running. Recent developments in the field of synthetic biochemistry have started to address the issue of ATP homeostasis. A cell-free molecular rheostat for control of ATP levels has been reported, employing two parallel pathways and regulation by free inorganic phosphate 26 , but the system has not been implemented in vesicles. Photosynthetic artificial organelles have been constructed that form ATP on the outside of small vesicles, encapsulated in giant vesicles, allowing optical control of ATP dependent reactions 27 , 28 . Here, we present the construction of a molecular system integrated into a cell-like container with control of solute fluxes and tunable supply of energy to fuel ATP-requiring processes. We have equipped the vesicles with sensors for online readout of the internal ATP/ADP ratio and pH, allowing us to conclude that the system enables long-term metabolic energy conservation and physicochemical homeostasis. Results A system for sustained production of ATP The conversion of arginine into ornithine, ammonia plus carbon dioxide yields ATP in three enzymatic steps (Fig. 1a ) 29 . For sustainable energy conservation in a compartmentalized system, the import of substrates and excretion of products have to be efficient, which can be achieved by coupling the solute fluxes. The antiporter ArcD2 facilitates the stoichiometric exchange of the substrate arginine for the product ornithine (Fig. 1b ) 30 , which is important for maintaining the metabolic network away from equilibrium. The thermodynamics of the arginine conversion under standard conditions are given in Fig. 1c . The equilibrium constant of the conversion of citrulline plus phosphate into ornithine plus carbamoyl-phosphate is highly unfavorable, but the overall standard Gibbs free energy difference (ΔG 0 ) of the breakdown of arginine is negative. Since the actual ΔG is determined by ΔG 0 and the concentration of the reactants, the antiport reaction favors an even more negative ΔG by maintaining an out-to-in gradient of arginine and in-to-out gradient of ornithine (Fig. 1d ). We anticipate that NH 3 and CO 2 will passively diffuse out of the cell. Fig. 1 Layout and thermodynamics of the system. a Schematic representation of the arginine breakdown pathway. b Structures of arginine, citrulline and ornithine at neutral pH. c Thermodynamics of arginine conversion for the", "role": "user" }, { "content": "Scientists at the University of Groningen have constructed synthetic vesicles in which ATP, the main energy carrier in living cells, is produced. The vesicles use the ATP to maintain their volume and their ionic strength homeostasis. This metabolic network will eventually be used in the creation of synthetic cells—but it can already be used to study ATP-dependent processes. The researchers described the synthetic system in an article that was published in Nature Communications on 18 September. \"Our aim is the bottom-up construction of a synthetic cell that can sustain itself and that can grow and divide,\" explains University of Groningen Professor of Biochemistry Bert Poolman. He is part of a Dutch consortium that obtained a Gravitation grant in 2017 from the Netherlands Organisation for Scientific Research to realize this ambition. Different groups of scientists are producing different modules for the cell and Poolman's group was tasked with energy production. Equilibrium All living cells produce ATP as an energy carrier but achieving sustainable production of ATP in a test tube is not a small task. \"In known synthetic systems, all components for the reaction were included inside a vesicle. However, after about half an hour, the reaction reached equilibrium and ATP production declined,\" Poolman explains. \"We wanted our system to stay away from equilibrium, just like in living systems.\" It took three Ph.D. students in his group nearly four years to construct such a system. A lipid vesicle was fitted out with a transport protein that could import the substrate arginine and export the product ornithine. Inside the vesicle, enzymes were present that broke down the arginine into ornithine. The free energy that this reaction provided was used to link phosphate to ADP, forming ATP. Ammonium and carbon dioxide were produced as waste products that diffused through the membrane. \"The export of ornithine produced inside the vesicle drives the import of arginine, which keeps the system running for as long as the vesicles are provided with arginine,\" explains Poolman. Transport protein To create an out-of-equilibrium system, the ATP is used to maintain ionic strength inside the vesicle. A biological sensor measures ionic strength and if this becomes too high, it activates a transport protein that imports a substance called glycine betaine. This increases the cell volume and consequently reduces the ionic strength. \"The transport protein is powered by ATP, so we have both production and use of ATP inside the vesicle.\" The system was left to run for 16 hours in the longest experiment that the scientists have performed. \"This is quite long—some bacteria can divide after just 20 minutes,\" says Poolman. \"The current system should suffice for a synthetic cell that divides once every few hours.\" Eventually, different modules like this one will be combined to create a synthetic cell that will function autonomously by synthesizing its own proteins from a synthetic genome. Artificial chromosome The current system is based on biochemical components. However, Poolman's colleagues at Wageningen University & Research are busy collecting the genes needed for the production of enzymes used by the system and incorporating them into an artificial chromosome. Others are working on lipid and protein synthesis, for example, or cell division. The final synthetic cell should contain DNA for all these modules and operate them autonomously like a living cell, but in this case, engineered from the bottom-up and including new properties. However, this is many years away. \"In the meantime, we are already using our ATP-producing system to study ATP-dependent processes and advance the field of membrane transport,\" says Poolman. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract One of the grand challenges in chemistry is the construction of functional out-of-equilibrium networks, which are typical of living cells. Building such a system from molecular components requires control over the formation and degradation of the interacting chemicals and homeostasis of the internal physical-chemical conditions. The provision and consumption of ATP lies at the heart of this challenge. Here we report the in vitro construction of a pathway in vesicles for sustained ATP production that is maintained away from equilibrium by control of energy dissipation. We maintain a constant level of ATP with varying load on the system. The pathway enables us to control the transmembrane fluxes of osmolytes and to demonstrate basic physicochemical homeostasis. Our work demonstrates metabolic energy conservation and cell volume regulatory mechanisms in a cell-like system at a level of complexity minimally needed for life. Introduction The generation and consumption of ATP lies at the heart of life. Complex networks of proteins, nucleic acids and small molecules sustain the essential processes of gene expression and cell division that characterize living cells, but without ATP they are non-functional. Herein lies one of the major challenges in the construction of synthetic cell-like systems. Other processes, such as achieving tunable DNA replication, efficient transcription and translation, and vesicle division 1 , 2 are essentially secondary to the solution of a controlled energy supply. Metabolic energy conservation is a prerequisite for synthetic systems no matter how complex. Energy is critical not just for (macro)molecular syntheses but also for maintaining the cytoplasm in a state compatible with metabolism through control over pH, ionic strength and solute composition. Here we have addressed that issue and show that we can control ATP production and ionic homeostasis in synthetic vesicles. The bottom-up construction of synthetic cells from molecular components 3 differs in concept and strategy from the top–down approach to engineer minimal cells, pioneered by the J. Craig Venter institute 4 . Yet, both approaches address what tasks a living cell should minimally perform and how this can be accomplished with a minimal set of components. New biochemical functions and regulatory principles will be discovered as we make progress toward constructing a minimal cell. In the field of bottom-up synthetic biology (perhaps better called synthetic biochemistry), work is progressing toward establishing new information storage systems 5 , replication of DNA by self-encoded proteins 6 , the engineering of gene and protein networks 7 , 8 , formation of skeletal-like networks 9 , biosynthesis of lipids 10 , 11 , 12 , division of vesicles 13 , 14 , development of non-lipid compartment systems 15 , 16 and chemical homeostasis through self-replication 17 , 18 . Protein synthesis has been realized using recombinant elements 19 , which have been incorporated into vesicles 20 , 21 or water-in-oil droplets 16 . However, long-term sustained synthesis of chemicals is a bottleneck in the development and application of synthetic cell-like systems 22 , 23 . At the root of the poor performance of reconstituted systems are challenges that relate to sustained production of nucleotides, import of substrate(s) and export of waste product(s), control of the internal physicochemical conditions (pH, ionic strength, crowding) and stability of the lipid-bounded compartment, all of which require constant energy dissipation. Inspired by the challenges of the bottom-up construction of a living cell, we focus on the development of new open vesicle systems that sustain nucleotide levels and electrochemical gradients to allow further functionalities to be integrated. ATP is especially crucial, not only as a source of metabolic energy for most biological processes, but also as a hydrotrope, influencing the viscosity and possibly the structure of the cytosol 24 . Energy consumption in a growing cell is dominated by polymerization reactions and maintenance processes 25 , so regeneration of ATP is required to keep the cell running. Recent developments in the field of synthetic biochemistry have started to address the issue of ATP homeostasis. A cell-free molecular rheostat for control of ATP levels has been reported, employing two parallel pathways and regulation by free inorganic phosphate 26 , but the system has not been implemented in vesicles. Photosynthetic artificial organelles have been constructed that form ATP on the outside of small vesicles, encapsulated in giant vesicles, allowing optical control of ATP dependent reactions 27 , 28 . Here, we present the construction of a molecular system integrated into a cell-like container with control of solute fluxes and tunable supply of energy to fuel ATP-requiring processes. We have equipped the vesicles with sensors for online readout of the internal ATP/ADP ratio and pH, allowing us to conclude that the system enables long-term metabolic energy conservation and physicochemical homeostasis. Results A system for sustained production of ATP The conversion of arginine into ornithine, ammonia plus carbon dioxide yields ATP in three enzymatic steps (Fig. 1a ) 29 . For sustainable energy conservation in a compartmentalized system, the import of substrates and excretion of products have to be efficient, which can be achieved by coupling the solute fluxes. The antiporter ArcD2 facilitates the stoichiometric exchange of the substrate arginine for the product ornithine (Fig. 1b ) 30 , which is important for maintaining the metabolic network away from equilibrium. The thermodynamics of the arginine conversion under standard conditions are given in Fig. 1c . The equilibrium constant of the conversion of citrulline plus phosphate into ornithine plus carbamoyl-phosphate is highly unfavorable, but the overall standard Gibbs free energy difference (ΔG 0 ) of the breakdown of arginine is negative. Since the actual ΔG is determined by ΔG 0 and the concentration of the reactants, the antiport reaction favors an even more negative ΔG by maintaining an out-to-in gradient of arginine and in-to-out gradient of ornithine (Fig. 1d ). We anticipate that NH 3 and CO 2 will passively diffuse out of the cell. Fig. 1 Layout and thermodynamics of the system. a Schematic representation of the arginine breakdown pathway. b Structures of arginine, citrulline and ornithine at neutral pH. c Thermodynamics of arginine conversion for the<|im_end|> <|im_start|>assistant Scientists at the University of Groningen have constructed synthetic vesicles in which ATP, the main energy carrier in living cells, is produced. The vesicles use the ATP to maintain their volume and their ionic strength homeostasis. This metabolic network will eventually be used in the creation of synthetic cells—but it can already be used to study ATP-dependent processes. The researchers described the synthetic system in an article that was published in Nature Communications on 18 September. "Our aim is the bottom-up construction of a synthetic cell that can sustain itself and that can grow and divide," explains University of Groningen Professor of Biochemistry Bert Poolman. He is part of a Dutch consortium that obtained a Gravitation grant in 2017 from the Netherlands Organisation for Scientific Research to realize this ambition. Different groups of scientists are producing different modules for the cell and Poolman's group was tasked with energy production. Equilibrium All living cells produce ATP as an energy carrier but achieving sustainable production of ATP in a test tube is not a small task. "In known synthetic systems, all components for the reaction were included inside a vesicle. However, after about half an hour, the reaction reached equilibrium and ATP production declined," Poolman explains. "We wanted our system to stay away from equilibrium, just like in living systems." It took three Ph.D. students in his group nearly four years to construct such a system. A lipid vesicle was fitted out with a transport protein that could import the substrate arginine and export the product ornithine. Inside the vesicle, enzymes were present that broke down the arginine into ornithine. The free energy that this reaction provided was used to link phosphate to ADP, forming ATP. Ammonium and carbon dioxide were produced as waste products that diffused through the membrane. "The export of ornithine produced inside the vesicle drives the import of arginine, which keeps the system running for as long as the vesicles are provided with arginine," explains Poolman. Transport protein To create an out-of-equilibrium system, the ATP is used to maintain ionic strength inside the vesicle. A biological sensor measures ionic strength and if this becomes too high, it activates a transport protein that imports a substance called glycine betaine. This increases the cell volume and consequently reduces the ionic strength. "The transport protein is powered by ATP, so we have both production and use of ATP inside the vesicle." The system was left to run for 16 hours in the longest experiment that the scientists have performed. "This is quite long—some bacteria can divide after just 20 minutes," says Poolman. "The current system should suffice for a synthetic cell that divides once every few hours." Eventually, different modules like this one will be combined to create a synthetic cell that will function autonomously by synthesizing its own proteins from a synthetic genome. Artificial chromosome The current system is based on biochemical components. However, Poolman's colleagues at Wageningen University & Research are busy collecting the genes needed for the production of enzymes used by the system and incorporating them into an artificial chromosome. Others are working on lipid and protein synthesis, for example, or cell division. The final synthetic cell should contain DNA for all these modules and operate them autonomously like a living cell, but in this case, engineered from the bottom-up and including new properties. However, this is many years away. "In the meantime, we are already using our ATP-producing system to study ATP-dependent processes and advance the field of membrane transport," says Poolman. <|im_end|>

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2,058

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Bottom-up fabrication via on-surface molecular self-assembly is a way to create defect-free, low-dimensional nanomaterials. For bottom-up fabrication to succeed, precursor molecules which correctly assemble into the target structure must be first identified. Here we present an informatics technique which connects self-assembled structures with particular chemical properties of the precursor molecules. Application of this method produces a visual output (a dendrogram) that functions much like the periodic table, but whereas the periodic table puts atoms into categories according to the way in which they bond to each other, the dendrogram put molecules into categories according to the way in which they arrange in a self-assembled structure. By applying this method to the case of functionalized bianthracene precursors adsorbed to copper(111), we identify the functional groups needed to assemble one-dimensional chains, two-dimensional tilings, and other shapes. This methodology can therefore help to identify appropriate precursor molecules for forming target nanomaterials via bottom-up fabrication. Introduction Bottom-up fabrication, which refers to the spontaneous formation of new materials via self-assembly of molecule precursors, is a way to create low-dimensional nanomaterials with atomic-scale structural precision 1 , 2 . In order to successfully assemble a specific nanomaterial via bottom-up fabrication, precursor molecules that interact and align correctly with each other during the self-assembly process must be first identified. It is therefore a major problem that the connection between precursor molecule structure and the outcome of the self-assembly process is yet to be fully elucidated. An area where bottom-up fabrication is receiving a great deal of attention is the synthesis of graphene nanoribbons (GNRs) 3 , 4 , 5 , 6 , 7 , 8 , 9 . In one scheme for bottom-up GNR synthesis, bianthracene precursor molecules possessing bromine (Br) functional groups (10,10′-dibromo-9,9′-bianthracne, or Br 2 BA) undergo a self-assembly process upon deposition onto a copper(111) (Cu(111)) surface, resulting in chain-shaped ‘islands’ (Fig. 1a ). These chain-shaped islands consist of closely-packed rows of bianthracene molecules stabilized through π stacking interactions and strong epitaxial interactions with the metal substrate. Upon heating, a chemical reaction occurs between the Br 2 BA molecules, and the chain-shaped islands turn into GNRs with a (3,1)-chiral edge structure (The scheme shown in Fig. 1a differs from the one discussed in reference 3 , which involves a gold surface, carbon–bromine bond cleavage, and covalent bond formation between precursor molecules instead of islands. Note that some authors have suggested that this bond cleavage scheme operates on copper(111) surfaces as well (see ref. [ 10 ] ) 4 , 5 , 6 , 10 . The important point is that the islands apparently act as intermediate states during the GNR fabrication process 5 . Methods for controlling island shape should therefore be indispensable for bottom-up formation of GNRs with novel shapes. Fig. 1 Self-assembly of bianthracene precursors on copper(111). a Bottom-up fabrication of graphene nanoribbons via deposition of dibromo-biranthracene (Br 2 BA) on a copper 111 (Cu(111)) surface. The molecules form chain-shaped ‘islands’ via self-assembly, which undergo a chemical reaction to form graphene nanoribbons upon heating 5 . The Cu(111) surface is in the plane of the page, but not shown explicitly. Bromine functional groups are indicated by the red circles. b Some typical islands formed at 200 K by various bianthracene molecules possessing different functional groups (as predicted by the GAMMA model 11 ). The percentages are probabilities of forming isolated chain-shaped islands. Functional groups are indicated by the red circles. Gray spheres = carbon, white spheres = hydrogen, red–brown spheres = bromine, and blue spheres = nitrogen atoms. All molecule structures were drawn in Materials Studio Visualizer 28 Full size image A useful feature of the above system is that by simply varying the functional group attached to the bianthracene unit, we can systematically explore the connection between precursor molecule structure and the self-assembly outcome. In fact whereas bromine-functionalized bianthracene (Br 2 BA) produces (3,1)-chiral edge GNRs when deposited on Cu(111), hydrogen-functionalized bianthracene (H 2 BA) is known to produce the same GNRs but with slightly longer lengths 6 . The propensity to form chain-shaped islands therefore appears to be stronger for H 2 BA than Br 2 BA. On the other hand, methyl-functionalized bianthracene ((CH 3 ) 2 BA) on Cu(111) does not produce chain-shaped islands at all, and tends to assemble into relatively formless islands 11 . Simulations using GAMMA (generalized block assembly machine learning equivalence class sampling) modeling [ 11 ] also predict a strong dependence of island shape on functional group (Fig. 1b). By connecting functional group properties with the outcome of bianthracene molecular self-assembly, we would be able to identify new bianthracene precursors for fabricating GNRs with novel shapes, and will also gain insights relevant to bottom-up fabrication on metal surfaces in general. In this article, we use an informatics technique called hierarchical clustering to connect the chemical properties of precursor molecules with the outcome of the molecular self-assembly process. Given a specific substrate and family of candidate precursor molecules, this analysis shows how to choose chemical properties from this family in order to assemble a desired type of structure. By ‘family’, we mean a series of molecules which are structurally homologous but differ only in chemical functionality. To demonstrate the application of our technique, we consider the substrate Cu(111) and the family of bianthracene precursor molecules (X 2 BA). Members of this precursor family differ only in the type of functional group X attached at the 10 and 10′ carbons of the bianthracene unit. By application of our technique, we make the following deductions about functionalized bianthracene self-assembly on Cu(111) substrates: (i) electronically inert functional groups (such as H) are associated with the formation of chain-shaped islands in high yield; (ii) electronegative functional groups (such as F, Br, Cl, CHCH 2 , and NH 2 ) are associated with a reduced yield of chain-shaped islands and the concurrent formation of chain clusters and defective chains; (iii) Functional groups whose orbitals can hybridize with the bianthracene orbitals (such as CH 3 or CF 3 , via hybridization", "role": "user" }, { "content": "A new approach could help materials scientists identify the appropriate molecules to use in order to synthesize target nanomaterials. The method was developed by Daniel Packwood of Kyoto University's Institute for Integrated Cell-Material Sciences (iCeMS) and Taro Hitosugi of the Tokyo Institute of Technology. It involves connecting the chemical properties of molecules with the nanostructures that form as a result of their interaction. A machine learning technique generates data that is then used to develop a diagram that categorizes different molecules according to the nano-sized shapes they form. Fabricating nanomaterials using a bottom-up approach requires finding precursor molecules that interact and align correctly with each other as they self-assemble. But it's been a major challenge knowing how precursor molecules will interact and what shapes they will form. Bottom-up fabrication of graphene nanoribbons is receiving much attention due to their potential use in electronics, tissue engineering, construction, and bio-imaging. One way to synthesise them is by using bianthracene precursor molecules that have bromine functional groups attached to them. The bromine groups interact with a copper substrate to form nano-sized chains. When these chains are heated, they turn into graphene nanoribbons. Packwood and Hitosugi tested their simulator using this method for building graphene nanoribbons. The model uses data about the chemical properties of a variety of molecules that can be attached to bianthracene to functionalize it and facilitate its interaction with copper. The data went through a series of processes that ultimately led to the formation of a dendrogram. This showed that attaching hydrogen molecules to bianthracene led to the development of strong one-dimensional nano-chains. Fluorine, bromine, chlorine, amidogen and vinyl functional groups led to the formation of moderately strong nano-chains. Trifluoromethyl and methyl functional groups led to the formation of weak one-dimensional islands of molecules, and hydroxide and aldehyde groups led to the formation of strong two-dimensional tile-shaped islands. The information produced in the dendogram changed based on the temperature data provided. The above categories apply when the interactions are conducted at -73°C. The results changed with warmer temperatures. The researchers recommend applying the data at low temperatures where the effect of the functional groups' chemical properties on nano-shapes are most clear. The technique can be applied to other substrates and precursor molecules. The researchers describe their method as analogous to the periodic table of chemical elements, which groups atoms based on how they bond to each other. \"However, in order to truly prove that the dendrograms or other informatics-based approaches can be as valuable to materials science as the periodic table, we must incorporate them in a real bottom-up nanomaterial fabrication experiment,\" the researchers conclude in their study published in the journal Nature Communications. \"We are currently pursuing this direction in our laboratories.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Bottom-up fabrication via on-surface molecular self-assembly is a way to create defect-free, low-dimensional nanomaterials. For bottom-up fabrication to succeed, precursor molecules which correctly assemble into the target structure must be first identified. Here we present an informatics technique which connects self-assembled structures with particular chemical properties of the precursor molecules. Application of this method produces a visual output (a dendrogram) that functions much like the periodic table, but whereas the periodic table puts atoms into categories according to the way in which they bond to each other, the dendrogram put molecules into categories according to the way in which they arrange in a self-assembled structure. By applying this method to the case of functionalized bianthracene precursors adsorbed to copper(111), we identify the functional groups needed to assemble one-dimensional chains, two-dimensional tilings, and other shapes. This methodology can therefore help to identify appropriate precursor molecules for forming target nanomaterials via bottom-up fabrication. Introduction Bottom-up fabrication, which refers to the spontaneous formation of new materials via self-assembly of molecule precursors, is a way to create low-dimensional nanomaterials with atomic-scale structural precision 1 , 2 . In order to successfully assemble a specific nanomaterial via bottom-up fabrication, precursor molecules that interact and align correctly with each other during the self-assembly process must be first identified. It is therefore a major problem that the connection between precursor molecule structure and the outcome of the self-assembly process is yet to be fully elucidated. An area where bottom-up fabrication is receiving a great deal of attention is the synthesis of graphene nanoribbons (GNRs) 3 , 4 , 5 , 6 , 7 , 8 , 9 . In one scheme for bottom-up GNR synthesis, bianthracene precursor molecules possessing bromine (Br) functional groups (10,10′-dibromo-9,9′-bianthracne, or Br 2 BA) undergo a self-assembly process upon deposition onto a copper(111) (Cu(111)) surface, resulting in chain-shaped ‘islands’ (Fig. 1a ). These chain-shaped islands consist of closely-packed rows of bianthracene molecules stabilized through π stacking interactions and strong epitaxial interactions with the metal substrate. Upon heating, a chemical reaction occurs between the Br 2 BA molecules, and the chain-shaped islands turn into GNRs with a (3,1)-chiral edge structure (The scheme shown in Fig. 1a differs from the one discussed in reference 3 , which involves a gold surface, carbon–bromine bond cleavage, and covalent bond formation between precursor molecules instead of islands. Note that some authors have suggested that this bond cleavage scheme operates on copper(111) surfaces as well (see ref. [ 10 ] ) 4 , 5 , 6 , 10 . The important point is that the islands apparently act as intermediate states during the GNR fabrication process 5 . Methods for controlling island shape should therefore be indispensable for bottom-up formation of GNRs with novel shapes. Fig. 1 Self-assembly of bianthracene precursors on copper(111). a Bottom-up fabrication of graphene nanoribbons via deposition of dibromo-biranthracene (Br 2 BA) on a copper 111 (Cu(111)) surface. The molecules form chain-shaped ‘islands’ via self-assembly, which undergo a chemical reaction to form graphene nanoribbons upon heating 5 . The Cu(111) surface is in the plane of the page, but not shown explicitly. Bromine functional groups are indicated by the red circles. b Some typical islands formed at 200 K by various bianthracene molecules possessing different functional groups (as predicted by the GAMMA model 11 ). The percentages are probabilities of forming isolated chain-shaped islands. Functional groups are indicated by the red circles. Gray spheres = carbon, white spheres = hydrogen, red–brown spheres = bromine, and blue spheres = nitrogen atoms. All molecule structures were drawn in Materials Studio Visualizer 28 Full size image A useful feature of the above system is that by simply varying the functional group attached to the bianthracene unit, we can systematically explore the connection between precursor molecule structure and the self-assembly outcome. In fact whereas bromine-functionalized bianthracene (Br 2 BA) produces (3,1)-chiral edge GNRs when deposited on Cu(111), hydrogen-functionalized bianthracene (H 2 BA) is known to produce the same GNRs but with slightly longer lengths 6 . The propensity to form chain-shaped islands therefore appears to be stronger for H 2 BA than Br 2 BA. On the other hand, methyl-functionalized bianthracene ((CH 3 ) 2 BA) on Cu(111) does not produce chain-shaped islands at all, and tends to assemble into relatively formless islands 11 . Simulations using GAMMA (generalized block assembly machine learning equivalence class sampling) modeling [ 11 ] also predict a strong dependence of island shape on functional group (Fig. 1b). By connecting functional group properties with the outcome of bianthracene molecular self-assembly, we would be able to identify new bianthracene precursors for fabricating GNRs with novel shapes, and will also gain insights relevant to bottom-up fabrication on metal surfaces in general. In this article, we use an informatics technique called hierarchical clustering to connect the chemical properties of precursor molecules with the outcome of the molecular self-assembly process. Given a specific substrate and family of candidate precursor molecules, this analysis shows how to choose chemical properties from this family in order to assemble a desired type of structure. By ‘family’, we mean a series of molecules which are structurally homologous but differ only in chemical functionality. To demonstrate the application of our technique, we consider the substrate Cu(111) and the family of bianthracene precursor molecules (X 2 BA). Members of this precursor family differ only in the type of functional group X attached at the 10 and 10′ carbons of the bianthracene unit. By application of our technique, we make the following deductions about functionalized bianthracene self-assembly on Cu(111) substrates: (i) electronically inert functional groups (such as H) are associated with the formation of chain-shaped islands in high yield; (ii) electronegative functional groups (such as F, Br, Cl, CHCH 2 , and NH 2 ) are associated with a reduced yield of chain-shaped islands and the concurrent formation of chain clusters and defective chains; (iii) Functional groups whose orbitals can hybridize with the bianthracene orbitals (such as CH 3 or CF 3 , via hybridization<|im_end|> <|im_start|>assistant A new approach could help materials scientists identify the appropriate molecules to use in order to synthesize target nanomaterials. The method was developed by Daniel Packwood of Kyoto University's Institute for Integrated Cell-Material Sciences (iCeMS) and Taro Hitosugi of the Tokyo Institute of Technology. It involves connecting the chemical properties of molecules with the nanostructures that form as a result of their interaction. A machine learning technique generates data that is then used to develop a diagram that categorizes different molecules according to the nano-sized shapes they form. Fabricating nanomaterials using a bottom-up approach requires finding precursor molecules that interact and align correctly with each other as they self-assemble. But it's been a major challenge knowing how precursor molecules will interact and what shapes they will form. Bottom-up fabrication of graphene nanoribbons is receiving much attention due to their potential use in electronics, tissue engineering, construction, and bio-imaging. One way to synthesise them is by using bianthracene precursor molecules that have bromine functional groups attached to them. The bromine groups interact with a copper substrate to form nano-sized chains. When these chains are heated, they turn into graphene nanoribbons. Packwood and Hitosugi tested their simulator using this method for building graphene nanoribbons. The model uses data about the chemical properties of a variety of molecules that can be attached to bianthracene to functionalize it and facilitate its interaction with copper. The data went through a series of processes that ultimately led to the formation of a dendrogram. This showed that attaching hydrogen molecules to bianthracene led to the development of strong one-dimensional nano-chains. Fluorine, bromine, chlorine, amidogen and vinyl functional groups led to the formation of moderately strong nano-chains. Trifluoromethyl and methyl functional groups led to the formation of weak one-dimensional islands of molecules, and hydroxide and aldehyde groups led to the formation of strong two-dimensional tile-shaped islands. The information produced in the dendogram changed based on the temperature data provided. The above categories apply when the interactions are conducted at -73°C. The results changed with warmer temperatures. The researchers recommend applying the data at low temperatures where the effect of the functional groups' chemical properties on nano-shapes are most clear. The technique can be applied to other substrates and precursor molecules. The researchers describe their method as analogous to the periodic table of chemical elements, which groups atoms based on how they bond to each other. "However, in order to truly prove that the dendrograms or other informatics-based approaches can be as valuable to materials science as the periodic table, we must incorporate them in a real bottom-up nanomaterial fabrication experiment," the researchers conclude in their study published in the journal Nature Communications. "We are currently pursuing this direction in our laboratories." <|im_end|>

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35715, 11, 323, 279, 8957, 35831, 30100, 2543, 1139, 480, 27416, 82, 449, 264, 320, 18, 11, 16, 7435, 331, 37478, 6964, 6070, 320, 791, 13155, 6982, 304, 23966, 13, 220, 16, 64, 44642, 505, 279, 832, 14407, 304, 5905, 220, 18, 1174, 902, 18065, 264, 6761, 7479, 11, 12782, 4235, 65, 442, 483, 11049, 11551, 68256, 11, 323, 1080, 838, 306, 11049, 18488, 1990, 71261, 35715, 4619, 315, 30100, 13, 7181, 430, 1063, 12283, 617, 12090, 430, 420, 11049, 11551, 68256, 13155, 27149, 389, 24166, 7, 5037, 8, 27529, 439, 1664, 320, 4151, 2098, 13, 510, 220, 605, 2331, 883, 220, 19, 1174, 220, 20, 1174, 220, 21, 1174, 220, 605, 662, 578, 3062, 1486, 374, 430, 279, 30100, 14132, 1180, 439, 29539, 5415, 2391, 279, 480, 27416, 59251, 1920, 220, 20, 662, 19331, 369, 26991, 13218, 6211, 1288, 9093, 387, 64284, 369, 5740, 5352, 18488, 315, 480, 27416, 82, 449, 11775, 21483, 13, 23966, 13, 220, 16, 10323, 12, 15343, 315, 97589, 339, 20554, 1994, 5956, 34291, 389, 24166, 7, 5037, 570, 264, 26821, 5352, 59251, 315, 66192, 20622, 269, 581, 47620, 4669, 65374, 315, 42168, 99639, 1481, 404, 32329, 20554, 1994, 320, 6971, 220, 17, 34589, 8, 389, 264, 24166, 220, 5037, 320, 45919, 7, 5037, 595, 7479, 13, 578, 35715, 1376, 8957, 35831, 3451, 285, 8329, 529, 4669, 659, 12, 15343, 11, 902, 37771, 264, 11742, 13010, 311, 1376, 66192, 20622, 269, 581, 47620, 5304, 24494, 220, 20, 662, 578, 27560, 7, 5037, 8, 7479, 374, 304, 279, 11277, 315, 279, 2199, 11, 719, 539, 6982, 21650, 13, 65698, 483, 16003, 5315, 527, 16717, 555, 279, 2579, 26432, 13, 293, 4427, 14595, 30100, 14454, 520, 220, 1049, 735, 555, 5370, 97589, 339, 20554, 1994, 35715, 60662, 2204, 16003, 5315, 320, 300, 19698, 555, 279, 82911, 4940, 1646, 220, 806, 7609, 578, 54208, 527, 49316, 315, 30164, 25181, 8957, 35831, 30100, 13, 55550, 5315, 527, 16717, 555, 279, 2579, 26432, 13, 24255, 66818, 284, 12782, 11, 4251, 66818, 284, 35784, 11, 2579, 4235, 65561, 66818, 284, 94571, 483, 11, 323, 6437, 66818, 284, 47503, 33299, 13, 2052, 43030, 14726, 1051, 15107, 304, 32009, 19074, 20796, 3213, 220, 1591, 8797, 1404, 2217, 362, 5505, 4668, 315, 279, 3485, 1887, 374, 430, 555, 5042, 29865, 279, 16003, 1912, 12673, 311, 279, 97589, 339, 20554, 1994, 5089, 11, 584, 649, 60826, 13488, 279, 3717, 1990, 71261, 43030, 6070, 323, 279, 659, 12, 15343, 15632, 13, 763, 2144, 20444, 94571, 483, 99616, 1534, 97589, 339, 20554, 1994, 320, 6971, 220, 17, 34589, 8, 19159, 320, 18, 11, 16, 7435, 331, 37478, 6964, 480, 27416, 82, 994, 54568, 389, 27560, 7, 5037, 705, 35784, 99616, 1534, 97589, 339, 20554, 1994, 320, 39, 220, 17, 34589, 8, 374, 3967, 311, 8356, 279, 1890, 480, 27416, 82, 719, 449, 10284, 5129, 29416, 220, 21, 662, 578, 95323, 311, 1376, 8957, 35831, 30100, 9093, 8111, 311, 387, 16643, 369, 473, 220, 17, 34589, 1109, 3320, 220, 17, 34589, 13, 1952, 279, 1023, 1450, 11, 79574, 99616, 1534, 97589, 339, 20554, 1994, 1819, 2198, 220, 18, 883, 220, 17, 34589, 8, 389, 27560, 7, 5037, 8, 1587, 539, 8356, 8957, 35831, 30100, 520, 682, 11, 323, 28335, 311, 42840, 1139, 12309, 1376, 1752, 30100, 220, 806, 662, 4567, 7607, 1701, 82911, 4940, 320, 25615, 1534, 2565, 14956, 5780, 6975, 85262, 538, 25936, 8, 34579, 510, 220, 806, 2331, 1101, 7168, 264, 3831, 44393, 315, 13218, 6211, 389, 16003, 1912, 320, 30035, 13, 220, 16, 65, 570, 3296, 21583, 16003, 1912, 6012, 449, 279, 15632, 315, 97589, 339, 20554, 1994, 31206, 659, 12, 15343, 11, 584, 1053, 387, 3025, 311, 10765, 502, 97589, 339, 20554, 1994, 5956, 34291, 369, 13354, 1113, 480, 27416, 82, 449, 11775, 21483, 11, 323, 690, 1101, 8895, 26793, 9959, 311, 5740, 5352, 59251, 389, 9501, 27529, 304, 4689, 13, 763, 420, 4652, 11, 584, 1005, 459, 6179, 29470, 15105, 2663, 70994, 59454, 311, 4667, 279, 11742, 6012, 315, 71261, 35715, 449, 279, 15632, 315, 279, 31206, 659, 12, 15343, 1920, 13, 16644, 264, 3230, 54057, 323, 3070, 315, 9322, 71261, 35715, 11, 420, 6492, 5039, 1268, 311, 5268, 11742, 6012, 505, 420, 3070, 304, 2015, 311, 42840, 264, 12974, 955, 315, 6070, 13, 3296, 3451, 19521, 20182, 584, 3152, 264, 4101, 315, 35715, 902, 527, 2080, 43024, 5105, 1640, 788, 719, 1782, 1193, 304, 11742, 15293, 13, 2057, 20461, 279, 3851, 315, 1057, 15105, 11, 584, 2980, 279, 54057, 27560, 7, 5037, 8, 323, 279, 3070, 315, 97589, 339, 20554, 1994, 71261, 35715, 320, 55, 220, 17, 34589, 570, 17384, 315, 420, 71261, 3070, 1782, 1193, 304, 279, 955, 315, 16003, 1912, 1630, 12673, 520, 279, 220, 605, 323, 220, 605, 39615, 35872, 2439, 315, 279, 97589, 339, 20554, 1994, 5089, 13, 3296, 3851, 315, 1057, 15105, 11, 584, 1304, 279, 2768, 71737, 922, 16003, 1534, 97589, 339, 20554, 1994, 659, 12, 15343, 389, 27560, 7, 5037, 8, 16146, 988, 25, 320, 72, 8, 71870, 81073, 16003, 5315, 320, 21470, 439, 473, 8, 527, 5938, 449, 279, 18488, 315, 8957, 35831, 30100, 304, 1579, 7692, 26, 320, 3893, 8, 43906, 606, 70, 1413, 16003, 5315, 320, 21470, 439, 435, 11, 3320, 11, 2493, 11, 6969, 2198, 220, 17, 1174, 323, 35931, 220, 17, 883, 527, 5938, 449, 264, 11293, 7692, 315, 8957, 35831, 30100, 323, 279, 35135, 18488, 315, 8957, 28066, 323, 64903, 27271, 26, 320, 35694, 8, 55550, 5315, 6832, 27605, 1147, 649, 26038, 553, 449, 279, 97589, 339, 20554, 1994, 27605, 1147, 320, 21470, 439, 6969, 220, 18, 477, 21459, 220, 18, 1174, 4669, 26038, 2065, 128257, 198, 128256, 78191, 198, 32, 502, 5603, 1436, 1520, 7384, 14248, 10765, 279, 8475, 35715, 311, 1005, 304, 2015, 311, 6925, 27985, 2218, 20622, 316, 2229, 82, 13, 578, 1749, 574, 8040, 555, 15469, 14114, 6798, 315, 82122, 3907, 596, 10181, 369, 50521, 14299, 5364, 2229, 23199, 320, 72, 43270, 4931, 8, 323, 350, 17606, 16261, 437, 51640, 315, 279, 27286, 10181, 315, 12053, 13, 1102, 18065, 21583, 279, 11742, 6012, 315, 35715, 449, 279, 51593, 47194, 430, 1376, 439, 264, 1121, 315, 872, 16628, 13, 362, 5780, 6975, 15105, 27983, 828, 430, 374, 1243, 1511, 311, 2274, 264, 13861, 430, 22824, 4861, 2204, 35715, 4184, 311, 279, 51593, 28935, 21483, 814, 1376, 13, 37407, 1113, 20622, 316, 2229, 82, 1701, 264, 5740, 5352, 5603, 7612, 9455, 71261, 35715, 430, 16681, 323, 5398, 12722, 449, 1855, 1023, 439, 814, 659, 33534, 16167, 13, 2030, 433, 596, 1027, 264, 3682, 8815, 14392, 1268, 71261, 35715, 690, 16681, 323, 1148, 21483, 814, 690, 1376, 13, 26821, 5352, 59251, 315, 66192, 20622, 269, 581, 47620, 374, 12588, 1790, 6666, 4245, 311, 872, 4754, 1005, 304, 31591, 11, 20438, 15009, 11, 8246, 11, 323, 17332, 38025, 4210, 13, 3861, 1648, 311, 52389, 1082, 1124, 374, 555, 1701, 97589, 339, 20554, 1994, 71261, 35715, 430, 617, 94571, 483, 16003, 5315, 12673, 311, 1124, 13, 578, 94571, 483, 5315, 16681, 449, 264, 24166, 54057, 311, 1376, 51593, 28935, 27271, 13, 3277, 1521, 27271, 527, 32813, 11, 814, 2543, 1139, 66192, 20622, 269, 581, 47620, 13, 14114, 6798, 323, 16261, 437, 51640, 12793, 872, 42991, 1701, 420, 1749, 369, 4857, 66192, 20622, 269, 581, 47620, 13, 578, 1646, 5829, 828, 922, 279, 11742, 6012, 315, 264, 8205, 315, 35715, 430, 649, 387, 12673, 311, 97589, 339, 20554, 1994, 311, 16003, 553, 433, 323, 28696, 1202, 16628, 449, 24166, 13, 578, 828, 4024, 1555, 264, 4101, 315, 11618, 430, 13967, 6197, 311, 279, 18488, 315, 264, 90052, 87220, 13, 1115, 8710, 430, 72908, 35784, 35715, 311, 97589, 339, 20554, 1994, 6197, 311, 279, 4500, 315, 3831, 832, 33520, 51593, 11843, 1771, 13, 61626, 269, 483, 11, 94571, 483, 11, 85206, 11, 23442, 11968, 323, 34549, 16003, 5315, 6197, 311, 279, 18488, 315, 70351, 3831, 51593, 11843, 1771, 13, 1183, 333, 10036, 269, 316, 42972, 323, 79574, 16003, 5315, 6197, 311, 279, 18488, 315, 7621, 832, 33520, 30100, 315, 35715, 11, 323, 17055, 87, 579, 323, 453, 86836, 5315, 6197, 311, 279, 18488, 315, 3831, 1403, 33520, 10228, 35831, 30100, 13, 578, 2038, 9124, 304, 279, 90052, 13255, 5614, 3196, 389, 279, 9499, 828, 3984, 13, 578, 3485, 11306, 3881, 994, 279, 22639, 527, 13375, 520, 482, 5958, 32037, 13, 578, 3135, 5614, 449, 46039, 20472, 13, 578, 12074, 7079, 19486, 279, 828, 520, 3428, 20472, 1405, 279, 2515, 315, 279, 16003, 5315, 6, 11742, 6012, 389, 51593, 7666, 9521, 527, 1455, 2867, 13, 578, 15105, 649, 387, 9435, 311, 1023, 16146, 988, 323, 71261, 35715, 13, 578, 12074, 7664, 872, 1749, 439, 79283, 311, 279, 39445, 2007, 315, 11742, 5540, 11, 902, 5315, 33299, 3196, 389, 1268, 814, 11049, 311, 1855, 1023, 13, 330, 11458, 11, 304, 2015, 311, 9615, 12391, 430, 279, 90052, 299, 51870, 477, 1023, 6179, 29470, 6108, 20414, 649, 387, 439, 15525, 311, 7384, 8198, 439, 279, 39445, 2007, 11, 584, 2011, 33435, 1124, 304, 264, 1972, 5740, 5352, 20622, 316, 2229, 59251, 9526, 1359, 279, 12074, 32194, 304, 872, 4007, 4756, 304, 279, 8486, 22037, 26545, 13, 330, 1687, 527, 5131, 34118, 420, 5216, 304, 1057, 70760, 1210, 220, 128257, 198 ]

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 Brown fat activates uncoupled respiration in response to cold temperature and contributes to systemic metabolic homeostasis. To date, the metabolic action of brown fat has been primarily attributed to its role in fuel oxidation and uncoupling protein 1 (UCP1)-mediated thermogenesis. Whether brown fat engages other tissues through secreted factors remains largely unexplored. Here we show that neuregulin 4 (Nrg4), a member of the epidermal growth factor (EGF) family of extracellular ligands, is highly expressed in adipose tissues, enriched in brown fat and markedly increased during brown adipocyte differentiation. Adipose tissue Nrg4 expression was reduced in rodent and human obesity. Gain- and loss-of-function studies in mice demonstrated that Nrg4 protects against diet-induced insulin resistance and hepatic steatosis through attenuating hepatic lipogenic signaling. Mechanistically, Nrg4 activates ErbB3 and ErbB4 signaling in hepatocytes and negatively regulates de novo lipogenesis mediated by LXR and SREBP1c in a cell-autonomous manner. These results establish Nrg4 as a brown fat–enriched endocrine factor with therapeutic potential for the treatment of obesity-associated disorders, including type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). Main Brown adipose tissue (BAT) defends against excess cold stimulation through its upregulation of mitochondrial UCP1, which links fuel oxidation to heat generation 1 , 2 , while also playing an important role in whole-body energy balance and fuel metabolism. Genetic ablation of BAT via transgenic expression of diphtheria toxin A renders mice prone to the development of obesity 3 , whereas activation of BAT thermogenesis by cold exposure has been linked to increased energy expenditure, reduced adiposity and lower plasma lipids 4 , 5 , 6 . Recent work has demonstrated that metabolically active BAT is present in adult humans 7 , 8 , 9 , 10 , raising the prospect that augmenting brown fat abundance and/or function may provide an effective avenue for the treatment of obesity and its associated metabolic disorders 11 , 12 . Although BAT in humans shares key molecular and metabolic characteristics with the classical rodent BAT, it appears to contain both classical and brown-like (beige/brite) 13 , 14 adipocytes with distinct molecular signatures and developmental origins 15 , 16 , 17 . Brown adipocytes actively take up glucose and fatty acids for oxidation by mitochondria, and the rate of fuel utilization is increased under thermogenic conditions. Surprisingly, while mice lacking UCP1 had heightened sensitivity to cold 18 , they were resistant to diet-induced obesity at ambient temperatures and became more prone to weight gain only at thermoneutrality 19 , 20 . The latter is in stark contrast to the obesity-prone phenotype in mice that lack brown fat as a result of genetic ablation 3 . These paradoxical findings strongly suggest that brown fat exerts effects on systemic nutrient and energy metabolism beyond its intrinsic ability to carry out uncoupled respiration. We postulated that brown fat may release factors that act non-cell-autonomously on other tissues to modulate systemic energy metabolism. Secreted factors are important in mediating metabolic cross-talk among tissues to maintain systemic nutrient and energy homeostasis. Adipose tissue hormones 21 , 22 , 23 , gut-derived fibroblast growth factors 24 , 25 , myokines 26 , 27 and bone-derived factors 28 participate in nutrient sensing and coordinate key aspects of metabolic homeostasis. The EGF family of extracellular ligands has been implicated in the regulation of tissue development and tumorigenesis via the ErbB family of receptor tyrosine kinases 29 , 30 , 31 . EGF receptor and ErbB2 are uniquely important in engaging a subset of EGFs in cancer cell growth and survival. Interestingly, a distinct subgroup of growth factors called neuregulins (Nrg1–Nrg4) also contain EGF-like domains and primarily signal through ErbB3 and ErbB4 to regulate diverse biological processes 29 . Here we identified Nrg4 as a previously unknown BAT-enriched secreted factor that attenuates hepatic lipogenic signaling and preserves glucose and lipid homeostasis in obesity. Thus, impaired Nrg4 signaling may contribute to the development of type 2 diabetes and NAFLD. Results Identification of Nrg4 as a brown fat–enriched secreted protein To identify BAT-enriched secreted factors, we analyzed the expression profile of the mouse secretome gene set across 12 tissues ( GSE10246 , Gene Expression Omnibus) and during brown adipocyte differentiation. The secretome database contains a set of 2,169 mouse genes predicted to encode secreted proteins 32 , 1,378 of which have probe sets on Affymetrix mouse genome MOE430 chips. Our analysis identified a cluster of 26 genes whose expression is enriched in mouse brown fat and induced during differentiation of immortalized brown preadipocytes ( Fig. 1a ). Among these, Nrg4 exhibited a highly restricted pattern of expression in adipose tissues. Quantitative PCR (qPCR) analysis indicated that Nrg4 mRNA expression was enriched in BAT and also present at a lower level in white adipose tissue (WAT) ( Fig. 1b ). In contrast, its expression in other tissues, including skeletal muscle, liver, brain and heart, was relatively low. Consistent with microarray data, Nrg4 expression was markedly induced during adipocyte differentiation ( Fig. 1c ), reaching a higher level in differentiated immortalized brown adipocytes than in 3T3-L1 white adipocytes and primary hepatocytes ( Fig. 1b ). Nrg4 expression in BAT, but not inguinal and epididymal WAT, was elevated by acute cold exposure, whereas its expression in both BAT and inguinal WAT was augmented by cold acclimation ( Fig. 1d ). Nrg4 expression was induced by norepinephrine in differentiated brown adipocytes but not 3T3-L1 adipocytes ( Fig. 1e ). Figure 1: Identification of Nrg4 as a brown fat–enriched secreted protein. ( a ) Clustering analysis of genes predicted to encode secreted proteins that are induced during brown adipocyte (BAC) differentiation and enriched in BAT. ( b ) Quantitative PCR (qPCR) analysis of Nrg4 mRNA expression in mouse tissues (left, n = 3) and cultured adipocytes and hepatocytes (right, n = 3 for each). Data represent mean ± s.d. * P < 0.05, BAC versus 3T3-L1 or primary hepatocytes from WT mice (Hep). ( c ) qPCR analysis of Nrg4 and Ucp1 mRNA expression during BAC differentiation ( n = 3). Data represent means", "role": "user" }, { "content": "Researchers at the University of Michigan have discovered how a previously unknown hormone serves as a messenger from fat cells to the liver and are investigating the potential of developing a new treatment for metabolic disorders. Jiandie Lin of the Life Sciences Institute described how in mice the hormone, NRG4, is secreted by so-called brown fat cells and communicates with the liver to regulate the conversion of sugar into fat. Mice without NRG4 became obese and developed hallmarks of type 2 diabetes and fatty liver disease. When scientists genetically elevated NRG4 levels in these mice, however, the animals were protected from these metabolic disorders when fed a high-calorie, high-fat diet. The research was published today in Nature Medicine. Brown fat is darker due to its high mitochondrial content, and has been widely assumed to generate heat and \"burn\" calories through a process called thermogenesis. However, Lin said, there was a paradox in the research field: When scientists disrupted brown fat formation, mice became more prone to obesity, but the removal of the protein responsible for generating heat only had modest effects on body weight. \"So we figured that brown fat must be doing something besides dissipating heat,\" Lin said. Could brown fat be secreting a hormone that allowed the fat cells to communicate with other tissues in the body in a way that prevents obesity? And if so, could that hormone be used as a therapeutic to treat obesity and related metabolic disorders in humans? The researchers identified NRG4, a hormone that is made primarily by brown fat in mice. Mice lacking NRG4 developed more severe obesity and related disorders when fed a high-fat diet, while mice with genetically higher levels of NRG4 were protected from the deleterious effects of the same diet. Once bound to its receptor on liver cells, NRG4 reduces the conversion of sugar into fat, a process thought to promote disorders associated with obesity, particularly fatty liver. Without NRG4, the liver is abnormally active in converting sugar into fat, leading to metabolic disorders. \"In all models of obesity, NRG4 expression is reduced,\" Lin said. And in humans, the amount of NRG correlates negatively with obesity. \"We think obesity is a state of NRG4 deficiency,\" he said. While the amount of NRG4 is three to five times higher in brown fat than in white, humans have many more white fat cells than brown. \"Probably both types of fat cells are involved,\" Lin said. The researchers are in the process of studying NRG4 as a treatment for type 2 diabetes and fatty liver disease. \"Realistically, there are still many challenges to figuring out how it acts in the body and might be used as a drug,\" Lin said. \"But in general, we know that NRG4 is beneficial for body metabolism and are excited about its potential.\" Jiandie Lin is a faculty member in the Life Sciences Institute, where his lab is located and his research conducted. He is also an associate professor in the Department of Cell and Developmental Biology at the U-M Medical School. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Brown fat activates uncoupled respiration in response to cold temperature and contributes to systemic metabolic homeostasis. To date, the metabolic action of brown fat has been primarily attributed to its role in fuel oxidation and uncoupling protein 1 (UCP1)-mediated thermogenesis. Whether brown fat engages other tissues through secreted factors remains largely unexplored. Here we show that neuregulin 4 (Nrg4), a member of the epidermal growth factor (EGF) family of extracellular ligands, is highly expressed in adipose tissues, enriched in brown fat and markedly increased during brown adipocyte differentiation. Adipose tissue Nrg4 expression was reduced in rodent and human obesity. Gain- and loss-of-function studies in mice demonstrated that Nrg4 protects against diet-induced insulin resistance and hepatic steatosis through attenuating hepatic lipogenic signaling. Mechanistically, Nrg4 activates ErbB3 and ErbB4 signaling in hepatocytes and negatively regulates de novo lipogenesis mediated by LXR and SREBP1c in a cell-autonomous manner. These results establish Nrg4 as a brown fat–enriched endocrine factor with therapeutic potential for the treatment of obesity-associated disorders, including type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). Main Brown adipose tissue (BAT) defends against excess cold stimulation through its upregulation of mitochondrial UCP1, which links fuel oxidation to heat generation 1 , 2 , while also playing an important role in whole-body energy balance and fuel metabolism. Genetic ablation of BAT via transgenic expression of diphtheria toxin A renders mice prone to the development of obesity 3 , whereas activation of BAT thermogenesis by cold exposure has been linked to increased energy expenditure, reduced adiposity and lower plasma lipids 4 , 5 , 6 . Recent work has demonstrated that metabolically active BAT is present in adult humans 7 , 8 , 9 , 10 , raising the prospect that augmenting brown fat abundance and/or function may provide an effective avenue for the treatment of obesity and its associated metabolic disorders 11 , 12 . Although BAT in humans shares key molecular and metabolic characteristics with the classical rodent BAT, it appears to contain both classical and brown-like (beige/brite) 13 , 14 adipocytes with distinct molecular signatures and developmental origins 15 , 16 , 17 . Brown adipocytes actively take up glucose and fatty acids for oxidation by mitochondria, and the rate of fuel utilization is increased under thermogenic conditions. Surprisingly, while mice lacking UCP1 had heightened sensitivity to cold 18 , they were resistant to diet-induced obesity at ambient temperatures and became more prone to weight gain only at thermoneutrality 19 , 20 . The latter is in stark contrast to the obesity-prone phenotype in mice that lack brown fat as a result of genetic ablation 3 . These paradoxical findings strongly suggest that brown fat exerts effects on systemic nutrient and energy metabolism beyond its intrinsic ability to carry out uncoupled respiration. We postulated that brown fat may release factors that act non-cell-autonomously on other tissues to modulate systemic energy metabolism. Secreted factors are important in mediating metabolic cross-talk among tissues to maintain systemic nutrient and energy homeostasis. Adipose tissue hormones 21 , 22 , 23 , gut-derived fibroblast growth factors 24 , 25 , myokines 26 , 27 and bone-derived factors 28 participate in nutrient sensing and coordinate key aspects of metabolic homeostasis. The EGF family of extracellular ligands has been implicated in the regulation of tissue development and tumorigenesis via the ErbB family of receptor tyrosine kinases 29 , 30 , 31 . EGF receptor and ErbB2 are uniquely important in engaging a subset of EGFs in cancer cell growth and survival. Interestingly, a distinct subgroup of growth factors called neuregulins (Nrg1–Nrg4) also contain EGF-like domains and primarily signal through ErbB3 and ErbB4 to regulate diverse biological processes 29 . Here we identified Nrg4 as a previously unknown BAT-enriched secreted factor that attenuates hepatic lipogenic signaling and preserves glucose and lipid homeostasis in obesity. Thus, impaired Nrg4 signaling may contribute to the development of type 2 diabetes and NAFLD. Results Identification of Nrg4 as a brown fat–enriched secreted protein To identify BAT-enriched secreted factors, we analyzed the expression profile of the mouse secretome gene set across 12 tissues ( GSE10246 , Gene Expression Omnibus) and during brown adipocyte differentiation. The secretome database contains a set of 2,169 mouse genes predicted to encode secreted proteins 32 , 1,378 of which have probe sets on Affymetrix mouse genome MOE430 chips. Our analysis identified a cluster of 26 genes whose expression is enriched in mouse brown fat and induced during differentiation of immortalized brown preadipocytes ( Fig. 1a ). Among these, Nrg4 exhibited a highly restricted pattern of expression in adipose tissues. Quantitative PCR (qPCR) analysis indicated that Nrg4 mRNA expression was enriched in BAT and also present at a lower level in white adipose tissue (WAT) ( Fig. 1b ). In contrast, its expression in other tissues, including skeletal muscle, liver, brain and heart, was relatively low. Consistent with microarray data, Nrg4 expression was markedly induced during adipocyte differentiation ( Fig. 1c ), reaching a higher level in differentiated immortalized brown adipocytes than in 3T3-L1 white adipocytes and primary hepatocytes ( Fig. 1b ). Nrg4 expression in BAT, but not inguinal and epididymal WAT, was elevated by acute cold exposure, whereas its expression in both BAT and inguinal WAT was augmented by cold acclimation ( Fig. 1d ). Nrg4 expression was induced by norepinephrine in differentiated brown adipocytes but not 3T3-L1 adipocytes ( Fig. 1e ). Figure 1: Identification of Nrg4 as a brown fat–enriched secreted protein. ( a ) Clustering analysis of genes predicted to encode secreted proteins that are induced during brown adipocyte (BAC) differentiation and enriched in BAT. ( b ) Quantitative PCR (qPCR) analysis of Nrg4 mRNA expression in mouse tissues (left, n = 3) and cultured adipocytes and hepatocytes (right, n = 3 for each). Data represent mean ± s.d. * P < 0.05, BAC versus 3T3-L1 or primary hepatocytes from WT mice (Hep). ( c ) qPCR analysis of Nrg4 and Ucp1 mRNA expression during BAC differentiation ( n = 3). Data represent means<|im_end|> <|im_start|>assistant Researchers at the University of Michigan have discovered how a previously unknown hormone serves as a messenger from fat cells to the liver and are investigating the potential of developing a new treatment for metabolic disorders. Jiandie Lin of the Life Sciences Institute described how in mice the hormone, NRG4, is secreted by so-called brown fat cells and communicates with the liver to regulate the conversion of sugar into fat. Mice without NRG4 became obese and developed hallmarks of type 2 diabetes and fatty liver disease. When scientists genetically elevated NRG4 levels in these mice, however, the animals were protected from these metabolic disorders when fed a high-calorie, high-fat diet. The research was published today in Nature Medicine. Brown fat is darker due to its high mitochondrial content, and has been widely assumed to generate heat and "burn" calories through a process called thermogenesis. However, Lin said, there was a paradox in the research field: When scientists disrupted brown fat formation, mice became more prone to obesity, but the removal of the protein responsible for generating heat only had modest effects on body weight. "So we figured that brown fat must be doing something besides dissipating heat," Lin said. Could brown fat be secreting a hormone that allowed the fat cells to communicate with other tissues in the body in a way that prevents obesity? And if so, could that hormone be used as a therapeutic to treat obesity and related metabolic disorders in humans? The researchers identified NRG4, a hormone that is made primarily by brown fat in mice. Mice lacking NRG4 developed more severe obesity and related disorders when fed a high-fat diet, while mice with genetically higher levels of NRG4 were protected from the deleterious effects of the same diet. Once bound to its receptor on liver cells, NRG4 reduces the conversion of sugar into fat, a process thought to promote disorders associated with obesity, particularly fatty liver. Without NRG4, the liver is abnormally active in converting sugar into fat, leading to metabolic disorders. "In all models of obesity, NRG4 expression is reduced," Lin said. And in humans, the amount of NRG correlates negatively with obesity. "We think obesity is a state of NRG4 deficiency," he said. While the amount of NRG4 is three to five times higher in brown fat than in white, humans have many more white fat cells than brown. "Probably both types of fat cells are involved," Lin said. The researchers are in the process of studying NRG4 as a treatment for type 2 diabetes and fatty liver disease. "Realistically, there are still many challenges to figuring out how it acts in the body and might be used as a drug," Lin said. "But in general, we know that NRG4 is beneficial for body metabolism and are excited about its potential." Jiandie Lin is a faculty member in the Life Sciences Institute, where his lab is located and his research conducted. He is also an associate professor in the Department of Cell and Developmental Biology at the U-M Medical School. <|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 Low-dimensional electronic systems have traditionally been obtained by electrostatically confining electrons, either in heterostructures or in intrinsically nanoscale materials such as single molecules, nanowires and graphene. Recently, a new method has emerged with the recognition that symmetry-protected topological (SPT) phases 1 , 2 , which occur in systems with an energy gap to quasiparticle excitations (such as insulators or superconductors), can host robust surface states that remain gapless as long as the relevant global symmetry remains unbroken. The nature of the charge carriers in SPT surface states is intimately tied to the symmetry of the bulk, resulting in one- and two-dimensional electronic systems with novel properties. For example, time reversal symmetry endows the massless charge carriers on the surface of a three-dimensional topological insulator with helicity, fixing the orientation of their spin relative to their momentum 3 , 4 . Weakly breaking this symmetry generates a gap on the surface 5 , resulting in charge carriers with finite effective mass and exotic spin textures 6 . Analogous manipulations have yet to be demonstrated in two-dimensional topological insulators, where the primary example of a SPT phase is the quantum spin Hall state 7 , 8 . Here we demonstrate experimentally that charge-neutral monolayer graphene has a quantum spin Hall state 9 , 10 when it is subjected to a very large magnetic field angled with respect to the graphene plane. In contrast to time-reversal-symmetric systems 7 , this state is protected by a symmetry of planar spin rotations that emerges as electron spins in a half-filled Landau level are polarized by the large magnetic field. The properties of the resulting helical edge states can be modulated by balancing the applied field against an intrinsic antiferromagnetic instability 11 , 12 , 13 , which tends to spontaneously break the spin-rotation symmetry. In the resulting canted antiferromagnetic state, we observe transport signatures of gapped edge states, which constitute a new kind of one-dimensional electronic system with a tunable bandgap and an associated spin texture 14 . Main In the integer quantum Hall effect, the topology of the bulk Landau-level energy bands requires the existence of gapless edge states at any interface with the vacuum. The metrological precision of the Hall quantization can be traced to the inability of these edge states to backscatter due to the physical separation of modes with opposite momenta by the insulating sample bulk. In contrast, counterpropagating boundary states in a SPT insulator coexist spatially but are prevented from backscattering by a symmetry of the experimental system 3 , 4 . The local symmetry that protects transport in SPT surface states is unlikely to be as robust as the inherently nonlocal physical separation that protects the quantum Hall effect. However, it enables the creation of new electronic systems in which momentum and some quantum number such as spin are coupled, potentially leading to devices with new functionality. Most experimentally realized SPT phases are based on time reversal symmetry (TRS), with counterpropagating states protected from intermixing by the Kramers degeneracy. However, intensive efforts are under way to search for topological phases protected by symmetries other than time reversal in new experimental systems 15 , 16 . Our approach is inspired by the similarity between the TRS quantum spin Hall (QSH) state and overlapping electron- and hole-like copies of the quantum Hall effect, with the two copies having opposite spin polarizations. This state is protected by spin conservation rather than the orthogonality of states in a Kramers doublet 3 , as with the TRS QSH observed in systems with strong spin–orbit coupling. Nevertheless, it is expected to reproduce the characteristic experimental signatures of the TRS QSH, with gapless helical edge states enclosing an insulating bulk 9 , 10 . Two requirements are necessary for such a QSH state. First, the spin–orbit coupling must be weak, so that spin remains a good quantum number. Second, the energy gap between electron- and hole-like Landau levels must be small enough to be invertible by the Zeeman splitting. Both of these conditions are met in graphene, which is a gapless semimetal with very weak spin–orbit coupling 17 . The graphene Landau-level structure is characterized by the existence of a fourfold spin- and valley-degenerate Landau level at zero energy 18 (zLL). Near the sample boundary, the zLL splits into one positively dispersing (electron-like) and one negatively dispersing (hole-like) mode per spin projection. Consequently, a spin-symmetry-protected QSH state is expected when the spin degeneracy is lifted by an external magnetic field, resulting in a bulk energy gap at charge neutrality and electron- and hole-like states with opposite spin polarizations that cross at the sample edge 9 , 10 . Experimentally, charge-neutral monolayer graphene does not exhibit the expected phenomenology of the QSH state, becoming strongly insulating instead at high magnetic fields 19 . Although the precise nature of this insulating state has remained elusive, its origin can be traced to the strong Coulomb interactions within the graphene zLL. At integer filling factors, ν , the Coulomb energy is minimized by forming antisymmetric orbital wavefunctions, forcing the combined spin–valley isospin part of the wavefunction to be symmetric. The resulting possible ground states lie on a degenerate manifold of states fully polarized in the approximately SU(4)-symmetric isospin space 20 , encompassing a variety of different spin and valley orders. In the real experimental system, the state at any given filling factor (such as ν = 0) is determined by the competition between SU(4) symmetry-breaking effects. The most obvious such anisotropy is the Zeeman effect, which naturally favours a spin-polarized state, but the sublattice structure of the zLL adds additional interaction anisotropies 21 that can favour spin-unpolarized ground states characterized by lattice-scale spin- or charge-density-wave order 11 , 12 , 13 , 22 . This interplay can be probed experimentally by changing the in-plane component of the magnetic field, which changes the Zeeman energy but does not affect orbital energies, and previous observations indeed confirm that the state responsible for the ν = 0 insulator is spin unpolarized 23", "role": "user" }, { "content": "(Phys.org) —Graphene has become an all-purpose wonder material, spurring armies of researchers to explore new possibilities for this two-dimensional lattice of pure carbon. But new research at MIT has found additional potential for the material by uncovering unexpected features that show up under some extreme conditions—features that could render graphene suitable for exotic uses such as quantum computing. The research is published this week in the journal Nature, in a paper by professors Pablo Jarillo-Herrero and Ray Ashoori, postdocs Andrea Young and Ben Hunt, graduate student Javier Sanchez-Yamaguchi, and three others. Under an extremely powerful magnetic field and at extremely low temperature, the researchers found, graphene can effectively filter electrons according to the direction of their spin, something that cannot be done by any conventional electronic system. Under typical conditions, sheets of graphene behave as normal conductors: Apply a voltage, and current flows throughout the two-dimensional flake. If you turn on a magnetic field perpendicular to the graphene flake, however, the behavior changes: Current flows only along the edge, while the bulk remains insulating. Moreover, this current flows only in one direction—clockwise or counterclockwise, depending on the orientation of the magnetic field—in a phenomenon known as the quantum Hall effect. In the new work, the researchers found that if they applied a second powerful magnetic field—this time in the same plane as the graphene flake—the material's behavior changes yet again: Electrons can move around the conducting edge in either direction, with electrons that have one kind of spin moving clockwise while those with the opposite spin move counterclockwise. \"We created an unusual kind of conductor along the edge,\" says Young, a Pappalardo Postdoctoral Fellow in MIT's physics department and the paper's lead author, \"virtually a one-dimensional wire.\" The segregation of electrons according to spin is \"a normal feature of topological insulators,\" he says, \"but graphene is not normally a topological insulator. We're getting the same effect in a very different material system.\" What's more, by varying the magnetic field, \"we can turn these edge states on and off,\" Young says. That switching capability means that, in principle, \"we can make circuits and transistors out of these,\" he says, which has not been realized before in conventional topological insulators. There is another benefit of this spin selectivity, Young says: It prevents a phenomenon called \"backscattering,\" which could disrupt the motion of the electrons. As a result, imperfections that would ordinarily ruin the electronic properties of the material have little effect. \"Even if the edges are 'dirty,' electrons are transmitted along this edge nearly perfectly,\" he says. Jarillo-Herrero, the Mitsui Career Development Associate Professor of Physics at MIT, says the behavior seen in these graphene flakes was predicted, but never seen before. This work, he says, is the first time such spin-selective behavior has been demonstrated in a single sheet of graphene, and also the first time anyone has demonstrated the ability \"to transition between these two regimes.\" That could ultimately lead to a novel way of making a kind of quantum computer, Jarillo-Herrero says, something that researchers have tried to do, without success, for decades. But because of the extreme conditions required, Young says, \"this would be a very specialized machine\" used only for high-priority computational tasks, such as in national laboratories. Ashoori, a professor of physics, points out that the newly discovered edge states have a number of surprising properties. For example, although gold is an exceptionally good electrical conductor, when dabs of gold are added to the edge of the graphene flakes, they cause the electrical resistance to increase. The gold dabs allow the electrons to backscatter into the oppositely traveling state by mixing the electron spins; the more gold is added, the more the resistance goes up. This research represents \"a new direction\" in topological insulators, Young says. \"We don't really know what it might lead to, but it opens our thinking about the kind of electrical devices we can make.\" The experiments required the use of a magnetic field with a strength of 35 tesla—\"about 10 times more than in an MRI machine,\" Jarillo-Herrero says—and a temperature of just 0.3 degrees Celsius above absolute zero. However, the team is already pursuing ways of observing a similar effect at magnetic fields of just one tesla—similar to a strong kitchen magnet—and at higher temperatures. Philip Kim, a professor of physics at Columbia University who was not involved in this work, says, \"The authors here have beautifully demonstrated excellent quantization of the conductance,\" as predicted by theory. He adds, \"This is very nice work that may connect topological insulator physics to the physics of graphene with interactions. This work is a good example how the two most popular topics in condensed matter physics are connected each other.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Low-dimensional electronic systems have traditionally been obtained by electrostatically confining electrons, either in heterostructures or in intrinsically nanoscale materials such as single molecules, nanowires and graphene. Recently, a new method has emerged with the recognition that symmetry-protected topological (SPT) phases 1 , 2 , which occur in systems with an energy gap to quasiparticle excitations (such as insulators or superconductors), can host robust surface states that remain gapless as long as the relevant global symmetry remains unbroken. The nature of the charge carriers in SPT surface states is intimately tied to the symmetry of the bulk, resulting in one- and two-dimensional electronic systems with novel properties. For example, time reversal symmetry endows the massless charge carriers on the surface of a three-dimensional topological insulator with helicity, fixing the orientation of their spin relative to their momentum 3 , 4 . Weakly breaking this symmetry generates a gap on the surface 5 , resulting in charge carriers with finite effective mass and exotic spin textures 6 . Analogous manipulations have yet to be demonstrated in two-dimensional topological insulators, where the primary example of a SPT phase is the quantum spin Hall state 7 , 8 . Here we demonstrate experimentally that charge-neutral monolayer graphene has a quantum spin Hall state 9 , 10 when it is subjected to a very large magnetic field angled with respect to the graphene plane. In contrast to time-reversal-symmetric systems 7 , this state is protected by a symmetry of planar spin rotations that emerges as electron spins in a half-filled Landau level are polarized by the large magnetic field. The properties of the resulting helical edge states can be modulated by balancing the applied field against an intrinsic antiferromagnetic instability 11 , 12 , 13 , which tends to spontaneously break the spin-rotation symmetry. In the resulting canted antiferromagnetic state, we observe transport signatures of gapped edge states, which constitute a new kind of one-dimensional electronic system with a tunable bandgap and an associated spin texture 14 . Main In the integer quantum Hall effect, the topology of the bulk Landau-level energy bands requires the existence of gapless edge states at any interface with the vacuum. The metrological precision of the Hall quantization can be traced to the inability of these edge states to backscatter due to the physical separation of modes with opposite momenta by the insulating sample bulk. In contrast, counterpropagating boundary states in a SPT insulator coexist spatially but are prevented from backscattering by a symmetry of the experimental system 3 , 4 . The local symmetry that protects transport in SPT surface states is unlikely to be as robust as the inherently nonlocal physical separation that protects the quantum Hall effect. However, it enables the creation of new electronic systems in which momentum and some quantum number such as spin are coupled, potentially leading to devices with new functionality. Most experimentally realized SPT phases are based on time reversal symmetry (TRS), with counterpropagating states protected from intermixing by the Kramers degeneracy. However, intensive efforts are under way to search for topological phases protected by symmetries other than time reversal in new experimental systems 15 , 16 . Our approach is inspired by the similarity between the TRS quantum spin Hall (QSH) state and overlapping electron- and hole-like copies of the quantum Hall effect, with the two copies having opposite spin polarizations. This state is protected by spin conservation rather than the orthogonality of states in a Kramers doublet 3 , as with the TRS QSH observed in systems with strong spin–orbit coupling. Nevertheless, it is expected to reproduce the characteristic experimental signatures of the TRS QSH, with gapless helical edge states enclosing an insulating bulk 9 , 10 . Two requirements are necessary for such a QSH state. First, the spin–orbit coupling must be weak, so that spin remains a good quantum number. Second, the energy gap between electron- and hole-like Landau levels must be small enough to be invertible by the Zeeman splitting. Both of these conditions are met in graphene, which is a gapless semimetal with very weak spin–orbit coupling 17 . The graphene Landau-level structure is characterized by the existence of a fourfold spin- and valley-degenerate Landau level at zero energy 18 (zLL). Near the sample boundary, the zLL splits into one positively dispersing (electron-like) and one negatively dispersing (hole-like) mode per spin projection. Consequently, a spin-symmetry-protected QSH state is expected when the spin degeneracy is lifted by an external magnetic field, resulting in a bulk energy gap at charge neutrality and electron- and hole-like states with opposite spin polarizations that cross at the sample edge 9 , 10 . Experimentally, charge-neutral monolayer graphene does not exhibit the expected phenomenology of the QSH state, becoming strongly insulating instead at high magnetic fields 19 . Although the precise nature of this insulating state has remained elusive, its origin can be traced to the strong Coulomb interactions within the graphene zLL. At integer filling factors, ν , the Coulomb energy is minimized by forming antisymmetric orbital wavefunctions, forcing the combined spin–valley isospin part of the wavefunction to be symmetric. The resulting possible ground states lie on a degenerate manifold of states fully polarized in the approximately SU(4)-symmetric isospin space 20 , encompassing a variety of different spin and valley orders. In the real experimental system, the state at any given filling factor (such as ν = 0) is determined by the competition between SU(4) symmetry-breaking effects. The most obvious such anisotropy is the Zeeman effect, which naturally favours a spin-polarized state, but the sublattice structure of the zLL adds additional interaction anisotropies 21 that can favour spin-unpolarized ground states characterized by lattice-scale spin- or charge-density-wave order 11 , 12 , 13 , 22 . This interplay can be probed experimentally by changing the in-plane component of the magnetic field, which changes the Zeeman energy but does not affect orbital energies, and previous observations indeed confirm that the state responsible for the ν = 0 insulator is spin unpolarized 23<|im_end|> <|im_start|>assistant (Phys.org) —Graphene has become an all-purpose wonder material, spurring armies of researchers to explore new possibilities for this two-dimensional lattice of pure carbon. But new research at MIT has found additional potential for the material by uncovering unexpected features that show up under some extreme conditions—features that could render graphene suitable for exotic uses such as quantum computing. The research is published this week in the journal Nature, in a paper by professors Pablo Jarillo-Herrero and Ray Ashoori, postdocs Andrea Young and Ben Hunt, graduate student Javier Sanchez-Yamaguchi, and three others. Under an extremely powerful magnetic field and at extremely low temperature, the researchers found, graphene can effectively filter electrons according to the direction of their spin, something that cannot be done by any conventional electronic system. Under typical conditions, sheets of graphene behave as normal conductors: Apply a voltage, and current flows throughout the two-dimensional flake. If you turn on a magnetic field perpendicular to the graphene flake, however, the behavior changes: Current flows only along the edge, while the bulk remains insulating. Moreover, this current flows only in one direction—clockwise or counterclockwise, depending on the orientation of the magnetic field—in a phenomenon known as the quantum Hall effect. In the new work, the researchers found that if they applied a second powerful magnetic field—this time in the same plane as the graphene flake—the material's behavior changes yet again: Electrons can move around the conducting edge in either direction, with electrons that have one kind of spin moving clockwise while those with the opposite spin move counterclockwise. "We created an unusual kind of conductor along the edge," says Young, a Pappalardo Postdoctoral Fellow in MIT's physics department and the paper's lead author, "virtually a one-dimensional wire." The segregation of electrons according to spin is "a normal feature of topological insulators," he says, "but graphene is not normally a topological insulator. We're getting the same effect in a very different material system." What's more, by varying the magnetic field, "we can turn these edge states on and off," Young says. That switching capability means that, in principle, "we can make circuits and transistors out of these," he says, which has not been realized before in conventional topological insulators. There is another benefit of this spin selectivity, Young says: It prevents a phenomenon called "backscattering," which could disrupt the motion of the electrons. As a result, imperfections that would ordinarily ruin the electronic properties of the material have little effect. "Even if the edges are 'dirty,' electrons are transmitted along this edge nearly perfectly," he says. Jarillo-Herrero, the Mitsui Career Development Associate Professor of Physics at MIT, says the behavior seen in these graphene flakes was predicted, but never seen before. This work, he says, is the first time such spin-selective behavior has been demonstrated in a single sheet of graphene, and also the first time anyone has demonstrated the ability "to transition between these two regimes." That could ultimately lead to a novel way of making a kind of quantum computer, Jarillo-Herrero says, something that researchers have tried to do, without success, for decades. But because of the extreme conditions required, Young says, "this would be a very specialized machine" used only for high-priority computational tasks, such as in national laboratories. Ashoori, a professor of physics, points out that the newly discovered edge states have a number of surprising properties. For example, although gold is an exceptionally good electrical conductor, when dabs of gold are added to the edge of the graphene flakes, they cause the electrical resistance to increase. The gold dabs allow the electrons to backscatter into the oppositely traveling state by mixing the electron spins; the more gold is added, the more the resistance goes up. This research represents "a new direction" in topological insulators, Young says. "We don't really know what it might lead to, but it opens our thinking about the kind of electrical devices we can make." The experiments required the use of a magnetic field with a strength of 35 tesla—"about 10 times more than in an MRI machine," Jarillo-Herrero says—and a temperature of just 0.3 degrees Celsius above absolute zero. However, the team is already pursuing ways of observing a similar effect at magnetic fields of just one tesla—similar to a strong kitchen magnet—and at higher temperatures. Philip Kim, a professor of physics at Columbia University who was not involved in this work, says, "The authors here have beautifully demonstrated excellent quantization of the conductance," as predicted by theory. He adds, "This is very nice work that may connect topological insulator physics to the physics of graphene with interactions. This work is a good example how the two most popular topics in condensed matter physics are connected each other." <|im_end|>

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264, 832, 33520, 9244, 1210, 578, 64244, 315, 57678, 4184, 311, 12903, 374, 330, 64, 4725, 4668, 315, 1948, 5848, 1672, 42391, 1359, 568, 2795, 11, 330, 8248, 66192, 374, 539, 14614, 264, 1948, 5848, 1672, 10733, 13, 1226, 2351, 3794, 279, 1890, 2515, 304, 264, 1633, 2204, 3769, 1887, 1210, 3639, 596, 810, 11, 555, 29865, 279, 24924, 2115, 11, 330, 906, 649, 2543, 1521, 6964, 5415, 389, 323, 1022, 1359, 13566, 2795, 13, 3011, 28865, 23099, 3445, 430, 11, 304, 17966, 11, 330, 906, 649, 1304, 46121, 323, 1380, 380, 1105, 704, 315, 1521, 1359, 568, 2795, 11, 902, 706, 539, 1027, 15393, 1603, 304, 21349, 1948, 5848, 1672, 42391, 13, 2684, 374, 2500, 8935, 315, 420, 12903, 3373, 1968, 11, 13566, 2795, 25, 1102, 29034, 264, 25885, 2663, 330, 1445, 2445, 31436, 1359, 902, 1436, 24927, 279, 11633, 315, 279, 57678, 13, 1666, 264, 1121, 11, 17190, 25384, 430, 1053, 98081, 38339, 279, 14683, 6012, 315, 279, 3769, 617, 2697, 2515, 13, 330, 13461, 422, 279, 13116, 527, 364, 54588, 2965, 57678, 527, 34699, 3235, 420, 6964, 7154, 14268, 1359, 568, 2795, 13, 31651, 22532, 11529, 618, 2382, 11, 279, 60676, 2005, 41576, 11050, 33468, 17054, 315, 28415, 520, 15210, 11, 2795, 279, 7865, 3970, 304, 1521, 66192, 82723, 574, 19698, 11, 719, 2646, 3970, 1603, 13, 1115, 990, 11, 568, 2795, 11, 374, 279, 1176, 892, 1778, 12903, 21090, 535, 7865, 706, 1027, 21091, 304, 264, 3254, 11071, 315, 66192, 11, 323, 1101, 279, 1176, 892, 5606, 706, 21091, 279, 5845, 330, 998, 9320, 1990, 1521, 1403, 61911, 1210, 3011, 1436, 13967, 3063, 311, 264, 11775, 1648, 315, 3339, 264, 3169, 315, 31228, 6500, 11, 31651, 22532, 11529, 618, 2382, 2795, 11, 2555, 430, 12074, 617, 6818, 311, 656, 11, 2085, 2450, 11, 369, 11026, 13, 2030, 1606, 315, 279, 14560, 4787, 2631, 11, 13566, 2795, 11, 330, 576, 1053, 387, 264, 1633, 28175, 5780, 1, 1511, 1193, 369, 1579, 2320, 8948, 55580, 9256, 11, 1778, 439, 304, 5426, 70760, 13, 14937, 10922, 72, 11, 264, 14561, 315, 22027, 11, 3585, 704, 430, 279, 13945, 11352, 6964, 5415, 617, 264, 1396, 315, 15206, 6012, 13, 1789, 3187, 11, 8051, 6761, 374, 459, 48298, 1695, 20314, 61856, 11, 994, 294, 3518, 315, 6761, 527, 3779, 311, 279, 6964, 315, 279, 66192, 82723, 11, 814, 5353, 279, 20314, 13957, 311, 5376, 13, 578, 6761, 294, 3518, 2187, 279, 57678, 311, 1203, 71350, 1139, 279, 8081, 275, 989, 21646, 1614, 555, 27890, 279, 17130, 45858, 26, 279, 810, 6761, 374, 3779, 11, 279, 810, 279, 13957, 5900, 709, 13, 1115, 3495, 11105, 330, 64, 502, 5216, 1, 304, 1948, 5848, 1672, 42391, 11, 13566, 2795, 13, 330, 1687, 1541, 956, 2216, 1440, 1148, 433, 2643, 3063, 311, 11, 719, 433, 16264, 1057, 7422, 922, 279, 3169, 315, 20314, 7766, 584, 649, 1304, 1210, 578, 21896, 2631, 279, 1005, 315, 264, 24924, 2115, 449, 264, 8333, 315, 220, 1758, 51309, 4355, 93830, 9274, 220, 605, 3115, 810, 1109, 304, 459, 52460, 5780, 1359, 31651, 22532, 11529, 618, 2382, 2795, 17223, 264, 9499, 315, 1120, 220, 15, 13, 18, 12628, 62447, 3485, 10973, 7315, 13, 4452, 11, 279, 2128, 374, 2736, 34118, 5627, 315, 46071, 264, 4528, 2515, 520, 24924, 5151, 315, 1120, 832, 51309, 4355, 2345, 65387, 311, 264, 3831, 9979, 33297, 17223, 520, 5190, 20472, 13, 26241, 13818, 11, 264, 14561, 315, 22027, 520, 19326, 3907, 889, 574, 539, 6532, 304, 420, 990, 11, 2795, 11, 330, 791, 12283, 1618, 617, 32719, 21091, 9250, 10484, 2065, 315, 279, 6929, 685, 1359, 439, 19698, 555, 10334, 13, 1283, 11621, 11, 330, 2028, 374, 1633, 6555, 990, 430, 1253, 4667, 1948, 5848, 1672, 10733, 22027, 311, 279, 22027, 315, 66192, 449, 22639, 13, 1115, 990, 374, 264, 1695, 3187, 1268, 279, 1403, 1455, 5526, 13650, 304, 75826, 5030, 22027, 527, 8599, 1855, 1023, 1210, 220, 128257, 198 ]

2,382

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Minmi is the only known genus of ankylosaurian dinosaur from Australia. Seven specimens are known, all from the Lower Cretaceous of Queensland. Only two of these have been described in any detail: the holotype specimen Minmi paravertebra from the Bungil Formation near Roma, and a near complete skeleton from the Allaru Mudstone on Marathon Station near Richmond, preliminarily referred to a possible new species of Minmi . The Marathon specimen represents one of the world’s most complete ankylosaurian skeletons and the best-preserved dinosaurian fossil from eastern Gondwana. Moreover, among ankylosaurians, its skull is one of only a few in which the majority of sutures have not been obliterated by dermal ossifications or surface remodelling. Recent preparation of the Marathon specimen has revealed new details of the palate and narial regions, permitting a comprehensive description and thus providing new insights cranial osteology of a basal ankylosaurian. The skull has also undergone computed tomography, digital segmentation and 3D computer visualisation enabling the reconstruction of its nasal cavity and endocranium. The airways of the Marathon specimen are more complicated than non-ankylosaurian dinosaurs but less so than derived ankylosaurians. The cranial (brain) endocast is superficially similar to those of other ankylosaurians but is strongly divergent in many important respects. The inner ear is extremely large and unlike that of any dinosaur yet known. Based on a high number of diagnostic differences between the skull of the Marathon specimen and other ankylosaurians, we consider it prudent to assign this specimen to a new genus and species of ankylosaurian. Kunbarrasaurus ieversi gen. et sp. nov. represents the second genus of ankylosaurian from Australia and is characterised by an unusual melange of both primitive and derived characters, shedding new light on the evolution of the ankylosaurian skull. Cite this as Leahey LG, Molnar RE, Carpenter K, Witmer LM, Salisbury SW. 2015 . Cranial osteology of the ankylosaurian dinosaur formerly known as Minmi sp. (Ornithischia: Thyreophora) from the Lower Cretaceous Allaru Mudstone of Richmond, Queensland, Australia . PeerJ 3 : e1475 Main article text Introduction In 1989 the near-complete skeleton of an armoured dinosaur (QM F18101) was found in the upper Albian–(?)lower Cenomanian Allaru Mudstone on Marathon Station near Richmond, north-western Queensland, Australia by Mr. Ian Ievers ( Fig. 1 ). The fossil was collected and initial preparation was undertaken at the Queensland Museum. Recognising the scientific value of the specimen prior to preparation being completed, Molnar (1996a) published a partial description, and preliminarily assigned the specimen to Minmi —the only genus of ankylosaurian known from Australia. This assignment was based solely on its possession of paravertebral elements (ossified aponeuroses and tendons associated with the epaxial musculature), which were a diagnostic feature of Minmi paravertebra ( Molnar, 1980 ). A complete description of the Marathon specimen and an assessment of its phylogenetic relationships, particularly its preliminary taxonomic assignment to Minmi, were planned for future research Molnar (1996a) . Figure 1: Locality map for Australian eurypodan thyreophoran fossils. 1, Stegosaurian? footprint (QM F5701), Walloon Coal Measures, Balgowan Colliery, Balgowan (Bajocian–Bathonian); 2, Minmi paravertebra holotype (QM F10329) ( Molnar, 1980 ), Minmi Member, Bungil Formation (Valanginian–Barremian); 3, Thyreophoran trackways, Broome Sandstone, Dampier Peninsula, Western Australia (Valanginian–Barremian); 4, Ankylosauria indet. (see Barrett et al., 2010 ) ‘Flat Rocks’ Wonthaggi Formation (upper Hauterivian–Albian); 5, NMV P216739, ‘Lake Copco–Dinosaur Cove’ Eumeralla Formation (middle upper Aptian to lower middle Albian) ( Barrett et al., 2010 ); 6, QM F33286; 7, AM F119849 and AM F35259; 8, Kunbarrasaurus ieversi gen. et sp. nov. (formerly Minmi sp.) (QM F18101); 9, QM F33565 and QM F33566; 10, QM F44324-28. Legend: Dark Green, Toolebuc Formation (late middle–early late Albian); Green, Allaru Formation (upper Albian–(?)lower Cenomanian); Light green, Mackunda Formation (upper Albian–lower Cenomanian); Lightest green, Winton Formation (late Albian–early Turonian). Download full-size image DOI: 10.7717/peerj.1475/fig-1 In total, seven ankylosaurian fossils from the Lower Cretaceous of Queensland have been attributed to Minmi , in most instances tentatively. Only two of these specimens have been described in any detail: the holotype Minmi paravertebra QM F10329 from the lower Aptian ( Burger, 1980 ; Burger, 1993 ; Chan, 2009 ; Cook, Bryan & Draper, 2013 ) Minmi Member of the Bungil Formation near Roma ( Molnar, 1980 ); and the Marathon specimen QM F18101 (preliminary assigned to Minmi sp. by Molnar, 1996a ; discussed herein) ( Fig. 1 ). The remaining five specimens were all discovered in the sediments of the north-western region of Queensland and include: QM F33286 from the upper middle–lower upper Albian ( Gray, McKillop & McKellar, 2002 ; Cook, Bryan & Draper, 2013 ) Toolebuc Formation of Julia Creek; AM F119849 and AM F35259 from the Toolebuc Formation near Hughenden; and, QM F33565 and QM F33566 from the Allaru Mudstone near Hughenden ( Fig. 1 ). Examination of these other specimens is currently being conducted as part of a broader study on Australian ankylosaurians. In addition to the aforementioned specimens, fragmentary ankylosaurian material is also known from broadly coeval sediments in other parts of Queensland ( Leahey & Salisbury, 2013 ) and Victoria ( Barrett et al., 2010 ) ( Fig. 1 ). Due to their isolated and/or fragmentary nature, taxonomic assignment of these specimens has not advanced beyond Ankylosauria indet. Ichnological evidence of other thyreophorans is also known from Middle Jurassic (Bajocian–Bathonian) Walloon Coal Measures at Balgowan, Darling Downs, Queensland ( Hill, Playford & Woods, 1966 : 30–31; replica QM F5701) and the Lower Cretaceous (Valanginian–Barremian) Broome Sandstone of the Dampier Peninsula, Western Australia ( Fig. 1 ) ( Long, 1990 ; Long, 1992 ; Long, 1998 ; Long, 2002 ; Molnar, 1991 ; Thulborn, Hamley & Foulkes, 1994 ; Thulborn, 1998 ; Rich & Vickers-Rich, 2003 ; Scanlon, 2006 ; McCrea et al., 2012 ). The Marathon specimen (QM F18101) represents the most complete dinosaurian fossil from eastern Gondwana (Australia, New Zealand, India and Antarctica), and the most complete ankylosaurian fossil from Gondwana. It is also one of the world’s most complete ankylosaurians. Moreover, it includes one of the few ankylosaurian skulls in which most", "role": "user" }, { "content": "It has a parrot-like beak, bones in its skin and an inner ear similar to a turtle. Meet Kunbarrasaurus, Australia's newest dinosaur. The skeleton of Kunbarrasaurus (koon-ba-rah-sore-rus) was discovered in 1989, but new research from a team led by University of Queensland experts has revealed the dinosaur is a distinctly different species than previously thought. UQ School of Biological Sciences PhD student Lucy Leahey said the fossil represented the most complete dinosaur so far discovered in Australia and one of the best-preserved ankylosaur fossils in the world. \"Ankylosaurs were a group of four-legged, herbivorous dinosaurs, closely related to stegosaurs,\" Ms Leahey said. \"Like crocodiles, they had bones in their skin and are commonly referred to as 'armoured' dinosaurs.\" \"When it was first studied back in the 1990s, the fossil was placed it in the same genus as Australia's only other named ankylosaur, Minmi, which is based on some bones from Roma in south-western Queensland.\" The team's research found the fossil was different to the Roma Minmi, and distinct enough from all other ankylosaurs to warrant a new name. \"Kunbarra is the word for 'shield' in the Mayi language of the Wunumara people from the Richmond area, and the species name honours the person who originally found the fossil, Mr Ian Ievers. It means 'Ievers' shield lizard,\" Ms Leahey said. Research that started in 2007 involved careful preparation of the palate of the dinosaur at the Denver Museum of Nature and Science, along with CT scanning at the Mater Adult Hospital. Lucy Leahey working on the holotype skeleton of Kunbarrasaurus ieversi. Credit: Steve Salisbury. Professor Lawrence Witmer from the Ohio University Heritage College of Osteopathic Medicine used the information to create a 3D reconstruction of the brain, inner ear and nasal cavities, which can be viewed here. \"The CT reconstruction revealed that Kunbarrasaurus had a more complicated airway than other dinosaurs, but less so than ankylosaurs from the Northern Hemisphere,\" Professor Witmer said. \"The inner ear is proportionately enormous and unlike anything we have seen before in a dinosaur. \"It looks more like the inner ear of a Tuatara or a turtle. Exactly what the consequences of this are we are still unsure.\" UQ's Dr Steve Salisbury said the findings made it clear that the Kunbarrasaurus specimen should be considered as a new dinosaur. Lucy Leahey (right) and Rob Ievers (middle) and at the site where the skeleton of Kunbarrasaurus ieversi was discovered on Marathon Station, near Richmond, north-western Queensland. Credit: Lucy Leahey. \"The sheep-sized herbivore formerly known as Minmi sp. is now known to have had a parrot-like beak, breathed through a nasal passage that looped back on itself, and had an inner ear more like a tuatara than a dinosaur,\" he said. \"Our work has also revealed that Kunbarrasaurus is more primitive than the majority of other well-known ankylosaurs from North America and Asia.\" \"It appears to represent an early, less heavily 'armoured' member of the group, close to the point at which the ankylosaurs diverged from the other main lineage of armoured dinosaurs, the stegosaurs.\" The holotype skeleton of Kunbarrasaurus ieversi (QM F18101), Australia’s most complete dinosaur fossil, and one of the world’s most complete ankylosaurians. Credit: Anthony O’Toole and Lucy Leahey The skeleton of Kunbarrasaurus ieversi is on display at the Queensland Museum (Southbank). The research is available online in the open access journal PeerJ. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Minmi is the only known genus of ankylosaurian dinosaur from Australia. Seven specimens are known, all from the Lower Cretaceous of Queensland. Only two of these have been described in any detail: the holotype specimen Minmi paravertebra from the Bungil Formation near Roma, and a near complete skeleton from the Allaru Mudstone on Marathon Station near Richmond, preliminarily referred to a possible new species of Minmi . The Marathon specimen represents one of the world’s most complete ankylosaurian skeletons and the best-preserved dinosaurian fossil from eastern Gondwana. Moreover, among ankylosaurians, its skull is one of only a few in which the majority of sutures have not been obliterated by dermal ossifications or surface remodelling. Recent preparation of the Marathon specimen has revealed new details of the palate and narial regions, permitting a comprehensive description and thus providing new insights cranial osteology of a basal ankylosaurian. The skull has also undergone computed tomography, digital segmentation and 3D computer visualisation enabling the reconstruction of its nasal cavity and endocranium. The airways of the Marathon specimen are more complicated than non-ankylosaurian dinosaurs but less so than derived ankylosaurians. The cranial (brain) endocast is superficially similar to those of other ankylosaurians but is strongly divergent in many important respects. The inner ear is extremely large and unlike that of any dinosaur yet known. Based on a high number of diagnostic differences between the skull of the Marathon specimen and other ankylosaurians, we consider it prudent to assign this specimen to a new genus and species of ankylosaurian. Kunbarrasaurus ieversi gen. et sp. nov. represents the second genus of ankylosaurian from Australia and is characterised by an unusual melange of both primitive and derived characters, shedding new light on the evolution of the ankylosaurian skull. Cite this as Leahey LG, Molnar RE, Carpenter K, Witmer LM, Salisbury SW. 2015 . Cranial osteology of the ankylosaurian dinosaur formerly known as Minmi sp. (Ornithischia: Thyreophora) from the Lower Cretaceous Allaru Mudstone of Richmond, Queensland, Australia . PeerJ 3 : e1475 Main article text Introduction In 1989 the near-complete skeleton of an armoured dinosaur (QM F18101) was found in the upper Albian–(?)lower Cenomanian Allaru Mudstone on Marathon Station near Richmond, north-western Queensland, Australia by Mr. Ian Ievers ( Fig. 1 ). The fossil was collected and initial preparation was undertaken at the Queensland Museum. Recognising the scientific value of the specimen prior to preparation being completed, Molnar (1996a) published a partial description, and preliminarily assigned the specimen to Minmi —the only genus of ankylosaurian known from Australia. This assignment was based solely on its possession of paravertebral elements (ossified aponeuroses and tendons associated with the epaxial musculature), which were a diagnostic feature of Minmi paravertebra ( Molnar, 1980 ). A complete description of the Marathon specimen and an assessment of its phylogenetic relationships, particularly its preliminary taxonomic assignment to Minmi, were planned for future research Molnar (1996a) . Figure 1: Locality map for Australian eurypodan thyreophoran fossils. 1, Stegosaurian? footprint (QM F5701), Walloon Coal Measures, Balgowan Colliery, Balgowan (Bajocian–Bathonian); 2, Minmi paravertebra holotype (QM F10329) ( Molnar, 1980 ), Minmi Member, Bungil Formation (Valanginian–Barremian); 3, Thyreophoran trackways, Broome Sandstone, Dampier Peninsula, Western Australia (Valanginian–Barremian); 4, Ankylosauria indet. (see Barrett et al., 2010 ) ‘Flat Rocks’ Wonthaggi Formation (upper Hauterivian–Albian); 5, NMV P216739, ‘Lake Copco–Dinosaur Cove’ Eumeralla Formation (middle upper Aptian to lower middle Albian) ( Barrett et al., 2010 ); 6, QM F33286; 7, AM F119849 and AM F35259; 8, Kunbarrasaurus ieversi gen. et sp. nov. (formerly Minmi sp.) (QM F18101); 9, QM F33565 and QM F33566; 10, QM F44324-28. Legend: Dark Green, Toolebuc Formation (late middle–early late Albian); Green, Allaru Formation (upper Albian–(?)lower Cenomanian); Light green, Mackunda Formation (upper Albian–lower Cenomanian); Lightest green, Winton Formation (late Albian–early Turonian). Download full-size image DOI: 10.7717/peerj.1475/fig-1 In total, seven ankylosaurian fossils from the Lower Cretaceous of Queensland have been attributed to Minmi , in most instances tentatively. Only two of these specimens have been described in any detail: the holotype Minmi paravertebra QM F10329 from the lower Aptian ( Burger, 1980 ; Burger, 1993 ; Chan, 2009 ; Cook, Bryan & Draper, 2013 ) Minmi Member of the Bungil Formation near Roma ( Molnar, 1980 ); and the Marathon specimen QM F18101 (preliminary assigned to Minmi sp. by Molnar, 1996a ; discussed herein) ( Fig. 1 ). The remaining five specimens were all discovered in the sediments of the north-western region of Queensland and include: QM F33286 from the upper middle–lower upper Albian ( Gray, McKillop & McKellar, 2002 ; Cook, Bryan & Draper, 2013 ) Toolebuc Formation of Julia Creek; AM F119849 and AM F35259 from the Toolebuc Formation near Hughenden; and, QM F33565 and QM F33566 from the Allaru Mudstone near Hughenden ( Fig. 1 ). Examination of these other specimens is currently being conducted as part of a broader study on Australian ankylosaurians. In addition to the aforementioned specimens, fragmentary ankylosaurian material is also known from broadly coeval sediments in other parts of Queensland ( Leahey & Salisbury, 2013 ) and Victoria ( Barrett et al., 2010 ) ( Fig. 1 ). Due to their isolated and/or fragmentary nature, taxonomic assignment of these specimens has not advanced beyond Ankylosauria indet. Ichnological evidence of other thyreophorans is also known from Middle Jurassic (Bajocian–Bathonian) Walloon Coal Measures at Balgowan, Darling Downs, Queensland ( Hill, Playford & Woods, 1966 : 30–31; replica QM F5701) and the Lower Cretaceous (Valanginian–Barremian) Broome Sandstone of the Dampier Peninsula, Western Australia ( Fig. 1 ) ( Long, 1990 ; Long, 1992 ; Long, 1998 ; Long, 2002 ; Molnar, 1991 ; Thulborn, Hamley & Foulkes, 1994 ; Thulborn, 1998 ; Rich & Vickers-Rich, 2003 ; Scanlon, 2006 ; McCrea et al., 2012 ). The Marathon specimen (QM F18101) represents the most complete dinosaurian fossil from eastern Gondwana (Australia, New Zealand, India and Antarctica), and the most complete ankylosaurian fossil from Gondwana. It is also one of the world’s most complete ankylosaurians. Moreover, it includes one of the few ankylosaurian skulls in which most<|im_end|> <|im_start|>assistant It has a parrot-like beak, bones in its skin and an inner ear similar to a turtle. Meet Kunbarrasaurus, Australia's newest dinosaur. The skeleton of Kunbarrasaurus (koon-ba-rah-sore-rus) was discovered in 1989, but new research from a team led by University of Queensland experts has revealed the dinosaur is a distinctly different species than previously thought. UQ School of Biological Sciences PhD student Lucy Leahey said the fossil represented the most complete dinosaur so far discovered in Australia and one of the best-preserved ankylosaur fossils in the world. "Ankylosaurs were a group of four-legged, herbivorous dinosaurs, closely related to stegosaurs," Ms Leahey said. "Like crocodiles, they had bones in their skin and are commonly referred to as 'armoured' dinosaurs." "When it was first studied back in the 1990s, the fossil was placed it in the same genus as Australia's only other named ankylosaur, Minmi, which is based on some bones from Roma in south-western Queensland." The team's research found the fossil was different to the Roma Minmi, and distinct enough from all other ankylosaurs to warrant a new name. "Kunbarra is the word for 'shield' in the Mayi language of the Wunumara people from the Richmond area, and the species name honours the person who originally found the fossil, Mr Ian Ievers. It means 'Ievers' shield lizard," Ms Leahey said. Research that started in 2007 involved careful preparation of the palate of the dinosaur at the Denver Museum of Nature and Science, along with CT scanning at the Mater Adult Hospital. Lucy Leahey working on the holotype skeleton of Kunbarrasaurus ieversi. Credit: Steve Salisbury. Professor Lawrence Witmer from the Ohio University Heritage College of Osteopathic Medicine used the information to create a 3D reconstruction of the brain, inner ear and nasal cavities, which can be viewed here. "The CT reconstruction revealed that Kunbarrasaurus had a more complicated airway than other dinosaurs, but less so than ankylosaurs from the Northern Hemisphere," Professor Witmer said. "The inner ear is proportionately enormous and unlike anything we have seen before in a dinosaur. "It looks more like the inner ear of a Tuatara or a turtle. Exactly what the consequences of this are we are still unsure." UQ's Dr Steve Salisbury said the findings made it clear that the Kunbarrasaurus specimen should be considered as a new dinosaur. Lucy Leahey (right) and Rob Ievers (middle) and at the site where the skeleton of Kunbarrasaurus ieversi was discovered on Marathon Station, near Richmond, north-western Queensland. Credit: Lucy Leahey. "The sheep-sized herbivore formerly known as Minmi sp. is now known to have had a parrot-like beak, breathed through a nasal passage that looped back on itself, and had an inner ear more like a tuatara than a dinosaur," he said. "Our work has also revealed that Kunbarrasaurus is more primitive than the majority of other well-known ankylosaurs from North America and Asia." "It appears to represent an early, less heavily 'armoured' member of the group, close to the point at which the ankylosaurs diverged from the other main lineage of armoured dinosaurs, the stegosaurs." The holotype skeleton of Kunbarrasaurus ieversi (QM F18101), Australia’s most complete dinosaur fossil, and one of the world’s most complete ankylosaurians. Credit: Anthony O’Toole and Lucy Leahey The skeleton of Kunbarrasaurus ieversi is on display at the Queensland Museum (Southbank). The research is available online in the open access journal PeerJ. <|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 stability of organic solar cells is a key issue to promote practical applications. Herein, we demonstrate that the device performance of organic solar cells is enhanced by an Ir/IrO x electron-transporting layer, benefiting from its suitable work function and heterogeneous distribution of surface energy in nanoscale. Notably, the champion Ir/IrO x -based devices exhibit superior stabilities under shelf storing ( T 80 = 56696 h), thermal aging ( T 70 = 13920 h), and maximum power point tracking ( T 80 = 1058 h), compared to the ZnO-based devices. It can be attributed to the stable morphology of photoactive layer resulting from the optimized molecular distribution of the donor and acceptor and the absence of photocatalysis in the Ir/IrO x -based devices, which helps to maintain the improved charge extraction and inhibited charge recombination in the aged devices. This work provides a reliable and efficient electron-transporting material toward stable organic solar cells. Introduction During the past several years, the power conversion efficiency (PCE) of organic solar cells (OSCs) has been enhanced rapidly 1 , 2 , 3 with the development of polymer donors and non-fullerene acceptors 4 . Currently, improving the lifetime of OSCs is the top priority to promote practical applications 5 , 6 , 7 , 8 , 9 . Except for the material and morphology of the active layer 10 , 11 , 12 , the hole/electron-transporting layer (HTL/ETL) 13 , 14 and device structure 15 also determine the stability. The inverted structure has been proven to be a feasible strategy for achieving superior device stability 15 . Traditional metal oxides (such as TiO x 16 , 17 and ZnO 5 , 14 ) used as the electron-transporting materials in inverted OSCs usually suffer from unfavorable light-soaking 18 or photocatalysis problem 14 . Efforts have been devoted to seeking reliable cathode interfacial materials, including nonconjugated electrolytes (such as PEI 19 and PEIE 20 ), conjugated polyelectrolytes (such as PFN-Br 21 and PDNIT-F3N 22 ), and conjugated small-molecular electrolytes (such as PDINO 23 and PDINN 24 , 25 ), etc. However, the long-term stability of OSCs is still unsatisfactory, and stable electron-transporting materials are urgently needed. In this contribution, we provide a reliable and efficient electron-transporting material for stable OSCs. Iridium/Iridium oxide (Ir/IrO x ) nanoparticles are synthesized through the solution process and utilized as an electron-transporting material in OSCs. The enhanced PCE of Ir/IrO x -based devices compared with one of the ZnO-based devices originates from its suitable work function, the regulation of the optical field, and the heterogeneous surface energy distribution in the nanoscale (HeD-SE). Benefiting from the well-organized and stable bulk-heterojunction (BHJ) film and the absence of photocatalysis, the Ir/IrO x -based devices exhibit excellent long-term stability under shelf storing ( T 80 = 56,696 h vs. 12,075 h, which is the time when the PCE of the device decreases to the 80% of initial PCE), thermal aging ( T 70 = 13,920 h vs. 2198 h, the time when the PCE of the device decreases to the 70% of initial PCE), and maximum power point (MPP) tracking ( T 80 = 1058 h vs. 586 h) compared with the ZnO-based devices. The impact of Ir/IrO x on the morphological evolution of BHJ films is further discussed in detail to explore the degradation mechanism. Moreover, the stability of OSCs under thermal circulation and ultraviolet (UV)-irradiation are also improved by the Ir/IrO x ETL, which illustrates that the possibility of operating under extreme environments can be increased by applying Ir/IrO x . Results Characterization of Ir/IrO x In this study, Ir/IrO x nanoparticles have been selected as an electron-transporting material since iridium (Ir) -based nanoparticles exhibit excellent charge-transfer ability in electrocatalysis 26 , 27 , 28 , 29 . The Ir/IrO x nanoparticles were prepared through the mild colloid solution method 30 , 31 with IrCl 3 ·3H 2 O precursor under Ar atmosphere (Fig. 1a and Supplementary Fig. 1 ). Compared with the ZnO precursor solution, the colloidal solution of iridium-based nanoparticles shows better stability after storing in the air for 2 years (Supplementary Fig. 2 ). The mean diameter of the nanoparticle is 1.50 ± 0.30 nm measured by the special aberration-corrected transmission electron microscope (AC-TEM) (Fig. 1b and Supplementary Fig. 3 ). The cross-sectional TEM patterns (Fig. 1b and Supplementary Fig. 4 ) demonstrate that Ir/IrO x nanoparticles can be deposited on the ITO substrate to form a condensed and uniform film, whose mean thickness is 4.66 ± 0.37 nm (Supplementary Fig. 5 ). Fig. 1: Characterization of Ir/IrO x . a The synthesis process of Ir/IrO x nanoparticles. In the synthesis route, the Δ represents heating at 160 °C. b The cross-sectional transmission electron microscope (TEM) patterns of Ir/IrO x samples spin-coated on ITO, which was prepared by a focused ion beam (FIB). The insert is the high-resolution image of a single Ir/IrO x nanoparticle on copper mesh, which was characterized by a special aberration-corrected transmission electron microscope (AC-TEM). c The Ir 4f X-ray photoelectron spectroscopy (XPS) plot of Ir/IrO x nanoparticles. d The ultraviolet photoelectron spectroscopy (UPS) characterizations of ITO (gray), ZnO (blue), and Ir/IrO x (red). The Peak-force quantitative nanomechanical mappings ( PFQNM) morphology ( e, f ) and adhesion ( g, h ) patterns of ZnO and Ir/IrO x films. Full size image The X-ray photoelectron spectroscopy (XPS) characterization assisted to determine the oxidation state of nanoparticles (Supplementary Fig. 6 ). In the Ir 4 f core-level spectrum (Fig. 1c ), two groups of peaks located at 60.23/63.26 eV and 62.79/65.24 eV are attributed to the metallic Ir and IrO x 32 , 33 , respectively. Energy level matching is an important basis for selecting an ETL. By characterizations of ultraviolet photoelectron spectroscopy (UPS, Fig. 1d ), the work function (WF) of the Ir/IrO x and ZnO were determined to be 4.05 eV and 4.22 eV, respectively. Besides, the WFs of the bare ITO and ITO modified by glycol (solvent), NaOH in glycol (pH = 10), and", "role": "user" }, { "content": "In recent years, the device efficiency of organic solar cells (OSCs) has been significantly improved, but the unsatisfactory stability restricts future commercialization processing. Inverted device structure has been widely adopted to enhance the device stability of OSCs. However, zinc oxide (ZnO), the most commonly used electron-transporting material, is photocatalytic active, which could accelerate the decomposition of the active layers under continuous light illumination, and then lead to the degradation of device performance. Therefore, developing new electron-transporting materials is extremely critical for utilizing efficient and stable OSCs. Recently, Prof. Zhou Huiqiong's group from National Center for Nanoscience and Technology (NCNST) of the Chinese Academy of Science (CAS) has developed a new electron transport material Ir/IrOx to enhance the stability of OSCs. The study was published online in Nature Communications. Prof. Zhou's group has carried out a series of studies focused on the stability of OSCs. By incorporating organic electron transport material PFN-Br into the ZnO layer, the surface energy of the interface layer was regulated, resulting in the enhanced device stability (Journal of Materials Chemistry A ). Furthermore, the polyaspartic acid (PASP) film was deposited on the ZnO film to suppress the degradation caused by illumination, leading to the improved stability of organic solar cells. (Journal of Materials Chemistry C). In this study, the Ir/IrOx nanoparticles prepared by the mild colloid solution method were utilized as the electron-transporting material in organic solar cells instead of the common ZnO layer. Benefiting from the suitable work function, heterogeneous surface energy distribution in nanoscale and optimized optical field, the Ir/IrOx-based devices exhibited more efficient charge extraction and suppressed charge recombination compared with the ZnO-based devices, leading to improved device performance. Due to the absence of photocatalysis, the active layer deposited on Ir/IrOx film exhibited more stable component distribution and morphology, elongating the lifetime of Ir/IrOx-based devices under storage in inert atmosphere, thermal aging and maximum-power-point (MPP) tracking conditions. In particular, the T70 lifetime of Ir/IrOx-based devices under thermal aging exceeded 10,000 hours. Moreover, the better stability of Ir/IrOx-based devices under UV irradiation and thermal cycling between -40℃ and 85℃ illustrated the huge potential of OSCs with Ir/IrOx operating under extreme environments. \"The appropriate optoelectric properties and photocatalytic inactivity of Ir/IrOx allow us to investigate the mechanism of photo-induced degradation in OSCs, finally achieving the enhanced device stability under various aging condition,\" said Prof. Zhou. \"We envision that our results are also helpful to the related work focused on the intrinsic stability of OSCs.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 stability of organic solar cells is a key issue to promote practical applications. Herein, we demonstrate that the device performance of organic solar cells is enhanced by an Ir/IrO x electron-transporting layer, benefiting from its suitable work function and heterogeneous distribution of surface energy in nanoscale. Notably, the champion Ir/IrO x -based devices exhibit superior stabilities under shelf storing ( T 80 = 56696 h), thermal aging ( T 70 = 13920 h), and maximum power point tracking ( T 80 = 1058 h), compared to the ZnO-based devices. It can be attributed to the stable morphology of photoactive layer resulting from the optimized molecular distribution of the donor and acceptor and the absence of photocatalysis in the Ir/IrO x -based devices, which helps to maintain the improved charge extraction and inhibited charge recombination in the aged devices. This work provides a reliable and efficient electron-transporting material toward stable organic solar cells. Introduction During the past several years, the power conversion efficiency (PCE) of organic solar cells (OSCs) has been enhanced rapidly 1 , 2 , 3 with the development of polymer donors and non-fullerene acceptors 4 . Currently, improving the lifetime of OSCs is the top priority to promote practical applications 5 , 6 , 7 , 8 , 9 . Except for the material and morphology of the active layer 10 , 11 , 12 , the hole/electron-transporting layer (HTL/ETL) 13 , 14 and device structure 15 also determine the stability. The inverted structure has been proven to be a feasible strategy for achieving superior device stability 15 . Traditional metal oxides (such as TiO x 16 , 17 and ZnO 5 , 14 ) used as the electron-transporting materials in inverted OSCs usually suffer from unfavorable light-soaking 18 or photocatalysis problem 14 . Efforts have been devoted to seeking reliable cathode interfacial materials, including nonconjugated electrolytes (such as PEI 19 and PEIE 20 ), conjugated polyelectrolytes (such as PFN-Br 21 and PDNIT-F3N 22 ), and conjugated small-molecular electrolytes (such as PDINO 23 and PDINN 24 , 25 ), etc. However, the long-term stability of OSCs is still unsatisfactory, and stable electron-transporting materials are urgently needed. In this contribution, we provide a reliable and efficient electron-transporting material for stable OSCs. Iridium/Iridium oxide (Ir/IrO x ) nanoparticles are synthesized through the solution process and utilized as an electron-transporting material in OSCs. The enhanced PCE of Ir/IrO x -based devices compared with one of the ZnO-based devices originates from its suitable work function, the regulation of the optical field, and the heterogeneous surface energy distribution in the nanoscale (HeD-SE). Benefiting from the well-organized and stable bulk-heterojunction (BHJ) film and the absence of photocatalysis, the Ir/IrO x -based devices exhibit excellent long-term stability under shelf storing ( T 80 = 56,696 h vs. 12,075 h, which is the time when the PCE of the device decreases to the 80% of initial PCE), thermal aging ( T 70 = 13,920 h vs. 2198 h, the time when the PCE of the device decreases to the 70% of initial PCE), and maximum power point (MPP) tracking ( T 80 = 1058 h vs. 586 h) compared with the ZnO-based devices. The impact of Ir/IrO x on the morphological evolution of BHJ films is further discussed in detail to explore the degradation mechanism. Moreover, the stability of OSCs under thermal circulation and ultraviolet (UV)-irradiation are also improved by the Ir/IrO x ETL, which illustrates that the possibility of operating under extreme environments can be increased by applying Ir/IrO x . Results Characterization of Ir/IrO x In this study, Ir/IrO x nanoparticles have been selected as an electron-transporting material since iridium (Ir) -based nanoparticles exhibit excellent charge-transfer ability in electrocatalysis 26 , 27 , 28 , 29 . The Ir/IrO x nanoparticles were prepared through the mild colloid solution method 30 , 31 with IrCl 3 ·3H 2 O precursor under Ar atmosphere (Fig. 1a and Supplementary Fig. 1 ). Compared with the ZnO precursor solution, the colloidal solution of iridium-based nanoparticles shows better stability after storing in the air for 2 years (Supplementary Fig. 2 ). The mean diameter of the nanoparticle is 1.50 ± 0.30 nm measured by the special aberration-corrected transmission electron microscope (AC-TEM) (Fig. 1b and Supplementary Fig. 3 ). The cross-sectional TEM patterns (Fig. 1b and Supplementary Fig. 4 ) demonstrate that Ir/IrO x nanoparticles can be deposited on the ITO substrate to form a condensed and uniform film, whose mean thickness is 4.66 ± 0.37 nm (Supplementary Fig. 5 ). Fig. 1: Characterization of Ir/IrO x . a The synthesis process of Ir/IrO x nanoparticles. In the synthesis route, the Δ represents heating at 160 °C. b The cross-sectional transmission electron microscope (TEM) patterns of Ir/IrO x samples spin-coated on ITO, which was prepared by a focused ion beam (FIB). The insert is the high-resolution image of a single Ir/IrO x nanoparticle on copper mesh, which was characterized by a special aberration-corrected transmission electron microscope (AC-TEM). c The Ir 4f X-ray photoelectron spectroscopy (XPS) plot of Ir/IrO x nanoparticles. d The ultraviolet photoelectron spectroscopy (UPS) characterizations of ITO (gray), ZnO (blue), and Ir/IrO x (red). The Peak-force quantitative nanomechanical mappings ( PFQNM) morphology ( e, f ) and adhesion ( g, h ) patterns of ZnO and Ir/IrO x films. Full size image The X-ray photoelectron spectroscopy (XPS) characterization assisted to determine the oxidation state of nanoparticles (Supplementary Fig. 6 ). In the Ir 4 f core-level spectrum (Fig. 1c ), two groups of peaks located at 60.23/63.26 eV and 62.79/65.24 eV are attributed to the metallic Ir and IrO x 32 , 33 , respectively. Energy level matching is an important basis for selecting an ETL. By characterizations of ultraviolet photoelectron spectroscopy (UPS, Fig. 1d ), the work function (WF) of the Ir/IrO x and ZnO were determined to be 4.05 eV and 4.22 eV, respectively. Besides, the WFs of the bare ITO and ITO modified by glycol (solvent), NaOH in glycol (pH = 10), and<|im_end|> <|im_start|>assistant In recent years, the device efficiency of organic solar cells (OSCs) has been significantly improved, but the unsatisfactory stability restricts future commercialization processing. Inverted device structure has been widely adopted to enhance the device stability of OSCs. However, zinc oxide (ZnO), the most commonly used electron-transporting material, is photocatalytic active, which could accelerate the decomposition of the active layers under continuous light illumination, and then lead to the degradation of device performance. Therefore, developing new electron-transporting materials is extremely critical for utilizing efficient and stable OSCs. Recently, Prof. Zhou Huiqiong's group from National Center for Nanoscience and Technology (NCNST) of the Chinese Academy of Science (CAS) has developed a new electron transport material Ir/IrOx to enhance the stability of OSCs. The study was published online in Nature Communications. Prof. Zhou's group has carried out a series of studies focused on the stability of OSCs. By incorporating organic electron transport material PFN-Br into the ZnO layer, the surface energy of the interface layer was regulated, resulting in the enhanced device stability (Journal of Materials Chemistry A ). Furthermore, the polyaspartic acid (PASP) film was deposited on the ZnO film to suppress the degradation caused by illumination, leading to the improved stability of organic solar cells. (Journal of Materials Chemistry C). In this study, the Ir/IrOx nanoparticles prepared by the mild colloid solution method were utilized as the electron-transporting material in organic solar cells instead of the common ZnO layer. Benefiting from the suitable work function, heterogeneous surface energy distribution in nanoscale and optimized optical field, the Ir/IrOx-based devices exhibited more efficient charge extraction and suppressed charge recombination compared with the ZnO-based devices, leading to improved device performance. Due to the absence of photocatalysis, the active layer deposited on Ir/IrOx film exhibited more stable component distribution and morphology, elongating the lifetime of Ir/IrOx-based devices under storage in inert atmosphere, thermal aging and maximum-power-point (MPP) tracking conditions. In particular, the T70 lifetime of Ir/IrOx-based devices under thermal aging exceeded 10,000 hours. Moreover, the better stability of Ir/IrOx-based devices under UV irradiation and thermal cycling between -40℃ and 85℃ illustrated the huge potential of OSCs with Ir/IrOx operating under extreme environments. "The appropriate optoelectric properties and photocatalytic inactivity of Ir/IrOx allow us to investigate the mechanism of photo-induced degradation in OSCs, finally achieving the enhanced device stability under various aging condition," said Prof. Zhou. "We envision that our results are also helpful to the related work focused on the intrinsic stability of OSCs." <|im_end|>

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2,156

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Ubiquitination governs oscillation of cyclin-dependent kinase (CDK) activity through a periodic degradation of cyclins for orderly cell cycle progression; however, the mechanism that maintains the constant CDK protein levels throughout the cell cycle remains unclear. Here we show that CDK6 is modified by small ubiquitin-like modifier-1 (SUMO1) in glioblastoma, and that CDK6 SUMOylation stabilizes the protein and drives the cell cycle for the cancer development and progression. CDK6 is also a substrate of ubiquitin; however, CDK6 SUMOylation at Lys 216 blocks its ubiquitination at Lys 147 and inhibits the ubiquitin-mediated CDK6 degradation. Throughout the cell cycle, CDK1 phosphorylates the SUMO-specific enzyme, ubiquitin-conjugating enzyme9 (UBC9) that in turn mediates CDK6 SUMOylation during mitosis; CDK6 remains SUMOylated in G1 phase and drives the cell cycle through G1/S transition. Thus, SUMO1–CDK6 conjugation constitutes a mechanism of cell cycle control and inhibition of this SUMOylation pathway may provide a strategy for treatment of glioblastoma. Introduction SUMO is a conserved member of the ubiquitin-related protein family 1 , 2 . Human genome encodes four SUMO isoforms: small ubiquitin-like modifier 1–4 (SUMO1–4); however, it is unclear whether SUMO4 can be conjugated and SUMO2 and SUMO3 are commonly referred to as SUMO2/3 because they share 97% amino-acid sequence and cannot be distinguished by any antibodies 3 . In contrast, SUMO1 is distinct from SUMO2/3 because it shares only 50% amino acids homology. SUMO conjugation, that is, SUMOylation is now established as a key posttranslational modification pathway distinct from ubiquitination. Ubiquitin is covalently attached to a lysine residue of substrates through catalytic reactions by ubiquitin activating enzyme (E1), conjugating enzyme (E2) and ligase (E3) and the conjugated ubiquitin is removed by deubiquitinating enzymes 4 . In this ubiquitination process, E3 ligases directly transfer ubiquitin to substrates. In contrast, SUMO E3 ligases may not be required for SUMOylation since UBC9 binds substrates directly 5 . SUMO modifies a large set of substrates 6 , 7 , but its modification pathway is surprisingly simple and composed of an E1 (SUMO-activating enzyme 1/2; SAE1/2), an E2 (UBC9), a handful E3 ligases and less than dozen SUMO-specific proteases (SENPs) 8 , 9 . This is in sharp contrast to ubiquitin pathway that consists of tens of E2, hundreds of E3 and more than fifty proteases 10 . One of the well established functions of ubiquitin is to target proteins to the 26S proteasome for degradation; however, recent studies indicate that SUMO regulates ubiquitin-mediated proteolysis 11 . Clearly, more SUMO enzymes and regulatory mechanisms are emerging that regulate diverse biological processes 12 . Ubiquitination is well known for regulation of cell cycle through degradation of cyclins. The cell cycle is driven mainly by four CDKs: the interphase CDK2, CDK4 and CDK6 and the mitotic CDK1 13 . These kinases are activated by binding to their activating cyclins and forming specific complex in each cell cycle phase: CDK4/6-cyclin D complexes in G1 phase, CDK2–cyclin E complex in S phase and CDK1–cyclin A/B complexes in G2/M phases. This periodicity is governed by oscillation of CDK activity through periodic ubiquitin-mediated degradation of CDK-activating cyclins 14 . Two ubiquitin E3 ligase complexes control the ubiquitin-mediated proteolysis of cyclins through the cell cycle: the Skp1-cullin 1-F-box complex destroys cyclins from G1 to M phase and the anaphase-promoting complex/cyclosome degrades M to G1 phase cyclins. In contrast, the CDK protein levels are constant through the cell cycle, but the mechanisms that maintain CDK proteins are unclear. In human cancers, the elevation of CDK proteins is linked to gene amplification and overexpression 15 ; however, the amplification occurs only in a small set of human cancers according to cancer genomes 16 , 17 . Recent studies indicate the role of SUMOylation in cancer development and progression 18 . SENP1 removes SUMO from reptin and release its repression of metastasis suppressor gene KAI1 (ref. 19 ); oncogenic Ras induces carcinogenesis through inhibition of MEK SUMOylation 20 ; and SUMOylation-defective microphthalmia-associated transcription factor predisposes to melanoma and renal cell carcinoma 21 ; SAE2 contributes to Myc-dependent cancer formation 22 . Here, we investigate how SUMOylation regulates development and progression of glioblastoma, the most common and lethal human brain cancer 23 . Through biochemical and functional analyses of CDK6 in glioblastoma, we unveil the molecular cascades of SUMOylation, ubiquitination and phosphorylation in regulation of CDK6 protein through the cell cycle using the tumour tissues, cell lines, initiating cells and xenografts 24 . The results reveal an active SUMO1 conjugation pathway in glioblastoma and show that CDK6 SUMOylation stabilizes the protein and its kinase activity through inhibition of its ubiquitination and the ubiquitin-mediated degradation. CDK1 phosphorylates UBC9 that in turn mediates CDK6 SUMOylation during mitosis and CDK6 SUMOylation remains from M to G1 phase and thus drives the cell cycle through G1–S transition. Selective inhibition of SUMO1 induces G1 arrest and inhibits cell growth and the formation and progression of the tumour-initiating cell-derived glioblastomas. This study unveils the mechanisms by which SUMO1–CDK6 conjugation contributes to the development and progression of glioblastoma and proves the principle that inhibition of this SUMO1 conjugation may provide a therapeutic benefit against this devastating human disease. Results SUMO1 conjugation drives the cell cycle through G1/S transition To investigate the role of SUMO1 in human glioblastoma, we examined the protein levels of SUMO enzymes in patient-derived tumour tissues as compared with normal brain tissues. SUMOylation is reversible due to the presence of SENPs that remove conjugated SUMO from its substrates 8 , 9 . To protect the conjugation, tissues were lysed in a sodium dodecyl sulphate (SDS) denaturing buffer supplemented with the SUMO protease inhibitor N -ethylmaleimide (NEM) 7 . Western blotting revealed the elevated levels of SEA1, UBC9 and SUMO1-conjugated proteins in the tumours as compared with normal brains ( Fig. 1a ); thus, SUMO1 conjugation is overactive in glioblastoma. To confirm this at cell levels, we examined glioblastoma-derived cell lines and human brain-derived astrocytes 25 and showed the elevation of SUMO1-conjugated proteins in the cell lines as compared with normal human astrocytes ( Fig. 1b ). Figure", "role": "user" }, { "content": "Scientists at the Montreal Neurological Institute and Hospital, McGill University and McGill University Health Centre have shown that a member of the protein family known as SUMO (small ubiquitin-like modifier) is a key to why tumour cells multiply uncontrollably, especially in the case of glioblastoma. The SUMO family proteins modify other proteins and the SUMOylation of proteins are critical for many cellular processes. Identifying SUMO's role in the cancer cell growth will lead to a new strategy for glioblastoma treatment. Glioblastoma is the most common and lethal brain cancer. Current standard treatments include surgical resection, adjuvant chemotherapy and radiotherapy. Despite the treatments, patients' survive about a year and half. The cancer continues growing in part due to the presence of the cancer stem cells. It is critical to understand cancer growing pathways in the stem cells for development of stem cells targeted therapies. The molecular mechanisms that control cancer growth through cell cycle progression, involve a whole host of proteins and many aspects of this complex process are still unknown. One group of proteins termed cyclin-dependent kinases (CDKs) drive the cell cycle; yet, it is unclear why the cancer cells maintain a large amount of CDK proteins. \"In investigation of the cell cycle of human glioblastoma, we uncovered that CDK6 is modified by SUMO1.CDK6 sumoylation inhibits its degradation and thus stabilizes CDK6 protein in the cancer,\" says Dr. Anita Bellail, a researcher at the Montreal Neurological Institute and Hospital, McGill University and McGill University Health Centre, and lead author on the paper published in Nature Communications. Co-authors on the paper include Jeffrey J. Olson of the Department of Neurosurgery at Emory University and Chunhai \"Charlie\" Hao, Department of Pathology, Montreal Neurological Institute and Hospital at McGill University and McGill University Health Centre. \"We found that CDK6 sumoylation is required for the renewal and growth of the cancer stem cells in glioblastoma. Inhibition of SUMO1 eliminates the stem cells and suppresses the cancer progression.\" Their finding adds concrete evidence to recent studies examining sumoylation pathways in human cancer development and progression. With the new understanding of how SUMO affects the cell cycle in cancer stem cells, this group of scientists are currently screening for SUMO1 targeted new drugs for the treatments of human glioblastoma. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Ubiquitination governs oscillation of cyclin-dependent kinase (CDK) activity through a periodic degradation of cyclins for orderly cell cycle progression; however, the mechanism that maintains the constant CDK protein levels throughout the cell cycle remains unclear. Here we show that CDK6 is modified by small ubiquitin-like modifier-1 (SUMO1) in glioblastoma, and that CDK6 SUMOylation stabilizes the protein and drives the cell cycle for the cancer development and progression. CDK6 is also a substrate of ubiquitin; however, CDK6 SUMOylation at Lys 216 blocks its ubiquitination at Lys 147 and inhibits the ubiquitin-mediated CDK6 degradation. Throughout the cell cycle, CDK1 phosphorylates the SUMO-specific enzyme, ubiquitin-conjugating enzyme9 (UBC9) that in turn mediates CDK6 SUMOylation during mitosis; CDK6 remains SUMOylated in G1 phase and drives the cell cycle through G1/S transition. Thus, SUMO1–CDK6 conjugation constitutes a mechanism of cell cycle control and inhibition of this SUMOylation pathway may provide a strategy for treatment of glioblastoma. Introduction SUMO is a conserved member of the ubiquitin-related protein family 1 , 2 . Human genome encodes four SUMO isoforms: small ubiquitin-like modifier 1–4 (SUMO1–4); however, it is unclear whether SUMO4 can be conjugated and SUMO2 and SUMO3 are commonly referred to as SUMO2/3 because they share 97% amino-acid sequence and cannot be distinguished by any antibodies 3 . In contrast, SUMO1 is distinct from SUMO2/3 because it shares only 50% amino acids homology. SUMO conjugation, that is, SUMOylation is now established as a key posttranslational modification pathway distinct from ubiquitination. Ubiquitin is covalently attached to a lysine residue of substrates through catalytic reactions by ubiquitin activating enzyme (E1), conjugating enzyme (E2) and ligase (E3) and the conjugated ubiquitin is removed by deubiquitinating enzymes 4 . In this ubiquitination process, E3 ligases directly transfer ubiquitin to substrates. In contrast, SUMO E3 ligases may not be required for SUMOylation since UBC9 binds substrates directly 5 . SUMO modifies a large set of substrates 6 , 7 , but its modification pathway is surprisingly simple and composed of an E1 (SUMO-activating enzyme 1/2; SAE1/2), an E2 (UBC9), a handful E3 ligases and less than dozen SUMO-specific proteases (SENPs) 8 , 9 . This is in sharp contrast to ubiquitin pathway that consists of tens of E2, hundreds of E3 and more than fifty proteases 10 . One of the well established functions of ubiquitin is to target proteins to the 26S proteasome for degradation; however, recent studies indicate that SUMO regulates ubiquitin-mediated proteolysis 11 . Clearly, more SUMO enzymes and regulatory mechanisms are emerging that regulate diverse biological processes 12 . Ubiquitination is well known for regulation of cell cycle through degradation of cyclins. The cell cycle is driven mainly by four CDKs: the interphase CDK2, CDK4 and CDK6 and the mitotic CDK1 13 . These kinases are activated by binding to their activating cyclins and forming specific complex in each cell cycle phase: CDK4/6-cyclin D complexes in G1 phase, CDK2–cyclin E complex in S phase and CDK1–cyclin A/B complexes in G2/M phases. This periodicity is governed by oscillation of CDK activity through periodic ubiquitin-mediated degradation of CDK-activating cyclins 14 . Two ubiquitin E3 ligase complexes control the ubiquitin-mediated proteolysis of cyclins through the cell cycle: the Skp1-cullin 1-F-box complex destroys cyclins from G1 to M phase and the anaphase-promoting complex/cyclosome degrades M to G1 phase cyclins. In contrast, the CDK protein levels are constant through the cell cycle, but the mechanisms that maintain CDK proteins are unclear. In human cancers, the elevation of CDK proteins is linked to gene amplification and overexpression 15 ; however, the amplification occurs only in a small set of human cancers according to cancer genomes 16 , 17 . Recent studies indicate the role of SUMOylation in cancer development and progression 18 . SENP1 removes SUMO from reptin and release its repression of metastasis suppressor gene KAI1 (ref. 19 ); oncogenic Ras induces carcinogenesis through inhibition of MEK SUMOylation 20 ; and SUMOylation-defective microphthalmia-associated transcription factor predisposes to melanoma and renal cell carcinoma 21 ; SAE2 contributes to Myc-dependent cancer formation 22 . Here, we investigate how SUMOylation regulates development and progression of glioblastoma, the most common and lethal human brain cancer 23 . Through biochemical and functional analyses of CDK6 in glioblastoma, we unveil the molecular cascades of SUMOylation, ubiquitination and phosphorylation in regulation of CDK6 protein through the cell cycle using the tumour tissues, cell lines, initiating cells and xenografts 24 . The results reveal an active SUMO1 conjugation pathway in glioblastoma and show that CDK6 SUMOylation stabilizes the protein and its kinase activity through inhibition of its ubiquitination and the ubiquitin-mediated degradation. CDK1 phosphorylates UBC9 that in turn mediates CDK6 SUMOylation during mitosis and CDK6 SUMOylation remains from M to G1 phase and thus drives the cell cycle through G1–S transition. Selective inhibition of SUMO1 induces G1 arrest and inhibits cell growth and the formation and progression of the tumour-initiating cell-derived glioblastomas. This study unveils the mechanisms by which SUMO1–CDK6 conjugation contributes to the development and progression of glioblastoma and proves the principle that inhibition of this SUMO1 conjugation may provide a therapeutic benefit against this devastating human disease. Results SUMO1 conjugation drives the cell cycle through G1/S transition To investigate the role of SUMO1 in human glioblastoma, we examined the protein levels of SUMO enzymes in patient-derived tumour tissues as compared with normal brain tissues. SUMOylation is reversible due to the presence of SENPs that remove conjugated SUMO from its substrates 8 , 9 . To protect the conjugation, tissues were lysed in a sodium dodecyl sulphate (SDS) denaturing buffer supplemented with the SUMO protease inhibitor N -ethylmaleimide (NEM) 7 . Western blotting revealed the elevated levels of SEA1, UBC9 and SUMO1-conjugated proteins in the tumours as compared with normal brains ( Fig. 1a ); thus, SUMO1 conjugation is overactive in glioblastoma. To confirm this at cell levels, we examined glioblastoma-derived cell lines and human brain-derived astrocytes 25 and showed the elevation of SUMO1-conjugated proteins in the cell lines as compared with normal human astrocytes ( Fig. 1b ). Figure<|im_end|> <|im_start|>assistant Scientists at the Montreal Neurological Institute and Hospital, McGill University and McGill University Health Centre have shown that a member of the protein family known as SUMO (small ubiquitin-like modifier) is a key to why tumour cells multiply uncontrollably, especially in the case of glioblastoma. The SUMO family proteins modify other proteins and the SUMOylation of proteins are critical for many cellular processes. Identifying SUMO's role in the cancer cell growth will lead to a new strategy for glioblastoma treatment. Glioblastoma is the most common and lethal brain cancer. Current standard treatments include surgical resection, adjuvant chemotherapy and radiotherapy. Despite the treatments, patients' survive about a year and half. The cancer continues growing in part due to the presence of the cancer stem cells. It is critical to understand cancer growing pathways in the stem cells for development of stem cells targeted therapies. The molecular mechanisms that control cancer growth through cell cycle progression, involve a whole host of proteins and many aspects of this complex process are still unknown. One group of proteins termed cyclin-dependent kinases (CDKs) drive the cell cycle; yet, it is unclear why the cancer cells maintain a large amount of CDK proteins. "In investigation of the cell cycle of human glioblastoma, we uncovered that CDK6 is modified by SUMO1.CDK6 sumoylation inhibits its degradation and thus stabilizes CDK6 protein in the cancer," says Dr. Anita Bellail, a researcher at the Montreal Neurological Institute and Hospital, McGill University and McGill University Health Centre, and lead author on the paper published in Nature Communications. Co-authors on the paper include Jeffrey J. Olson of the Department of Neurosurgery at Emory University and Chunhai "Charlie" Hao, Department of Pathology, Montreal Neurological Institute and Hospital at McGill University and McGill University Health Centre. "We found that CDK6 sumoylation is required for the renewal and growth of the cancer stem cells in glioblastoma. Inhibition of SUMO1 eliminates the stem cells and suppresses the cancer progression." Their finding adds concrete evidence to recent studies examining sumoylation pathways in human cancer development and progression. With the new understanding of how SUMO affects the cell cycle in cancer stem cells, this group of scientists are currently screening for SUMO1 targeted new drugs for the treatments of human glioblastoma. <|im_end|>

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]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract As the United Nations develops a post-2020 global biodiversity framework for the Convention on Biological Diversity, attention is focusing on how new goals and targets for ecosystem conservation might serve its vision of ‘living in harmony with nature’ 1 , 2 . Advancing dual imperatives to conserve biodiversity and sustain ecosystem services requires reliable and resilient generalizations and predictions about ecosystem responses to environmental change and management 3 . Ecosystems vary in their biota 4 , service provision 5 and relative exposure to risks 6 , yet there is no globally consistent classification of ecosystems that reflects functional responses to change and management. This hampers progress on developing conservation targets and sustainability goals. Here we present the International Union for Conservation of Nature (IUCN) Global Ecosystem Typology, a conceptually robust, scalable, spatially explicit approach for generalizations and predictions about functions, biota, risks and management remedies across the entire biosphere. The outcome of a major cross-disciplinary collaboration, this novel framework places all of Earth’s ecosystems into a unifying theoretical context to guide the transformation of ecosystem policy and management from global to local scales. This new information infrastructure will support knowledge transfer for ecosystem-specific management and restoration, globally standardized ecosystem risk assessments, natural capital accounting and progress on the post-2020 global biodiversity framework. Main Sustaining ecosystem functions and services requires an understanding of ecological processes and mechanisms that drive ecosystem change 6 . Ecosystem functioning not only underpins biomass production, but also depends on and regulates the stocks and fluxes of resources, energy and biota 7 . These functions, together with ecological processes and species traits—collectively referred to as ‘ecosystem properties’ (see Supplementary Information , Glossary)—define and sustain ecosystem identity and shape ecosystem responses to environmental change, including anthropogenic changes 8 . Ecosystems with different species compositions may show functional convergence if their biota share similar traits and contribute to similar ecological processes (for example, in ref. 9 ). Together with ecosystem function, the identity of constituent biota is central to biodiversity concepts, conservation goals and human values 10 . Although ecosystem functions and ecological processes support both the diversity of biota and human well-being, global assessments of ecosystems 11 , 12 continue to rely heavily on species metrics or simplistic land-cover proxies that convey limited information about ecosystems themselves. This limits our ability to diagnose trends and to design and resource on-ground management and policy solutions for slowing and reversing current declines in biodiversity and ecosystem services. To serve the dual needs of sustaining ecosystem services and conserving biodiversity, ecosystem assessments require a global typology to frame comparisons and standardize data aggregation for analysing ecosystem trends and diagnosing their causes. To support applications throughout Earth’s diverse ecosystems, users and scales of analysis, this typology should encapsulate: (1) ecosystem functions and ecological processes; (2) their characteristic biota; (3) conceptual consistency throughout the whole biosphere; (4) a scalable structure; (5) spatially explicit units; and (6) descriptive detail and minimal complexity (see Supplementary Information, Appendix 1 and Supplementary Table 1.1 for rationale). We used these 6 design criteria to review a sample of 23 global-scale ecological typologies, finding none that explicitly represented both ecosystem functions and biota (Supplementary Table 1.2 ). This limits the ability of ecosystem managers to learn from related ecosystems with similar operating mechanisms and drivers of change. Only three typologies encompassed the whole biosphere, but these lacked a clear theoretical basis, limiting their ability to generalize about properties of ecosystems grouped together. Ecological classifications based on tested and established theory are more likely to be robust to new information than classifications based only on observed patterns and correlations, which may prove unstable when new information emerges. Many typologies that we examined either did not describe their units in sufficient detail for reliable identification, or required diagnostic features that are difficult to observe. Others were based on biophysical attributes or biogeography, but approaches differed across terrestrial, freshwater and marine domains, precluding a truly global approach. In this study, we developed a Global Ecosystem Typology that meets all six design principles, thereby providing a stronger foundation for systematic ecosystem assessments, sustainable management and biodiversity conservation. Conceptual foundations We developed a conceptual model to inform the construction of the Global Ecosystem Typology, consistent with the six design principles, and to serve as a template for describing the units of classification. The model (Fig. 1 ) frames working hypotheses about the processes (or ‘drivers’) that shape ecosystem properties and the interactions among drivers and properties. Ecosystem properties are attributes of ecosystems and their component biota that result from assembly processes 13 . They include aggregate ecosystem functions (productivity, stocks and fluxes), ecological processes (for example, trophic networks), structural features (for example, 3D spatial structure and diversity) and species-level traits of characteristic organisms (for example, ecophysiology, life histories and morphology). Fig. 1: The generic model of ecosystem assembly underlying the Global Ecosystem Typology. Boxes represent abiotic (resources, the ambient environment and disturbance regimes) and biotic (biotic interactions and human activity) drivers that filter assemblages and form evolutionary pressures that in turn, shape ecosystem-level properties (inner green circle). The range of major organizational scales at which drivers operate are shown in parentheses, followed by a list of the major expressions of the drivers. The species pool is the set of ‘available’ traits on which the assembly filters and evolutionary pressures operate over short and longer time frames, respectively. Species pools are dynamic products of vicariance, dispersal and evolution that depend on biogeographic context and history. The outer green circle (dashed line) represents the contemporary dispersal filter that mediates the biota currently subjected to local selection by the abiotic and biotic filters and pressures. The inner green circle represents the properties (aggregate ecosystem functions and species-level traits) that characterize the ecosystem. Closed arrows show the influence of filtering processes on ecosystem properties. Feedbacks can occur whereby ecosystem properties modulate filtering processes (examples are indicated by bidirectional arrows). Interactions among drivers include indirect effects of human activity on assembly through other drivers (black open arrows) and", "role": "user" }, { "content": "A global cross-disciplinary team of scientists led by UNSW Sydney researchers has developed the first comprehensive classification of the world's ecosystems across land, rivers and wetlands, and seas. The ecosystem typology will enable more coordinated and effective biodiversity conservation, critical for human well-being. The extensive collaboration includes the International Union for Conservation of Nature (IUCN), which comprises about 1400 member organizations, including countries; the IUCN Commission on Ecosystem Management; the PLuS Alliance—Arizona State University, King's College London and UNSW Sydney; and more than 100 specialist ecosystem scientists around the world. The study, published today in Nature, explores the science that underpins the typology, as well as how it can help achieve objectives in global policy that flow to individual countries. With UNSW's support, IUCN launched the first public version of the typology in 2020 and, since then, the researchers have refined and updated it. The research team was led by Professor David Keith with Professor Richard Kingsford from UNSW's Centre for Ecosystem Science, and Professor Emily Nicholson from Deakin University. \"For the first time, we have a common platform that identifies, defines and describes the full suite of the whole planet's ecosystems,\" said Professor Keith. \"It may seem rather odd that we haven't had this before, but historically scientists have forged advances by working somewhat separately in marine, freshwater and terrestrial ecosystems. This is the first time that all of this detailed knowledge has been brought together into a single framework taking advantage of common theory across the disciplines.\" The typology allows us to understand broad global patterns, including the transformation of ecosystems by people. Ten percent of ecosystems are artificially created and maintained by humans but occupy more than 30 percent of the Earth's land surface—what is left is home to 94 percent of threatened species on the IUCN Red List. At a policy level, this is the first time we've had this kind of overview, Professor Kingsford said. \"It's very hard to see the big picture on a jigsaw puzzle until you have all the pieces in place—and that's what we now have. We have a much more substantial foundation to move ahead with a new era of ecosystem conservation and management policy.\" At a more general level, the overview allows policymakers and industry to plan their initiatives in full context. For governments and non-government organizations (NGOs) working in a range of countries, the overview can inform decisions about how ecosystem protection and restoration efforts can achieve maximum conservation benefit, and where development infrastructure is best placed to minimize impact. \"Efforts on biodiversity conservation have largely centered at the species level, because it's seen to be more tangible,\" said Professor Keith. \"But a broader focus on both ecosystems and species is more likely to succeed in conserving all plants and animals, as well as the essential services that nature provides people.\" Globally, countries coordinate their efforts under the umbrella of the United Nations Convention on Biological Diversity (CBD), which is coming up for renewal at the end of 2022. Delegates from 193 countries will meet in December at the 15th Conference of Parties in Montreal, Canada, to agree on the post-2020 agenda for CBD. Preparations for that meeting indicate a stronger emphasis on ecosystem conservation and management in the coming decades. \"The global ecosystem typology will make it possible to account for ongoing ecosystem change, identify threatened ecosystem types, and plan better preventative action and restoration under a renewed agenda for the CBD,\" said Professor Nicholson. This typology marks a breakthrough for sustainable management of the world's ecosystems, said Dr. Angela Andrade, Chair of IUCN's Commission on Ecosystem Management and one of the authors. \"It will enable real progress on United Nations Sustainable Development Goals and Environmental Accounting, and should help place ecosystems at the forefront of the United Nations' post-2020 agenda for conserving biological diversity.\" To make that a reality, we need a full set of high quality maps for all major ecosystem types, Professor Keith said. \"We are already well down that path, but we need help to surmount the considerable challenges by exploiting recent advances in computer and satellite technology, along with global networks of citizen scientists.\" The ecosystem typology Ecosystems provide homes and vital life support for all plants and animals, and supply essential ecosystem services that sustain business, culture and human well-being. Those services—such as provision of clean air and water, carbon sequestration, reduced risks of disasters and outdoor recreational opportunities that sustain mental health—are sometimes regarded as free, but ecosystem degradation incurs costs for tapping alternative resources, disaster relief and reconstruction, and to health budgets. All of the world's ecosystems show hallmarks of human influence, and many are under acute risks of collapse, with consequences for habitats of species, genetic diversity, ecosystem services, sustainable development and human well-being. The global ecosystem typology describes the diversity of tropical forests, big rivers, coral reefs and other ecosystems that have typically been the focus of public attention. But it also includes little-known ecosystems of deep ocean trenches, seamounts, lakes beneath the ice sheets and microscopic ecosystems within rocks. \"We don't think often about what's in the deep oceans, for example,\" said Professor Keith. \"There's a tremendous variety of life down there and it's organized into a number of different ecosystems. And those ecosystems are beginning to feel the impact of human expansion. \"The deep trenches in the ocean are filling up with microplastics, and we're starting to look at mining volcanic vents for minerals. We need to make decisions about those kinds of environments, just as we do about coral reefs and rainforests.\" A hierarchical structure The new typology has a hierarchical structure with six levels. The top level divides the planet into major realms, including terrestrial, freshwater, marine and subterranean ecosystems. The second and third levels include 25 biomes and 110 ecosystem functional groups, based on the ecological processes that shape different ecosystems and the functions that their key components perform. These functional groups will frame blueprints for sustainable ecosystem management. The lower levels of the hierarchy are based on finer ecosystem features and enable the integration of existing national classifications. These national ecosystem classifications and maps benefit from detailed scientific observations and considerable investment over many years. They are critical to conservation because many countries have built their environmental governance and regulations around them, as well as their protected area networks. For the first time, a globally agreed typology enables these many different systems to be reconciled across national borders, while supporting their ongoing use in each country. What are the next steps? The next major frontier for improved ecosystem management is to establish global maps and monitoring, Professor Keith said. \"Although many of the world's 110 ecosystem types are already served with high quality maps updatable with satellite technology, the data for some other types is still rudimentary.\" \"We can't plan effectively where to protect ecosystems or how to manage them sustainably unless we have reliable maps for the full range of ecosystem types, and integrate them into decision-making and monitoring systems,\" he 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 As the United Nations develops a post-2020 global biodiversity framework for the Convention on Biological Diversity, attention is focusing on how new goals and targets for ecosystem conservation might serve its vision of ‘living in harmony with nature’ 1 , 2 . Advancing dual imperatives to conserve biodiversity and sustain ecosystem services requires reliable and resilient generalizations and predictions about ecosystem responses to environmental change and management 3 . Ecosystems vary in their biota 4 , service provision 5 and relative exposure to risks 6 , yet there is no globally consistent classification of ecosystems that reflects functional responses to change and management. This hampers progress on developing conservation targets and sustainability goals. Here we present the International Union for Conservation of Nature (IUCN) Global Ecosystem Typology, a conceptually robust, scalable, spatially explicit approach for generalizations and predictions about functions, biota, risks and management remedies across the entire biosphere. The outcome of a major cross-disciplinary collaboration, this novel framework places all of Earth’s ecosystems into a unifying theoretical context to guide the transformation of ecosystem policy and management from global to local scales. This new information infrastructure will support knowledge transfer for ecosystem-specific management and restoration, globally standardized ecosystem risk assessments, natural capital accounting and progress on the post-2020 global biodiversity framework. Main Sustaining ecosystem functions and services requires an understanding of ecological processes and mechanisms that drive ecosystem change 6 . Ecosystem functioning not only underpins biomass production, but also depends on and regulates the stocks and fluxes of resources, energy and biota 7 . These functions, together with ecological processes and species traits—collectively referred to as ‘ecosystem properties’ (see Supplementary Information , Glossary)—define and sustain ecosystem identity and shape ecosystem responses to environmental change, including anthropogenic changes 8 . Ecosystems with different species compositions may show functional convergence if their biota share similar traits and contribute to similar ecological processes (for example, in ref. 9 ). Together with ecosystem function, the identity of constituent biota is central to biodiversity concepts, conservation goals and human values 10 . Although ecosystem functions and ecological processes support both the diversity of biota and human well-being, global assessments of ecosystems 11 , 12 continue to rely heavily on species metrics or simplistic land-cover proxies that convey limited information about ecosystems themselves. This limits our ability to diagnose trends and to design and resource on-ground management and policy solutions for slowing and reversing current declines in biodiversity and ecosystem services. To serve the dual needs of sustaining ecosystem services and conserving biodiversity, ecosystem assessments require a global typology to frame comparisons and standardize data aggregation for analysing ecosystem trends and diagnosing their causes. To support applications throughout Earth’s diverse ecosystems, users and scales of analysis, this typology should encapsulate: (1) ecosystem functions and ecological processes; (2) their characteristic biota; (3) conceptual consistency throughout the whole biosphere; (4) a scalable structure; (5) spatially explicit units; and (6) descriptive detail and minimal complexity (see Supplementary Information, Appendix 1 and Supplementary Table 1.1 for rationale). We used these 6 design criteria to review a sample of 23 global-scale ecological typologies, finding none that explicitly represented both ecosystem functions and biota (Supplementary Table 1.2 ). This limits the ability of ecosystem managers to learn from related ecosystems with similar operating mechanisms and drivers of change. Only three typologies encompassed the whole biosphere, but these lacked a clear theoretical basis, limiting their ability to generalize about properties of ecosystems grouped together. Ecological classifications based on tested and established theory are more likely to be robust to new information than classifications based only on observed patterns and correlations, which may prove unstable when new information emerges. Many typologies that we examined either did not describe their units in sufficient detail for reliable identification, or required diagnostic features that are difficult to observe. Others were based on biophysical attributes or biogeography, but approaches differed across terrestrial, freshwater and marine domains, precluding a truly global approach. In this study, we developed a Global Ecosystem Typology that meets all six design principles, thereby providing a stronger foundation for systematic ecosystem assessments, sustainable management and biodiversity conservation. Conceptual foundations We developed a conceptual model to inform the construction of the Global Ecosystem Typology, consistent with the six design principles, and to serve as a template for describing the units of classification. The model (Fig. 1 ) frames working hypotheses about the processes (or ‘drivers’) that shape ecosystem properties and the interactions among drivers and properties. Ecosystem properties are attributes of ecosystems and their component biota that result from assembly processes 13 . They include aggregate ecosystem functions (productivity, stocks and fluxes), ecological processes (for example, trophic networks), structural features (for example, 3D spatial structure and diversity) and species-level traits of characteristic organisms (for example, ecophysiology, life histories and morphology). Fig. 1: The generic model of ecosystem assembly underlying the Global Ecosystem Typology. Boxes represent abiotic (resources, the ambient environment and disturbance regimes) and biotic (biotic interactions and human activity) drivers that filter assemblages and form evolutionary pressures that in turn, shape ecosystem-level properties (inner green circle). The range of major organizational scales at which drivers operate are shown in parentheses, followed by a list of the major expressions of the drivers. The species pool is the set of ‘available’ traits on which the assembly filters and evolutionary pressures operate over short and longer time frames, respectively. Species pools are dynamic products of vicariance, dispersal and evolution that depend on biogeographic context and history. The outer green circle (dashed line) represents the contemporary dispersal filter that mediates the biota currently subjected to local selection by the abiotic and biotic filters and pressures. The inner green circle represents the properties (aggregate ecosystem functions and species-level traits) that characterize the ecosystem. Closed arrows show the influence of filtering processes on ecosystem properties. Feedbacks can occur whereby ecosystem properties modulate filtering processes (examples are indicated by bidirectional arrows). Interactions among drivers include indirect effects of human activity on assembly through other drivers (black open arrows) and<|im_end|> <|im_start|>assistant A global cross-disciplinary team of scientists led by UNSW Sydney researchers has developed the first comprehensive classification of the world's ecosystems across land, rivers and wetlands, and seas. The ecosystem typology will enable more coordinated and effective biodiversity conservation, critical for human well-being. The extensive collaboration includes the International Union for Conservation of Nature (IUCN), which comprises about 1400 member organizations, including countries; the IUCN Commission on Ecosystem Management; the PLuS Alliance—Arizona State University, King's College London and UNSW Sydney; and more than 100 specialist ecosystem scientists around the world. The study, published today in Nature, explores the science that underpins the typology, as well as how it can help achieve objectives in global policy that flow to individual countries. With UNSW's support, IUCN launched the first public version of the typology in 2020 and, since then, the researchers have refined and updated it. The research team was led by Professor David Keith with Professor Richard Kingsford from UNSW's Centre for Ecosystem Science, and Professor Emily Nicholson from Deakin University. "For the first time, we have a common platform that identifies, defines and describes the full suite of the whole planet's ecosystems," said Professor Keith. "It may seem rather odd that we haven't had this before, but historically scientists have forged advances by working somewhat separately in marine, freshwater and terrestrial ecosystems. This is the first time that all of this detailed knowledge has been brought together into a single framework taking advantage of common theory across the disciplines." The typology allows us to understand broad global patterns, including the transformation of ecosystems by people. Ten percent of ecosystems are artificially created and maintained by humans but occupy more than 30 percent of the Earth's land surface—what is left is home to 94 percent of threatened species on the IUCN Red List. At a policy level, this is the first time we've had this kind of overview, Professor Kingsford said. "It's very hard to see the big picture on a jigsaw puzzle until you have all the pieces in place—and that's what we now have. We have a much more substantial foundation to move ahead with a new era of ecosystem conservation and management policy." At a more general level, the overview allows policymakers and industry to plan their initiatives in full context. For governments and non-government organizations (NGOs) working in a range of countries, the overview can inform decisions about how ecosystem protection and restoration efforts can achieve maximum conservation benefit, and where development infrastructure is best placed to minimize impact. "Efforts on biodiversity conservation have largely centered at the species level, because it's seen to be more tangible," said Professor Keith. "But a broader focus on both ecosystems and species is more likely to succeed in conserving all plants and animals, as well as the essential services that nature provides people." Globally, countries coordinate their efforts under the umbrella of the United Nations Convention on Biological Diversity (CBD), which is coming up for renewal at the end of 2022. Delegates from 193 countries will meet in December at the 15th Conference of Parties in Montreal, Canada, to agree on the post-2020 agenda for CBD. Preparations for that meeting indicate a stronger emphasis on ecosystem conservation and management in the coming decades. "The global ecosystem typology will make it possible to account for ongoing ecosystem change, identify threatened ecosystem types, and plan better preventative action and restoration under a renewed agenda for the CBD," said Professor Nicholson. This typology marks a breakthrough for sustainable management of the world's ecosystems, said Dr. Angela Andrade, Chair of IUCN's Commission on Ecosystem Management and one of the authors. "It will enable real progress on United Nations Sustainable Development Goals and Environmental Accounting, and should help place ecosystems at the forefront of the United Nations' post-2020 agenda for conserving biological diversity." To make that a reality, we need a full set of high quality maps for all major ecosystem types, Professor Keith said. "We are already well down that path, but we need help to surmount the considerable challenges by exploiting recent advances in computer and satellite technology, along with global networks of citizen scientists." The ecosystem typology Ecosystems provide homes and vital life support for all plants and animals, and supply essential ecosystem services that sustain business, culture and human well-being. Those services—such as provision of clean air and water, carbon sequestration, reduced risks of disasters and outdoor recreational opportunities that sustain mental health—are sometimes regarded as free, but ecosystem degradation incurs costs for tapping alternative resources, disaster relief and reconstruction, and to health budgets. All of the world's ecosystems show hallmarks of human influence, and many are under acute risks of collapse, with consequences for habitats of species, genetic diversity, ecosystem services, sustainable development and human well-being. The global ecosystem typology describes the diversity of tropical forests, big rivers, coral reefs and other ecosystems that have typically been the focus of public attention. But it also includes little-known ecosystems of deep ocean trenches, seamounts, lakes beneath the ice sheets and microscopic ecosystems within rocks. "We don't think often about what's in the deep oceans, for example," said Professor Keith. "There's a tremendous variety of life down there and it's organized into a number of different ecosystems. And those ecosystems are beginning to feel the impact of human expansion. "The deep trenches in the ocean are filling up with microplastics, and we're starting to look at mining volcanic vents for minerals. We need to make decisions about those kinds of environments, just as we do about coral reefs and rainforests." A hierarchical structure The new typology has a hierarchical structure with six levels. The top level divides the planet into major realms, including terrestrial, freshwater, marine and subterranean ecosystems. The second and third levels include 25 biomes and 110 ecosystem functional groups, based on the ecological processes that shape different ecosystems and the functions that their key components perform. These functional groups will frame blueprints for sustainable ecosystem management. The lower levels of the hierarchy are based on finer ecosystem features and enable the integration of existing national classifications. These national ecosystem classifications and maps benefit from detailed scientific observations and considerable investment over many years. They are critical to conservation because many countries have built their environmental governance and regulations around them, as well as their protected area networks. For the first time, a globally agreed typology enables these many different systems to be reconciled across national borders, while supporting their ongoing use in each country. What are the next steps? The next major frontier for improved ecosystem management is to establish global maps and monitoring, Professor Keith said. "Although many of the world's 110 ecosystem types are already served with high quality maps updatable with satellite technology, the data for some other types is still rudimentary." "We can't plan effectively where to protect ecosystems or how to manage them sustainably unless we have reliable maps for the full range of ecosystem types, and integrate them into decision-making and monitoring systems," he said. <|im_end|>

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2,745

[ { "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 The accurate, continuous analysis of healthcare-relevant gases such as nitrogen oxides (NO x ) in a humid environment remains elusive for low-cost, stretchable gas sensing devices. This study presents the design and demonstration of a moisture-resistant, stretchable NO x gas sensor based on laser-induced graphene (LIG). Sandwiched between a soft elastomeric substrate and a moisture-resistant semipermeable encapsulant, the LIG sensing and electrode layer is first optimized by tuning laser processing parameters such as power, image density, and defocus distance. The gas sensor, using a needlelike LIG prepared with optimal laser processing parameters, exhibits a large response of 4.18‰ ppm −1 to NO and 6.66‰ ppm −1 to NO 2 , an ultralow detection limit of 8.3 ppb to NO and 4.0 ppb to NO 2 , fast response/recovery, and excellent selectivity. The design of a stretchable serpentine structure in the LIG electrode and strain isolation from the stiff island allows the gas sensor to be stretched by 30%. Combined with a moisture-resistant property against a relative humidity of 90%, the reported gas sensor has further been demonstrated to monitor the personal local environment during different times of the day and analyze human breath samples to classify patients with respiratory diseases from healthy volunteers. Moisture-resistant, stretchable NO x gas sensors can expand the capability of wearable devices to detect biomarkers from humans and exposed environments for early disease diagnostics. Introduction Wearable electronic devices can conform to the skin to capture mechanical 1 , thermal 2 , chemical 3 , electrical 4 , and biological signals 5 , 6 for future health monitoring. The increasing interest in personal air quality monitoring and breath analysis has also spurred the demand for wearable gas sensors to accurately and continuously detect various health-relevant gases 7 , 8 , 9 . The nitrogen oxides (collectively termed NO x ) generated from fuel combustion and petroleum refining are major atmospheric pollutants that lead to bronchitis and emphysema with heart-aggravating conditions 10 , 11 , 12 , 13 . Meanwhile, nitric oxide (NO), as an essential biomarker for airway inflammation, is of high interest for the noninvasive diagnosis and monitoring of respiratory diseases such as lung cancer and ventilator-associated pneumonia 14 . The NO concentration in the exhaled breath of asthma patients exceeds hundreds of parts per billion (ppb), whereas the level is less than several tens of ppb for healthy subjects 15 , 16 , 17 , 18 , 19 , 20 . Studies on detecting NO x have explored diverse sensitive nanomaterials such as graphene 21 , metal oxides 22 , conducting polymers 23 , and carbon nanotubes 24 . Compared with electrochemical cells, field-effect transistors, and other types of gas sensors, wearable graphene-based chemiresistive NO x gas sensors from simple fabrication processes show low noise and high mechanical strength 25 , 26 , 27 , 28 , 29 , 30 , 31 . Unfortunately, graphene-based gas sensors without proper surface modification exhibit low sensitivity and poor selectivity due to few active sites and nonselective molecular adsorption 29 , 30 , 31 . The recently explored highly porous 3D laser-induced graphene (LIG) conveniently prepared by a fast, cost-effective, environmentally friendly laser scribing process 32 , 33 , 34 supplies many active surface sites for gas-solid interactions for gas sensing 35 , 36 . In addition to exploring LIG with a high specific surface area and low contact resistance as a sensing electrode for detecting NO 2 gas 37 , LIG can also be combined with other nanomaterials to form a P-N junction with increased carrier mobility to detect NO 2 38 , 39 . Additionally, the changed thermal conductivity of pristine LIG in a vacuum environment allows for the detection of O 2 , N 2 , and CO 2 36 . LIG-based NO x gas sensors remain undeveloped. As water molecules often occupy the active sites on the surface of sensing materials, the relative humidity (RH) often influences the adsorption and equilibrium processes of the target gas, resulting in large response fluctuations, especially in breath with an RH of 50–95% 40 , 41 , 42 , 43 . Attempts to mitigate the RH effect include the use of coated hydrophobic self-assembled monolayers (SAMs) 44 , 45 , coated moisture barrier layers 46 , integrated heating elements 47 , or electronic nose algorithms 48 , 49 . However, these methods usually increase the fabrication complexity and cost of the resulting sensing devices. Therefore, it is imperative to develop a facile strategy to design and fabricate moisture-resistant, stretchable NO x gas sensors with a large response, rapid response/recovery rates, low limit of detection (LOD), and excellent selectivity to monitor local air quality and analyze breath for disease diagnostics. Here, we design and demonstrate a moisture-resistant, stretchable LIG-based NO x gas sensor, with the LIG sensing/electrode region sandwiched between semipermeable polydimethylsiloxane (PDMS) membrane and a soft elastomeric substrate. Tuning the laser processing parameters (e.g., laser power, image density, and defocus distance) yields a LIG with different morphologies (e.g., sheet, needle, closed rose petal, and collapsed hole-like microstructure), defect levels, and specific surface areas. A needlelike LIG with a large specific surface area of 296 m 2 /g and small defects of I D /I G ≈ 0.46 is obtained with optimal laser processing parameters (i.e., power of 0.6 W, image density of 500 PPI, and defocus distance of 0 mm). The resulting sensor exhibits a large response of 6‰ (or 4‰), fast response/recovery of 134/388 s (or 113/296 s), and ultralow LOD of 4.0 ppb (or 8.3 ppb) to NO 2 (or NO) at room temperature. Combining a high stretchability of 30% and a moisture-resistant property against an RH of 90%, the water-resistant, stretchable LIG-based gas sensing device has successfully detected outdoor air quality at different times of the day and analyzed the clinical breath samples to accurately classify patients with respiratory diseases from healthy human subjects. Results and discussion Fabrication of moisture-resistant, stretchable LIG-based gas sensors Produced by fuel combustion, automobile exhaust, and industrial waste gas,", "role": "user" }, { "content": "Accurate, continuous monitoring of nitrogen dioxide and other gases in humid environments is now possible, thanks to a new water-resistant gas sensor developed by Huanyu \"Larry\" Cheng, the James L. Henderson Jr. Memorial Associate Professor of Engineering Science and Mechanics, and his team. The sensor detects nitrogen dioxide in breath, the concentration of which may indicate potential pulmonary diseases, or in particular environments to monitor air quality. The team's approach was published in Microsystems & Nanoengineering. While Cheng previously developed a sensor that was waterproof, that sensor could only detect temperature and motion. Cheng also has developed a highly customizable microscale gas sensor, as well as a flexible, porous and sensitive gas sensor. Humidity, sweat or other moisture exposure, however, rendered the sensors unusable. \"We cannot avoid humidity levels in the environment, which is why we wanted to emphasize the moisture-resistant property,\" Cheng said. The researchers used the same laser-induced graphene (LIG)—a speedy, cost-effective, environmentally friendly fabrication method that uses laser writing to assemble two-dimensional graphene layers—as they did for the previous gas sensors. This time, however, they also added a soft elastomeric polymer substrate and a moisture-resistant, semi-permeable membrane to either side of the LIG sensing layer. The new sensor is stretchable and soft, making it possible to wear on the skin for a long time, according to the researchers. Credit: Provided by Li Yang \"Laser-induced graphene is hydrophilic, so it intrinsically is a water-absorbing material,\" Cheng said. \"Water will naturally get down into the material and change its properties. If you have water molecules absorbed by the sensor, that will change the response. By using a semi-permeable membrane with the LIG, we can block the water or moisture from the outside but still allow the permeation of the target gas molecule. Since the new material is stretchable and soft, it can be worn on the skin for a long time without causing irritation.\" To test the sensors, the researchers used them to evaluate the breath of 30 individuals. They found that the sensor response values were more than four times greater for patients who had chronic obstructive pulmonary disease (COPD) or asthma than for those who did not, meaning that people with COPD or asthma had more than four times the amount of nitrogen dioxide in their exhalation. \"With this sensor, we are much closer to the actual application of helping a patient,\" said co-author Li Yang, associate professor in the School of Health Sciences and Biomedical Engineering at Hebei University of Technology. \"This sensor could be used for the early screening process, to make someone aware of the potential condition that may develop into a bigger concern later, and also for the existing COPD or asthma patient to monitor the environment for potential exposure to nitrogen dioxide so they can take early prevention measures, like avoiding certain areas with higher nitrogen dioxide levels.\" Cheng said that eventually this sensor could be used for monitoring not only individual well-being but also to better understand the health of a population. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 accurate, continuous analysis of healthcare-relevant gases such as nitrogen oxides (NO x ) in a humid environment remains elusive for low-cost, stretchable gas sensing devices. This study presents the design and demonstration of a moisture-resistant, stretchable NO x gas sensor based on laser-induced graphene (LIG). Sandwiched between a soft elastomeric substrate and a moisture-resistant semipermeable encapsulant, the LIG sensing and electrode layer is first optimized by tuning laser processing parameters such as power, image density, and defocus distance. The gas sensor, using a needlelike LIG prepared with optimal laser processing parameters, exhibits a large response of 4.18‰ ppm −1 to NO and 6.66‰ ppm −1 to NO 2 , an ultralow detection limit of 8.3 ppb to NO and 4.0 ppb to NO 2 , fast response/recovery, and excellent selectivity. The design of a stretchable serpentine structure in the LIG electrode and strain isolation from the stiff island allows the gas sensor to be stretched by 30%. Combined with a moisture-resistant property against a relative humidity of 90%, the reported gas sensor has further been demonstrated to monitor the personal local environment during different times of the day and analyze human breath samples to classify patients with respiratory diseases from healthy volunteers. Moisture-resistant, stretchable NO x gas sensors can expand the capability of wearable devices to detect biomarkers from humans and exposed environments for early disease diagnostics. Introduction Wearable electronic devices can conform to the skin to capture mechanical 1 , thermal 2 , chemical 3 , electrical 4 , and biological signals 5 , 6 for future health monitoring. The increasing interest in personal air quality monitoring and breath analysis has also spurred the demand for wearable gas sensors to accurately and continuously detect various health-relevant gases 7 , 8 , 9 . The nitrogen oxides (collectively termed NO x ) generated from fuel combustion and petroleum refining are major atmospheric pollutants that lead to bronchitis and emphysema with heart-aggravating conditions 10 , 11 , 12 , 13 . Meanwhile, nitric oxide (NO), as an essential biomarker for airway inflammation, is of high interest for the noninvasive diagnosis and monitoring of respiratory diseases such as lung cancer and ventilator-associated pneumonia 14 . The NO concentration in the exhaled breath of asthma patients exceeds hundreds of parts per billion (ppb), whereas the level is less than several tens of ppb for healthy subjects 15 , 16 , 17 , 18 , 19 , 20 . Studies on detecting NO x have explored diverse sensitive nanomaterials such as graphene 21 , metal oxides 22 , conducting polymers 23 , and carbon nanotubes 24 . Compared with electrochemical cells, field-effect transistors, and other types of gas sensors, wearable graphene-based chemiresistive NO x gas sensors from simple fabrication processes show low noise and high mechanical strength 25 , 26 , 27 , 28 , 29 , 30 , 31 . Unfortunately, graphene-based gas sensors without proper surface modification exhibit low sensitivity and poor selectivity due to few active sites and nonselective molecular adsorption 29 , 30 , 31 . The recently explored highly porous 3D laser-induced graphene (LIG) conveniently prepared by a fast, cost-effective, environmentally friendly laser scribing process 32 , 33 , 34 supplies many active surface sites for gas-solid interactions for gas sensing 35 , 36 . In addition to exploring LIG with a high specific surface area and low contact resistance as a sensing electrode for detecting NO 2 gas 37 , LIG can also be combined with other nanomaterials to form a P-N junction with increased carrier mobility to detect NO 2 38 , 39 . Additionally, the changed thermal conductivity of pristine LIG in a vacuum environment allows for the detection of O 2 , N 2 , and CO 2 36 . LIG-based NO x gas sensors remain undeveloped. As water molecules often occupy the active sites on the surface of sensing materials, the relative humidity (RH) often influences the adsorption and equilibrium processes of the target gas, resulting in large response fluctuations, especially in breath with an RH of 50–95% 40 , 41 , 42 , 43 . Attempts to mitigate the RH effect include the use of coated hydrophobic self-assembled monolayers (SAMs) 44 , 45 , coated moisture barrier layers 46 , integrated heating elements 47 , or electronic nose algorithms 48 , 49 . However, these methods usually increase the fabrication complexity and cost of the resulting sensing devices. Therefore, it is imperative to develop a facile strategy to design and fabricate moisture-resistant, stretchable NO x gas sensors with a large response, rapid response/recovery rates, low limit of detection (LOD), and excellent selectivity to monitor local air quality and analyze breath for disease diagnostics. Here, we design and demonstrate a moisture-resistant, stretchable LIG-based NO x gas sensor, with the LIG sensing/electrode region sandwiched between semipermeable polydimethylsiloxane (PDMS) membrane and a soft elastomeric substrate. Tuning the laser processing parameters (e.g., laser power, image density, and defocus distance) yields a LIG with different morphologies (e.g., sheet, needle, closed rose petal, and collapsed hole-like microstructure), defect levels, and specific surface areas. A needlelike LIG with a large specific surface area of 296 m 2 /g and small defects of I D /I G ≈ 0.46 is obtained with optimal laser processing parameters (i.e., power of 0.6 W, image density of 500 PPI, and defocus distance of 0 mm). The resulting sensor exhibits a large response of 6‰ (or 4‰), fast response/recovery of 134/388 s (or 113/296 s), and ultralow LOD of 4.0 ppb (or 8.3 ppb) to NO 2 (or NO) at room temperature. Combining a high stretchability of 30% and a moisture-resistant property against an RH of 90%, the water-resistant, stretchable LIG-based gas sensing device has successfully detected outdoor air quality at different times of the day and analyzed the clinical breath samples to accurately classify patients with respiratory diseases from healthy human subjects. Results and discussion Fabrication of moisture-resistant, stretchable LIG-based gas sensors Produced by fuel combustion, automobile exhaust, and industrial waste gas,<|im_end|> <|im_start|>assistant Accurate, continuous monitoring of nitrogen dioxide and other gases in humid environments is now possible, thanks to a new water-resistant gas sensor developed by Huanyu "Larry" Cheng, the James L. Henderson Jr. Memorial Associate Professor of Engineering Science and Mechanics, and his team. The sensor detects nitrogen dioxide in breath, the concentration of which may indicate potential pulmonary diseases, or in particular environments to monitor air quality. The team's approach was published in Microsystems & Nanoengineering. While Cheng previously developed a sensor that was waterproof, that sensor could only detect temperature and motion. Cheng also has developed a highly customizable microscale gas sensor, as well as a flexible, porous and sensitive gas sensor. Humidity, sweat or other moisture exposure, however, rendered the sensors unusable. "We cannot avoid humidity levels in the environment, which is why we wanted to emphasize the moisture-resistant property," Cheng said. The researchers used the same laser-induced graphene (LIG)—a speedy, cost-effective, environmentally friendly fabrication method that uses laser writing to assemble two-dimensional graphene layers—as they did for the previous gas sensors. This time, however, they also added a soft elastomeric polymer substrate and a moisture-resistant, semi-permeable membrane to either side of the LIG sensing layer. The new sensor is stretchable and soft, making it possible to wear on the skin for a long time, according to the researchers. Credit: Provided by Li Yang "Laser-induced graphene is hydrophilic, so it intrinsically is a water-absorbing material," Cheng said. "Water will naturally get down into the material and change its properties. If you have water molecules absorbed by the sensor, that will change the response. By using a semi-permeable membrane with the LIG, we can block the water or moisture from the outside but still allow the permeation of the target gas molecule. Since the new material is stretchable and soft, it can be worn on the skin for a long time without causing irritation." To test the sensors, the researchers used them to evaluate the breath of 30 individuals. They found that the sensor response values were more than four times greater for patients who had chronic obstructive pulmonary disease (COPD) or asthma than for those who did not, meaning that people with COPD or asthma had more than four times the amount of nitrogen dioxide in their exhalation. "With this sensor, we are much closer to the actual application of helping a patient," said co-author Li Yang, associate professor in the School of Health Sciences and Biomedical Engineering at Hebei University of Technology. "This sensor could be used for the early screening process, to make someone aware of the potential condition that may develop into a bigger concern later, and also for the existing COPD or asthma patient to monitor the environment for potential exposure to nitrogen dioxide so they can take early prevention measures, like avoiding certain areas with higher nitrogen dioxide levels." Cheng said that eventually this sensor could be used for monitoring not only individual well-being but also to better understand the health of a population. <|im_end|>

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2,035

[ { "content": "You are a great 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: Breast cancer is the most common cancer in younger women (aged ⩽ 40 years) in the United Kingdom. PREDICT ( ) is an online prognostic tool developed to help determine the best available treatment and outcome for early breast cancer. This study was conducted to establish how well PREDICT performs in estimating survival in a large cohort of younger women recruited to the UK POSH study. Methods: The POSH cohort includes data from 3000 women aged ⩽ 40 years at breast cancer diagnosis. Study end points were overall and breast cancer-specific survival at 5, 8, and 10 years. Evaluation of PREDICT included model discrimination and comparison of the number of predicted versus observed events. Results: PREDICT provided accurate long-term (8- and 10-year) survival estimates for younger women. Five-year estimates were less accurate, with the tool overestimating survival by 25% overall, and by 56% for patients with oestrogen receptor (ER)-positive tumours. PREDICT underestimated survival at 5 years among patients with ER-negative tumours. Conclusions: PREDICT is a useful tool for providing reliable long-term (10-year) survival estimates for younger patients. However, for more accurate short-term estimates, the model requires further calibration using more data from young onset cases. Short-term prediction may be most relevant for the increasing number of women considering risk-reducing bilateral mastectomy. Main Breast cancer is the most common cancer in women in the United Kingdom, with around 50 000 newly diagnosed cases each year ( Cancer Research UK, 2014 ). Approximately 4% of cases are in younger women (aged ⩽ 40 years at diagnosis) yet it remains the most frequent malignancy in women of this age group ( Cancer Research UK, 2014 ). Determining the long-term outcome and potential benefits from systemic adjuvant treatments for early-stage breast cancer has been improved through the use of a number of currently available predictive tools, including the Nottingham Prognostic Index (NPI), Adjuvant! and PREDICT. These tools have become increasingly sophisticated; incorporating a growing number of prognostic factors, enabling a move from categorising patients into broad prognostic groups to providing survival estimates at a patient level. However, many existing prognostic tools have only been validated in a small number of younger women, in which an overestimation of up to 30% in overall survival (OS) is reported in younger women ( Engelhardt et al, 2014 ). Materials and Methods Existing tools The original NPI was based on 387 patients treated in a single institution and used tumour size, grade, and lymph node status to provide a prognostic index ( Haybittle et al, 1982 ). The tool was later validated ( Todd et al, 1987 ; D’Eredita et al, 2001 ) and updated to provide survival estimates by NPI group ( Blamey et al, 2007a ), and at a patient level ( Blamey et al, 2007b ). Adjuvant! is an online decision aid tool, which was developed in 2001, based on 34 252 women aged 36–69 years from multiple institutions in the United States, and incorporated the patient’s age, tumour size and grade, oestrogen receptor (ER) status, and number of positive nodes, to provide individual 10-year outcomes ( Ravdin et al, 2001 ). The tool was later validated in patients from Canada ( Olivotto et al, 2005 ) and the United Kingdom ( Campbell et al, 2009 ). Adjuvant! makes an adjustment for women under 35 years, based on data from 415 patients; however, this applies only to patients with ER-positive tumours ( Aebi et al, 2000 ). The online breast cancer prognostic and treatment benefit tool, PREDICT, is used to estimate survival for individual patients based on known pathological prognostic factors, including age at diagnosis, mode of detection, tumour grade, tumour size, ER and nodal status, and type of therapy. The tool was developed in the United Kingdom, based on 5694 women aged 23–95 years (401 aged ⩽ 40 years), from multiple institutions in East Anglia, and validated in two further cohorts: 5468 women aged 22–93 years from the West Midlands Cancer Intelligence Unit ( Wishart et al, 2010 ); and the same cohort used for the validation of Adjuvant! ( Wishart et al, 2011 ). An updated version of PREDICT ( ) now incorporates human epidermal growth factor receptor 2 (HER2) status ( Wishart et al, 2012 ). The updated tool was validated using 1653 patients with information on HER2 from the same cohort of 3140 women from Canada used in the previous validations of PREDICT and Adjuvant!, and was shown to provide accurate OS and breast cancer-specific survival (BCSS) estimates at 10 years. The results demonstrated that the incorporation of HER2 status improved the tool, with predicted overall and breast cancer-specific deaths within 8.4% and 2.5% of those observed ( P =0.05 and P =0.60, respectively). However, the results indicated that PREDICT underestimated the number of deaths in women aged 20–35 years by 32% for both OS and BCSS ( Wishart et al, 2012 ). Although PREDICT was successfully validated in a large cohort, only 159 (9.6%) of these women from Canada were aged ⩽ 40 years at diagnosis. However, young age at diagnosis is associated with lower survival rates compared with older patients ( El Saghir et al, 2006 ; Adami et al, 1986 ). The reasons for the differing effects remain unclear; studies have shown that lower survival rates coupled with higher relapse rates in younger patients are independent of other known prognostic factors ( de la Rochefordiere et al, 1993 ; Nixon et al, 1994 ). Younger patients may receive less significant survival benefits from hormonal therapy after adjuvant chemotherapy than older patients ( Ahn et al, 2007 ). Furthermore, studies of premenopausal and perimenopausal women with breast cancer have found that chemotherapy alone was insufficient for younger patients, and perhaps tailored treatments should be investigated ( Aebi et al, 2000 ; Colleoni et al, 2006 ). The aim of this study was to investigate the performance of the updated PREDICT tool in a large cohort of women aged ⩽ 40 years at breast cancer diagnosis in terms", "role": "user" }, { "content": "An online computer programme that helps to predict the most suitable treatment for breast cancer has been found to underestimate the number of women under 40 who will die from the disease by 25 per cent, according to a study published in the British Journal of Cancer today. Researchers carried out an evaluation of the PREDICT computer programme which was developed after studying thousands of UK women of all ages with breast cancer. The programme itself has been well validated as a predictor of prognosis. However its accuracy among young women – who represent less than five percent of all breast cancer cases in the UK – might be affected by the fact that data from only a small number of young women were included when the programme was developed, and this could be making its five-year predictions for patients in this age group less accurate. The disease can behave differently in younger women compared with older patients and can sometimes be more aggressive. Researchers from Southampton and Cambridge, supported by Cancer Research UK and University Hospital Southampton NHS Foundation Trust, looked at how accurately the PREDICT online programme estimates the number of deaths in patients diagnosed with breast cancer before the age of 41. PREDICT is one of several prediction computer programmes available to doctors and patients, and is one of the few freely available online. The researchers used information from 3,000 young women diagnosed with oestrogen receptor (ER) positive and ER negative breast cancer in the UK between 2000 and 2008. When considering all cases together, PREDICT underestimated the number of deaths within five years of diagnosis by 25 per cent, with around 610 deaths occurring in total compared with around 460 predicted. Evaluation co-author Professor Diana Eccles said: \"This research emphasises growing understanding that breast cancer in young women can behave differently, so making predictions using information from mainly older women may not always be accurate enough for younger patients and doctors trying to make important decisions about treatment. \"The computer programme was developed using information from breast cancer patients of all ages, but included data from only a small number of very young women. This could explain why it isn't as accurate as we would like for younger patients. Our findings will be used to help the group in Cambridge to develop the software further, giving more accurate estimates for younger women.\" Researchers found that PREDICT's longer-term estimates of how many young women would die within eight and 10 years of diagnosis were more accurate. But the pattern of underestimating deaths in women with ER positive tumours and overestimating deaths in those with ER negative tumours largely persisted. Findings from this evaluation will be used to further develop the software and increase its accuracy for the young age group. Breast cancer is the most common cancer in the UK, with just under 50,000 newly diagnosed cases in women each year. Less than five per cent of cases are in women diagnosed before the age of 40. Martin Ledwick, head information nurse at Cancer Research UK said: \"Computer programmes like PREDICT add to the information that doctors and women have when agreeing on treatment, which might be hormone therapy, chemotherapy or surgery. This evaluation had limitations but it provides valuable data to help improve PREDICT's accuracy for younger women.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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: Breast cancer is the most common cancer in younger women (aged ⩽ 40 years) in the United Kingdom. PREDICT ( ) is an online prognostic tool developed to help determine the best available treatment and outcome for early breast cancer. This study was conducted to establish how well PREDICT performs in estimating survival in a large cohort of younger women recruited to the UK POSH study. Methods: The POSH cohort includes data from 3000 women aged ⩽ 40 years at breast cancer diagnosis. Study end points were overall and breast cancer-specific survival at 5, 8, and 10 years. Evaluation of PREDICT included model discrimination and comparison of the number of predicted versus observed events. Results: PREDICT provided accurate long-term (8- and 10-year) survival estimates for younger women. Five-year estimates were less accurate, with the tool overestimating survival by 25% overall, and by 56% for patients with oestrogen receptor (ER)-positive tumours. PREDICT underestimated survival at 5 years among patients with ER-negative tumours. Conclusions: PREDICT is a useful tool for providing reliable long-term (10-year) survival estimates for younger patients. However, for more accurate short-term estimates, the model requires further calibration using more data from young onset cases. Short-term prediction may be most relevant for the increasing number of women considering risk-reducing bilateral mastectomy. Main Breast cancer is the most common cancer in women in the United Kingdom, with around 50 000 newly diagnosed cases each year ( Cancer Research UK, 2014 ). Approximately 4% of cases are in younger women (aged ⩽ 40 years at diagnosis) yet it remains the most frequent malignancy in women of this age group ( Cancer Research UK, 2014 ). Determining the long-term outcome and potential benefits from systemic adjuvant treatments for early-stage breast cancer has been improved through the use of a number of currently available predictive tools, including the Nottingham Prognostic Index (NPI), Adjuvant! and PREDICT. These tools have become increasingly sophisticated; incorporating a growing number of prognostic factors, enabling a move from categorising patients into broad prognostic groups to providing survival estimates at a patient level. However, many existing prognostic tools have only been validated in a small number of younger women, in which an overestimation of up to 30% in overall survival (OS) is reported in younger women ( Engelhardt et al, 2014 ). Materials and Methods Existing tools The original NPI was based on 387 patients treated in a single institution and used tumour size, grade, and lymph node status to provide a prognostic index ( Haybittle et al, 1982 ). The tool was later validated ( Todd et al, 1987 ; D’Eredita et al, 2001 ) and updated to provide survival estimates by NPI group ( Blamey et al, 2007a ), and at a patient level ( Blamey et al, 2007b ). Adjuvant! is an online decision aid tool, which was developed in 2001, based on 34 252 women aged 36–69 years from multiple institutions in the United States, and incorporated the patient’s age, tumour size and grade, oestrogen receptor (ER) status, and number of positive nodes, to provide individual 10-year outcomes ( Ravdin et al, 2001 ). The tool was later validated in patients from Canada ( Olivotto et al, 2005 ) and the United Kingdom ( Campbell et al, 2009 ). Adjuvant! makes an adjustment for women under 35 years, based on data from 415 patients; however, this applies only to patients with ER-positive tumours ( Aebi et al, 2000 ). The online breast cancer prognostic and treatment benefit tool, PREDICT, is used to estimate survival for individual patients based on known pathological prognostic factors, including age at diagnosis, mode of detection, tumour grade, tumour size, ER and nodal status, and type of therapy. The tool was developed in the United Kingdom, based on 5694 women aged 23–95 years (401 aged ⩽ 40 years), from multiple institutions in East Anglia, and validated in two further cohorts: 5468 women aged 22–93 years from the West Midlands Cancer Intelligence Unit ( Wishart et al, 2010 ); and the same cohort used for the validation of Adjuvant! ( Wishart et al, 2011 ). An updated version of PREDICT ( ) now incorporates human epidermal growth factor receptor 2 (HER2) status ( Wishart et al, 2012 ). The updated tool was validated using 1653 patients with information on HER2 from the same cohort of 3140 women from Canada used in the previous validations of PREDICT and Adjuvant!, and was shown to provide accurate OS and breast cancer-specific survival (BCSS) estimates at 10 years. The results demonstrated that the incorporation of HER2 status improved the tool, with predicted overall and breast cancer-specific deaths within 8.4% and 2.5% of those observed ( P =0.05 and P =0.60, respectively). However, the results indicated that PREDICT underestimated the number of deaths in women aged 20–35 years by 32% for both OS and BCSS ( Wishart et al, 2012 ). Although PREDICT was successfully validated in a large cohort, only 159 (9.6%) of these women from Canada were aged ⩽ 40 years at diagnosis. However, young age at diagnosis is associated with lower survival rates compared with older patients ( El Saghir et al, 2006 ; Adami et al, 1986 ). The reasons for the differing effects remain unclear; studies have shown that lower survival rates coupled with higher relapse rates in younger patients are independent of other known prognostic factors ( de la Rochefordiere et al, 1993 ; Nixon et al, 1994 ). Younger patients may receive less significant survival benefits from hormonal therapy after adjuvant chemotherapy than older patients ( Ahn et al, 2007 ). Furthermore, studies of premenopausal and perimenopausal women with breast cancer have found that chemotherapy alone was insufficient for younger patients, and perhaps tailored treatments should be investigated ( Aebi et al, 2000 ; Colleoni et al, 2006 ). The aim of this study was to investigate the performance of the updated PREDICT tool in a large cohort of women aged ⩽ 40 years at breast cancer diagnosis in terms<|im_end|> <|im_start|>assistant An online computer programme that helps to predict the most suitable treatment for breast cancer has been found to underestimate the number of women under 40 who will die from the disease by 25 per cent, according to a study published in the British Journal of Cancer today. Researchers carried out an evaluation of the PREDICT computer programme which was developed after studying thousands of UK women of all ages with breast cancer. The programme itself has been well validated as a predictor of prognosis. However its accuracy among young women – who represent less than five percent of all breast cancer cases in the UK – might be affected by the fact that data from only a small number of young women were included when the programme was developed, and this could be making its five-year predictions for patients in this age group less accurate. The disease can behave differently in younger women compared with older patients and can sometimes be more aggressive. Researchers from Southampton and Cambridge, supported by Cancer Research UK and University Hospital Southampton NHS Foundation Trust, looked at how accurately the PREDICT online programme estimates the number of deaths in patients diagnosed with breast cancer before the age of 41. PREDICT is one of several prediction computer programmes available to doctors and patients, and is one of the few freely available online. The researchers used information from 3,000 young women diagnosed with oestrogen receptor (ER) positive and ER negative breast cancer in the UK between 2000 and 2008. When considering all cases together, PREDICT underestimated the number of deaths within five years of diagnosis by 25 per cent, with around 610 deaths occurring in total compared with around 460 predicted. Evaluation co-author Professor Diana Eccles said: "This research emphasises growing understanding that breast cancer in young women can behave differently, so making predictions using information from mainly older women may not always be accurate enough for younger patients and doctors trying to make important decisions about treatment. "The computer programme was developed using information from breast cancer patients of all ages, but included data from only a small number of very young women. This could explain why it isn't as accurate as we would like for younger patients. Our findings will be used to help the group in Cambridge to develop the software further, giving more accurate estimates for younger women." Researchers found that PREDICT's longer-term estimates of how many young women would die within eight and 10 years of diagnosis were more accurate. But the pattern of underestimating deaths in women with ER positive tumours and overestimating deaths in those with ER negative tumours largely persisted. Findings from this evaluation will be used to further develop the software and increase its accuracy for the young age group. Breast cancer is the most common cancer in the UK, with just under 50,000 newly diagnosed cases in women each year. Less than five per cent of cases are in women diagnosed before the age of 40. Martin Ledwick, head information nurse at Cancer Research UK said: "Computer programmes like PREDICT add to the information that doctors and women have when agreeing on treatment, which might be hormone therapy, chemotherapy or surgery. This evaluation had limitations but it provides valuable data to help improve PREDICT's accuracy for younger women." <|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 genus Ebolavirus comprises some of the deadliest viruses for primates and humans and associated disease outbreaks are increasing in Africa. Different evidence suggests that bats are putative reservoir hosts and play a major role in the transmission cycle of these filoviruses. Thus, detailed knowledge about their distribution might improve risk estimations of where future disease outbreaks might occur. A MaxEnt niche modelling approach based on climatic variables and land cover was used to investigate the potential distribution of 9 bat species associated to the Zaire ebolavirus . This viral species has led to major Ebola outbreaks in Africa and is known for causing high mortalities. Modelling results suggest suitable areas mainly in the areas near the coasts of West Africa with extensions into Central Africa, where almost all of the 9 species studied find suitable habitat conditions. Previous spillover events and outbreak sites of the virus are covered by the modelled distribution of 3 bat species that have been tested positive for the virus not only using serology tests but also PCR methods. Modelling the habitat suitability of the bats is an important step that can benefit public information campaigns and may ultimately help control future outbreaks of the disease. Introduction Today, many infectious diseases occurring in humans are zoonotic and originate from infected wild animals 1 . Among these emerging diseases, diseases caused by filoviruses pose major health threats, since these viruses belong to the most lethal primate pathogens with average death rates of 50% 2 , 3 . In recent years, the genus Ebolavirus has gained much attention. The genus Ebolavirus was first identified in 1976 in the area of present-day Democratic Republic of the Congo (near the Ebola River) and the species of this genus are endemic in at least 14 African countries today. Until today, five viral species of the genus Ebolavirus , namely the Zaire ebolavirus (ZEBOV), the Sudan ebolavirus , the Taï Forest ebolavirus , the Bundibugyo ebolavirus and the Reston ebolavirus are known. While the first four species are assumed to be endemic to Africa and have led to numerous disease outbreaks in several African countries so far 4 , 5 , Reston ebolavirus is probably native to Asian countries, e.g. the Philippines and China 3 , 6 , 7 . Similar to the Marburg virus, the different species within the genus Ebolavirus , except Reston ebolavirus , cause haemorrhagic fever, which includes various symptoms like fever, vomiting, diarrhoea and muscle pain 4 , 8 . Besides their common symptoms, the five viral species differ in their pathogenicity, from asymptotic infections caused by Reston ebolavirus in humans to high mortality rates of up to 77–88% in case of ZEBOV infections 6 , 9 , 10 , 11 . The largest outbreak of the Ebola virus disease (EVD) until today occurred in Western Africa between 2014 and 2016. Starting in December 2013 with a probable spillover of the virus from infected bats 12 , the epidemic spread to other parts of Africa. The largest impact and number of EVD cases were recorded in Guinea, Sierra Leone and Liberia. During this epidemic, over 15,000 laboratory-confirmed Ebola cases and over 11,000 deaths were reported 4 , 8 . In addition, the outbreak that has started in 2018 in the Democratic Republic of the Congo (North Kivu Province) and the surrounding countries evidently suggests that rapid surveys and further investigations are ever more relevant. Single Ebola cases have also been reported from Europe (e.g. Spain or the Netherlands) and the USA 5 , 8 and can be linked to previous stays or aid missions in the affected areas. Until today, the transmission cycle of ZEBOV, especially within the animal reservoirs, has not been fully understood. Although many of the human Ebola outbreaks in Africa can be linked to infected great apes and duikers, these animals are not regarded as the natural reservoir hosts of the virus due to their high mortality rates 6 , 13 , 14 . Since the virus’ first detection more than 40 years ago, a number of possible reservoir hosts (including bats, birds, reptiles, molluscs, arthropods and plants) have been under consideration for potential reservoir hosts 5 , 6 , 15 , 16 . Peterson et al. suggested that an Ebola reservoir host is likely to be a small mammal, which would not show many symptoms 17 . Additionally, some studies revealed that among mammalian taxa (with the exception of rodents), bats seem to be a major reservoir hosts bearing a large number of zoonotic pathogens, e.g. viruses like the Marburg virus or Hendra and Nipah viruses 18 , 19 . In particular, the long-term infection and asymptomatic survival following an infection with the virus is considered a key aspect for reservoir hosts and may indicate a co-evolution between the reservoir and the virus 13 , 17 , 19 , 20 . In a laboratory experiment by Swanepoel et al., the authors showed that while plants, reptiles, invertebrates and some vertebrates had been refractory to the infections in experimental inoculation, ZEBOV was able to replicate in three bat species ( Tadarida condylura (= Mops condylurus ), T. pumila , and Epomophorus wahlbergi ) 6 . In additional laboratory experiments, the authors could also isolate the virus in the faeces of these bats 21 days after the inoculation of the virus 6 . Until today, antibodies against the different Ebola species have been detected in at least 14 bat species, including 9 species which had antibodies against ZEBOV ( Eidolon helvum , Epomophorus gambianus , Lissonycteris angolensis , Micropteropus pusillus , Mops condylurus , Rousettus aegyptiacus, Epomops franqueti, Hypsignathus monstrosus , and Myonycteris torquata ). Whereas these 9 bat species had been all tested positive for ZEBOV using serology methods, only Epomops franqueti, Hypsignathus monstrosus and Myonycteris torquata had additionally been tested positive by PCR methods 9 , 15 , 16 , 21 , 22 , 23 , 24 . PCR evidences for Rousettus aegyptiacus have been ambiguous and inconsistent 16 ,", "role": "user" }, { "content": "The Ebola virus is considered one of the world's most dangerous pathogens. During the most severe outbreak to date in West Africa, over 11,000 deaths were documented between 2014 and 2016. Single cases are repeatedly reported from Europe as well, which are connected to previous travels to affected regions. An important source of infection are so-called reservoir hosts that carry the virus without being affected by it. For the various types of the Ebola virus, the most likely involve reservoir hosts are various species of bats and fruit bats. For the first time, scientists investigated where nine of such bat and fruit bat species may encounter suitable habitats and climatic conditions in Africa. \"Zaire ebolavirus is one of the most dangerous Ebola viruses. It kills up to 88 percent of those infected with it. To prevent or curb outbreaks of this virus, it is essential to know exactly where potential hotspots of infection may lurk,\" explains parasitologist Prof. Dr. Sven Klimpel of the Goethe University in Frankfurt and the Senckenberg Biodiversity and Climate Research Center. Based on ecological niche modeling, his team was able to show that the respective bat and fruit bat species are able to thrive in West and East Africa, including large parts of Central Africa. A wide belt of potential habitats extends from Guinea, Sierra Leone, and Liberia in the west across the Central African Republic, the Republic of the Congo and the Democratic Republic of the Congo to Sudan andUganda in the East. A few of the studied bats and fruit bats may even occur in the eastern part of South Africa. In a second step, the researchers compared the potential habitats with range maps of the bat and fruit bat species that were generated by the International Union for the Conservation of Nature (IUCN) on the basis of observations of these animals. In addition, the team considered where a Zaireebolavirus endemic has broken out in the past. The results were surprising: \"The modeled habitats of the Zaire ebolavirus hosts are larger than their previously known ranges. It is possible that the bats and fruit bats have not yet been able to reach habitats beyond these ranges due to the presence of certain barriers,\" says Klimpel. \"Another, more worrying explanation could be that science has hitherto underestimated the range of Ebola-transmitting bat and fruit bat species. In this case, the models would provide a more realistic picture,\" explains Dr. Lisa Koch, the study's lead author from Goethe University. Regions affected by Ebola outbreaks often suffer not only from health effects, but also from economic and social effects of the epidemic. The study's findings suggest to keep a closer eye on diseases that occur in the modeled ranges of the reservoir hosts and to inform the public about potential Ebola infections, ultimately alleviating the consequences of an epidemic. With regard to Europe, Klimpel states: \"Ebola viruses, just like the SARS-CoV-2 (Coronavirus), are viruses from the animal kingdom that can be transmitted to humans. It can be expected that diseases of this type will occur more frequently in the future, since humans have increasing contact with wild animals, and globalization facilitates the spread of viruses around the world. In Europe, with its overall efficient health system, Ebola infections are certainly going to remain isolated incidents in the future. Nonetheless, in view of these trends it would be beneficial to intensively train and further educate physicians and nursing personnel in the treatment of tropical infectious diseases in our latitudes as well.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 genus Ebolavirus comprises some of the deadliest viruses for primates and humans and associated disease outbreaks are increasing in Africa. Different evidence suggests that bats are putative reservoir hosts and play a major role in the transmission cycle of these filoviruses. Thus, detailed knowledge about their distribution might improve risk estimations of where future disease outbreaks might occur. A MaxEnt niche modelling approach based on climatic variables and land cover was used to investigate the potential distribution of 9 bat species associated to the Zaire ebolavirus . This viral species has led to major Ebola outbreaks in Africa and is known for causing high mortalities. Modelling results suggest suitable areas mainly in the areas near the coasts of West Africa with extensions into Central Africa, where almost all of the 9 species studied find suitable habitat conditions. Previous spillover events and outbreak sites of the virus are covered by the modelled distribution of 3 bat species that have been tested positive for the virus not only using serology tests but also PCR methods. Modelling the habitat suitability of the bats is an important step that can benefit public information campaigns and may ultimately help control future outbreaks of the disease. Introduction Today, many infectious diseases occurring in humans are zoonotic and originate from infected wild animals 1 . Among these emerging diseases, diseases caused by filoviruses pose major health threats, since these viruses belong to the most lethal primate pathogens with average death rates of 50% 2 , 3 . In recent years, the genus Ebolavirus has gained much attention. The genus Ebolavirus was first identified in 1976 in the area of present-day Democratic Republic of the Congo (near the Ebola River) and the species of this genus are endemic in at least 14 African countries today. Until today, five viral species of the genus Ebolavirus , namely the Zaire ebolavirus (ZEBOV), the Sudan ebolavirus , the Taï Forest ebolavirus , the Bundibugyo ebolavirus and the Reston ebolavirus are known. While the first four species are assumed to be endemic to Africa and have led to numerous disease outbreaks in several African countries so far 4 , 5 , Reston ebolavirus is probably native to Asian countries, e.g. the Philippines and China 3 , 6 , 7 . Similar to the Marburg virus, the different species within the genus Ebolavirus , except Reston ebolavirus , cause haemorrhagic fever, which includes various symptoms like fever, vomiting, diarrhoea and muscle pain 4 , 8 . Besides their common symptoms, the five viral species differ in their pathogenicity, from asymptotic infections caused by Reston ebolavirus in humans to high mortality rates of up to 77–88% in case of ZEBOV infections 6 , 9 , 10 , 11 . The largest outbreak of the Ebola virus disease (EVD) until today occurred in Western Africa between 2014 and 2016. Starting in December 2013 with a probable spillover of the virus from infected bats 12 , the epidemic spread to other parts of Africa. The largest impact and number of EVD cases were recorded in Guinea, Sierra Leone and Liberia. During this epidemic, over 15,000 laboratory-confirmed Ebola cases and over 11,000 deaths were reported 4 , 8 . In addition, the outbreak that has started in 2018 in the Democratic Republic of the Congo (North Kivu Province) and the surrounding countries evidently suggests that rapid surveys and further investigations are ever more relevant. Single Ebola cases have also been reported from Europe (e.g. Spain or the Netherlands) and the USA 5 , 8 and can be linked to previous stays or aid missions in the affected areas. Until today, the transmission cycle of ZEBOV, especially within the animal reservoirs, has not been fully understood. Although many of the human Ebola outbreaks in Africa can be linked to infected great apes and duikers, these animals are not regarded as the natural reservoir hosts of the virus due to their high mortality rates 6 , 13 , 14 . Since the virus’ first detection more than 40 years ago, a number of possible reservoir hosts (including bats, birds, reptiles, molluscs, arthropods and plants) have been under consideration for potential reservoir hosts 5 , 6 , 15 , 16 . Peterson et al. suggested that an Ebola reservoir host is likely to be a small mammal, which would not show many symptoms 17 . Additionally, some studies revealed that among mammalian taxa (with the exception of rodents), bats seem to be a major reservoir hosts bearing a large number of zoonotic pathogens, e.g. viruses like the Marburg virus or Hendra and Nipah viruses 18 , 19 . In particular, the long-term infection and asymptomatic survival following an infection with the virus is considered a key aspect for reservoir hosts and may indicate a co-evolution between the reservoir and the virus 13 , 17 , 19 , 20 . In a laboratory experiment by Swanepoel et al., the authors showed that while plants, reptiles, invertebrates and some vertebrates had been refractory to the infections in experimental inoculation, ZEBOV was able to replicate in three bat species ( Tadarida condylura (= Mops condylurus ), T. pumila , and Epomophorus wahlbergi ) 6 . In additional laboratory experiments, the authors could also isolate the virus in the faeces of these bats 21 days after the inoculation of the virus 6 . Until today, antibodies against the different Ebola species have been detected in at least 14 bat species, including 9 species which had antibodies against ZEBOV ( Eidolon helvum , Epomophorus gambianus , Lissonycteris angolensis , Micropteropus pusillus , Mops condylurus , Rousettus aegyptiacus, Epomops franqueti, Hypsignathus monstrosus , and Myonycteris torquata ). Whereas these 9 bat species had been all tested positive for ZEBOV using serology methods, only Epomops franqueti, Hypsignathus monstrosus and Myonycteris torquata had additionally been tested positive by PCR methods 9 , 15 , 16 , 21 , 22 , 23 , 24 . PCR evidences for Rousettus aegyptiacus have been ambiguous and inconsistent 16 ,<|im_end|> <|im_start|>assistant The Ebola virus is considered one of the world's most dangerous pathogens. During the most severe outbreak to date in West Africa, over 11,000 deaths were documented between 2014 and 2016. Single cases are repeatedly reported from Europe as well, which are connected to previous travels to affected regions. An important source of infection are so-called reservoir hosts that carry the virus without being affected by it. For the various types of the Ebola virus, the most likely involve reservoir hosts are various species of bats and fruit bats. For the first time, scientists investigated where nine of such bat and fruit bat species may encounter suitable habitats and climatic conditions in Africa. "Zaire ebolavirus is one of the most dangerous Ebola viruses. It kills up to 88 percent of those infected with it. To prevent or curb outbreaks of this virus, it is essential to know exactly where potential hotspots of infection may lurk," explains parasitologist Prof. Dr. Sven Klimpel of the Goethe University in Frankfurt and the Senckenberg Biodiversity and Climate Research Center. Based on ecological niche modeling, his team was able to show that the respective bat and fruit bat species are able to thrive in West and East Africa, including large parts of Central Africa. A wide belt of potential habitats extends from Guinea, Sierra Leone, and Liberia in the west across the Central African Republic, the Republic of the Congo and the Democratic Republic of the Congo to Sudan andUganda in the East. A few of the studied bats and fruit bats may even occur in the eastern part of South Africa. In a second step, the researchers compared the potential habitats with range maps of the bat and fruit bat species that were generated by the International Union for the Conservation of Nature (IUCN) on the basis of observations of these animals. In addition, the team considered where a Zaireebolavirus endemic has broken out in the past. The results were surprising: "The modeled habitats of the Zaire ebolavirus hosts are larger than their previously known ranges. It is possible that the bats and fruit bats have not yet been able to reach habitats beyond these ranges due to the presence of certain barriers," says Klimpel. "Another, more worrying explanation could be that science has hitherto underestimated the range of Ebola-transmitting bat and fruit bat species. In this case, the models would provide a more realistic picture," explains Dr. Lisa Koch, the study's lead author from Goethe University. Regions affected by Ebola outbreaks often suffer not only from health effects, but also from economic and social effects of the epidemic. The study's findings suggest to keep a closer eye on diseases that occur in the modeled ranges of the reservoir hosts and to inform the public about potential Ebola infections, ultimately alleviating the consequences of an epidemic. With regard to Europe, Klimpel states: "Ebola viruses, just like the SARS-CoV-2 (Coronavirus), are viruses from the animal kingdom that can be transmitted to humans. It can be expected that diseases of this type will occur more frequently in the future, since humans have increasing contact with wild animals, and globalization facilitates the spread of viruses around the world. In Europe, with its overall efficient health system, Ebola infections are certainly going to remain isolated incidents in the future. Nonetheless, in view of these trends it would be beneficial to intensively train and further educate physicians and nursing personnel in the treatment of tropical infectious diseases in our latitudes as well." <|im_end|>

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2,111

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Puberty marks numerous physiological processes which are initiated by central activation of the hypothalamic–pituitary–gonadal axis, followed by development of secondary sexual characteristics. To a large extent, pubertal timing is heritable, but current knowledge of genetic polymorphisms only explains few months in the large inter-individual variation in the timing of puberty. We have analysed longitudinal genome-wide changes in DNA methylation in peripheral blood samples (n = 102) obtained from 51 healthy children before and after pubertal onset. We show that changes in single methylation sites are tightly associated with physiological pubertal transition and altered reproductive hormone levels. These methylation sites cluster in and around genes enriched for biological functions related to pubertal development. Importantly, we identified that methylation of the genomic region containing the promoter of TRIP6 was co-ordinately regulated as a function of pubertal development. In accordance, immunohistochemistry identified TRIP6 in adult, but not pre-pubertal, testicular Leydig cells and circulating TRIP6 levels doubled during puberty. Using elastic net prediction models, methylation patterns predicted pubertal development more accurately than chronological age. We demonstrate for the first time that pubertal attainment of secondary sexual characteristics is mirrored by changes in DNA methylation patterns in peripheral blood. Thus, modulations of the epigenome seem involved in regulation of the individual pubertal timing. Introduction Puberty is associated with the development of secondary sexual characteristics and attainment of adult reproductive capacity. This transition from child to adult phenotype is initiated by central activation of the hypothalamic–pituitary–gonadal (HPG) axis resulting in stimulation of steroid hormone synthesis. The ages at which puberty starts vary markedly both among healthy boys (9–14 years) and girls (8–13 years) and is to a large extent (60%) heritable 1 . Candidate gene approaches have identified single genes associated with pubertal extremes like precocious puberty 2 or absence of puberty 3 . However, no single gene appears to account for the large variation in pubertal timing among children with normally timed puberty. In fact, recent genome-wide association studies explain very little of this normal variation 4 , 5 , and the largest genetic effect on pubertal onset has been found by a candidate gene approach within FSHR and FSHB 6 . Furthermore, the secular trend of declining age at pubertal onset in both sexes in the western world has been observed over just a few decades, and must therefore be attributed to other factors than genetic variation. Profiling of DNA methylation patterns (methylation of cytosine in the context of a CpG site) in lymphocytes from human peripheral blood samples has been used to predict physiological outcomes or prospectively associate patterns with events earlier in life. Some of the most successful studies include prediction of biological aging 7 , 8 , 9 , 10 , 11 , 12 , associations with smoking 13 , 14 , and obesity 15 , 16 as well as persistent changes in adults following in utero famine during the second world war 17 , 18 . A link between self-reported menarcheal age and peripheral blood DNA methylation patterns has previously been investigated 19 but the results were rather inconclusive due to study design and technical aspects. In this longitudinal study of healthy Danish boys and girls with repeated blood sampling, we investigated the relationship between individual changes in genome-wide DNA methylation patterns and pubertal development. We identified several CpGs and CpG islands that closely followed pubertal transition suggesting important novel regulators of pubertal onset. Results From our longitudinal cohort (the COPENHAGEN puberty cohort) of healthy boys and girls, followed clinically during pubertal development, we included 22 girls and 32 boys who all had blood samples drawn for DNA isolation before and after onset of puberty. Pubertal onset was identified by thorough clinical investigation and defined as a testicular volume of ≥4 ml, or Tanner breast stage ≥B2 for boys and girls, respectively. The mean age between two examinations where this threshold was reached was used as their age of pubertal onset. Pre-pubertal blood samples were drawn at a mean age of 9.1 and 8.3 years corresponding to −2.5 and −1.8 years prior to pubertal onset for boys and girls, respectively. Post-pubertal samples were drawn at a mean age of 15.1 and 14 years and 3.5 and 4 years after pubertal onset for boys and girls, respectively ( Fig. 1a , Table 1 ). Two girls and one boy were excluded for technical reasons. We observed a slight tendency towards lower DNA methylation levels in open sea and in shores and shelf of CpG islands when pre-pubertal were compared to post-pubertal children and significantly (p = 0.001) higher DNA methylation levels of CpG islands in girls compared to boys ( Supplementary Figure 1 ). Figure 1: Identification of CpGs associated with pubertal age. ( a ) From the COPENHAGEN puberty study of children followed longitudinally, selected pre- and post-pubertal samples from 31 boys and 20 girls were included in the study. Time relative to onset of puberty as measured by a testicular volume of 4 ml or breast tanner stage B2 or above was calculated and defined as the pubertal age. ( b ) Genomic inflation of the genome-wide DNA methylation patterns correlating with pubertal age were corrected by applying an improved surrogate variant analysis (SmartSVA) resulting in a genomic inflation factor of 1.2 and a qq-plot leaving 457 significant CpG sites at a FDR of 0.05 (red). ( c ) Manhattan plot of the significant CpG sites reveal a distribution across all autosomes. ( d ) Unsupervised hierarchical centroid clustering of CpGs associated with pubertal age. The resulting dendrograms were colour coded according to their height and divided samples into two major groups that nearly uniquely represented pre- and post-pubertal boys and girls. ( e ) Gene ontology analysis of all significant CpGs revealed several ontologies (p-value < 0.05) that could be related to pubertal development. Biological process gene ontologies were plotted in a sematic space, using REVIGO, that groups related ontologies together. Full size image Table 1 Summary data on the pre- and post-pubertal boys and girls included", "role": "user" }, { "content": "Danish researchers have discovered a possible epigenetic link between the environment and pubertal timing. To a large extent, pubertal timing is heritable, but the underlying genetic causes are still unexplained. Researchers have now studied how chemical modifications of the human genome (so-called epigenetic modifications) change when girls and boys enter puberty. The results indicate that such epigenetic changes are involved in defining the onset of puberty. Danish girls' pubertal onset has decreased from 11 to 10 years. Similar, but less pronounced, changes have been observed in boys. This has led researchers to question the involvement of genetics and recognize that genes are not alone in influencing a child's pubertal timing. In this new study from EDMaRC at Rigshospitalet, Copenhagen, researchers therefore focused on the role of epigenetics and have found a number of areas in the human genome, which is controlled epigenetically during puberty. The researchers found that these epigenetic changes cause the upregulation of genes that are important for pubertal development. One of the newly discovered 'puberty genes' is TRIP6 (Thyroid Hormone Receptor Interactor 6), which is increasingly expressed through puberty, due to changes in the epigenetic control of the gene. Epigenetics is a leading mechanism by which our environment communicates with our genes. Environmental and lifestyle factors in the broadest sense can affect the epigenetic regulation of genes and thereby control whether, where and to what extent the genes are expressed. The identified epigenetic changes during puberty are therefore our best lead towards understanding how environmental factors can affect pubertal onset. \"To our knowledge, this study is the first to demonstrate how the environment can affect the pubertal onset in humans. It gives us a significant insight in to the crucial role of epigenetic factors on our reproductive development,\" says Professor Anders Juul, Senior author of the study. \"We've seen a tendency of especially girls starting puberty earlier than before and this study emphasizes the importance of understanding the role of environmental impact on pubertal development,\" he adds. Highly specific changes in methylation of a child's DNA could differentiate children according to whether they had entered puberty or not and thus may be used to predict a child's pubertal stage. \"Changes in the DNA methylation patterns can be caused by many different factors. However, we could see very specific changes when children went through puberty, and have subsequently shown that this also leads to changes in the expression of the methylated genes,\" says Senior Researcher in epigenetics Kristian Almstrup, who led the study. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Puberty marks numerous physiological processes which are initiated by central activation of the hypothalamic–pituitary–gonadal axis, followed by development of secondary sexual characteristics. To a large extent, pubertal timing is heritable, but current knowledge of genetic polymorphisms only explains few months in the large inter-individual variation in the timing of puberty. We have analysed longitudinal genome-wide changes in DNA methylation in peripheral blood samples (n = 102) obtained from 51 healthy children before and after pubertal onset. We show that changes in single methylation sites are tightly associated with physiological pubertal transition and altered reproductive hormone levels. These methylation sites cluster in and around genes enriched for biological functions related to pubertal development. Importantly, we identified that methylation of the genomic region containing the promoter of TRIP6 was co-ordinately regulated as a function of pubertal development. In accordance, immunohistochemistry identified TRIP6 in adult, but not pre-pubertal, testicular Leydig cells and circulating TRIP6 levels doubled during puberty. Using elastic net prediction models, methylation patterns predicted pubertal development more accurately than chronological age. We demonstrate for the first time that pubertal attainment of secondary sexual characteristics is mirrored by changes in DNA methylation patterns in peripheral blood. Thus, modulations of the epigenome seem involved in regulation of the individual pubertal timing. Introduction Puberty is associated with the development of secondary sexual characteristics and attainment of adult reproductive capacity. This transition from child to adult phenotype is initiated by central activation of the hypothalamic–pituitary–gonadal (HPG) axis resulting in stimulation of steroid hormone synthesis. The ages at which puberty starts vary markedly both among healthy boys (9–14 years) and girls (8–13 years) and is to a large extent (60%) heritable 1 . Candidate gene approaches have identified single genes associated with pubertal extremes like precocious puberty 2 or absence of puberty 3 . However, no single gene appears to account for the large variation in pubertal timing among children with normally timed puberty. In fact, recent genome-wide association studies explain very little of this normal variation 4 , 5 , and the largest genetic effect on pubertal onset has been found by a candidate gene approach within FSHR and FSHB 6 . Furthermore, the secular trend of declining age at pubertal onset in both sexes in the western world has been observed over just a few decades, and must therefore be attributed to other factors than genetic variation. Profiling of DNA methylation patterns (methylation of cytosine in the context of a CpG site) in lymphocytes from human peripheral blood samples has been used to predict physiological outcomes or prospectively associate patterns with events earlier in life. Some of the most successful studies include prediction of biological aging 7 , 8 , 9 , 10 , 11 , 12 , associations with smoking 13 , 14 , and obesity 15 , 16 as well as persistent changes in adults following in utero famine during the second world war 17 , 18 . A link between self-reported menarcheal age and peripheral blood DNA methylation patterns has previously been investigated 19 but the results were rather inconclusive due to study design and technical aspects. In this longitudinal study of healthy Danish boys and girls with repeated blood sampling, we investigated the relationship between individual changes in genome-wide DNA methylation patterns and pubertal development. We identified several CpGs and CpG islands that closely followed pubertal transition suggesting important novel regulators of pubertal onset. Results From our longitudinal cohort (the COPENHAGEN puberty cohort) of healthy boys and girls, followed clinically during pubertal development, we included 22 girls and 32 boys who all had blood samples drawn for DNA isolation before and after onset of puberty. Pubertal onset was identified by thorough clinical investigation and defined as a testicular volume of ≥4 ml, or Tanner breast stage ≥B2 for boys and girls, respectively. The mean age between two examinations where this threshold was reached was used as their age of pubertal onset. Pre-pubertal blood samples were drawn at a mean age of 9.1 and 8.3 years corresponding to −2.5 and −1.8 years prior to pubertal onset for boys and girls, respectively. Post-pubertal samples were drawn at a mean age of 15.1 and 14 years and 3.5 and 4 years after pubertal onset for boys and girls, respectively ( Fig. 1a , Table 1 ). Two girls and one boy were excluded for technical reasons. We observed a slight tendency towards lower DNA methylation levels in open sea and in shores and shelf of CpG islands when pre-pubertal were compared to post-pubertal children and significantly (p = 0.001) higher DNA methylation levels of CpG islands in girls compared to boys ( Supplementary Figure 1 ). Figure 1: Identification of CpGs associated with pubertal age. ( a ) From the COPENHAGEN puberty study of children followed longitudinally, selected pre- and post-pubertal samples from 31 boys and 20 girls were included in the study. Time relative to onset of puberty as measured by a testicular volume of 4 ml or breast tanner stage B2 or above was calculated and defined as the pubertal age. ( b ) Genomic inflation of the genome-wide DNA methylation patterns correlating with pubertal age were corrected by applying an improved surrogate variant analysis (SmartSVA) resulting in a genomic inflation factor of 1.2 and a qq-plot leaving 457 significant CpG sites at a FDR of 0.05 (red). ( c ) Manhattan plot of the significant CpG sites reveal a distribution across all autosomes. ( d ) Unsupervised hierarchical centroid clustering of CpGs associated with pubertal age. The resulting dendrograms were colour coded according to their height and divided samples into two major groups that nearly uniquely represented pre- and post-pubertal boys and girls. ( e ) Gene ontology analysis of all significant CpGs revealed several ontologies (p-value < 0.05) that could be related to pubertal development. Biological process gene ontologies were plotted in a sematic space, using REVIGO, that groups related ontologies together. Full size image Table 1 Summary data on the pre- and post-pubertal boys and girls included<|im_end|> <|im_start|>assistant Danish researchers have discovered a possible epigenetic link between the environment and pubertal timing. To a large extent, pubertal timing is heritable, but the underlying genetic causes are still unexplained. Researchers have now studied how chemical modifications of the human genome (so-called epigenetic modifications) change when girls and boys enter puberty. The results indicate that such epigenetic changes are involved in defining the onset of puberty. Danish girls' pubertal onset has decreased from 11 to 10 years. Similar, but less pronounced, changes have been observed in boys. This has led researchers to question the involvement of genetics and recognize that genes are not alone in influencing a child's pubertal timing. In this new study from EDMaRC at Rigshospitalet, Copenhagen, researchers therefore focused on the role of epigenetics and have found a number of areas in the human genome, which is controlled epigenetically during puberty. The researchers found that these epigenetic changes cause the upregulation of genes that are important for pubertal development. One of the newly discovered 'puberty genes' is TRIP6 (Thyroid Hormone Receptor Interactor 6), which is increasingly expressed through puberty, due to changes in the epigenetic control of the gene. Epigenetics is a leading mechanism by which our environment communicates with our genes. Environmental and lifestyle factors in the broadest sense can affect the epigenetic regulation of genes and thereby control whether, where and to what extent the genes are expressed. The identified epigenetic changes during puberty are therefore our best lead towards understanding how environmental factors can affect pubertal onset. "To our knowledge, this study is the first to demonstrate how the environment can affect the pubertal onset in humans. It gives us a significant insight in to the crucial role of epigenetic factors on our reproductive development," says Professor Anders Juul, Senior author of the study. "We've seen a tendency of especially girls starting puberty earlier than before and this study emphasizes the importance of understanding the role of environmental impact on pubertal development," he adds. Highly specific changes in methylation of a child's DNA could differentiate children according to whether they had entered puberty or not and thus may be used to predict a child's pubertal stage. "Changes in the DNA methylation patterns can be caused by many different factors. However, we could see very specific changes when children went through puberty, and have subsequently shown that this also leads to changes in the expression of the methylated genes," says Senior Researcher in epigenetics Kristian Almstrup, who led the study. <|im_end|>

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13305, 323, 7724, 11, 15947, 13, 578, 3152, 4325, 1990, 1403, 69570, 1405, 420, 12447, 574, 8813, 574, 1511, 439, 872, 4325, 315, 6814, 531, 278, 42080, 13, 5075, 2320, 392, 531, 278, 6680, 10688, 1051, 15107, 520, 264, 3152, 4325, 315, 220, 24, 13, 16, 323, 220, 23, 13, 18, 1667, 12435, 311, 25173, 17, 13, 20, 323, 25173, 16, 13, 23, 1667, 4972, 311, 6814, 531, 278, 42080, 369, 13305, 323, 7724, 11, 15947, 13, 3962, 2320, 392, 531, 278, 10688, 1051, 15107, 520, 264, 3152, 4325, 315, 220, 868, 13, 16, 323, 220, 975, 1667, 323, 220, 18, 13, 20, 323, 220, 19, 1667, 1306, 6814, 531, 278, 42080, 369, 13305, 323, 7724, 11, 15947, 320, 23966, 13, 220, 16, 64, 1174, 6771, 220, 16, 7609, 9220, 7724, 323, 832, 8334, 1051, 28544, 369, 11156, 8125, 13, 1226, 13468, 264, 8275, 31954, 7119, 4827, 15922, 21747, 79933, 5990, 304, 1825, 9581, 323, 304, 63263, 323, 28745, 315, 65356, 38, 30100, 994, 864, 2320, 392, 531, 278, 1051, 7863, 311, 1772, 2320, 392, 531, 278, 2911, 323, 12207, 320, 79, 284, 220, 15, 13, 4119, 8, 5190, 15922, 21747, 79933, 5990, 315, 65356, 38, 30100, 304, 7724, 7863, 311, 13305, 320, 99371, 19575, 220, 16, 7609, 19575, 220, 16, 25, 59776, 315, 65356, 82252, 5938, 449, 6814, 531, 278, 4325, 13, 320, 264, 883, 5659, 279, 356, 32033, 39, 1929, 965, 87398, 4007, 315, 2911, 8272, 49704, 38745, 11, 4183, 864, 12, 323, 1772, 2320, 392, 531, 278, 10688, 505, 220, 2148, 13305, 323, 220, 508, 7724, 1051, 5343, 304, 279, 4007, 13, 4212, 8844, 311, 42080, 315, 87398, 439, 17303, 555, 264, 1296, 24553, 8286, 315, 220, 19, 16116, 477, 17659, 259, 4992, 6566, 426, 17, 477, 3485, 574, 16997, 323, 4613, 439, 279, 6814, 531, 278, 4325, 13, 320, 293, 883, 9500, 3151, 25544, 315, 279, 33869, 25480, 15922, 21747, 79933, 12912, 35983, 1113, 449, 6814, 531, 278, 4325, 1051, 37065, 555, 19486, 459, 13241, 73950, 11678, 6492, 320, 34917, 50, 13114, 8, 13239, 304, 264, 81064, 25544, 8331, 315, 220, 16, 13, 17, 323, 264, 56639, 12, 4569, 9564, 220, 21675, 5199, 65356, 38, 6732, 520, 264, 435, 7842, 315, 220, 15, 13, 2304, 320, 1171, 570, 320, 272, 883, 29890, 7234, 315, 279, 5199, 65356, 38, 6732, 16805, 264, 8141, 4028, 682, 47972, 20969, 13, 320, 294, 883, 1252, 13066, 79090, 70994, 59219, 59454, 315, 65356, 82252, 5938, 449, 6814, 531, 278, 4325, 13, 578, 13239, 90052, 299, 51870, 1051, 12745, 47773, 4184, 311, 872, 2673, 323, 18255, 10688, 1139, 1403, 3682, 5315, 430, 7154, 42329, 15609, 864, 12, 323, 1772, 2320, 392, 531, 278, 13305, 323, 7724, 13, 320, 384, 883, 24983, 84369, 6492, 315, 682, 5199, 65356, 82252, 10675, 3892, 14848, 9268, 320, 79, 19625, 366, 220, 15, 13, 2304, 8, 430, 1436, 387, 5552, 311, 6814, 531, 278, 4500, 13, 63711, 1920, 15207, 14848, 9268, 1051, 68683, 304, 264, 5347, 780, 3634, 11, 1701, 66923, 61589, 11, 430, 5315, 5552, 14848, 9268, 3871, 13, 8797, 1404, 2217, 6771, 220, 16, 22241, 828, 389, 279, 864, 12, 323, 1772, 2320, 392, 531, 278, 13305, 323, 7724, 5343, 128257, 198, 128256, 78191, 198, 39125, 819, 12074, 617, 11352, 264, 3284, 4248, 6569, 5411, 2723, 1990, 279, 4676, 323, 6814, 531, 278, 18912, 13, 2057, 264, 3544, 13112, 11, 6814, 531, 278, 18912, 374, 1077, 15729, 11, 719, 279, 16940, 19465, 11384, 527, 2103, 653, 81950, 13, 59250, 617, 1457, 20041, 1268, 11742, 29882, 315, 279, 3823, 33869, 320, 708, 19434, 4248, 6569, 5411, 29882, 8, 2349, 994, 7724, 323, 13305, 3810, 87398, 13, 578, 3135, 13519, 430, 1778, 4248, 6569, 5411, 4442, 527, 6532, 304, 27409, 279, 42080, 315, 87398, 13, 44780, 7724, 6, 6814, 531, 278, 42080, 706, 25983, 505, 220, 806, 311, 220, 605, 1667, 13, 22196, 11, 719, 2753, 38617, 11, 4442, 617, 1027, 13468, 304, 13305, 13, 1115, 706, 6197, 12074, 311, 3488, 279, 22315, 315, 56104, 323, 15641, 430, 21389, 527, 539, 7636, 304, 66700, 264, 1716, 596, 6814, 531, 278, 18912, 13, 763, 420, 502, 4007, 505, 99117, 64, 7532, 520, 52632, 939, 4890, 6388, 1169, 11, 64161, 11, 12074, 9093, 10968, 389, 279, 3560, 315, 4248, 6569, 25265, 323, 617, 1766, 264, 1396, 315, 5789, 304, 279, 3823, 33869, 11, 902, 374, 14400, 4248, 6569, 37774, 2391, 87398, 13, 578, 12074, 1766, 430, 1521, 4248, 6569, 5411, 4442, 5353, 279, 709, 1610, 2987, 315, 21389, 430, 527, 3062, 369, 6814, 531, 278, 4500, 13, 3861, 315, 279, 13945, 11352, 364, 9780, 1368, 21389, 6, 374, 5091, 3378, 21, 320, 1016, 88, 1607, 92208, 606, 1050, 15709, 5783, 5739, 220, 21, 705, 902, 374, 15098, 13605, 1555, 87398, 11, 4245, 311, 4442, 304, 279, 4248, 6569, 5411, 2585, 315, 279, 15207, 13, 11266, 6569, 25265, 374, 264, 6522, 17383, 555, 902, 1057, 4676, 92606, 449, 1057, 21389, 13, 25027, 323, 19433, 9547, 304, 279, 7353, 478, 5647, 649, 7958, 279, 4248, 6569, 5411, 19812, 315, 21389, 323, 28592, 2585, 3508, 11, 1405, 323, 311, 1148, 13112, 279, 21389, 527, 13605, 13, 578, 11054, 4248, 6569, 5411, 4442, 2391, 87398, 527, 9093, 1057, 1888, 3063, 7119, 8830, 1268, 12434, 9547, 649, 7958, 6814, 531, 278, 42080, 13, 330, 1271, 1057, 6677, 11, 420, 4007, 374, 279, 1176, 311, 20461, 1268, 279, 4676, 649, 7958, 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1708, 76, 90499, 11, 889, 6197, 279, 4007, 13, 220, 128257, 198 ]

1,934

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The development of small-molecule pharmacological chaperones as therapeutics for protein misfolding diseases has proven challenging, partly because their mechanism of action remains unclear. Here we study Fe-TMPyP, a tetrapyrrole that binds to the prion protein PrP and inhibits misfolding, examining its effects on PrP folding at the single-molecule level with force spectroscopy. Single PrP molecules are unfolded with and without Fe-TMPyP present using optical tweezers. Ligand binding to the native structure increases the unfolding force significantly and alters the transition state for unfolding, making it more brittle and raising the barrier height. Fe-TMPyP also binds the unfolded state, delaying native refolding. Furthermore, Fe-TMPyP binding blocks the formation of a stable misfolded dimer by interfering with intermolecular interactions, acting in a similar manner to some molecular chaperones. The ligand thus promotes native folding by stabilizing the native state while also suppressing interactions driving aggregation. Introduction Misfolded proteins are an important feature of many neurodegenerative diseases, from Alzheimer’s and Parkinson’s to amyotrophic lateral sclerosis (ALS) and prionopathies, collecting in characteristic amyloid plaques 1 , 2 . Misfolding is normally held in check in the cell through the action of molecular chaperones, which help proteins find their native structure, preventing misfolding in the first place 3 , or the proteasome, which degrades incorrectly folded products 4 . However, this proteostatic machinery is likely overwhelmed in misfolded diseases 5 , 6 , allowing misfolded protein species—including the prefibrillar oligomers thought to be the most neurotoxic species 1 , 7 , 8 —to accumulate. Such a picture has motivated the development of small-molecule drugs that could act as pharmacological chaperones to promote native folding of disease-related proteins 9 , 10 . Such strategies have yielded a number of compounds with promising potential 11 , 12 , but it has proven challenging to improve their performance and develop effective therapeutics, in part because the mechanism of action of putative pharmacological chaperones is not known. Single-molecule methods such as fluorescence and force spectroscopy provide a powerful new approach for addressing this question, because their ability to detect rare and transient states, identify and characterize different subpopulations in a heterogeneous ensemble, and follow conformational changes in a single molecule with high resolution 13 is ideally suited to probing misfolding processes 14 , 15 . Single-molecule approaches have been deployed successfully to study protein misfolding and aggregation, for example identifying misfolded states, determining misfolding pathways, detecting transient oligomeric intermediates and exploring the interactions stabilizing amyloid fibrils 7 , 16 , 17 , 18 , 19 , 20 , 21 , 22 . They have also started to be applied to unravel the mechanisms of molecular chaperones 23 , showing for example that chaperones help correct folding of substrate proteins by unfolding misfolded molecules to give them a new chance to refold, altering the folding rates of domains, and blocking tertiary contacts in the transition state 23 , 24 , 25 , 26 , 27 . However, there has been little single-molecule work to date on pharmacological chaperones, aside from studies of their effects on amyloid stability 22 . Here we use single-molecule force spectroscopy (SMFS), wherein a single molecule is held under tension by an applied load and its extension is measured as its structure changes in response to the load 28 , to investigate the effect of a ligand with anti-prion activity on the folding of the prion protein PrP. Misfolding of PrP causes prion diseases such as Creutzfeldt–Jakob disease, scrapie and bovine spongiform encephalopathy. The native, cellular form of PrP, rich in α-helices and denoted PrP C , is converted into a toxic, β-rich form, denoted PrP Sc , which has the ability to recruit further PrP C molecules and thereby propagate the disease 29 , 30 . The structure of PrP Sc remains controversial 31 , 32 , 33 , as does the molecular mechanism of the conversion of PrP C (refs 2 , 30 ). Despite these uncertainties about the central aspects of the molecular basis for prion diseases, however, several putative small-molecule chaperones with anti-prion activity have been discovered using cellular and/or animal models of disease 34 , 35 . Examples include sulphonated dyes such as congo red and its derivatives (for example, curcumin), 36 , 37 certain polyanions 38 , 39 , 2-aminothiozoles 40 and various heterocyclic compounds 41 , 42 , 43 , 44 , 45 . Notable examples of the latter include cyclic tetrapyrroles 11 , 46 such as phthalocyanines and porphyrins, which have been found to inhibit PrP Sc accumulation in cell culture 46 , 47 and protein misfolding cyclic amplification assays 47 , as well as to increase the survival times in animal models 11 , 48 . However, the mechanism of anti-prion action has not yet been determined for any of these molecules. Since deciphering how such ligands work could provide clues to the molecular mechanism for conversion of PrP C into PrP Sc and help design improved drugs, we investigated the effects of ligand binding on individual PrP molecules using SMFS. SMFS has previously been used to characterize the native folding pathway of PrP, measuring the folding energy landscape and hence properties of the transition state 49 , as well as to discover misfolding pathways available to PrP that might lead to aggregated structures 17 , reveal the sequence of steps leading to stable misfolded dimeric forms 21 , and probe the properties of the monomeric units comprising amyloid fibrils 50 . However, it has not yet been used to study the effects of an anti-prion ligand binding to PrP. Here we present the first such study, probing the effects of the anti-prion ligand iron(III) meso- tetra ( N -methyl-4-pyridyl-porphine), hereafter denoted Fe-TMPyP, on the unfolding of PrP at the single-molecule level. Fe-TMPyP is known to bind to PrP with 1:1 stoichiometry and a dissociation constant of 11±1 μM, in a binding pocket located at one end of the molecule where it interacts with strand 1, helices 2 and 3, and the loop between strand 1", "role": "user" }, { "content": "A team of scientists from the University of Alberta is examining compounds with anti-prion properties, which can alter the misfolding of proteins in rare but universally fatal prion diseases like Mad Cow and Creutzfeld-Jakob. Their results have just been published in Nature Communications. \"The goal of our work is to figure out how to address protein misfolding diseases,\" says Michael Woodside, professor in the Department of Physics, cross-appointed at the National Institute for Nanotechnology. \"There are a number of things that can go wrong if you don't have the right protein structure. There's a wide range of diseases associated one way or another when proteins convert into the wrong shape.\" These diseases include not only Mad Cow and Creutzfeld-Jakob, but also Alzheimer's, ALS, Parkinson's, and Huntington's. Woodside explains that though the causes of diseases associated with protein misfolding are often hotly debated, it is undeniable that the misfolding of proteins in each creates a cascade-like effect of problems. He and his colleagues—including Valerie Sim from the U of A Faculty of Medicine and Dentistry—are working to get at the root of the problem, right down to the molecular level. \"Our results are surprisingly similar to how some of the machinery in healthy cells functions to keep misfolded proteins at bay,\" says Woodside. \"What we have found is that the effect of the anti-prion compound is more complex than we originally thought. It not only stabilizes the correct structure, it also inhibits the interactions that drive the formation of stable incorrect structures.\" Woodside explains that in a healthy body, \"chaperone\" proteins ward off molecules with incorrect structures. If enough protein molecules change into the wrong structure, the chaperones can be overwhelmed, allowing the misfolded proteins to accumulate. In the case of prion proteins, the misfolded proteins become infectious and neurotoxic, causing the misfolding to spiral out of control and kill neurons. The anti-prion compound Woodside's group studied is geared to maintain the native cell structure and prevent misfolding, but the drug discovery and development process has been hampered by incomplete understanding of how these compounds act. \"We are addressing a problem that has proven really difficult,\" says Woodside. \"I don't know how many billions of dollars have been spent on failed drugs for neurodegenerative diseases. Part of this is lack of clarity in what is going on at the molecular level in these very complex diseases and the need for better tools like the custom tools that we have developed.\" A biophysicist, Woodside works with custom-designed and custom-built laser tweezers to study these protein folding and misfolding processes at the single molecular level. His research explores a broad range of science from physics to biochemistry. Biophysics—understanding the basic rules of science that govern essential interactions in biology—is one of the fastest growing fields in physics. And in this vein, Woodside aims to take an extremely complex problem back to basics. \"We are measuring very small forces in single molecule biology systems. Watching these folding processes at the molecular level provides us a lot of exquisitely detailed biophysical information. We want to understand what a single protein molecule does when it comes into contact with therapeutic drugs. What do the dynamics of this folding look like in the presence of the compound?\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The development of small-molecule pharmacological chaperones as therapeutics for protein misfolding diseases has proven challenging, partly because their mechanism of action remains unclear. Here we study Fe-TMPyP, a tetrapyrrole that binds to the prion protein PrP and inhibits misfolding, examining its effects on PrP folding at the single-molecule level with force spectroscopy. Single PrP molecules are unfolded with and without Fe-TMPyP present using optical tweezers. Ligand binding to the native structure increases the unfolding force significantly and alters the transition state for unfolding, making it more brittle and raising the barrier height. Fe-TMPyP also binds the unfolded state, delaying native refolding. Furthermore, Fe-TMPyP binding blocks the formation of a stable misfolded dimer by interfering with intermolecular interactions, acting in a similar manner to some molecular chaperones. The ligand thus promotes native folding by stabilizing the native state while also suppressing interactions driving aggregation. Introduction Misfolded proteins are an important feature of many neurodegenerative diseases, from Alzheimer’s and Parkinson’s to amyotrophic lateral sclerosis (ALS) and prionopathies, collecting in characteristic amyloid plaques 1 , 2 . Misfolding is normally held in check in the cell through the action of molecular chaperones, which help proteins find their native structure, preventing misfolding in the first place 3 , or the proteasome, which degrades incorrectly folded products 4 . However, this proteostatic machinery is likely overwhelmed in misfolded diseases 5 , 6 , allowing misfolded protein species—including the prefibrillar oligomers thought to be the most neurotoxic species 1 , 7 , 8 —to accumulate. Such a picture has motivated the development of small-molecule drugs that could act as pharmacological chaperones to promote native folding of disease-related proteins 9 , 10 . Such strategies have yielded a number of compounds with promising potential 11 , 12 , but it has proven challenging to improve their performance and develop effective therapeutics, in part because the mechanism of action of putative pharmacological chaperones is not known. Single-molecule methods such as fluorescence and force spectroscopy provide a powerful new approach for addressing this question, because their ability to detect rare and transient states, identify and characterize different subpopulations in a heterogeneous ensemble, and follow conformational changes in a single molecule with high resolution 13 is ideally suited to probing misfolding processes 14 , 15 . Single-molecule approaches have been deployed successfully to study protein misfolding and aggregation, for example identifying misfolded states, determining misfolding pathways, detecting transient oligomeric intermediates and exploring the interactions stabilizing amyloid fibrils 7 , 16 , 17 , 18 , 19 , 20 , 21 , 22 . They have also started to be applied to unravel the mechanisms of molecular chaperones 23 , showing for example that chaperones help correct folding of substrate proteins by unfolding misfolded molecules to give them a new chance to refold, altering the folding rates of domains, and blocking tertiary contacts in the transition state 23 , 24 , 25 , 26 , 27 . However, there has been little single-molecule work to date on pharmacological chaperones, aside from studies of their effects on amyloid stability 22 . Here we use single-molecule force spectroscopy (SMFS), wherein a single molecule is held under tension by an applied load and its extension is measured as its structure changes in response to the load 28 , to investigate the effect of a ligand with anti-prion activity on the folding of the prion protein PrP. Misfolding of PrP causes prion diseases such as Creutzfeldt–Jakob disease, scrapie and bovine spongiform encephalopathy. The native, cellular form of PrP, rich in α-helices and denoted PrP C , is converted into a toxic, β-rich form, denoted PrP Sc , which has the ability to recruit further PrP C molecules and thereby propagate the disease 29 , 30 . The structure of PrP Sc remains controversial 31 , 32 , 33 , as does the molecular mechanism of the conversion of PrP C (refs 2 , 30 ). Despite these uncertainties about the central aspects of the molecular basis for prion diseases, however, several putative small-molecule chaperones with anti-prion activity have been discovered using cellular and/or animal models of disease 34 , 35 . Examples include sulphonated dyes such as congo red and its derivatives (for example, curcumin), 36 , 37 certain polyanions 38 , 39 , 2-aminothiozoles 40 and various heterocyclic compounds 41 , 42 , 43 , 44 , 45 . Notable examples of the latter include cyclic tetrapyrroles 11 , 46 such as phthalocyanines and porphyrins, which have been found to inhibit PrP Sc accumulation in cell culture 46 , 47 and protein misfolding cyclic amplification assays 47 , as well as to increase the survival times in animal models 11 , 48 . However, the mechanism of anti-prion action has not yet been determined for any of these molecules. Since deciphering how such ligands work could provide clues to the molecular mechanism for conversion of PrP C into PrP Sc and help design improved drugs, we investigated the effects of ligand binding on individual PrP molecules using SMFS. SMFS has previously been used to characterize the native folding pathway of PrP, measuring the folding energy landscape and hence properties of the transition state 49 , as well as to discover misfolding pathways available to PrP that might lead to aggregated structures 17 , reveal the sequence of steps leading to stable misfolded dimeric forms 21 , and probe the properties of the monomeric units comprising amyloid fibrils 50 . However, it has not yet been used to study the effects of an anti-prion ligand binding to PrP. Here we present the first such study, probing the effects of the anti-prion ligand iron(III) meso- tetra ( N -methyl-4-pyridyl-porphine), hereafter denoted Fe-TMPyP, on the unfolding of PrP at the single-molecule level. Fe-TMPyP is known to bind to PrP with 1:1 stoichiometry and a dissociation constant of 11±1 μM, in a binding pocket located at one end of the molecule where it interacts with strand 1, helices 2 and 3, and the loop between strand 1<|im_end|> <|im_start|>assistant A team of scientists from the University of Alberta is examining compounds with anti-prion properties, which can alter the misfolding of proteins in rare but universally fatal prion diseases like Mad Cow and Creutzfeld-Jakob. Their results have just been published in Nature Communications. "The goal of our work is to figure out how to address protein misfolding diseases," says Michael Woodside, professor in the Department of Physics, cross-appointed at the National Institute for Nanotechnology. "There are a number of things that can go wrong if you don't have the right protein structure. There's a wide range of diseases associated one way or another when proteins convert into the wrong shape." These diseases include not only Mad Cow and Creutzfeld-Jakob, but also Alzheimer's, ALS, Parkinson's, and Huntington's. Woodside explains that though the causes of diseases associated with protein misfolding are often hotly debated, it is undeniable that the misfolding of proteins in each creates a cascade-like effect of problems. He and his colleagues—including Valerie Sim from the U of A Faculty of Medicine and Dentistry—are working to get at the root of the problem, right down to the molecular level. "Our results are surprisingly similar to how some of the machinery in healthy cells functions to keep misfolded proteins at bay," says Woodside. "What we have found is that the effect of the anti-prion compound is more complex than we originally thought. It not only stabilizes the correct structure, it also inhibits the interactions that drive the formation of stable incorrect structures." Woodside explains that in a healthy body, "chaperone" proteins ward off molecules with incorrect structures. If enough protein molecules change into the wrong structure, the chaperones can be overwhelmed, allowing the misfolded proteins to accumulate. In the case of prion proteins, the misfolded proteins become infectious and neurotoxic, causing the misfolding to spiral out of control and kill neurons. The anti-prion compound Woodside's group studied is geared to maintain the native cell structure and prevent misfolding, but the drug discovery and development process has been hampered by incomplete understanding of how these compounds act. "We are addressing a problem that has proven really difficult," says Woodside. "I don't know how many billions of dollars have been spent on failed drugs for neurodegenerative diseases. Part of this is lack of clarity in what is going on at the molecular level in these very complex diseases and the need for better tools like the custom tools that we have developed." A biophysicist, Woodside works with custom-designed and custom-built laser tweezers to study these protein folding and misfolding processes at the single molecular level. His research explores a broad range of science from physics to biochemistry. Biophysics—understanding the basic rules of science that govern essential interactions in biology—is one of the fastest growing fields in physics. And in this vein, Woodside aims to take an extremely complex problem back to basics. "We are measuring very small forces in single molecule biology systems. Watching these folding processes at the molecular level provides us a lot of exquisitely detailed biophysical information. We want to understand what a single protein molecule does when it comes into contact with therapeutic drugs. What do the dynamics of this folding look like in the presence of the compound?" <|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 Daily experience suggests that we perceive distances near us linearly. However, the actual geometry of spatial representation in the brain is unknown. Here we report that neurons in the CA1 region of rat hippocampus that mediate spatial perception represent space according to a non-linear hyperbolic geometry. This geometry uses an exponential scale and yields greater positional information than a linear scale. We found that the size of the representation matches the optimal predictions for the number of CA1 neurons. The representations also dynamically expanded proportional to the logarithm of time that the animal spent exploring the environment, in correspondence with the maximal mutual information that can be received. The dynamic changes tracked even small variations due to changes in the running speed of the animal. These results demonstrate how neural circuits achieve efficient representations using dynamic hyperbolic geometry. Main Many aspects of our daily lives can be described using hierarchical systems. As we decide how to spend an afternoon, we may choose to read a book in a coffee shop or go to a shopping mall, which gives rise to a set of new questions: what coffee, which store and so forth, instantiating a decision tree 1 , 2 . Spatial navigation provides an example of decision-making in which hierarchical planning is useful 3 . Hierarchical organization in networks can provide several advantages, including achieving maximally informative representation of input signals 4 and efficient routing of signals in cases where network links are subject to change 5 . The latter property is especially useful for neural networks where connections between neurons change over time. However, to realize these advantages, the networks should be organized hierarchically in such a way as to follow a hidden hyperbolic geometry 5 . Unlike Euclidean geometry, hyperbolic geometry is negatively curved. This results in an exponential expansion of volume with the distance from the center, perceptual compression of large distances and distortions in the shortest distance paths between points, which now curve toward the representation center (Fig. 1a ) 6 . Thus, hyperbolic organization would go against the everyday intuition that the brain represents distances around us linearly. Fig. 1: Construction of hierarchical organization of place cell responses that reflects underlying hyperbolic geometry. a , A Poincaré disk model of 2D hyperbolic geometry is shown for visualization of its similarity to a tree structure. Each curve represents the geodesic between the two connected points, and all triangles have the same size. b , Illustration of the construction of hierarchical representation from neuronal response properties. The tree structure does not have to be perfect to allow for mapping onto a hyperbolic geometry 14 . Some loops can be present (dashed lines) due to partial overlap between disks of neurons from different orders in the hierarchy. c , Place field size versus location of 264 place fields from 63 putative pyramidal cells from dorsal CA1 of a rat running on a 48-m-long linear track (Fig. 3b and Supplementary Fig. 1 ) 20 . d , Histogram of place field sizes shown in c . Gray line shows the maximum likelihood exponential fit. P value of χ 2 GOF test is 0.851 (χ 2 = 5.56 and d.f. = 10). Inset shows the same plot with log-scale on the y axis. The straight line shows the least-squares linear regression with slope forced to be the exponent of the exponential fit. Source data Full size image We investigated whether hyperbolic geometry underlies neural networks by analyzing responses of sets of neurons from the dorsal CA1 region of the hippocampus. This region is considered essential for spatial representation 7 , 8 , 9 and trajectory planning 10 . CA1 neurons respond at specific spatial locations, termed place fields 11 . We will first illustrate the main idea by describing how neurons can be organized into a hierarchical tree-like network using a simplified picture where each neuron has only one place field in an environment. We will then follow up with analyses that take into account the presence of multiple place fields per neuron 12 . Results Geometry of neural representation in CA1 The idea that hyperbolic geometry potentially underlies the neural representation of space follows from the construction illustrated in Fig. 1b . Each point in the two-dimensional (2D) plane represents an abstract neural response property, and a disk represents the collection of all the properties for one neuron in CA1. The more two disks overlap, the more similar the response properties of the corresponding two neurons are and, thus, the higher their response correlation. We now assign neurons that have larger disks in the plane to higher positions within the hierarchy (quantified by the z coordinate in the three-dimensional (3D) space) compared to neurons with smaller disks. The x,y coordinates are taken directly as the center positions of their disks. A link from a higher-to-lower-tier neuron is made if the larger disk contains (at least partially) the smaller disk. The resulting construction generates an approximate tree-like structure. The tree-like structure can, in turn, be viewed as a discrete mesh over the underlying hyperbolic geometry 13 , 14 . The leaves of the tree correspond to peripheral points, whereas roots of the tree correspond to positions closer to the origin of the hyperbolic geometry (Fig. 1a ). We note that, in general, the plane can be of any dimension and is drawn here as 2D mainly for illustrative purposes. In the simplified case of each neuron having only one place field, the plane can be interpreted as physical space and the disks as being the place fields of the neurons. In this setting, the distribution of one-dimensional (1D) place field sizes should follow approximately an exponential distribution: $$p\\left( s \\right) = \\frac{{\\zeta \\sinh \\left( {\\zeta \\left( {s_{\\max } - s} \\right)} \\right)}}{{\\cosh \\left( {\\zeta s_{\\max }} \\right) - 1}} \\approx \\zeta e^{ - \\zeta s}$$ (1) where p ( s ) is the probability density of place field sizes, and s max is the maximal place field size. The", "role": "user" }, { "content": "Young children sometimes believe that the moon is following them, or that they can reach out and touch it. It appears to be much closer than is proportional to its true distance. As we move about our daily lives, we tend to think that we navigate space in a linear way. But Salk scientists have discovered that time spent exploring an environment causes neural representations to grow in surprising ways. The findings, published in Nature Neuroscience on December 29, 2022, show that neurons in the hippocampus essential for spatial navigation, memory, and planning represent space in a manner that conforms to a nonlinear hyperbolic geometry—a three-dimensional expanse that grows outward exponentially. (In other words, it's shaped like the interior of an expanding hourglass.) The researchers also found that the size of that space grows with time spent in a place. And the size is increasing in a logarithmic fashion that matches the maximal possible increase in information being processed by the brain. This discovery provides valuable methods for analyzing data on neurocognitive disorders involving learning and memory, such as Alzheimer's disease. \"Our study demonstrates that the brain does not always act in a linear manner. Instead, neural networks function along an expanding curve, which can be analyzed and understood using hyperbolic geometry and information theory,\" says Salk Professor Tatyana Sharpee, holder of the Edwin K. Hunter Chair, who led the study. \"It is exciting to see that neural responses in this area of the brain formed a map that expanded with experience based on the amount of time devoted in a given place. The effect even held for miniscule deviations in time when animal ran more slowly or faster through the environment.\" Sharpee's lab uses advanced computational approaches to better understand how the brain works. They recently pioneered the use of hyperbolic geometry to better understand biological signals like smell molecules, as well as the perception of smell. In the current study, the scientists found that hyperbolic geometry guides neural responses as well. Hyperbolic maps of sensory molecules and events are perceived with hyperbolic neural maps. The space representations dynamically expanded in correlation with the amount of time the rat spent exploring each environment. And, when a rat moved more slowly through an environment, it gained more information about the space, which caused the neural representations to grow even more. \"The findings provide a novel perspective on how neural representations can be altered with experience,\" says Huanqiu Zhang, a graduate student in Sharpee's lab. \"The geometric principles identified in our study can also guide future endeavors in understanding neural activity in various brain systems.\" \"You would think that hyperbolic geometry only applies on a cosmic scale, but that is not true,\" says Sharpee. \"Our brains work much slower than the speed of light, which could be a reason that hyperbolic effects are observed on graspable spaces instead of astronomical ones. Next, we would like to learn more about how these dynamic hyperbolic representations in the brain grow, interact, and communicate with one another.\" Other authors include P. Dylan Rich of Princeton University and Albert K. Lee of the Janelia Research Campus at the Howard Hughes Medical Institute. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Daily experience suggests that we perceive distances near us linearly. However, the actual geometry of spatial representation in the brain is unknown. Here we report that neurons in the CA1 region of rat hippocampus that mediate spatial perception represent space according to a non-linear hyperbolic geometry. This geometry uses an exponential scale and yields greater positional information than a linear scale. We found that the size of the representation matches the optimal predictions for the number of CA1 neurons. The representations also dynamically expanded proportional to the logarithm of time that the animal spent exploring the environment, in correspondence with the maximal mutual information that can be received. The dynamic changes tracked even small variations due to changes in the running speed of the animal. These results demonstrate how neural circuits achieve efficient representations using dynamic hyperbolic geometry. Main Many aspects of our daily lives can be described using hierarchical systems. As we decide how to spend an afternoon, we may choose to read a book in a coffee shop or go to a shopping mall, which gives rise to a set of new questions: what coffee, which store and so forth, instantiating a decision tree 1 , 2 . Spatial navigation provides an example of decision-making in which hierarchical planning is useful 3 . Hierarchical organization in networks can provide several advantages, including achieving maximally informative representation of input signals 4 and efficient routing of signals in cases where network links are subject to change 5 . The latter property is especially useful for neural networks where connections between neurons change over time. However, to realize these advantages, the networks should be organized hierarchically in such a way as to follow a hidden hyperbolic geometry 5 . Unlike Euclidean geometry, hyperbolic geometry is negatively curved. This results in an exponential expansion of volume with the distance from the center, perceptual compression of large distances and distortions in the shortest distance paths between points, which now curve toward the representation center (Fig. 1a ) 6 . Thus, hyperbolic organization would go against the everyday intuition that the brain represents distances around us linearly. Fig. 1: Construction of hierarchical organization of place cell responses that reflects underlying hyperbolic geometry. a , A Poincaré disk model of 2D hyperbolic geometry is shown for visualization of its similarity to a tree structure. Each curve represents the geodesic between the two connected points, and all triangles have the same size. b , Illustration of the construction of hierarchical representation from neuronal response properties. The tree structure does not have to be perfect to allow for mapping onto a hyperbolic geometry 14 . Some loops can be present (dashed lines) due to partial overlap between disks of neurons from different orders in the hierarchy. c , Place field size versus location of 264 place fields from 63 putative pyramidal cells from dorsal CA1 of a rat running on a 48-m-long linear track (Fig. 3b and Supplementary Fig. 1 ) 20 . d , Histogram of place field sizes shown in c . Gray line shows the maximum likelihood exponential fit. P value of χ 2 GOF test is 0.851 (χ 2 = 5.56 and d.f. = 10). Inset shows the same plot with log-scale on the y axis. The straight line shows the least-squares linear regression with slope forced to be the exponent of the exponential fit. Source data Full size image We investigated whether hyperbolic geometry underlies neural networks by analyzing responses of sets of neurons from the dorsal CA1 region of the hippocampus. This region is considered essential for spatial representation 7 , 8 , 9 and trajectory planning 10 . CA1 neurons respond at specific spatial locations, termed place fields 11 . We will first illustrate the main idea by describing how neurons can be organized into a hierarchical tree-like network using a simplified picture where each neuron has only one place field in an environment. We will then follow up with analyses that take into account the presence of multiple place fields per neuron 12 . Results Geometry of neural representation in CA1 The idea that hyperbolic geometry potentially underlies the neural representation of space follows from the construction illustrated in Fig. 1b . Each point in the two-dimensional (2D) plane represents an abstract neural response property, and a disk represents the collection of all the properties for one neuron in CA1. The more two disks overlap, the more similar the response properties of the corresponding two neurons are and, thus, the higher their response correlation. We now assign neurons that have larger disks in the plane to higher positions within the hierarchy (quantified by the z coordinate in the three-dimensional (3D) space) compared to neurons with smaller disks. The x,y coordinates are taken directly as the center positions of their disks. A link from a higher-to-lower-tier neuron is made if the larger disk contains (at least partially) the smaller disk. The resulting construction generates an approximate tree-like structure. The tree-like structure can, in turn, be viewed as a discrete mesh over the underlying hyperbolic geometry 13 , 14 . The leaves of the tree correspond to peripheral points, whereas roots of the tree correspond to positions closer to the origin of the hyperbolic geometry (Fig. 1a ). We note that, in general, the plane can be of any dimension and is drawn here as 2D mainly for illustrative purposes. In the simplified case of each neuron having only one place field, the plane can be interpreted as physical space and the disks as being the place fields of the neurons. In this setting, the distribution of one-dimensional (1D) place field sizes should follow approximately an exponential distribution: $$p\left( s \right) = \frac{{\zeta \sinh \left( {\zeta \left( {s_{\max } - s} \right)} \right)}}{{\cosh \left( {\zeta s_{\max }} \right) - 1}} \approx \zeta e^{ - \zeta s}$$ (1) where p ( s ) is the probability density of place field sizes, and s max is the maximal place field size. The<|im_end|> <|im_start|>assistant Young children sometimes believe that the moon is following them, or that they can reach out and touch it. It appears to be much closer than is proportional to its true distance. As we move about our daily lives, we tend to think that we navigate space in a linear way. But Salk scientists have discovered that time spent exploring an environment causes neural representations to grow in surprising ways. The findings, published in Nature Neuroscience on December 29, 2022, show that neurons in the hippocampus essential for spatial navigation, memory, and planning represent space in a manner that conforms to a nonlinear hyperbolic geometry—a three-dimensional expanse that grows outward exponentially. (In other words, it's shaped like the interior of an expanding hourglass.) The researchers also found that the size of that space grows with time spent in a place. And the size is increasing in a logarithmic fashion that matches the maximal possible increase in information being processed by the brain. This discovery provides valuable methods for analyzing data on neurocognitive disorders involving learning and memory, such as Alzheimer's disease. "Our study demonstrates that the brain does not always act in a linear manner. Instead, neural networks function along an expanding curve, which can be analyzed and understood using hyperbolic geometry and information theory," says Salk Professor Tatyana Sharpee, holder of the Edwin K. Hunter Chair, who led the study. "It is exciting to see that neural responses in this area of the brain formed a map that expanded with experience based on the amount of time devoted in a given place. The effect even held for miniscule deviations in time when animal ran more slowly or faster through the environment." Sharpee's lab uses advanced computational approaches to better understand how the brain works. They recently pioneered the use of hyperbolic geometry to better understand biological signals like smell molecules, as well as the perception of smell. In the current study, the scientists found that hyperbolic geometry guides neural responses as well. Hyperbolic maps of sensory molecules and events are perceived with hyperbolic neural maps. The space representations dynamically expanded in correlation with the amount of time the rat spent exploring each environment. And, when a rat moved more slowly through an environment, it gained more information about the space, which caused the neural representations to grow even more. "The findings provide a novel perspective on how neural representations can be altered with experience," says Huanqiu Zhang, a graduate student in Sharpee's lab. "The geometric principles identified in our study can also guide future endeavors in understanding neural activity in various brain systems." "You would think that hyperbolic geometry only applies on a cosmic scale, but that is not true," says Sharpee. "Our brains work much slower than the speed of light, which could be a reason that hyperbolic effects are observed on graspable spaces instead of astronomical ones. Next, we would like to learn more about how these dynamic hyperbolic representations in the brain grow, interact, and communicate with one another." Other authors include P. Dylan Rich of Princeton University and Albert K. Lee of the Janelia Research Campus at the Howard Hughes Medical Institute. <|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 ubiquitin–proteasome system (UPS) and macroautophagy (autophagy) are central to normal proteostasis and interdependent in that autophagy is known to compensate for the UPS to alleviate ensuing proteotoxic stress that impairs cell function. UPS and autophagy dysfunctions are believed to have a major role in the pathomechanisms of neurodegenerative disease. Here we show that continued 26S proteasome dysfunction in mouse brain cortical neurons causes paranuclear accumulation of fragmented dysfunctional mitochondria, associated with earlier recruitment of Parkin and lysine 48-linked ubiquitination of mitochondrial outer membrane (MOM) proteins, including Mitofusin-2. Early events also include phosphorylation of p62/SQSTM1 (p62) and increased optineurin, as well as autophagosomal LC3B and removal of some mitochondria, supporting the induction of selective autophagy. Inhibition of the degradation of ubiquitinated MOM proteins with continued 26S proteasome dysfunction at later stages may impede efficient mitophagy. However, continued 26S proteasome dysfunction also decreases the levels of essential autophagy proteins ATG9 and LC3B, which is characterised by decreases in their gene expression, ultimately leading to impaired autophagy. Intriguingly, serine 351 phosphorylation of p62 did not enhance its binding to Keap1 or stabilise the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor in this neuronal context. Nrf2 protein levels were markedly decreased despite transcriptional activation of the Nrf2 gene. Our study reveals novel insights into the interplay between the UPS and autophagy in neurons and is imperative to understanding neurodegenerative disease where long-term proteasome inhibition has been implicated. Main Efficient protein degradation is crucial for proteostasis. The ubiquitin–proteasome system (UPS) and macroautophagy (autophagy) are the two major cellular catabolic pathways. The UPS is restricted to soluble proteins, whereas autophagy is involved in the degradation of a wider variety of substrates, including misfolded soluble proteins, protein aggregates and cellular organelles. Autophagy is known to compensate for impairment of the UPS and alleviate ensuing proteotoxic stress that impairs cell function. 1 The UPS is regulated by a refined ubiquitin signalling system, tagging unwanted proteins with ubiquitin chains as a signal for their degradation by the 26S proteasome. 2 Autophagic degradation also has the ability to be selective for its cargo via ubiquitin signalling, removing aggregated proteins, organelles and intracellular microbes. 3 , 4 , 5 Selective autophagy is coordinated by autophagy receptors linking cargos tagged with ubiquitin chains to the autophagosomal membrane. p62/SQSTM1 (p62) is a well-characterised autophagy receptor, but additional receptors such as neighbour of BRCA1 gene 1 (NBR1), nuclear dot protein 52 kDa (NDP52) and Optineurin (OPTN) have been identified, and the regulatory mechanisms of selective autophagy are emerging. Recent evidence demonstrates that phosphorylation of p62 at multiple sites specifies its function in selective autophagy. Phosphorylation of p62’s ubiquitin-associated (UBA) domain at serine (S) 409 by unc-51-like autophagy-activating kinase 1 then S403 by TANK-binding kinase 1 and/or casein kinase 2 increases its binding affinity for ubiquitin, promoting translocation to the ubiquitinated cargo. 6 , 7 Following phosphorylation of the UBA domain of p62, S351 phosphorylation in the Kelch-like ECH-associated protein 1 (Keap1)-interacting region (KIR) by mammalian target of rapamycin complex 1 (mTORC1) takes place on ubiquitinated cargos. S351 phosphorylation of p62 increases its binding affinity for Keap1, competitively inhibiting Keap1’s interaction with nuclear factor erythroid 2-related factor 2 (Nrf2) and sequestering Keap1 on autophagic cargos, coupling selective autophagy to activation of the Keap1–Nrf2 antioxidant pathway via stabilisation of Nrf2. 8 , 9 The transcription factor Nrf2 is normally constitutively degraded by the UPS; its binding partner Keap1 is a component of the E3 ubiquitin ligase complex that ubiquitinates Nrf2. 10 Stabilised Nrf2 moves into the nucleus to activate the transcription of cytoprotective genes. 11 Ubiquitin is found in the inclusion bodies in most neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease and amyotrophic lateral sclerosis. 12 The characteristics of ubiquitin in this context remain unknown, but increasing evidence makes it plausible that UPS and autophagy dysfunctions cause aberrant accumulation of proteins and neurodegeneration. 13 Aging is the major risk factor shared by sporadic neurodegenerative diseases and studies show cellular protein degradation systems become less efficient with age. 14 , 15 Recently, a role for the UPS in AD pathogenesis was firmly supported by pooled genome-wide association studies. 16 Furthermore, conditional knockout studies in mice indicate that proteasomal and autophagic degradation have a causal link to neurodegenerative diseases in general. 17 , 18 , 19 , 20 Understanding the interplay between and contribution of the UPS and autophagy to proteostasis in neurons is imperative to understanding neurodegenerative disease. Here we investigate this in mouse brain cortical neurons with 26S proteasome dysfunction. We demonstrate short-term (early) 26S proteasome dysfunction induces selective autophagy, but long-term (continued) dysfunction decreases autophagy characterised by downregulation of essential autophagy genes. Furthermore, despite 26S proteasome dysfunction leading to S351 phosphorylation of p62 and early transcriptional activation of Nrf2, the Nrf2 protein is not stabilised in brain. Results 26S proteasome dysfunction in mouse forebrain neurons 26S proteasome dysfunction was restricted to mouse forebrain neurons by crossing floxed Psmc1 mice ( Psmc1 fl/fl ), an essential ATPase subunit of the 19S regulatory particle of the 26S proteasome, with mice expressing Cre recombinase under the control of the calcium calmodulin-dependent protein kinase II α ( CamKIIα ) promoter ( Psmc1 fl/fl ; CaMKIIα-Cre ) as described previously. 17 Here ubiquitin immunostaining revealed sparse 26S proteasome-impaired neurons in Psmc1 fl/fl ; CaMKIIα-Cre cortices at 2 weeks old; significant accumulation of ubiquitinated proteins was evident from 3 weeks old ( Supplementary Figure S1A ), consistent with previous observations. 17 The levels of synaptic and neuronal marker proteins were similar at 3 and 4 weeks old, but significantly decreased in Psmc1 fl/fl ; CaMKIIα-Cre cortices by 6 weeks old, reflecting progressive synaptic dysfunction and neurodegeneration ( Supplementary Figure S1B ). Mitochondrial fragmentation and mitophagy in 26S proteasome-impaired neurons In a qualitative study, we previously described 26S proteasome dysfunction in mouse nigral neurons in vivo caused paranuclear accumulation of morphologically abnormal mitochondria. 21 Here we show similar paranuclear accumulation of morphologically abnormal mitochondria in cortical neuron electron micrographs (EMs) and quantification analyses of mitochondria at 6", "role": "user" }, { "content": "A fault with the natural waste disposal system that helps to keep our brain cell 'batteries' healthy may contribute to neurodegenerative disease, a new study has found. The research, led by academics at The University of Nottingham and published in the journal Cell Death and Disease, centres on problems with mitochondria – the powerhouses which produce energy within a cell. The results support previous evidence that patients with Parkinson's Disease have faults with brain mitochondria which contributes to dysfunction and death within their neurons. Dr Lynn Bedford, in the University's School of Life Sciences, said: \"The study highlights the importance of the ubiquitin proteasome system (UPS) for healthy mitochondria. The UPS is like a waste disposal system that removes small unwanted proteins from inside cells. \"If waste is not removed it will build up over time and become toxic, causing cells to go wrong and eventually die.\" Faults in this system may play an important role in neurodegenerative diseases such as Parkinson's and Alzheimer's because they are caused by the death of neurons – the network through which we transfer information in our brain. Harmful molecules Using gene targeting in mice, the researchers have discovered that a faulty UPS in neurons leads to damaged mitochondria that produce less energy. Damages mitochondria are also known to produce harmful molecules that injure the cell – oxidative stress – so it is vital that the brain is able to keep mending, removing and replacing them. The study also found that when the UPS was faulty, the damaged mitochondria were not removed from neurons in the normal way by the process of autophagy, the disposal system that breaks down larger parts in the cell like mitochondria. The research was conducted in collaboration with experts at Nottingham Trent University, the University of Dundee, Nottingham University Hospitals NHS Trust and Great Ormond Street Hospital for Children NHS Trust in the UK and the University of Tripoli in Libya. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 ubiquitin–proteasome system (UPS) and macroautophagy (autophagy) are central to normal proteostasis and interdependent in that autophagy is known to compensate for the UPS to alleviate ensuing proteotoxic stress that impairs cell function. UPS and autophagy dysfunctions are believed to have a major role in the pathomechanisms of neurodegenerative disease. Here we show that continued 26S proteasome dysfunction in mouse brain cortical neurons causes paranuclear accumulation of fragmented dysfunctional mitochondria, associated with earlier recruitment of Parkin and lysine 48-linked ubiquitination of mitochondrial outer membrane (MOM) proteins, including Mitofusin-2. Early events also include phosphorylation of p62/SQSTM1 (p62) and increased optineurin, as well as autophagosomal LC3B and removal of some mitochondria, supporting the induction of selective autophagy. Inhibition of the degradation of ubiquitinated MOM proteins with continued 26S proteasome dysfunction at later stages may impede efficient mitophagy. However, continued 26S proteasome dysfunction also decreases the levels of essential autophagy proteins ATG9 and LC3B, which is characterised by decreases in their gene expression, ultimately leading to impaired autophagy. Intriguingly, serine 351 phosphorylation of p62 did not enhance its binding to Keap1 or stabilise the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor in this neuronal context. Nrf2 protein levels were markedly decreased despite transcriptional activation of the Nrf2 gene. Our study reveals novel insights into the interplay between the UPS and autophagy in neurons and is imperative to understanding neurodegenerative disease where long-term proteasome inhibition has been implicated. Main Efficient protein degradation is crucial for proteostasis. The ubiquitin–proteasome system (UPS) and macroautophagy (autophagy) are the two major cellular catabolic pathways. The UPS is restricted to soluble proteins, whereas autophagy is involved in the degradation of a wider variety of substrates, including misfolded soluble proteins, protein aggregates and cellular organelles. Autophagy is known to compensate for impairment of the UPS and alleviate ensuing proteotoxic stress that impairs cell function. 1 The UPS is regulated by a refined ubiquitin signalling system, tagging unwanted proteins with ubiquitin chains as a signal for their degradation by the 26S proteasome. 2 Autophagic degradation also has the ability to be selective for its cargo via ubiquitin signalling, removing aggregated proteins, organelles and intracellular microbes. 3 , 4 , 5 Selective autophagy is coordinated by autophagy receptors linking cargos tagged with ubiquitin chains to the autophagosomal membrane. p62/SQSTM1 (p62) is a well-characterised autophagy receptor, but additional receptors such as neighbour of BRCA1 gene 1 (NBR1), nuclear dot protein 52 kDa (NDP52) and Optineurin (OPTN) have been identified, and the regulatory mechanisms of selective autophagy are emerging. Recent evidence demonstrates that phosphorylation of p62 at multiple sites specifies its function in selective autophagy. Phosphorylation of p62’s ubiquitin-associated (UBA) domain at serine (S) 409 by unc-51-like autophagy-activating kinase 1 then S403 by TANK-binding kinase 1 and/or casein kinase 2 increases its binding affinity for ubiquitin, promoting translocation to the ubiquitinated cargo. 6 , 7 Following phosphorylation of the UBA domain of p62, S351 phosphorylation in the Kelch-like ECH-associated protein 1 (Keap1)-interacting region (KIR) by mammalian target of rapamycin complex 1 (mTORC1) takes place on ubiquitinated cargos. S351 phosphorylation of p62 increases its binding affinity for Keap1, competitively inhibiting Keap1’s interaction with nuclear factor erythroid 2-related factor 2 (Nrf2) and sequestering Keap1 on autophagic cargos, coupling selective autophagy to activation of the Keap1–Nrf2 antioxidant pathway via stabilisation of Nrf2. 8 , 9 The transcription factor Nrf2 is normally constitutively degraded by the UPS; its binding partner Keap1 is a component of the E3 ubiquitin ligase complex that ubiquitinates Nrf2. 10 Stabilised Nrf2 moves into the nucleus to activate the transcription of cytoprotective genes. 11 Ubiquitin is found in the inclusion bodies in most neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease and amyotrophic lateral sclerosis. 12 The characteristics of ubiquitin in this context remain unknown, but increasing evidence makes it plausible that UPS and autophagy dysfunctions cause aberrant accumulation of proteins and neurodegeneration. 13 Aging is the major risk factor shared by sporadic neurodegenerative diseases and studies show cellular protein degradation systems become less efficient with age. 14 , 15 Recently, a role for the UPS in AD pathogenesis was firmly supported by pooled genome-wide association studies. 16 Furthermore, conditional knockout studies in mice indicate that proteasomal and autophagic degradation have a causal link to neurodegenerative diseases in general. 17 , 18 , 19 , 20 Understanding the interplay between and contribution of the UPS and autophagy to proteostasis in neurons is imperative to understanding neurodegenerative disease. Here we investigate this in mouse brain cortical neurons with 26S proteasome dysfunction. We demonstrate short-term (early) 26S proteasome dysfunction induces selective autophagy, but long-term (continued) dysfunction decreases autophagy characterised by downregulation of essential autophagy genes. Furthermore, despite 26S proteasome dysfunction leading to S351 phosphorylation of p62 and early transcriptional activation of Nrf2, the Nrf2 protein is not stabilised in brain. Results 26S proteasome dysfunction in mouse forebrain neurons 26S proteasome dysfunction was restricted to mouse forebrain neurons by crossing floxed Psmc1 mice ( Psmc1 fl/fl ), an essential ATPase subunit of the 19S regulatory particle of the 26S proteasome, with mice expressing Cre recombinase under the control of the calcium calmodulin-dependent protein kinase II α ( CamKIIα ) promoter ( Psmc1 fl/fl ; CaMKIIα-Cre ) as described previously. 17 Here ubiquitin immunostaining revealed sparse 26S proteasome-impaired neurons in Psmc1 fl/fl ; CaMKIIα-Cre cortices at 2 weeks old; significant accumulation of ubiquitinated proteins was evident from 3 weeks old ( Supplementary Figure S1A ), consistent with previous observations. 17 The levels of synaptic and neuronal marker proteins were similar at 3 and 4 weeks old, but significantly decreased in Psmc1 fl/fl ; CaMKIIα-Cre cortices by 6 weeks old, reflecting progressive synaptic dysfunction and neurodegeneration ( Supplementary Figure S1B ). Mitochondrial fragmentation and mitophagy in 26S proteasome-impaired neurons In a qualitative study, we previously described 26S proteasome dysfunction in mouse nigral neurons in vivo caused paranuclear accumulation of morphologically abnormal mitochondria. 21 Here we show similar paranuclear accumulation of morphologically abnormal mitochondria in cortical neuron electron micrographs (EMs) and quantification analyses of mitochondria at 6<|im_end|> <|im_start|>assistant A fault with the natural waste disposal system that helps to keep our brain cell 'batteries' healthy may contribute to neurodegenerative disease, a new study has found. The research, led by academics at The University of Nottingham and published in the journal Cell Death and Disease, centres on problems with mitochondria – the powerhouses which produce energy within a cell. The results support previous evidence that patients with Parkinson's Disease have faults with brain mitochondria which contributes to dysfunction and death within their neurons. Dr Lynn Bedford, in the University's School of Life Sciences, said: "The study highlights the importance of the ubiquitin proteasome system (UPS) for healthy mitochondria. The UPS is like a waste disposal system that removes small unwanted proteins from inside cells. "If waste is not removed it will build up over time and become toxic, causing cells to go wrong and eventually die." Faults in this system may play an important role in neurodegenerative diseases such as Parkinson's and Alzheimer's because they are caused by the death of neurons – the network through which we transfer information in our brain. Harmful molecules Using gene targeting in mice, the researchers have discovered that a faulty UPS in neurons leads to damaged mitochondria that produce less energy. Damages mitochondria are also known to produce harmful molecules that injure the cell – oxidative stress – so it is vital that the brain is able to keep mending, removing and replacing them. The study also found that when the UPS was faulty, the damaged mitochondria were not removed from neurons in the normal way by the process of autophagy, the disposal system that breaks down larger parts in the cell like mitochondria. The research was conducted in collaboration with experts at Nottingham Trent University, the University of Dundee, Nottingham University Hospitals NHS Trust and Great Ormond Street Hospital for Children NHS Trust in the UK and the University of Tripoli in Libya. <|im_end|>

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5934, 554, 279, 2849, 1389, 79401, 8631, 1389, 779, 433, 374, 16595, 430, 279, 8271, 374, 3025, 311, 2567, 296, 2518, 11, 18054, 323, 25935, 1124, 13, 578, 4007, 1101, 1766, 430, 994, 279, 58146, 574, 58671, 11, 279, 20727, 55042, 4298, 1051, 539, 7108, 505, 34313, 304, 279, 4725, 1648, 555, 279, 1920, 315, 3154, 5237, 82770, 11, 279, 34545, 1887, 430, 18808, 1523, 8294, 5596, 304, 279, 2849, 1093, 55042, 4298, 13, 578, 3495, 574, 13375, 304, 20632, 449, 11909, 520, 67659, 48620, 3907, 11, 279, 3907, 315, 75015, 2176, 11, 67659, 3907, 85397, 37381, 17236, 323, 8681, 2582, 12669, 6825, 15429, 369, 15394, 37381, 17236, 304, 279, 6560, 323, 279, 3907, 315, 27852, 14559, 304, 38059, 13, 220, 128257, 198 ]

2,043

[ { "content": "You are a great 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 Autism is a lifelong neurodevelopmental difference and disability, yet there is limited research examining parenting in autistic mothers. Objective To explore autistic mothers’ experience of the perinatal period and parenthood. This includes pregnancy, childbirth, the postpartum period, self-perception of parenting strengths and weaknesses, communication with professionals in relation to one’s child, mental health difficulties and the social experience of motherhood. It also includes disclosing one’s diagnosis of autism in parenting contexts. Methods We used a community-based participatory research model, and recruited an advisory panel, with whom we co-developed an anonymous, online survey for autistic mothers. The online survey was completed by autistic and non-autistic mothers, and we compared their responses using Chi-squared analysis. Sample Autistic mothers ( n = 355), and non-autistic mothers ( n = 132), each of whom had at least one autistic child, were included in our final analysis. Results There were differences in education, gender identity and age of mother at birth of first child. Autistic mothers were more likely to have experienced additional psychiatric conditions, including pre- or post-partum depression, and reported greater difficulties in areas such as multi-tasking, coping with domestic responsibilities and creating social opportunities for their child. They were also more likely to report feeling misunderstood by professionals, and reported greater anxiety, higher rates of selective mutism, and not knowing which details were appropriate to share with professionals. They were also more likely to find motherhood an isolating experience, to worry about others judging their parenting, or feel unable to turn to others for support in parenting. However, despite these challenges, autistic mothers were able to act in the best interest of their child, putting their child’s needs first. Conclusions Autistic mothers face unique challenges and the stigma associated with autism may further exacerbate communication difficulties. Greater understanding and acceptance amongst individuals who interact with autistic mothers is needed, and autistic mothers would benefit from additional and better-tailored support. Terminology This article uses identity-first language because autistic individuals have reported a preference for identity-first language (autistic person) rather than person-first language (person with autism) [ 1 ]. Introduction Autism is a neurodevelopmental condition, diagnosed by difficulties in social-communication alongside a strong preference for repetition, difficulties in adjusting to unexpected change, and a profile of atypical sensory sensitivity. The prevalence of autism is estimated at 1–2% of the population, diagnosed more often in males than females, with a sex ratio of 3:1 (male:female) [ 2 , 3 , 4 ]. Little attention has been paid to parenthood in autistic adults, despite autism being a lifelong condition [ 5 ]. There are currently no estimates of the number of autistic adults who are parents. Between 17 and 23% of parents of autistic children have the ‘broader autism phenotype’ [ 6 , 7 ] and autism is partly genetic [ 8 ]. Therefore, it is possible that a number of mothers of autistic children may have undiagnosed autism and, because women are on average diagnosed later in life than men [ 9 ], some may not receive their diagnosis until they are already parents themselves. Whilst there is some literature on how the presence of an autistic child impacts family dynamics and parents [ 10 , 11 ], the experience of autistic mothers themselves is relatively unexplored. To date, only the experience of pregnancy, childbirth and the postpartum period in autistic women have been studied [ 12 , 13 ]. Using qualitative methods, these studies highlighted themes important to autistic mothers [ 12 , 13 ]: Heightened sensory experiences during the perinatal period, including breastfeeding; the desire for clear guidance from healthcare professionals and family; stress that follows from the perceived pressure to be a patient and perfect mother; and the stigmatisation of autistic mothers as ‘bad parents’ by healthcare professionals. However, further research of autistic motherhood, beyond the perinatal period, is needed. The experiences of mothers with intellectual disabilities and psychiatric conditions, which are often co-morbid with autism [ 14 ], may inform our understanding of the possible experiences of autistic mothers. Although not all autistic women have an additional diagnosis of a psychiatric condition or intellectual disability, mothers with these diagnoses may face similar challenges to autistic mothers as these conditions are all neurodevelopmental, psychological or behavioural in nature. For women with intellectual disabilities and psychiatric conditions, motherhood is often a desirable experience [ 15 , 16 ], but for mothers with a psychiatric condition, the stigma associated with their condition has a major impact on how they view themselves as mothers. One study showed they felt as though the concept of the ‘ideal mother’ was incompatible with the negative connotations of their psychiatric condition [ 15 ]. Stigma also presents a major barrier to accessing services or seeking support from friends and family. For mothers who fear judgment of their parenting ability and fear potentially losing their child to child protection services, fear of stigmatisation may impede them from accessing services needed by their children. This may be part of a wider feeling of being stigmatised that autistic adults report [ 17 ]. Such fears could be well founded as parents with an intellectual disability often face more scrutiny by social services [ 18 ] and are at a higher risk of having their parental rights terminated [ 19 ]. Autistic individuals are at increased risk of mental health difficulties, compared to neurotypical individuals [ 20 ]. It is unclear how this might affect autistic mothers. Feelings of isolation, fear of judgment and the stigma of autism may have an adverse effect on mental health, especially in the early stages of motherhood where women are still adjusting to their new identity [ 16 ]. A history of depression is one the highest risk factors for postpartum depression [ 21 ]. Given the co-morbidity of depression and autism [ 20 ], we would expect autistic mothers to be at higher risk for postpartum depression than are neurotypical mothers, which could isolate them further. This may mean that autistic women require additional", "role": "user" }, { "content": "(HealthDay)—The idea of marijuana causing a psychotic breakdown sounds like something out of the camp film classic \"Reefer Madness,\" but many experts argue it's not that far-fetched. As legalization of recreational marijuana spreads across the United States, more people are showing up in ERs with psychotic symptoms after consuming too much pot, said Dr. Itai Danovitch, chairman of psychiatry and behavioral neurosciences at Cedars-Sinai in Los Angeles. \"If somebody gets too high, they use more than intended, they can have psychotic symptoms. That typically resolves as the drug wears off,\" Danovitch said. \"After it's worn off, there's no subsequent psychosis. That's just a direct effect of over-intoxication.\" But some unlucky souls with a family history of mental illness might wind up with a full-fledged psychotic disorder that will require extended treatment, Danovitch noted. \"That risk is concentrated among a minority of people who have an existing vulnerability to develop a psychotic disorder, a family history of psychosis,\" Danovitch said. \"There are environmental factors that influence whether somebody develops schizophrenia who has a risk. It appears cannabis probably is one of those factors.\" Vaping a potent form of THC—the intoxicating ingredient in pot—prompted a psychotic episode last year in 24-year-old Madison McIntosh of Scottsdale, Ariz., according to U.S. Today. McIntosh appeared at the driving range where he worked on his day off, wandering around and talking babble for 12 hours straight. His family rushed him to a hospital, where he told his father that he was seeing double rainbows. Doctors diagnosed him with cannabis use disorder and unspecified psychosis. McIntosh remembers feeling \"out of it, delusional,\" at the driving range, where he thought people were following him. \"I was pretty scared,\" he told U.S. Today of the March incident. \"I didn't know where I was at.\" Disagreement over pot-psychosis link Despite anecdotes like these, skeptics argue that the science on a potential link between pot and psychosis remains far from solid. \"It would appear to be premature, at best, and sensational, at worst, to opine that a strong causal relationship exists between cannabis exposure and psychiatric disorders, given the lack of consensus among experts in the field and the fact that rates of psychosis and mental illness have largely remained static over the decades while at the same time rates of cannabis use have fluctuated dramatically,\" said Paul Armentano. He is deputy director of NORML, a nonprofit calling for the reform of marijuana laws. \"This latter fact undermines the theory that cannabis exposure is a direct cause of psychiatric illness in otherwise non-predisposed subjects, and instead indicates that those most likely to express psychotic symptoms possess a predisposition to both cannabis use and psychotic behaviors,\" Armentano added. Still, a study published recently in the Lancet journal found that daily marijuana use may increase the risk of a first-time psychotic episode by three to five times, depending on the potency of the pot. The Lancet study reported that in the three sites with the greatest consumption of high-potency cannabis, daily use of high-potency cannabis was associated with the greatest increase in the odds for psychotic disorder—four times greater in Paris, five times greater in London, and more than nine times greater in Amsterdam. These temporary psychotic episodes are \"not a common marijuana experience, but it's common given how prevalently marijuana is used,\" Danovitch said. The risk of so-called \"transient psychosis\" has grown with both the increasing potency of new pot strains and the increased use of edible marijuana products, said Dr. Scott Krakower, assistant unit chief of psychiatry at Zucker Hillside Hospital in Glen Oaks, N.Y. \"You can ingest a large amount of high-potency agents in a quick period of time,\" Krakower explained. \"It's not going to take you a lot with edibles to hit a very high dose of marijuana. If you're not regulating yourself, you could go up pretty fast without even realizing it.\" Link strongest in those vulnerable to mental illness But there's a small proportion of people whose existing vulnerability to mental illness makes them more likely to have lasting psychosis if they use too much pot, studies have found. The risk for schizophrenia following substance-induced psychosis is about 11%, with the strongest association among vulnerable users of pot, according to a 2019 study in the American Journal of Psychiatry. Danovitch said he counsels young people to consider their genetic risk for mental illness before they use marijuana. \"If they have a family history of serious mental illness, their risk may be really different from that of their peers,\" Danovitch said. \"It's important that they be aware and informed about that.\" Emily Feinstein, executive vice president at the Center on Addiction, seconded those concerns regarding young users. \"The research is clear that adolescent marijuana use is associated with an increased risk of schizophrenia or psychotic symptoms in young people with a potential vulnerability to mental illness,\" Feinstein said. \"The harms of marijuana are amplified in adolescents and young adults, whose developing brains are more vulnerable to the impact of THC,\" she noted. \"Parents should be especially concerned if their children are using high-concentrate THC products.\" Armentano agreed that the \"growing concerns over this potential relationship ought to be taken seriously and they provide an argument in favor of better regulation of the plant so that it can be better kept out of the hands of young people and so that targeted warnings be directed toward those adults who may be at higher risk for an adverse reaction. \"Maintaining cannabis prohibition, unfortunately, achieves neither result,\" Armentano 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 Background Autism is a lifelong neurodevelopmental difference and disability, yet there is limited research examining parenting in autistic mothers. Objective To explore autistic mothers’ experience of the perinatal period and parenthood. This includes pregnancy, childbirth, the postpartum period, self-perception of parenting strengths and weaknesses, communication with professionals in relation to one’s child, mental health difficulties and the social experience of motherhood. It also includes disclosing one’s diagnosis of autism in parenting contexts. Methods We used a community-based participatory research model, and recruited an advisory panel, with whom we co-developed an anonymous, online survey for autistic mothers. The online survey was completed by autistic and non-autistic mothers, and we compared their responses using Chi-squared analysis. Sample Autistic mothers ( n = 355), and non-autistic mothers ( n = 132), each of whom had at least one autistic child, were included in our final analysis. Results There were differences in education, gender identity and age of mother at birth of first child. Autistic mothers were more likely to have experienced additional psychiatric conditions, including pre- or post-partum depression, and reported greater difficulties in areas such as multi-tasking, coping with domestic responsibilities and creating social opportunities for their child. They were also more likely to report feeling misunderstood by professionals, and reported greater anxiety, higher rates of selective mutism, and not knowing which details were appropriate to share with professionals. They were also more likely to find motherhood an isolating experience, to worry about others judging their parenting, or feel unable to turn to others for support in parenting. However, despite these challenges, autistic mothers were able to act in the best interest of their child, putting their child’s needs first. Conclusions Autistic mothers face unique challenges and the stigma associated with autism may further exacerbate communication difficulties. Greater understanding and acceptance amongst individuals who interact with autistic mothers is needed, and autistic mothers would benefit from additional and better-tailored support. Terminology This article uses identity-first language because autistic individuals have reported a preference for identity-first language (autistic person) rather than person-first language (person with autism) [ 1 ]. Introduction Autism is a neurodevelopmental condition, diagnosed by difficulties in social-communication alongside a strong preference for repetition, difficulties in adjusting to unexpected change, and a profile of atypical sensory sensitivity. The prevalence of autism is estimated at 1–2% of the population, diagnosed more often in males than females, with a sex ratio of 3:1 (male:female) [ 2 , 3 , 4 ]. Little attention has been paid to parenthood in autistic adults, despite autism being a lifelong condition [ 5 ]. There are currently no estimates of the number of autistic adults who are parents. Between 17 and 23% of parents of autistic children have the ‘broader autism phenotype’ [ 6 , 7 ] and autism is partly genetic [ 8 ]. Therefore, it is possible that a number of mothers of autistic children may have undiagnosed autism and, because women are on average diagnosed later in life than men [ 9 ], some may not receive their diagnosis until they are already parents themselves. Whilst there is some literature on how the presence of an autistic child impacts family dynamics and parents [ 10 , 11 ], the experience of autistic mothers themselves is relatively unexplored. To date, only the experience of pregnancy, childbirth and the postpartum period in autistic women have been studied [ 12 , 13 ]. Using qualitative methods, these studies highlighted themes important to autistic mothers [ 12 , 13 ]: Heightened sensory experiences during the perinatal period, including breastfeeding; the desire for clear guidance from healthcare professionals and family; stress that follows from the perceived pressure to be a patient and perfect mother; and the stigmatisation of autistic mothers as ‘bad parents’ by healthcare professionals. However, further research of autistic motherhood, beyond the perinatal period, is needed. The experiences of mothers with intellectual disabilities and psychiatric conditions, which are often co-morbid with autism [ 14 ], may inform our understanding of the possible experiences of autistic mothers. Although not all autistic women have an additional diagnosis of a psychiatric condition or intellectual disability, mothers with these diagnoses may face similar challenges to autistic mothers as these conditions are all neurodevelopmental, psychological or behavioural in nature. For women with intellectual disabilities and psychiatric conditions, motherhood is often a desirable experience [ 15 , 16 ], but for mothers with a psychiatric condition, the stigma associated with their condition has a major impact on how they view themselves as mothers. One study showed they felt as though the concept of the ‘ideal mother’ was incompatible with the negative connotations of their psychiatric condition [ 15 ]. Stigma also presents a major barrier to accessing services or seeking support from friends and family. For mothers who fear judgment of their parenting ability and fear potentially losing their child to child protection services, fear of stigmatisation may impede them from accessing services needed by their children. This may be part of a wider feeling of being stigmatised that autistic adults report [ 17 ]. Such fears could be well founded as parents with an intellectual disability often face more scrutiny by social services [ 18 ] and are at a higher risk of having their parental rights terminated [ 19 ]. Autistic individuals are at increased risk of mental health difficulties, compared to neurotypical individuals [ 20 ]. It is unclear how this might affect autistic mothers. Feelings of isolation, fear of judgment and the stigma of autism may have an adverse effect on mental health, especially in the early stages of motherhood where women are still adjusting to their new identity [ 16 ]. A history of depression is one the highest risk factors for postpartum depression [ 21 ]. Given the co-morbidity of depression and autism [ 20 ], we would expect autistic mothers to be at higher risk for postpartum depression than are neurotypical mothers, which could isolate them further. This may mean that autistic women require additional<|im_end|> <|im_start|>assistant (HealthDay)—The idea of marijuana causing a psychotic breakdown sounds like something out of the camp film classic "Reefer Madness," but many experts argue it's not that far-fetched. As legalization of recreational marijuana spreads across the United States, more people are showing up in ERs with psychotic symptoms after consuming too much pot, said Dr. Itai Danovitch, chairman of psychiatry and behavioral neurosciences at Cedars-Sinai in Los Angeles. "If somebody gets too high, they use more than intended, they can have psychotic symptoms. That typically resolves as the drug wears off," Danovitch said. "After it's worn off, there's no subsequent psychosis. That's just a direct effect of over-intoxication." But some unlucky souls with a family history of mental illness might wind up with a full-fledged psychotic disorder that will require extended treatment, Danovitch noted. "That risk is concentrated among a minority of people who have an existing vulnerability to develop a psychotic disorder, a family history of psychosis," Danovitch said. "There are environmental factors that influence whether somebody develops schizophrenia who has a risk. It appears cannabis probably is one of those factors." Vaping a potent form of THC—the intoxicating ingredient in pot—prompted a psychotic episode last year in 24-year-old Madison McIntosh of Scottsdale, Ariz., according to U.S. Today. McIntosh appeared at the driving range where he worked on his day off, wandering around and talking babble for 12 hours straight. His family rushed him to a hospital, where he told his father that he was seeing double rainbows. Doctors diagnosed him with cannabis use disorder and unspecified psychosis. McIntosh remembers feeling "out of it, delusional," at the driving range, where he thought people were following him. "I was pretty scared," he told U.S. Today of the March incident. "I didn't know where I was at." Disagreement over pot-psychosis link Despite anecdotes like these, skeptics argue that the science on a potential link between pot and psychosis remains far from solid. "It would appear to be premature, at best, and sensational, at worst, to opine that a strong causal relationship exists between cannabis exposure and psychiatric disorders, given the lack of consensus among experts in the field and the fact that rates of psychosis and mental illness have largely remained static over the decades while at the same time rates of cannabis use have fluctuated dramatically," said Paul Armentano. He is deputy director of NORML, a nonprofit calling for the reform of marijuana laws. "This latter fact undermines the theory that cannabis exposure is a direct cause of psychiatric illness in otherwise non-predisposed subjects, and instead indicates that those most likely to express psychotic symptoms possess a predisposition to both cannabis use and psychotic behaviors," Armentano added. Still, a study published recently in the Lancet journal found that daily marijuana use may increase the risk of a first-time psychotic episode by three to five times, depending on the potency of the pot. The Lancet study reported that in the three sites with the greatest consumption of high-potency cannabis, daily use of high-potency cannabis was associated with the greatest increase in the odds for psychotic disorder—four times greater in Paris, five times greater in London, and more than nine times greater in Amsterdam. These temporary psychotic episodes are "not a common marijuana experience, but it's common given how prevalently marijuana is used," Danovitch said. The risk of so-called "transient psychosis" has grown with both the increasing potency of new pot strains and the increased use of edible marijuana products, said Dr. Scott Krakower, assistant unit chief of psychiatry at Zucker Hillside Hospital in Glen Oaks, N.Y. "You can ingest a large amount of high-potency agents in a quick period of time," Krakower explained. "It's not going to take you a lot with edibles to hit a very high dose of marijuana. If you're not regulating yourself, you could go up pretty fast without even realizing it." Link strongest in those vulnerable to mental illness But there's a small proportion of people whose existing vulnerability to mental illness makes them more likely to have lasting psychosis if they use too much pot, studies have found. The risk for schizophrenia following substance-induced psychosis is about 11%, with the strongest association among vulnerable users of pot, according to a 2019 study in the American Journal of Psychiatry. Danovitch said he counsels young people to consider their genetic risk for mental illness before they use marijuana. "If they have a family history of serious mental illness, their risk may be really different from that of their peers," Danovitch said. "It's important that they be aware and informed about that." Emily Feinstein, executive vice president at the Center on Addiction, seconded those concerns regarding young users. "The research is clear that adolescent marijuana use is associated with an increased risk of schizophrenia or psychotic symptoms in young people with a potential vulnerability to mental illness," Feinstein said. "The harms of marijuana are amplified in adolescents and young adults, whose developing brains are more vulnerable to the impact of THC," she noted. "Parents should be especially concerned if their children are using high-concentrate THC products." Armentano agreed that the "growing concerns over this potential relationship ought to be taken seriously and they provide an argument in favor of better regulation of the plant so that it can be better kept out of the hands of young people and so that targeted warnings be directed toward those adults who may be at higher risk for an adverse reaction. "Maintaining cannabis prohibition, unfortunately, achieves neither result," Armentano 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 Brain function relies on the coordination of activity across multiple, recurrently connected brain areas. For instance, sensory information encoded in early sensory areas is relayed to, and further processed by, higher cortical areas and then fed back. However, the way in which feedforward and feedback signaling interact with one another is incompletely understood. Here we investigate this question by leveraging simultaneous neuronal population recordings in early and midlevel visual areas (V1–V2 and V1–V4). Using a dimensionality reduction approach, we find that population interactions are feedforward-dominated shortly after stimulus onset and feedback-dominated during spontaneous activity. The population activity patterns most correlated across areas were distinct during feedforward- and feedback-dominated periods. These results suggest that feedforward and feedback signaling rely on separate “channels”, which allows feedback signals to not directly affect activity that is fed forward. Introduction Most brain functions rely on the coordination of activity across multiple areas 1 , 2 . Activity does not follow a purely feedforward path between brain areas: areas are often reciprocally connected, and signals passed from one area to the next are often processed and fed back 3 , 4 , 5 , 6 . Understanding when feedforward and feedback signaling between areas is most dominant, and how these forms of signaling interact, is crucial for improving our understanding of computation in the brain. Previous studies have attempted to infer feedforward or feedback interactions between areas. One approach for identifying feedforward signaling is to present a stimulus and then compare the timing of neuronal response onsets across areas 7 , 8 , 9 , 10 . Similarly, feedback signaling can be inferred by studying time differences in the emergence of some forms of selectivity across areas 11 , 12 , 13 , 14 , 15 . Other studies have studied feedforward or feedback signaling by measuring activity simultaneously in two areas, and comparing temporal delays in pairwise spiking correlations 16 , 17 , 18 , 19 , 20 , 21 or phase delays in local field potentials (LFP) 22 , 23 , 24 , 25 . These studies have suggested that feedforward signaling occurs shortly after stimulus onset and that feedback signaling appears later. However, it is unknown how the relative dominance of feedforward and feedback interactions changes during stimulus presentation and when there is no stimulus present (i.e., spontaneous activity). To understand inter-areal interactions more deeply, it is now possible to record activity from large neuronal populations simultaneously in different cortical areas, and characterize what patterns of population activity are most related across those areas 19 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 . This approach has led to new proposals about how activity can be flexibly routed across brain areas (see ref. 34 for a review). In particular, simultaneous multi-area recordings have revealed properties of population activity patterns that are most related across areas in the context of sensory processing 29 , attention 30 , learning 31 , and motor control 32 , 33 . However, it is unknown how these population activity patterns relate to feedforward or feedback signaling between areas. Here, we leverage simultaneous recordings of neuronal populations in early and midlevel visual areas (V1–V2 and V1–V4) to examine the temporal dynamics of inter-areal interactions, as well as the population activity patterns involved in those interactions (Fig. 1 a). By analyzing the moment-by-moment relationship of the population activity across areas (without trial-averaging), we found that interactions were feedforward-dominated (V1 leading V2, and V1 leading V4) shortly after stimulus onset and gradually became feedback-dominated. In addition, we found that the population activity patterns involved in feedforward signaling were distinct from those involved in feedback signaling. This indicates that activity patterns in V1 that most affect downstream activity during feedforward processing are not the ones most affected by feedback signaling. Our results reveal both the dominant direction of signal flow between areas on a moment-by-moment basis and the distinct nature of population activity patterns involved in feedforward and feedback interactions. Fig. 1: Studying feedforward and feedback interactions using neuronal population activity. a Each circle represents a neuron in each area, with the shading representing the activity level of the neuron. The population activity patterns involved in feedforward signaling (top) might be distinct from those involved in feedback interactions (bottom). b Schematic showing a sagittal section of occipital cortex and the recording setup for the V1–V2 recordings. We simultaneously recorded V1 population activity using a 96-channel array and V2 population activity using a set of movable electrodes and tetrodes. c Schematic showing an overhead view of the recording setup for the V1–V4 awake recordings. We simultaneously recorded V1 and V4 population activity using one 96-channel and one 48-channel array in V1 and a 48-channel array in V4 in the first animal, and two 96-channel arrays in V1 and two 48-channel array in V4 in the second animal. Full size image Results We simultaneously recorded from neuronal populations in V1 (88 to 159 neurons; mean: 112.8 ± 12.3 SEM) and V2 (24 to 37 neurons; mean: 29.4 ± 2.4 SEM) in three anesthetized monkeys (Fig. 1 b; five recording sessions), as well as in V1 (34 to 128 neurons; mean: 66.6 ± 16.2 SEM) and V4 (12 to 84 neurons; mean: 58.8 ± 12.4 SEM) in two awake fixating monkeys (Fig. 1 c; five recording sessions). Animals were shown drifting gratings of different orientations (1280 ms stimulus duration for V1–V2; 200 ms for V1–V4), followed by a blank screen (1500 ms for V1–V2; 150 ms for V1–V4). Recording sites were chosen so that the spatial receptive fields of the V1 and V2/V4 populations overlapped (see ref. 19 and Supplementary Fig. 1 ). Temporal structure of inter-areal interactions We first characterized the temporal dynamics of the interaction between neuronal population spiking responses in V1 and V2. To do so, we asked: (1) how the interaction evolved during stimulus presentation and the subsequent period of spontaneous activity (which together constitute a trial); and (2) how the interaction", "role": "user" }, { "content": "Exploring how brain areas communicate with each other is the focus of a long-standing research collaboration between Carnegie Mellon University, Albert Einstein College of Medicine, and Champalimaud Research. The cross-continental team is simultaneously recording populations of neurons across multiple brain areas in the visual system and utilizing novel statistical methods to observe neural activity patterns being conveyed between the areas. Their latest findings reveal that feedforward and feedback signaling involve different neural activity patterns, lending fresh understanding into how the brain processes visual information. Myriad brain functions, such as seeing, hearing, and making decisions require multiple brain areas to communicate with one another. Researchers have previously studied pairs of neurons or some aggregate metric of neuronal activity across areas to assess how information is taken in, processed, and then acted upon in everyday life. Few groups have studied, in such detail, populations of neurons together to see what type of activity patterns are being communicated across brain areas. \"The idea of this study was to investigate how information flows across two areas in the visual cortex, V1 and V2,\" says João D. Semedo, first author of the work published in Nature Communications and former electrical and computer engineering Ph.D. student. \"We had strong reasons to believe that the areas communicated with one another, based on anatomy, but tracking the flow of signals between areas has proven to be really difficult.\" Semedo continues, \"Using pioneering technology from Dr. Kohn's lab, we have been able to record multiple brain areas at the same time, and within each of those brain areas, record many neurons. It is the activity of a group of neurons together that tells us what is specifically going on. Then, we applied statistical methods in a creative way to pull out signals that haven't been extracted before.\" In their analysis, the group identified directed interactions between brain areas and confirmed that patterns of activity in feedforward interactions (from V1 to V2) differed from patterns of activity in feedback interactions (from V2 to V1). Weekly meetings and a tight-knit, teamwork-driven approach has enabled the collaborators to stay connected on all aspects of the work and contributed to their success. \"Understanding what is communicated from one brain area to another is tough to disentangle, because signals are flowing in all directions, all the time,\" explains Adam Kohn, professor of neuroscience at the Albert Einstein College of Medicine. \"The thing that is most exciting to me about this work is the perspectives it opens for the future. If we can pinpoint the activity patterns that are involved in different signaling directions, it will be a big step forward in understanding how the brain works.\" More broadly, these methods could be applied to investigate the flow of communication in other areas of the brain, outside of the visual system. \"Studies like these increase our basic scientific understanding of how the brain works,\" says Byron Yu, professor of biomedical engineering and electrical and computer engineering. \"Many brain disorders involve a breakdown of communication between brain areas. This pioneering work could lead to novel treatments for such disorders, and even help us develop new methods to aid brain development and ways to learn.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Brain function relies on the coordination of activity across multiple, recurrently connected brain areas. For instance, sensory information encoded in early sensory areas is relayed to, and further processed by, higher cortical areas and then fed back. However, the way in which feedforward and feedback signaling interact with one another is incompletely understood. Here we investigate this question by leveraging simultaneous neuronal population recordings in early and midlevel visual areas (V1–V2 and V1–V4). Using a dimensionality reduction approach, we find that population interactions are feedforward-dominated shortly after stimulus onset and feedback-dominated during spontaneous activity. The population activity patterns most correlated across areas were distinct during feedforward- and feedback-dominated periods. These results suggest that feedforward and feedback signaling rely on separate “channels”, which allows feedback signals to not directly affect activity that is fed forward. Introduction Most brain functions rely on the coordination of activity across multiple areas 1 , 2 . Activity does not follow a purely feedforward path between brain areas: areas are often reciprocally connected, and signals passed from one area to the next are often processed and fed back 3 , 4 , 5 , 6 . Understanding when feedforward and feedback signaling between areas is most dominant, and how these forms of signaling interact, is crucial for improving our understanding of computation in the brain. Previous studies have attempted to infer feedforward or feedback interactions between areas. One approach for identifying feedforward signaling is to present a stimulus and then compare the timing of neuronal response onsets across areas 7 , 8 , 9 , 10 . Similarly, feedback signaling can be inferred by studying time differences in the emergence of some forms of selectivity across areas 11 , 12 , 13 , 14 , 15 . Other studies have studied feedforward or feedback signaling by measuring activity simultaneously in two areas, and comparing temporal delays in pairwise spiking correlations 16 , 17 , 18 , 19 , 20 , 21 or phase delays in local field potentials (LFP) 22 , 23 , 24 , 25 . These studies have suggested that feedforward signaling occurs shortly after stimulus onset and that feedback signaling appears later. However, it is unknown how the relative dominance of feedforward and feedback interactions changes during stimulus presentation and when there is no stimulus present (i.e., spontaneous activity). To understand inter-areal interactions more deeply, it is now possible to record activity from large neuronal populations simultaneously in different cortical areas, and characterize what patterns of population activity are most related across those areas 19 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 . This approach has led to new proposals about how activity can be flexibly routed across brain areas (see ref. 34 for a review). In particular, simultaneous multi-area recordings have revealed properties of population activity patterns that are most related across areas in the context of sensory processing 29 , attention 30 , learning 31 , and motor control 32 , 33 . However, it is unknown how these population activity patterns relate to feedforward or feedback signaling between areas. Here, we leverage simultaneous recordings of neuronal populations in early and midlevel visual areas (V1–V2 and V1–V4) to examine the temporal dynamics of inter-areal interactions, as well as the population activity patterns involved in those interactions (Fig. 1 a). By analyzing the moment-by-moment relationship of the population activity across areas (without trial-averaging), we found that interactions were feedforward-dominated (V1 leading V2, and V1 leading V4) shortly after stimulus onset and gradually became feedback-dominated. In addition, we found that the population activity patterns involved in feedforward signaling were distinct from those involved in feedback signaling. This indicates that activity patterns in V1 that most affect downstream activity during feedforward processing are not the ones most affected by feedback signaling. Our results reveal both the dominant direction of signal flow between areas on a moment-by-moment basis and the distinct nature of population activity patterns involved in feedforward and feedback interactions. Fig. 1: Studying feedforward and feedback interactions using neuronal population activity. a Each circle represents a neuron in each area, with the shading representing the activity level of the neuron. The population activity patterns involved in feedforward signaling (top) might be distinct from those involved in feedback interactions (bottom). b Schematic showing a sagittal section of occipital cortex and the recording setup for the V1–V2 recordings. We simultaneously recorded V1 population activity using a 96-channel array and V2 population activity using a set of movable electrodes and tetrodes. c Schematic showing an overhead view of the recording setup for the V1–V4 awake recordings. We simultaneously recorded V1 and V4 population activity using one 96-channel and one 48-channel array in V1 and a 48-channel array in V4 in the first animal, and two 96-channel arrays in V1 and two 48-channel array in V4 in the second animal. Full size image Results We simultaneously recorded from neuronal populations in V1 (88 to 159 neurons; mean: 112.8 ± 12.3 SEM) and V2 (24 to 37 neurons; mean: 29.4 ± 2.4 SEM) in three anesthetized monkeys (Fig. 1 b; five recording sessions), as well as in V1 (34 to 128 neurons; mean: 66.6 ± 16.2 SEM) and V4 (12 to 84 neurons; mean: 58.8 ± 12.4 SEM) in two awake fixating monkeys (Fig. 1 c; five recording sessions). Animals were shown drifting gratings of different orientations (1280 ms stimulus duration for V1–V2; 200 ms for V1–V4), followed by a blank screen (1500 ms for V1–V2; 150 ms for V1–V4). Recording sites were chosen so that the spatial receptive fields of the V1 and V2/V4 populations overlapped (see ref. 19 and Supplementary Fig. 1 ). Temporal structure of inter-areal interactions We first characterized the temporal dynamics of the interaction between neuronal population spiking responses in V1 and V2. To do so, we asked: (1) how the interaction evolved during stimulus presentation and the subsequent period of spontaneous activity (which together constitute a trial); and (2) how the interaction<|im_end|> <|im_start|>assistant Exploring how brain areas communicate with each other is the focus of a long-standing research collaboration between Carnegie Mellon University, Albert Einstein College of Medicine, and Champalimaud Research. The cross-continental team is simultaneously recording populations of neurons across multiple brain areas in the visual system and utilizing novel statistical methods to observe neural activity patterns being conveyed between the areas. Their latest findings reveal that feedforward and feedback signaling involve different neural activity patterns, lending fresh understanding into how the brain processes visual information. Myriad brain functions, such as seeing, hearing, and making decisions require multiple brain areas to communicate with one another. Researchers have previously studied pairs of neurons or some aggregate metric of neuronal activity across areas to assess how information is taken in, processed, and then acted upon in everyday life. Few groups have studied, in such detail, populations of neurons together to see what type of activity patterns are being communicated across brain areas. "The idea of this study was to investigate how information flows across two areas in the visual cortex, V1 and V2," says João D. Semedo, first author of the work published in Nature Communications and former electrical and computer engineering Ph.D. student. "We had strong reasons to believe that the areas communicated with one another, based on anatomy, but tracking the flow of signals between areas has proven to be really difficult." Semedo continues, "Using pioneering technology from Dr. Kohn's lab, we have been able to record multiple brain areas at the same time, and within each of those brain areas, record many neurons. It is the activity of a group of neurons together that tells us what is specifically going on. Then, we applied statistical methods in a creative way to pull out signals that haven't been extracted before." In their analysis, the group identified directed interactions between brain areas and confirmed that patterns of activity in feedforward interactions (from V1 to V2) differed from patterns of activity in feedback interactions (from V2 to V1). Weekly meetings and a tight-knit, teamwork-driven approach has enabled the collaborators to stay connected on all aspects of the work and contributed to their success. "Understanding what is communicated from one brain area to another is tough to disentangle, because signals are flowing in all directions, all the time," explains Adam Kohn, professor of neuroscience at the Albert Einstein College of Medicine. "The thing that is most exciting to me about this work is the perspectives it opens for the future. If we can pinpoint the activity patterns that are involved in different signaling directions, it will be a big step forward in understanding how the brain works." More broadly, these methods could be applied to investigate the flow of communication in other areas of the brain, outside of the visual system. "Studies like these increase our basic scientific understanding of how the brain works," says Byron Yu, professor of biomedical engineering and electrical and computer engineering. "Many brain disorders involve a breakdown of communication between brain areas. This pioneering work could lead to novel treatments for such disorders, and even help us develop new methods to aid brain development and ways to learn." <|im_end|>

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2,001

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Hydrogen, the smallest and most abundant element in nature, can be efficiently incorporated within a solid and drastically modify its electronic and structural state. In most semiconductors interstitial hydrogen binds to defects and is known to be amphoteric, namely it can act either as a donor (H + ) or an acceptor (H − ) of charge, nearly always counteracting the prevailing conductivity type. Here we demonstrate that hydrogenation resolves an outstanding challenge in chalcogenide classes of three-dimensional (3D) topological insulators and magnets — the control of intrinsic bulk conduction that denies access to quantum surface transport, imposing severe thickness limits on the bulk. With electrons donated by a reversible binding of H + ions to Te(Se) chalcogens, carrier densities are reduced by over 10 20 cm −3 , allowing tuning the Fermi level into the bulk bandgap to enter surface/edge current channels without altering carrier mobility or the bandstructure. The hydrogen-tuned topological nanostructures are stable at room temperature and tunable disregarding bulk size, opening a breadth of device platforms for harnessing emergent topological states. Introduction The ability to control carrier density—a key parameter of the electronic state of condensed matter—is central to achieving access to the topologically protected surface states in three-dimensional (3D) topological materials (TIs) that ideally are insulating in the bulk 1 . In the absence of magnetic dopants, the 2D electronic surface states with Dirac-type (linear) energy-momentum dispersion 1 , 2 , 3 are gapless and fully spin-polarized, with protection against backscattering by local disorder guaranteed by time-reversal symmetry. These important layered van der Waals (vdW) quantum materials have narrow ( ≲ 300 meV) bulk gaps and charge carriers donated by intrinsic lattice defects 4 . As a result, the conduction through the bulk and its intermixing with the surface channels is what largely denies direct access to the surface currents sought for the implementation in topological spintronics and fault-tolerant quantum computing 5 . Recent realizations of a nontrivial quantum anomalous Hall (QAH) state, featuring dissipation-free chiral edge currents 6 , made it apparent that when long-range magnetism and band topology combine 7 the problem of bulk conduction can be particularly acute. Magnetic dopants, by breaking time-reversal symmetry, gap out the Dirac surface channels 8 , and when the Fermi level is in the Dirac (mass) gap the QAH state is expected to emerge. However, in addition to magnetic moment, the dopants also donate charge. Indeed, QAH was first observed in heavily Cr-doped (Bi,Sb) 2 Te 3 ultrathin films 9 in which to minimize bulk conduction a non-stoichiometric alloying of the constituent elements was employed and the film thickness had to be precisely controlled. Moreover, doping disorder restricted QAH temperature to the mK range. In a newly discovered important class of intrinsic topological magnets (ITM) 10 the doping and alloying disorders are avoided because the magnetic dopants are arranged as an atomic layer in a layered vdW crystal structure. For example, the Mn-based ITM MnBi 2 Te 4 consists of Te–Bi–Te–Mn–Te–Bi–Te septuple layers (SLs), separated by vdW gaps and coupled antiferromagnetically 11 . As a consequence, the anomalous Hall (near) quantization was observed at somewhat higher temperatures 12 . However, such materials show high bulk carrier densities (typically > 10 20 cm −3 ) 13 , 14 , and observation of QAH required delicate tuning of charge density that was again only possible in ultrathin (3–5 nm) samples with odd number of SLs. In thicker (hundreds of nanometers) samples ferromagnetism and quantization could be achieved when SLs were separated by a topological spacer 15 yet tuning to quantization of either ferromagnetic (FM) or antiferromagnetic (AFM) ITMs without imposing severe thickness constraints is a major obstacle to realizing novel topological states. Here we demonstrate a remarkably efficient and facile way to reversibly tune bulk carrier densities by over ≃ 10 20 cm −3 in different classes of layered TIs 4 by using insertion and extraction of ionic hydrogen to achieve access to topological surface states. The source of H + ions is a dilute aqueous hydrochloric acid (HCl) solution, which leaves the TI crystal structure as well as electronic bands intact and has an extra benefit of removing native surface oxide while passivating surfaces and preventing reoxidation under exposure to air. We show that H + in TIs, by preferentially forming an H–Te(Se) moiety within vdW gaps, donates electrons to the system and moves Fermi level E F from the bulk valence (BVB) to bulk conduction (BCB) bands, crossing the bulk bandgap to display an ambipolar p - to n- type conductance conversion at the charge neutrality point. The process is fully reversible, as hydrogen-chalcogen moiety can be disassociated by a low-temperature annealing protocol under which hydrogen is easily removed. It is also multiply-cyclable and reproducible, thereby resolving one of the key limitations of magnetic and nonmagnetic TIs. In contrast with charge compensation by doping or alloying during growth 14 , 16 , the post-growth hydrogenation can tune E F to charge neutrality without altering the band structure and can be effective in single crystals and in nano-devices, where the evolution of resistance under hydrogenation is easily monitored over time. Results Reaching charge neutrality and beyond in Bi 2 Te 3 by hydrogenation The ultralight hydrogen diffuses rapidly and easily incorporates into many materials 17 , although it shows qualitatively different behavior in different hosts 18 . Widely practiced in technology to passivate Si dangling bonds or enhance catalytic activity 19 , hydrogenation is also known to modify both electronic and structural states 20 in a variety of diverse materials systems 21 , 22 —it was found effective in turning graphene into graphane 23 , inducing new magnetic phases in complex perovskites 24 , and modulating insulator-to-metal transition in a correlated Mott oxide VO 2 25 . To ascertain the effects of hydrogen uptake on charge transport in the TIs we first chose well-characterized Bi 2 Te 3 crystals with the conductivity flavor initially of a net acceptor type. The level of hydrogenation was controlled by", "role": "user" }, { "content": "A team led by City College of New York physicist Lia Krusin-Elbaum is behind research that could open a breadth of new quantum device platforms for harnessing emergent topological states for nano-spintronics and fault-tolerant quantum computing. The group of physicists and chemists has invented a new facile and powerful technique that uses ionic hydrogen to reduce charge carrier density in the bulk of three-dimensional (3D) topological insulators and magnets. The result is that robust non-dissipative surface or edge quantum conduction channels can be accessed for manipulation and control. Their research, \"Topological surface currents accessed through reversible hydrogenation of the three-dimensional bulk,\" appears in the journal Nature Communications. The novel hydrogen-tuning technique of chalcogen-based topological materials and nanostructures implemented in a laboratory chamber uses insertion and extraction of ionic hydrogen from dilute aqueous hydrochloric acid (HCl) solution, which leaves the layered topological crystal structure as well as electronic bands intact and has an extra benefit of removing native surface oxide while passivating surfaces. In this process—which the City College team tests in the Krusin Lab for two-dimensional electrical transport—electrons are donated by a reversible binding of H+ ions to chalcogens, such as Te or Se, and bulk carrier densities are reduced by orders of magnitude to achieve access to robust topological surface states without altering carrier mobility or the bandstructure. \"The main advance of this work is that the new hydrogenation process is fully reversible, as hydrogen-chalcogen moiety can be disassociated by a low-temperature annealing protocol under which hydrogen is easily removed,\" said Krusin-Elbaum, professor in CCNY's Division of Science. \"It is also multiply-cyclable and reproducible, thereby resolving one of the key limitations of magnetic and nonmagnetic topological insulators and can be applied not only post-growth to materials but also to fully fabricated nanodevices.\" The research in the Krusin Lab centers on exploring novel quantum phenomena such as Quantum Anomalous Hall (QAH) effect, which describes an insulator that conducts dissipationless current in discrete channels on its surfaces, 2D superconductivity, and axion state phenomena featuring a quantized thermal transport, all with the potential if industrialized to advance energy-efficient technologies. Krusin-Elbaum and her team said that the technique they have demonstrated is very general and ultimately may advance the potential of intrinsic topological magnets to transform future quantum electronics. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Hydrogen, the smallest and most abundant element in nature, can be efficiently incorporated within a solid and drastically modify its electronic and structural state. In most semiconductors interstitial hydrogen binds to defects and is known to be amphoteric, namely it can act either as a donor (H + ) or an acceptor (H − ) of charge, nearly always counteracting the prevailing conductivity type. Here we demonstrate that hydrogenation resolves an outstanding challenge in chalcogenide classes of three-dimensional (3D) topological insulators and magnets — the control of intrinsic bulk conduction that denies access to quantum surface transport, imposing severe thickness limits on the bulk. With electrons donated by a reversible binding of H + ions to Te(Se) chalcogens, carrier densities are reduced by over 10 20 cm −3 , allowing tuning the Fermi level into the bulk bandgap to enter surface/edge current channels without altering carrier mobility or the bandstructure. The hydrogen-tuned topological nanostructures are stable at room temperature and tunable disregarding bulk size, opening a breadth of device platforms for harnessing emergent topological states. Introduction The ability to control carrier density—a key parameter of the electronic state of condensed matter—is central to achieving access to the topologically protected surface states in three-dimensional (3D) topological materials (TIs) that ideally are insulating in the bulk 1 . In the absence of magnetic dopants, the 2D electronic surface states with Dirac-type (linear) energy-momentum dispersion 1 , 2 , 3 are gapless and fully spin-polarized, with protection against backscattering by local disorder guaranteed by time-reversal symmetry. These important layered van der Waals (vdW) quantum materials have narrow ( ≲ 300 meV) bulk gaps and charge carriers donated by intrinsic lattice defects 4 . As a result, the conduction through the bulk and its intermixing with the surface channels is what largely denies direct access to the surface currents sought for the implementation in topological spintronics and fault-tolerant quantum computing 5 . Recent realizations of a nontrivial quantum anomalous Hall (QAH) state, featuring dissipation-free chiral edge currents 6 , made it apparent that when long-range magnetism and band topology combine 7 the problem of bulk conduction can be particularly acute. Magnetic dopants, by breaking time-reversal symmetry, gap out the Dirac surface channels 8 , and when the Fermi level is in the Dirac (mass) gap the QAH state is expected to emerge. However, in addition to magnetic moment, the dopants also donate charge. Indeed, QAH was first observed in heavily Cr-doped (Bi,Sb) 2 Te 3 ultrathin films 9 in which to minimize bulk conduction a non-stoichiometric alloying of the constituent elements was employed and the film thickness had to be precisely controlled. Moreover, doping disorder restricted QAH temperature to the mK range. In a newly discovered important class of intrinsic topological magnets (ITM) 10 the doping and alloying disorders are avoided because the magnetic dopants are arranged as an atomic layer in a layered vdW crystal structure. For example, the Mn-based ITM MnBi 2 Te 4 consists of Te–Bi–Te–Mn–Te–Bi–Te septuple layers (SLs), separated by vdW gaps and coupled antiferromagnetically 11 . As a consequence, the anomalous Hall (near) quantization was observed at somewhat higher temperatures 12 . However, such materials show high bulk carrier densities (typically > 10 20 cm −3 ) 13 , 14 , and observation of QAH required delicate tuning of charge density that was again only possible in ultrathin (3–5 nm) samples with odd number of SLs. In thicker (hundreds of nanometers) samples ferromagnetism and quantization could be achieved when SLs were separated by a topological spacer 15 yet tuning to quantization of either ferromagnetic (FM) or antiferromagnetic (AFM) ITMs without imposing severe thickness constraints is a major obstacle to realizing novel topological states. Here we demonstrate a remarkably efficient and facile way to reversibly tune bulk carrier densities by over ≃ 10 20 cm −3 in different classes of layered TIs 4 by using insertion and extraction of ionic hydrogen to achieve access to topological surface states. The source of H + ions is a dilute aqueous hydrochloric acid (HCl) solution, which leaves the TI crystal structure as well as electronic bands intact and has an extra benefit of removing native surface oxide while passivating surfaces and preventing reoxidation under exposure to air. We show that H + in TIs, by preferentially forming an H–Te(Se) moiety within vdW gaps, donates electrons to the system and moves Fermi level E F from the bulk valence (BVB) to bulk conduction (BCB) bands, crossing the bulk bandgap to display an ambipolar p - to n- type conductance conversion at the charge neutrality point. The process is fully reversible, as hydrogen-chalcogen moiety can be disassociated by a low-temperature annealing protocol under which hydrogen is easily removed. It is also multiply-cyclable and reproducible, thereby resolving one of the key limitations of magnetic and nonmagnetic TIs. In contrast with charge compensation by doping or alloying during growth 14 , 16 , the post-growth hydrogenation can tune E F to charge neutrality without altering the band structure and can be effective in single crystals and in nano-devices, where the evolution of resistance under hydrogenation is easily monitored over time. Results Reaching charge neutrality and beyond in Bi 2 Te 3 by hydrogenation The ultralight hydrogen diffuses rapidly and easily incorporates into many materials 17 , although it shows qualitatively different behavior in different hosts 18 . Widely practiced in technology to passivate Si dangling bonds or enhance catalytic activity 19 , hydrogenation is also known to modify both electronic and structural states 20 in a variety of diverse materials systems 21 , 22 —it was found effective in turning graphene into graphane 23 , inducing new magnetic phases in complex perovskites 24 , and modulating insulator-to-metal transition in a correlated Mott oxide VO 2 25 . To ascertain the effects of hydrogen uptake on charge transport in the TIs we first chose well-characterized Bi 2 Te 3 crystals with the conductivity flavor initially of a net acceptor type. The level of hydrogenation was controlled by<|im_end|> <|im_start|>assistant A team led by City College of New York physicist Lia Krusin-Elbaum is behind research that could open a breadth of new quantum device platforms for harnessing emergent topological states for nano-spintronics and fault-tolerant quantum computing. The group of physicists and chemists has invented a new facile and powerful technique that uses ionic hydrogen to reduce charge carrier density in the bulk of three-dimensional (3D) topological insulators and magnets. The result is that robust non-dissipative surface or edge quantum conduction channels can be accessed for manipulation and control. Their research, "Topological surface currents accessed through reversible hydrogenation of the three-dimensional bulk," appears in the journal Nature Communications. The novel hydrogen-tuning technique of chalcogen-based topological materials and nanostructures implemented in a laboratory chamber uses insertion and extraction of ionic hydrogen from dilute aqueous hydrochloric acid (HCl) solution, which leaves the layered topological crystal structure as well as electronic bands intact and has an extra benefit of removing native surface oxide while passivating surfaces. In this process—which the City College team tests in the Krusin Lab for two-dimensional electrical transport—electrons are donated by a reversible binding of H+ ions to chalcogens, such as Te or Se, and bulk carrier densities are reduced by orders of magnitude to achieve access to robust topological surface states without altering carrier mobility or the bandstructure. "The main advance of this work is that the new hydrogenation process is fully reversible, as hydrogen-chalcogen moiety can be disassociated by a low-temperature annealing protocol under which hydrogen is easily removed," said Krusin-Elbaum, professor in CCNY's Division of Science. "It is also multiply-cyclable and reproducible, thereby resolving one of the key limitations of magnetic and nonmagnetic topological insulators and can be applied not only post-growth to materials but also to fully fabricated nanodevices." The research in the Krusin Lab centers on exploring novel quantum phenomena such as Quantum Anomalous Hall (QAH) effect, which describes an insulator that conducts dissipationless current in discrete channels on its surfaces, 2D superconductivity, and axion state phenomena featuring a quantized thermal transport, all with the potential if industrialized to advance energy-efficient technologies. Krusin-Elbaum and her team said that the technique they have demonstrated is very general and ultimately may advance the potential of intrinsic topological magnets to transform future quantum electronics. <|im_end|>

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1,933

[ { "content": "You are a great 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 bacteria, ribosomes stalled on truncated mRNAs that lack a stop codon are rescued by the transfer-messenger RNA (tmRNA), alternative rescue factor A (ArfA) or ArfB systems 1 . Although tmRNA–ribosome and ArfB–ribosome structures have been determined 2 , 3 , 4 , 5 , 6 , 7 , how ArfA recognizes the presence of truncated mRNAs and recruits the canonical termination release factor RF2 to rescue the stalled ribosomes is unclear. Here we present a cryo-electron microscopy reconstruction of the Escherichia coli 70S ribosome stalled on a truncated mRNA in the presence of ArfA and RF2. The structure shows that the C terminus of ArfA binds within the mRNA entry channel on the small ribosomal subunit, and explains how ArfA distinguishes between ribosomes that bear truncated or full-length mRNAs. The N terminus of ArfA establishes several interactions with the decoding domain of RF2, and this finding illustrates how ArfA recruits RF2 to the stalled ribosome. Furthermore, ArfA is shown to stabilize a unique conformation of the switch loop of RF2, which mimics the canonical translation termination state by directing the catalytically important GGQ motif within domain 3 of RF2 towards the peptidyl-transferase centre of the ribosome. Thus, our structure reveals not only how ArfA recruits RF2 to the ribosome but also how it promotes an active conformation of RF2 to enable translation termination in the absence of a stop codon. Main Premature transcription termination or truncation of a full-length mRNA can lead to mRNAs lacking a stop codon. Ribosomes translating these truncated mRNAs become trapped at the 3′ end of the mRNA because translation elongation or termination cannot occur. In bacteria, these stalled ribosomes are recognized and recycled by the tmRNA rescue system (reviewed in ref. 1 ). A subset of bacteria, such as E. coli , can survive without the tmRNA system owing to the presence ArfA 8 . The synthetic lethality arising from inactivation of both the tmRNA and ArfA rescue systems can be alleviated by overexpression of ArfB 9 . Collectively, these studies illustrate the physiological importance that the rescue of stalled ribosomes has for cell viability. Structural studies have revealed how ribosomes stalled on truncated mRNA are recognized and recycled by the tmRNA–SmpB complex 6 , 7 or ArfB 5 . In the case of ArfB, the empty mRNA channel of the ribosome is probed by the C-terminal helix, positioning the N-terminal catalytic GGQ-containing domain at the peptidyl-transferase centre (PTC) to trigger peptidyl-tRNA hydrolysis 5 . Similarly, in the tmRNA–SmpB complex, the C-terminal helix of SmpB recognizes the empty mRNA channel and positions the tRNA-like domain of tmRNA at the PTC to enable peptidyltransfer 6 , 7 . Translation then continues on the mRNA-like domain of tmRNA, which encodes a short peptide targeting the incompletely translated nascent polypeptide chain for degradation 1 . Biochemical studies have demonstrated that ArfA represents a back-up system for tmRNA 10 , 11 . The arfA mRNA contains a stem–loop that acts as a transcription terminator as well as a substrate for RNase III cleavage 10 , 11 , 12 . In the presence of tmRNA, the short ArfA product produced from the truncated arfA mRNA is tagged by tmRNA and targeted for degradation. However, in the absence of tmRNA, the short ArfA product is not degraded and assumes the role of recycling ribosomes stalled on truncated mRNAs 10 , 11 . The full-length E. coli ArfA protein is 72 amino acids long and contains a C-terminal hydrophobic region that leads to aggregation of the protein in vivo 10 . Shorter forms of ArfA that result from truncated arfA mRNAs and lack the terminal 17–18 amino acids retain full recycling activity 10 , 11 . ArfA alone is insufficient to recycle ribosomes stalled on truncated mRNAs and requires the assistance of the canonical termination release factor RF2 to hydrolyse the peptidyl-tRNA on the ribosome 13 , 14 ( Fig. 1a–c ). A mechanistic understanding of how ArfA recognizes ribosomes stalled on truncated mRNAs, recruits RF2 and stabilizes the active conformation of RF2 has so far been hampered by the lack of an ArfA–RF2–ribosome structure. Figure 1: Cryo-EM structure of ArfA-RF2-SRC. a – c , Schematic representation of ArfA–RF2-mediated rescue of ribosomes stalled on truncated mRNA (TR-mRNA). d , Transverse section of the cryo-EM map of ArfA-RF2-SRC, highlighting the 30S (yellow) and 50S (grey) subunits, P-tRNA (green), TR-mRNA (blue), RF2 (orange) and ArfA (red). e , Electron density for ArfA, coloured according to local resolution. f , Electron density (mesh) with molecular model for ArfA (red). g , Model for ArfA with features highlighted corresponding to the schematic of the ArfA protein, including helical region (green), β-strand (blue) and KKGK (orange) and RKGK (yellow) motifs. PowerPoint slide Full size image To generate a suitable complex for structural analysis, in vitro translation reactions were performed with a truncated mRNA in the presence and absence of ArfAΔ17 (lacking residues 56–72) and/or RF2. As reported previously 13 , 14 , the presence of both ArfA and RF2 was required for efficient recycling of the peptidyl-tRNA ( Extended Data Fig. 1 ). By contrast, replacing wild-type RF2 with the catalytically inactive RF2-GAQ mutant (in which the tripeptide Gly-Gly-Gln is converted to Gly-Ala-Gln) prevented peptidyl-tRNA hydrolysis and recycling ( Extended Data Fig. 1 ), as described previously 13 . Cryo-electron microscopy (cryo-EM) analysis of the ArfAΔ17–RF2-GAQ–stalled ribosomal complex (hereafter referred to as ArfA-RF2-SRC) and in silico sorting of this dataset yielded a major subpopulation of ribosomal particles that contained stoichiometric occupancy of P-tRNA, ArfA and RF2 ( Extended Data Fig. 2 ). Subsequent refinement resulted in a final reconstruction of ArfA-RF2-SRC ( Fig. 1d ) with an average resolution of 3.1 Å ( Extended Data Fig. 3 and Extended Data Table 1 ). The electron density for most of ArfA was well-resolved with local resolution mostly within the range of 3.0 to 3.5 Å ( Fig. 1e ), enabling a molecular model to be built de novo for residues 2–46 of ArfA ( Fig. 1f,", "role": "user" }, { "content": "Ludwig Maximilian University of Munich researchers have elucidated a mechanism that recycles bacterial ribosomes stalled on messenger RNAs that lack termination codons. The protein involved provides a potential target for future antibiotics. So-called multidrug-resistant bacteria - strains that have become resistant to conventional antibiotics - pose an increasingly serious medical problem, which underlines the urgent need to develop new antibiotics that attack novel targets. \"Many of the most effective antibiotics act by inhibiting various steps in protein synthesis on bacterial ribosomes,\" as LMU biochemist Daniel Wilson points out. The search is now on for agents that interfere with aspects of the process that have so far been overlooked in this context. One of these processes is the recycling of stalled ribosomes. Wilson and his research group have just completed a comprehensive structural study of ribosome recycling. The results of the study, which appears in the leading journal Nature, may identify promising points of attack for future antibiotics. Ribosomes are the organelles that translate the nucleotide sequences encoded in messenger RNA molecules (mRNAs) into the amino-acid sequences of the corresponding proteins. The ribosome \"reads\" the nucleotide sequence in a fixed direction and is released from the mRNA only when it reaches a defined termination signal. Errors in synthesis or processing may, however, lead to the production of mRNAs that lack termination signals, causing the ribosome to stall while still attached to the mRNA and the growing protein. Cells have evolved several ways of detaching stalled ribosomes from the truncated mRNAs and recycling them for re-use. Wilson's team has now employed cryo-electron microscopy to determine the structure of the bacterial recycling factor ArfA. Their analysis reveals how ArfA recognizes the stalled ribosome on a defective mRNA and recruits a so-called release factor, which detaches the incomplete protein. This then enables the stalled ribosome to be released from the mRNA in the normal manner by dissociation into its two component subunits. The subunits are then free to interact with another mRNA, thus allowing protein synthesis to proceed. \"Our results could facilitate the development of new antibiotics that act by inhibiting ArfA-mediated ribosome recycling,\" says Wilson. Since recycling of human ribosomes is dependent on factors that are unrelated to ArfA, such inhibitors should act specifically on the bacterial ribosome, and kill the bacterial cell by gradually cutting off the supply of free ribosomes. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 bacteria, ribosomes stalled on truncated mRNAs that lack a stop codon are rescued by the transfer-messenger RNA (tmRNA), alternative rescue factor A (ArfA) or ArfB systems 1 . Although tmRNA–ribosome and ArfB–ribosome structures have been determined 2 , 3 , 4 , 5 , 6 , 7 , how ArfA recognizes the presence of truncated mRNAs and recruits the canonical termination release factor RF2 to rescue the stalled ribosomes is unclear. Here we present a cryo-electron microscopy reconstruction of the Escherichia coli 70S ribosome stalled on a truncated mRNA in the presence of ArfA and RF2. The structure shows that the C terminus of ArfA binds within the mRNA entry channel on the small ribosomal subunit, and explains how ArfA distinguishes between ribosomes that bear truncated or full-length mRNAs. The N terminus of ArfA establishes several interactions with the decoding domain of RF2, and this finding illustrates how ArfA recruits RF2 to the stalled ribosome. Furthermore, ArfA is shown to stabilize a unique conformation of the switch loop of RF2, which mimics the canonical translation termination state by directing the catalytically important GGQ motif within domain 3 of RF2 towards the peptidyl-transferase centre of the ribosome. Thus, our structure reveals not only how ArfA recruits RF2 to the ribosome but also how it promotes an active conformation of RF2 to enable translation termination in the absence of a stop codon. Main Premature transcription termination or truncation of a full-length mRNA can lead to mRNAs lacking a stop codon. Ribosomes translating these truncated mRNAs become trapped at the 3′ end of the mRNA because translation elongation or termination cannot occur. In bacteria, these stalled ribosomes are recognized and recycled by the tmRNA rescue system (reviewed in ref. 1 ). A subset of bacteria, such as E. coli , can survive without the tmRNA system owing to the presence ArfA 8 . The synthetic lethality arising from inactivation of both the tmRNA and ArfA rescue systems can be alleviated by overexpression of ArfB 9 . Collectively, these studies illustrate the physiological importance that the rescue of stalled ribosomes has for cell viability. Structural studies have revealed how ribosomes stalled on truncated mRNA are recognized and recycled by the tmRNA–SmpB complex 6 , 7 or ArfB 5 . In the case of ArfB, the empty mRNA channel of the ribosome is probed by the C-terminal helix, positioning the N-terminal catalytic GGQ-containing domain at the peptidyl-transferase centre (PTC) to trigger peptidyl-tRNA hydrolysis 5 . Similarly, in the tmRNA–SmpB complex, the C-terminal helix of SmpB recognizes the empty mRNA channel and positions the tRNA-like domain of tmRNA at the PTC to enable peptidyltransfer 6 , 7 . Translation then continues on the mRNA-like domain of tmRNA, which encodes a short peptide targeting the incompletely translated nascent polypeptide chain for degradation 1 . Biochemical studies have demonstrated that ArfA represents a back-up system for tmRNA 10 , 11 . The arfA mRNA contains a stem–loop that acts as a transcription terminator as well as a substrate for RNase III cleavage 10 , 11 , 12 . In the presence of tmRNA, the short ArfA product produced from the truncated arfA mRNA is tagged by tmRNA and targeted for degradation. However, in the absence of tmRNA, the short ArfA product is not degraded and assumes the role of recycling ribosomes stalled on truncated mRNAs 10 , 11 . The full-length E. coli ArfA protein is 72 amino acids long and contains a C-terminal hydrophobic region that leads to aggregation of the protein in vivo 10 . Shorter forms of ArfA that result from truncated arfA mRNAs and lack the terminal 17–18 amino acids retain full recycling activity 10 , 11 . ArfA alone is insufficient to recycle ribosomes stalled on truncated mRNAs and requires the assistance of the canonical termination release factor RF2 to hydrolyse the peptidyl-tRNA on the ribosome 13 , 14 ( Fig. 1a–c ). A mechanistic understanding of how ArfA recognizes ribosomes stalled on truncated mRNAs, recruits RF2 and stabilizes the active conformation of RF2 has so far been hampered by the lack of an ArfA–RF2–ribosome structure. Figure 1: Cryo-EM structure of ArfA-RF2-SRC. a – c , Schematic representation of ArfA–RF2-mediated rescue of ribosomes stalled on truncated mRNA (TR-mRNA). d , Transverse section of the cryo-EM map of ArfA-RF2-SRC, highlighting the 30S (yellow) and 50S (grey) subunits, P-tRNA (green), TR-mRNA (blue), RF2 (orange) and ArfA (red). e , Electron density for ArfA, coloured according to local resolution. f , Electron density (mesh) with molecular model for ArfA (red). g , Model for ArfA with features highlighted corresponding to the schematic of the ArfA protein, including helical region (green), β-strand (blue) and KKGK (orange) and RKGK (yellow) motifs. PowerPoint slide Full size image To generate a suitable complex for structural analysis, in vitro translation reactions were performed with a truncated mRNA in the presence and absence of ArfAΔ17 (lacking residues 56–72) and/or RF2. As reported previously 13 , 14 , the presence of both ArfA and RF2 was required for efficient recycling of the peptidyl-tRNA ( Extended Data Fig. 1 ). By contrast, replacing wild-type RF2 with the catalytically inactive RF2-GAQ mutant (in which the tripeptide Gly-Gly-Gln is converted to Gly-Ala-Gln) prevented peptidyl-tRNA hydrolysis and recycling ( Extended Data Fig. 1 ), as described previously 13 . Cryo-electron microscopy (cryo-EM) analysis of the ArfAΔ17–RF2-GAQ–stalled ribosomal complex (hereafter referred to as ArfA-RF2-SRC) and in silico sorting of this dataset yielded a major subpopulation of ribosomal particles that contained stoichiometric occupancy of P-tRNA, ArfA and RF2 ( Extended Data Fig. 2 ). Subsequent refinement resulted in a final reconstruction of ArfA-RF2-SRC ( Fig. 1d ) with an average resolution of 3.1 Å ( Extended Data Fig. 3 and Extended Data Table 1 ). The electron density for most of ArfA was well-resolved with local resolution mostly within the range of 3.0 to 3.5 Å ( Fig. 1e ), enabling a molecular model to be built de novo for residues 2–46 of ArfA ( Fig. 1f,<|im_end|> <|im_start|>assistant Ludwig Maximilian University of Munich researchers have elucidated a mechanism that recycles bacterial ribosomes stalled on messenger RNAs that lack termination codons. The protein involved provides a potential target for future antibiotics. So-called multidrug-resistant bacteria - strains that have become resistant to conventional antibiotics - pose an increasingly serious medical problem, which underlines the urgent need to develop new antibiotics that attack novel targets. "Many of the most effective antibiotics act by inhibiting various steps in protein synthesis on bacterial ribosomes," as LMU biochemist Daniel Wilson points out. The search is now on for agents that interfere with aspects of the process that have so far been overlooked in this context. One of these processes is the recycling of stalled ribosomes. Wilson and his research group have just completed a comprehensive structural study of ribosome recycling. The results of the study, which appears in the leading journal Nature, may identify promising points of attack for future antibiotics. Ribosomes are the organelles that translate the nucleotide sequences encoded in messenger RNA molecules (mRNAs) into the amino-acid sequences of the corresponding proteins. The ribosome "reads" the nucleotide sequence in a fixed direction and is released from the mRNA only when it reaches a defined termination signal. Errors in synthesis or processing may, however, lead to the production of mRNAs that lack termination signals, causing the ribosome to stall while still attached to the mRNA and the growing protein. Cells have evolved several ways of detaching stalled ribosomes from the truncated mRNAs and recycling them for re-use. Wilson's team has now employed cryo-electron microscopy to determine the structure of the bacterial recycling factor ArfA. Their analysis reveals how ArfA recognizes the stalled ribosome on a defective mRNA and recruits a so-called release factor, which detaches the incomplete protein. This then enables the stalled ribosome to be released from the mRNA in the normal manner by dissociation into its two component subunits. The subunits are then free to interact with another mRNA, thus allowing protein synthesis to proceed. "Our results could facilitate the development of new antibiotics that act by inhibiting ArfA-mediated ribosome recycling," says Wilson. Since recycling of human ribosomes is dependent on factors that are unrelated to ArfA, such inhibitors should act specifically on the bacterial ribosome, and kill the bacterial cell by gradually cutting off the supply of free ribosomes. <|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 Contagious yawning, emotional contagion and empathy are characterized by the activation of similar neurophysiological states or responses in an observed individual and an observer. For example, it is hard to keep one’s mouth closed when imagining someone yawning, or not feeling distressed while observing other individuals perceiving pain. The evolutionary origin of these widespread phenomena is unclear, since a direct benefit is not always apparent. We explore a game theoretical model for the evolution of mind-reading strategies, used to predict and respond to others’ behavior. In particular we explore the evolutionary scenarios favoring simulative strategies, which recruit overlapping neural circuits when performing as well as when observing a specific behavior. We show that these mechanisms are advantageous in complex environments, by allowing an observer to use information about its own behavior to interpret that of others. However, without inhibition of the recruited neural circuits, the observer would perform the corresponding downstream action, rather than produce the appropriate social response. We identify evolutionary trade-offs that could hinder this inhibition, leading to emotional contagion as a by-product of mind-reading. The interaction of this model with kinship is complex. We show that empathy likely evolved in a scenario where kin- and other indirect benefits co-opt strategies originally evolved for mind-reading, and that this model explains observed patterns of emotional contagion with kin or group members. Introduction Learning enables organisms to adapt flexibly to their environment without waiting for natural selection to take its long and arduous route. However, the more complex the environment, the slower the adaptive gain from either learning or evolution. One of the most complex and relevant environments that organisms encounter is the social milieu. Here individuals are presented with a multitude of other individuals, each with a complex adaptive responses. Predicting these “black boxes”, a process called mind-reading 1 , is hard. Thus accurate social predictions would require a long adaptive process, requiring accurate information about each perceived stimulus and the possible responses. Luckily a shortcut is available: the organism holds an almost identical copy of the “black box” - its own decision making apparatus or neural circuitry, which can be used to extrapolate inferences concerning others’ behavior. Information acquired over evolutionary time and information acquired through individual learning can thus be used to speed up adaptation to social encounters 2 . Since the discovery of mirror neurons 3 , 4 , a large number of neurophysiological studies have shown that similar brain regions are activated when observing and when performing a specific action, or perceiving a given emotional or sensory stimulus 4 , 5 , 6 , 7 , 8 . These mirroring phenomena supported the view that an observer can decipher an actor ’s actions and states through at least a partial simulation of those same neural circuits and internal states elicited as an actor, in what de Waal termed “perception-action mechanisms” PAMs 9 , 10 . Neuroscientists proposed that these brain regions, activated both as observers or as actors , possibly underlie “shared representations” of the perceived stimuli and actions 11 . For an observer, a potential advantage of activating the as-actor neural configuration is to have access to information about one’s own sensory and motor programs. In the social context this information might help to interpret social cues and infer an observed actor’s actions or intentions 12 , allowing to solve the complex “black box” problem. We adopt here the term “simulation” to indicate any mind-reading strategy that relies on self-information experienced as an actor, rather than information acquired via observation of others 10 . Simulative strategies face possible disadvantages and computational obstacles: the secondary activation of as-actor neural circuits during observation has to be discriminated precisely from primary activations of the same circuits when performing the corresponding action oneself. Otherwise, the partial activation of neural configuration which are usually used in the as-actor context may prime the corresponding autonomic and somatic responses, and unless properly inhibited would then evoke in the observer the responses of an actor 4 , 9 , 13 . We define these events in which a simulative observer performs the same action as an observed actor as accidental coordination ( C ; Fig. 1a–d ). A pathological lack of inhibition results in compulsive imitation, as in echopraxia and echolalia, the involuntary repetition of others’ actions or language 14 , respectively. In specific situations, accidental coordination can be advantageous. However in the context of mind-reading and social interactions, individuals are often characterized by different states or competing motivations, thus for an observer it is generally not advantageous to copy blindly the action of an observed actor. The potential cost of accidental coordination is two-folded: first, it hinders the observer from performing the most appropriate response to an actor’s behavior; second, it might imply further specific costs: for instance, contagious distress 15 , 16 can interfere with an optimal decision making, and potentially lead to costly actions, such as alarm calls or aggressive behavior (Fig. 1c ). A well documented example, in which the first inherent cost is apparent, is motor interference , in which the observation of a movement impairs the performance of an incongruent movement in the observer 13 . For this reason, the inhibition of accidental coordination is likely shaped by natural selection, and of primary importance in mind-reading and mirroring processes 14 , 17 . Figure 1 Cognitive circuits connecting stimuli ( s ∈ S ), actions ( a ∈ A ) and their representations ( \$\\hat{s}\\in \\hat{S}\$ and â ∈ Â ), for a contagious distress example. An actor (in red) perceives a dangerous stimulus ( s + i e.g. a social interaction with an aggressive individual, in gray) and associates (thick arrow) its representation \${\\hat{s}}_{+i}\$ to a neural circuit underlying a fight-or-flight response \${\\hat{a}}_{+i}\$ , in turn responding aggressively and defending itself (action a + i , B ). ( b – d ) An observer (in blue) perceives ( a ) as a social stimulus s − i and can perform an appropriate response", "role": "user" }, { "content": "Researchers at the Max Planck Institute and the Santa Fe Institute have developed a new model to explain the evolutionary origins of empathy and other related phenomena, such as emotional contagion and contagious yawning. The model suggests that the origin of a broad range of empathetic responses lies in cognitive simulation. It shifts the theoretical focus from a top-down approach that begins with cooperation to one that begins with a single cognitive mechanism. According to Fabrizio Mafessoni, who is a post-doctoral researcher at the Max Planck Institute for Evolutionary Anthropology, standard theoretical models of the origins of empathy tend to focus on scenarios in which coordination or cooperation are favored. Mafessoni, and his co-author Michael Lachmann, a theoretical biologist and Professor at the Santa Fe Institute, explored the possibility that the cognitive processes underlying a broad range of empathetic responses—including emotional contagion, contagious yawning, and pathologies like echopraxia (compulsive repetition of others' movements) and echolalia (compulsive repetition of others' speech)—could evolve in the absence of kin selection or any other mechanism directly favoring cooperation or coordination. Mafessoni and Lachmann posited that animals, including humans, can engage in the act of simulating the minds of others. We cannot read other minds—they are like black boxes to us. But, as Lachmann explains, all agents share almost identical \"black boxes\" with members of their species, and \"they are constantly running simulations of what other minds might be doing.\" This ongoing as-actor simulation is not necessarily geared toward cooperation: it's just something humans and animals do spontaneously. An example of this process is represented by mirror neurons: it has been known for some time that the same neurons engaged in planning a hand movement are also used when observing the hand movement of others. Mafessoni and Lachmann wondered what the consequences would be if they were to extend that process of understanding to any social interaction. When they modeled outcomes rooted in cognitive simulation, they found that actors engaged in as-actor simulation produce a variety of systems typically explained in terms of cooperation or kin-selection. They also found that an observer can occasionally coordinate with an actor even when this outcome is not advantageous. Their model suggests that empathetic systems do not evolve solely because agents are disposed to cooperation and kin-selection. They also evolve because animals simulate others to envision their actions. According to Mafessoni, \"the very origin of empathy may lie in the need to understand other individuals.\" For Lachmann, their findings \"completely change how we think about humans and animals.\" Their model is grounded in a single, cognitive mechanism that unifies a broad set of phenomena under one explanation. It therefore has theoretical import for a wide range of fields, including cognitive psychology, anthropology, neuroscience, complex systems, and evolutionary biology. Its power stems from both its unifying clarity and its theoretical interest in the limits of cooperation as an explanatory frame. The study 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 Contagious yawning, emotional contagion and empathy are characterized by the activation of similar neurophysiological states or responses in an observed individual and an observer. For example, it is hard to keep one’s mouth closed when imagining someone yawning, or not feeling distressed while observing other individuals perceiving pain. The evolutionary origin of these widespread phenomena is unclear, since a direct benefit is not always apparent. We explore a game theoretical model for the evolution of mind-reading strategies, used to predict and respond to others’ behavior. In particular we explore the evolutionary scenarios favoring simulative strategies, which recruit overlapping neural circuits when performing as well as when observing a specific behavior. We show that these mechanisms are advantageous in complex environments, by allowing an observer to use information about its own behavior to interpret that of others. However, without inhibition of the recruited neural circuits, the observer would perform the corresponding downstream action, rather than produce the appropriate social response. We identify evolutionary trade-offs that could hinder this inhibition, leading to emotional contagion as a by-product of mind-reading. The interaction of this model with kinship is complex. We show that empathy likely evolved in a scenario where kin- and other indirect benefits co-opt strategies originally evolved for mind-reading, and that this model explains observed patterns of emotional contagion with kin or group members. Introduction Learning enables organisms to adapt flexibly to their environment without waiting for natural selection to take its long and arduous route. However, the more complex the environment, the slower the adaptive gain from either learning or evolution. One of the most complex and relevant environments that organisms encounter is the social milieu. Here individuals are presented with a multitude of other individuals, each with a complex adaptive responses. Predicting these “black boxes”, a process called mind-reading 1 , is hard. Thus accurate social predictions would require a long adaptive process, requiring accurate information about each perceived stimulus and the possible responses. Luckily a shortcut is available: the organism holds an almost identical copy of the “black box” - its own decision making apparatus or neural circuitry, which can be used to extrapolate inferences concerning others’ behavior. Information acquired over evolutionary time and information acquired through individual learning can thus be used to speed up adaptation to social encounters 2 . Since the discovery of mirror neurons 3 , 4 , a large number of neurophysiological studies have shown that similar brain regions are activated when observing and when performing a specific action, or perceiving a given emotional or sensory stimulus 4 , 5 , 6 , 7 , 8 . These mirroring phenomena supported the view that an observer can decipher an actor ’s actions and states through at least a partial simulation of those same neural circuits and internal states elicited as an actor, in what de Waal termed “perception-action mechanisms” PAMs 9 , 10 . Neuroscientists proposed that these brain regions, activated both as observers or as actors , possibly underlie “shared representations” of the perceived stimuli and actions 11 . For an observer, a potential advantage of activating the as-actor neural configuration is to have access to information about one’s own sensory and motor programs. In the social context this information might help to interpret social cues and infer an observed actor’s actions or intentions 12 , allowing to solve the complex “black box” problem. We adopt here the term “simulation” to indicate any mind-reading strategy that relies on self-information experienced as an actor, rather than information acquired via observation of others 10 . Simulative strategies face possible disadvantages and computational obstacles: the secondary activation of as-actor neural circuits during observation has to be discriminated precisely from primary activations of the same circuits when performing the corresponding action oneself. Otherwise, the partial activation of neural configuration which are usually used in the as-actor context may prime the corresponding autonomic and somatic responses, and unless properly inhibited would then evoke in the observer the responses of an actor 4 , 9 , 13 . We define these events in which a simulative observer performs the same action as an observed actor as accidental coordination ( C ; Fig. 1a–d ). A pathological lack of inhibition results in compulsive imitation, as in echopraxia and echolalia, the involuntary repetition of others’ actions or language 14 , respectively. In specific situations, accidental coordination can be advantageous. However in the context of mind-reading and social interactions, individuals are often characterized by different states or competing motivations, thus for an observer it is generally not advantageous to copy blindly the action of an observed actor. The potential cost of accidental coordination is two-folded: first, it hinders the observer from performing the most appropriate response to an actor’s behavior; second, it might imply further specific costs: for instance, contagious distress 15 , 16 can interfere with an optimal decision making, and potentially lead to costly actions, such as alarm calls or aggressive behavior (Fig. 1c ). A well documented example, in which the first inherent cost is apparent, is motor interference , in which the observation of a movement impairs the performance of an incongruent movement in the observer 13 . For this reason, the inhibition of accidental coordination is likely shaped by natural selection, and of primary importance in mind-reading and mirroring processes 14 , 17 . Figure 1 Cognitive circuits connecting stimuli ( s ∈ S ), actions ( a ∈ A ) and their representations ( $\hat{s}\in \hat{S}$ and â ∈ Â ), for a contagious distress example. An actor (in red) perceives a dangerous stimulus ( s + i e.g. a social interaction with an aggressive individual, in gray) and associates (thick arrow) its representation ${\hat{s}}_{+i}$ to a neural circuit underlying a fight-or-flight response ${\hat{a}}_{+i}$ , in turn responding aggressively and defending itself (action a + i , B ). ( b – d ) An observer (in blue) perceives ( a ) as a social stimulus s − i and can perform an appropriate response<|im_end|> <|im_start|>assistant Researchers at the Max Planck Institute and the Santa Fe Institute have developed a new model to explain the evolutionary origins of empathy and other related phenomena, such as emotional contagion and contagious yawning. The model suggests that the origin of a broad range of empathetic responses lies in cognitive simulation. It shifts the theoretical focus from a top-down approach that begins with cooperation to one that begins with a single cognitive mechanism. According to Fabrizio Mafessoni, who is a post-doctoral researcher at the Max Planck Institute for Evolutionary Anthropology, standard theoretical models of the origins of empathy tend to focus on scenarios in which coordination or cooperation are favored. Mafessoni, and his co-author Michael Lachmann, a theoretical biologist and Professor at the Santa Fe Institute, explored the possibility that the cognitive processes underlying a broad range of empathetic responses—including emotional contagion, contagious yawning, and pathologies like echopraxia (compulsive repetition of others' movements) and echolalia (compulsive repetition of others' speech)—could evolve in the absence of kin selection or any other mechanism directly favoring cooperation or coordination. Mafessoni and Lachmann posited that animals, including humans, can engage in the act of simulating the minds of others. We cannot read other minds—they are like black boxes to us. But, as Lachmann explains, all agents share almost identical "black boxes" with members of their species, and "they are constantly running simulations of what other minds might be doing." This ongoing as-actor simulation is not necessarily geared toward cooperation: it's just something humans and animals do spontaneously. An example of this process is represented by mirror neurons: it has been known for some time that the same neurons engaged in planning a hand movement are also used when observing the hand movement of others. Mafessoni and Lachmann wondered what the consequences would be if they were to extend that process of understanding to any social interaction. When they modeled outcomes rooted in cognitive simulation, they found that actors engaged in as-actor simulation produce a variety of systems typically explained in terms of cooperation or kin-selection. They also found that an observer can occasionally coordinate with an actor even when this outcome is not advantageous. Their model suggests that empathetic systems do not evolve solely because agents are disposed to cooperation and kin-selection. They also evolve because animals simulate others to envision their actions. According to Mafessoni, "the very origin of empathy may lie in the need to understand other individuals." For Lachmann, their findings "completely change how we think about humans and animals." Their model is grounded in a single, cognitive mechanism that unifies a broad set of phenomena under one explanation. It therefore has theoretical import for a wide range of fields, including cognitive psychology, anthropology, neuroscience, complex systems, and evolutionary biology. Its power stems from both its unifying clarity and its theoretical interest in the limits of cooperation as an explanatory frame. The study is published in Scientific Reports. <|im_end|>

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11, 304, 902, 279, 1176, 38088, 2853, 374, 10186, 11, 374, 9048, 32317, 1174, 304, 902, 279, 22695, 315, 264, 7351, 3242, 4825, 279, 5178, 315, 459, 28093, 911, 11942, 7351, 304, 279, 22842, 220, 1032, 662, 1789, 420, 2944, 11, 279, 61478, 315, 50016, 38793, 374, 4461, 27367, 555, 5933, 6727, 11, 323, 315, 6156, 12939, 304, 4059, 12, 6285, 323, 8822, 90679, 11618, 220, 975, 1174, 220, 1114, 662, 19575, 220, 16, 73235, 46121, 21583, 56688, 320, 274, 49435, 328, 7026, 6299, 320, 264, 49435, 362, 883, 323, 872, 44713, 320, 1144, 11781, 9379, 85486, 11281, 258, 1144, 9379, 90, 50, 11281, 8, 323, 29005, 49435, 46433, 7026, 369, 264, 89534, 35104, 3187, 13, 1556, 12360, 320, 258, 2579, 8, 62822, 1924, 264, 11660, 39535, 320, 274, 489, 602, 384, 1326, 13, 264, 3674, 16628, 449, 459, 19738, 3927, 11, 304, 18004, 8, 323, 40531, 320, 339, 875, 18404, 8, 1202, 13340, 1144, 2358, 59, 9379, 85486, 3500, 15511, 10, 72, 11281, 8, 311, 264, 30828, 16622, 16940, 264, 4465, 27609, 77303, 2077, 1144, 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1,894

[ { "content": "You are a great 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 Altered intestinal microbiota composition in later life is associated with inflammaging, declining tissue function, and increased susceptibility to age-associated chronic diseases, including neurodegenerative dementias. Here, we tested the hypothesis that manipulating the intestinal microbiota influences the development of major comorbidities associated with aging and, in particular, inflammation affecting the brain and retina. Methods Using fecal microbiota transplantation, we exchanged the intestinal microbiota of young (3 months), old (18 months), and aged (24 months) mice. Whole metagenomic shotgun sequencing and metabolomics were used to develop a custom analysis workflow, to analyze the changes in gut microbiota composition and metabolic potential. Effects of age and microbiota transfer on the gut barrier, retina, and brain were assessed using protein assays, immunohistology, and behavioral testing. Results We show that microbiota composition profiles and key species enriched in young or aged mice are successfully transferred by FMT between young and aged mice and that FMT modulates resulting metabolic pathway profiles. The transfer of aged donor microbiota into young mice accelerates age-associated central nervous system (CNS) inflammation, retinal inflammation, and cytokine signaling and promotes loss of key functional protein in the eye, effects which are coincident with increased intestinal barrier permeability. Conversely, these detrimental effects can be reversed by the transfer of young donor microbiota. Conclusions These findings demonstrate that the aging gut microbiota drives detrimental changes in the gut–brain and gut–retina axes suggesting that microbial modulation may be of therapeutic benefit in preventing inflammation-related tissue decline in later life. { \"name\": \"40168_2022_1243_MOESM1_ESM.mp4\", \"description\": \"40168_2022_1243_MOESM1_ESM.mp4\", \"thumbnailUrl\": \" \"uploadDate\": \"2022-03-14T22:01:51.000+0000\", \"contentUrl\": \" \"duration\": \"PT1M42.16S\", \"@context\": \" \"@type\": \"VideoObject\" } Video abstract Graphical abstract Background Aging is characterized by declining cell, tissue, and organ function and increasing susceptibility to chronic and debilitating diseases. Particularly vulnerable are tissues of the central nervous system (CNS) and the eye, which have high sensitivity to metabolic dysregulation, and the gastrointestinal (GI) epithelial barrier, which must maintain rapid cellular turnover and barrier integrity while faced with constant exposure to environmental insults [ 14 , 85 ]. Comprising bacteria, viruses, fungi, protozoa, and archaea, the intestinal microbiota contributes to the life-long health of the host, playing key roles in the development and maintenance of the host immune system and the intestinal epithelial barrier [ 111 ]. During aging, the intestinal microbiota undergoes changes in the community structure and function, with samples from elderly individuals showing changes in the proportions of different taxa, increased inter-individual variability, and altered diversity. These changes can adversely affect the host metabolism and immunity [ 25 , 26 , 27 , 40 , 64 , 86 , 110 , 112 , 118 ] and are associated with the development of cardiovascular, autoimmune, metabolic, and neurodegenerative disorders [ 17 , 90 , 122 , 132 ]. Microbiota transfer studies in fly and fish models of aging suggest a direct role of the microbiota in regulating lifespan and age-associated disease pathogenesis. Young flies fed homogenates from aged flies had significantly decreased lifespan and increased incidence of intestinal barrier dysfunction, compared with flies fed homogenates from young animals [ 27 ]. In the short-lived African killifish, the transfer of young donor microbiota to aged individuals ameliorated behavioral decline and extended lifespan [ 110 ]. Similar beneficial effects have been reported in aged mice receiving microbiota from young mice to extend life span [ 8 , 61 ] or halt the functional decline in the mucosal immune system [ 112 ]. One of the major organ systems adversely affected by aging and inflammaging is the brain, with various lines of investigation providing evidence for a “microbiota–gut–brain axis” via which gut microbes can influence brain health via various mechanisms. These include complex and interlinked hormonal signaling, immune signaling, and neural signaling networks in the host, which can be modulated by gut microbial products and which can in turn modify the gut microbiota composition and function [ 90 ]. Sequencing studies showing associations between particular gut microbiota profiles and various diseases in humans, along with studies modifying the gut bacterial composition in animal models, by probiotic administration or microbiota transfer, implicate the gut microbiota as a key regulator of systemic homeostasis, including neuroinflammation and behavioral disorders [ 16 , 106 ]. One possible scenario is that changes in the gut microbiota composition or function trigger or, contribute to, the decline of normal gut epithelial barrier function, which in turn drives systemic chronic inflammation that has detrimental effects on various tissues around the body. In aging, detrimental changes in the diversity, composition, or function of the gut microbiota could therefore promote neuroinflammation and functional decline in the CNS. In the aged GI tract, compromised epithelial and mucosal cell turnover, integrity, and function [ 32 , 36 , 76 , 83 ] can lead to increased epithelial barrier permeability [ 19 , 75 , 118 , 120 ], with the increased possibility of luminal microbial and dietary antigens gaining access to the circulation. This, together with declining immune cell function and immunosenescence, promotes a state of elevated systemic inflammation termed “inflammaging” [ 39 , 40 , 118 ], contributing to the functional decline in the intestine and CNS in old age [ 10 , 13 , 48 ]. In the brain, microglial cells play multiple roles in regulating inflammatory responses and neural functioning and are now considered central to the pathology of neurodegenerative diseases [ 48 ]. Studies using germ-free mice, antibiotic treatment, and selective microbial colonization suggest that the intestinal microbiota can regulate microglial maturation and function in the enteric and central nervous systems [ 37 , 54 ]. Attenuation of pathology following microbial modulation, in transgenic mouse models of Alzheimer’s disease [ 57 , 115 ], also supports a role for the microbiota in inflammaging in the brain. As an extension of the CNS, the eye is exposed to multiple stressors, including oxidative stress-inducing UV light and age-related immune dysregulation, and is vulnerable to energy insufficiency resulting from altered circulation and metabolism in old age [ 72 ]. With advancing age, the outer retina", "role": "user" }, { "content": "In the search for eternal youth, poo transplants may seem like an unlikely way to reverse the aging process. However, scientists at the Quadram Institute and the University of East Anglia have provided evidence, from research in mice, that transplanting fecal microbiota from young into old mice can reverse hallmarks of aging in the gut, eyes, and brain. In the reverse experiment, microbes from aged mice induced inflammation in the brain of young recipients and depleted a key protein required for normal vision. These findings show that gut microbes play a role in the regulating some of the detrimental effects of aging and open up the possibility of gut microbe-based therapies to combat decline in later life. Prof Simon Carding, from UEA's Norwich Medical School and head of the Gut Microbes and Health Research Program at the Quadram Institute, said: \"This ground-breaking study provides tantalizing evidence for the direct involvement of gut microbes in aging and the functional decline of brain function and vision and offers a potential solution in the form of gut microbe replacement therapy.\" It has been known for some time that the population of microbes that we carry around in our gut, collectively called the gut microbiota, is linked to health. Most diseases are associated with changes in the types and behavior of bacteria, viruses, fungi and other microbes in an individual's gut. Some of these changes in microbiota composition happen as we age, adversely affecting metabolism and immunity, and this has been associated with age-related disorders including inflammatory bowel diseases, along with cardiovascular, autoimmune, metabolic and neurodegenerative disorders. To better understand the effects of these changes in the microbiota in old age, scientists from the Quadram Institute transferred the gut microbes from aged mice into healthy young mice, and vice versa. They then looked at how this affected inflammatory hallmarks of aging in the gut, brain and eye, which suffer from declining function in later life. The study, published in the journal Microbiome, found that the microbiota from old donors led to loss of integrity of the lining of the gut, allowing bacterial products to cross into the circulation, which results in triggering the immune system and inflammation in the brain and eyes. Age-related chronic inflammation, known as inflammaging, has been associated with the activation of specific immune cells found in brain. These cells were also over-activated in the young mice who received aged microbiome transplants. In the eye, the team also found specific proteins associated with retinal degeneration were elevated in the young mice receiving microbiota from old donors. In old mice, these detrimental changes in the gut, eye and brain could be reversed by transplanting the gut microbiota from young mice. In ongoing studies, the team are now working to understand how long these positive effects can last, and to identify the beneficial components of the young donor microbiota and how they impact on organs distant from the gut. The microbiota of young mice, and the old mice who received young microbiota transplants were enriched in beneficial bacteria that have previously been associated with good health in both mice and humans. The researchers have also analyzed the products which these bacteria produce by breaking down elements of our diet. This has uncovered significant shifts in particular lipids (fats) and vitamin metabolism, which may be linked to the changes seen in inflammatory cells in the eye and brain. Similar pathways exist in humans, and the human gut microbiota also changes significantly in later life, but the researchers caution about extrapolating their results directly to humans until similar studies in elderly humans can be performed. A new facility for Microbiota Replacement Therapy (MRT), also known as Fecal Microbiota Transplantation (FMT) is being built in the Quadram Institute that will facilitate such trials, as well as other trials for microbiota-related conditions. Lead author of the study, Dr. Aimee Parker from the Quadram Institute said: \"We were excited to find that by changing the gut microbiota of elderly individuals, we could rescue indicators of age-associated decline commonly seen in degenerative conditions of the eye and brain. \"Our results provide more evidence of the important links between microbes in the gut and healthy aging of tissues and organs around the body. We hope that our findings will contribute ultimately to understanding how we can manipulate our diet and our gut bacteria to maximize good health in later life.\" \"Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain\" is published in the journal Microbiome. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 Altered intestinal microbiota composition in later life is associated with inflammaging, declining tissue function, and increased susceptibility to age-associated chronic diseases, including neurodegenerative dementias. Here, we tested the hypothesis that manipulating the intestinal microbiota influences the development of major comorbidities associated with aging and, in particular, inflammation affecting the brain and retina. Methods Using fecal microbiota transplantation, we exchanged the intestinal microbiota of young (3 months), old (18 months), and aged (24 months) mice. Whole metagenomic shotgun sequencing and metabolomics were used to develop a custom analysis workflow, to analyze the changes in gut microbiota composition and metabolic potential. Effects of age and microbiota transfer on the gut barrier, retina, and brain were assessed using protein assays, immunohistology, and behavioral testing. Results We show that microbiota composition profiles and key species enriched in young or aged mice are successfully transferred by FMT between young and aged mice and that FMT modulates resulting metabolic pathway profiles. The transfer of aged donor microbiota into young mice accelerates age-associated central nervous system (CNS) inflammation, retinal inflammation, and cytokine signaling and promotes loss of key functional protein in the eye, effects which are coincident with increased intestinal barrier permeability. Conversely, these detrimental effects can be reversed by the transfer of young donor microbiota. Conclusions These findings demonstrate that the aging gut microbiota drives detrimental changes in the gut–brain and gut–retina axes suggesting that microbial modulation may be of therapeutic benefit in preventing inflammation-related tissue decline in later life. { "name": "40168_2022_1243_MOESM1_ESM.mp4", "description": "40168_2022_1243_MOESM1_ESM.mp4", "thumbnailUrl": " "uploadDate": "2022-03-14T22:01:51.000+0000", "contentUrl": " "duration": "PT1M42.16S", "@context": " "@type": "VideoObject" } Video abstract Graphical abstract Background Aging is characterized by declining cell, tissue, and organ function and increasing susceptibility to chronic and debilitating diseases. Particularly vulnerable are tissues of the central nervous system (CNS) and the eye, which have high sensitivity to metabolic dysregulation, and the gastrointestinal (GI) epithelial barrier, which must maintain rapid cellular turnover and barrier integrity while faced with constant exposure to environmental insults [ 14 , 85 ]. Comprising bacteria, viruses, fungi, protozoa, and archaea, the intestinal microbiota contributes to the life-long health of the host, playing key roles in the development and maintenance of the host immune system and the intestinal epithelial barrier [ 111 ]. During aging, the intestinal microbiota undergoes changes in the community structure and function, with samples from elderly individuals showing changes in the proportions of different taxa, increased inter-individual variability, and altered diversity. These changes can adversely affect the host metabolism and immunity [ 25 , 26 , 27 , 40 , 64 , 86 , 110 , 112 , 118 ] and are associated with the development of cardiovascular, autoimmune, metabolic, and neurodegenerative disorders [ 17 , 90 , 122 , 132 ]. Microbiota transfer studies in fly and fish models of aging suggest a direct role of the microbiota in regulating lifespan and age-associated disease pathogenesis. Young flies fed homogenates from aged flies had significantly decreased lifespan and increased incidence of intestinal barrier dysfunction, compared with flies fed homogenates from young animals [ 27 ]. In the short-lived African killifish, the transfer of young donor microbiota to aged individuals ameliorated behavioral decline and extended lifespan [ 110 ]. Similar beneficial effects have been reported in aged mice receiving microbiota from young mice to extend life span [ 8 , 61 ] or halt the functional decline in the mucosal immune system [ 112 ]. One of the major organ systems adversely affected by aging and inflammaging is the brain, with various lines of investigation providing evidence for a “microbiota–gut–brain axis” via which gut microbes can influence brain health via various mechanisms. These include complex and interlinked hormonal signaling, immune signaling, and neural signaling networks in the host, which can be modulated by gut microbial products and which can in turn modify the gut microbiota composition and function [ 90 ]. Sequencing studies showing associations between particular gut microbiota profiles and various diseases in humans, along with studies modifying the gut bacterial composition in animal models, by probiotic administration or microbiota transfer, implicate the gut microbiota as a key regulator of systemic homeostasis, including neuroinflammation and behavioral disorders [ 16 , 106 ]. One possible scenario is that changes in the gut microbiota composition or function trigger or, contribute to, the decline of normal gut epithelial barrier function, which in turn drives systemic chronic inflammation that has detrimental effects on various tissues around the body. In aging, detrimental changes in the diversity, composition, or function of the gut microbiota could therefore promote neuroinflammation and functional decline in the CNS. In the aged GI tract, compromised epithelial and mucosal cell turnover, integrity, and function [ 32 , 36 , 76 , 83 ] can lead to increased epithelial barrier permeability [ 19 , 75 , 118 , 120 ], with the increased possibility of luminal microbial and dietary antigens gaining access to the circulation. This, together with declining immune cell function and immunosenescence, promotes a state of elevated systemic inflammation termed “inflammaging” [ 39 , 40 , 118 ], contributing to the functional decline in the intestine and CNS in old age [ 10 , 13 , 48 ]. In the brain, microglial cells play multiple roles in regulating inflammatory responses and neural functioning and are now considered central to the pathology of neurodegenerative diseases [ 48 ]. Studies using germ-free mice, antibiotic treatment, and selective microbial colonization suggest that the intestinal microbiota can regulate microglial maturation and function in the enteric and central nervous systems [ 37 , 54 ]. Attenuation of pathology following microbial modulation, in transgenic mouse models of Alzheimer’s disease [ 57 , 115 ], also supports a role for the microbiota in inflammaging in the brain. As an extension of the CNS, the eye is exposed to multiple stressors, including oxidative stress-inducing UV light and age-related immune dysregulation, and is vulnerable to energy insufficiency resulting from altered circulation and metabolism in old age [ 72 ]. With advancing age, the outer retina<|im_end|> <|im_start|>assistant In the search for eternal youth, poo transplants may seem like an unlikely way to reverse the aging process. However, scientists at the Quadram Institute and the University of East Anglia have provided evidence, from research in mice, that transplanting fecal microbiota from young into old mice can reverse hallmarks of aging in the gut, eyes, and brain. In the reverse experiment, microbes from aged mice induced inflammation in the brain of young recipients and depleted a key protein required for normal vision. These findings show that gut microbes play a role in the regulating some of the detrimental effects of aging and open up the possibility of gut microbe-based therapies to combat decline in later life. Prof Simon Carding, from UEA's Norwich Medical School and head of the Gut Microbes and Health Research Program at the Quadram Institute, said: "This ground-breaking study provides tantalizing evidence for the direct involvement of gut microbes in aging and the functional decline of brain function and vision and offers a potential solution in the form of gut microbe replacement therapy." It has been known for some time that the population of microbes that we carry around in our gut, collectively called the gut microbiota, is linked to health. Most diseases are associated with changes in the types and behavior of bacteria, viruses, fungi and other microbes in an individual's gut. Some of these changes in microbiota composition happen as we age, adversely affecting metabolism and immunity, and this has been associated with age-related disorders including inflammatory bowel diseases, along with cardiovascular, autoimmune, metabolic and neurodegenerative disorders. To better understand the effects of these changes in the microbiota in old age, scientists from the Quadram Institute transferred the gut microbes from aged mice into healthy young mice, and vice versa. They then looked at how this affected inflammatory hallmarks of aging in the gut, brain and eye, which suffer from declining function in later life. The study, published in the journal Microbiome, found that the microbiota from old donors led to loss of integrity of the lining of the gut, allowing bacterial products to cross into the circulation, which results in triggering the immune system and inflammation in the brain and eyes. Age-related chronic inflammation, known as inflammaging, has been associated with the activation of specific immune cells found in brain. These cells were also over-activated in the young mice who received aged microbiome transplants. In the eye, the team also found specific proteins associated with retinal degeneration were elevated in the young mice receiving microbiota from old donors. In old mice, these detrimental changes in the gut, eye and brain could be reversed by transplanting the gut microbiota from young mice. In ongoing studies, the team are now working to understand how long these positive effects can last, and to identify the beneficial components of the young donor microbiota and how they impact on organs distant from the gut. The microbiota of young mice, and the old mice who received young microbiota transplants were enriched in beneficial bacteria that have previously been associated with good health in both mice and humans. The researchers have also analyzed the products which these bacteria produce by breaking down elements of our diet. This has uncovered significant shifts in particular lipids (fats) and vitamin metabolism, which may be linked to the changes seen in inflammatory cells in the eye and brain. Similar pathways exist in humans, and the human gut microbiota also changes significantly in later life, but the researchers caution about extrapolating their results directly to humans until similar studies in elderly humans can be performed. A new facility for Microbiota Replacement Therapy (MRT), also known as Fecal Microbiota Transplantation (FMT) is being built in the Quadram Institute that will facilitate such trials, as well as other trials for microbiota-related conditions. Lead author of the study, Dr. Aimee Parker from the Quadram Institute said: "We were excited to find that by changing the gut microbiota of elderly individuals, we could rescue indicators of age-associated decline commonly seen in degenerative conditions of the eye and brain. "Our results provide more evidence of the important links between microbes in the gut and healthy aging of tissues and organs around the body. We hope that our findings will contribute ultimately to understanding how we can manipulate our diet and our gut bacteria to maximize good health in later life." "Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain" is published in the journal Microbiome. <|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 Multiplexed imaging technologies enable the study of biological tissues at single-cell resolution while preserving spatial information. Currently, high-dimension imaging data analysis is technology-specific and requires multiple tools, restricting analytical scalability and result reproducibility. Here we present SIMPLI (Single-cell Identification from MultiPLexed Images), a flexible and technology-agnostic software that unifies all steps of multiplexed imaging data analysis. After raw image processing, SIMPLI performs a spatially resolved, single-cell analysis of the tissue slide as well as cell-independent quantifications of marker expression to investigate features undetectable at the cell level. SIMPLI is highly customisable and can run on desktop computers as well as high-performance computing environments, enabling workflow parallelisation for large datasets. SIMPLI produces multiple tabular and graphical outputs at each step of the analysis. Its containerised implementation and minimum configuration requirements make SIMPLI a portable and reproducible solution for multiplexed imaging data analysis. Software is available at “SIMPLI [ ]”. Introduction A detailed investigation of tissue composition and function in health and disease requires spatially resolved, single-cell approaches that precisely quantify cell types and states as well as their interactions in situ. Recent technological advances have enabled to stain histological sections with multiple tagged antibodies that are subsequently detected using fluorescence microscopy or mass spectrometry 1 . High-dimensional imaging approaches such as imaging mass cytometry (IMC) 2 , multiplexed ion beam imaging (MIBI) 3 , co-detection by indexing (CODEX) 4 , multiplexed immunofluorescence (mIF, including cycIF) 5 and multiplexed immunohistochemistry (mIHC) 6 , 7 enable quantification and localisation of cells in sections from formalin-fixed paraffin-embedded (FFPE) tissues, including clinical diagnostic samples. This is of particular value for mapping the tissue-level characteristics of disease conditions and predicting the outcome of therapies that depend on the tissue environment, such as cancer immunotherapy. For example, a recent IMC phenotypic screen of breast cancer subtypes revealed the association between the heterogeneity of somatic mutations and that of the tumour microenvironment 8 . Similarly, a CODEX-based profile of FFPE tissue microarrays from high-risk colorectal cancer patients correlated PD1 + CD4 + T cells with patient survival 9 . The analysis of multiplexed images requires the conversion of pixel intensity data into single-cell data, which can then be characterised phenotypically, quantified comparatively and localised spatially in the tissue. Currently available tools are technology specific and cover only some steps of the whole analytical workflow (Table 1 ). For example, several computational approaches have been developed to process raw images and extract single-cell data either interactively (Ilastik 10 , CellProfiler4 11 , CODEX Toolkit 4 ) or via command line (imcyto 12 , ImcSegmentationPipeline 13 ). Distinct sets of tools can then perform cell phenotyping (CellProfiler Analyst 14 , Cytomapper 15 , Immunocluster 16 ) or analyse cell–cell spatial interactions (CytoMap 17 , ImaCytE 18 , SPIAT 19 , neighbouRhood 20 ). Similarly, a few tools enable direct pixel-based analysis through pixel classification 10 or quantification of pixel positive areas 11 . Despite such a variety of tools, none of them can perform all of the required analytical steps in a common pipeline. Two exceptions are histoCAT++ 21 and QuPath 22 , which however have been developed specifically for interactive use and are not well suited for the analysis of large datasets. Moreover, all of these tools rely on ad hoc configuration files and input formats, making the analysis challenging for users with limited computational skills and restricting the scalability, portability and reproducibility in different computing environments. Table 1 Features of representative tools for the analysis of multiplexed imaging data. Full size table Here we introduce SIMPLI (Single-cell Identification from MultiPLexed Images), a tool that combines processing of raw images, extraction of single-cell data, and spatially resolved quantification of cell types or functional states into a single pipeline (Table 1 ). This is achieved through the integration of well-established tools and newly developed scripts into the same workflow, enabling ad hoc configurations of the analysis while ensuring interoperability between its different parts. SIMPLI can be run on desktop computers as well as on high-performance-computing environments, where it can be easily applied to large datasets due to automatic workflow parallelisation. To demonstrate the flexibility of SIMPLI to work with different technologies and experimental conditions, we analyse the phenotypes and spatial distribution of cells in different tissues (human colon, appendix, colorectal cancer) using multiplexed images obtained with distinct technologies (IMC, mIF, CODEX). Results Overview of the SIMPLI analytical workflow SIMPLI performs the analysis of multiplexed imaging data in three steps (Methods, Fig. 1 ) integrating well-established and newly developed standalone processes (Supplementary Fig. 1 ). Each process can be run independently or even skipped with the possibility of using alternative input data at each point of the workflow. Fig. 1: Schematics of the SIMPLI workflow. a Raw images are extracted from IMC or MIBI data or directly imported from other imaging technologies. After their optional normalisation, these images are thresholded to remove the background noise and produce tissue compartments or marker masks. The resulting images can be analysed using a cell-based or a pixel-based approach. b In the cell-based analysis, single cells are segmented with deterministic or deep learning models and phenotyped using unsupervised or supervised approaches. The distribution of cells in the tissue can then be investigated through a spatial analysis of homotypic or heterotypic aggregations. c In the pixel-based approach, areas positive for a user-defined combination of markers are measured and normalised over the area of the whole image or of the masks defining compartments or areas positive for certain markers. Full size image The first step of SIMPLI consists of processing raw data from single or multi-channel images or text files from a variety of high-dimensional imaging technologies (Fig. 1a and Supplementary Fig. 1a ). After data extraction, pixel values for each marker can be optionally normalised by rescaling them in each sample. This allows the user to apply the same thresholds for background noise reduction across samples. Alternatively, the normalisation step can be skipped and sample-specific thresholds can be applied directly to individual, non-normalised images to", "role": "user" }, { "content": "A team of researchers from the King's College London Schools of Cancer & Pharmaceutical Sciences and Immunology and Microbial Sciences and the Cancer Systems Biology laboratory at the Francis Crick Institute, led by Professor Francesca Ciccarelli, have published new paper showcasing novel software for the analysis of complex tissue imaging data. Recently developed multiplexed imaging technologies, such imaging mass cytometry (IMC), enable detailed investigation of tissue cell composition that are of particular value for mapping the tissue-level characteristics of disease and predicting the outcome of therapies that depend on the tissue environment, such as cancer immunotherapy. These techniques usually produce large amounts of high dimensional data that are difficult to analyze and often require multiple tools and users with computational expertise. SIMPLI (Single-cell Identification from MultiPlexed Images) is a flexible software that unifies all steps of multiplexed imaging data analysis, providing an improved alternative to high-dimension imaging data analysis also for non-specialists. SIMPLI performs a spatially resolved, single-cell analysis of each tissue slide as well as cell-independent quantifications of marker expression to investigate features undetectable at the cell level. It also produces tabular and graphical outputs that faciliate the visual inspection of results at each step of the analysis. \"When we started to work with high dimensional IMC data a couple of years ago, there were not many tools for their analysis. It has been a lot of fun do develop our own tool thanks to the talent of Michele Bortolomeazzi, a Ph.D. student funded by the CRUK KHP Centre, and taking advantage of the vast expertise in tissue histology of Professor Jo Spencer,\" said Prof. Francesca Ciccarelli. To test the performance and versatility of SIMPLI, the researchers analyzed images that had been obtained with different imaging technologies, including but not limited to IMC, and were diverse in origin, size and resolution. King's College London has been one of the first Institutions in Europe to host a Helios imaging mass cytometer, which is available in the BRC Flow Cytometry Platform. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Multiplexed imaging technologies enable the study of biological tissues at single-cell resolution while preserving spatial information. Currently, high-dimension imaging data analysis is technology-specific and requires multiple tools, restricting analytical scalability and result reproducibility. Here we present SIMPLI (Single-cell Identification from MultiPLexed Images), a flexible and technology-agnostic software that unifies all steps of multiplexed imaging data analysis. After raw image processing, SIMPLI performs a spatially resolved, single-cell analysis of the tissue slide as well as cell-independent quantifications of marker expression to investigate features undetectable at the cell level. SIMPLI is highly customisable and can run on desktop computers as well as high-performance computing environments, enabling workflow parallelisation for large datasets. SIMPLI produces multiple tabular and graphical outputs at each step of the analysis. Its containerised implementation and minimum configuration requirements make SIMPLI a portable and reproducible solution for multiplexed imaging data analysis. Software is available at “SIMPLI [ ]”. Introduction A detailed investigation of tissue composition and function in health and disease requires spatially resolved, single-cell approaches that precisely quantify cell types and states as well as their interactions in situ. Recent technological advances have enabled to stain histological sections with multiple tagged antibodies that are subsequently detected using fluorescence microscopy or mass spectrometry 1 . High-dimensional imaging approaches such as imaging mass cytometry (IMC) 2 , multiplexed ion beam imaging (MIBI) 3 , co-detection by indexing (CODEX) 4 , multiplexed immunofluorescence (mIF, including cycIF) 5 and multiplexed immunohistochemistry (mIHC) 6 , 7 enable quantification and localisation of cells in sections from formalin-fixed paraffin-embedded (FFPE) tissues, including clinical diagnostic samples. This is of particular value for mapping the tissue-level characteristics of disease conditions and predicting the outcome of therapies that depend on the tissue environment, such as cancer immunotherapy. For example, a recent IMC phenotypic screen of breast cancer subtypes revealed the association between the heterogeneity of somatic mutations and that of the tumour microenvironment 8 . Similarly, a CODEX-based profile of FFPE tissue microarrays from high-risk colorectal cancer patients correlated PD1 + CD4 + T cells with patient survival 9 . The analysis of multiplexed images requires the conversion of pixel intensity data into single-cell data, which can then be characterised phenotypically, quantified comparatively and localised spatially in the tissue. Currently available tools are technology specific and cover only some steps of the whole analytical workflow (Table 1 ). For example, several computational approaches have been developed to process raw images and extract single-cell data either interactively (Ilastik 10 , CellProfiler4 11 , CODEX Toolkit 4 ) or via command line (imcyto 12 , ImcSegmentationPipeline 13 ). Distinct sets of tools can then perform cell phenotyping (CellProfiler Analyst 14 , Cytomapper 15 , Immunocluster 16 ) or analyse cell–cell spatial interactions (CytoMap 17 , ImaCytE 18 , SPIAT 19 , neighbouRhood 20 ). Similarly, a few tools enable direct pixel-based analysis through pixel classification 10 or quantification of pixel positive areas 11 . Despite such a variety of tools, none of them can perform all of the required analytical steps in a common pipeline. Two exceptions are histoCAT++ 21 and QuPath 22 , which however have been developed specifically for interactive use and are not well suited for the analysis of large datasets. Moreover, all of these tools rely on ad hoc configuration files and input formats, making the analysis challenging for users with limited computational skills and restricting the scalability, portability and reproducibility in different computing environments. Table 1 Features of representative tools for the analysis of multiplexed imaging data. Full size table Here we introduce SIMPLI (Single-cell Identification from MultiPLexed Images), a tool that combines processing of raw images, extraction of single-cell data, and spatially resolved quantification of cell types or functional states into a single pipeline (Table 1 ). This is achieved through the integration of well-established tools and newly developed scripts into the same workflow, enabling ad hoc configurations of the analysis while ensuring interoperability between its different parts. SIMPLI can be run on desktop computers as well as on high-performance-computing environments, where it can be easily applied to large datasets due to automatic workflow parallelisation. To demonstrate the flexibility of SIMPLI to work with different technologies and experimental conditions, we analyse the phenotypes and spatial distribution of cells in different tissues (human colon, appendix, colorectal cancer) using multiplexed images obtained with distinct technologies (IMC, mIF, CODEX). Results Overview of the SIMPLI analytical workflow SIMPLI performs the analysis of multiplexed imaging data in three steps (Methods, Fig. 1 ) integrating well-established and newly developed standalone processes (Supplementary Fig. 1 ). Each process can be run independently or even skipped with the possibility of using alternative input data at each point of the workflow. Fig. 1: Schematics of the SIMPLI workflow. a Raw images are extracted from IMC or MIBI data or directly imported from other imaging technologies. After their optional normalisation, these images are thresholded to remove the background noise and produce tissue compartments or marker masks. The resulting images can be analysed using a cell-based or a pixel-based approach. b In the cell-based analysis, single cells are segmented with deterministic or deep learning models and phenotyped using unsupervised or supervised approaches. The distribution of cells in the tissue can then be investigated through a spatial analysis of homotypic or heterotypic aggregations. c In the pixel-based approach, areas positive for a user-defined combination of markers are measured and normalised over the area of the whole image or of the masks defining compartments or areas positive for certain markers. Full size image The first step of SIMPLI consists of processing raw data from single or multi-channel images or text files from a variety of high-dimensional imaging technologies (Fig. 1a and Supplementary Fig. 1a ). After data extraction, pixel values for each marker can be optionally normalised by rescaling them in each sample. This allows the user to apply the same thresholds for background noise reduction across samples. Alternatively, the normalisation step can be skipped and sample-specific thresholds can be applied directly to individual, non-normalised images to<|im_end|> <|im_start|>assistant A team of researchers from the King's College London Schools of Cancer & Pharmaceutical Sciences and Immunology and Microbial Sciences and the Cancer Systems Biology laboratory at the Francis Crick Institute, led by Professor Francesca Ciccarelli, have published new paper showcasing novel software for the analysis of complex tissue imaging data. Recently developed multiplexed imaging technologies, such imaging mass cytometry (IMC), enable detailed investigation of tissue cell composition that are of particular value for mapping the tissue-level characteristics of disease and predicting the outcome of therapies that depend on the tissue environment, such as cancer immunotherapy. These techniques usually produce large amounts of high dimensional data that are difficult to analyze and often require multiple tools and users with computational expertise. SIMPLI (Single-cell Identification from MultiPlexed Images) is a flexible software that unifies all steps of multiplexed imaging data analysis, providing an improved alternative to high-dimension imaging data analysis also for non-specialists. SIMPLI performs a spatially resolved, single-cell analysis of each tissue slide as well as cell-independent quantifications of marker expression to investigate features undetectable at the cell level. It also produces tabular and graphical outputs that faciliate the visual inspection of results at each step of the analysis. "When we started to work with high dimensional IMC data a couple of years ago, there were not many tools for their analysis. It has been a lot of fun do develop our own tool thanks to the talent of Michele Bortolomeazzi, a Ph.D. student funded by the CRUK KHP Centre, and taking advantage of the vast expertise in tissue histology of Professor Jo Spencer," said Prof. Francesca Ciccarelli. To test the performance and versatility of SIMPLI, the researchers analyzed images that had been obtained with different imaging technologies, including but not limited to IMC, and were diverse in origin, size and resolution. King's College London has been one of the first Institutions in Europe to host a Helios imaging mass cytometer, which is available in the BRC Flow Cytometry Platform. <|im_end|>

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1,815

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Endogenous retroviruses (ERVs) comprise a significant portion of mammalian genomes. Although specific ERV loci feature regulatory roles for host gene expression, most ERV integrations are transcriptionally repressed by Setdb1-mediated H3K9me3 and DNA methylation. However, the protein network which regulates the deposition of these chromatin modifications is still incompletely understood. Here, we perform a genome-wide single guide RNA (sgRNA) screen for genes involved in ERV silencing and identify the GHKL ATPase protein Morc3 as a top-scoring hit. Morc3 knock-out (ko) cells display de-repression, reduced H3K9me3, and increased chromatin accessibility of distinct ERV families. We find that the Morc3 ATPase cycle and Morc3 SUMOylation are important for ERV chromatin regulation. Proteomic analyses reveal that Morc3 mutant proteins fail to interact with the histone H3.3 chaperone Daxx. This interaction depends on Morc3 SUMOylation and Daxx SUMO binding. Notably, in Morc3 ko cells, we observe strongly reduced histone H3.3 on Morc3 binding sites. Thus, our data demonstrate Morc3 as a critical regulator of Daxx-mediated histone H3.3 incorporation to ERV regions. Introduction Endogenous retroviruses compose a significant portion of mammalian genomes. During evolution, most ERV integrations in mammals were highly mutated or partially deleted and are thus unable to generate functional retroviral particles. However, remnant ERVs harbor binding sites for transcription factors and can act as regulatory elements to drive host gene expression 1 , 2 , 3 , 4 , 5 , 6 . This physiological role for the regulation of normal development is contrasted by pathological effects of aberrant ERV regulation in neurological diseases 7 and cancer 8 , 9 , 10 . Many ERV families are thus transcriptionally repressed by a silencing pathway that involves the formation of H3K9me3 heterochromatin 11 , 12 . The current model for H3K9me3 establishment on ERVs is based on sequence-specific binding of KRAB-ZnF proteins, which recruit the co-repressor Trim28 and the histone methyltransferase Setdb1 12 , 13 , 14 . The establishment of DNA methylation is likely to happen during early embryogenesis, and maintenance of high methylation levels on ERVs is later ensured by Uhrf1/Dnmt1 15 , 16 . However, recent data indicate that Dnmt1/Uhrf1 can also induce de novo DNA methylation on ERVs 17 . Full establishment of H3K9me3 and DNA methylation, as well as reduced chromatin accessibility on ERVs, require activities, such as histone H3.3 deposition by Atrx/Daxx 18 , 19 , 20 , 21 , chromatin remodeling by Smarcad1 22 , and chromatin assembly by Chaf1a/b 23 . In ES cells, chromatin remodeling activities enforce a dynamic exchange of Histone H3.3 24 . In this context, histone H3.3 deposition is necessary to replace evicted nucleosomes and ensure low chromatin accessibility 24 . Currently, it is not clear how histone H3.3 turnover is regulated and coordinated with other chromatin-modifying activities to restrict chromatin accessibility and to mediate heterochromatin spreading on ERVs. We have previously identified a small heterochromatin inducing sequence (SHIN) in Intracisternal A Type particle (IAP) elements 20 . The SHIN sequence is a 160 bp region from the GAG coding sequence in IAPEz elements. Genomic insertions of reporters containing the SHIN sequence attract Setdb1-dependent H3K9me3 20 . Using a genome-wide single-guide RNA (sgRNA) screen for genes involved in SHIN silencing we now identified Morc3 as a player in ERV silencing. Morc3 is a GHKL type ATPase protein that can form a closed dimer in the ATP-bound state 25 . It further contains a CW-type zinc finger domain that negatively regulates ATPase activity 26 . The binding of ligands, such as histone H3K4me3 or influenza virus protein NS1 peptides, to the CW domain, relieves suppression of ATPase activity and could regulate the turnover of ATPase domain-mediated dimerization and opening 27 , 28 . Although H3K4me3-mediated interaction of Morc3 with promoter regions in mouse ES cells was reported 25 , the molecular roles of Morc3 in transcriptional regulation or chromatin organization are currently unclear. We demonstrate that Morc3 binds ERV sequences and that loss of Morc3 results in increased chromatin accessibility, reduced H3K9me3, and de-repression of ERVs. We detect an interaction of Morc3 with the histone H3.3 chaperone Daxx, which depends on the Morc3-ATPase cycle and SUMOylation. This interaction is crucial for Daxx-mediated histone H3.3 incorporation as Morc3 ko ES cells lose H3.3 on ERVs. Thus, our data indicate Morc3 as a regulator of Daxx-mediated histone H3.3 incorporation. Results Identification of Morc3 as an ERV silencing factor To identify factors regulating IAPEz silencing we performed a genome-wide sgRNA screen based on the integration of an IAP SHIN reporter in mouse ES cells (T90 cells, Fig. 1a ). This reporter contains a doxycycline-inducible promoter driving the expression of EGFP and a zeocin resistance gene. In the wild-type condition, doxycycline induction results in poor reporter activation due to its heterochromatic state, whereas impaired SHIN silencing allows doxycycline-induced reporter activity 20 . We used a pooled genome-wide lentiviral sgRNA library 29 to transduce T90 ES cells, followed by doxycycline induction to activate the reporter locus. Reporter activity also results in zeocin resistance. Therefore, we applied zeocin selection to detect cells with an activated reporter resulting from impaired heterochromatin. As a control, we collected a second pool of cells without selection pressure. We then identified the sgRNAs which were enriched in the zeocin selected cells (Fig. 1b , Supplementary Data 1 ). Top enriched sgRNAs targeted the major known ERV silencing factors, such as Dnmt1 , Uhrf1 , Setdb1 , Trim28 , and Atrx / Daxx (Fig. 1b ). Another top hit was Morc3, a protein not previously implicated in ERV silencing. Due to the mode of selection with zeocin, we also identified genes that might be related to zeocin resistance, DNA damage repair, and apoptosis (Supplementary Data 1 ). We compared our data with a similar screen for IAP silencing factors which was recently published 30 . Overall, we found very little overlap between the two screens. Only the major silencing factors, such as Atrx, Daxx, Dnmt1, Uhrf1, Trim28, and our top hit Morc3 were present in both datasets (Supplementary Fig. S1a ). Different silencing inducing", "role": "user" }, { "content": "Over time, many endogenous retrovirus (ERV) sequences have integrated into the human genome, and now play important roles in normal gene regulation. However, high levels of expression of ERV transcripts can lead to disorders such as autoimmune diseases and cancers. Based on a genome-wide screen, a team led by Gunnar Schotta at LMU's Biomedical Center has identified the protein Morc3 as a new factor involved in the silencing of ERVs. Whether a given gene is expressed is largely determined by how its DNA sequence is packaged by histone proteins in the complex known as chromatin. The new study shows that Morc3 triggers a modification of packaging by enabling the localized incorporation of the histone variant H3.3 into chromatin, which is mediated by the protein Daxx. This modification results in the formation of a condensed chromatin structure that inhibits the activation of ERV genes. The study is published in Nature Communications. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Endogenous retroviruses (ERVs) comprise a significant portion of mammalian genomes. Although specific ERV loci feature regulatory roles for host gene expression, most ERV integrations are transcriptionally repressed by Setdb1-mediated H3K9me3 and DNA methylation. However, the protein network which regulates the deposition of these chromatin modifications is still incompletely understood. Here, we perform a genome-wide single guide RNA (sgRNA) screen for genes involved in ERV silencing and identify the GHKL ATPase protein Morc3 as a top-scoring hit. Morc3 knock-out (ko) cells display de-repression, reduced H3K9me3, and increased chromatin accessibility of distinct ERV families. We find that the Morc3 ATPase cycle and Morc3 SUMOylation are important for ERV chromatin regulation. Proteomic analyses reveal that Morc3 mutant proteins fail to interact with the histone H3.3 chaperone Daxx. This interaction depends on Morc3 SUMOylation and Daxx SUMO binding. Notably, in Morc3 ko cells, we observe strongly reduced histone H3.3 on Morc3 binding sites. Thus, our data demonstrate Morc3 as a critical regulator of Daxx-mediated histone H3.3 incorporation to ERV regions. Introduction Endogenous retroviruses compose a significant portion of mammalian genomes. During evolution, most ERV integrations in mammals were highly mutated or partially deleted and are thus unable to generate functional retroviral particles. However, remnant ERVs harbor binding sites for transcription factors and can act as regulatory elements to drive host gene expression 1 , 2 , 3 , 4 , 5 , 6 . This physiological role for the regulation of normal development is contrasted by pathological effects of aberrant ERV regulation in neurological diseases 7 and cancer 8 , 9 , 10 . Many ERV families are thus transcriptionally repressed by a silencing pathway that involves the formation of H3K9me3 heterochromatin 11 , 12 . The current model for H3K9me3 establishment on ERVs is based on sequence-specific binding of KRAB-ZnF proteins, which recruit the co-repressor Trim28 and the histone methyltransferase Setdb1 12 , 13 , 14 . The establishment of DNA methylation is likely to happen during early embryogenesis, and maintenance of high methylation levels on ERVs is later ensured by Uhrf1/Dnmt1 15 , 16 . However, recent data indicate that Dnmt1/Uhrf1 can also induce de novo DNA methylation on ERVs 17 . Full establishment of H3K9me3 and DNA methylation, as well as reduced chromatin accessibility on ERVs, require activities, such as histone H3.3 deposition by Atrx/Daxx 18 , 19 , 20 , 21 , chromatin remodeling by Smarcad1 22 , and chromatin assembly by Chaf1a/b 23 . In ES cells, chromatin remodeling activities enforce a dynamic exchange of Histone H3.3 24 . In this context, histone H3.3 deposition is necessary to replace evicted nucleosomes and ensure low chromatin accessibility 24 . Currently, it is not clear how histone H3.3 turnover is regulated and coordinated with other chromatin-modifying activities to restrict chromatin accessibility and to mediate heterochromatin spreading on ERVs. We have previously identified a small heterochromatin inducing sequence (SHIN) in Intracisternal A Type particle (IAP) elements 20 . The SHIN sequence is a 160 bp region from the GAG coding sequence in IAPEz elements. Genomic insertions of reporters containing the SHIN sequence attract Setdb1-dependent H3K9me3 20 . Using a genome-wide single-guide RNA (sgRNA) screen for genes involved in SHIN silencing we now identified Morc3 as a player in ERV silencing. Morc3 is a GHKL type ATPase protein that can form a closed dimer in the ATP-bound state 25 . It further contains a CW-type zinc finger domain that negatively regulates ATPase activity 26 . The binding of ligands, such as histone H3K4me3 or influenza virus protein NS1 peptides, to the CW domain, relieves suppression of ATPase activity and could regulate the turnover of ATPase domain-mediated dimerization and opening 27 , 28 . Although H3K4me3-mediated interaction of Morc3 with promoter regions in mouse ES cells was reported 25 , the molecular roles of Morc3 in transcriptional regulation or chromatin organization are currently unclear. We demonstrate that Morc3 binds ERV sequences and that loss of Morc3 results in increased chromatin accessibility, reduced H3K9me3, and de-repression of ERVs. We detect an interaction of Morc3 with the histone H3.3 chaperone Daxx, which depends on the Morc3-ATPase cycle and SUMOylation. This interaction is crucial for Daxx-mediated histone H3.3 incorporation as Morc3 ko ES cells lose H3.3 on ERVs. Thus, our data indicate Morc3 as a regulator of Daxx-mediated histone H3.3 incorporation. Results Identification of Morc3 as an ERV silencing factor To identify factors regulating IAPEz silencing we performed a genome-wide sgRNA screen based on the integration of an IAP SHIN reporter in mouse ES cells (T90 cells, Fig. 1a ). This reporter contains a doxycycline-inducible promoter driving the expression of EGFP and a zeocin resistance gene. In the wild-type condition, doxycycline induction results in poor reporter activation due to its heterochromatic state, whereas impaired SHIN silencing allows doxycycline-induced reporter activity 20 . We used a pooled genome-wide lentiviral sgRNA library 29 to transduce T90 ES cells, followed by doxycycline induction to activate the reporter locus. Reporter activity also results in zeocin resistance. Therefore, we applied zeocin selection to detect cells with an activated reporter resulting from impaired heterochromatin. As a control, we collected a second pool of cells without selection pressure. We then identified the sgRNAs which were enriched in the zeocin selected cells (Fig. 1b , Supplementary Data 1 ). Top enriched sgRNAs targeted the major known ERV silencing factors, such as Dnmt1 , Uhrf1 , Setdb1 , Trim28 , and Atrx / Daxx (Fig. 1b ). Another top hit was Morc3, a protein not previously implicated in ERV silencing. Due to the mode of selection with zeocin, we also identified genes that might be related to zeocin resistance, DNA damage repair, and apoptosis (Supplementary Data 1 ). We compared our data with a similar screen for IAP silencing factors which was recently published 30 . Overall, we found very little overlap between the two screens. Only the major silencing factors, such as Atrx, Daxx, Dnmt1, Uhrf1, Trim28, and our top hit Morc3 were present in both datasets (Supplementary Fig. S1a ). Different silencing inducing<|im_end|> <|im_start|>assistant Over time, many endogenous retrovirus (ERV) sequences have integrated into the human genome, and now play important roles in normal gene regulation. However, high levels of expression of ERV transcripts can lead to disorders such as autoimmune diseases and cancers. Based on a genome-wide screen, a team led by Gunnar Schotta at LMU's Biomedical Center has identified the protein Morc3 as a new factor involved in the silencing of ERVs. Whether a given gene is expressed is largely determined by how its DNA sequence is packaged by histone proteins in the complex known as chromatin. The new study shows that Morc3 triggers a modification of packaging by enabling the localized incorporation of the histone variant H3.3 into chromatin, which is mediated by the protein Daxx. This modification results in the formation of a condensed chromatin structure that inhibits the activation of ERV genes. The study is published in Nature Communications. <|im_end|>

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1,791

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Nearly all classes of coding and non-coding RNA undergo post-transcriptional modification, including RNA methylation. Methylated nucleotides are among the evolutionarily most-conserved features of transfer (t)RNA and ribosomal (r)RNA 1 , 2 . Many contemporary methyltransferases use the universal cofactor S -adenosylmethionine (SAM) as a methyl-group donor. SAM and other nucleotide-derived cofactors are considered to be evolutionary leftovers from an RNA world, in which ribozymes may have catalysed essential metabolic reactions beyond self-replication 3 . Chemically diverse ribozymes seem to have been lost in nature, but may be reconstructed in the laboratory by in vitro selection. Here we report a methyltransferase ribozyme that catalyses the site-specific installation of 1-methyladenosine in a substrate RNA, using O 6 -methylguanine as a small-molecule cofactor. The ribozyme shows a broad RNA-sequence scope, as exemplified by site-specific adenosine methylation in various RNAs. This finding provides fundamental insights into the catalytic abilities of RNA, serves a synthetic tool to install 1-methyladenosine in RNA and may pave the way to in vitro evolution of other methyltransferase and demethylase ribozymes. Main More than 70 methylated nucleotides have important functional roles in present-day RNA 4 , 5 . Nucleotide modifications are mostly known for shaping the structures and tuning the functions of non-coding rRNA, tRNA and small nuclear (sn)RNA, but some also influence gene-expression programs by regulating the fate and function of messenger (m)RNA 6 , 7 , 8 . The majority of methylated nucleotides currently known in RNA are installed through post-synthetic (that is, post- or co-transcriptional) methylation by protein enzymes that use SAM as the universal methyl-group donor. Methyltransferases are considered ancient enzymes, and methylated nucleotides have also been discussed as molecular fossils of the early Earth produced by prebiotic methylating agents 9 , 10 . For the era preceding modern life based on DNA and proteins, RNA has been proposed to have functioned both as primary genetic material and as a catalyst or ribozyme 11 . Ribozymes have been discovered in nature, where they catalyse RNA cleavage and ligation reactions—mostly in the context of RNA splicing and retrotransposition 12 , 13 , 14 . In vitro-selected ribozymes have been evolved to act as RNA ligases and replicases that are able to reproduce themselves or their ancestors, and that are able to produce functional RNAs (including ribozymes and aptamers) 15 , 16 , 17 . Self-alkylating ribozymes have been described using reactive iodo- or chloro-acetyl derivatives 18 , 19 , 20 , or electrophilic epoxides 21 , but the design of earlier in vitro selection strategies prevented the emergence of catalysts that are capable of transferring a one-carbon unit. Thus, ribozymes that catalyse RNA methylation have so far remained unknown. This lack of ribozymes that act as methyltransferases seems surprising, as numerous natural aptamers are known to specifically bind nucleotide-derived metabolites associated with methyl-group transfer or one-carbon metabolism, including SAM, methylene tetrahydrofolate (THF) and adenosylcobalamin (vitamin B12) 22 , 23 . These aptamers are found as components of riboswitches that regulate the expression of associated genes, which are often involved in the biosynthesis of the respective metabolite or its transport across membranes 24 . Six classes of SAM-binding riboswitches accommodate the ligand with its reactive methyl group in various different conformations 25 , 26 ; however, these RNAs apparently avoid self-methylation. Therefore, it has remained an open question whether RNA can catalyse site-specific methylation reactions to produce defined methylated RNA products. Previously, in vitro selection efforts have identified SAM-binding aptamers, but methyl transfer reactions were not observed—probably because the aptamer established a binding site for the adenine moiety of the cofactor, but did not specifically interact with its 5′ substituent 27 . We speculated that methyl-group donors other than SAM or methylene-THF could be substrates for RNA-catalysed RNA methylation, and took inspiration from an enzyme class that is responsible for the repair of alkylated DNA (that is, catalyses the demethylation of DNA). The O 6 -methylguanine (m 6 G) DNA methyltransferase releases unmodified DNA, accompanied by the irreversible methylation of the protein 28 . By analogy, we hypothesized that RNA-catalysed methyl transfer would result in methylated RNA upon release of guanine. Using in vitro selection, we identified a ribozyme that uses m 6 G as a small-molecule methyl-group donor and catalyses site-specific methylation of adenosine at position N1, resulting in position-specific installation of 1-methyladenosine (m 1 A) in the target RNA (Fig. 1a ). Fig. 1: Methyltransferase ribozyme-catalysed synthesis of m 1 A in RNA using m 6 G as methyl-group donor. a , Reaction scheme with intermolecular hybridization of ribozyme to target RNA. b , Sequences and predicted secondary structure of CA13 and CA21 ribozymes identified by in vitro selection, and their trans -activity for modification of a 22-nt RNA (designated SL) with BG-NH 2 or BG, analysed by 20% denaturing PAGE (100 μM guanine derivative, 40 mM MgCl 2 , pH 7.5, 37 °C, and time points 0, 0.5, 1, 2 and 5 h). Representative images of three independent experiments with similar results. c , Methyltransferase ribozyme MTR1 with stabilized stem-loop shows efficient methyl-group transfer. The insert shows a gel image of a 3′-fluorescein-labelled 13-mer RNA substrate reacted with MTR1 and m 6 G (10 μM). The observed rate constant k obs was determined with a 3′-fluorescein-labelled 17-mer RNA at 5 concentrations of m 6 G, ranging from 5 to 200 μM. The red line represents a curve fit to k obs = k max [m 6 G]/( K m,app + [m 6 G]). Individual data points (white) ( n = 3), mean ± s.e.m. (black). P, product; S, substrate. d , Structures of m 6 G analogues tested. Gel image shows that product formation occurs with m 6 G, and to a minor extent with m 6 dG (24-h reaction time, 25 °C, with 100 μM m 6 G or analogue). Representative image from two independent experiments. G, guanine. Source data Full size image Search for methyltransferase ribozymes In vitro selection is a powerful method for enriching functional RNAs by repeated cycles of selection", "role": "user" }, { "content": "Enzymes enable biochemical reactions that would otherwise not take place on their own. In nature, it is mostly proteins that function as enzymes. However, other molecules can also perform enzymatic reactions—for example ribonucleic acids—RNAs. These are then called ribozymes. In this field, the research group of chemistry professor Claudia Höbartner is now reporting a scientific breakthrough: Her team at Julius-Maximilians-Universität Würzburg (JMU) in Bavaria, Germany, has developed a ribozyme that can attach a very specific small chemical change at a very specific location in a target RNA. More precisely: the ribozyme transfers a single methyl group to an exactly defined nitrogen atom of the target RNA. This makes it the first known methyl transferase ribozyme in the world. Accordingly, Höbartner's group has given it the short name MTR1. In the journal Nature the group presents details about the new ribozyme. In the target RNA, it produces the methylated nucleoside 1-methyladenosine (m1A). The methyl group is transferred from a free methylated guanine nucleobase (O6-methylguanine, m6G) in a binding pocket of the ribozyme. Ribozymes in evolution The ribozyme discovered at the JMU Institute of Organic Chemistry sheds light on an interesting aspect of evolution. According to the \"RNA world hypothesis,\" RNA was one of the first information-storing and enzymatically active molecules. Ribozymes similar to those developed by Claudia Höbartner and her team may have produced methylated RNAs in the course of evolution. This in turn may have led to a greater structural and thus functional diversity of RNA molecules. In nature, methyl groups are installed on RNAs by specialized protein enzymes. These proteins use cofactors that contain RNA-like components. \"It is reasonable to assume that these cofactors could be evolutionary 'leftovers' of earlier enzymatically active RNAs. Our discovery may therefore mimic a ribozyme that has possibly been lost in nature a long time ago,\" says Claudia Höbartner. In the laboratory, new or naturally extinct ribozymes can be found by a method called in vitro evolution. \"It starts from many different sequences of synthetic RNA, and is analogous to finding a needle in the haystack,\" says co-author Mohammad Ghaem Maghami, a postdoctoral researcher in the Höbartner group. New ribozyme also acts on natural RNA The authors have also been able to show that MTR1 can install a single methyl group not only on synthetic RNA structures but also on natural RNA strands found in cells. This news is likely to attract great attention from cell biologists, among others. The reason for this is that the methylation of RNA can be considered as a biochemical on or off switch. It has a key role in the functioning of RNA structures and can control many life processes in the cell. The newly developed ribozyme MTR1 is expected to be a useful tool for a wide range of research areas in the future. \"For example, it could help to better understand the interaction of methylation, structure, and function of RNA,\" explains JMU Ph.D. student Carolin Scheitl, the first author of the publication in Nature. The next steps of the researchers Many new projects will build on these results. Höbartner's group intends to solve the structure of their new ribozyme and reveal the detailed chemical mechanism of the RNA-catalyzed methylation. With the methods now established, her team will also be able to develop ribozymes for a variety of other reactions. According to the JMU professor, these ribozymes also offer an excellent possibility to control Watson-Crick base pairing and to install fluorescent labels for RNA imaging. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Nearly all classes of coding and non-coding RNA undergo post-transcriptional modification, including RNA methylation. Methylated nucleotides are among the evolutionarily most-conserved features of transfer (t)RNA and ribosomal (r)RNA 1 , 2 . Many contemporary methyltransferases use the universal cofactor S -adenosylmethionine (SAM) as a methyl-group donor. SAM and other nucleotide-derived cofactors are considered to be evolutionary leftovers from an RNA world, in which ribozymes may have catalysed essential metabolic reactions beyond self-replication 3 . Chemically diverse ribozymes seem to have been lost in nature, but may be reconstructed in the laboratory by in vitro selection. Here we report a methyltransferase ribozyme that catalyses the site-specific installation of 1-methyladenosine in a substrate RNA, using O 6 -methylguanine as a small-molecule cofactor. The ribozyme shows a broad RNA-sequence scope, as exemplified by site-specific adenosine methylation in various RNAs. This finding provides fundamental insights into the catalytic abilities of RNA, serves a synthetic tool to install 1-methyladenosine in RNA and may pave the way to in vitro evolution of other methyltransferase and demethylase ribozymes. Main More than 70 methylated nucleotides have important functional roles in present-day RNA 4 , 5 . Nucleotide modifications are mostly known for shaping the structures and tuning the functions of non-coding rRNA, tRNA and small nuclear (sn)RNA, but some also influence gene-expression programs by regulating the fate and function of messenger (m)RNA 6 , 7 , 8 . The majority of methylated nucleotides currently known in RNA are installed through post-synthetic (that is, post- or co-transcriptional) methylation by protein enzymes that use SAM as the universal methyl-group donor. Methyltransferases are considered ancient enzymes, and methylated nucleotides have also been discussed as molecular fossils of the early Earth produced by prebiotic methylating agents 9 , 10 . For the era preceding modern life based on DNA and proteins, RNA has been proposed to have functioned both as primary genetic material and as a catalyst or ribozyme 11 . Ribozymes have been discovered in nature, where they catalyse RNA cleavage and ligation reactions—mostly in the context of RNA splicing and retrotransposition 12 , 13 , 14 . In vitro-selected ribozymes have been evolved to act as RNA ligases and replicases that are able to reproduce themselves or their ancestors, and that are able to produce functional RNAs (including ribozymes and aptamers) 15 , 16 , 17 . Self-alkylating ribozymes have been described using reactive iodo- or chloro-acetyl derivatives 18 , 19 , 20 , or electrophilic epoxides 21 , but the design of earlier in vitro selection strategies prevented the emergence of catalysts that are capable of transferring a one-carbon unit. Thus, ribozymes that catalyse RNA methylation have so far remained unknown. This lack of ribozymes that act as methyltransferases seems surprising, as numerous natural aptamers are known to specifically bind nucleotide-derived metabolites associated with methyl-group transfer or one-carbon metabolism, including SAM, methylene tetrahydrofolate (THF) and adenosylcobalamin (vitamin B12) 22 , 23 . These aptamers are found as components of riboswitches that regulate the expression of associated genes, which are often involved in the biosynthesis of the respective metabolite or its transport across membranes 24 . Six classes of SAM-binding riboswitches accommodate the ligand with its reactive methyl group in various different conformations 25 , 26 ; however, these RNAs apparently avoid self-methylation. Therefore, it has remained an open question whether RNA can catalyse site-specific methylation reactions to produce defined methylated RNA products. Previously, in vitro selection efforts have identified SAM-binding aptamers, but methyl transfer reactions were not observed—probably because the aptamer established a binding site for the adenine moiety of the cofactor, but did not specifically interact with its 5′ substituent 27 . We speculated that methyl-group donors other than SAM or methylene-THF could be substrates for RNA-catalysed RNA methylation, and took inspiration from an enzyme class that is responsible for the repair of alkylated DNA (that is, catalyses the demethylation of DNA). The O 6 -methylguanine (m 6 G) DNA methyltransferase releases unmodified DNA, accompanied by the irreversible methylation of the protein 28 . By analogy, we hypothesized that RNA-catalysed methyl transfer would result in methylated RNA upon release of guanine. Using in vitro selection, we identified a ribozyme that uses m 6 G as a small-molecule methyl-group donor and catalyses site-specific methylation of adenosine at position N1, resulting in position-specific installation of 1-methyladenosine (m 1 A) in the target RNA (Fig. 1a ). Fig. 1: Methyltransferase ribozyme-catalysed synthesis of m 1 A in RNA using m 6 G as methyl-group donor. a , Reaction scheme with intermolecular hybridization of ribozyme to target RNA. b , Sequences and predicted secondary structure of CA13 and CA21 ribozymes identified by in vitro selection, and their trans -activity for modification of a 22-nt RNA (designated SL) with BG-NH 2 or BG, analysed by 20% denaturing PAGE (100 μM guanine derivative, 40 mM MgCl 2 , pH 7.5, 37 °C, and time points 0, 0.5, 1, 2 and 5 h). Representative images of three independent experiments with similar results. c , Methyltransferase ribozyme MTR1 with stabilized stem-loop shows efficient methyl-group transfer. The insert shows a gel image of a 3′-fluorescein-labelled 13-mer RNA substrate reacted with MTR1 and m 6 G (10 μM). The observed rate constant k obs was determined with a 3′-fluorescein-labelled 17-mer RNA at 5 concentrations of m 6 G, ranging from 5 to 200 μM. The red line represents a curve fit to k obs = k max [m 6 G]/( K m,app + [m 6 G]). Individual data points (white) ( n = 3), mean ± s.e.m. (black). P, product; S, substrate. d , Structures of m 6 G analogues tested. Gel image shows that product formation occurs with m 6 G, and to a minor extent with m 6 dG (24-h reaction time, 25 °C, with 100 μM m 6 G or analogue). Representative image from two independent experiments. G, guanine. Source data Full size image Search for methyltransferase ribozymes In vitro selection is a powerful method for enriching functional RNAs by repeated cycles of selection<|im_end|> <|im_start|>assistant Enzymes enable biochemical reactions that would otherwise not take place on their own. In nature, it is mostly proteins that function as enzymes. However, other molecules can also perform enzymatic reactions—for example ribonucleic acids—RNAs. These are then called ribozymes. In this field, the research group of chemistry professor Claudia Höbartner is now reporting a scientific breakthrough: Her team at Julius-Maximilians-Universität Würzburg (JMU) in Bavaria, Germany, has developed a ribozyme that can attach a very specific small chemical change at a very specific location in a target RNA. More precisely: the ribozyme transfers a single methyl group to an exactly defined nitrogen atom of the target RNA. This makes it the first known methyl transferase ribozyme in the world. Accordingly, Höbartner's group has given it the short name MTR1. In the journal Nature the group presents details about the new ribozyme. In the target RNA, it produces the methylated nucleoside 1-methyladenosine (m1A). The methyl group is transferred from a free methylated guanine nucleobase (O6-methylguanine, m6G) in a binding pocket of the ribozyme. Ribozymes in evolution The ribozyme discovered at the JMU Institute of Organic Chemistry sheds light on an interesting aspect of evolution. According to the "RNA world hypothesis," RNA was one of the first information-storing and enzymatically active molecules. Ribozymes similar to those developed by Claudia Höbartner and her team may have produced methylated RNAs in the course of evolution. This in turn may have led to a greater structural and thus functional diversity of RNA molecules. In nature, methyl groups are installed on RNAs by specialized protein enzymes. These proteins use cofactors that contain RNA-like components. "It is reasonable to assume that these cofactors could be evolutionary 'leftovers' of earlier enzymatically active RNAs. Our discovery may therefore mimic a ribozyme that has possibly been lost in nature a long time ago," says Claudia Höbartner. In the laboratory, new or naturally extinct ribozymes can be found by a method called in vitro evolution. "It starts from many different sequences of synthetic RNA, and is analogous to finding a needle in the haystack," says co-author Mohammad Ghaem Maghami, a postdoctoral researcher in the Höbartner group. New ribozyme also acts on natural RNA The authors have also been able to show that MTR1 can install a single methyl group not only on synthetic RNA structures but also on natural RNA strands found in cells. This news is likely to attract great attention from cell biologists, among others. The reason for this is that the methylation of RNA can be considered as a biochemical on or off switch. It has a key role in the functioning of RNA structures and can control many life processes in the cell. The newly developed ribozyme MTR1 is expected to be a useful tool for a wide range of research areas in the future. "For example, it could help to better understand the interaction of methylation, structure, and function of RNA," explains JMU Ph.D. student Carolin Scheitl, the first author of the publication in Nature. The next steps of the researchers Many new projects will build on these results. Höbartner's group intends to solve the structure of their new ribozyme and reveal the detailed chemical mechanism of the RNA-catalyzed methylation. With the methods now established, her team will also be able to develop ribozymes for a variety of other reactions. According to the JMU professor, these ribozymes also offer an excellent possibility to control Watson-Crick base pairing and to install fluorescent labels for RNA imaging. <|im_end|>

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315, 296, 220, 21, 480, 11, 24950, 505, 220, 20, 311, 220, 1049, 33983, 44, 13, 578, 2579, 1584, 11105, 264, 16029, 5052, 311, 597, 7600, 284, 597, 1973, 510, 76, 220, 21, 480, 9968, 7, 735, 296, 11, 680, 489, 510, 76, 220, 21, 480, 10927, 30440, 828, 3585, 320, 5902, 8, 320, 308, 284, 220, 18, 705, 3152, 20903, 274, 1770, 749, 13, 320, 11708, 570, 393, 11, 2027, 26, 328, 11, 54057, 13, 294, 1174, 71150, 315, 296, 220, 21, 480, 24291, 1157, 12793, 13, 45482, 2217, 5039, 430, 2027, 18488, 13980, 449, 296, 220, 21, 480, 11, 323, 311, 264, 9099, 13112, 449, 296, 220, 21, 294, 38, 320, 1187, 2902, 13010, 892, 11, 220, 914, 37386, 34, 11, 449, 220, 1041, 33983, 44, 296, 220, 21, 480, 477, 91343, 570, 38366, 2217, 505, 1403, 9678, 21896, 13, 480, 11, 1709, 92356, 13, 8922, 828, 8797, 1404, 2217, 7694, 369, 79574, 25163, 521, 20735, 9700, 79809, 763, 55004, 6727, 374, 264, 8147, 1749, 369, 31518, 287, 16003, 46916, 2170, 555, 11763, 25492, 315, 6727, 128257, 198, 128256, 78191, 198, 1737, 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706, 2728, 433, 279, 2875, 836, 386, 2434, 16, 13, 763, 279, 8486, 22037, 279, 1912, 18911, 3649, 922, 279, 502, 20735, 9700, 31218, 13, 763, 279, 2218, 41214, 11, 433, 19159, 279, 79574, 660, 31484, 437, 579, 220, 16, 1474, 42972, 21825, 437, 483, 320, 76, 16, 32, 570, 578, 79574, 1912, 374, 23217, 505, 264, 1949, 79574, 660, 1709, 92356, 31484, 677, 521, 320, 46, 21, 1474, 42972, 8890, 92356, 11, 296, 21, 38, 8, 304, 264, 11212, 18301, 315, 279, 20735, 9700, 31218, 13, 64205, 9700, 79809, 304, 15740, 578, 20735, 9700, 31218, 11352, 520, 279, 622, 60274, 10181, 315, 44037, 42846, 77039, 3177, 389, 459, 7185, 13189, 315, 15740, 13, 10771, 311, 279, 330, 31820, 1917, 31178, 1359, 41214, 574, 832, 315, 279, 1176, 2038, 5594, 5620, 323, 32011, 7167, 4642, 35715, 13, 64205, 9700, 79809, 4528, 311, 1884, 8040, 555, 81156, 71364, 41679, 1215, 323, 1077, 2128, 1253, 617, 9124, 79574, 660, 46916, 2170, 304, 279, 3388, 315, 15740, 13, 1115, 304, 2543, 1253, 617, 6197, 311, 264, 7191, 24693, 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430, 386, 2434, 16, 649, 4685, 264, 3254, 79574, 1912, 539, 1193, 389, 28367, 41214, 14726, 719, 1101, 389, 5933, 41214, 69864, 1766, 304, 7917, 13, 1115, 3754, 374, 4461, 311, 9504, 2294, 6666, 505, 2849, 6160, 22012, 11, 4315, 3885, 13, 578, 2944, 369, 420, 374, 430, 279, 21747, 79933, 315, 41214, 649, 387, 6646, 439, 264, 93532, 389, 477, 1022, 3480, 13, 1102, 706, 264, 1401, 3560, 304, 279, 31301, 315, 41214, 14726, 323, 649, 2585, 1690, 2324, 11618, 304, 279, 2849, 13, 578, 13945, 8040, 20735, 9700, 31218, 386, 2434, 16, 374, 3685, 311, 387, 264, 5505, 5507, 369, 264, 7029, 2134, 315, 3495, 5789, 304, 279, 3938, 13, 330, 2520, 3187, 11, 433, 1436, 1520, 311, 2731, 3619, 279, 16628, 315, 21747, 79933, 11, 6070, 11, 323, 734, 315, 41214, 1359, 15100, 622, 60274, 2405, 920, 13, 5575, 10463, 258, 54772, 275, 75, 11, 279, 1176, 3229, 315, 279, 17009, 304, 22037, 13, 578, 1828, 7504, 315, 279, 12074, 9176, 502, 7224, 690, 1977, 389, 1521, 3135, 13, 71364, 41679, 1215, 596, 1912, 44330, 311, 11886, 279, 6070, 315, 872, 502, 20735, 9700, 31218, 323, 16805, 279, 11944, 11742, 17383, 315, 279, 41214, 1824, 4306, 88, 16284, 21747, 79933, 13, 3161, 279, 5528, 1457, 9749, 11, 1077, 2128, 690, 1101, 387, 3025, 311, 2274, 20735, 9700, 79809, 369, 264, 8205, 315, 1023, 25481, 13, 10771, 311, 279, 622, 60274, 14561, 11, 1521, 20735, 9700, 79809, 1101, 3085, 459, 9250, 13336, 311, 2585, 32580, 7813, 12938, 2385, 48813, 323, 311, 4685, 74864, 9382, 369, 41214, 32758, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The human serotonin transporter (hSERT) mediates uptake of serotonin from the synaptic cleft and thereby terminates serotonergic signalling. We have previously found by single-molecule microscopy that SERT forms stable higher-order oligomers of differing stoichiometry at the plasma membrane of living cells. Here, we report that SERT oligomer assembly at the endoplasmic reticulum (ER) membrane follows a dynamic equilibration process, characterized by rapid exchange of subunits between different oligomers, and by a concentration dependence of the degree of oligomerization. After trafficking to the plasma membrane, however, the SERT stoichiometry is fixed. Stabilization of the oligomeric SERT complexes is mediated by the direct binding to phosphoinositide phosphatidylinositol-4,5-biphosphate (PIP 2 ). The observed spatial decoupling of oligomer formation from the site of oligomer operation provides cells with the ability to define protein quaternary structures independent of protein density at the cell surface. Introduction The human serotonin transporter (SERT) is a 12-pass transmembrane protein targeted to presynaptic nerve terminals and belongs to the neurotransmitter:sodium symporter (NSS) or solute carrier 6 (SLC6) family 1 . These transmembrane proteins mediate the high-affinity uptake of neurotransmitters from the synaptic cleft and are, hence, of pivotal importance for synaptic signal transmission by terminating chemical signal transduction between neurons. SERT is the target for antidepressants like serotonin-selective reuptake inhibitors 2 as well as for illicitly used drugs such as amphetamines 3 ; the latter act by reversing the transport direction of SERT, provoking release of serotonin (5-HT) into the extracellular space 4 . Biochemical and spectroscopic studies have reported that SERT is present as oligomeric complexes at the plasma membrane 5 , 6 , 7 , 8 , 9 . Likewise, oligomerization of a number of other NSS family members has been described 10 . The oligomeric state, however, does not seem to be crucial for uptake activity: for example, it was found that oligomerization-deficient mutants of the GABA transporter (GAT1) retain unchanged transport activity 11 . Currently, two possible roles of NSS oligomerization are discussed: (i) oligomerization of correctly folded proteins is necessary to pass the quality control for trafficking from the endoplasmic reticulum (ER) 12 , in the case of SERT specifically by allowing the interaction with SEC24C (refs 13 , 14 ). (ii) It has been reported that oligomerization is a prerequisite for the reverse operation of the transporter which affords substrate release 15 . Using single-molecule fluorescence microscopy, we have previously discovered that SERT forms a broad distribution of assemblies ranging from monomers up to pentamers 7 . The homo-association at the plasma membrane did not depend on SERT surface density and was stable at least over 10 min. We proposed a model based on kinetic trapping of oligomers at the plasma membrane, subsequent to an equilibration which occurred at an unknown subcellular organelle. The site of equilibration and the mechanism behind kinetic trapping, however, remained unclear. Some arguments pointed our interest to the negatively charged phospholipid phosphatidylinositol-4,5-biphosphate (PIP 2 ). PIP 2 is part of a number of signalling pathways, for example, endo- and exocytosis, cell adhesion, cell motility, phagocytosis or G protein-coupled receptor signalling 16 . It is a minor phospholipid that is mainly found at the cytoplasmic leaflet of the plasma membrane, where it occurs at a surface density of about σ PIP ∼ 20,000–60,000 molecules μm −2 (ref. 17 ). Pronounced differences exist in the subcellular localization of PIP 2 : PIP 2 comprises about 1% of total lipid at the plasma membrane 17 , whereas only trace amounts of PIP 2 are present at the ER 18 . PIP 2 binding to transmembrane proteins is frequently observed, for example, for ion channels, where it regulates channel activity by influencing the open probability 19 . Likewise, we have recently found that the functional activity of SERT and the dopamine transporter (DAT) was influenced by PIP 2 binding 20 , 21 : upon enzymatic depletion of PIP 2 or mutation of identified PIP 2 binding sites, amphetamine-induced substrate efflux was markedly reduced whereas uptake rates were essentially unaffected. Similarly, while the oligomeric configuration does not seem to influence neurotransmitter uptake 11 , amphetamine-induced neurotransmitter release has been shown to rely on the quaternary arrangement 15 . In the present study, we quantify the degree of SERT oligomerization at different subcellular localizations of Chinese hamster ovary (CHO) cells and analyse the kinetics of protomer turnover. We find evidence that SERT oligomers are pre-formed at the ER following a dynamic equilibrium model. At the plasma membrane, kinetic trapping arrests the oligomers at the pre-set stoichiometry. Our data suggest that the different subcellular concentrations of PIP 2 mediate the differential SERT oligomerization behaviour, likely by direct physical connection of SERT protomers. Results SERT oligomerization depends on subcellular localization First, we addressed if SERT oligomerization differs between the plasma membrane and the ER. Monomeric GFP (mGFP) was inserted at the cytosolic N-terminus of SERT to allow for visualization (mGFP–SERT) 22 . Plasma membrane-localized mGFP–SERT was recorded at the bottom cell membrane via total internal reflection fluorescence (TIRF) microscopy. To retain SERT in the ER, we overexpressed a dominant-negative mutant of Sar1a (Sar1a-T39N) 13 , a small GTPase that regulates the assembly of COPII vesicles for plasma membrane trafficking. Sar1a-T39N is a GDP-restricted mutant which prevents the formation of COPII in a dominant-negative manner, thereby arresting SERT in the ER. ER-retained mGFP–SERT was studied at junctions between ER and the plasma membrane, where single-molecule tracking at high signal-to-noise ratio using TIRF microscopy is feasible 23 , 24 . We used the ‘Thinning out clusters while conserving stoichiometry’ (TOCCSL) technique previously established in our lab 7 , 25 , 26 , 27 to determine the oligomeric state of mGFP–SERT. TOCCSL extends fluorescence recovery after photobleaching (FRAP) to the level of single-molecule fluorescence microscopy ( Fig. 1a ). Typically, the high density of fluorescently labelled proteins results in a homogenously labelled surface, thereby precluding direct single-molecule measurements ( Fig. 1a ,i). In TOCCSL, a small area of the cell membrane is irreversibly photobleached by a strong laser pulse", "role": "user" }, { "content": "Neurotransmitter transporters are some of the most popular transport proteins in research as they play a major role in the processing of signals in the brain. A joint study by TU Wien and the Medical University of Vienna has now successfully demonstrated for the first time the structural impact of membrane lipids on medically relevant serotonin transporters. The membrane of a cell is composed of a lipid bilayer. Lipids are good chemical and electrical insulators, which are ideally suited to separating the inside of the cell from the outside of the cell. But membranes also harbour a large number of proteins, some of which regulate the controlled exchange of substances across the membrane. While the majority of proteins are able to move freely within the lipid layers, they are found in groups with surprising frequency. The bonds between proteins may be fixed and permanent; or protein molecules may come together, split and come together again in another configuration. The research interests of the groups involved in the study, who were led by Prof. Gerhard Schütz from the Institute of Applied Physics at TU Wien and Prof. Harald Sitte from the Institute of Pharmacology at the Medical University of Vienna, concern how these interactions work, and this could shed further light on how the cell membrane and the membrane proteins embedded in it function. Molecule tracking Due to their size, protein molecules cannot be seen with the naked eye, which is why it is necessary to use a microscope to track them. However, the challenge lies in filtering out precisely those proteins which are of interest from the large number of other proteins in a cell. \"Together with Prof. Harald Sitte from the Medical University of Vienna, at present we are particularly interested in the serotonin transporter (SERT), a protein that is important for the uptake of the neurotransmitter serotonin in the brain. In order to be able to observe it under a microscope, it is marked with a fluorescent biomolecule, a 'green fluorescent protein' (GFP)' explains Prof. Schütz. A molecular biological method is used to combine the GFP with the SERT and it then acts like a coloured balloon. \"The 'single molecule microscopy' method enables us to determine from the strength of the signal from the points of light observed whether the molecule in question is moving around by itself or with other molecules of the same type.\" As a biophysicist, Schütz is not only interested in the fact that the proteins move around together but also in why the two molecules stick together, in other words how the underlying interaction mechanisms work. PIP2 (Phosphatidylinositol-4,5-bisphosphate) is a central signal molecule that is predominantly found on the side of the cell membrane facing the inside of the cell. It binds perfectly to the SERT, with amazing consequences. If only a low concentration of PIP2 is available, the oligomerisation of the SERT behaves as expected: low SERT concentrations mainly produce monomers, while high concentrations lead to the formation of oligomers. \"It is not just that we are seeing a large number of oligomers, we also know that they exchange molecules with each other,\" says Schütz of his research. However, if there are high levels of PIP2 available, on average oligomers that are identical in size will always be produced, regardless of the SERT concentration. \"It is as though the SERT proteins were locked in a predefined arrangement.\" Exploring cluster formation To investigate the underlying mechanisms of this amazing oligomer formation, you have to look inside the cell. One cell area - the endoplasmic reticulum - acts as the place where all membrane proteins, including SERT, are produced. This is in fact PIP2-free, meaning that SERT should have different levels of oligomerisation there, depending on the concentration of SERT. This has actually been observed too. \"We assume that SERT oligomerises after it is produced in the endoplasmic reticulum, but that this process is initially reversible. It is only when the protein reaches the cell membrane that the predefined level of oligomerisation is fixed by PIP2,\" says Schütz. \"These observations are confirmed by specific changes to the protein structure that we inserted into the serotonin transporter,\" says Sitte. \"We were able to identify the position of the point mutations extremely accurately using computer models which Dr Thomas Stockner created as part of this study. The mutated SERT molecules exhibit a behaviour that makes it almost impossible for this locking to occur. And the medical relevance of our observation lies in the importance of oligomerisation for the behaviour of different psychostimulants, such as amphetamines: these can only have an effect if sufficient bonded SERT molecules are evident in the membrane.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 human serotonin transporter (hSERT) mediates uptake of serotonin from the synaptic cleft and thereby terminates serotonergic signalling. We have previously found by single-molecule microscopy that SERT forms stable higher-order oligomers of differing stoichiometry at the plasma membrane of living cells. Here, we report that SERT oligomer assembly at the endoplasmic reticulum (ER) membrane follows a dynamic equilibration process, characterized by rapid exchange of subunits between different oligomers, and by a concentration dependence of the degree of oligomerization. After trafficking to the plasma membrane, however, the SERT stoichiometry is fixed. Stabilization of the oligomeric SERT complexes is mediated by the direct binding to phosphoinositide phosphatidylinositol-4,5-biphosphate (PIP 2 ). The observed spatial decoupling of oligomer formation from the site of oligomer operation provides cells with the ability to define protein quaternary structures independent of protein density at the cell surface. Introduction The human serotonin transporter (SERT) is a 12-pass transmembrane protein targeted to presynaptic nerve terminals and belongs to the neurotransmitter:sodium symporter (NSS) or solute carrier 6 (SLC6) family 1 . These transmembrane proteins mediate the high-affinity uptake of neurotransmitters from the synaptic cleft and are, hence, of pivotal importance for synaptic signal transmission by terminating chemical signal transduction between neurons. SERT is the target for antidepressants like serotonin-selective reuptake inhibitors 2 as well as for illicitly used drugs such as amphetamines 3 ; the latter act by reversing the transport direction of SERT, provoking release of serotonin (5-HT) into the extracellular space 4 . Biochemical and spectroscopic studies have reported that SERT is present as oligomeric complexes at the plasma membrane 5 , 6 , 7 , 8 , 9 . Likewise, oligomerization of a number of other NSS family members has been described 10 . The oligomeric state, however, does not seem to be crucial for uptake activity: for example, it was found that oligomerization-deficient mutants of the GABA transporter (GAT1) retain unchanged transport activity 11 . Currently, two possible roles of NSS oligomerization are discussed: (i) oligomerization of correctly folded proteins is necessary to pass the quality control for trafficking from the endoplasmic reticulum (ER) 12 , in the case of SERT specifically by allowing the interaction with SEC24C (refs 13 , 14 ). (ii) It has been reported that oligomerization is a prerequisite for the reverse operation of the transporter which affords substrate release 15 . Using single-molecule fluorescence microscopy, we have previously discovered that SERT forms a broad distribution of assemblies ranging from monomers up to pentamers 7 . The homo-association at the plasma membrane did not depend on SERT surface density and was stable at least over 10 min. We proposed a model based on kinetic trapping of oligomers at the plasma membrane, subsequent to an equilibration which occurred at an unknown subcellular organelle. The site of equilibration and the mechanism behind kinetic trapping, however, remained unclear. Some arguments pointed our interest to the negatively charged phospholipid phosphatidylinositol-4,5-biphosphate (PIP 2 ). PIP 2 is part of a number of signalling pathways, for example, endo- and exocytosis, cell adhesion, cell motility, phagocytosis or G protein-coupled receptor signalling 16 . It is a minor phospholipid that is mainly found at the cytoplasmic leaflet of the plasma membrane, where it occurs at a surface density of about σ PIP ∼ 20,000–60,000 molecules μm −2 (ref. 17 ). Pronounced differences exist in the subcellular localization of PIP 2 : PIP 2 comprises about 1% of total lipid at the plasma membrane 17 , whereas only trace amounts of PIP 2 are present at the ER 18 . PIP 2 binding to transmembrane proteins is frequently observed, for example, for ion channels, where it regulates channel activity by influencing the open probability 19 . Likewise, we have recently found that the functional activity of SERT and the dopamine transporter (DAT) was influenced by PIP 2 binding 20 , 21 : upon enzymatic depletion of PIP 2 or mutation of identified PIP 2 binding sites, amphetamine-induced substrate efflux was markedly reduced whereas uptake rates were essentially unaffected. Similarly, while the oligomeric configuration does not seem to influence neurotransmitter uptake 11 , amphetamine-induced neurotransmitter release has been shown to rely on the quaternary arrangement 15 . In the present study, we quantify the degree of SERT oligomerization at different subcellular localizations of Chinese hamster ovary (CHO) cells and analyse the kinetics of protomer turnover. We find evidence that SERT oligomers are pre-formed at the ER following a dynamic equilibrium model. At the plasma membrane, kinetic trapping arrests the oligomers at the pre-set stoichiometry. Our data suggest that the different subcellular concentrations of PIP 2 mediate the differential SERT oligomerization behaviour, likely by direct physical connection of SERT protomers. Results SERT oligomerization depends on subcellular localization First, we addressed if SERT oligomerization differs between the plasma membrane and the ER. Monomeric GFP (mGFP) was inserted at the cytosolic N-terminus of SERT to allow for visualization (mGFP–SERT) 22 . Plasma membrane-localized mGFP–SERT was recorded at the bottom cell membrane via total internal reflection fluorescence (TIRF) microscopy. To retain SERT in the ER, we overexpressed a dominant-negative mutant of Sar1a (Sar1a-T39N) 13 , a small GTPase that regulates the assembly of COPII vesicles for plasma membrane trafficking. Sar1a-T39N is a GDP-restricted mutant which prevents the formation of COPII in a dominant-negative manner, thereby arresting SERT in the ER. ER-retained mGFP–SERT was studied at junctions between ER and the plasma membrane, where single-molecule tracking at high signal-to-noise ratio using TIRF microscopy is feasible 23 , 24 . We used the ‘Thinning out clusters while conserving stoichiometry’ (TOCCSL) technique previously established in our lab 7 , 25 , 26 , 27 to determine the oligomeric state of mGFP–SERT. TOCCSL extends fluorescence recovery after photobleaching (FRAP) to the level of single-molecule fluorescence microscopy ( Fig. 1a ). Typically, the high density of fluorescently labelled proteins results in a homogenously labelled surface, thereby precluding direct single-molecule measurements ( Fig. 1a ,i). In TOCCSL, a small area of the cell membrane is irreversibly photobleached by a strong laser pulse<|im_end|> <|im_start|>assistant Neurotransmitter transporters are some of the most popular transport proteins in research as they play a major role in the processing of signals in the brain. A joint study by TU Wien and the Medical University of Vienna has now successfully demonstrated for the first time the structural impact of membrane lipids on medically relevant serotonin transporters. The membrane of a cell is composed of a lipid bilayer. Lipids are good chemical and electrical insulators, which are ideally suited to separating the inside of the cell from the outside of the cell. But membranes also harbour a large number of proteins, some of which regulate the controlled exchange of substances across the membrane. While the majority of proteins are able to move freely within the lipid layers, they are found in groups with surprising frequency. The bonds between proteins may be fixed and permanent; or protein molecules may come together, split and come together again in another configuration. The research interests of the groups involved in the study, who were led by Prof. Gerhard Schütz from the Institute of Applied Physics at TU Wien and Prof. Harald Sitte from the Institute of Pharmacology at the Medical University of Vienna, concern how these interactions work, and this could shed further light on how the cell membrane and the membrane proteins embedded in it function. Molecule tracking Due to their size, protein molecules cannot be seen with the naked eye, which is why it is necessary to use a microscope to track them. However, the challenge lies in filtering out precisely those proteins which are of interest from the large number of other proteins in a cell. "Together with Prof. Harald Sitte from the Medical University of Vienna, at present we are particularly interested in the serotonin transporter (SERT), a protein that is important for the uptake of the neurotransmitter serotonin in the brain. In order to be able to observe it under a microscope, it is marked with a fluorescent biomolecule, a 'green fluorescent protein' (GFP)' explains Prof. Schütz. A molecular biological method is used to combine the GFP with the SERT and it then acts like a coloured balloon. "The 'single molecule microscopy' method enables us to determine from the strength of the signal from the points of light observed whether the molecule in question is moving around by itself or with other molecules of the same type." As a biophysicist, Schütz is not only interested in the fact that the proteins move around together but also in why the two molecules stick together, in other words how the underlying interaction mechanisms work. PIP2 (Phosphatidylinositol-4,5-bisphosphate) is a central signal molecule that is predominantly found on the side of the cell membrane facing the inside of the cell. It binds perfectly to the SERT, with amazing consequences. If only a low concentration of PIP2 is available, the oligomerisation of the SERT behaves as expected: low SERT concentrations mainly produce monomers, while high concentrations lead to the formation of oligomers. "It is not just that we are seeing a large number of oligomers, we also know that they exchange molecules with each other," says Schütz of his research. However, if there are high levels of PIP2 available, on average oligomers that are identical in size will always be produced, regardless of the SERT concentration. "It is as though the SERT proteins were locked in a predefined arrangement." Exploring cluster formation To investigate the underlying mechanisms of this amazing oligomer formation, you have to look inside the cell. One cell area - the endoplasmic reticulum - acts as the place where all membrane proteins, including SERT, are produced. This is in fact PIP2-free, meaning that SERT should have different levels of oligomerisation there, depending on the concentration of SERT. This has actually been observed too. "We assume that SERT oligomerises after it is produced in the endoplasmic reticulum, but that this process is initially reversible. It is only when the protein reaches the cell membrane that the predefined level of oligomerisation is fixed by PIP2," says Schütz. "These observations are confirmed by specific changes to the protein structure that we inserted into the serotonin transporter," says Sitte. "We were able to identify the position of the point mutations extremely accurately using computer models which Dr Thomas Stockner created as part of this study. The mutated SERT molecules exhibit a behaviour that makes it almost impossible for this locking to occur. And the medical relevance of our observation lies in the importance of oligomerisation for the behaviour of different psychostimulants, such as amphetamines: these can only have an effect if sufficient bonded SERT molecules are evident in the membrane." <|im_end|>

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2,510

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Lung cancer is the leading cause of cancer-associated mortality worldwide 1 . Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS . We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET , ROS1 , ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource. Main Lung cancer is the leading cause of cancer-related death worldwide, and represents 18% of cancer-related mortality and 11% of cancer incidence 1 . Yet, the biological mechanisms that underlie this aggressive tumour behaviour remain poorly understood. Multiregion sequencing provides an opportunity to leverage observed intratumour heterogeneity (ITH) to infer tumour phylogeny 2 , 3 , 4 . However, previous studies that used multiregion sequencing of primary tumour samples, herein referred to as ‘regions’, have been limited to 100 patients or fewer for a given tumour type, which limits statistical power for genomic and clinical analyses 5 . The functional relevance of ITH has also been subject to debate, with important consequences for personalized medicine 6 , 7 , 8 . Tracking non-small cell lung cancer (NSCLC) evolution through therapy (TRACERx) (ClinicalTrials.gov identifier: NCT01888601 ) is a prospective multicentre cancer study designed to delineate tumour evolution from diagnosis and surgical resection to either cure or disease recurrence. The co-primary endpoints of TRACERx are to determine the association between ITH and clinical outcome and the effect of adjuvant platinum-based chemotherapy on ITH in relapsed disease (the latter of which is explored in a companion article 9 ). In 2017, an analysis of the first 100 patients enrolled into TRACERx revealed pervasive genomic ITH and a significant association between somatic copy number alteration (SCNA) heterogeneity and poor prognosis 3 . However, no relationship between mutational ITH and outcome was observed. In this project, we extend our understanding of the evolutionary underpinnings of NSCLC and further investigate the relationship between established and new measures of ITH and clinical outcome. To achieve this, we leveraged multiregion exome primary tumour data from the first 421 patients prospectively enrolled into TRACERx. Prospective recruitment of 421 patients into TRACERx The TRACERx 421 cohort represents the first 421 patients prospectively recruited across 19 hospital sites in the United Kingdom. Recruitment conformed to a study protocol 3 implemented and monitored by the Cancer Research UK and University College London Cancer Trials Centre (Fig. 1 and Supplementary Table 1 ). Recruitment was broadly representative of an early-stage operable NSCLC population in the United Kingdom according to ethnicity, age, sex and smoking status. The cohort consisted of 233 males and 188 females, with a median age of 69 years (range of 34–92 years), and 210 patients with stage I disease, 132 with stage II disease and 79 with stage III disease (of which 98 patients have been previously reported 3 ). In total, 1,644 tumour regions sampled either at primary surgery (1,554) or during follow-up (90) passed quality control. These tumour samples were subjected to whole-exome sequencing (WES) at a median depth of 413× (interquartile range (IQR) = 367–474) and included in the analyses. Fig. 1: Longitudinal patient timelines for the TRACERx 421 cohort. The timing of clinical events including treatment, relapse or detection of a new primary and either time of death or latest follow-up is depicted for the 421 patients enrolled into the TRACERx study. Patients are arranged by histology and the presence or absence of a new lesion detected during follow-up. CRUK identifiers are coloured on the basis of whether the patient did not develop a new lesion after surgery (black) or if the first event after surgery was classified as recurrence (dark grey) or a new primary tumour (light grey). The overall patient stage at surgery and smoking status is depicted alongside metrics of ITH measured using multiregion WES of surgically excised samples including mutational ITH (the fraction of subclonal mutations), SCNA ITH (the fraction of the aberrant genome with subclonal SCNAs) and the estimated number of truncal and subclonal WGDs using our method ParallelGDDetect. Full size image These 421 patients harboured 432 genomically independent tumours at surgery as follows: 248 LUADs; 138 lung squamous cell carcinomas (LUSCs); and 46 ‘other’ NSCLC histological subtypes, including 14 adenosquamous, 14 pleomorphic, 8 large cell neuroendocrine, 6 large cell carcinomas, 1 carcinosarcoma and 3 tumours of mixed histology (Extended Data Figs. 1 and 2 ). If tissue was available for sequencing from several spatially distinct tumours in the same patient, WES-based assessment of shared clonal origin ( Methods ) generally agreed with clinical diagnosis of either multiple primary lung cancers or the presence of metastases on the basis of histology and the disease course. WES-based assessment of clonal origin was consistent with the clinical classification of multiple tumours in 6 out of 6 (100%) synchronous primary tumours and", "role": "user" }, { "content": "Knowing whether a tumor might grow or spread to other parts of a patient's body could be key to survival—and now scientists are one step closer to unlocking the ability to predict just that. In a series of seven papers published today (Wednesday, April 12) in Nature and Nature Medicine, researchers based at the Francis Crick Institute and University College London (UCL) describe how changes to cancer cells' DNA are enabling them to anticipate how those cells will behave in the future. This includes where and when cancer will spread to other parts of the body in a process known as metastasis, which is responsible for most cancer deaths worldwide. The findings could one day allow doctors to use a blood test to predict how a patient's cancer may grow and spread, enabling them to track it and rapidly adapt treatment in real-time. It also offers a possible route through which clinicians could analyze the disease's risk of returning following surgery. While the research was carried out on patients with lung cancer, the scientists say their findings could also be applied to other cancer types, such as skin cancer or kidney cancer. These studies are the culmination of 9 years of research from Cancer Research UK's £14 million TRACERx study—the first long-term study of how lung cancer evolves. TRACERx is a nation-wide research effort, involving more than 800 patients in clinical trials and a community of 250 investigators who based at 13 hospital sites across the U.K. Lead researcher based at the Francis Crick Institute in London, UCL and Cancer Research UK's Chief Clinician, Professor Charles Swanton, said, \"TRACERx recognizes that cancer is not static and the way we treat patients shouldn't be either. \"What makes the TRACERx project particularly powerful is that it treats tumors as ever-changing 'ecosystems' made up of diverse cancer cell populations. \"By looking at the tumor in its entirety, we can observe how these cell populations interact and even compete with one another, which is helping us to glean valuable insights into the likelihood that a tumor will return and when this might happen. We can also observe how the tumor is likely to evolve over time, spread and respond to treatment, offering hope to millions of patients in the future.\" In these seven studies, researchers at the Crick and UCL followed 421 of the 842 TRACERx participants from when they were diagnosed to monitor how their tumors changed over time. The patients had non-small cell lung cancer (NSCLC), the most common type of lung cancer. Among the major findings in the seven papers, the researchers found that: Tumors can be made up of many different populations of cancer cells which carry sets of genes that are constantly changing. The more diverse these tumors are, the more likely the patient's cancer will return within one year of treatment.Some patterns of DNA changes when observed in a patient's tumor indicate what their cancer might do next.These patterns could indicate to doctors which parts of a tumor might grow and spread to other parts of the body in the future.Blood tests could be used to monitor these changes to tumor DNA in real time, helping doctors pick up on early signs that cancer is returning or not responding to treatment. Constant changes to cells allow tumors to thrive Tumors are made up of different \"populations\" of cancer cells which all carry different genetic mutations. The more diverse these mutations are, the more that tumors can evolve and gain resistance to treatments. The researchers found that specific patterns of genetic mutations in cell populations enable the cancer to return in a patient quicker—within one year of surgery. Credit: Phospho Biomedical Animation These patterns of mutations also indicate whether a tumor is more likely to spread to other areas of the body beyond the lungs and chest. Armed with this information, doctors could one day predict if someone with early-stage cancer, who should be treated successfully with surgery, may end up seeing their cancer return. In another discovery, researchers found that the genetic diversity of cell populations within a tumor not only stems from genetic changes, but also from the way that genes are expressed. Changes in gene expression can affect important aspects of cancer biology, including whether a tumor will return after surgery. In this instance, the researchers suggest that doctors treating lung cancer patients could intervene early by identifying those whose cancer is most at risk of returning after surgery and following up with further treatment, to help prevent the cancer from coming back. Identifying what leads cancer to spread The researchers also looked more closely at how lung cancer spread in the TRACERx participants. They identified which cells in a tumor were most likely to be responsible for a cancer spreading (metastasis) in the future because these cells were more likely to harbor certain changes in their genes. These indicate that a cell has a higher chance of leaving the tumor and moving to other parts of the body, where it then grows into a new tumor. Metastasis is responsible for the majority of cancer deaths, so understanding which parts of the tumor are responsible for triggering this process could allow researchers to target treatments specifically to prevent cancer from spreading. Transforming how we track people's cancers The TRACERx scientists also investigated whether they could track changes in the tumor and features of its genetic diversity without the need for surgery or biopsies, a type of invasive medical procedure that involves taking a small sample of tissue and examining it in a lab. By analyzing DNA released into the bloodstream from tumor cells, known as circulating tumor DNA (ctDNA), they found that the presence of ctDNA in the blood before or after surgery suggested that the patient's cancer was highly likely to return in the future. The presence of tumor DNA in the blood isn't the only indicator that cancer might spread or come back. Researchers found that microscopic patterns created by the arrangement of tumor cells are linked with the risk of cancer returning. Executive director of research at Cancer Research UK, Dr. Iain Foulkes, said, \"A blood test that reads ctDNA could let doctors track someone's cancer in real time, allowing them to personalize treatments to that patient. \"Currently, the best option we have to monitor a patient's tumor is to extract tissue either through a biopsy or during surgery. Both are invasive and time-consuming options which give us a limited snapshot of how that tumor is behaving at a given point in time. \"Analysis of ctDNA would give us a fuller picture of how the tumor is changing over the course of the patient's disease using minimally invasive blood tests. It would allow doctors to treat people more proactively, taking swift action to change a treatment plan that's not working.\" TRACERx has already entered its next phase, known as TRACERx EVO, which will receive just under £15 million in additional funding over the next seven years to further our understanding of tumor evolution and use that knowledge to change how patients with cancer are treated. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Lung cancer is the leading cause of cancer-associated mortality worldwide 1 . Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS . We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET , ROS1 , ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource. Main Lung cancer is the leading cause of cancer-related death worldwide, and represents 18% of cancer-related mortality and 11% of cancer incidence 1 . Yet, the biological mechanisms that underlie this aggressive tumour behaviour remain poorly understood. Multiregion sequencing provides an opportunity to leverage observed intratumour heterogeneity (ITH) to infer tumour phylogeny 2 , 3 , 4 . However, previous studies that used multiregion sequencing of primary tumour samples, herein referred to as ‘regions’, have been limited to 100 patients or fewer for a given tumour type, which limits statistical power for genomic and clinical analyses 5 . The functional relevance of ITH has also been subject to debate, with important consequences for personalized medicine 6 , 7 , 8 . Tracking non-small cell lung cancer (NSCLC) evolution through therapy (TRACERx) (ClinicalTrials.gov identifier: NCT01888601 ) is a prospective multicentre cancer study designed to delineate tumour evolution from diagnosis and surgical resection to either cure or disease recurrence. The co-primary endpoints of TRACERx are to determine the association between ITH and clinical outcome and the effect of adjuvant platinum-based chemotherapy on ITH in relapsed disease (the latter of which is explored in a companion article 9 ). In 2017, an analysis of the first 100 patients enrolled into TRACERx revealed pervasive genomic ITH and a significant association between somatic copy number alteration (SCNA) heterogeneity and poor prognosis 3 . However, no relationship between mutational ITH and outcome was observed. In this project, we extend our understanding of the evolutionary underpinnings of NSCLC and further investigate the relationship between established and new measures of ITH and clinical outcome. To achieve this, we leveraged multiregion exome primary tumour data from the first 421 patients prospectively enrolled into TRACERx. Prospective recruitment of 421 patients into TRACERx The TRACERx 421 cohort represents the first 421 patients prospectively recruited across 19 hospital sites in the United Kingdom. Recruitment conformed to a study protocol 3 implemented and monitored by the Cancer Research UK and University College London Cancer Trials Centre (Fig. 1 and Supplementary Table 1 ). Recruitment was broadly representative of an early-stage operable NSCLC population in the United Kingdom according to ethnicity, age, sex and smoking status. The cohort consisted of 233 males and 188 females, with a median age of 69 years (range of 34–92 years), and 210 patients with stage I disease, 132 with stage II disease and 79 with stage III disease (of which 98 patients have been previously reported 3 ). In total, 1,644 tumour regions sampled either at primary surgery (1,554) or during follow-up (90) passed quality control. These tumour samples were subjected to whole-exome sequencing (WES) at a median depth of 413× (interquartile range (IQR) = 367–474) and included in the analyses. Fig. 1: Longitudinal patient timelines for the TRACERx 421 cohort. The timing of clinical events including treatment, relapse or detection of a new primary and either time of death or latest follow-up is depicted for the 421 patients enrolled into the TRACERx study. Patients are arranged by histology and the presence or absence of a new lesion detected during follow-up. CRUK identifiers are coloured on the basis of whether the patient did not develop a new lesion after surgery (black) or if the first event after surgery was classified as recurrence (dark grey) or a new primary tumour (light grey). The overall patient stage at surgery and smoking status is depicted alongside metrics of ITH measured using multiregion WES of surgically excised samples including mutational ITH (the fraction of subclonal mutations), SCNA ITH (the fraction of the aberrant genome with subclonal SCNAs) and the estimated number of truncal and subclonal WGDs using our method ParallelGDDetect. Full size image These 421 patients harboured 432 genomically independent tumours at surgery as follows: 248 LUADs; 138 lung squamous cell carcinomas (LUSCs); and 46 ‘other’ NSCLC histological subtypes, including 14 adenosquamous, 14 pleomorphic, 8 large cell neuroendocrine, 6 large cell carcinomas, 1 carcinosarcoma and 3 tumours of mixed histology (Extended Data Figs. 1 and 2 ). If tissue was available for sequencing from several spatially distinct tumours in the same patient, WES-based assessment of shared clonal origin ( Methods ) generally agreed with clinical diagnosis of either multiple primary lung cancers or the presence of metastases on the basis of histology and the disease course. WES-based assessment of clonal origin was consistent with the clinical classification of multiple tumours in 6 out of 6 (100%) synchronous primary tumours and<|im_end|> <|im_start|>assistant Knowing whether a tumor might grow or spread to other parts of a patient's body could be key to survival—and now scientists are one step closer to unlocking the ability to predict just that. In a series of seven papers published today (Wednesday, April 12) in Nature and Nature Medicine, researchers based at the Francis Crick Institute and University College London (UCL) describe how changes to cancer cells' DNA are enabling them to anticipate how those cells will behave in the future. This includes where and when cancer will spread to other parts of the body in a process known as metastasis, which is responsible for most cancer deaths worldwide. The findings could one day allow doctors to use a blood test to predict how a patient's cancer may grow and spread, enabling them to track it and rapidly adapt treatment in real-time. It also offers a possible route through which clinicians could analyze the disease's risk of returning following surgery. While the research was carried out on patients with lung cancer, the scientists say their findings could also be applied to other cancer types, such as skin cancer or kidney cancer. These studies are the culmination of 9 years of research from Cancer Research UK's £14 million TRACERx study—the first long-term study of how lung cancer evolves. TRACERx is a nation-wide research effort, involving more than 800 patients in clinical trials and a community of 250 investigators who based at 13 hospital sites across the U.K. Lead researcher based at the Francis Crick Institute in London, UCL and Cancer Research UK's Chief Clinician, Professor Charles Swanton, said, "TRACERx recognizes that cancer is not static and the way we treat patients shouldn't be either. "What makes the TRACERx project particularly powerful is that it treats tumors as ever-changing 'ecosystems' made up of diverse cancer cell populations. "By looking at the tumor in its entirety, we can observe how these cell populations interact and even compete with one another, which is helping us to glean valuable insights into the likelihood that a tumor will return and when this might happen. We can also observe how the tumor is likely to evolve over time, spread and respond to treatment, offering hope to millions of patients in the future." In these seven studies, researchers at the Crick and UCL followed 421 of the 842 TRACERx participants from when they were diagnosed to monitor how their tumors changed over time. The patients had non-small cell lung cancer (NSCLC), the most common type of lung cancer. Among the major findings in the seven papers, the researchers found that: Tumors can be made up of many different populations of cancer cells which carry sets of genes that are constantly changing. The more diverse these tumors are, the more likely the patient's cancer will return within one year of treatment.Some patterns of DNA changes when observed in a patient's tumor indicate what their cancer might do next.These patterns could indicate to doctors which parts of a tumor might grow and spread to other parts of the body in the future.Blood tests could be used to monitor these changes to tumor DNA in real time, helping doctors pick up on early signs that cancer is returning or not responding to treatment. Constant changes to cells allow tumors to thrive Tumors are made up of different "populations" of cancer cells which all carry different genetic mutations. The more diverse these mutations are, the more that tumors can evolve and gain resistance to treatments. The researchers found that specific patterns of genetic mutations in cell populations enable the cancer to return in a patient quicker—within one year of surgery. Credit: Phospho Biomedical Animation These patterns of mutations also indicate whether a tumor is more likely to spread to other areas of the body beyond the lungs and chest. Armed with this information, doctors could one day predict if someone with early-stage cancer, who should be treated successfully with surgery, may end up seeing their cancer return. In another discovery, researchers found that the genetic diversity of cell populations within a tumor not only stems from genetic changes, but also from the way that genes are expressed. Changes in gene expression can affect important aspects of cancer biology, including whether a tumor will return after surgery. In this instance, the researchers suggest that doctors treating lung cancer patients could intervene early by identifying those whose cancer is most at risk of returning after surgery and following up with further treatment, to help prevent the cancer from coming back. Identifying what leads cancer to spread The researchers also looked more closely at how lung cancer spread in the TRACERx participants. They identified which cells in a tumor were most likely to be responsible for a cancer spreading (metastasis) in the future because these cells were more likely to harbor certain changes in their genes. These indicate that a cell has a higher chance of leaving the tumor and moving to other parts of the body, where it then grows into a new tumor. Metastasis is responsible for the majority of cancer deaths, so understanding which parts of the tumor are responsible for triggering this process could allow researchers to target treatments specifically to prevent cancer from spreading. Transforming how we track people's cancers The TRACERx scientists also investigated whether they could track changes in the tumor and features of its genetic diversity without the need for surgery or biopsies, a type of invasive medical procedure that involves taking a small sample of tissue and examining it in a lab. By analyzing DNA released into the bloodstream from tumor cells, known as circulating tumor DNA (ctDNA), they found that the presence of ctDNA in the blood before or after surgery suggested that the patient's cancer was highly likely to return in the future. The presence of tumor DNA in the blood isn't the only indicator that cancer might spread or come back. Researchers found that microscopic patterns created by the arrangement of tumor cells are linked with the risk of cancer returning. Executive director of research at Cancer Research UK, Dr. Iain Foulkes, said, "A blood test that reads ctDNA could let doctors track someone's cancer in real time, allowing them to personalize treatments to that patient. "Currently, the best option we have to monitor a patient's tumor is to extract tissue either through a biopsy or during surgery. Both are invasive and time-consuming options which give us a limited snapshot of how that tumor is behaving at a given point in time. "Analysis of ctDNA would give us a fuller picture of how the tumor is changing over the course of the patient's disease using minimally invasive blood tests. It would allow doctors to treat people more proactively, taking swift action to change a treatment plan that's not working." TRACERx has already entered its next phase, known as TRACERx EVO, which will receive just under £15 million in additional funding over the next seven years to further our understanding of tumor evolution and use that knowledge to change how patients with cancer are treated. <|im_end|>

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2,871

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Peptide nanostructures are biodegradable and are suitable for many biomedical applications. However, to be useful imaging probes, the limited intrinsic optical properties of peptides must be overcome. Here we show the formation of tryptophan–phenylalanine dipeptide nanoparticles (DNPs) that can shift the peptide's intrinsic fluorescent signal from the ultraviolet to the visible range. The visible emission signal allows the DNPs to act as imaging and sensing probes. The peptide design is inspired by the red shift seen in the yellow fluorescent protein that results from π – π stacking and by the enhanced fluorescence intensity seen in the green fluorescent protein mutant, BFPms1, which results from the structure rigidification by Zn (II) . We show that DNPs are photostable, biocompatible and have a narrow emission bandwidth and visible fluorescence properties. DNPs functionalized with the MUC1 aptamer and doxorubicin can target cancer cells and can be used to image and monitor drug release in real time. Main Owing to their intrinsic low toxicity and high translational values, peptide nanostructures have great potential for their use in biological and biomedical applications 1 , 2 . Among the various peptide nanostructures, peptide nanoparticles with fluorescence properties are highly sought after because of their promising biodegradability. However, peptides have limited intrinsic optical properties that restrict their applicability as productive and efficient imaging probes. The addition of organic fluorophores 3 or quantum dots (QDs) 4 has been proposed as a means to modify peptides for fluorescent imaging. Unfortunately, organic fluorescence dyes often suffer from a high susceptibility to photobleaching and limited specificity when bioconjugating to specific sites 5 , 6 . As for QDs, cytotoxicity remains a concern for biomedical applications 7 , 8 . To date, several studies have been conducted that focused on manipulating peptide self-assembly into the desired nanoarchitectures 9 , 10 . Nonetheless, it remains unclear as to whether fluorescent peptide nanoparticles can be synthesized through self-assembly to change the intrinsic optical properties of peptide nanostructures. Inspired by organized assemblies in nature, we demonstrate the formation of tryptophan–phenylalanine (Trp-Phe) nanoparticles that can shift the peptide's intrinsic fluorescence signal from the ultraviolet to the visible range. The visible emission signal allows the dipeptide nanoparticles (DNPs) to act as imaging and sensing probes. The overall design was inspired by the molecular mechanism that results in the red shift seen in the yellow fluorescent protein (YFP) and the enhanced fluorescence intensity seen in the green fluorescent mutant protein BFPms1. The red shift in YFP results from π – π stacking and the enhanced intensity in BFPms1 results from the structure rigidification by Zn (II) . Our experimental data show that the DNPs are photostable, biocompatible and have a narrow emission bandwidth as well as visible fluorescence properties. In addition, the DNPs functionalized with the MUC1 aptamer and doxorubicin (DOX) can target cancer cells, and image and monitor drug release in real time. Bioinspired self-assembly of the DNPs Since their discovery in the 1960s 11 , green fluorescent proteins (GFPs) have emerged as one of the most widely utilized proteins because of their visible fluorescence properties. The YFP has the longest wavelength emission among all GFP variants 12 , and red shifts relative to the GFP because of the π – π stacking interactions between the tyrosine (Tyr) and the phenolate anion of the chromophore 13 ( Fig. 1a ) as a result of a Thr203Tyr substitution introduced by mutation. The π – π stacking interaction reduces the excited-state energy, and increases the excitation and emission wavelengths by up to 24 nm compared with those of wild-type GFP 14 . The π – π stacking interaction has been proposed as a driving force for aromatic dipeptide self-assembly 15 , 16 . However, BFPms1, a mutant protein that originates from GFP, shows a high binding affinity to Zn (II) . This enhances the quantum yield and fluorescence intensity 17 ( Fig. 1b ). Furthermore, the Zn (II) chelation structure reduces fluorophore mobility to limit further the energy dissipation through thermal relaxation pathways. Figure 1: Design of the self-assembled fluorescent DNPs through bioinspiration by the molecular principles that underlie the GFP family. a , YFP (Protein Database (PDB) entry 1HUY ) and the chemical structure of its chromophore. The fluorescence red shift seen in the YFP results from a Thr203Tyr substitution, which leads to the π – π stacking interactions between the Tyr and the phenolate anion of the chromophore. The π – π stacking interactions reduce the excited state energy and increase both the excitation and emission wavelengths by up to 24 nm compared with those of wild-type GFPs. Green, β-sheet structure; purple, α-helix structure. b , Blue fluorescent protein (BFP; PDB entry 1KYS ) and the chemical structure of its chromophore. Zn (II) binding rigidifies the chromophore imidazole, reduces fluorophore mobility and further limits the energy dissipation through thermal relaxation pathways, and thereby results in the enhanced fluorescence seen in BFP. c , Bioinspired synthesis of the fluorescent DNPs with Trp-Phe dipeptides as the basic unit (left). Through hydrogen bonding, π – π stacking interactions and Zn (II) coordinations (middle), the dipeptide self-assembles to form spherical nanoparticles (right). Both H-Trp-Phe-OH and OH-Phe-Trp-H represent Trp-Phe dipeptides. d , The atomic force microscopy (AFM) image of the DNPs shows uniform spherical nanoparticles of approximately 160 nm. e , FTIR absorption spectrum in the amide I region of 1 mg ml –1 DNPs in water shows the presence of well-ordered aggregates for the Trp-Phe dipeptides. a.u., arbitrary units. Full size image Inspired by the molecular mechanisms described above, we proposed to utilize the effects of π – π stacking interaction and metal coordination to tune the fluorescence properties of the peptide assembly from the ultraviolet to the visible range. Here, dipeptides composed of natural aromatic amino acids, including Trp, Tyr or Phe, were chosen as the basic units to synthesize the fluorescent DNPs. Tryptophan was chosen because of its long emission wavelength and high quantum yield compared with the those of three aromatic amino acids 18 . To", "role": "user" }, { "content": "Tracking the path of chemotherapy drugs in real time and at a cellular level could revolutionize cancer care and help doctors sort out why two patients might respond differently to the same treatment. Researchers at The Ohio State University have found a way to light up a common cancer drug so they can see where the chemo goes and how long it takes to get there. They've devised an organic technique for creating this scientific guiding star and in doing so have opened up a new frontier in their field. Previous efforts have been limited by dyes that faded quickly and by toxic elements, particularly metals. A study published this week in the journal Nature Nanotechnology highlighted two novel accomplishments. First, the researchers created a luminescent molecule, called a peptide and made up of two amino acids. Then they hitched that light to the cancer medication so that it revealed the chemo's arrival within cells. \"This is very important for personalized medicine. We really want to see what's going on when we give chemo drugs and this work paves the way for the exciting endeavor,\" said Dr. Mingjun Zhang, the biomedical engineering professor who led the study. Biomedical engineers strive to find techniques that behave naturally within the body and leave without doing harm. This research holds promise for doing just that because the peptide is one that should easily coexist with human cells and leave as harmlessly as it entered. \"You can combine your drug with this luminescent vehicle,\" Zhang said of the tiny fluorescent particle devised in his lab. \"Composed of natural amino acids, the nanoparticle is inherently biocompatible. Our biological machines can easily take care of it.\" This work was done in petri dishes in Zhang's lab and work in animals is currently underway. In the body or tissue of an animal or person, scientists would watch the fluorescent signal with an optical detection system, he said. Zhang and his colleagues sandwiched their peptide to a common chemotherapy drug so that its light was hidden until the two elements peeled apart upon entering the cells. Zhang was particularly delighted to see that the blue peptide, which can be seen under ultraviolet light, maintained its luminescence for extended periods of time. Previous work to track drugs using organic dyes has been hampered by their tendency to fade with time. \"You can label it and you can attach it to a drug and see where the drug goes and when it is released,\" Zhang said. And it could be that the biomedical advance can give patients and their doctors information on how well and how quickly a medication is working for them. \"Maybe for some people a drug is taking effect in a few minutes and for somebody else it's hours and for somebody else it never takes effect,\" Zhang said. The research team used doxorubicin, a widely used chemotherapy drug, for their lab work, but the discovery could apply to different types of treatments. Better understanding of the complex interplay of cells and drugs is critical to development of treatments that are finely tuned for individual patients. The Ohio State work builds on research that earned a trio of scientists the 2008 Nobel Prize in Chemistry. Their work on green fluorescent protein found in jelly fish led to the discovery that scientists could illuminate cellular-level activity that had previously been cloaked in mystery. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Peptide nanostructures are biodegradable and are suitable for many biomedical applications. However, to be useful imaging probes, the limited intrinsic optical properties of peptides must be overcome. Here we show the formation of tryptophan–phenylalanine dipeptide nanoparticles (DNPs) that can shift the peptide's intrinsic fluorescent signal from the ultraviolet to the visible range. The visible emission signal allows the DNPs to act as imaging and sensing probes. The peptide design is inspired by the red shift seen in the yellow fluorescent protein that results from π – π stacking and by the enhanced fluorescence intensity seen in the green fluorescent protein mutant, BFPms1, which results from the structure rigidification by Zn (II) . We show that DNPs are photostable, biocompatible and have a narrow emission bandwidth and visible fluorescence properties. DNPs functionalized with the MUC1 aptamer and doxorubicin can target cancer cells and can be used to image and monitor drug release in real time. Main Owing to their intrinsic low toxicity and high translational values, peptide nanostructures have great potential for their use in biological and biomedical applications 1 , 2 . Among the various peptide nanostructures, peptide nanoparticles with fluorescence properties are highly sought after because of their promising biodegradability. However, peptides have limited intrinsic optical properties that restrict their applicability as productive and efficient imaging probes. The addition of organic fluorophores 3 or quantum dots (QDs) 4 has been proposed as a means to modify peptides for fluorescent imaging. Unfortunately, organic fluorescence dyes often suffer from a high susceptibility to photobleaching and limited specificity when bioconjugating to specific sites 5 , 6 . As for QDs, cytotoxicity remains a concern for biomedical applications 7 , 8 . To date, several studies have been conducted that focused on manipulating peptide self-assembly into the desired nanoarchitectures 9 , 10 . Nonetheless, it remains unclear as to whether fluorescent peptide nanoparticles can be synthesized through self-assembly to change the intrinsic optical properties of peptide nanostructures. Inspired by organized assemblies in nature, we demonstrate the formation of tryptophan–phenylalanine (Trp-Phe) nanoparticles that can shift the peptide's intrinsic fluorescence signal from the ultraviolet to the visible range. The visible emission signal allows the dipeptide nanoparticles (DNPs) to act as imaging and sensing probes. The overall design was inspired by the molecular mechanism that results in the red shift seen in the yellow fluorescent protein (YFP) and the enhanced fluorescence intensity seen in the green fluorescent mutant protein BFPms1. The red shift in YFP results from π – π stacking and the enhanced intensity in BFPms1 results from the structure rigidification by Zn (II) . Our experimental data show that the DNPs are photostable, biocompatible and have a narrow emission bandwidth as well as visible fluorescence properties. In addition, the DNPs functionalized with the MUC1 aptamer and doxorubicin (DOX) can target cancer cells, and image and monitor drug release in real time. Bioinspired self-assembly of the DNPs Since their discovery in the 1960s 11 , green fluorescent proteins (GFPs) have emerged as one of the most widely utilized proteins because of their visible fluorescence properties. The YFP has the longest wavelength emission among all GFP variants 12 , and red shifts relative to the GFP because of the π – π stacking interactions between the tyrosine (Tyr) and the phenolate anion of the chromophore 13 ( Fig. 1a ) as a result of a Thr203Tyr substitution introduced by mutation. The π – π stacking interaction reduces the excited-state energy, and increases the excitation and emission wavelengths by up to 24 nm compared with those of wild-type GFP 14 . The π – π stacking interaction has been proposed as a driving force for aromatic dipeptide self-assembly 15 , 16 . However, BFPms1, a mutant protein that originates from GFP, shows a high binding affinity to Zn (II) . This enhances the quantum yield and fluorescence intensity 17 ( Fig. 1b ). Furthermore, the Zn (II) chelation structure reduces fluorophore mobility to limit further the energy dissipation through thermal relaxation pathways. Figure 1: Design of the self-assembled fluorescent DNPs through bioinspiration by the molecular principles that underlie the GFP family. a , YFP (Protein Database (PDB) entry 1HUY ) and the chemical structure of its chromophore. The fluorescence red shift seen in the YFP results from a Thr203Tyr substitution, which leads to the π – π stacking interactions between the Tyr and the phenolate anion of the chromophore. The π – π stacking interactions reduce the excited state energy and increase both the excitation and emission wavelengths by up to 24 nm compared with those of wild-type GFPs. Green, β-sheet structure; purple, α-helix structure. b , Blue fluorescent protein (BFP; PDB entry 1KYS ) and the chemical structure of its chromophore. Zn (II) binding rigidifies the chromophore imidazole, reduces fluorophore mobility and further limits the energy dissipation through thermal relaxation pathways, and thereby results in the enhanced fluorescence seen in BFP. c , Bioinspired synthesis of the fluorescent DNPs with Trp-Phe dipeptides as the basic unit (left). Through hydrogen bonding, π – π stacking interactions and Zn (II) coordinations (middle), the dipeptide self-assembles to form spherical nanoparticles (right). Both H-Trp-Phe-OH and OH-Phe-Trp-H represent Trp-Phe dipeptides. d , The atomic force microscopy (AFM) image of the DNPs shows uniform spherical nanoparticles of approximately 160 nm. e , FTIR absorption spectrum in the amide I region of 1 mg ml –1 DNPs in water shows the presence of well-ordered aggregates for the Trp-Phe dipeptides. a.u., arbitrary units. Full size image Inspired by the molecular mechanisms described above, we proposed to utilize the effects of π – π stacking interaction and metal coordination to tune the fluorescence properties of the peptide assembly from the ultraviolet to the visible range. Here, dipeptides composed of natural aromatic amino acids, including Trp, Tyr or Phe, were chosen as the basic units to synthesize the fluorescent DNPs. Tryptophan was chosen because of its long emission wavelength and high quantum yield compared with the those of three aromatic amino acids 18 . To<|im_end|> <|im_start|>assistant Tracking the path of chemotherapy drugs in real time and at a cellular level could revolutionize cancer care and help doctors sort out why two patients might respond differently to the same treatment. Researchers at The Ohio State University have found a way to light up a common cancer drug so they can see where the chemo goes and how long it takes to get there. They've devised an organic technique for creating this scientific guiding star and in doing so have opened up a new frontier in their field. Previous efforts have been limited by dyes that faded quickly and by toxic elements, particularly metals. A study published this week in the journal Nature Nanotechnology highlighted two novel accomplishments. First, the researchers created a luminescent molecule, called a peptide and made up of two amino acids. Then they hitched that light to the cancer medication so that it revealed the chemo's arrival within cells. "This is very important for personalized medicine. We really want to see what's going on when we give chemo drugs and this work paves the way for the exciting endeavor," said Dr. Mingjun Zhang, the biomedical engineering professor who led the study. Biomedical engineers strive to find techniques that behave naturally within the body and leave without doing harm. This research holds promise for doing just that because the peptide is one that should easily coexist with human cells and leave as harmlessly as it entered. "You can combine your drug with this luminescent vehicle," Zhang said of the tiny fluorescent particle devised in his lab. "Composed of natural amino acids, the nanoparticle is inherently biocompatible. Our biological machines can easily take care of it." This work was done in petri dishes in Zhang's lab and work in animals is currently underway. In the body or tissue of an animal or person, scientists would watch the fluorescent signal with an optical detection system, he said. Zhang and his colleagues sandwiched their peptide to a common chemotherapy drug so that its light was hidden until the two elements peeled apart upon entering the cells. Zhang was particularly delighted to see that the blue peptide, which can be seen under ultraviolet light, maintained its luminescence for extended periods of time. Previous work to track drugs using organic dyes has been hampered by their tendency to fade with time. "You can label it and you can attach it to a drug and see where the drug goes and when it is released," Zhang said. And it could be that the biomedical advance can give patients and their doctors information on how well and how quickly a medication is working for them. "Maybe for some people a drug is taking effect in a few minutes and for somebody else it's hours and for somebody else it never takes effect," Zhang said. The research team used doxorubicin, a widely used chemotherapy drug, for their lab work, but the discovery could apply to different types of treatments. Better understanding of the complex interplay of cells and drugs is critical to development of treatments that are finely tuned for individual patients. The Ohio State work builds on research that earned a trio of scientists the 2008 Nobel Prize in Chemistry. Their work on green fluorescent protein found in jelly fish led to the discovery that scientists could illuminate cellular-level activity that had previously been cloaked in mystery. <|im_end|>

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2,065

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract CeRhIn 5 provides a textbook example of quantum criticality in a heavy fermion system: Pressure suppresses local-moment antiferromagnetic (AFM) order and induces superconductivity in a dome around the associated quantum critical point (QCP) near p c ≈ 23 kbar. Strong magnetic fields also suppress the AFM order at a field-induced QCP at B c ≈ 50 T. In its vicinity, a nematic phase at B * ≈ 28 T characterized by a large in-plane resistivity anisotropy emerges. Here, we directly investigate the interrelation between these phenomena via magnetoresistivity measurements under high pressure. As pressure increases, the nematic transition shifts to higher fields, until it vanishes just below p c . While pressure suppresses magnetic order in zero field as p c is approached, we find magnetism to strengthen under strong magnetic fields due to suppression of the Kondo effect. We reveal a strongly non-mean-field-like phase diagram, much richer than the common local-moment description of CeRhIn 5 would suggest. Introduction The physical properties of cerium-based heavy-fermion superconductors are strongly governed by the Ce 4 f 1 electrons and their interaction with the itinerant charge carriers 1 , 2 . Due to the small scale of the relevant energies associated with the hybridization of the 4 f -electrons with the conduction bands, small changes in the chemical composition, magnetic field, or pressure strongly influence the ground state and frequently lead to quantum critical phenomena 3 , 4 , 5 , 6 , 7 . Here we focus on CeRhIn 5 , a local-moment antiferromagnet characterized by a Néel temperature of T N = 3.85 K 8 . The antiferromagnetic (AFM) order is suppressed under pressure, and superconductivity emerges in a dome located around the associated AFM quantum critical point (QCP) at p c ≈ 23 kbar 9 . The picture of pressure-induced quantum criticality is further supported by the observation of non-Fermi-liquid behavior in its vicinity 9 , 10 , 11 . Recent experiments have provided evidence for a second QCP at ambient pressure and under strong magnetic fields, B c ( p = 0) ≈ 50 T 12 , 13 . The temperature dependence of the resistivity at the field-induced QCP is well described by a similar power law, ρ ( B = 50 T, p = 0) ∝ T 0.91 , compared to the behavior at the zero-field QCP, ρ ( B = 0, p = 23 kbar) ∝ T 0.85 9 , 13 . Interestingly, the magnitude of B c is almost completely independent of the field orientation, despite the presence of magnetic anisotropy χ c / χ a ≈ 2 14 . This isotropy of B c provides a first hint that CeRhIn 5 in high magnetic fields goes beyond a simplistic picture of a local-moment magnet. Recently, a field-induced phase transition was observed at intermediate magnetic fields B * ≥ 28 T 12 , 15 , 16 , and a nematic character of this high-field phase has been reported, based on the sudden emergence of an in-plane resistivity anisotropy 13 . Magnetic probes, such as magnetization and torque, however, show hardly any features in the relevant field-temperature range 13 , 14 , thus rendering a metamagnetic origin of the B * transition unlikely. A nematic state, as proposed, electronically breaks the C 4 rotational symmetry in the ( a , b ) plane, and hence must be reflected by a small lattice distortion 17 , which has recently been verified by magnetostriction experiments confirming the thermodynamic character of the transition at B * 18 . For these reasons we shall refer to the sudden and strong field-induced transport anisotropy at B * as nematic for simplicity. Yet its microscopic origin remains a highly active area of research, and the nematic picture is constantly expanded, refined as well as challenged. The main open questions concern the explicitly symmetry-breaking role of the in-plane magnetic field 19 , for example, through a modification of the crystal-electric-field schemes, as well as potential changes of the microscopic magnetic ordering that might remain undetected by measurements of the averaged magnetization and torque. Here, the recent breakthroughs in pulsed magnetic field neutron scattering 20 and other microscopic techniques would be most insightful. One of the main results of the present work is to trace the field scale, B * ( p ), into the high-pressure regime regardless of its origin. CeRhIn 5 presents a unique opportunity to tune a highly correlated system between a diverse set of ground states, including unconventional superconductivity, local-moment magnetism, a putative (spin- or charge-) nematic, and a heavy Fermi liquid 8 , 13 , 21 , 22 . Here we chart the unknown territory of combined high field/high pressure, to serve as a testbed for theoretical approaches tackling this problem. Most importantly, the entire phase diagram can be mapped within one clean single crystal, hence avoiding the complexities of sample dependence and non-stoichiometry, by the use of the two least invasive tuning parameters, pressure and magnetic field. While conceptually appealing, this presents a formidable experimental challenge: transport experiments on metallic samples in pulsed magnetic fields need to be combined with diamond-anvil pressure cells (DACs) and 3 He temperatures. Inspired by previous experiments in high fields and high pressures 23 , 24 , 25 , 26 , we here present a new approach combining focused ion beam (FIB) crystal micromachining 27 and DACs 26 made from plastic for multi-terminal measurements of transport anisotropy (SEM images of the devices can be found in Fig. 1 a and Supplementary Fig. 1 ). To minimize heating due to eddy currents in pulsed magnetic fields, the body of the pressure cell and the 3 He cryostat was made entirely from plastic (for further details see “Methods”). In the following, we detail three main experimental observations uncovered by this study: first, the nematic onset field B * , characterized by an anisotropy jump and a first-order-like hysteretic behavior, grows with applied pressure from 28 T at ambient pressure to around 40 T for close", "role": "user" }, { "content": "An international team of scientists from the Helmholtz-Zentrum Dresden-Rossendorf (HZDR), the Max Planck Institute for Chemical Physics of Solids, and colleagues from the USA and Switzerland have successfully combined various extreme experimental conditions in a completely unique way, revealing exciting insights into the mysterious conducting properties of the crystalline metal CeRhIn5. In the journal Nature Communications, they report on their exploration of previously uncharted regions of the phase diagram of this metal, which is considered a promising model system for understanding unconventional superconductors. \"First, we apply a thin layer of gold to a microscopically small single crystal. Then we use an ion beam to carve out tiny microstructures. At the ends of these structures, we attach ultra-thin platinum tapes to measure resistance along different directions under extremely high pressures, which we generate with a diamond anvil pressure cell. In addition, we apply very powerful magnetic fields to the sample at temperatures near absolute zero.\" To the average person, this may sound like an overzealous physicist's whimsical fancy, but in fact, it is an actual description of the experimental work conducted by Dr. Toni Helm from HZDR's High Magnetic Field Laboratory (HLD) and his colleagues from Tallahassee, Los Alamos, Lausanne and Dresden. Well, at least in part, because this description only hints at the many challenges involved in combining such extremes concurrently. This great effort is, of course, not an end in itself: the researchers are trying to get to the bottom of some fundamental questions of solid state physics. The sample studied is cer-rhodium-indium-five (CeRhIn5), a metal with surprising properties that are not fully understood yet. Scientists describe it as an unconventional electrical conductor with extremely heavy charge carriers, in which, under certain conditions, electrical current can flow without losses. It is assumed that the key to this superconductivity lies in the metal's magnetic properties. The central issues investigated by physicists working with such correlated electron systems include: How do heavy electrons organize collectively? How can this cause magnetism and superconductivity? And what is the relationship between these physical phenomena? An expedition through the phase diagram The physicists are particularly interested in the metal's phase diagram, a kind of map whose coordinates are pressure, magnetic field strength, and temperature. If the map is to be meaningful, the scientists have to uncover as many locations as possible in this system of coordinates, just like a cartographer exploring unknown territory. In fact, the emerging diagram is not unlike the terrain of a landscape. As they reduce temperature to almost four degrees above absolute zero, the physicists observe magnetic order in the metal sample. At this point, they have a number of options: They can cool the sample down even further and expose it to high pressures, forcing a transition into the superconducting state. If, on the other hand, they solely increase the external magnetic field to 600,000 times the strength of the earth's magnetic field, the magnetic order is also suppressed; however, the material enters a state called 'electronically nematic.' This term is borrowed from the physics of liquid crystals, where it describes a certain spatial orientation of molecules with a long-range order over larger areas. The scientists assume that the electronically nematic state is closely linked to the phenomenon of unconventional superconductivity. The experimental environment at HLD provides optimum conditions for such a complex measurement project. The large magnets generate relatively long-lasting pulses and offer sufficient space for complex measurement methods under extreme conditions. Experiments at the limit afford a glimpse of the future The experiments have a few additional special characteristics. For example, working with high-pulsed magnetic fields creates eddy currents in the metallic parts of the experimental setup, which can generate unwanted heat. The scientists have therefore manufactured the central components from a special plastic material that suppresses this effect and functions reliably near absolute zero. Through the microfabrication by focused ion beams, they produce a sample geometry that guarantees a high-quality measurement signal. \"Microstructuring will become much more important in future experiments. That's why we brought this technology into the laboratory right away,\" says Helm, adding: \"So we now have ways to access and gradually penetrate into dimensions where quantum mechanical effects play a major role.\" He is also certain that the know-how he and his team have acquired will contribute to research on high-temperature superconductors or novel quantum technologies. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract CeRhIn 5 provides a textbook example of quantum criticality in a heavy fermion system: Pressure suppresses local-moment antiferromagnetic (AFM) order and induces superconductivity in a dome around the associated quantum critical point (QCP) near p c ≈ 23 kbar. Strong magnetic fields also suppress the AFM order at a field-induced QCP at B c ≈ 50 T. In its vicinity, a nematic phase at B * ≈ 28 T characterized by a large in-plane resistivity anisotropy emerges. Here, we directly investigate the interrelation between these phenomena via magnetoresistivity measurements under high pressure. As pressure increases, the nematic transition shifts to higher fields, until it vanishes just below p c . While pressure suppresses magnetic order in zero field as p c is approached, we find magnetism to strengthen under strong magnetic fields due to suppression of the Kondo effect. We reveal a strongly non-mean-field-like phase diagram, much richer than the common local-moment description of CeRhIn 5 would suggest. Introduction The physical properties of cerium-based heavy-fermion superconductors are strongly governed by the Ce 4 f 1 electrons and their interaction with the itinerant charge carriers 1 , 2 . Due to the small scale of the relevant energies associated with the hybridization of the 4 f -electrons with the conduction bands, small changes in the chemical composition, magnetic field, or pressure strongly influence the ground state and frequently lead to quantum critical phenomena 3 , 4 , 5 , 6 , 7 . Here we focus on CeRhIn 5 , a local-moment antiferromagnet characterized by a Néel temperature of T N = 3.85 K 8 . The antiferromagnetic (AFM) order is suppressed under pressure, and superconductivity emerges in a dome located around the associated AFM quantum critical point (QCP) at p c ≈ 23 kbar 9 . The picture of pressure-induced quantum criticality is further supported by the observation of non-Fermi-liquid behavior in its vicinity 9 , 10 , 11 . Recent experiments have provided evidence for a second QCP at ambient pressure and under strong magnetic fields, B c ( p = 0) ≈ 50 T 12 , 13 . The temperature dependence of the resistivity at the field-induced QCP is well described by a similar power law, ρ ( B = 50 T, p = 0) ∝ T 0.91 , compared to the behavior at the zero-field QCP, ρ ( B = 0, p = 23 kbar) ∝ T 0.85 9 , 13 . Interestingly, the magnitude of B c is almost completely independent of the field orientation, despite the presence of magnetic anisotropy χ c / χ a ≈ 2 14 . This isotropy of B c provides a first hint that CeRhIn 5 in high magnetic fields goes beyond a simplistic picture of a local-moment magnet. Recently, a field-induced phase transition was observed at intermediate magnetic fields B * ≥ 28 T 12 , 15 , 16 , and a nematic character of this high-field phase has been reported, based on the sudden emergence of an in-plane resistivity anisotropy 13 . Magnetic probes, such as magnetization and torque, however, show hardly any features in the relevant field-temperature range 13 , 14 , thus rendering a metamagnetic origin of the B * transition unlikely. A nematic state, as proposed, electronically breaks the C 4 rotational symmetry in the ( a , b ) plane, and hence must be reflected by a small lattice distortion 17 , which has recently been verified by magnetostriction experiments confirming the thermodynamic character of the transition at B * 18 . For these reasons we shall refer to the sudden and strong field-induced transport anisotropy at B * as nematic for simplicity. Yet its microscopic origin remains a highly active area of research, and the nematic picture is constantly expanded, refined as well as challenged. The main open questions concern the explicitly symmetry-breaking role of the in-plane magnetic field 19 , for example, through a modification of the crystal-electric-field schemes, as well as potential changes of the microscopic magnetic ordering that might remain undetected by measurements of the averaged magnetization and torque. Here, the recent breakthroughs in pulsed magnetic field neutron scattering 20 and other microscopic techniques would be most insightful. One of the main results of the present work is to trace the field scale, B * ( p ), into the high-pressure regime regardless of its origin. CeRhIn 5 presents a unique opportunity to tune a highly correlated system between a diverse set of ground states, including unconventional superconductivity, local-moment magnetism, a putative (spin- or charge-) nematic, and a heavy Fermi liquid 8 , 13 , 21 , 22 . Here we chart the unknown territory of combined high field/high pressure, to serve as a testbed for theoretical approaches tackling this problem. Most importantly, the entire phase diagram can be mapped within one clean single crystal, hence avoiding the complexities of sample dependence and non-stoichiometry, by the use of the two least invasive tuning parameters, pressure and magnetic field. While conceptually appealing, this presents a formidable experimental challenge: transport experiments on metallic samples in pulsed magnetic fields need to be combined with diamond-anvil pressure cells (DACs) and 3 He temperatures. Inspired by previous experiments in high fields and high pressures 23 , 24 , 25 , 26 , we here present a new approach combining focused ion beam (FIB) crystal micromachining 27 and DACs 26 made from plastic for multi-terminal measurements of transport anisotropy (SEM images of the devices can be found in Fig. 1 a and Supplementary Fig. 1 ). To minimize heating due to eddy currents in pulsed magnetic fields, the body of the pressure cell and the 3 He cryostat was made entirely from plastic (for further details see “Methods”). In the following, we detail three main experimental observations uncovered by this study: first, the nematic onset field B * , characterized by an anisotropy jump and a first-order-like hysteretic behavior, grows with applied pressure from 28 T at ambient pressure to around 40 T for close<|im_end|> <|im_start|>assistant An international team of scientists from the Helmholtz-Zentrum Dresden-Rossendorf (HZDR), the Max Planck Institute for Chemical Physics of Solids, and colleagues from the USA and Switzerland have successfully combined various extreme experimental conditions in a completely unique way, revealing exciting insights into the mysterious conducting properties of the crystalline metal CeRhIn5. In the journal Nature Communications, they report on their exploration of previously uncharted regions of the phase diagram of this metal, which is considered a promising model system for understanding unconventional superconductors. "First, we apply a thin layer of gold to a microscopically small single crystal. Then we use an ion beam to carve out tiny microstructures. At the ends of these structures, we attach ultra-thin platinum tapes to measure resistance along different directions under extremely high pressures, which we generate with a diamond anvil pressure cell. In addition, we apply very powerful magnetic fields to the sample at temperatures near absolute zero." To the average person, this may sound like an overzealous physicist's whimsical fancy, but in fact, it is an actual description of the experimental work conducted by Dr. Toni Helm from HZDR's High Magnetic Field Laboratory (HLD) and his colleagues from Tallahassee, Los Alamos, Lausanne and Dresden. Well, at least in part, because this description only hints at the many challenges involved in combining such extremes concurrently. This great effort is, of course, not an end in itself: the researchers are trying to get to the bottom of some fundamental questions of solid state physics. The sample studied is cer-rhodium-indium-five (CeRhIn5), a metal with surprising properties that are not fully understood yet. Scientists describe it as an unconventional electrical conductor with extremely heavy charge carriers, in which, under certain conditions, electrical current can flow without losses. It is assumed that the key to this superconductivity lies in the metal's magnetic properties. The central issues investigated by physicists working with such correlated electron systems include: How do heavy electrons organize collectively? How can this cause magnetism and superconductivity? And what is the relationship between these physical phenomena? An expedition through the phase diagram The physicists are particularly interested in the metal's phase diagram, a kind of map whose coordinates are pressure, magnetic field strength, and temperature. If the map is to be meaningful, the scientists have to uncover as many locations as possible in this system of coordinates, just like a cartographer exploring unknown territory. In fact, the emerging diagram is not unlike the terrain of a landscape. As they reduce temperature to almost four degrees above absolute zero, the physicists observe magnetic order in the metal sample. At this point, they have a number of options: They can cool the sample down even further and expose it to high pressures, forcing a transition into the superconducting state. If, on the other hand, they solely increase the external magnetic field to 600,000 times the strength of the earth's magnetic field, the magnetic order is also suppressed; however, the material enters a state called 'electronically nematic.' This term is borrowed from the physics of liquid crystals, where it describes a certain spatial orientation of molecules with a long-range order over larger areas. The scientists assume that the electronically nematic state is closely linked to the phenomenon of unconventional superconductivity. The experimental environment at HLD provides optimum conditions for such a complex measurement project. The large magnets generate relatively long-lasting pulses and offer sufficient space for complex measurement methods under extreme conditions. Experiments at the limit afford a glimpse of the future The experiments have a few additional special characteristics. For example, working with high-pulsed magnetic fields creates eddy currents in the metallic parts of the experimental setup, which can generate unwanted heat. The scientists have therefore manufactured the central components from a special plastic material that suppresses this effect and functions reliably near absolute zero. Through the microfabrication by focused ion beams, they produce a sample geometry that guarantees a high-quality measurement signal. "Microstructuring will become much more important in future experiments. That's why we brought this technology into the laboratory right away," says Helm, adding: "So we now have ways to access and gradually penetrate into dimensions where quantum mechanical effects play a major role." He is also certain that the know-how he and his team have acquired will contribute to research on high-temperature superconductors or novel quantum technologies. <|im_end|>

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38973, 1229, 7269, 374, 1664, 7633, 555, 264, 4528, 2410, 2383, 11, 17839, 223, 320, 426, 284, 220, 1135, 350, 11, 281, 284, 220, 15, 8, 12264, 251, 350, 220, 15, 13, 5925, 1174, 7863, 311, 279, 7865, 520, 279, 7315, 19677, 1229, 7269, 11, 17839, 223, 320, 426, 284, 220, 15, 11, 281, 284, 220, 1419, 597, 2308, 8, 12264, 251, 350, 220, 15, 13, 5313, 220, 24, 1174, 220, 1032, 662, 58603, 11, 279, 26703, 315, 426, 272, 374, 4661, 6724, 9678, 315, 279, 2115, 17140, 11, 8994, 279, 9546, 315, 24924, 459, 285, 354, 18237, 100897, 272, 611, 100897, 264, 118792, 220, 17, 220, 975, 662, 1115, 69551, 18237, 315, 426, 272, 5825, 264, 1176, 13310, 430, 24703, 73262, 644, 220, 20, 304, 1579, 24924, 5151, 5900, 7953, 264, 78630, 6945, 315, 264, 2254, 1474, 13209, 33297, 13, 42096, 11, 264, 2115, 38973, 10474, 9320, 574, 13468, 520, 29539, 24924, 5151, 426, 353, 63247, 220, 1591, 350, 220, 717, 1174, 220, 868, 1174, 220, 845, 1174, 323, 264, 308, 12519, 3752, 315, 420, 1579, 19677, 10474, 706, 1027, 5068, 11, 3196, 389, 279, 11210, 49179, 315, 459, 304, 90649, 22884, 1968, 459, 285, 354, 18237, 220, 1032, 662, 63755, 63610, 11, 1778, 439, 33297, 2065, 323, 42131, 11, 4869, 11, 1501, 20781, 904, 4519, 304, 279, 9959, 2115, 12, 35658, 2134, 220, 1032, 1174, 220, 975, 1174, 8617, 21568, 264, 88848, 39100, 6371, 315, 279, 426, 353, 9320, 17821, 13, 362, 308, 12519, 1614, 11, 439, 11223, 11, 71870, 18808, 279, 356, 220, 19, 92371, 46220, 304, 279, 320, 264, 1174, 293, 883, 11277, 11, 323, 16472, 2011, 387, 27000, 555, 264, 2678, 55372, 50971, 220, 1114, 1174, 902, 706, 6051, 1027, 24884, 555, 8622, 11269, 52230, 21896, 50096, 279, 30945, 61002, 3752, 315, 279, 9320, 520, 426, 353, 220, 972, 662, 1789, 1521, 8125, 584, 4985, 8464, 311, 279, 11210, 323, 3831, 2115, 38973, 7710, 459, 285, 354, 18237, 520, 426, 353, 439, 308, 12519, 369, 40075, 13, 14968, 1202, 90090, 6371, 8625, 264, 7701, 4642, 3158, 315, 3495, 11, 323, 279, 308, 12519, 6945, 374, 15320, 17626, 11, 38291, 439, 1664, 439, 29991, 13, 578, 1925, 1825, 4860, 4747, 279, 21650, 46220, 55407, 3560, 315, 279, 304, 90649, 24924, 2115, 220, 777, 1174, 369, 3187, 11, 1555, 264, 17466, 315, 279, 26110, 37081, 2265, 19677, 31956, 11, 439, 1664, 439, 4754, 4442, 315, 279, 90090, 24924, 22106, 430, 2643, 7293, 2073, 295, 1599, 555, 22323, 315, 279, 37956, 33297, 2065, 323, 42131, 13, 5810, 11, 279, 3293, 42445, 82, 304, 7893, 32424, 24924, 2115, 73404, 72916, 220, 508, 323, 1023, 90090, 12823, 1053, 387, 1455, 70162, 13, 3861, 315, 279, 1925, 3135, 315, 279, 3118, 990, 374, 311, 11917, 279, 2115, 5569, 11, 426, 353, 320, 281, 7026, 1139, 279, 1579, 89561, 17942, 15851, 315, 1202, 6371, 13, 24703, 73262, 644, 220, 20, 18911, 264, 5016, 6776, 311, 26306, 264, 7701, 49393, 1887, 1990, 264, 17226, 743, 315, 5015, 5415, 11, 2737, 73978, 2307, 77752, 1968, 11, 2254, 1474, 13209, 33297, 2191, 11, 264, 2231, 1413, 320, 42682, 12, 477, 6900, 63096, 308, 12519, 11, 323, 264, 8987, 99362, 72, 14812, 220, 23, 1174, 220, 1032, 1174, 220, 1691, 1174, 220, 1313, 662, 5810, 584, 9676, 279, 9987, 18455, 315, 11093, 1579, 2115, 59235, 7410, 11, 311, 8854, 439, 264, 1296, 2788, 369, 32887, 20414, 57911, 420, 3575, 13, 7648, 23659, 11, 279, 4553, 10474, 13861, 649, 387, 24784, 2949, 832, 4335, 3254, 26110, 11, 16472, 31526, 279, 84140, 315, 6205, 44393, 323, 2536, 5594, 78, 41652, 7133, 11, 555, 279, 1005, 315, 279, 1403, 3325, 53354, 42438, 5137, 11, 7410, 323, 24924, 2115, 13, 6104, 7434, 1870, 33352, 11, 420, 18911, 264, 54829, 22772, 8815, 25, 7710, 21896, 389, 46258, 10688, 304, 7893, 32424, 24924, 5151, 1205, 311, 387, 11093, 449, 22996, 19415, 46352, 7410, 7917, 320, 72402, 82, 8, 323, 220, 18, 1283, 20472, 13, 65925, 555, 3766, 21896, 304, 1579, 5151, 323, 1579, 40850, 220, 1419, 1174, 220, 1187, 1174, 220, 914, 1174, 220, 1627, 1174, 584, 1618, 3118, 264, 502, 5603, 35271, 10968, 28772, 24310, 320, 37, 3336, 8, 26110, 19748, 442, 613, 5859, 220, 1544, 323, 40296, 82, 220, 1627, 1903, 505, 12466, 369, 7447, 91723, 22323, 315, 7710, 459, 285, 354, 18237, 320, 84839, 5448, 315, 279, 7766, 649, 387, 1766, 304, 23966, 13, 220, 16, 264, 323, 99371, 23966, 13, 220, 16, 7609, 2057, 30437, 24494, 4245, 311, 1608, 10470, 60701, 304, 7893, 32424, 24924, 5151, 11, 279, 2547, 315, 279, 7410, 2849, 323, 279, 220, 18, 1283, 16106, 109524, 574, 1903, 11622, 505, 12466, 320, 2000, 4726, 3649, 1518, 1054, 18337, 65312, 763, 279, 2768, 11, 584, 7872, 2380, 1925, 22772, 24654, 43522, 555, 420, 4007, 25, 1176, 11, 279, 308, 12519, 42080, 2115, 426, 353, 1174, 32971, 555, 459, 459, 285, 354, 18237, 7940, 323, 264, 1176, 24747, 12970, 54119, 5411, 7865, 11, 28815, 449, 9435, 7410, 505, 220, 1591, 350, 520, 35288, 7410, 311, 2212, 220, 1272, 350, 369, 3345, 128257, 198, 128256, 78191, 198, 2127, 6625, 2128, 315, 14248, 505, 279, 16183, 53016, 6312, 89, 11419, 306, 10952, 86545, 11151, 3746, 8188, 69, 320, 62859, 7842, 705, 279, 7639, 9878, 377, 10181, 369, 36424, 28415, 315, 11730, 3447, 11, 323, 18105, 505, 279, 7427, 323, 30221, 617, 7946, 11093, 5370, 14560, 22772, 4787, 304, 264, 6724, 5016, 1648, 11, 31720, 13548, 26793, 1139, 279, 26454, 31474, 6012, 315, 279, 64568, 483, 9501, 24703, 73262, 644, 20, 13, 763, 279, 8486, 22037, 26545, 11, 814, 1934, 389, 872, 27501, 315, 8767, 653, 91918, 13918, 315, 279, 10474, 13861, 315, 420, 9501, 11, 902, 374, 6646, 264, 26455, 1646, 1887, 369, 8830, 73978, 2307, 77752, 1105, 13, 330, 5451, 11, 584, 3881, 264, 15792, 6324, 315, 6761, 311, 264, 8162, 2445, 454, 2740, 2678, 3254, 26110, 13, 5112, 584, 1005, 459, 28772, 24310, 311, 80737, 704, 13987, 8162, 47194, 13, 2468, 279, 10548, 315, 1521, 14726, 11, 584, 15866, 24955, 7716, 258, 63327, 52796, 311, 6767, 13957, 3235, 2204, 18445, 1234, 9193, 1579, 40850, 11, 902, 584, 7068, 449, 264, 22996, 459, 46352, 7410, 2849, 13, 763, 5369, 11, 584, 3881, 1633, 8147, 24924, 5151, 311, 279, 6205, 520, 20472, 3221, 10973, 7315, 1210, 2057, 279, 5578, 1732, 11, 420, 1253, 5222, 1093, 459, 927, 3059, 30543, 83323, 596, 70205, 950, 27555, 11, 719, 304, 2144, 11, 433, 374, 459, 5150, 4096, 315, 279, 22772, 990, 13375, 555, 2999, 13, 90402, 63142, 505, 473, 57, 7842, 596, 5234, 63755, 8771, 32184, 320, 39, 12615, 8, 323, 813, 18105, 505, 42202, 93066, 4151, 11, 9853, 1708, 10808, 11, 5034, 355, 20991, 323, 86545, 13, 8489, 11, 520, 3325, 304, 961, 11, 1606, 420, 4096, 1193, 31743, 520, 279, 1690, 11774, 6532, 304, 35271, 1778, 69971, 79126, 13, 1115, 2294, 5149, 374, 11, 315, 3388, 11, 539, 459, 842, 304, 5196, 25, 279, 12074, 527, 4560, 311, 636, 311, 279, 5740, 315, 1063, 16188, 4860, 315, 6573, 1614, 22027, 13, 578, 6205, 20041, 374, 10362, 3880, 71, 47876, 18251, 2411, 36399, 320, 43270, 73262, 644, 20, 705, 264, 9501, 449, 15206, 6012, 430, 527, 539, 7373, 16365, 3686, 13, 57116, 7664, 433, 439, 459, 73978, 20314, 61856, 449, 9193, 8987, 6900, 35991, 11, 304, 902, 11, 1234, 3738, 4787, 11, 20314, 1510, 649, 6530, 2085, 18151, 13, 1102, 374, 19655, 430, 279, 1401, 311, 420, 2307, 77752, 1968, 15812, 304, 279, 9501, 596, 24924, 6012, 13, 578, 8792, 4819, 27313, 555, 98417, 3318, 449, 1778, 49393, 17130, 6067, 2997, 25, 2650, 656, 8987, 57678, 31335, 45925, 30, 2650, 649, 420, 5353, 33297, 2191, 323, 2307, 77752, 1968, 30, 1628, 1148, 374, 279, 5133, 1990, 1521, 7106, 44247, 30, 1556, 51264, 1555, 279, 10474, 13861, 578, 98417, 527, 8104, 8173, 304, 279, 9501, 596, 10474, 13861, 11, 264, 3169, 315, 2472, 6832, 14259, 527, 7410, 11, 24924, 2115, 8333, 11, 323, 9499, 13, 1442, 279, 2472, 374, 311, 387, 23222, 11, 279, 14248, 617, 311, 45063, 439, 1690, 10687, 439, 3284, 304, 420, 1887, 315, 14259, 11, 1120, 1093, 264, 7558, 42606, 24919, 9987, 18455, 13, 763, 2144, 11, 279, 24084, 13861, 374, 539, 20426, 279, 25911, 315, 264, 18921, 13, 1666, 814, 8108, 9499, 311, 4661, 3116, 12628, 3485, 10973, 7315, 11, 279, 98417, 23846, 24924, 2015, 304, 279, 9501, 6205, 13, 2468, 420, 1486, 11, 814, 617, 264, 1396, 315, 2671, 25, 2435, 649, 7155, 279, 6205, 1523, 1524, 4726, 323, 29241, 433, 311, 1579, 40850, 11, 25957, 264, 9320, 1139, 279, 2307, 77752, 287, 1614, 13, 1442, 11, 389, 279, 1023, 1450, 11, 814, 21742, 5376, 279, 9434, 24924, 2115, 311, 220, 5067, 11, 931, 3115, 279, 8333, 315, 279, 9578, 596, 24924, 2115, 11, 279, 24924, 2015, 374, 1101, 56089, 26, 4869, 11, 279, 3769, 29933, 264, 1614, 2663, 364, 75603, 2740, 308, 12519, 3238, 1115, 4751, 374, 46664, 505, 279, 22027, 315, 14812, 48473, 11, 1405, 433, 16964, 264, 3738, 29079, 17140, 315, 35715, 449, 264, 1317, 31608, 2015, 927, 8294, 5789, 13, 578, 14248, 9855, 430, 279, 71870, 308, 12519, 1614, 374, 15499, 10815, 311, 279, 25885, 315, 73978, 2307, 77752, 1968, 13, 578, 22772, 4676, 520, 473, 12615, 5825, 54767, 4787, 369, 1778, 264, 6485, 19179, 2447, 13, 578, 3544, 73780, 7068, 12309, 1317, 65265, 66557, 323, 3085, 14343, 3634, 369, 6485, 19179, 5528, 1234, 14560, 4787, 13, 1398, 50732, 520, 279, 4017, 10150, 264, 40942, 315, 279, 3938, 578, 21896, 617, 264, 2478, 5217, 3361, 17910, 13, 1789, 3187, 11, 3318, 449, 1579, 2320, 14630, 291, 24924, 5151, 11705, 1608, 10470, 60701, 304, 279, 46258, 5596, 315, 279, 22772, 6642, 11, 902, 649, 7068, 36021, 8798, 13, 578, 14248, 617, 9093, 28648, 279, 8792, 6956, 505, 264, 3361, 12466, 3769, 430, 28321, 288, 420, 2515, 323, 5865, 57482, 3221, 10973, 7315, 13, 17331, 279, 8162, 86254, 367, 555, 10968, 28772, 51045, 11, 814, 8356, 264, 6205, 17484, 430, 36755, 264, 1579, 22867, 19179, 8450, 13, 330, 35709, 63272, 690, 3719, 1790, 810, 3062, 304, 3938, 21896, 13, 3011, 596, 3249, 584, 7263, 420, 5557, 1139, 279, 27692, 1314, 3201, 1359, 2795, 63142, 11, 7999, 25, 330, 4516, 584, 1457, 617, 5627, 311, 2680, 323, 27115, 64855, 1139, 15696, 1405, 31228, 22936, 6372, 1514, 264, 3682, 3560, 1210, 1283, 374, 1101, 3738, 430, 279, 1440, 58523, 568, 323, 813, 2128, 617, 19426, 690, 17210, 311, 3495, 389, 1579, 12, 35658, 2307, 77752, 1105, 477, 11775, 31228, 14645, 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 Endurance athletes exhibit sinus bradycardia, that is a slow resting heart rate, associated with a higher incidence of sinus node (pacemaker) disease and electronic pacemaker implantation. Here we show that training-induced bradycardia is not a consequence of changes in the activity of the autonomic nervous system but is caused by intrinsic electrophysiological changes in the sinus node. We demonstrate that training-induced bradycardia persists after blockade of the autonomous nervous system in vivo in mice and in vitro in the denervated sinus node. We also show that a widespread remodelling of pacemaker ion channels, notably a downregulation of HCN4 and the corresponding ionic current, I f . Block of I f abolishes the difference in heart rate between trained and sedentary animals in vivo and in vitro . We further observe training-induced downregulation of Tbx3 and upregulation of NRSF and miR-1 (transcriptional regulators) that explains the downregulation of HCN4. Our findings provide a molecular explanation for the potentially pathological heart rate adaptation to exercise training. Introduction Athletes are considered the healthiest members of society and yet, paradoxically, the incidence of arrhythmias, ranging from the benign to the pathological, is known to be higher in athletes, especially in elderly athletes with a lifelong training history 1 , 2 , 3 , 4 , 5 , 6 , 7 . Emerging data suggest that long-term training for and competing in extreme endurance events such as marathons, ultra-marathons, ironman distance triathlons and long distance bicycle races may induce pathological remodelling of the heart and potentially create a substrate for arrhythmogenesis 8 . Furthermore, there is a rise in the number of individuals participating in gruelling ultra-endurance events. For example, each year there are >500 marathon races in Europe and America, and >1 million participants and this figure is projected to rise by at least 5% each year 9 . Sinus bradycardia, defined by a resting heart rate <60 beats min −1 , is the most frequent rhythm disturbance in response to exercise training; the heart rate can be ~30 beats min −1 and even lower at night 5 , 10 , 11 . Although the bradycardia is usually a benign physiological adaptation (to maintain a normal cardiac output and blood pressure despite the training-induced increase in stroke volume), it can become a pathological condition resembling sinus node disease 5 , 6 , 7 . The most compelling evidence of a link between training and sick sinus syndrome comes from a study of former professional cyclists 7 . Their average heart rate was lower, a maximal RR interval of >2.5 s was more common, sick sinus syndrome was more frequent and pacemaker implantation for bradyarrythmias was more frequent relative to a control group with matched cardiac risk factors 7 . Similarly, a high incidence of pacemaker implantation has been reported in elderly marathon runners 12 . The training-induced bradycardia is widely attributed to the autonomic nervous system–an increase in vagal tone induced by training 13 , 14 . However, slower resting heart rates are observed in athletes even after complete block of the autonomic nervous system 15 . We hypothesized that, instead, the training-induced bradycardia is primarily because of an intrinsic change in the sinus node, the pacemaker of the heart, in particular, to a remodelling of the ion channels that govern pacemaking. We show that this is the case. An improved understanding of the athletes’s heart could ultimately lead to better-informed lifestyle choices for the athlete. Results Exercise training produces an intrinsic sinus bradycardia Rats were trained for 12 weeks (1 h per day, 5 days per week) by aerobic interval training (uphill running), alternating between 4 min at 85–90% of the maximum O 2 uptake ( ) and 2 min active recovery at 50% of . As expected, in the trained, but not sedentary, rats there was an increase in ( Fig. 1a ). The electrocardiogram (ECG) was recorded in vivo (from unrestrained and conscious rats; Fig. 1c ) and, as with human athletes, there was a resting bradycardia in the trained rats: the RR interval (interval between heart beats; Fig. 1c,d ) of the rats at rest was significantly longer than that of age- and sex-matched sedentary rats; the corresponding heart rate ( Fig. 1e ) was significantly slower than that of the sedentary rats. The training-induced bradycardia could be the result of altered autonomic nerve activity to the heart (for example, increased vagal tone) or a change in the intrinsic properties of the sinus node. To distinguish between the two hypotheses, we measured the cycle length (equivalent to the RR interval) in the denervated sinus node (isolated in vitro preparation used) and this too was significantly longer in the trained rats ( Fig. 1d ); the corresponding rate was significantly slower ( Fig. 1e ). In the rat, there was a significant correlation between the rate in vitro and ( Fig. 1b ). Figure 1: Exercise training induces sinus bradycardia and remodelling of the sinus node. ( a ) Increase in in the rat following the 12-week training period. Normalized of sedentary and trained rats before and after the 12-week training period shown ( n =11 per group). In all bar graphs: black bars represent data from sedentary animals and hatched bars represent data from trained animals. ( b ) Significant correlation between heart rate in vitro and normalized in sedentary and trained rats (measured after 12-week training period). Each point corresponds to a different animal. Data fit with a straight line by linear regression ( n =5/9; R 2 and P values shown). ( c ) Representative ECG traces obtained from sedentary and trained (unrestrained and conscious) rats and mice demonstrating longer RR intervals in trained animals. ( d , e ) Mean (+s.e.m.) RR intervals ( d ) and corresponding heart rates ( e ) measured in vivo (rats, n =5/9; mice, n =6/8) and in vitro (from isolated sinus node preparations; rats, n =5/9; mice, n =6/7) in sedentary and trained animals. ( f ) Mean (+s.e.m.)", "role": "user" }, { "content": "A new study by The University of Manchester has shed light on why athletes are more likely to have abnormal heart rhythms. Elderly athletes with a lifelong history of training and competing in endurance events like marathons, triathlons and iron man challenges can have heart rhythm disturbances, known as arrhythmias. The Manchester research in rodents, funded by the British Heart Foundation, shows molecular changes in the heart's pacemaker occur in response to exercise training. The finding, reported in Nature Communications, overturns the commonly held belief that an increased activity of the autonomic nervous system causes this specific reaction to endurance training. While normal adults have resting heart rates between 60-100 beats per minute, hearts of endurance athletes can beat only 30 times per minute or even lower at night time when there can be long pauses between heart beats. Cyclists Sir Chris Hoy and Miguel Indurain reportedly had resting heart rates of 30 and 28 beats per minute. Dr Alicia D'Souza, from The University of Manchester and first author on the paper, said: \"The heart rate is set by the heart's pacemaker, but this is controlled by the nervous system. The 'vagal' nerves lower the heart rate and therefore it was assumed the low heart rate of athletes is the result of over activity of the vagal nerves. \"But our research shows this is not the case. Actually the heart's pacemaker changes in response to training and in particular there is a decrease in an important pacemaker protein, known as HCN4, and this is responsible for the low heart rate.\" The researchers say these molecular changes in the sinus node - the cardiac structure responsible for generating heart rhythm - may help us to understand the more frequent occurrence of heart rhythm disturbances or even loss of consciousness in athletes. Professor Mark Boyett, lead researcher on the study, added: \"This is important because although normally a low resting heart rate of an athlete does not cause problems, elderly athletes with a lifelong training history are more likely to need an artificial electronic pacemaker fitted.\" More than 500 marathons take place in Europe and America each year with around one million participants. The number of people taking part is set to increase by 5% each year. But Professor Boyett said: \"Although endurance exercise training can have harmful effects on the heart, it is more than outweighed by the beneficial effects.\" Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, said: \"This study shows the heart's electrical wiring changes in mice that exercise for long periods, and these changes in heart rhythm are sustained afterwards. \"If the findings are reproduced in humans they could have implications for heart health in older athletes. But much more research is needed before we could draw that conclusion.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Endurance athletes exhibit sinus bradycardia, that is a slow resting heart rate, associated with a higher incidence of sinus node (pacemaker) disease and electronic pacemaker implantation. Here we show that training-induced bradycardia is not a consequence of changes in the activity of the autonomic nervous system but is caused by intrinsic electrophysiological changes in the sinus node. We demonstrate that training-induced bradycardia persists after blockade of the autonomous nervous system in vivo in mice and in vitro in the denervated sinus node. We also show that a widespread remodelling of pacemaker ion channels, notably a downregulation of HCN4 and the corresponding ionic current, I f . Block of I f abolishes the difference in heart rate between trained and sedentary animals in vivo and in vitro . We further observe training-induced downregulation of Tbx3 and upregulation of NRSF and miR-1 (transcriptional regulators) that explains the downregulation of HCN4. Our findings provide a molecular explanation for the potentially pathological heart rate adaptation to exercise training. Introduction Athletes are considered the healthiest members of society and yet, paradoxically, the incidence of arrhythmias, ranging from the benign to the pathological, is known to be higher in athletes, especially in elderly athletes with a lifelong training history 1 , 2 , 3 , 4 , 5 , 6 , 7 . Emerging data suggest that long-term training for and competing in extreme endurance events such as marathons, ultra-marathons, ironman distance triathlons and long distance bicycle races may induce pathological remodelling of the heart and potentially create a substrate for arrhythmogenesis 8 . Furthermore, there is a rise in the number of individuals participating in gruelling ultra-endurance events. For example, each year there are >500 marathon races in Europe and America, and >1 million participants and this figure is projected to rise by at least 5% each year 9 . Sinus bradycardia, defined by a resting heart rate <60 beats min −1 , is the most frequent rhythm disturbance in response to exercise training; the heart rate can be ~30 beats min −1 and even lower at night 5 , 10 , 11 . Although the bradycardia is usually a benign physiological adaptation (to maintain a normal cardiac output and blood pressure despite the training-induced increase in stroke volume), it can become a pathological condition resembling sinus node disease 5 , 6 , 7 . The most compelling evidence of a link between training and sick sinus syndrome comes from a study of former professional cyclists 7 . Their average heart rate was lower, a maximal RR interval of >2.5 s was more common, sick sinus syndrome was more frequent and pacemaker implantation for bradyarrythmias was more frequent relative to a control group with matched cardiac risk factors 7 . Similarly, a high incidence of pacemaker implantation has been reported in elderly marathon runners 12 . The training-induced bradycardia is widely attributed to the autonomic nervous system–an increase in vagal tone induced by training 13 , 14 . However, slower resting heart rates are observed in athletes even after complete block of the autonomic nervous system 15 . We hypothesized that, instead, the training-induced bradycardia is primarily because of an intrinsic change in the sinus node, the pacemaker of the heart, in particular, to a remodelling of the ion channels that govern pacemaking. We show that this is the case. An improved understanding of the athletes’s heart could ultimately lead to better-informed lifestyle choices for the athlete. Results Exercise training produces an intrinsic sinus bradycardia Rats were trained for 12 weeks (1 h per day, 5 days per week) by aerobic interval training (uphill running), alternating between 4 min at 85–90% of the maximum O 2 uptake ( ) and 2 min active recovery at 50% of . As expected, in the trained, but not sedentary, rats there was an increase in ( Fig. 1a ). The electrocardiogram (ECG) was recorded in vivo (from unrestrained and conscious rats; Fig. 1c ) and, as with human athletes, there was a resting bradycardia in the trained rats: the RR interval (interval between heart beats; Fig. 1c,d ) of the rats at rest was significantly longer than that of age- and sex-matched sedentary rats; the corresponding heart rate ( Fig. 1e ) was significantly slower than that of the sedentary rats. The training-induced bradycardia could be the result of altered autonomic nerve activity to the heart (for example, increased vagal tone) or a change in the intrinsic properties of the sinus node. To distinguish between the two hypotheses, we measured the cycle length (equivalent to the RR interval) in the denervated sinus node (isolated in vitro preparation used) and this too was significantly longer in the trained rats ( Fig. 1d ); the corresponding rate was significantly slower ( Fig. 1e ). In the rat, there was a significant correlation between the rate in vitro and ( Fig. 1b ). Figure 1: Exercise training induces sinus bradycardia and remodelling of the sinus node. ( a ) Increase in in the rat following the 12-week training period. Normalized of sedentary and trained rats before and after the 12-week training period shown ( n =11 per group). In all bar graphs: black bars represent data from sedentary animals and hatched bars represent data from trained animals. ( b ) Significant correlation between heart rate in vitro and normalized in sedentary and trained rats (measured after 12-week training period). Each point corresponds to a different animal. Data fit with a straight line by linear regression ( n =5/9; R 2 and P values shown). ( c ) Representative ECG traces obtained from sedentary and trained (unrestrained and conscious) rats and mice demonstrating longer RR intervals in trained animals. ( d , e ) Mean (+s.e.m.) RR intervals ( d ) and corresponding heart rates ( e ) measured in vivo (rats, n =5/9; mice, n =6/8) and in vitro (from isolated sinus node preparations; rats, n =5/9; mice, n =6/7) in sedentary and trained animals. ( f ) Mean (+s.e.m.)<|im_end|> <|im_start|>assistant A new study by The University of Manchester has shed light on why athletes are more likely to have abnormal heart rhythms. Elderly athletes with a lifelong history of training and competing in endurance events like marathons, triathlons and iron man challenges can have heart rhythm disturbances, known as arrhythmias. The Manchester research in rodents, funded by the British Heart Foundation, shows molecular changes in the heart's pacemaker occur in response to exercise training. The finding, reported in Nature Communications, overturns the commonly held belief that an increased activity of the autonomic nervous system causes this specific reaction to endurance training. While normal adults have resting heart rates between 60-100 beats per minute, hearts of endurance athletes can beat only 30 times per minute or even lower at night time when there can be long pauses between heart beats. Cyclists Sir Chris Hoy and Miguel Indurain reportedly had resting heart rates of 30 and 28 beats per minute. Dr Alicia D'Souza, from The University of Manchester and first author on the paper, said: "The heart rate is set by the heart's pacemaker, but this is controlled by the nervous system. The 'vagal' nerves lower the heart rate and therefore it was assumed the low heart rate of athletes is the result of over activity of the vagal nerves. "But our research shows this is not the case. Actually the heart's pacemaker changes in response to training and in particular there is a decrease in an important pacemaker protein, known as HCN4, and this is responsible for the low heart rate." The researchers say these molecular changes in the sinus node - the cardiac structure responsible for generating heart rhythm - may help us to understand the more frequent occurrence of heart rhythm disturbances or even loss of consciousness in athletes. Professor Mark Boyett, lead researcher on the study, added: "This is important because although normally a low resting heart rate of an athlete does not cause problems, elderly athletes with a lifelong training history are more likely to need an artificial electronic pacemaker fitted." More than 500 marathons take place in Europe and America each year with around one million participants. The number of people taking part is set to increase by 5% each year. But Professor Boyett said: "Although endurance exercise training can have harmful effects on the heart, it is more than outweighed by the beneficial effects." Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, said: "This study shows the heart's electrical wiring changes in mice that exercise for long periods, and these changes in heart rhythm are sustained afterwards. "If the findings are reproduced in humans they could have implications for heart health in older athletes. But much more research is needed before we could draw that conclusion." <|im_end|>

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1,965

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Epigenome editing with the CRISPR (clustered, regularly interspaced, short palindromic repeats)-Cas9 platform is a promising technology for modulating gene expression to direct cell phenotype and to dissect the causal epigenetic mechanisms of gene regulation. Fusions of nuclease-inactive dCas9 to the Krüppel-associated box (KRAB) repressor (dCas9-KRAB) can silence target gene expression, but the genome-wide specificity and the extent of heterochromatin formation catalyzed by dCas9-KRAB are not known. We targeted dCas9-KRAB to the HS2 enhancer, a distal regulatory element that orchestrates the expression of multiple globin genes, and observed highly specific induction of H3K9 trimethylation (H3K9me3) at the enhancer and decreased chromatin accessibility of both the enhancer and its promoter targets. Targeted epigenetic modification of HS2 silenced the expression of multiple globin genes, with minimal off-target changes in global gene expression. These results demonstrate that repression mediated by dCas9-KRAB is sufficiently specific to disrupt the activity of individual enhancers via local modification of the epigenome. Main Custom control over epigenetic regulation is becoming increasingly attainable with the expansion of genome engineering technologies that combine epigenetic modulators with programmable DNA-targeting platforms. Engineered zinc-finger proteins, transcription activator–like effectors and the CRISPR-dCas9 system can localize effector domains to target genomic regions in order to control epigenetic states 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 . In the CRISPR-dCas9 system adapted from Streptococcus pyogenes , codelivery of a single guide RNA (sgRNA) directs dCas9 binding through an 18–20-nt protospacer region complementary to the target genomic sequence 13 , 14 , 15 . The ease and versatility of this RNA-guided epigenome-editing platform have enabled its rapid application for designing gene regulatory networks, screening for cellular phenotypes and directing cell fate 9 , 16 , 17 , 18 , 19 , 20 , 21 . Site-specific epigenome engineering with the CRISPR-dCas9 system is also a promising technology for investigating the function of distal regulatory elements 9 , 10 . Large-scale efforts to map the human epigenome have revealed more than 1 million DNase I–hypersensitive sites (DHSs), many of which probably act as cell-type-specific enhancers 22 , 23 , 24 . Epigenome editing proteins can be targeted to candidate regulatory elements in order to modify local chromatin structure and determine the role of these distal elements in influencing endogenous gene expression. For targeted gene repression, the most commonly used effector is the KRAB domain 1 , 3 , 6 . When localized to DNA, KRAB recruits a heterochromatin-forming complex that causes histone methylation and deacetylation 25 , 26 , 27 , 28 . dCas9-KRAB fusions have effectively silenced noncoding RNAs and single genes when targeted to promoter regions, 5′ untranslated regions and proximal enhancer elements 6 , 9 , 16 , 18 . Libraries of sgRNAs targeting dCas9-KRAB to genomic regions proximal to transcription start sites have also been used for high-throughput gene-silencing screens 16 . Unmodified dCas9 is known to bind at off-target loci containing a 5-bp seed sequence followed by a protospacer-adjacent motif 29 , 30 . The potential for binding and subsequent epigenome editing by dCas9-KRAB at off-target sites has not been evaluated. Off-target activity is a particular concern given recent evidence that the addition of a KRAB domain to a targeted zinc-finger protein can dramatically increase off-target interactions 31 . Other studies also suggest that targeting the KRAB domain to genomic loci with other DNA-binding proteins can lead to long-range, stable H3K9me3 and chromatin condensation 2 , 25 , 26 , 27 , 32 , 33 . If similar issues arise with the dCas9-KRAB platform, long-range epigenetic effects will convolute loss-of-function screens and the annotation of gene regulatory elements. Therefore, we sought to evaluate the genome-wide specificity of gene regulation, DNA binding and chromatin remodeling catalyzed by dCas9-KRAB targeted to an endogenous distal regulatory element. We targeted dCas9-KRAB to the HS2 enhancer in the globin locus control region (LCR) 34 . The LCR contains five DHS enhancer regions (HS1–5) that orchestrate the expression of hemoglobin subunit genes in erythroid cells during development. Studies of HS2 have revealed fundamental mechanisms of enhancer activity such as transcription-factor binding, maintenance of chromatin accessibility, and chromatin looping to globin promoters 35 , 36 , 37 , 38 . Here we demonstrate that targeting dCas9-KRAB to the HS2 enhancer disrupted the expression of multiple globin genes. Genome-wide analysis of dCas9-KRAB binding and repression activity established that RNA-guided synthetic repressors are highly specific for endogenous target loci. Deposition of H3K9me3 was limited to the intended HS2 region, leading to decreased chromatin accessibility at both the targeted enhancer and its associated promoters. These results demonstrate that dCas9-KRAB can alter the local epigenome of individual enhancers, and they support the use of dCas9-KRAB as a highly specific epigenome editing tool for directing cell phenotype and revealing connections between regulatory elements and gene expression. Results dCas9-KRAB silences globin genes from a distal enhancer To find optimal sgRNAs for repression of the HS2 enhancer by dCas9-KRAB, we designed a panel of 21 sgRNAs (Cr1–Cr21) to cover the 400-bp core of the HS2 enhancer ( Fig. 1a and Supplementary Table 1 ). Each sgRNA was transiently transfected into human K562 erythroid leukemia cells that were modified to stably express dCas9 or dCas9-KRAB ( Supplementary Fig. 1a ). The activity of each sgRNA was screened 3 d after transfection by quantitative real-time PCR (qRT-PCR) for expression of HBE1 , HBG1 and HBG2 ( HBG1/2 ), and HBB mRNA ( Supplementary Fig. 1b–d ). Because of the sequence similarity between HBG1 and HBG2 , PCR primers do not distinguish between the two transcripts. When transfected into K562 cells expressing dCas9-KRAB, most of the 21 sgRNAs caused decreased expression of HBE1 and HBG1/2 . The sgRNAs had no effect on globin gene expression in unmodified K562 cells or when designed to target the IL1RN promoter as a negative control 7 , demonstrating that the effects were both HS2- and dCas9-specific. Reduced globin gene expression probably resulted from a combination of steric blocking", "role": "user" }, { "content": "Researchers have demonstrated the exceptional specificity of a new way to switch sequences of the human genome on or off without editing the underlying genetic code. Originally discovered as an antiviral system in bacteria, CRISPR/Cas9 is one of the hottest topics in genetic research today. By engineering a version of that system, researchers can both edit DNA sequences and control which genes are used. Previous studies, however, showed that editing human DNA sequences with the system is not always as precise as researchers would like. Those results raised concerns about the use of CRISPR technology in studying human diseases. As a potential solution, some researchers added more versatility to the system by using CRISPR to target portions of DNA that control which genes are active. But instead of using the genetic cutting tool Cas9 that is often employed, they inactivated the cutting function of Cas9 and attached proteins that control the packaging of the genome. By unraveling or tightly bundling these regions of the genome, they could effectively turn them on and off. While the technique had been shown to work well, whether or not it had off-target effects had not been investigated. Now, a team of researchers from Duke University have shown that these gene-controlling methods are capable of the high degree of precision required for basic science and medical research. The study appears online on October 26, 2015 in Nature Methods. \"The primary advantage of CRISPR over previous technologies is the ability to use a genetic scalpel rather than a sledgehammer,\" said Charles Gersbach, associate professor of biomedical engineering at Duke University. \"Many labs across the world are using these tools on the assumption that they're getting specific effects, but there had not been a comprehensive analysis to prove it. These experiments show exceptional specificity, demonstrating that the technology is capable of targeting single sequences of the genome.\" The power to control the genome's switches would be especially important for studying and potentially treating human diseases such as cancer, cardiovascular disease, neurodegenerative conditions and diabetes, which can be driven by mutations in control regions of the genome. The hope is that overriding one of these switches could uncover and fix the root causes of many diseases. It could also help researchers understand and change how different people respond to drugs. But only if the CRISPR technique is specific enough. Soon after CRISPR was first described for editing human genes, several papers revealed that the technique can sometimes have off-target effects. This presents problems for gene therapy treatments and fundamental science projects, where researchers want to alter the function of specific genes without causing unintended side effects. An alternative strategy was developed to switch on and off the genomic regions that control when genes are used without modifying the DNA sequence at all. In some cases, these switches can control several related genes at once, allowing researchers to strike chords instead of individual notes. \"Looking at the specificity of these tools is technically very challenging,\" said Timothy Reddy, assistant professor of biostatistics and bioinformatics at Duke. \"Finding a change in sequence or gene activity is relatively straightforward if you're focusing on one concentrated area in the genome. But looking at how turning off one enhancer switch affects the activity and structure of the whole genome requires more specialized techniques.\" Gersbach turned to Reddy and colleague Gregory Crawford, who all work together in adjacent laboratories and offices in Duke's Center for Genomic and Computational Biology, for help with these more specialized techniques. Reddy has focused his career on investigating how gene switches work across the human genome, how those switches differ between individuals and the implications of these insights for human traits and diseases. Crawford, associate professor of pediatrics, has spent more than a decade developing techniques to identify control regions across the genome and how they vary between cell types, during development or in response to drug treatment. \"Current methods for controlling gene switches, including drugs used in clinical trials, change the activity of many switches across the genome simultaneously, creating thousands of off-target effects,\" said Crawford. \"What is desperately needed is a technology for manipulating one element at a time.\" It fell to Pratiksha Thakore, a PhD student in Gersbach's lab, to integrate the expertise of all three laboratories for studying the specificity of CRISPR in controlling these switches. While the results can't prove that every experiment will have the same high level of precision, it provides a blueprint for researchers to assess these effects. \"By integrating genomics and genome engineering, we have developed a method to comprehensively interrogate how this genetic silencing system works and also suggested ways the technology can be used in the future,\" said Thakore. \"We also learned some new things about gene regulation, and it turned out that in this context CRISPR can achieve a much higher level of specificity than we expected.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Epigenome editing with the CRISPR (clustered, regularly interspaced, short palindromic repeats)-Cas9 platform is a promising technology for modulating gene expression to direct cell phenotype and to dissect the causal epigenetic mechanisms of gene regulation. Fusions of nuclease-inactive dCas9 to the Krüppel-associated box (KRAB) repressor (dCas9-KRAB) can silence target gene expression, but the genome-wide specificity and the extent of heterochromatin formation catalyzed by dCas9-KRAB are not known. We targeted dCas9-KRAB to the HS2 enhancer, a distal regulatory element that orchestrates the expression of multiple globin genes, and observed highly specific induction of H3K9 trimethylation (H3K9me3) at the enhancer and decreased chromatin accessibility of both the enhancer and its promoter targets. Targeted epigenetic modification of HS2 silenced the expression of multiple globin genes, with minimal off-target changes in global gene expression. These results demonstrate that repression mediated by dCas9-KRAB is sufficiently specific to disrupt the activity of individual enhancers via local modification of the epigenome. Main Custom control over epigenetic regulation is becoming increasingly attainable with the expansion of genome engineering technologies that combine epigenetic modulators with programmable DNA-targeting platforms. Engineered zinc-finger proteins, transcription activator–like effectors and the CRISPR-dCas9 system can localize effector domains to target genomic regions in order to control epigenetic states 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 . In the CRISPR-dCas9 system adapted from Streptococcus pyogenes , codelivery of a single guide RNA (sgRNA) directs dCas9 binding through an 18–20-nt protospacer region complementary to the target genomic sequence 13 , 14 , 15 . The ease and versatility of this RNA-guided epigenome-editing platform have enabled its rapid application for designing gene regulatory networks, screening for cellular phenotypes and directing cell fate 9 , 16 , 17 , 18 , 19 , 20 , 21 . Site-specific epigenome engineering with the CRISPR-dCas9 system is also a promising technology for investigating the function of distal regulatory elements 9 , 10 . Large-scale efforts to map the human epigenome have revealed more than 1 million DNase I–hypersensitive sites (DHSs), many of which probably act as cell-type-specific enhancers 22 , 23 , 24 . Epigenome editing proteins can be targeted to candidate regulatory elements in order to modify local chromatin structure and determine the role of these distal elements in influencing endogenous gene expression. For targeted gene repression, the most commonly used effector is the KRAB domain 1 , 3 , 6 . When localized to DNA, KRAB recruits a heterochromatin-forming complex that causes histone methylation and deacetylation 25 , 26 , 27 , 28 . dCas9-KRAB fusions have effectively silenced noncoding RNAs and single genes when targeted to promoter regions, 5′ untranslated regions and proximal enhancer elements 6 , 9 , 16 , 18 . Libraries of sgRNAs targeting dCas9-KRAB to genomic regions proximal to transcription start sites have also been used for high-throughput gene-silencing screens 16 . Unmodified dCas9 is known to bind at off-target loci containing a 5-bp seed sequence followed by a protospacer-adjacent motif 29 , 30 . The potential for binding and subsequent epigenome editing by dCas9-KRAB at off-target sites has not been evaluated. Off-target activity is a particular concern given recent evidence that the addition of a KRAB domain to a targeted zinc-finger protein can dramatically increase off-target interactions 31 . Other studies also suggest that targeting the KRAB domain to genomic loci with other DNA-binding proteins can lead to long-range, stable H3K9me3 and chromatin condensation 2 , 25 , 26 , 27 , 32 , 33 . If similar issues arise with the dCas9-KRAB platform, long-range epigenetic effects will convolute loss-of-function screens and the annotation of gene regulatory elements. Therefore, we sought to evaluate the genome-wide specificity of gene regulation, DNA binding and chromatin remodeling catalyzed by dCas9-KRAB targeted to an endogenous distal regulatory element. We targeted dCas9-KRAB to the HS2 enhancer in the globin locus control region (LCR) 34 . The LCR contains five DHS enhancer regions (HS1–5) that orchestrate the expression of hemoglobin subunit genes in erythroid cells during development. Studies of HS2 have revealed fundamental mechanisms of enhancer activity such as transcription-factor binding, maintenance of chromatin accessibility, and chromatin looping to globin promoters 35 , 36 , 37 , 38 . Here we demonstrate that targeting dCas9-KRAB to the HS2 enhancer disrupted the expression of multiple globin genes. Genome-wide analysis of dCas9-KRAB binding and repression activity established that RNA-guided synthetic repressors are highly specific for endogenous target loci. Deposition of H3K9me3 was limited to the intended HS2 region, leading to decreased chromatin accessibility at both the targeted enhancer and its associated promoters. These results demonstrate that dCas9-KRAB can alter the local epigenome of individual enhancers, and they support the use of dCas9-KRAB as a highly specific epigenome editing tool for directing cell phenotype and revealing connections between regulatory elements and gene expression. Results dCas9-KRAB silences globin genes from a distal enhancer To find optimal sgRNAs for repression of the HS2 enhancer by dCas9-KRAB, we designed a panel of 21 sgRNAs (Cr1–Cr21) to cover the 400-bp core of the HS2 enhancer ( Fig. 1a and Supplementary Table 1 ). Each sgRNA was transiently transfected into human K562 erythroid leukemia cells that were modified to stably express dCas9 or dCas9-KRAB ( Supplementary Fig. 1a ). The activity of each sgRNA was screened 3 d after transfection by quantitative real-time PCR (qRT-PCR) for expression of HBE1 , HBG1 and HBG2 ( HBG1/2 ), and HBB mRNA ( Supplementary Fig. 1b–d ). Because of the sequence similarity between HBG1 and HBG2 , PCR primers do not distinguish between the two transcripts. When transfected into K562 cells expressing dCas9-KRAB, most of the 21 sgRNAs caused decreased expression of HBE1 and HBG1/2 . The sgRNAs had no effect on globin gene expression in unmodified K562 cells or when designed to target the IL1RN promoter as a negative control 7 , demonstrating that the effects were both HS2- and dCas9-specific. Reduced globin gene expression probably resulted from a combination of steric blocking<|im_end|> <|im_start|>assistant Researchers have demonstrated the exceptional specificity of a new way to switch sequences of the human genome on or off without editing the underlying genetic code. Originally discovered as an antiviral system in bacteria, CRISPR/Cas9 is one of the hottest topics in genetic research today. By engineering a version of that system, researchers can both edit DNA sequences and control which genes are used. Previous studies, however, showed that editing human DNA sequences with the system is not always as precise as researchers would like. Those results raised concerns about the use of CRISPR technology in studying human diseases. As a potential solution, some researchers added more versatility to the system by using CRISPR to target portions of DNA that control which genes are active. But instead of using the genetic cutting tool Cas9 that is often employed, they inactivated the cutting function of Cas9 and attached proteins that control the packaging of the genome. By unraveling or tightly bundling these regions of the genome, they could effectively turn them on and off. While the technique had been shown to work well, whether or not it had off-target effects had not been investigated. Now, a team of researchers from Duke University have shown that these gene-controlling methods are capable of the high degree of precision required for basic science and medical research. The study appears online on October 26, 2015 in Nature Methods. "The primary advantage of CRISPR over previous technologies is the ability to use a genetic scalpel rather than a sledgehammer," said Charles Gersbach, associate professor of biomedical engineering at Duke University. "Many labs across the world are using these tools on the assumption that they're getting specific effects, but there had not been a comprehensive analysis to prove it. These experiments show exceptional specificity, demonstrating that the technology is capable of targeting single sequences of the genome." The power to control the genome's switches would be especially important for studying and potentially treating human diseases such as cancer, cardiovascular disease, neurodegenerative conditions and diabetes, which can be driven by mutations in control regions of the genome. The hope is that overriding one of these switches could uncover and fix the root causes of many diseases. It could also help researchers understand and change how different people respond to drugs. But only if the CRISPR technique is specific enough. Soon after CRISPR was first described for editing human genes, several papers revealed that the technique can sometimes have off-target effects. This presents problems for gene therapy treatments and fundamental science projects, where researchers want to alter the function of specific genes without causing unintended side effects. An alternative strategy was developed to switch on and off the genomic regions that control when genes are used without modifying the DNA sequence at all. In some cases, these switches can control several related genes at once, allowing researchers to strike chords instead of individual notes. "Looking at the specificity of these tools is technically very challenging," said Timothy Reddy, assistant professor of biostatistics and bioinformatics at Duke. "Finding a change in sequence or gene activity is relatively straightforward if you're focusing on one concentrated area in the genome. But looking at how turning off one enhancer switch affects the activity and structure of the whole genome requires more specialized techniques." Gersbach turned to Reddy and colleague Gregory Crawford, who all work together in adjacent laboratories and offices in Duke's Center for Genomic and Computational Biology, for help with these more specialized techniques. Reddy has focused his career on investigating how gene switches work across the human genome, how those switches differ between individuals and the implications of these insights for human traits and diseases. Crawford, associate professor of pediatrics, has spent more than a decade developing techniques to identify control regions across the genome and how they vary between cell types, during development or in response to drug treatment. "Current methods for controlling gene switches, including drugs used in clinical trials, change the activity of many switches across the genome simultaneously, creating thousands of off-target effects," said Crawford. "What is desperately needed is a technology for manipulating one element at a time." It fell to Pratiksha Thakore, a PhD student in Gersbach's lab, to integrate the expertise of all three laboratories for studying the specificity of CRISPR in controlling these switches. While the results can't prove that every experiment will have the same high level of precision, it provides a blueprint for researchers to assess these effects. "By integrating genomics and genome engineering, we have developed a method to comprehensively interrogate how this genetic silencing system works and also suggested ways the technology can be used in the future," said Thakore. "We also learned some new things about gene regulation, and it turned out that in this context CRISPR can achieve a much higher level of specificity than we expected." <|im_end|>

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13509, 258, 15207, 7645, 4762, 19543, 505, 264, 10824, 315, 357, 11893, 22978, 128257, 198, 128256, 78191, 198, 60210, 617, 21091, 279, 25363, 76041, 315, 264, 502, 1648, 311, 3480, 24630, 315, 279, 3823, 33869, 389, 477, 1022, 2085, 16039, 279, 16940, 19465, 2082, 13, 25842, 11352, 439, 459, 3276, 344, 37478, 1887, 304, 24032, 11, 12904, 1669, 6616, 11547, 300, 24, 374, 832, 315, 279, 38391, 13650, 304, 19465, 3495, 3432, 13, 3296, 15009, 264, 2373, 315, 430, 1887, 11, 12074, 649, 2225, 4600, 15922, 24630, 323, 2585, 902, 21389, 527, 1511, 13, 30013, 7978, 11, 4869, 11, 8710, 430, 16039, 3823, 15922, 24630, 449, 279, 1887, 374, 539, 2744, 439, 24473, 439, 12074, 1053, 1093, 13, 13266, 3135, 9408, 10742, 922, 279, 1005, 315, 12904, 1669, 6616, 5557, 304, 21630, 3823, 19338, 13, 1666, 264, 4754, 6425, 11, 1063, 12074, 3779, 810, 60112, 311, 279, 1887, 555, 1701, 12904, 1669, 6616, 311, 2218, 19885, 315, 15922, 430, 2585, 902, 21389, 527, 4642, 13, 2030, 4619, 315, 1701, 279, 19465, 14713, 5507, 11301, 24, 430, 374, 3629, 20011, 11, 814, 304, 31262, 279, 14713, 734, 315, 11301, 24, 323, 12673, 28896, 430, 2585, 279, 24066, 315, 279, 33869, 13, 3296, 75073, 287, 477, 40069, 10581, 2785, 1521, 13918, 315, 279, 33869, 11, 814, 1436, 13750, 2543, 1124, 389, 323, 1022, 13, 6104, 279, 15105, 1047, 1027, 6982, 311, 990, 1664, 11, 3508, 477, 539, 433, 1047, 1022, 18996, 6372, 1047, 539, 1027, 27313, 13, 4800, 11, 264, 2128, 315, 12074, 505, 27453, 3907, 617, 6982, 430, 1521, 15207, 35172, 16608, 5528, 527, 13171, 315, 279, 1579, 8547, 315, 16437, 2631, 369, 6913, 8198, 323, 6593, 3495, 13, 578, 4007, 8111, 2930, 389, 6664, 220, 1627, 11, 220, 679, 20, 304, 22037, 19331, 13, 330, 791, 6156, 9610, 315, 12904, 1669, 6616, 927, 3766, 14645, 374, 279, 5845, 311, 1005, 264, 19465, 24964, 48624, 4856, 1109, 264, 274, 4995, 46434, 1359, 1071, 15274, 480, 388, 35638, 11, 22712, 14561, 315, 94612, 15009, 520, 27453, 3907, 13, 330, 8607, 51048, 4028, 279, 1917, 527, 1701, 1521, 7526, 389, 279, 25329, 430, 814, 2351, 3794, 3230, 6372, 11, 719, 1070, 1047, 539, 1027, 264, 16195, 6492, 311, 12391, 433, 13, 4314, 21896, 1501, 25363, 76041, 11, 45296, 430, 279, 5557, 374, 13171, 315, 25103, 3254, 24630, 315, 279, 33869, 1210, 578, 2410, 311, 2585, 279, 33869, 596, 32267, 1053, 387, 5423, 3062, 369, 21630, 323, 13893, 27723, 3823, 19338, 1778, 439, 9572, 11, 41713, 8624, 11, 18247, 451, 7642, 1413, 4787, 323, 20335, 11, 902, 649, 387, 16625, 555, 34684, 304, 2585, 13918, 315, 279, 33869, 13, 578, 3987, 374, 430, 68971, 832, 315, 1521, 32267, 1436, 45063, 323, 5155, 279, 3789, 11384, 315, 1690, 19338, 13, 1102, 1436, 1101, 1520, 12074, 3619, 323, 2349, 1268, 2204, 1274, 6013, 311, 11217, 13, 2030, 1193, 422, 279, 12904, 1669, 6616, 15105, 374, 3230, 3403, 13, 32862, 1306, 12904, 1669, 6616, 574, 1176, 7633, 369, 16039, 3823, 21389, 11, 3892, 16064, 10675, 430, 279, 15105, 649, 7170, 617, 1022, 18996, 6372, 13, 1115, 18911, 5435, 369, 15207, 15419, 22972, 323, 16188, 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2,551

[ { "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 The observed trend in Earth’s energy imbalance (TEEI), a measure of the acceleration of heat uptake by the planet, is a fundamental indicator of perturbations to climate. Satellite observations (2001–2020) reveal a significant positive globally-averaged TEEI of 0.38 ± 0.24 Wm −2 decade −1 , but the contributing drivers have yet to be understood. Using climate model simulations, we show that it is exceptionally unlikely (<1% probability) that this trend can be explained by internal variability. Instead, TEEI is achieved only upon accounting for the increase in anthropogenic radiative forcing and the associated climate response. TEEI is driven by a large decrease in reflected solar radiation and a small increase in emitted infrared radiation. This is because recent changes in forcing and feedbacks are additive in the solar spectrum, while being nearly offset by each other in the infrared. We conclude that the satellite record provides clear evidence of a human-influenced climate system. Introduction Earth’s energy imbalance (EEI) is the difference between the incoming solar radiation (S 0 ), and the reflected shortwave radiation (RSW) plus the outgoing longwave radiation (OLR), at the top of the atmosphere 1 , 2 , 3 . Thus, EEI is a fundamental measure of the degree to which the Earth’s global climate system is out of balance. A trend in EEI measures the acceleration of heat uptake by the planet and hence is an indicator of perturbations to the coupled atmosphere-ocean-land-ice system 4 , 5 , 6 , 7 , 8 . The mean EEI during 2005–2015 was estimated to be 0.71 ± 0.10 Wm −2 . Oceans store 90% of this excess heat 9 . Because of this close relationship between EEI and ocean heating, EEI trends have an important bearing on the warming of the global climate system, sea-level rise, and marine health 3 . In addition, understanding historical trends in EEI and its components improves the modeling of the projections of future climate change 10 , 11 , which in turn forms the basis for policymaking and mitigation efforts 12 . In the contemporary climate system, internal variability ( ϵ ), effective radiative forcing ( ΔERF ), and the radiative response ( λ Δ T s ) change EEI 13 , 14 , 15 , 16 . Thus, an anomaly in EEI can be expressed as the sum of these three terms. $${{\\Delta}} {{{EEI}}}={{\\Delta}} {{{ERF}}}+\\lambda {{{\\mathrm{\\varDelta}}}} {T}_{s}+\\epsilon$$ (1) Climate feedbacks and surface temperature are represented by λ and Δ T s , respectively. Hereafter, the term radiative forcing refers to the effective radiative forcing, which comprises external forcings including natural (e.g., solar and volcanic) and anthropogenic (e.g., well-mixed greenhouse gases and aerosols), as well as rapid adjustments in response to the forcing 13 . Satellite observations by Clouds and the Earth’s Radiant Energy System Energy Balance and Filled (CERES EBAF) have provided an uninterrupted two-decade-long time series (January 2001–December 2020) of EEI along with S 0 , RSW, and OLR, allowing the study of TEEI 17 . While the mean EEI in CERES data is adjusted to be consistent with in-situ ocean observations, the interannual variations and trends observed by CERES are reliable, as evidenced by the excellent agreement between the three satellites CERES derives its data from refs. 17 , 18 . While we know that TEEI is influenced by internal variability in the climate system, external forcings, and climate feedbacks, the extent of the contribution from each has not been previously determined 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 . In particular, due to the inherent noise in the Earth system, a single observed 20-year time series of EEI is only one of many possible time series that internal variability could produce 31 , 32 , and therefore, it is imperative to quantify the contribution of internal variability ( ϵ ) to TEEI. We focus here on the investigation of the trend in EEI (TEEI). In particular, the contributions to TEEI by the drivers of the OLR and RSW trends, are an unexplored and unquantified area in the explanation of the observed satellite record. We use Coupled Model Intercomparison Project Phase 6 (CMIP6) experiments and design a hierarchy of climate model experiments with the Geophysical Fluid Dynamics Laboratory Coupled/Atmospheric Model 4.0 (GFDL CM4/AM4) 11 , 33 to better understand the contributions of the three components of Eq. ( 1 ) to the CERES-observed TEEI, thereby providing an assessment of the relative importance of anthropogenically induced changes versus internal variability changes. We show that anthropogenic forcing and the associated climate response yield the observed positive TEEI. Results Trends in CERES observations The trends in EEI (TEEI), RSW, and OLR are computed by taking the linear fits of the ΔEEI, ΔRSW, and ΔOLR time series, respectively. The observed ΔEEI time series yields a significant positive trend of 0.38 ± 0.24 Wm −2 decade −1 (Figs. 1 a, 2 , 3 a, 4 and Supplementary Fig. 1a ; uncertainty given by 95% confidence interval (CI); hereafter all mentions of uncertainty are given by CI unless otherwise specified). The 95% CI consists of uncertainty due to observational error, as well as uncertainty due to internal variability (latter quantified by standard error associated with linear fit 17 , 30 , 34 , 35 ) (see “Methods” section). Although there is excellent agreement between the individual satellites CERES derives its data from, there is, however, the potential for systematic errors associated with the observed trend due to instrument drift. We attach an estimate of 0.20 Wm −2 decade −1 (assuming a normal distribution) to CERES trends, based on best realistic appraisals of observational uncertainty (N. Loeb, CERES Science Project Lead, personal communication) 36 , 37 , 38 . Fig. 1: Global-mean Earth’s radiation budget time series. Interannual anomalies (denoted by Δ) in a , Earth’s Energy Imbalance (EEI), b , reflected shortwave radiation (RSW), c , outgoing longwave radiation (OLR) during 2001–2020. Blue and orange shading each represent", "role": "user" }, { "content": "Sunlight in, reflected and emitted energy out. That's the fundamental energy balance sheet for our planet. If Earth's clouds, oceans, ice caps and land surfaces send as much energy back up to space as the sun shines down on us, then our planet maintains equilibrium. But for decades, that system has been out of balance. Sunlight continues to pour in, and Earth isn't releasing enough, either as reflected solar radiation or as emitted infrared radiation. The extra heat trapped around our globe—some 90% of which is stored in the ocean—adds energy to worldwide climate systems and manifests in many ways: Higher temperatures, rising sea levels, floods, droughts, more powerful blizzards and hurricanes, and deadlier extreme events. While climate scientists have warned for a half-century that this was the inevitable result of adding too much carbon dioxide to the atmosphere, so-called climate deniers have continued to suggest that the observed changes might be a fluke—just natural variation. \"Until now, scientists have believed that because of the short observational record, we can't deduce if the increase in the imbalance is due to humans or climatic 'noise,'\" said Shiv Priyam Raghuraman, a graduate student in atmospheric and oceanic sciences (AOS) at Princeton. \"Our study shows that even with the given observational record, it is almost impossible to have such a large increase in the imbalance just by Earth doing its own oscillations and variations.\" He and his co-authors used satellite observations from 2001 to 2020 and found that Earth's \"energy imbalance\" is growing. Raghuraman worked with David Paynter of the Geophysical Fluid Dynamics Laboratory (GFDL), a NOAA-funded national laboratory located on Princeton's Forrestal Campus, and V. \"Ram\" Ramaswamy, director of GFDL and a lecturer with the rank of professor in geosciences and AOS at Princeton University. Their paper appears today in Nature Communications. \"It is exceptionally unlikely—less than 1% probability—that this trend can be explained by natural variations in the climate system,\" said Raghuraman. So what has caused the growing energy imbalance? \"We always think, 'Increasing greenhouse gases means trapping more infrared heat'—the classic greenhouse effect becomes larger,\" said Raghuraman. \"This is correct, but the flip side is that the resulting warmer planet now also radiates more infrared heat away to space, so the greenhouse gas heating impact is canceled. Instead, much of the imbalance increase comes from the fact that we are receiving the same amount of sunlight but reflecting back less, because increased greenhouse gases cause cloud cover changes, less aerosols in the air to reflect sunlight—that is, cleaner air over the U.S. and Europe—and sea-ice decreases.\" (Bright white sea ice reflects much more sunlight than sea water, so as sea ice melts, Earth is becoming less reflective.) In addition, the Princeton and GFDL researchers noted that oceans store 90% of this excess heat. Because of this close relationship between the growing energy imbalance and ocean heating, the Earth's energy imbalance has important connections to marine health, sea-level rise and the warming of the global climate system. The researchers hope that tracking the historical trends in this energy imbalance and understanding its components will improve the models of future climate change that drive policymaking and mitigation efforts. \"The satellite record provides clear evidence of a human-influenced climate system,\" they said. \"Knowing that human activity is responsible for the acceleration of planetary heat uptake implies the need for significant policy and societal action to reduce anthropogenic greenhouse gas emissions to curb further increases in Earth's energy imbalance.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 observed trend in Earth’s energy imbalance (TEEI), a measure of the acceleration of heat uptake by the planet, is a fundamental indicator of perturbations to climate. Satellite observations (2001–2020) reveal a significant positive globally-averaged TEEI of 0.38 ± 0.24 Wm −2 decade −1 , but the contributing drivers have yet to be understood. Using climate model simulations, we show that it is exceptionally unlikely (<1% probability) that this trend can be explained by internal variability. Instead, TEEI is achieved only upon accounting for the increase in anthropogenic radiative forcing and the associated climate response. TEEI is driven by a large decrease in reflected solar radiation and a small increase in emitted infrared radiation. This is because recent changes in forcing and feedbacks are additive in the solar spectrum, while being nearly offset by each other in the infrared. We conclude that the satellite record provides clear evidence of a human-influenced climate system. Introduction Earth’s energy imbalance (EEI) is the difference between the incoming solar radiation (S 0 ), and the reflected shortwave radiation (RSW) plus the outgoing longwave radiation (OLR), at the top of the atmosphere 1 , 2 , 3 . Thus, EEI is a fundamental measure of the degree to which the Earth’s global climate system is out of balance. A trend in EEI measures the acceleration of heat uptake by the planet and hence is an indicator of perturbations to the coupled atmosphere-ocean-land-ice system 4 , 5 , 6 , 7 , 8 . The mean EEI during 2005–2015 was estimated to be 0.71 ± 0.10 Wm −2 . Oceans store 90% of this excess heat 9 . Because of this close relationship between EEI and ocean heating, EEI trends have an important bearing on the warming of the global climate system, sea-level rise, and marine health 3 . In addition, understanding historical trends in EEI and its components improves the modeling of the projections of future climate change 10 , 11 , which in turn forms the basis for policymaking and mitigation efforts 12 . In the contemporary climate system, internal variability ( ϵ ), effective radiative forcing ( ΔERF ), and the radiative response ( λ Δ T s ) change EEI 13 , 14 , 15 , 16 . Thus, an anomaly in EEI can be expressed as the sum of these three terms. $${{\Delta}} {{{EEI}}}={{\Delta}} {{{ERF}}}+\lambda {{{\mathrm{\varDelta}}}} {T}_{s}+\epsilon$$ (1) Climate feedbacks and surface temperature are represented by λ and Δ T s , respectively. Hereafter, the term radiative forcing refers to the effective radiative forcing, which comprises external forcings including natural (e.g., solar and volcanic) and anthropogenic (e.g., well-mixed greenhouse gases and aerosols), as well as rapid adjustments in response to the forcing 13 . Satellite observations by Clouds and the Earth’s Radiant Energy System Energy Balance and Filled (CERES EBAF) have provided an uninterrupted two-decade-long time series (January 2001–December 2020) of EEI along with S 0 , RSW, and OLR, allowing the study of TEEI 17 . While the mean EEI in CERES data is adjusted to be consistent with in-situ ocean observations, the interannual variations and trends observed by CERES are reliable, as evidenced by the excellent agreement between the three satellites CERES derives its data from refs. 17 , 18 . While we know that TEEI is influenced by internal variability in the climate system, external forcings, and climate feedbacks, the extent of the contribution from each has not been previously determined 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 . In particular, due to the inherent noise in the Earth system, a single observed 20-year time series of EEI is only one of many possible time series that internal variability could produce 31 , 32 , and therefore, it is imperative to quantify the contribution of internal variability ( ϵ ) to TEEI. We focus here on the investigation of the trend in EEI (TEEI). In particular, the contributions to TEEI by the drivers of the OLR and RSW trends, are an unexplored and unquantified area in the explanation of the observed satellite record. We use Coupled Model Intercomparison Project Phase 6 (CMIP6) experiments and design a hierarchy of climate model experiments with the Geophysical Fluid Dynamics Laboratory Coupled/Atmospheric Model 4.0 (GFDL CM4/AM4) 11 , 33 to better understand the contributions of the three components of Eq. ( 1 ) to the CERES-observed TEEI, thereby providing an assessment of the relative importance of anthropogenically induced changes versus internal variability changes. We show that anthropogenic forcing and the associated climate response yield the observed positive TEEI. Results Trends in CERES observations The trends in EEI (TEEI), RSW, and OLR are computed by taking the linear fits of the ΔEEI, ΔRSW, and ΔOLR time series, respectively. The observed ΔEEI time series yields a significant positive trend of 0.38 ± 0.24 Wm −2 decade −1 (Figs. 1 a, 2 , 3 a, 4 and Supplementary Fig. 1a ; uncertainty given by 95% confidence interval (CI); hereafter all mentions of uncertainty are given by CI unless otherwise specified). The 95% CI consists of uncertainty due to observational error, as well as uncertainty due to internal variability (latter quantified by standard error associated with linear fit 17 , 30 , 34 , 35 ) (see “Methods” section). Although there is excellent agreement between the individual satellites CERES derives its data from, there is, however, the potential for systematic errors associated with the observed trend due to instrument drift. We attach an estimate of 0.20 Wm −2 decade −1 (assuming a normal distribution) to CERES trends, based on best realistic appraisals of observational uncertainty (N. Loeb, CERES Science Project Lead, personal communication) 36 , 37 , 38 . Fig. 1: Global-mean Earth’s radiation budget time series. Interannual anomalies (denoted by Δ) in a , Earth’s Energy Imbalance (EEI), b , reflected shortwave radiation (RSW), c , outgoing longwave radiation (OLR) during 2001–2020. Blue and orange shading each represent<|im_end|> <|im_start|>assistant Sunlight in, reflected and emitted energy out. That's the fundamental energy balance sheet for our planet. If Earth's clouds, oceans, ice caps and land surfaces send as much energy back up to space as the sun shines down on us, then our planet maintains equilibrium. But for decades, that system has been out of balance. Sunlight continues to pour in, and Earth isn't releasing enough, either as reflected solar radiation or as emitted infrared radiation. The extra heat trapped around our globe—some 90% of which is stored in the ocean—adds energy to worldwide climate systems and manifests in many ways: Higher temperatures, rising sea levels, floods, droughts, more powerful blizzards and hurricanes, and deadlier extreme events. While climate scientists have warned for a half-century that this was the inevitable result of adding too much carbon dioxide to the atmosphere, so-called climate deniers have continued to suggest that the observed changes might be a fluke—just natural variation. "Until now, scientists have believed that because of the short observational record, we can't deduce if the increase in the imbalance is due to humans or climatic 'noise,'" said Shiv Priyam Raghuraman, a graduate student in atmospheric and oceanic sciences (AOS) at Princeton. "Our study shows that even with the given observational record, it is almost impossible to have such a large increase in the imbalance just by Earth doing its own oscillations and variations." He and his co-authors used satellite observations from 2001 to 2020 and found that Earth's "energy imbalance" is growing. Raghuraman worked with David Paynter of the Geophysical Fluid Dynamics Laboratory (GFDL), a NOAA-funded national laboratory located on Princeton's Forrestal Campus, and V. "Ram" Ramaswamy, director of GFDL and a lecturer with the rank of professor in geosciences and AOS at Princeton University. Their paper appears today in Nature Communications. "It is exceptionally unlikely—less than 1% probability—that this trend can be explained by natural variations in the climate system," said Raghuraman. So what has caused the growing energy imbalance? "We always think, 'Increasing greenhouse gases means trapping more infrared heat'—the classic greenhouse effect becomes larger," said Raghuraman. "This is correct, but the flip side is that the resulting warmer planet now also radiates more infrared heat away to space, so the greenhouse gas heating impact is canceled. Instead, much of the imbalance increase comes from the fact that we are receiving the same amount of sunlight but reflecting back less, because increased greenhouse gases cause cloud cover changes, less aerosols in the air to reflect sunlight—that is, cleaner air over the U.S. and Europe—and sea-ice decreases." (Bright white sea ice reflects much more sunlight than sea water, so as sea ice melts, Earth is becoming less reflective.) In addition, the Princeton and GFDL researchers noted that oceans store 90% of this excess heat. Because of this close relationship between the growing energy imbalance and ocean heating, the Earth's energy imbalance has important connections to marine health, sea-level rise and the warming of the global climate system. The researchers hope that tracking the historical trends in this energy imbalance and understanding its components will improve the models of future climate change that drive policymaking and mitigation efforts. "The satellite record provides clear evidence of a human-influenced climate system," they said. "Knowing that human activity is responsible for the acceleration of planetary heat uptake implies the need for significant policy and societal action to reduce anthropogenic greenhouse gas emissions to curb further increases in Earth's energy imbalance." <|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 Van der Waals moiré materials have emerged as a highly controllable platform to study electronic correlation phenomena 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 . Robust correlated insulating states have recently been discovered at both integer and fractional filling factors of semiconductor moiré systems 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 . In this study we explored the thermodynamic properties of these states by measuring the gate capacitance of MoSe 2 /WS 2 moiré superlattices. We observed a series of incompressible states for filling factors 0–8 and anomalously large capacitance in the intervening compressible regions. The anomalously large capacitance, which was nearly 60% above the device’s geometrical capacitance, was most pronounced at small filling factors, below the melting temperature of the charge-ordered states, and for small sample–gate separation. It is a manifestation of the device-geometry-dependent Coulomb interaction between electrons and phase mixing of the charge-ordered states. Based on these results, we were able to extract the thermodynamic gap of the correlated insulating states and the device’s electronic entropy and specific heat capacity. Our findings establish capacitance as a powerful probe of the correlated states in semiconductor moiré systems and demonstrate control of these states via sample–gate coupling. Main The capacitance of a parallel plate capacitor is a thermodynamic probe of a sample that serves as one of the plate electrodes 18 . The electric potential eV ( e denoting the elementary charge) required to maintain a sheet charge carrier density n in equilibrium is usually expressed as the sum of two independent contributions, eV = ϕ + μ . Here, ϕ = ne 2 / C g is the electrostatic potential from the ideal (or geometrical) capacitance per unit area, C g = ε / d , where ε is the permittivity and d is the thickness of the medium between the two electrodes, and μ is the chemical potential of the sample. The differential capacitance per unit area \$C = e\\frac{{{\\mathrm{d}}n}}{{{\\mathrm{d}}V}}\$ follows from the relation \$C^{ - 1} = C_{\\mathrm{g}}^{ - 1} + C_{\\mathrm{Q}}^{ - 1}\$ , where \$C_{\\mathrm{Q}} = e^2\\frac{{{\\mathrm{d}}n}}{{{\\mathrm{d}}\\mu }}\$ is the sample’s quantum capacitance, which represents its electronic compressibility or thermodynamic density of states (DOS) 19 . For an incompressible (insulating) state, one anticipates C < C g . The capacitance can also exceed C g , which is frequently referred to as negative compressibility, as a result of electron Coulomb correlations in the sample 20 , 21 , 22 , 23 , 24 , 25 . Such a treatment is appropriate in the high-density regime ( nd 2 >> 1), in which the interaction between electrons in the sample does not depend on device geometry 26 . For a moiré superlattice of period a M , the electron Wannier function is localized at each moiré site and the effective carrier density ‘resets’ after each integer filling of the superlattice. When d is comparable to or smaller than a M , the system is in the low-density regime for all filling factors and the above treatment is in general no longer appropriate. In this work, we have established capacitance as a probe of the emergent electronic states in moiré superlattices in this new regime. We investigated the effect of screening of the extended Coulomb interaction by varying sample–gate separation d . When two monolayers of semiconducting transition metal dichalcogenides (TMDs) are overlaid with a small twist angle or lattice mismatch, a moiré superlattice of long period is formed. The superlattice potential causes extra Bragg reflection of electrons and induces flat moiré minibands for enhanced correlations. Robust correlated insulating states have been observed at both integer and fractional filling factors of superlattices 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 . A single-band extended Hubbard model with twofold valley pseudospin degeneracy is believed to capture the essential low-energy physics of TMD heterobilayers 27 . In particular, the insulating state at filling factor ν = 1 (that is, one particle per moiré superlattice cell or half-filling of the first moiré miniband) is understood to originate from a strong on-site Coulomb repulsion U compared with the lattice kinetic hopping t 27 , 28 . The charge-ordered insulating states at fractional fillings highlight the importance of the extended Coulomb interaction in addition to U 10 , 15 , 29 , 30 . To date, the detection of these states has relied heavily on optical techniques, largely due to the challenges in achieving good TMD–metal contacts for electrical studies, particularly at low charge density and low temperature. Because of the different length scales of the Coulomb interactions that are responsible for the correlated insulating states at the integer and fractional filling factors, the degree of sample–gate coupling is expected to be different. We report here the capacitance of field-effect devices comprising MoSe 2 /WS 2 heterobilayers (Fig. 1a ) as a function of filling factor spanning up to four electron moiré minibands ( ν = 0–8). The angle-aligned MoSe 2 /WS 2 heterobilayers form a triangular moiré superlattice with a M ≈ 8 nm (corresponding to a moiré density of 1.9 × 10 12 cm −2 ) because there is ~4% lattice mismatch between these materials. The MoSe 2 /WS 2 heterobilayer has a type I band alignment 31 ; the lowest-energy electron moiré minibands are formed by states near the conduction band minimum of MoSe 2 and are weakly coupled to the states in WS 2 (Fig. 1b ). We achieved good n -type contacts to the heterobilayer for capacitance measurements down to 10 K by using platinum electrodes 32 and heavily doping the contact region under a large global back gate voltage V b . The electron density in the heterobilayer can be tuned by varying the local top gate voltage V t . We measured both", "role": "user" }, { "content": "In recent years, electronics engineers have been experimenting with new materials that could be used to study electronic correlation phenomena. Van der Waals (vdW) moiré materials are particularly promising for examining these phenomena. VdW materials are composed of strongly bonded two-dimensional (2D) layers that are bound in the third dimension through weaker dispersion forces. The term moiré, on the other hand, refers to a specific pattern produced when an opaque ruled pattern with gaps is placed onto a similar pattern. Studies have recently unveiled robust and correlated insulating states at both integer and fractional filling factors of semiconducting materials with a moiré pattern. Researchers at Cornell University and the National Institute for Materials Science in Japan have recently carried out a study exploring the thermodynamic properties of these robust correlated states. Their paper, published in Nature Nanotechnology, ultimately showed that capacitance (i.e., the ability of a system to store electric charge) can play a key role in probing correlated states of semiconductor moiré materials. This recent study was in part based on a previous research effort by the same team, which unveiled the presence of an abundance of electron crystals in semiconductor moiré materials. One of the main objectives of the team's new study was to better understand these electron crystal states by collecting thermodynamics measurements. \"Our study also draws inspiration from theoretical calculations by our friend Veit Elser, who is a co-author in the paper,\" Kin Fai Mak, one of the researchers who carried out the study, told TechXplore. \"Veit calculated the capacitance for a parallel plate capacitor that has the sample as one plate and a metallic gate as another plate.\" Typically, the capacitance of a parallel plate capacitor such as the one investigated by Elser would only be defined by its geometry (e.g., the distance between the two plates). Surprisingly, however, his calculations suggested that the capacitance when the sample plate is in a phase mixture of electron crystals could in fact be infinite. \"This could be huge, as it can significantly enhances the capability of the device to store charge,\" Mak said. To test this idea experimentally, Mak and his colleagues measured the capacitance of a parallel capacitor that has the sample of interest (i.e., the moiré sample) as one plate and a thin sheet of metal as the second plate. \"The two plates were separated by an experimentally variable distance,\" Mak said. \"The capacitance is intimately connected to the electronic compressibility (a thermodynamic quantity) of the sample, which is a measure of how compressible the electrons are when they are subjected to an external electric field.\" The team carefully measured how compressible the electrons in their sample were when exposed to an external electric field as a function of electron density and temperature. This allowed them to derive two additional thermodynamic measurements (i.e., the electronic entropy and specific heat capacity) from the existing data, using renowned and established rules of thermodynamic relations. \"One of the most important achievements of our study was a significant enhancement of the measured capacitance compared to the geometrical value,\" Mak said. \"To the best of our knowledge, this is probably the largest enhancement reported to date. Because of sample disorders, however, the observed enhancement is far from infinity as predicted by Veit's original calculations. One could imagine further capacitance enhancement with better samples in the future.\" The recent findings gathered by this team of researchers could have important implications for the development of electronic devices. In fact, their work demonstrates that the capacitance of semiconductor moiré superlattices can be significantly enhanced, which means that the charge storage of devices made of these materials could be improved. In addition, the team gathered valuable quantitative measurements of the thermodynamic properties of the electron crystal states in semiconductor moiré superlattices. In the future, these measurements could help to better understand the nature of these exotic states of matter. \"Thermodynamic measurement is an important skill in physics, as it helps understand the nature of many emergent quantum states of matter,\" Mak added. \"There are so many exotic states recently discovered in moiré materials (e.g., superconductivity, correlated insulators, electron crystals, quantum anomalous Hall effect, etc.). Carrying out thermodynamic studies on these states will certainly help understand some of the mysteries in this field of research. In general, capacitance measurement is a very useful diagnostic tool for quantum matters.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Van der Waals moiré materials have emerged as a highly controllable platform to study electronic correlation phenomena 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 . Robust correlated insulating states have recently been discovered at both integer and fractional filling factors of semiconductor moiré systems 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 . In this study we explored the thermodynamic properties of these states by measuring the gate capacitance of MoSe 2 /WS 2 moiré superlattices. We observed a series of incompressible states for filling factors 0–8 and anomalously large capacitance in the intervening compressible regions. The anomalously large capacitance, which was nearly 60% above the device’s geometrical capacitance, was most pronounced at small filling factors, below the melting temperature of the charge-ordered states, and for small sample–gate separation. It is a manifestation of the device-geometry-dependent Coulomb interaction between electrons and phase mixing of the charge-ordered states. Based on these results, we were able to extract the thermodynamic gap of the correlated insulating states and the device’s electronic entropy and specific heat capacity. Our findings establish capacitance as a powerful probe of the correlated states in semiconductor moiré systems and demonstrate control of these states via sample–gate coupling. Main The capacitance of a parallel plate capacitor is a thermodynamic probe of a sample that serves as one of the plate electrodes 18 . The electric potential eV ( e denoting the elementary charge) required to maintain a sheet charge carrier density n in equilibrium is usually expressed as the sum of two independent contributions, eV = ϕ + μ . Here, ϕ = ne 2 / C g is the electrostatic potential from the ideal (or geometrical) capacitance per unit area, C g = ε / d , where ε is the permittivity and d is the thickness of the medium between the two electrodes, and μ is the chemical potential of the sample. The differential capacitance per unit area $C = e\frac{{{\mathrm{d}}n}}{{{\mathrm{d}}V}}$ follows from the relation $C^{ - 1} = C_{\mathrm{g}}^{ - 1} + C_{\mathrm{Q}}^{ - 1}$ , where $C_{\mathrm{Q}} = e^2\frac{{{\mathrm{d}}n}}{{{\mathrm{d}}\mu }}$ is the sample’s quantum capacitance, which represents its electronic compressibility or thermodynamic density of states (DOS) 19 . For an incompressible (insulating) state, one anticipates C < C g . The capacitance can also exceed C g , which is frequently referred to as negative compressibility, as a result of electron Coulomb correlations in the sample 20 , 21 , 22 , 23 , 24 , 25 . Such a treatment is appropriate in the high-density regime ( nd 2 >> 1), in which the interaction between electrons in the sample does not depend on device geometry 26 . For a moiré superlattice of period a M , the electron Wannier function is localized at each moiré site and the effective carrier density ‘resets’ after each integer filling of the superlattice. When d is comparable to or smaller than a M , the system is in the low-density regime for all filling factors and the above treatment is in general no longer appropriate. In this work, we have established capacitance as a probe of the emergent electronic states in moiré superlattices in this new regime. We investigated the effect of screening of the extended Coulomb interaction by varying sample–gate separation d . When two monolayers of semiconducting transition metal dichalcogenides (TMDs) are overlaid with a small twist angle or lattice mismatch, a moiré superlattice of long period is formed. The superlattice potential causes extra Bragg reflection of electrons and induces flat moiré minibands for enhanced correlations. Robust correlated insulating states have been observed at both integer and fractional filling factors of superlattices 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 . A single-band extended Hubbard model with twofold valley pseudospin degeneracy is believed to capture the essential low-energy physics of TMD heterobilayers 27 . In particular, the insulating state at filling factor ν = 1 (that is, one particle per moiré superlattice cell or half-filling of the first moiré miniband) is understood to originate from a strong on-site Coulomb repulsion U compared with the lattice kinetic hopping t 27 , 28 . The charge-ordered insulating states at fractional fillings highlight the importance of the extended Coulomb interaction in addition to U 10 , 15 , 29 , 30 . To date, the detection of these states has relied heavily on optical techniques, largely due to the challenges in achieving good TMD–metal contacts for electrical studies, particularly at low charge density and low temperature. Because of the different length scales of the Coulomb interactions that are responsible for the correlated insulating states at the integer and fractional filling factors, the degree of sample–gate coupling is expected to be different. We report here the capacitance of field-effect devices comprising MoSe 2 /WS 2 heterobilayers (Fig. 1a ) as a function of filling factor spanning up to four electron moiré minibands ( ν = 0–8). The angle-aligned MoSe 2 /WS 2 heterobilayers form a triangular moiré superlattice with a M ≈ 8 nm (corresponding to a moiré density of 1.9 × 10 12 cm −2 ) because there is ~4% lattice mismatch between these materials. The MoSe 2 /WS 2 heterobilayer has a type I band alignment 31 ; the lowest-energy electron moiré minibands are formed by states near the conduction band minimum of MoSe 2 and are weakly coupled to the states in WS 2 (Fig. 1b ). We achieved good n -type contacts to the heterobilayer for capacitance measurements down to 10 K by using platinum electrodes 32 and heavily doping the contact region under a large global back gate voltage V b . The electron density in the heterobilayer can be tuned by varying the local top gate voltage V t . We measured both<|im_end|> <|im_start|>assistant In recent years, electronics engineers have been experimenting with new materials that could be used to study electronic correlation phenomena. Van der Waals (vdW) moiré materials are particularly promising for examining these phenomena. VdW materials are composed of strongly bonded two-dimensional (2D) layers that are bound in the third dimension through weaker dispersion forces. The term moiré, on the other hand, refers to a specific pattern produced when an opaque ruled pattern with gaps is placed onto a similar pattern. Studies have recently unveiled robust and correlated insulating states at both integer and fractional filling factors of semiconducting materials with a moiré pattern. Researchers at Cornell University and the National Institute for Materials Science in Japan have recently carried out a study exploring the thermodynamic properties of these robust correlated states. Their paper, published in Nature Nanotechnology, ultimately showed that capacitance (i.e., the ability of a system to store electric charge) can play a key role in probing correlated states of semiconductor moiré materials. This recent study was in part based on a previous research effort by the same team, which unveiled the presence of an abundance of electron crystals in semiconductor moiré materials. One of the main objectives of the team's new study was to better understand these electron crystal states by collecting thermodynamics measurements. "Our study also draws inspiration from theoretical calculations by our friend Veit Elser, who is a co-author in the paper," Kin Fai Mak, one of the researchers who carried out the study, told TechXplore. "Veit calculated the capacitance for a parallel plate capacitor that has the sample as one plate and a metallic gate as another plate." Typically, the capacitance of a parallel plate capacitor such as the one investigated by Elser would only be defined by its geometry (e.g., the distance between the two plates). Surprisingly, however, his calculations suggested that the capacitance when the sample plate is in a phase mixture of electron crystals could in fact be infinite. "This could be huge, as it can significantly enhances the capability of the device to store charge," Mak said. To test this idea experimentally, Mak and his colleagues measured the capacitance of a parallel capacitor that has the sample of interest (i.e., the moiré sample) as one plate and a thin sheet of metal as the second plate. "The two plates were separated by an experimentally variable distance," Mak said. "The capacitance is intimately connected to the electronic compressibility (a thermodynamic quantity) of the sample, which is a measure of how compressible the electrons are when they are subjected to an external electric field." The team carefully measured how compressible the electrons in their sample were when exposed to an external electric field as a function of electron density and temperature. This allowed them to derive two additional thermodynamic measurements (i.e., the electronic entropy and specific heat capacity) from the existing data, using renowned and established rules of thermodynamic relations. "One of the most important achievements of our study was a significant enhancement of the measured capacitance compared to the geometrical value," Mak said. "To the best of our knowledge, this is probably the largest enhancement reported to date. Because of sample disorders, however, the observed enhancement is far from infinity as predicted by Veit's original calculations. One could imagine further capacitance enhancement with better samples in the future." The recent findings gathered by this team of researchers could have important implications for the development of electronic devices. In fact, their work demonstrates that the capacitance of semiconductor moiré superlattices can be significantly enhanced, which means that the charge storage of devices made of these materials could be improved. In addition, the team gathered valuable quantitative measurements of the thermodynamic properties of the electron crystal states in semiconductor moiré superlattices. In the future, these measurements could help to better understand the nature of these exotic states of matter. "Thermodynamic measurement is an important skill in physics, as it helps understand the nature of many emergent quantum states of matter," Mak added. "There are so many exotic states recently discovered in moiré materials (e.g., superconductivity, correlated insulators, electron crystals, quantum anomalous Hall effect, etc.). Carrying out thermodynamic studies on these states will certainly help understand some of the mysteries in this field of research. In general, capacitance measurement is a very useful diagnostic tool for quantum matters." <|im_end|>

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2,346

[ { "content": "You are a great 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 2D materials are vertically stacked, new physics emerges from interlayer orbital interactions and charge transfer modulated by the additional periodicity of interlayer atomic registry (moiré superlattice). Surprisingly, relatively little is known regarding the real-space distribution of the transferred charges within this framework. Here we provide the first experimental indications of a real-space, non-atomic lattice formed by interlayer coupling induced charge redistribution in vertically stacked Bi 2 Se 3 /transition metal dichalcogenide (TMD) 2D heterostructures. Robust enough to scatter 200 keV electron beams, this non-atomic lattice generates selected area diffraction patterns that correspond excellently with simulated patterns from moiré superlattices of the parent crystals suggesting their location at sites of high interlayer atomic registry. Density functional theory (DFT) predicts concentrated charge pools reside in the interlayer region, located at sites of high nearest-neighbor atomic registry, suggesting the non-atomic lattices are standalone, reside in the interlayer region, and are purely electronic. Interlayer coupling can trigger a variety of phenomena in vertical 2D heterostructures, including creating new excitons (both interlayer and moiré), 1,2 modifying e–h recombination pathways, 3,4 altering Raman vibrational modes, 5 shifting the absorption profile, 6 enabling super-dense storage of lithium, 7 and inducing superconductivity. 8 In many instances, these new properties are strongly modulated by the formation of moiré superlattices, where the periodic variations of atomic registry between the two layers generate a new “lattice” with significantly modified band structure, electronic, optical and magnetic properties. 8–10 Since it is possible to artificially stack 2D layers with arbitrary twist angles, understanding and controlling the enhanced interactions at sites of high atomic registry in twisted 2D bilayers has become the central focus of research by many theoretical 11 and experimental efforts 12 in recent times. Here, we show that interfaces of monolayer transition metal dichalcogenides (TMDs) with Bi 2 Se 3 contain a new periodic lattice of electron scatterers of non-atomic origin that generate an additional set of high-energy electron diffraction spots. These new patterns correspond to the moiré superlattices of the parent 2D heterostructures. We argue that these originate neither from the interference or multiple scattering features between the two parent crystals, nor from adsorption of foreign atoms ( e.g. , oxygen, bismuth, selenide), but rather from interlayer coupling induced charge redistribution into non-atomic scattering sites periodically spaced and oriented to match the moiré superlattice. Indeed, density functional theory (DFT) calculations corroborate that the interlayer coupling induces the formation of a purely-electronic charge lattice residing in the interlayer region which matches the orientation and size of the experimentally observed spots. Traditional dark-field TEM imaging, 10 high-resolution TEM imaging (Fig. S10 † ), 13 and STM 14,15 are able to visualize the moiré superlattices, but cannot independently probe the interlayer region or interlayer interaction because these measurements include the electrons’ interaction with both parent layers as well. In contrast, high-energy selected area electron diffraction (SAED) is able to probe the interlayer region of 2D materials, in part due to the small wavelength of the electrons (0.0251 Å at 200 keV) and the low scattering angles inherent to SAED (∼0.6°). The wavelength of the high-energy electrons are orders of magnitude smaller than the effective separation between the layers, which allows them to independently scatter from sites in the interlayer region, thereby greatly reducing the possibility of interference or multiple scattering features between the two parent crystals. Additionally, the very small scattering angles inherent to SAED, combined with the atomically thin nature of the samples, prevent strong reflections from the upper lattice becoming initial waves for the lower lattice. Hence, wave-interference and double diffraction effects present in multiple slit optical systems are very unlikely here (see section S4 † for amplifying discussion). Together, this indicates that the presence of moiré superlattice spots using SAED of 2D materials is due to the presence of non-atomic electron scattering sites, formed by interlayer coupling induced charge redistribution. Nearly all past works on 2D moiré lattices apply a 2D fast Fourier transform (FFT) of real-space images as a means to simulate moiré “diffraction” patterns, rather than showing their real appearance in, e.g. a SAED measurement. Previous work showed that the lower scattering probability of the incoming high-energy electrons, combined with the generally weaker scattering cross section of non-atomic scattering sites, make identifying and measuring moiré superlattice SAED spots in vertically-stacked 2D graphene structures difficult. 16 In fact, we were able to find only one published work that demonstrates moiré superlattice spots using high-energy SAED, where the results suggest moiré superlattice spot brightness in bilayer graphene 2D structures is influenced by the twist angle and atomic registry. 10 Our work indicates that the strong interlayer coupling in vertically-stacked Bi 2 Se 3 /TMD 2D heterostructures induces significant charge redistribution, a surprising discovery considering both Bi 2 Se 3 and TMD are considered to have “weak” van der Waals interlayer bonding. This is in contrast to layered graphene 2D structures which can have stronger π–π interlayer interactions, due to graphene's out-of-plane π orbitals. 17,18 Of note, this work demonstrates the effect in four different Bi 2 Se 3 /TMD 2D heterostructures, including a TMD alloy (Bi 2 Se 3 /MoS 2 , Bi 2 Se 3 /MoSe 2 , Bi 2 Se 3 /WS 2 , and Bi 2 Se 3 /MoSe 2−2 x S 2 x ), and at multiple twist angles. To the best of our knowledge, no previous work has demonstrated this effect on so many different samples and at such high electron energies (200 keV), suggesting that the interlayer coupling induced charge redistribution is particularly robust in this family of 2D heterostructures. Previous work demonstrates that Bi 2 Se 3 /TMD 2D heterostructures have a strong interlayer coupling that quenches the signature photoluminescence of monolayer TMDs and modifies the Raman spectra. 3,4,46 Further, the interlayer coupling appears to facilitate the formation of a moiré superlattice with its own unique bandstructure (Fig. S12 † ), and modify the recombination energy of the exciton quasiparticles (Fig. S11 † ). A follow-up work found strong interlayer couplings", "role": "user" }, { "content": "Humans have been studying electric charge for thousands of years, and the results have shaped modern civilization. Our daily lives depend on electric lighting, smartphones, cars, and computers, in ways that the first individuals to take note of a static shock or a bolt of lightning could never have imagined. Now, physicists at Northeastern have discovered a new way to manipulate electric charge. And the changes to the future of our technology could be monumental. \"When such phenomena are discovered, imagination is the limit,\" says Swastik Kar, an associate professor of physics. \"It could change the way we can detect and communicate signals. It could change the way we can sense things and the storage of information, and possibilities that we may not have even thought of yet.\" The ability to move, manipulate, and store electrons is key to the vast majority of modern technology, whether we're trying to harvest energy from the sun or play Plants vs. Zombies on our phone. In a paper published in Nanoscale, the researchers described a way to make electrons do something entirely new: Distribute themselves evenly into a stationary, crystalline pattern. \"I'm tempted to say it's almost like a new phase of matter,\" Kar says. \"Because it's just purely electronic.\" The phenomenon appeared while the researchers were running experiments with crystalline materials that are only a few atoms thick, known as 2-D materials. These materials are made up of a repeating pattern of atoms, like an endless checkerboard, and are so thin that the electrons in them can only move in two dimensions. Stacking these ultra-thin materials can create unusual effects as the layers interact at a quantum level. Kar and his colleagues were examining two such 2-D materials, bismuth selenide and a transition metal dichalcogenide, layered on top of each other like sheets of paper. That's when things started to get weird. Electrons should repel one another—they're negatively charged, and move away from other negatively charged things. But that's not what the electrons in these layers were doing. They were forming a stationary pattern. \"At certain angles, these materials seem to form a way to share their electrons that ends up forming this geometrically periodic third lattice,\" Kar says. \"A perfectly repeatable array of pure electronic puddles that resides between the two layers.\" At first, Kar assumed the result was a mistake. The crystalline structures of 2-D materials are too small to observe directly, so physicists use special microscopes that fire beams of electrons instead of light. As the electrons pass through the material, they interfere with each other and create a pattern. The specific pattern (and a bunch of math) can be used to recreate the shape of the 2-D material. University Distinguished Professor of physics Arun Bansil (left) and associate professor of physics Swastik Kar accidentally discovered a new way to manipulate electronic charge. Credit: Matthew Modoono/Northeastern University When the resulting pattern revealed a third layer that couldn't be coming from either of the other two, Kar thought something had gone wrong in the creation of the material or in the measurement process. Similar phenomena have been observed before, but only at extremely low temperatures. Kar's observations were at room temperature. \"Have you ever walked into a meadow and seen an apple tree with mangoes hanging from it?\" Kar asks. \"Of course we thought something was wrong. This couldn't be happening.\" But after repeated testing and experiments led by doctoral student Zachariah Hennighausen, their results remained the same. There was a new lattice-style pattern of charged spots appearing between the 2-D materials. And that pattern changed with the orientation of the two sandwiching layers. As Kar and his team had been working on the experimental investigation, Arun Bansil, a university distinguished professor of physics at Northeastern, and doctoral student Chistopher Lane were examining the theoretical possibilities, to understand how this could be happening. Electrons in a material are always bouncing around, Bansil explains, as they are pulled on by the positively charged nuclei of atoms and repelled by other negatively charged electrons. But in this case, something about the way these charges are laid out is pooling electrons in a specific pattern. \"They produce these regions where there are, if you like, ditches of some kind in the potential landscape, which are enough to force these electrons to create these puddles of charge,\" Bansil says. \"The only reason electrons will form into puddles is because there's a potential hole there.\" These ditches, so to speak, are created by a combination of quantum mechanical and physical factors, Bansil says. When two repeating patterns or grids are offset, they combine to create a new pattern (you can replicate this at home by overlapping the teeth of two flat combs). Each 2-D material has a repeating structure, and the researchers demonstrated that the pattern created when those materials are stacked determines where electrons will end up. \"That is where it becomes quantum mechanically favorable for the puddles to reside,\" Kar says. \"It's almost guiding those electron puddles to remain there and nowhere else. It is fascinating.\" While the understanding of this phenomenon is still in its infancy, it has the potential to impact the future of electronics, sensing and detection systems, and information processing. \"The excitement at this point is in being able to potentially demonstrate something that people have never thought could exist at room temperature before,\" Kar says. \"And now, the sky's the limit in terms of how we can harness it.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract When 2D materials are vertically stacked, new physics emerges from interlayer orbital interactions and charge transfer modulated by the additional periodicity of interlayer atomic registry (moiré superlattice). Surprisingly, relatively little is known regarding the real-space distribution of the transferred charges within this framework. Here we provide the first experimental indications of a real-space, non-atomic lattice formed by interlayer coupling induced charge redistribution in vertically stacked Bi 2 Se 3 /transition metal dichalcogenide (TMD) 2D heterostructures. Robust enough to scatter 200 keV electron beams, this non-atomic lattice generates selected area diffraction patterns that correspond excellently with simulated patterns from moiré superlattices of the parent crystals suggesting their location at sites of high interlayer atomic registry. Density functional theory (DFT) predicts concentrated charge pools reside in the interlayer region, located at sites of high nearest-neighbor atomic registry, suggesting the non-atomic lattices are standalone, reside in the interlayer region, and are purely electronic. Interlayer coupling can trigger a variety of phenomena in vertical 2D heterostructures, including creating new excitons (both interlayer and moiré), 1,2 modifying e–h recombination pathways, 3,4 altering Raman vibrational modes, 5 shifting the absorption profile, 6 enabling super-dense storage of lithium, 7 and inducing superconductivity. 8 In many instances, these new properties are strongly modulated by the formation of moiré superlattices, where the periodic variations of atomic registry between the two layers generate a new “lattice” with significantly modified band structure, electronic, optical and magnetic properties. 8–10 Since it is possible to artificially stack 2D layers with arbitrary twist angles, understanding and controlling the enhanced interactions at sites of high atomic registry in twisted 2D bilayers has become the central focus of research by many theoretical 11 and experimental efforts 12 in recent times. Here, we show that interfaces of monolayer transition metal dichalcogenides (TMDs) with Bi 2 Se 3 contain a new periodic lattice of electron scatterers of non-atomic origin that generate an additional set of high-energy electron diffraction spots. These new patterns correspond to the moiré superlattices of the parent 2D heterostructures. We argue that these originate neither from the interference or multiple scattering features between the two parent crystals, nor from adsorption of foreign atoms ( e.g. , oxygen, bismuth, selenide), but rather from interlayer coupling induced charge redistribution into non-atomic scattering sites periodically spaced and oriented to match the moiré superlattice. Indeed, density functional theory (DFT) calculations corroborate that the interlayer coupling induces the formation of a purely-electronic charge lattice residing in the interlayer region which matches the orientation and size of the experimentally observed spots. Traditional dark-field TEM imaging, 10 high-resolution TEM imaging (Fig. S10 † ), 13 and STM 14,15 are able to visualize the moiré superlattices, but cannot independently probe the interlayer region or interlayer interaction because these measurements include the electrons’ interaction with both parent layers as well. In contrast, high-energy selected area electron diffraction (SAED) is able to probe the interlayer region of 2D materials, in part due to the small wavelength of the electrons (0.0251 Å at 200 keV) and the low scattering angles inherent to SAED (∼0.6°). The wavelength of the high-energy electrons are orders of magnitude smaller than the effective separation between the layers, which allows them to independently scatter from sites in the interlayer region, thereby greatly reducing the possibility of interference or multiple scattering features between the two parent crystals. Additionally, the very small scattering angles inherent to SAED, combined with the atomically thin nature of the samples, prevent strong reflections from the upper lattice becoming initial waves for the lower lattice. Hence, wave-interference and double diffraction effects present in multiple slit optical systems are very unlikely here (see section S4 † for amplifying discussion). Together, this indicates that the presence of moiré superlattice spots using SAED of 2D materials is due to the presence of non-atomic electron scattering sites, formed by interlayer coupling induced charge redistribution. Nearly all past works on 2D moiré lattices apply a 2D fast Fourier transform (FFT) of real-space images as a means to simulate moiré “diffraction” patterns, rather than showing their real appearance in, e.g. a SAED measurement. Previous work showed that the lower scattering probability of the incoming high-energy electrons, combined with the generally weaker scattering cross section of non-atomic scattering sites, make identifying and measuring moiré superlattice SAED spots in vertically-stacked 2D graphene structures difficult. 16 In fact, we were able to find only one published work that demonstrates moiré superlattice spots using high-energy SAED, where the results suggest moiré superlattice spot brightness in bilayer graphene 2D structures is influenced by the twist angle and atomic registry. 10 Our work indicates that the strong interlayer coupling in vertically-stacked Bi 2 Se 3 /TMD 2D heterostructures induces significant charge redistribution, a surprising discovery considering both Bi 2 Se 3 and TMD are considered to have “weak” van der Waals interlayer bonding. This is in contrast to layered graphene 2D structures which can have stronger π–π interlayer interactions, due to graphene's out-of-plane π orbitals. 17,18 Of note, this work demonstrates the effect in four different Bi 2 Se 3 /TMD 2D heterostructures, including a TMD alloy (Bi 2 Se 3 /MoS 2 , Bi 2 Se 3 /MoSe 2 , Bi 2 Se 3 /WS 2 , and Bi 2 Se 3 /MoSe 2−2 x S 2 x ), and at multiple twist angles. To the best of our knowledge, no previous work has demonstrated this effect on so many different samples and at such high electron energies (200 keV), suggesting that the interlayer coupling induced charge redistribution is particularly robust in this family of 2D heterostructures. Previous work demonstrates that Bi 2 Se 3 /TMD 2D heterostructures have a strong interlayer coupling that quenches the signature photoluminescence of monolayer TMDs and modifies the Raman spectra. 3,4,46 Further, the interlayer coupling appears to facilitate the formation of a moiré superlattice with its own unique bandstructure (Fig. S12 † ), and modify the recombination energy of the exciton quasiparticles (Fig. S11 † ). A follow-up work found strong interlayer couplings<|im_end|> <|im_start|>assistant Humans have been studying electric charge for thousands of years, and the results have shaped modern civilization. Our daily lives depend on electric lighting, smartphones, cars, and computers, in ways that the first individuals to take note of a static shock or a bolt of lightning could never have imagined. Now, physicists at Northeastern have discovered a new way to manipulate electric charge. And the changes to the future of our technology could be monumental. "When such phenomena are discovered, imagination is the limit," says Swastik Kar, an associate professor of physics. "It could change the way we can detect and communicate signals. It could change the way we can sense things and the storage of information, and possibilities that we may not have even thought of yet." The ability to move, manipulate, and store electrons is key to the vast majority of modern technology, whether we're trying to harvest energy from the sun or play Plants vs. Zombies on our phone. In a paper published in Nanoscale, the researchers described a way to make electrons do something entirely new: Distribute themselves evenly into a stationary, crystalline pattern. "I'm tempted to say it's almost like a new phase of matter," Kar says. "Because it's just purely electronic." The phenomenon appeared while the researchers were running experiments with crystalline materials that are only a few atoms thick, known as 2-D materials. These materials are made up of a repeating pattern of atoms, like an endless checkerboard, and are so thin that the electrons in them can only move in two dimensions. Stacking these ultra-thin materials can create unusual effects as the layers interact at a quantum level. Kar and his colleagues were examining two such 2-D materials, bismuth selenide and a transition metal dichalcogenide, layered on top of each other like sheets of paper. That's when things started to get weird. Electrons should repel one another—they're negatively charged, and move away from other negatively charged things. But that's not what the electrons in these layers were doing. They were forming a stationary pattern. "At certain angles, these materials seem to form a way to share their electrons that ends up forming this geometrically periodic third lattice," Kar says. "A perfectly repeatable array of pure electronic puddles that resides between the two layers." At first, Kar assumed the result was a mistake. The crystalline structures of 2-D materials are too small to observe directly, so physicists use special microscopes that fire beams of electrons instead of light. As the electrons pass through the material, they interfere with each other and create a pattern. The specific pattern (and a bunch of math) can be used to recreate the shape of the 2-D material. University Distinguished Professor of physics Arun Bansil (left) and associate professor of physics Swastik Kar accidentally discovered a new way to manipulate electronic charge. Credit: Matthew Modoono/Northeastern University When the resulting pattern revealed a third layer that couldn't be coming from either of the other two, Kar thought something had gone wrong in the creation of the material or in the measurement process. Similar phenomena have been observed before, but only at extremely low temperatures. Kar's observations were at room temperature. "Have you ever walked into a meadow and seen an apple tree with mangoes hanging from it?" Kar asks. "Of course we thought something was wrong. This couldn't be happening." But after repeated testing and experiments led by doctoral student Zachariah Hennighausen, their results remained the same. There was a new lattice-style pattern of charged spots appearing between the 2-D materials. And that pattern changed with the orientation of the two sandwiching layers. As Kar and his team had been working on the experimental investigation, Arun Bansil, a university distinguished professor of physics at Northeastern, and doctoral student Chistopher Lane were examining the theoretical possibilities, to understand how this could be happening. Electrons in a material are always bouncing around, Bansil explains, as they are pulled on by the positively charged nuclei of atoms and repelled by other negatively charged electrons. But in this case, something about the way these charges are laid out is pooling electrons in a specific pattern. "They produce these regions where there are, if you like, ditches of some kind in the potential landscape, which are enough to force these electrons to create these puddles of charge," Bansil says. "The only reason electrons will form into puddles is because there's a potential hole there." These ditches, so to speak, are created by a combination of quantum mechanical and physical factors, Bansil says. When two repeating patterns or grids are offset, they combine to create a new pattern (you can replicate this at home by overlapping the teeth of two flat combs). Each 2-D material has a repeating structure, and the researchers demonstrated that the pattern created when those materials are stacked determines where electrons will end up. "That is where it becomes quantum mechanically favorable for the puddles to reside," Kar says. "It's almost guiding those electron puddles to remain there and nowhere else. It is fascinating." While the understanding of this phenomenon is still in its infancy, it has the potential to impact the future of electronics, sensing and detection systems, and information processing. "The excitement at this point is in being able to potentially demonstrate something that people have never thought could exist at room temperature before," Kar says. "And now, the sky's the limit in terms of how we can harness it." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Objective To characterise the clinical course of delirium for patients with COVID-19 in the intensive care unit, including postdischarge neuropsychological outcomes. Design Retrospective chart review and prospective survey study. Setting Intensive care units, large academic tertiary-care centre (USA). Participants Patients (n=148) with COVID-19 admitted to an intensive care unit at Michigan Medicine between 1 March 2020 and 31 May 2020 were eligible for inclusion. Primary and secondary outcome measures Delirium was the primary outcome, assessed via validated chart review method. Secondary outcomes included measures related to delirium, such as delirium duration, antipsychotic use, length of hospital and intensive care unit stay, inflammatory markers and final disposition. Neuroimaging data were also collected. Finally, a telephone survey was conducted between 1 and 2 months after discharge to determine neuropsychological function via the following tests: Family Confusion Assessment Method, Short Blessed Test, Patient-Reported Outcomes Measurement Information System Cognitive Abilities 4a and Patient-Health Questionnaire-9. Results Delirium was identified in 108/148 (73%) patients, with median (IQR) duration lasting 10 (4–17) days. In the delirium cohort, 50% (54/108) of patients were African American and delirious patients were more likely to be female (76/108, 70%) (absolute standardised differences >0.30). Sedation regimens, inflammation, delirium prevention protocol deviations and hypoxic-ischaemic injury were likely contributing factors, and the most common disposition for delirious patients was a skilled care facility (41/108, 38%). Among patients who were delirious during hospitalisation, 4/17 (24%) later screened positive for delirium at home based on caretaker assessment, 5/22 (23%) demonstrated signs of questionable cognitive impairment or cognitive impairment consistent with dementia and 3/25 (12%) screened positive for depression within 2 months after discharge. Conclusion Patients with COVID-19 commonly experience a prolonged course of delirium in the intensive care unit, likely with multiple contributing factors. Furthermore, neuropsychological impairment may persist after discharge. delirium & cognitive disorders COVID-19 adult intensive & critical care neurological injury Data availability statement Data will be made available on request via Data Use Agreement. No additional unpublished data are available. 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 59 news outlets Blogged by 6 Tweeted by 69 On 1 Facebook pages Referenced in 2 Wikipedia pages 102 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 delirium & cognitive disorders COVID-19 adult intensive & critical care neurological injury Strengths and limitations of this study The validated chart review method increases confidence in the delirium findings reported. Granular details included (ie, inflammatory profiles, neuroimaging findings and postdischarge neuropsychological function) provide a comprehensive assessment of delirium phenotype in this patient population along with related complications. As a single-centre study, findings are restricted to the institution included. Many patients were lost to follow-up after hospital discharge. Introduction The outbreak of SARS-CoV-2, the virus that causes COVID-19, emerged as a public health threat in December 2019 and was declared a pandemic by WHO in March 2020. Major neurological complications, such as encephalopathy, strokes, seizures and ataxia, have all been observed. 1–5 Delirium appears to be a common complication, with previous investigations demonstrating an incidence of approximately 65%–80% in the intensive care unit (ICU). 1 4 Delirium may occur due to direct coronavirus invasion of the central nervous system, 6 and systemic inflammatory responses may further exacerbate neurocognitive impairment. In the ICU, multiple delirium risk factors are often present and can increase risk in an additive manner. 7 Delirium is also associated with prolonged hospitalisation, long-term cognitive and functional impairment and increased mortality. 8–10 As such, there is a critical need to improve understanding of this syndrome in patients with COVID-19. While a high incidence of delirium has been reported in COVID-19 patients, fundamental questions persist. The clinical course of delirium, including average duration and postdischarge cognitive trajectory, remains incompletely understood. Pathophysiologic drivers of delirium require advanced understanding, and the extent to which standard prevention protocols are implemented is unclear. Such detailed understanding will contribute to delirium phenotyping of COVID-19 patients and provide insight into the clinical and neurocognitive burden associated with COVID-19. In this context, the objective of this study was to determine granular details associated with delirium in ICU patients with COVID-19. Specifically, the clinical course of delirium, presence of exacerbating factors, nature of prevention strategy implementation and postdischarge cognitive outcomes were all characterised. Methods Study design and overview This was a single-centre cohort study from Michigan Medicine. Detailed chart review data were collected from critically ill patients with COVID-19 (1 March 2020 to 31 May 2020), and postdischarge telephone surveys were conducted to test neuropsychological function after discharge. All study operations were conducted at Michigan Medicine, Ann Arbour MI USA, and approval was obtained from the University of Michigan Medical School Institutional Review Board (HUM00182646). A Health Insurance Portability and Accountability Act waiver was granted to retrospectively review patient medical records, and informed consent was not required for retrospective chart review. Patients who agreed to complete telephone surveys after discharge were consented over the telephone prior to survey administration using a comprehensive consent document. A waiver of documentation of consent was approved in conjunction with Institutional Review Board approval and as required by US Department of Health and Human Services regulations and policy. Finally, the Strengthening the Reporting of Observational Studies in Epidemiology checklist is included in the supplemental online material ( online supplemental table 1 ). These guidelines provide reporting standards for observational studies. 11", "role": "user" }, { "content": "More than a year into the COVID-19 pandemic, researchers are revealing the many devastating consequences that patients can face both during and after hospitalization. A new study of nearly 150 patients hospitalized for COVID at the beginning of the pandemic found that 73% had delirium, a serious disturbance in mental state wherein a patient is confused, agitated and unable to think clearly. Patients with delirium tended to be sicker, with more comorbidities like hypertension and diabetes, and appeared to have more severe COVID-related illness as well, said study author Phillip Vlisides, M.D., of the Department of Anesthesiology at Michigan Medicine. \"COVID is also associated with a number of other adverse outcomes that tend to prolong hospitalization and make recovery difficult,\" he added. Using patient medical records and telephone surveys following hospital discharge for a group of patients hospitalized in the intensive care unit between March and May 2020, the study team attempted to identify common threads amongst patients who developed delirium. Several factors are at play, said Vlisides. The disease itself can lead to reduced oxygen to the brain as well as the development of blood clots and stroke, resulting in cognitive impairment. In addition, inflammatory markers were greatly increased in patients with delirium. Confusion and agitation could be a result of inflammation of the brain. Adding insult to injury, care teams often were unable to perform standard delirium reduction techniques, such as exercises designed to get a patient moving or allowing visitors or objects from home to orient patients while in the hospital. Said Vlisides, \"Early on in the pandemic, we weren't performing standard delirium prevention protocols like we usually do. A big reason for that is early on in the pandemic in the pre-vaccine era, we had limited personal protective equipment and were trying to limit COVID exposure and disease transmission.\" Furthermore, there was a correlation between the use of sedatives and delirium—patients with delirium were sedated more often and frequently at higher doses. \"It is common to use IV sedatives in the ICU, particular for patients on a ventilator. However, from talking to nurses, we found that patients with severe COVID were inherently more delirious and agitated at baseline, perhaps prompting more sedative use.\" The study also found that cognitive impairment can persist even after discharge. Almost a third of patients did not have their delirium marked as resolved in their chart upon leaving the hospital and 40% of these patients required skilled nursing care. Almost a quarter of patients screened positive for delirium based on assessment by their caretaker. For some patients, these symptoms lasted for months. This can make managing the recovery process after hospitalization that much more difficult. \"A family member who is confused has limited ability to care for themselves and will require additional caretaking support, which is certainly a big challenge.\" Vlisides acknowledges that care teams are doing the best they can with the resources they have, especially as hospitals continue to fill with patients with COVID. \"Whatever creative ways we can implement delirium prevention protocols is likely to be very helpful,\" he said. \"That includes consistent communication with family members, bringing in pictures and objects from home, and video visits if family cannot safely visit.\" And for family and other caregivers struggling to care for loved ones, he urges they get help from their primary care physician as soon as possible. The take-home message is that for patients hospitalized with severe COVID-19, cognitive impairment—including depression and delirium—is highly likely, he added. \"Overall, this study highlights another reason why getting vaccinated and preventing severe illness is so important. There can be long term neurological complications that perhaps we don't talk about as much as we should.\" The paper was published in BMJ Open. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 characterise the clinical course of delirium for patients with COVID-19 in the intensive care unit, including postdischarge neuropsychological outcomes. Design Retrospective chart review and prospective survey study. Setting Intensive care units, large academic tertiary-care centre (USA). Participants Patients (n=148) with COVID-19 admitted to an intensive care unit at Michigan Medicine between 1 March 2020 and 31 May 2020 were eligible for inclusion. Primary and secondary outcome measures Delirium was the primary outcome, assessed via validated chart review method. Secondary outcomes included measures related to delirium, such as delirium duration, antipsychotic use, length of hospital and intensive care unit stay, inflammatory markers and final disposition. Neuroimaging data were also collected. Finally, a telephone survey was conducted between 1 and 2 months after discharge to determine neuropsychological function via the following tests: Family Confusion Assessment Method, Short Blessed Test, Patient-Reported Outcomes Measurement Information System Cognitive Abilities 4a and Patient-Health Questionnaire-9. Results Delirium was identified in 108/148 (73%) patients, with median (IQR) duration lasting 10 (4–17) days. In the delirium cohort, 50% (54/108) of patients were African American and delirious patients were more likely to be female (76/108, 70%) (absolute standardised differences >0.30). Sedation regimens, inflammation, delirium prevention protocol deviations and hypoxic-ischaemic injury were likely contributing factors, and the most common disposition for delirious patients was a skilled care facility (41/108, 38%). Among patients who were delirious during hospitalisation, 4/17 (24%) later screened positive for delirium at home based on caretaker assessment, 5/22 (23%) demonstrated signs of questionable cognitive impairment or cognitive impairment consistent with dementia and 3/25 (12%) screened positive for depression within 2 months after discharge. Conclusion Patients with COVID-19 commonly experience a prolonged course of delirium in the intensive care unit, likely with multiple contributing factors. Furthermore, neuropsychological impairment may persist after discharge. delirium & cognitive disorders COVID-19 adult intensive & critical care neurological injury Data availability statement Data will be made available on request via Data Use Agreement. No additional unpublished data are available. 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 59 news outlets Blogged by 6 Tweeted by 69 On 1 Facebook pages Referenced in 2 Wikipedia pages 102 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 delirium & cognitive disorders COVID-19 adult intensive & critical care neurological injury Strengths and limitations of this study The validated chart review method increases confidence in the delirium findings reported. Granular details included (ie, inflammatory profiles, neuroimaging findings and postdischarge neuropsychological function) provide a comprehensive assessment of delirium phenotype in this patient population along with related complications. As a single-centre study, findings are restricted to the institution included. Many patients were lost to follow-up after hospital discharge. Introduction The outbreak of SARS-CoV-2, the virus that causes COVID-19, emerged as a public health threat in December 2019 and was declared a pandemic by WHO in March 2020. Major neurological complications, such as encephalopathy, strokes, seizures and ataxia, have all been observed. 1–5 Delirium appears to be a common complication, with previous investigations demonstrating an incidence of approximately 65%–80% in the intensive care unit (ICU). 1 4 Delirium may occur due to direct coronavirus invasion of the central nervous system, 6 and systemic inflammatory responses may further exacerbate neurocognitive impairment. In the ICU, multiple delirium risk factors are often present and can increase risk in an additive manner. 7 Delirium is also associated with prolonged hospitalisation, long-term cognitive and functional impairment and increased mortality. 8–10 As such, there is a critical need to improve understanding of this syndrome in patients with COVID-19. While a high incidence of delirium has been reported in COVID-19 patients, fundamental questions persist. The clinical course of delirium, including average duration and postdischarge cognitive trajectory, remains incompletely understood. Pathophysiologic drivers of delirium require advanced understanding, and the extent to which standard prevention protocols are implemented is unclear. Such detailed understanding will contribute to delirium phenotyping of COVID-19 patients and provide insight into the clinical and neurocognitive burden associated with COVID-19. In this context, the objective of this study was to determine granular details associated with delirium in ICU patients with COVID-19. Specifically, the clinical course of delirium, presence of exacerbating factors, nature of prevention strategy implementation and postdischarge cognitive outcomes were all characterised. Methods Study design and overview This was a single-centre cohort study from Michigan Medicine. Detailed chart review data were collected from critically ill patients with COVID-19 (1 March 2020 to 31 May 2020), and postdischarge telephone surveys were conducted to test neuropsychological function after discharge. All study operations were conducted at Michigan Medicine, Ann Arbour MI USA, and approval was obtained from the University of Michigan Medical School Institutional Review Board (HUM00182646). A Health Insurance Portability and Accountability Act waiver was granted to retrospectively review patient medical records, and informed consent was not required for retrospective chart review. Patients who agreed to complete telephone surveys after discharge were consented over the telephone prior to survey administration using a comprehensive consent document. A waiver of documentation of consent was approved in conjunction with Institutional Review Board approval and as required by US Department of Health and Human Services regulations and policy. Finally, the Strengthening the Reporting of Observational Studies in Epidemiology checklist is included in the supplemental online material ( online supplemental table 1 ). These guidelines provide reporting standards for observational studies. 11<|im_end|> <|im_start|>assistant More than a year into the COVID-19 pandemic, researchers are revealing the many devastating consequences that patients can face both during and after hospitalization. A new study of nearly 150 patients hospitalized for COVID at the beginning of the pandemic found that 73% had delirium, a serious disturbance in mental state wherein a patient is confused, agitated and unable to think clearly. Patients with delirium tended to be sicker, with more comorbidities like hypertension and diabetes, and appeared to have more severe COVID-related illness as well, said study author Phillip Vlisides, M.D., of the Department of Anesthesiology at Michigan Medicine. "COVID is also associated with a number of other adverse outcomes that tend to prolong hospitalization and make recovery difficult," he added. Using patient medical records and telephone surveys following hospital discharge for a group of patients hospitalized in the intensive care unit between March and May 2020, the study team attempted to identify common threads amongst patients who developed delirium. Several factors are at play, said Vlisides. The disease itself can lead to reduced oxygen to the brain as well as the development of blood clots and stroke, resulting in cognitive impairment. In addition, inflammatory markers were greatly increased in patients with delirium. Confusion and agitation could be a result of inflammation of the brain. Adding insult to injury, care teams often were unable to perform standard delirium reduction techniques, such as exercises designed to get a patient moving or allowing visitors or objects from home to orient patients while in the hospital. Said Vlisides, "Early on in the pandemic, we weren't performing standard delirium prevention protocols like we usually do. A big reason for that is early on in the pandemic in the pre-vaccine era, we had limited personal protective equipment and were trying to limit COVID exposure and disease transmission." Furthermore, there was a correlation between the use of sedatives and delirium—patients with delirium were sedated more often and frequently at higher doses. "It is common to use IV sedatives in the ICU, particular for patients on a ventilator. However, from talking to nurses, we found that patients with severe COVID were inherently more delirious and agitated at baseline, perhaps prompting more sedative use." The study also found that cognitive impairment can persist even after discharge. Almost a third of patients did not have their delirium marked as resolved in their chart upon leaving the hospital and 40% of these patients required skilled nursing care. Almost a quarter of patients screened positive for delirium based on assessment by their caretaker. For some patients, these symptoms lasted for months. This can make managing the recovery process after hospitalization that much more difficult. "A family member who is confused has limited ability to care for themselves and will require additional caretaking support, which is certainly a big challenge." Vlisides acknowledges that care teams are doing the best they can with the resources they have, especially as hospitals continue to fill with patients with COVID. "Whatever creative ways we can implement delirium prevention protocols is likely to be very helpful," he said. "That includes consistent communication with family members, bringing in pictures and objects from home, and video visits if family cannot safely visit." And for family and other caregivers struggling to care for loved ones, he urges they get help from their primary care physician as soon as possible. The take-home message is that for patients hospitalized with severe COVID-19, cognitive impairment—including depression and delirium—is highly likely, he added. "Overall, this study highlights another reason why getting vaccinated and preventing severe illness is so important. There can be long term neurological complications that perhaps we don't talk about as much as we should." The paper was published in BMJ Open. <|im_end|>

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2,230

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Often, the interpretation of experiments concerning the manipulation of the energy distribution of laser-accelerated ion bunches is complicated by the multitude of competing dynamic processes simultaneously contributing to recorded ion signals. Here we demonstrate experimentally the acceleration of a clean proton bunch. This was achieved with a microscopic and three-dimensionally confined near critical density plasma, which evolves from a 1 µm diameter plastic sphere, which is levitated and positioned with micrometer precision in the focus of a Petawatt laser pulse. The emitted proton bunch is reproducibly observed with central energies between 20 and 40 MeV and narrow energy spread (down to 25%) showing almost no low-energetic background. Together with three-dimensional particle-in-cell simulations we track the complete acceleration process, evidencing the transition from organized acceleration to Coulomb repulsion. This reveals limitations of current high power lasers and viable paths to optimize laser-driven ion sources. Introduction Providing intense bursts of swift ions has gained particular interest 1 , 2 , 3 and proton kinetic energies exceeding 85 MeV have been recently demonstrated in various experiments 4 , 5 . The acceleration field is mediated via relativistic electrons, which induce MV/µm electric fields that vary in time and space. The correspondingly broad ion energy distributions could be narrowed by limiting the spatial extent of the ion reservoir on the surface of irradiated opaque foils 6 , 7 or by the use of droplets 8 , 9 . Reducing the foil thickness to the order of the laser skin depth also resulted in non-monotonic, peaked distributions with improved efficiency at higher ion energies 10 , 11 . Such radiation pressure or related volumetric acceleration mechanisms 12 have in common that the majority of electrons in the central part of the focus are coherently pushed by the light forces and then drag ions along. The experimentally observed ion signal, however, is typically blurred by superimposed ions from regions outside of this central part of the laser focus. The volumetric interaction of electrons with the laser field requires plasma densities around the critical density n c . Plasma densities above n c are opaque for the laser light. For densities smaller than n c plasmas are transparent. By virtue of their 10 µm wavelength CO 2 lasers enable to access such realms with readily available gas targets 13 , 14 . The low density does however limit the accelerated particle numbers severely. Spatially limited targets, so-called mass-limited targets, have attracted severe interest in theory 15 and experiment 9 , 16 , 17 . In this work, we exploit a so far inaccessible target parameter space by irradiating isolated, levitated plastic spheres of 1 µm diameter with a PW laser of 1.054 µm wavelength. In the rising edge of the laser pulse, the sphere expands to a few micrometer-sized plasma of approximately critical density for the near-infrared laser pulse. The single proton bunch generated in the interaction contains a large fraction of all target protons and are accelerated to narrow energy bands down to 5 MeV full-width at half-maximum (FWHM). Central energies for consecutive laser shots range from 20 to 40 MeV. Results Experimental setup The laser pulses provided by the PHELIX PW laser at GSI (see Methods) contained 150 J energy with a pulse duration of 500 fs and were focused to a diameter of 3.7 ± 0.3 µm (FWHM of intensity). Plastic spheres of 1 µm diameter and hollow spheres with an outer diameter of 1 µm and 100 nm wall thickness served as targets. The microscopic target size inhibited any kind of mechanical support. Hence, we used a Paul trap to levitate and position the targets. A direct opto-electronic feedback allowed us to position the targets with an accuracy of around ±1 µm in all three dimensions (see Methods). The dominant source of fluctuation in laser target overlap due to pointing jitter of the laser was minimized by placing the target 1 to 1.5 Rayleigh lengths out of focus, where the on-target peak laser intensity amounted up to 7 × 10 20 W/cm 2 (the peak intensity in best focus would have amounted to 2 × 10 21 W/cm 2 ). Pre-plasma expansion The excellent nanosecond contrast of the PHELIX laser prevents premature target ionization and has been demonstrated in previous experiments with sub-micrometer thin foil targets 18 . The measured autocorrelation trace in Fig. 1a was scaled to our estimated peak intensity. Considering that the plasma formation is related to the laser-induced damage threshold that we measured on various thin, transparent plastic foils, we estimate the start of relevant plasma dynamics 200–100 ps prior to the peak. Instead of treating the following complex and complicated, three-dimensional pre-expansion dynamics theoretically, we can draw important conclusions on the plasma conditions during the main pulse interaction by evaluating the experimentally recorded intensity patterns in Fig. 1b–d . The observed circular fringes can be considered as a result of an automatically generated inline-holography 19 , where the laser amplitude and phase in the center are disturbed by the target plasma and the outer regions are, depending on the size of plasma and laser focus, less or even not at all affected. We modeled the resulting intensity distributions at the plane of observation for different plasma dimensions (Fig. 1e–j ) (see Methods). Under these simplified assumptions, the fringe pattern compares best with the experimental images when the peak electron density is close to the critical density. The transverse extent of this critical density plasma exhibits an FWHM of 5.5–7.0 µm. We note that although many factors (such as target position with respect to focal plane, asymmetric shape, non-Gaussian distribution function of plasma and laser) influence the observed diffraction pattern, our analysis supports that the general appearance, i.e. the number of visible fringes and their contrast, remains relatively constant over a large range of densities, in line with the observation (Fig. 1b–d ) whenever we hit the target and successfully accelerated ions. Fig. 1 Pre-plasma formation. a Autocorrelation curve of the PHELIX laser pulse scaled to the maximum", "role": "user" }, { "content": "A research team led by physicists at LMU Munich reports a significant advance in laser-driven particle acceleration. Using tiny plastic beads as targets, they have produced proton bunches that possess unique features, opening up new opportunities for future studies. In their experiments, a team led by physicists at LMU Munich fired a powerful laser pulse at a micrometer-sized plastic sphere, blasting a bunch of protons from the target and accelerating them to velocities approaching the speed of light. The resulting velocity distribution is much narrower than that obtained when thin metal foils are used as targets. The physicist now present their research results in the scientific journal Nature Communications Recent years have seen remarkable advances in the development of a new approach to the acceleration of subatomic particles. This strategy makes use of the intense electric fields associated with pulsed, high-energy laser beams to accelerate electrons and protons to 'relativistic' velocities (i.e. speeds approaching that of light). Hitherto, the laser shot has generally been directed at a thin metal foil, generating and accelerating a plasma of free electrons and positively charged ions. Physicists at LMU have now replaced the foil target by a plastic microsphere with a diameter of one-millionth of a meter. These beads are so tiny that they cannot be stably positioned by mechanical means. Instead, the researchers use an electric field to levitate the target particle. Using a feedback circuit, the levitated bead can be trapped with sufficient precision to ensure that it does not drift off the beam axis. The electromagnetic trap was designed and built in the Department of Medical Physics at LMU. \"The basic approach is analogous to collisions between billiard balls. In our experiment, one of the balls is made of light and the other is our tiny levitated target,\" explains Peter Hilz, who led the experiments. This novel approach to the generation of proton beams will make experiments feasible which have hitherto been out of reach. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Often, the interpretation of experiments concerning the manipulation of the energy distribution of laser-accelerated ion bunches is complicated by the multitude of competing dynamic processes simultaneously contributing to recorded ion signals. Here we demonstrate experimentally the acceleration of a clean proton bunch. This was achieved with a microscopic and three-dimensionally confined near critical density plasma, which evolves from a 1 µm diameter plastic sphere, which is levitated and positioned with micrometer precision in the focus of a Petawatt laser pulse. The emitted proton bunch is reproducibly observed with central energies between 20 and 40 MeV and narrow energy spread (down to 25%) showing almost no low-energetic background. Together with three-dimensional particle-in-cell simulations we track the complete acceleration process, evidencing the transition from organized acceleration to Coulomb repulsion. This reveals limitations of current high power lasers and viable paths to optimize laser-driven ion sources. Introduction Providing intense bursts of swift ions has gained particular interest 1 , 2 , 3 and proton kinetic energies exceeding 85 MeV have been recently demonstrated in various experiments 4 , 5 . The acceleration field is mediated via relativistic electrons, which induce MV/µm electric fields that vary in time and space. The correspondingly broad ion energy distributions could be narrowed by limiting the spatial extent of the ion reservoir on the surface of irradiated opaque foils 6 , 7 or by the use of droplets 8 , 9 . Reducing the foil thickness to the order of the laser skin depth also resulted in non-monotonic, peaked distributions with improved efficiency at higher ion energies 10 , 11 . Such radiation pressure or related volumetric acceleration mechanisms 12 have in common that the majority of electrons in the central part of the focus are coherently pushed by the light forces and then drag ions along. The experimentally observed ion signal, however, is typically blurred by superimposed ions from regions outside of this central part of the laser focus. The volumetric interaction of electrons with the laser field requires plasma densities around the critical density n c . Plasma densities above n c are opaque for the laser light. For densities smaller than n c plasmas are transparent. By virtue of their 10 µm wavelength CO 2 lasers enable to access such realms with readily available gas targets 13 , 14 . The low density does however limit the accelerated particle numbers severely. Spatially limited targets, so-called mass-limited targets, have attracted severe interest in theory 15 and experiment 9 , 16 , 17 . In this work, we exploit a so far inaccessible target parameter space by irradiating isolated, levitated plastic spheres of 1 µm diameter with a PW laser of 1.054 µm wavelength. In the rising edge of the laser pulse, the sphere expands to a few micrometer-sized plasma of approximately critical density for the near-infrared laser pulse. The single proton bunch generated in the interaction contains a large fraction of all target protons and are accelerated to narrow energy bands down to 5 MeV full-width at half-maximum (FWHM). Central energies for consecutive laser shots range from 20 to 40 MeV. Results Experimental setup The laser pulses provided by the PHELIX PW laser at GSI (see Methods) contained 150 J energy with a pulse duration of 500 fs and were focused to a diameter of 3.7 ± 0.3 µm (FWHM of intensity). Plastic spheres of 1 µm diameter and hollow spheres with an outer diameter of 1 µm and 100 nm wall thickness served as targets. The microscopic target size inhibited any kind of mechanical support. Hence, we used a Paul trap to levitate and position the targets. A direct opto-electronic feedback allowed us to position the targets with an accuracy of around ±1 µm in all three dimensions (see Methods). The dominant source of fluctuation in laser target overlap due to pointing jitter of the laser was minimized by placing the target 1 to 1.5 Rayleigh lengths out of focus, where the on-target peak laser intensity amounted up to 7 × 10 20 W/cm 2 (the peak intensity in best focus would have amounted to 2 × 10 21 W/cm 2 ). Pre-plasma expansion The excellent nanosecond contrast of the PHELIX laser prevents premature target ionization and has been demonstrated in previous experiments with sub-micrometer thin foil targets 18 . The measured autocorrelation trace in Fig. 1a was scaled to our estimated peak intensity. Considering that the plasma formation is related to the laser-induced damage threshold that we measured on various thin, transparent plastic foils, we estimate the start of relevant plasma dynamics 200–100 ps prior to the peak. Instead of treating the following complex and complicated, three-dimensional pre-expansion dynamics theoretically, we can draw important conclusions on the plasma conditions during the main pulse interaction by evaluating the experimentally recorded intensity patterns in Fig. 1b–d . The observed circular fringes can be considered as a result of an automatically generated inline-holography 19 , where the laser amplitude and phase in the center are disturbed by the target plasma and the outer regions are, depending on the size of plasma and laser focus, less or even not at all affected. We modeled the resulting intensity distributions at the plane of observation for different plasma dimensions (Fig. 1e–j ) (see Methods). Under these simplified assumptions, the fringe pattern compares best with the experimental images when the peak electron density is close to the critical density. The transverse extent of this critical density plasma exhibits an FWHM of 5.5–7.0 µm. We note that although many factors (such as target position with respect to focal plane, asymmetric shape, non-Gaussian distribution function of plasma and laser) influence the observed diffraction pattern, our analysis supports that the general appearance, i.e. the number of visible fringes and their contrast, remains relatively constant over a large range of densities, in line with the observation (Fig. 1b–d ) whenever we hit the target and successfully accelerated ions. Fig. 1 Pre-plasma formation. a Autocorrelation curve of the PHELIX laser pulse scaled to the maximum<|im_end|> <|im_start|>assistant A research team led by physicists at LMU Munich reports a significant advance in laser-driven particle acceleration. Using tiny plastic beads as targets, they have produced proton bunches that possess unique features, opening up new opportunities for future studies. In their experiments, a team led by physicists at LMU Munich fired a powerful laser pulse at a micrometer-sized plastic sphere, blasting a bunch of protons from the target and accelerating them to velocities approaching the speed of light. The resulting velocity distribution is much narrower than that obtained when thin metal foils are used as targets. The physicist now present their research results in the scientific journal Nature Communications Recent years have seen remarkable advances in the development of a new approach to the acceleration of subatomic particles. This strategy makes use of the intense electric fields associated with pulsed, high-energy laser beams to accelerate electrons and protons to 'relativistic' velocities (i.e. speeds approaching that of light). Hitherto, the laser shot has generally been directed at a thin metal foil, generating and accelerating a plasma of free electrons and positively charged ions. Physicists at LMU have now replaced the foil target by a plastic microsphere with a diameter of one-millionth of a meter. These beads are so tiny that they cannot be stably positioned by mechanical means. Instead, the researchers use an electric field to levitate the target particle. Using a feedback circuit, the levitated bead can be trapped with sufficient precision to ensure that it does not drift off the beam axis. The electromagnetic trap was designed and built in the Department of Medical Physics at LMU. "The basic approach is analogous to collisions between billiard balls. In our experiment, one of the balls is made of light and the other is our tiny levitated target," explains Peter Hilz, who led the experiments. This novel approach to the generation of proton beams will make experiments feasible which have hitherto been out of reach. <|im_end|>

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1,713

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Botulinum neurotoxin E (BoNT/E) is one of the major causes of human botulism and paradoxically also a promising therapeutic agent. Here we determined the co-crystal structures of the receptor-binding domain of BoNT/E (H C E) in complex with its neuronal receptor synaptic vesicle glycoprotein 2A (SV2A) and a nanobody that serves as a ganglioside surrogate. These structures reveal that the protein-protein interactions between H C E and SV2 provide the crucial location and specificity information for H C E to recognize SV2A and SV2B, but not the closely related SV2C. At the same time, H C E exploits a separated sialic acid-binding pocket to mediate recognition of an N-glycan of SV2. Structure-based mutagenesis and functional studies demonstrate that both the protein-protein and protein-glycan associations are essential for SV2A-mediated cell entry of BoNT/E and for its potent neurotoxicity. Our studies establish the structural basis to understand the receptor-specificity of BoNT/E and to engineer BoNT/E variants for new clinical applications. Introduction Botulinum neurotoxins (BoNTs) are the causative agents of the neuroparalytic disease botulism 1 , 2 . There are seven major BoNT serotypes (termed BoNT/A–G), among which BoNT/A and BoNT/B are approved by the FDA for clinical and esthetic indications 3 , 4 . The extraordinary potency of BoNTs relies on highly specific recognition and uptake by motor neurons 5 , 6 . A widely accepted dual-receptor model suggests that the receptor-binding domain (H C ) of BoNTs synergistically binds complex gangliosides and specific protein receptors on the neuron surface 7 , 8 , 9 , 10 . Complex gangliosides are present abundantly on nerve cells and serve to enrich toxins, and most BoNTs possess a highly conserved ganglioside-binding “SxWY” motif 11 . However, BoNTs have developed diverse binding strategies for their corresponding protein receptors. For example, BoNT/A and BoNT/B exploit distinct protein receptors 12 , 13 , 14 , 15 , 16 , 17 , which may contribute to their differences in pharmacological and clinical profiles. BoNT/E has recently emerged as a promising new drug candidate due to its faster onset of action and shorter duration of effect when compared to BoNT/A and BoNT/B 18 , 19 , 20 , 21 , 22 , 23 , 24 . At the molecular level, BoNT/E recognizes synaptic vesicle glycoprotein 2 (SV2) 25 , 26 , a family of 12-transmembrane domain proteins that also serve as receptors for BoNT/A 12 , 17 , BoNT/D 27 , BoNT/F 28 , 29 , and the related tetanus neurotoxin 30 . SV2 comprises three homologous isoforms, SV2A, 2B, and 2C, in mammals. Despite their similar primary sequences (~60% identity), only SV2A and SV2B, but not SV2C, are able to mediate the cell entry of BoNT/E into cultured hippocampal and cortical neurons 25 , although it remains to be validated whether SV2C in motor neurons may still function as a receptor for BoNT/E 31 , 32 , 33 . This is in sharp contrast to BoNT/A, which is able to use all three SV2 isoforms for cell entry 12 . As the three SV2 isoforms have different tissue distributions in human 33 , 34 , 35 , the different specificities toward SV2 isoforms between BoNT/E and BoNT/A can contribute to potential differences in pharmacological and therapeutic features. How BoNT/E manages to distinguish SV2C from SV2A and SV2B remains a mystery. Prior studies revealed that the receptor-binding domain of BoNT/A (H C A) recognizes the open edge of the most C-terminal β-strand of the quadrilateral β-helix fold of SV2C luminal domain as well as the core saccharides of a neighboring N-glycan of SV2C, which together form a composite binding site for H C A 13 , 14 , 36 , 37 , 38 . However, the receptor-binding domain of BoNT/E (H C E) has an 8-amino acid deletion and many substitutions at the homologous H C A-like SV2-binding site (Supplementary Fig. 1a ), suggesting that BoNT/E exploits a distinct yet unknown mechanism to recognize SV2A and SV2B. In this study, we designed and characterized a fusion protein composed of the luminal domain of human SV2A and SV2C that maintains an SV2A-like binding capacity to BoNT/E (named SV2Ac). We also designed a fusion protein consisting of SV2Ac and a single-domain camelid antibody (a.k.a. VHH or nanobody, named G6) that binds to the ganglioside-binding site on H C E and acts as a ganglioside surrogate to enhance H C E–SV2A association. We then determined two crystal structures of H C E in complex with SV2Ac–VHH and SV2Ac–VHH plus sialic acid. These structures reveal that BoNT/E simultaneously recognizes both specific protein segments and an N-glycan of SV2A at two separated H C E sites. Complementary biophysical, cellular, and functional studies demonstrated that BoNT/E specifically recognizes SV2A and SV2B, but not SV2C, via the protein–protein interface, while it also grips the tip of the SV2 glycan at a distant site that strengthens the association. Both of the protein–protein and protein–glycan-binding modes between BoNT/E and SV2A are distinct from that between BoNT/A and SV2C 13 , 14 . These findings provide the structural basis to facilitate the therapeutic development and engineering of BoNT/E for novel neurotoxin products, as well as to inform new strategies for developing BoNT inhibitors. Results VHH-G6 blocks ganglioside binding of BoNT/E We expressed and purified the fourth luminal domain of human SV2A (residues F487–E581, referred to as SV2A-L4), which we previously identified as the BoNT/E-binding fragment 25 , 26 , as a secreted and glycosylated protein from human embryonic kidney 293 cells (HEK293) 13 , 39 . However, H C E was found to poorly bind SV2A-L4 and their interaction was barely detectable using a pull-down assay, making it unsuitable for structural studies. We hypothesized that the low affinity between H C E and SV2A-L4 was due to the lack of co-receptor gangliosides that are known to be essential for the cell entry of BoNT/E 25 , 26 , 28 . Complex gangliosides are present abundantly on nerve cell surfaces and serve to enrich toxins during the crucial early", "role": "user" }, { "content": "A team of researchers from the University of California, Irvine, have revealed the first crystal structures of the receptor-binding domain of botulinum neurotoxin E (BoNT/E) in complex with its human neuronal receptors, synaptic vesicle glycoprotein 2A (SV2A). This structure and other findings in the new study could be harnessed to engineer new BoNT/E variants with modified specificities toward different SV2 isoforms for new clinical developments. Published in Nature Communications, the study, titled, \"Structural basis for botulinum neurotoxin E recognition of synaptic vesicle protein 2,\" reveals a novel 3D structure that shows how BoNT/E simultaneously recognizes both specific protein segments and an N-glycan of its host receptor SV2A for effective neuronal binding and uptake. This mechanism is distinct from how BoNT/A (e.g. Botox) or BoNT/B (e.g. Myobloc) recognize their human receptors. Additionally, the team's findings demonstrate how BoNT/E is able to detect subtle differences in the primary sequences of three closely related SV2 isoforms, resulting in high selectivity towards SV2A and SV2B, but not SV2C, as its receptors. \"Since both BoNT/E and BoNT/A piggyback on human SV2 as receptors to sneak into neurons, we used to believe that they should use the same tactics. Surprisingly, our new crystal structure reveals that they, in fact, exploit distinct mechanisms to recognize SV2 for cell entry, which could partly explain the unique pharmacological and clinical profiles of BoNT/E,\" said Rongsheng Jin, Ph.D., professor in the Department of Physiology & Biophysics in the UCI School of Medicine. \"Our team's findings also provide new insights into how BoNT/E manages to selectively recognize SV2A and SV2B over SV2C as receptors, while BoNT/A could use all three SV2 isoforms. It suggests that BoNT/E and BoNT/A may target different subsets of human tissues and cells that express different amounts of SV2A, 2B, and 2C, which may also contribute to their different biologic properties. The new 3D structure reported here can serve as a blueprint for scientists in the field to engineer new BoNT/E variants with modified specificities toward different SV2 isoforms for new clinical developments,\" said Jin. BoNT/E, together with BoNT/A and BoNT/B, are the three major causes of human botulism. Despite this, BoNT/A and BoNT/B are approved drugs for a myriad of therapeutic and aesthetic uses, including Botox, Dysport, Xeomin, Jeuveau, Daxxify and Myobloc. Due to its unique pharmacological and clinical profiles, BoNT/E has attracted growing therapeutic interests and is currently in clinical trials for indications that may benefit from BoNT/E's faster onset of action and shorter duration. Currently, the global multibillion dollar BoNT market is almost exclusively contributed by products based on BoNT/A. Besides expanding toward treating new indications using BoNT/A, there are urgent needs to develop new BoNT products based on other toxin serotypes and/or protein engineering to broaden the therapeutic landscape. The UC has filed a patent on the use of the structural information described in this paper and in other unpublished findings to engineer BoNT/E for therapeutic and cosmetic 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 Botulinum neurotoxin E (BoNT/E) is one of the major causes of human botulism and paradoxically also a promising therapeutic agent. Here we determined the co-crystal structures of the receptor-binding domain of BoNT/E (H C E) in complex with its neuronal receptor synaptic vesicle glycoprotein 2A (SV2A) and a nanobody that serves as a ganglioside surrogate. These structures reveal that the protein-protein interactions between H C E and SV2 provide the crucial location and specificity information for H C E to recognize SV2A and SV2B, but not the closely related SV2C. At the same time, H C E exploits a separated sialic acid-binding pocket to mediate recognition of an N-glycan of SV2. Structure-based mutagenesis and functional studies demonstrate that both the protein-protein and protein-glycan associations are essential for SV2A-mediated cell entry of BoNT/E and for its potent neurotoxicity. Our studies establish the structural basis to understand the receptor-specificity of BoNT/E and to engineer BoNT/E variants for new clinical applications. Introduction Botulinum neurotoxins (BoNTs) are the causative agents of the neuroparalytic disease botulism 1 , 2 . There are seven major BoNT serotypes (termed BoNT/A–G), among which BoNT/A and BoNT/B are approved by the FDA for clinical and esthetic indications 3 , 4 . The extraordinary potency of BoNTs relies on highly specific recognition and uptake by motor neurons 5 , 6 . A widely accepted dual-receptor model suggests that the receptor-binding domain (H C ) of BoNTs synergistically binds complex gangliosides and specific protein receptors on the neuron surface 7 , 8 , 9 , 10 . Complex gangliosides are present abundantly on nerve cells and serve to enrich toxins, and most BoNTs possess a highly conserved ganglioside-binding “SxWY” motif 11 . However, BoNTs have developed diverse binding strategies for their corresponding protein receptors. For example, BoNT/A and BoNT/B exploit distinct protein receptors 12 , 13 , 14 , 15 , 16 , 17 , which may contribute to their differences in pharmacological and clinical profiles. BoNT/E has recently emerged as a promising new drug candidate due to its faster onset of action and shorter duration of effect when compared to BoNT/A and BoNT/B 18 , 19 , 20 , 21 , 22 , 23 , 24 . At the molecular level, BoNT/E recognizes synaptic vesicle glycoprotein 2 (SV2) 25 , 26 , a family of 12-transmembrane domain proteins that also serve as receptors for BoNT/A 12 , 17 , BoNT/D 27 , BoNT/F 28 , 29 , and the related tetanus neurotoxin 30 . SV2 comprises three homologous isoforms, SV2A, 2B, and 2C, in mammals. Despite their similar primary sequences (~60% identity), only SV2A and SV2B, but not SV2C, are able to mediate the cell entry of BoNT/E into cultured hippocampal and cortical neurons 25 , although it remains to be validated whether SV2C in motor neurons may still function as a receptor for BoNT/E 31 , 32 , 33 . This is in sharp contrast to BoNT/A, which is able to use all three SV2 isoforms for cell entry 12 . As the three SV2 isoforms have different tissue distributions in human 33 , 34 , 35 , the different specificities toward SV2 isoforms between BoNT/E and BoNT/A can contribute to potential differences in pharmacological and therapeutic features. How BoNT/E manages to distinguish SV2C from SV2A and SV2B remains a mystery. Prior studies revealed that the receptor-binding domain of BoNT/A (H C A) recognizes the open edge of the most C-terminal β-strand of the quadrilateral β-helix fold of SV2C luminal domain as well as the core saccharides of a neighboring N-glycan of SV2C, which together form a composite binding site for H C A 13 , 14 , 36 , 37 , 38 . However, the receptor-binding domain of BoNT/E (H C E) has an 8-amino acid deletion and many substitutions at the homologous H C A-like SV2-binding site (Supplementary Fig. 1a ), suggesting that BoNT/E exploits a distinct yet unknown mechanism to recognize SV2A and SV2B. In this study, we designed and characterized a fusion protein composed of the luminal domain of human SV2A and SV2C that maintains an SV2A-like binding capacity to BoNT/E (named SV2Ac). We also designed a fusion protein consisting of SV2Ac and a single-domain camelid antibody (a.k.a. VHH or nanobody, named G6) that binds to the ganglioside-binding site on H C E and acts as a ganglioside surrogate to enhance H C E–SV2A association. We then determined two crystal structures of H C E in complex with SV2Ac–VHH and SV2Ac–VHH plus sialic acid. These structures reveal that BoNT/E simultaneously recognizes both specific protein segments and an N-glycan of SV2A at two separated H C E sites. Complementary biophysical, cellular, and functional studies demonstrated that BoNT/E specifically recognizes SV2A and SV2B, but not SV2C, via the protein–protein interface, while it also grips the tip of the SV2 glycan at a distant site that strengthens the association. Both of the protein–protein and protein–glycan-binding modes between BoNT/E and SV2A are distinct from that between BoNT/A and SV2C 13 , 14 . These findings provide the structural basis to facilitate the therapeutic development and engineering of BoNT/E for novel neurotoxin products, as well as to inform new strategies for developing BoNT inhibitors. Results VHH-G6 blocks ganglioside binding of BoNT/E We expressed and purified the fourth luminal domain of human SV2A (residues F487–E581, referred to as SV2A-L4), which we previously identified as the BoNT/E-binding fragment 25 , 26 , as a secreted and glycosylated protein from human embryonic kidney 293 cells (HEK293) 13 , 39 . However, H C E was found to poorly bind SV2A-L4 and their interaction was barely detectable using a pull-down assay, making it unsuitable for structural studies. We hypothesized that the low affinity between H C E and SV2A-L4 was due to the lack of co-receptor gangliosides that are known to be essential for the cell entry of BoNT/E 25 , 26 , 28 . Complex gangliosides are present abundantly on nerve cell surfaces and serve to enrich toxins during the crucial early<|im_end|> <|im_start|>assistant A team of researchers from the University of California, Irvine, have revealed the first crystal structures of the receptor-binding domain of botulinum neurotoxin E (BoNT/E) in complex with its human neuronal receptors, synaptic vesicle glycoprotein 2A (SV2A). This structure and other findings in the new study could be harnessed to engineer new BoNT/E variants with modified specificities toward different SV2 isoforms for new clinical developments. Published in Nature Communications, the study, titled, "Structural basis for botulinum neurotoxin E recognition of synaptic vesicle protein 2," reveals a novel 3D structure that shows how BoNT/E simultaneously recognizes both specific protein segments and an N-glycan of its host receptor SV2A for effective neuronal binding and uptake. This mechanism is distinct from how BoNT/A (e.g. Botox) or BoNT/B (e.g. Myobloc) recognize their human receptors. Additionally, the team's findings demonstrate how BoNT/E is able to detect subtle differences in the primary sequences of three closely related SV2 isoforms, resulting in high selectivity towards SV2A and SV2B, but not SV2C, as its receptors. "Since both BoNT/E and BoNT/A piggyback on human SV2 as receptors to sneak into neurons, we used to believe that they should use the same tactics. Surprisingly, our new crystal structure reveals that they, in fact, exploit distinct mechanisms to recognize SV2 for cell entry, which could partly explain the unique pharmacological and clinical profiles of BoNT/E," said Rongsheng Jin, Ph.D., professor in the Department of Physiology & Biophysics in the UCI School of Medicine. "Our team's findings also provide new insights into how BoNT/E manages to selectively recognize SV2A and SV2B over SV2C as receptors, while BoNT/A could use all three SV2 isoforms. It suggests that BoNT/E and BoNT/A may target different subsets of human tissues and cells that express different amounts of SV2A, 2B, and 2C, which may also contribute to their different biologic properties. The new 3D structure reported here can serve as a blueprint for scientists in the field to engineer new BoNT/E variants with modified specificities toward different SV2 isoforms for new clinical developments," said Jin. BoNT/E, together with BoNT/A and BoNT/B, are the three major causes of human botulism. Despite this, BoNT/A and BoNT/B are approved drugs for a myriad of therapeutic and aesthetic uses, including Botox, Dysport, Xeomin, Jeuveau, Daxxify and Myobloc. Due to its unique pharmacological and clinical profiles, BoNT/E has attracted growing therapeutic interests and is currently in clinical trials for indications that may benefit from BoNT/E's faster onset of action and shorter duration. Currently, the global multibillion dollar BoNT market is almost exclusively contributed by products based on BoNT/A. Besides expanding toward treating new indications using BoNT/A, there are urgent needs to develop new BoNT products based on other toxin serotypes and/or protein engineering to broaden the therapeutic landscape. The UC has filed a patent on the use of the structural information described in this paper and in other unpublished findings to engineer BoNT/E for therapeutic and cosmetic 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 Metastatic colonization relies on interactions between disseminated cancer cells and the microenvironment in secondary organs. Here, we show that disseminated breast cancer cells evoke phenotypic changes in lung fibroblasts, forming a supportive metastatic niche. Colonization of the lungs confers an inflammatory phenotype in metastasis-associated fibroblasts. Specifically, IL-1α and IL-1β secreted by breast cancer cells induce CXCL9 and CXCL10 production in lung fibroblasts via NF-κB signaling, fueling the growth of lung metastases. Notably, we find that the chemokine receptor CXCR3, that binds CXCL9/10, is specifically expressed in a small subset of breast cancer cells, which exhibits tumor-initiating ability when co-transplanted with fibroblasts and has high JNK signaling that drives IL-1α/β expression. Importantly, disruption of the intercellular JNK-IL-1-CXCL9/10-CXCR3 axis reduces metastatic colonization in xenograft and syngeneic mouse models. These data mechanistically demonstrate an essential role for the molecular crosstalk between breast cancer cells and their fibroblast niche in the progression of metastasis. Introduction Metastasis remains the primary threat to the lives of cancer patients with few effective therapeutic options 1 . Growing evidence indicates that metastatic colonization is not only determined by genetic and epigenetic networks in cancer cells, but also by the microenvironment 2 , 3 . Disseminated cancer cells that successfully colonize distant organs manage to reeducate stromal cells and generate a metastatic niche that supports secondary tumor growth 4 . Thus, the tumor microenvironment likely offers opportunities for therapeutic intervention in metastatic cancer patients 5 . Fibroblasts form a heterogeneous group of mesenchymal cells that are commonly found within the tumor microenvironment. Cancer-associated fibroblasts (CAFs) have received considerable attention in recent years as regulators of tumor development 6 . In breast cancer, CAFs provide a cytokine and extracellular matrix (ECM) milieu that promotes growth and progression of primary tumors 7 , 8 , 9 , 10 . However, the precise molecular function of stromal fibroblasts at metastatic sites and their effect on metastatic progression is poorly understood. This is particularly relevant when considering the dynamic stromal changes that occur during reprogramming of the microenvironment from early colonization to the growth of overt metastasis. In this study, we explore the dynamic molecular interactions between disseminated breast cancer cells and fibroblasts during different stages of lung metastasis. We identify a paracrine interaction between metastatic breast cancer cells and metastasis-associated fibroblasts (MAFs). We find that breast cancer cells that have invaded the lungs secrete interleukin 1 alpha/beta (IL-1α/β) to induce the chemokines CXCL9/10 in MAFs. Moreover, we demonstrate that a subset of breast cancer cells with high metastatic potential expresses the cell surface receptor CXCR3, which binds CXCL9/10. CXCR3 + breast cancer cells express high levels of IL-1α/β via JNK signaling, suggesting that they can both induce CXCL9/10 in MAFs and benefit from these chemokines. Importantly, using mouse models we show that these molecular interactions play a crucial role in supporting proliferation of breast cancer cells and development of metastasis. Together, our data reveal an important crosstalk between breast cancer cells and MAFs that promotes metastatic initiation and progression to overt lung metastasis. Results Metastatic breast cancer cells activate fibroblasts in the lungs To investigate evolution of fibroblasts during metastatic colonization, we established experimental lung metastases by injecting MDA-MB-231 (MDA) human breast cancer cells or the highly metastatic derivative MDA-MB-231-LM2 (MDA-LM2) cells 11 intravenously into immunocompromised mice. At 1 week post injection (when lungs harbor primarily micrometastases) and at 3 weeks post injection (when macrometastases are prominent and widespread), we isolated fibroblasts using fluorescence-activated cell sorting (FACS) (Fig. 1a–c ). Considering the different capacity of MDA and MDA-LM2 cells to grow metastasis in the lungs, the experimental approach was designed to address the qualitative difference between MDA and MDA-LM2 associated fibroblasts in metastasis at each time point. Therefore, we selected individual mice with comparable MDA or MDA-LM2 metastatic loads for our analysis based on in vivo bioluminescence imaging (Supplementary Fig. 1a ). Lung fibroblasts were isolated by FACS using two positive selection markers, platelet-derived growth factor receptor (PDGFR)α and PDGFRβ, and a panel of negative selection markers (Fig. 1a and Supplementary Fig. 1b–d ). Purity of sorted fibroblasts was confirmed (Supplementary Fig. 2a, b ). Fibroblasts isolated from lungs with growing metastases were compared with fibroblasts from lungs of healthy, age-matched mice. We observed a striking correlation between the number of fibroblasts and metastatic burden (Fig. 1d, e ). Lungs harboring macrometastases exhibited a substantial increase in the number of fibroblasts compared with lungs with micrometastases or healthy lungs (Fig. 1f ). These data suggested that the fibroblast population in lung stroma expands extensively during metastatic colonization by breast cancer cells. Fig. 1: Metastatic breast cancer cells promote activation of fibroblasts during lung colonization. a Experimental setup for selection of fibroblasts from lungs of mice at different time points after intravenous injection of MDA-MB-231 (MDA) and MDA-MB-231-LM2 (MDA-LM2) breast cancer cells. b Size of metastatic nodules at week 1 or week 3 after intravenous injection of indicated breast cancer cells. Week 1, n = 257 (MDA) and n = 330 (MDA-LM2) metastatic nodules from six mice per group. Week 3, n = 236 (MDA) and n = 171 (MDA-LM2) nodules from six mice per group. c Representative examples of MDA and MDA-LM2 micrometastases (week 1) and macrometastases (week 3) expressing human vimentin as cancer cell-marker. Scale bar, 100 µm. Arrows point to micrometastases and dashed lines indicate margins of macrometastases. Correlation of total numbers of lung fibroblasts with lung bioluminescence from MDA ( d ) and MDA-LM2 ( e ) metastases. f Total number of fibroblasts from healthy and metastatic (MDA and MDA-LM2) lungs at micrometastatic and macrometastatic stages. Healthy fibroblasts, n = 5 mice; fibroblasts from micrometastasis MDA, n = 8 mice and MDA-LM2, n = 7 mice; fibroblasts from macrometastasis (MDA or MDA-LM2), n = 4 mice each group. Boxes depict median with upper and lower quartiles. Whiskers indicate minimum and maximum values and data points show biological replicates. P value was determined by unpaired two-tailed t test. g Principal component (PC) analysis of transcriptome of fibroblasts from metastatic", "role": "user" }, { "content": "In order to colonize other organs and grow into metastases, tumor cells that detach from the parent tumor need to manipulate their new microenvironment and create a 'metastatic niche.' Scientists from the German Cancer Research Center and the Heidelberg Institute for Stem Cell Technology and Experimental Medicine have now discovered that some cancer cells stimulate connective tissue cells in their environment to release transmitters that promote metastasis. This discovery plays a key role in better understanding how these dangerous metastases arise. If cancer cells detach from a tumor and move around the body, they are entering enemy territory. Many detached cancer cells do actually die before they manage to colonize other tissues and form metastases, because the body's immune system is geared toward protecting healthy tissue from intruders of all kinds. Moreover, these migrant cancer cells can only survive if they manage to manipulate the cells in their new environment to create a metastatic niche that helps the migrant cancer cells survive. Thordur Oskarsson and his team at the German Cancer Research Center (DKFZ) and at the Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH) are investigating how this metastatic niche arises. The scientists have now discovered both in cell cultures and in mice that some particularly aggressive breast cancer cells induce a situation similar to inflammation in lung tissue. This ultimately ensures that they can colonize the tissue and grow into metastases. Specifically, the detached tumor cells release two inflammatory signaling molecules, known as interleukins, which stimulate fibroblasts in the lung to release two further inflammatory signaling molecules into the microenvironment: CXCL9 and CXCL10. In turn, these attach to a receptor molecule that several aggressive migrant cancer cells carry on their surface, marking a decisive step in the process of growing into a metastasis. These aggressive breast cancer cells thus benefit directly from the inflammation and from the signaling molecules CXCL9 and CXCL10. \"Interestingly, the very tumor cells that stimulate the fibroblasts to produce CXCL9 and CXCL10 also have the relevant receptor for these cytokines and thus benefit from the process,\" explained Maren Pein, lead author of the study. \"That underlines how crucial the cellular communication between the detached cancer cells and the fibroblasts in their new microenvironment is for metastasis.\" Furthermore, the scientists prevented metastasis in the lung in an experimental setting by treating mice with an inhibitor that blocked the receptor molecule on the cancer cells. Tumor tissue samples from patients show that this cellular interaction probably plays a role in breast cancer patients too: Thus cancer cells that carry the relevant surface receptor and can therefore harness the interaction with fibroblasts to form metastases are also found in patients with metastatic breast cancer. Oskarsson emphasized that it was still too early to identify a new treatment approach from these findings. \"Our work is initially designed to help understand the underlying mechanisms that are necessary for metastases to actually arise,\" he explained. \"But we obviously hope that this better understanding will lead to us being able to prevent metastases some time 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 Metastatic colonization relies on interactions between disseminated cancer cells and the microenvironment in secondary organs. Here, we show that disseminated breast cancer cells evoke phenotypic changes in lung fibroblasts, forming a supportive metastatic niche. Colonization of the lungs confers an inflammatory phenotype in metastasis-associated fibroblasts. Specifically, IL-1α and IL-1β secreted by breast cancer cells induce CXCL9 and CXCL10 production in lung fibroblasts via NF-κB signaling, fueling the growth of lung metastases. Notably, we find that the chemokine receptor CXCR3, that binds CXCL9/10, is specifically expressed in a small subset of breast cancer cells, which exhibits tumor-initiating ability when co-transplanted with fibroblasts and has high JNK signaling that drives IL-1α/β expression. Importantly, disruption of the intercellular JNK-IL-1-CXCL9/10-CXCR3 axis reduces metastatic colonization in xenograft and syngeneic mouse models. These data mechanistically demonstrate an essential role for the molecular crosstalk between breast cancer cells and their fibroblast niche in the progression of metastasis. Introduction Metastasis remains the primary threat to the lives of cancer patients with few effective therapeutic options 1 . Growing evidence indicates that metastatic colonization is not only determined by genetic and epigenetic networks in cancer cells, but also by the microenvironment 2 , 3 . Disseminated cancer cells that successfully colonize distant organs manage to reeducate stromal cells and generate a metastatic niche that supports secondary tumor growth 4 . Thus, the tumor microenvironment likely offers opportunities for therapeutic intervention in metastatic cancer patients 5 . Fibroblasts form a heterogeneous group of mesenchymal cells that are commonly found within the tumor microenvironment. Cancer-associated fibroblasts (CAFs) have received considerable attention in recent years as regulators of tumor development 6 . In breast cancer, CAFs provide a cytokine and extracellular matrix (ECM) milieu that promotes growth and progression of primary tumors 7 , 8 , 9 , 10 . However, the precise molecular function of stromal fibroblasts at metastatic sites and their effect on metastatic progression is poorly understood. This is particularly relevant when considering the dynamic stromal changes that occur during reprogramming of the microenvironment from early colonization to the growth of overt metastasis. In this study, we explore the dynamic molecular interactions between disseminated breast cancer cells and fibroblasts during different stages of lung metastasis. We identify a paracrine interaction between metastatic breast cancer cells and metastasis-associated fibroblasts (MAFs). We find that breast cancer cells that have invaded the lungs secrete interleukin 1 alpha/beta (IL-1α/β) to induce the chemokines CXCL9/10 in MAFs. Moreover, we demonstrate that a subset of breast cancer cells with high metastatic potential expresses the cell surface receptor CXCR3, which binds CXCL9/10. CXCR3 + breast cancer cells express high levels of IL-1α/β via JNK signaling, suggesting that they can both induce CXCL9/10 in MAFs and benefit from these chemokines. Importantly, using mouse models we show that these molecular interactions play a crucial role in supporting proliferation of breast cancer cells and development of metastasis. Together, our data reveal an important crosstalk between breast cancer cells and MAFs that promotes metastatic initiation and progression to overt lung metastasis. Results Metastatic breast cancer cells activate fibroblasts in the lungs To investigate evolution of fibroblasts during metastatic colonization, we established experimental lung metastases by injecting MDA-MB-231 (MDA) human breast cancer cells or the highly metastatic derivative MDA-MB-231-LM2 (MDA-LM2) cells 11 intravenously into immunocompromised mice. At 1 week post injection (when lungs harbor primarily micrometastases) and at 3 weeks post injection (when macrometastases are prominent and widespread), we isolated fibroblasts using fluorescence-activated cell sorting (FACS) (Fig. 1a–c ). Considering the different capacity of MDA and MDA-LM2 cells to grow metastasis in the lungs, the experimental approach was designed to address the qualitative difference between MDA and MDA-LM2 associated fibroblasts in metastasis at each time point. Therefore, we selected individual mice with comparable MDA or MDA-LM2 metastatic loads for our analysis based on in vivo bioluminescence imaging (Supplementary Fig. 1a ). Lung fibroblasts were isolated by FACS using two positive selection markers, platelet-derived growth factor receptor (PDGFR)α and PDGFRβ, and a panel of negative selection markers (Fig. 1a and Supplementary Fig. 1b–d ). Purity of sorted fibroblasts was confirmed (Supplementary Fig. 2a, b ). Fibroblasts isolated from lungs with growing metastases were compared with fibroblasts from lungs of healthy, age-matched mice. We observed a striking correlation between the number of fibroblasts and metastatic burden (Fig. 1d, e ). Lungs harboring macrometastases exhibited a substantial increase in the number of fibroblasts compared with lungs with micrometastases or healthy lungs (Fig. 1f ). These data suggested that the fibroblast population in lung stroma expands extensively during metastatic colonization by breast cancer cells. Fig. 1: Metastatic breast cancer cells promote activation of fibroblasts during lung colonization. a Experimental setup for selection of fibroblasts from lungs of mice at different time points after intravenous injection of MDA-MB-231 (MDA) and MDA-MB-231-LM2 (MDA-LM2) breast cancer cells. b Size of metastatic nodules at week 1 or week 3 after intravenous injection of indicated breast cancer cells. Week 1, n = 257 (MDA) and n = 330 (MDA-LM2) metastatic nodules from six mice per group. Week 3, n = 236 (MDA) and n = 171 (MDA-LM2) nodules from six mice per group. c Representative examples of MDA and MDA-LM2 micrometastases (week 1) and macrometastases (week 3) expressing human vimentin as cancer cell-marker. Scale bar, 100 µm. Arrows point to micrometastases and dashed lines indicate margins of macrometastases. Correlation of total numbers of lung fibroblasts with lung bioluminescence from MDA ( d ) and MDA-LM2 ( e ) metastases. f Total number of fibroblasts from healthy and metastatic (MDA and MDA-LM2) lungs at micrometastatic and macrometastatic stages. Healthy fibroblasts, n = 5 mice; fibroblasts from micrometastasis MDA, n = 8 mice and MDA-LM2, n = 7 mice; fibroblasts from macrometastasis (MDA or MDA-LM2), n = 4 mice each group. Boxes depict median with upper and lower quartiles. Whiskers indicate minimum and maximum values and data points show biological replicates. P value was determined by unpaired two-tailed t test. g Principal component (PC) analysis of transcriptome of fibroblasts from metastatic<|im_end|> <|im_start|>assistant In order to colonize other organs and grow into metastases, tumor cells that detach from the parent tumor need to manipulate their new microenvironment and create a 'metastatic niche.' Scientists from the German Cancer Research Center and the Heidelberg Institute for Stem Cell Technology and Experimental Medicine have now discovered that some cancer cells stimulate connective tissue cells in their environment to release transmitters that promote metastasis. This discovery plays a key role in better understanding how these dangerous metastases arise. If cancer cells detach from a tumor and move around the body, they are entering enemy territory. Many detached cancer cells do actually die before they manage to colonize other tissues and form metastases, because the body's immune system is geared toward protecting healthy tissue from intruders of all kinds. Moreover, these migrant cancer cells can only survive if they manage to manipulate the cells in their new environment to create a metastatic niche that helps the migrant cancer cells survive. Thordur Oskarsson and his team at the German Cancer Research Center (DKFZ) and at the Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH) are investigating how this metastatic niche arises. The scientists have now discovered both in cell cultures and in mice that some particularly aggressive breast cancer cells induce a situation similar to inflammation in lung tissue. This ultimately ensures that they can colonize the tissue and grow into metastases. Specifically, the detached tumor cells release two inflammatory signaling molecules, known as interleukins, which stimulate fibroblasts in the lung to release two further inflammatory signaling molecules into the microenvironment: CXCL9 and CXCL10. In turn, these attach to a receptor molecule that several aggressive migrant cancer cells carry on their surface, marking a decisive step in the process of growing into a metastasis. These aggressive breast cancer cells thus benefit directly from the inflammation and from the signaling molecules CXCL9 and CXCL10. "Interestingly, the very tumor cells that stimulate the fibroblasts to produce CXCL9 and CXCL10 also have the relevant receptor for these cytokines and thus benefit from the process," explained Maren Pein, lead author of the study. "That underlines how crucial the cellular communication between the detached cancer cells and the fibroblasts in their new microenvironment is for metastasis." Furthermore, the scientists prevented metastasis in the lung in an experimental setting by treating mice with an inhibitor that blocked the receptor molecule on the cancer cells. Tumor tissue samples from patients show that this cellular interaction probably plays a role in breast cancer patients too: Thus cancer cells that carry the relevant surface receptor and can therefore harness the interaction with fibroblasts to form metastases are also found in patients with metastatic breast cancer. Oskarsson emphasized that it was still too early to identify a new treatment approach from these findings. "Our work is initially designed to help understand the underlying mechanisms that are necessary for metastases to actually arise," he explained. "But we obviously hope that this better understanding will lead to us being able to prevent metastases some time in the future." <|im_end|>

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2,296

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Nanofilamentous bacteriophages (bacterial viruses) are biofunctional, self-propagating, and monodisperse natural building blocks for virus-built materials. Minifying phage-built materials to microscale offers the promise of expanding the range function for these biomaterials to sprays and colloidal bioassays/biosensors. Here, we crosslink half a million self-organized phages as the sole structural component to construct each soft microgel. Through an in-house developed, biologics-friendly, high-throughput template method, over 35,000 phage-built microgels are produced from every square centimetre of a peelable microporous film template, constituting a 13-billion phage community. The phage-exclusive microgels exhibit a self-organized, highly-aligned nanofibrous texture and tunable auto-fluorescence. Further preservation of antimicrobial activity was achieved by making hybrid protein-phage microgels. When loaded with potent virulent phages, these microgels effectively reduce heavy loads of multidrug-resistant Escherichia coli O157:H7 on food products, leading to up to 6 logs reduction in 9 hours and rendering food contaminant free. Introduction Bacteriophages, also known as phages, are natural bacterial predators and their job in nature is to keep bacterial populations in check 1 , 2 . Phages infect bacteria in a highly targeted manner—some are able to identify and kill a single strain of bacteria in a heterogeneous population. It follows that when used for biocontrol in environments with a pre-existing commensal bacterial populations, such as certain food products or applications in agriculture, farming, or human therapeutic use, phages are less likely to disturb the delicate balance of such communities while still being able to eliminate harmful bacteria 3 . Foodborne diseases result in hundreds of thousands of deaths each year, almost a third of whom are young children 4 . Phage products have been approved by the US Food and Drug Administration for control of dangerous bacterial contaminants such as Escherichia coli , Salmonella , or Listeria in food products 5 , 6 . The use of phage for food safety has the distinct advantage that, unlike most antimicrobials, it will not impact the taste, texture, and nutritional quality of the food, and can be safely applied to decontaminate food products from farm to market to consumer plates 7 , 8 . However, widespread use is still limited. This is at least partly due to challenges in delivery and stability, which in turn limit the efficacy of the phage products 9 . Nature makes phages in a variety of shapes and sizes 10 . Phages are, in essence, proteinous nanoparticles that encase a genome, enabling the propagation of wild-type or genetically modified virions into a suspension of identical and monodisperse nanoparticles 11 . In addition, the phage surface chemistry can be customized with atomic precision via genetic engineering or chemical conjugation, making phage virions a powerful building block for multifunctional antimicrobial material 12 , 13 , 14 . We have previously reported a simple chemistry that was effective at crosslinking filamentous phage, yielding bulk soft material displaying the basic properties of a hydrogel 15 , 16 , 17 . Herein, we reinvented phage gels by developing a high-throughput manufacturing method that not only enabled generation of microgels made up entirely of viral nanoparticles, but also preserved the bioactivity of the phage building blocks in the process. Compared to polymeric microgels such as poly(N-isopropylacrylamide) 18 and poly(ethylene glycol) 19 , phage microgels remain unexplored, partly because of challenges in manufacturing such microgels. Common microgel preparation methods such as microfluidics 20 or the emulsion method 21 are not suitable for microgels encapsulated with or made from heat/solvent-sensitive chemicals or biomolecules (such as proteins and viruses) that must retain their bioactivity through the preparation process. Microgels offer major distinct advantages over bulk material. Namely, they have larger surface areas and thus more contact points for phage with contaminating bacteria as well as enhanced flow properties in suspensions, allowing for delivery via spray or injection, all of which make them a more versatile option for biocontrol in environmental, food, and medical applications 22 , 23 , 24 . Packing phages into soft, hydrated material further has the advantage of preservation against desiccation and harsh environments 25 , 26 . The hydrated structure of microgels offers the advantage of preserving desiccation-sensitive biomolecules. We report a biomolecule-friendly, high-throughput method to synthesize detachable phage microgel arrays, where a microporous mold, made through the breath figure method, was used without the need for large equipment or complex infrastructure. We demonstrate that two crosslinkers can each effectively assist the gelation of phage nanofilaments through different crosslinking reactions, leading to vastly different fluorescence profiles. We further show that the phage nanofilaments in these virus-exclusive microgels self-assemble into an orderly, highly aligned nanofibrous structure that serve as a high-load vehicle for protein and strong virulent phages to control multidrug-resistant E. coli O157:H7 in food products. Results and discussion Generation of bacteriophage microgels The gelation of phage aqueous suspension is based on the crosslinking reaction between M13 filamentous phage and a small molecule chemical crosslinker. The crosslinker, glutaraldehyde (GA), can react with multiple functional groups on the phage coat protein, notably amino groups on the lysine residues 15 , 27 , 28 . As shown in Fig. 1a , reaction 1, a GA molecule reacts with 2 amino groups on two phage capsids and forms Schiff bases connecting these two phages. It is worth mentioning that GA in aqueous solution is not limited to regular monomeric formation. For example, cyclic hemiacetal and cyclic hemiacetal oligomer are common forms of GA which can react with amine as well and form ether groups (Supplementary Fig. 1 ). All these possible reactions proceed simultaneously leading to a crosslinked network of phage nanofilaments. The formation of these side products, in addition to the well-documented self-polymerization of GA and the strong autofluorescence of the final gel 15 , make GA a non-ideal choice for certain applications. Therefore, we explored a second small molecule crosslinker 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), which proved capable of crosslinking phage through a different crosslinking mechanism 29 . An EDC molecule first reacts with a carboxyl group on the phage coat protein and forms an amine-reactive intermediate that quickly reacts with", "role": "user" }, { "content": "Researchers at McMaster University have created a powerful new weapon against bacterial contamination and infection. They have developed a way to coax bacteriophages—harmless viruses that eat bacteria—into linking together and forming microscopic beads. Those beads can safely be applied to food and other materials to rid them of harmful pathogens such as E. coli 0157. Each bead is about 20 microns, (one 50th of a millimeter) in diameter and is loaded with millions of phages. The McMaster engineering team behind the invention, led by professors Zeinab Hosseinidoust, who holds the Canada Research Chair in Bacteriophage Bioengineering, and Tohid Didar, who holds the Canada Research Chair in Nano-Biomaterials, and graduate student Lei Tian, have created a spray using nothing but the microbeads. The researchers' sprayable new super-disinfectant is food-safe and highly effective, as they describe in an article (the link will be active on publication) published today in the influential journal Nature Communications. Graduate student and Vanier scholar Shadman Khan worked with Tian to test the antibacterial spray on food products. \"When we spray it on food, we basically gather billions of mini-soldiers to protect our food from bacterial contamination,\" says Tian, who led the study as part of his Ph.D. research. The research builds on the same chemistry work that Hosseinidoust's lab had previously used to trigger phages to connect to one another in quantities sufficient to form a gel. \"They link together like microscopic Lego pieces,\" she says. \"This organized natural structure makes them much more durable and easier to package, store and use.\" Before the introduction of penicillin in the 1940s, research into phage disinfectants and therapies had been very promising, but interest in developing their potential dimmed once antibiotics made from penicillin came onto the market. With antimicrobial resistance now sapping the power of existing antibiotics, there is intense new interest in phage research. When phages—which occur naturally in the body and in the environment—contact target bacteria, they multiply, explosively increasing their antimicrobial power as they work. \"It's a chain reaction, creating a dynamic and ongoing response that is even more overpowering than antibiotics,\" Didar says. \"No other antibacterial product—not even bleach—has the special properties that phages do.\" Another major advantage of using phages in agriculture and food production is that they can be directed very specifically to take out harmful strains of bacteria without killing beneficial bacteria that enhance foods' taste, smell and texture. The new phage spray has promising potential for commercial application, the researchers say, especially since phages have already earned approval from the US Food and Drug Administration for use in food. The research paper shows the sprayable material can eliminate E. coli 0157 in lettuce and meat, which are often the sources of disease outbreaks. The researchers say the same approach can readily be used against other bacteria which cause food poisoning, such as Salmonella and Listeria—individually or in combination. Phage sprays could be used in food processing, packaging and cleaning, and even as a treatment for irrigation water and equipment, stopping contamination at the source, the researchers say. The research, completed under the umbrella of McMaster's Global Nexus for Pandemics and Biological Threats, combines and extends the previous work of Hosseinidoust's lab with work that Didar and other McMaster colleagues had done to create microscopic sensors and surfaces to detect and repel food pathogens. Co-authors on the paper also include Leon He, Kyle Jackson, Ahmed Saif and Zeqi Wan. The group next plans to test the new material's promising applications in medicine, where it might be used in disinfecting wounds, for example. Medical applications will take more time to be proven safe and effective, but a product made for disinfection in food processing could make it to market much more quickly. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Nanofilamentous bacteriophages (bacterial viruses) are biofunctional, self-propagating, and monodisperse natural building blocks for virus-built materials. Minifying phage-built materials to microscale offers the promise of expanding the range function for these biomaterials to sprays and colloidal bioassays/biosensors. Here, we crosslink half a million self-organized phages as the sole structural component to construct each soft microgel. Through an in-house developed, biologics-friendly, high-throughput template method, over 35,000 phage-built microgels are produced from every square centimetre of a peelable microporous film template, constituting a 13-billion phage community. The phage-exclusive microgels exhibit a self-organized, highly-aligned nanofibrous texture and tunable auto-fluorescence. Further preservation of antimicrobial activity was achieved by making hybrid protein-phage microgels. When loaded with potent virulent phages, these microgels effectively reduce heavy loads of multidrug-resistant Escherichia coli O157:H7 on food products, leading to up to 6 logs reduction in 9 hours and rendering food contaminant free. Introduction Bacteriophages, also known as phages, are natural bacterial predators and their job in nature is to keep bacterial populations in check 1 , 2 . Phages infect bacteria in a highly targeted manner—some are able to identify and kill a single strain of bacteria in a heterogeneous population. It follows that when used for biocontrol in environments with a pre-existing commensal bacterial populations, such as certain food products or applications in agriculture, farming, or human therapeutic use, phages are less likely to disturb the delicate balance of such communities while still being able to eliminate harmful bacteria 3 . Foodborne diseases result in hundreds of thousands of deaths each year, almost a third of whom are young children 4 . Phage products have been approved by the US Food and Drug Administration for control of dangerous bacterial contaminants such as Escherichia coli , Salmonella , or Listeria in food products 5 , 6 . The use of phage for food safety has the distinct advantage that, unlike most antimicrobials, it will not impact the taste, texture, and nutritional quality of the food, and can be safely applied to decontaminate food products from farm to market to consumer plates 7 , 8 . However, widespread use is still limited. This is at least partly due to challenges in delivery and stability, which in turn limit the efficacy of the phage products 9 . Nature makes phages in a variety of shapes and sizes 10 . Phages are, in essence, proteinous nanoparticles that encase a genome, enabling the propagation of wild-type or genetically modified virions into a suspension of identical and monodisperse nanoparticles 11 . In addition, the phage surface chemistry can be customized with atomic precision via genetic engineering or chemical conjugation, making phage virions a powerful building block for multifunctional antimicrobial material 12 , 13 , 14 . We have previously reported a simple chemistry that was effective at crosslinking filamentous phage, yielding bulk soft material displaying the basic properties of a hydrogel 15 , 16 , 17 . Herein, we reinvented phage gels by developing a high-throughput manufacturing method that not only enabled generation of microgels made up entirely of viral nanoparticles, but also preserved the bioactivity of the phage building blocks in the process. Compared to polymeric microgels such as poly(N-isopropylacrylamide) 18 and poly(ethylene glycol) 19 , phage microgels remain unexplored, partly because of challenges in manufacturing such microgels. Common microgel preparation methods such as microfluidics 20 or the emulsion method 21 are not suitable for microgels encapsulated with or made from heat/solvent-sensitive chemicals or biomolecules (such as proteins and viruses) that must retain their bioactivity through the preparation process. Microgels offer major distinct advantages over bulk material. Namely, they have larger surface areas and thus more contact points for phage with contaminating bacteria as well as enhanced flow properties in suspensions, allowing for delivery via spray or injection, all of which make them a more versatile option for biocontrol in environmental, food, and medical applications 22 , 23 , 24 . Packing phages into soft, hydrated material further has the advantage of preservation against desiccation and harsh environments 25 , 26 . The hydrated structure of microgels offers the advantage of preserving desiccation-sensitive biomolecules. We report a biomolecule-friendly, high-throughput method to synthesize detachable phage microgel arrays, where a microporous mold, made through the breath figure method, was used without the need for large equipment or complex infrastructure. We demonstrate that two crosslinkers can each effectively assist the gelation of phage nanofilaments through different crosslinking reactions, leading to vastly different fluorescence profiles. We further show that the phage nanofilaments in these virus-exclusive microgels self-assemble into an orderly, highly aligned nanofibrous structure that serve as a high-load vehicle for protein and strong virulent phages to control multidrug-resistant E. coli O157:H7 in food products. Results and discussion Generation of bacteriophage microgels The gelation of phage aqueous suspension is based on the crosslinking reaction between M13 filamentous phage and a small molecule chemical crosslinker. The crosslinker, glutaraldehyde (GA), can react with multiple functional groups on the phage coat protein, notably amino groups on the lysine residues 15 , 27 , 28 . As shown in Fig. 1a , reaction 1, a GA molecule reacts with 2 amino groups on two phage capsids and forms Schiff bases connecting these two phages. It is worth mentioning that GA in aqueous solution is not limited to regular monomeric formation. For example, cyclic hemiacetal and cyclic hemiacetal oligomer are common forms of GA which can react with amine as well and form ether groups (Supplementary Fig. 1 ). All these possible reactions proceed simultaneously leading to a crosslinked network of phage nanofilaments. The formation of these side products, in addition to the well-documented self-polymerization of GA and the strong autofluorescence of the final gel 15 , make GA a non-ideal choice for certain applications. Therefore, we explored a second small molecule crosslinker 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), which proved capable of crosslinking phage through a different crosslinking mechanism 29 . An EDC molecule first reacts with a carboxyl group on the phage coat protein and forms an amine-reactive intermediate that quickly reacts with<|im_end|> <|im_start|>assistant Researchers at McMaster University have created a powerful new weapon against bacterial contamination and infection. They have developed a way to coax bacteriophages—harmless viruses that eat bacteria—into linking together and forming microscopic beads. Those beads can safely be applied to food and other materials to rid them of harmful pathogens such as E. coli 0157. Each bead is about 20 microns, (one 50th of a millimeter) in diameter and is loaded with millions of phages. The McMaster engineering team behind the invention, led by professors Zeinab Hosseinidoust, who holds the Canada Research Chair in Bacteriophage Bioengineering, and Tohid Didar, who holds the Canada Research Chair in Nano-Biomaterials, and graduate student Lei Tian, have created a spray using nothing but the microbeads. The researchers' sprayable new super-disinfectant is food-safe and highly effective, as they describe in an article (the link will be active on publication) published today in the influential journal Nature Communications. Graduate student and Vanier scholar Shadman Khan worked with Tian to test the antibacterial spray on food products. "When we spray it on food, we basically gather billions of mini-soldiers to protect our food from bacterial contamination," says Tian, who led the study as part of his Ph.D. research. The research builds on the same chemistry work that Hosseinidoust's lab had previously used to trigger phages to connect to one another in quantities sufficient to form a gel. "They link together like microscopic Lego pieces," she says. "This organized natural structure makes them much more durable and easier to package, store and use." Before the introduction of penicillin in the 1940s, research into phage disinfectants and therapies had been very promising, but interest in developing their potential dimmed once antibiotics made from penicillin came onto the market. With antimicrobial resistance now sapping the power of existing antibiotics, there is intense new interest in phage research. When phages—which occur naturally in the body and in the environment—contact target bacteria, they multiply, explosively increasing their antimicrobial power as they work. "It's a chain reaction, creating a dynamic and ongoing response that is even more overpowering than antibiotics," Didar says. "No other antibacterial product—not even bleach—has the special properties that phages do." Another major advantage of using phages in agriculture and food production is that they can be directed very specifically to take out harmful strains of bacteria without killing beneficial bacteria that enhance foods' taste, smell and texture. The new phage spray has promising potential for commercial application, the researchers say, especially since phages have already earned approval from the US Food and Drug Administration for use in food. The research paper shows the sprayable material can eliminate E. coli 0157 in lettuce and meat, which are often the sources of disease outbreaks. The researchers say the same approach can readily be used against other bacteria which cause food poisoning, such as Salmonella and Listeria—individually or in combination. Phage sprays could be used in food processing, packaging and cleaning, and even as a treatment for irrigation water and equipment, stopping contamination at the source, the researchers say. The research, completed under the umbrella of McMaster's Global Nexus for Pandemics and Biological Threats, combines and extends the previous work of Hosseinidoust's lab with work that Didar and other McMaster colleagues had done to create microscopic sensors and surfaces to detect and repel food pathogens. Co-authors on the paper also include Leon He, Kyle Jackson, Ahmed Saif and Zeqi Wan. The group next plans to test the new material's promising applications in medicine, where it might be used in disinfecting wounds, for example. Medical applications will take more time to be proven safe and effective, but a product made for disinfection in food processing could make it to market much more quickly. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Understanding and control of the dynamic response of magnetic materials with a three-dimensional magnetization distribution is important both fundamentally and for technological applications. From a fundamental point of view, the internal magnetic structure and dynamics in bulk materials still need to be mapped 1 , including the dynamic properties of topological structures such as vortices 2 , magnetic singularities 3 or skyrmion lattices 4 . From a technological point of view, the response of inductive materials to magnetic fields and spin-polarized currents is essential for magnetic sensors and data storage devices 5 . Here, we demonstrate time-resolved magnetic laminography, a pump–probe technique, which offers access to the temporal evolution of a three-dimensional magnetic microdisc with nanoscale resolution, and with a synchrotron-limited temporal resolution of 70 ps. We image the dynamic response to a 500 MHz magnetic field of the complex three-dimensional magnetization in a two-phase bulk magnet with a lateral spatial resolution of 50 nm. This is achieved with a stroboscopic measurement consisting of eight time steps evenly spaced over 2 ns. These measurements map the spatial transition between domain wall motion and the dynamics of a uniform magnetic domain that is attributed to variations in the magnetization state across the phase boundary. Our technique, which probes three-dimensional magnetic structures with temporal resolution, enables the experimental investigation of functionalities arising from dynamic phenomena in bulk and three-dimensional patterned nanomagnets 6 . Main While magnetization dynamics have been measured in two-dimensional structures, and are well understood for isolated magnetic structures in thin films, such as vortices 7 , 8 , 9 , 10 , domain walls 11 , 12 , 13 , 14 and skyrmions 15 , 16 , until now insight into three-dimensional dynamics has only been possible through comparison with simulations 17 . Static three-dimensional magnetic imaging has recently been achieved using hard X-ray 18 , 19 , neutron 20 , 21 , 22 , electron 23 and soft X-ray 24 , 25 tomographies that provide a means to determine the three-dimensional magnetic configurations. Of these methods, synchrotron X-rays are unique due to their ability to provide high spatial resolution imaging of thick materials 18 , 26 , as well as element-specific information. Additionally, the pulsed time structure of synchrotron X-rays naturally provides the possibility to perform time-resolved measurements. Indeed, pump–probe measurements of material systems have proved to be a powerful tool for the measurement of MHz and GHz dynamics within a range of magnetic materials and systems 27 . Such time-resolved measurements generally require flat samples, which pose challenges when it comes to three-dimensional tomographic magnetic imaging. In particular, there is a ‘missing wedge’ due to high absorption of the sample at high angles, and it is necessary to alter the orientation of the sample with respect to the rotation axis part way through the measurement in order to measure all three components of the magnetization. As a result, until now it has not been possible to combine three-dimensional magnetic imaging with dynamic measurements. The imaging of magnetization dynamics in three dimensions becomes more feasible with an alternative geometry for three-dimensional imaging, laminography 28 . For magnetic imaging, as shown in this work, laminography provides access to all three components of the magnetization with a single axis of rotation and, by combining vectorial magnetic imaging with a pump–probe setup, it is possible to obtain the temporal evolution of the entire three-dimensional magnetization vector field. In this way, we can study surface excitations as well as the dynamics of buried three-dimensional magnetic domains and domain walls. Here, we image the as-grown three-dimensional magnetic state of a GdCo microdisc with a diameter of 5 μm and a thickness of 1.2 μm using magnetic laminography, and determine its dynamic response to a radio frequency (RF) magnetic field. The microdisc was patterned by milling a continuous film deposited on the back of a Si 3 N 4 membrane with a focused ion beam (see Fig. 1a (ii) for a scanning electron micrograph of the sample). A two-phase GdCo film was deposited by magnetron sputtering, first with the sample continuously rotating for the lower part, and then stationary for the top quarter of the thickness. On the front of the membrane a 300 nm-thick Cu stripline was patterned, through which an RF current was injected to produce an in-plane magnetic field excitation. Fig. 1: Time-resolved X-ray magnetic laminography. a , The experimental setup. For synchrotron X-ray magnetic laminography, ptychographic projections are measured with right- and left-handed circular polarization with the sample rotated around an axis that is at 61° with respect to the X-ray beam propagation direction. To observe the magnetization dynamics, the sample is fabricated on a Cu stripline (see magnified view in (i) along with a scanning electron micrograph of the sample in (ii)), and excited with a 500 MHz RF magnetic field produced by passing a current through the stripline. Magnetic laminography is then performed for a number of different delay times of the RF magnetic field with respect to the X-ray pulses. Scale bar, 2 μm (ii). b , The concept of pump–probe magnetic laminography is illustrated, where the RF magnetic field excitation (red oscillatory waveform) is frequency and phase matched to the incoming X-ray pulses (grey waveforms). By varying the time delay ( δt ) between the continuous RF magnetic field excitation (red) and the X-ray bunches (two temporal measurements, separated by δt , are indicated by the full and dashed grey waveforms), and repeating the laminography measurement for different δt , time resolved maps of the magnetization vector field are obtained. c , d , XMCD projections of the magnetic microdisc are shown for the sample at 0° ( c ) and 45° ( d ), respectively. Scale bars, 1 μm ( c , d ). Full size image The experimental setup is shown schematically in Fig. 1a , where the plane of the sample is tilted at an angle of 29° to the propagation direction of the X-rays. During the measurement the sample is rotated", "role": "user" }, { "content": "Scientists have developed a three-dimensional imaging technique to observe complex behaviours in magnets, including fast-moving waves and 'tornadoes' thousands of times thinner than a human hair. The team, from the Universities of Cambridge and Glasgow in the UK and ETH Zurich and the Paul Scherrer Institute in Switzerland, used their technique to observe how the magnetisation behaves, the first time this has been done in three dimensions. The technique, called time-resolved magnetic laminography, could be used to understand and control the behaviour of new types of magnets for next-generation data storage and processing. The results are reported in the journal Nature Nanotechnology. Magnets are widely used in applications from data storage to energy production and sensors. In order to understand why magnets behave the way they do, it is important to understand the structure of their magnetisation, and how that structure reacts to changing currents or magnetic fields. \"Until now, it hasn't been possible to actually measure how magnets respond to changing magnetic fields in three dimensions,\" said Dr. Claire Donnelly from Cambridge's Cavendish Laboratory, and the study's first author. \"We've only really been able to observe these behaviours in thin films, which are essentially two dimensional, and which therefore don't give us a complete picture.\" Credit: University of Cambridge Moving from two dimensions to three is highly complex, however. Modelling and visualising magnetic behaviour is relatively straightforward in two dimensions, but in three dimensions, the magnetisation can point in any direction and form patterns, which is what makes magnets so powerful. \"Not only is it important to know what patterns and structures this magnetisation forms, but it's essential to understand how it reacts to external stimuli,\" said Donnelly. \"These responses are interesting from a fundamental point of view, but they are crucial when it comes to magnetic devices used in technology and applications.\" One of the main challenges in investigating these responses is tied to the very reason magnetic materials are so relevant for so many applications: changes in the magnetisation typically are extremely small, and happen extremely fast. Magnetic configurations—so-called domain structures—exhibit features on the order of tens to hundreds of nanometres, thousands of times smaller than the width of a human hair, and typically react to magnetic fields and currents in billionths of a second. Now, Donnelly and her collaborators from the Paul Scherrer Institute, the University of Glasgow and ETH Zurich have developed a technique to look inside a magnet, visualise its nanostructure, and how it responds to a changing magnetic field in three dimensions, and at the size and timescales required. Credit: University of Cambridge The technique they developed, time-resolved magnetic laminography, uses powerful X-rays called synchrotron X-rays to probe the magnetic state from different directions at the nanoscale, and how it changes in response to a quickly alternating magnetic field. The resulting seven-dimensional dataset (three dimensions for the position, three for the direction and one for the time) is then obtained using a specially developed reconstruction algorithm, providing a map of the magnetisation dynamics with 70 picosecond temporal resolution, and 50 nanometre spatial resolution. What the researchers saw with their technique was like a nanoscale storm: patterns of waves and tornadoes moving side to side as the magnetic field changed. The movement of these tornadoes, or vortices, had previously only been observed in two dimensions. The researchers tested their technique using conventional magnets, but they say it could also be useful in the development of new types of magnets which exhibit new types of magnetism. These new magnets, such as 3-D-printed nanomagnets, could be useful for new types of high-density, high-efficiency data storage and processing. \"We can now investigate the dynamics of new types of systems that could open up new applications we haven't even thought of,\" said Donnelly. \"This new tool will help us to understand, and control, their behaviour.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 and control of the dynamic response of magnetic materials with a three-dimensional magnetization distribution is important both fundamentally and for technological applications. From a fundamental point of view, the internal magnetic structure and dynamics in bulk materials still need to be mapped 1 , including the dynamic properties of topological structures such as vortices 2 , magnetic singularities 3 or skyrmion lattices 4 . From a technological point of view, the response of inductive materials to magnetic fields and spin-polarized currents is essential for magnetic sensors and data storage devices 5 . Here, we demonstrate time-resolved magnetic laminography, a pump–probe technique, which offers access to the temporal evolution of a three-dimensional magnetic microdisc with nanoscale resolution, and with a synchrotron-limited temporal resolution of 70 ps. We image the dynamic response to a 500 MHz magnetic field of the complex three-dimensional magnetization in a two-phase bulk magnet with a lateral spatial resolution of 50 nm. This is achieved with a stroboscopic measurement consisting of eight time steps evenly spaced over 2 ns. These measurements map the spatial transition between domain wall motion and the dynamics of a uniform magnetic domain that is attributed to variations in the magnetization state across the phase boundary. Our technique, which probes three-dimensional magnetic structures with temporal resolution, enables the experimental investigation of functionalities arising from dynamic phenomena in bulk and three-dimensional patterned nanomagnets 6 . Main While magnetization dynamics have been measured in two-dimensional structures, and are well understood for isolated magnetic structures in thin films, such as vortices 7 , 8 , 9 , 10 , domain walls 11 , 12 , 13 , 14 and skyrmions 15 , 16 , until now insight into three-dimensional dynamics has only been possible through comparison with simulations 17 . Static three-dimensional magnetic imaging has recently been achieved using hard X-ray 18 , 19 , neutron 20 , 21 , 22 , electron 23 and soft X-ray 24 , 25 tomographies that provide a means to determine the three-dimensional magnetic configurations. Of these methods, synchrotron X-rays are unique due to their ability to provide high spatial resolution imaging of thick materials 18 , 26 , as well as element-specific information. Additionally, the pulsed time structure of synchrotron X-rays naturally provides the possibility to perform time-resolved measurements. Indeed, pump–probe measurements of material systems have proved to be a powerful tool for the measurement of MHz and GHz dynamics within a range of magnetic materials and systems 27 . Such time-resolved measurements generally require flat samples, which pose challenges when it comes to three-dimensional tomographic magnetic imaging. In particular, there is a ‘missing wedge’ due to high absorption of the sample at high angles, and it is necessary to alter the orientation of the sample with respect to the rotation axis part way through the measurement in order to measure all three components of the magnetization. As a result, until now it has not been possible to combine three-dimensional magnetic imaging with dynamic measurements. The imaging of magnetization dynamics in three dimensions becomes more feasible with an alternative geometry for three-dimensional imaging, laminography 28 . For magnetic imaging, as shown in this work, laminography provides access to all three components of the magnetization with a single axis of rotation and, by combining vectorial magnetic imaging with a pump–probe setup, it is possible to obtain the temporal evolution of the entire three-dimensional magnetization vector field. In this way, we can study surface excitations as well as the dynamics of buried three-dimensional magnetic domains and domain walls. Here, we image the as-grown three-dimensional magnetic state of a GdCo microdisc with a diameter of 5 μm and a thickness of 1.2 μm using magnetic laminography, and determine its dynamic response to a radio frequency (RF) magnetic field. The microdisc was patterned by milling a continuous film deposited on the back of a Si 3 N 4 membrane with a focused ion beam (see Fig. 1a (ii) for a scanning electron micrograph of the sample). A two-phase GdCo film was deposited by magnetron sputtering, first with the sample continuously rotating for the lower part, and then stationary for the top quarter of the thickness. On the front of the membrane a 300 nm-thick Cu stripline was patterned, through which an RF current was injected to produce an in-plane magnetic field excitation. Fig. 1: Time-resolved X-ray magnetic laminography. a , The experimental setup. For synchrotron X-ray magnetic laminography, ptychographic projections are measured with right- and left-handed circular polarization with the sample rotated around an axis that is at 61° with respect to the X-ray beam propagation direction. To observe the magnetization dynamics, the sample is fabricated on a Cu stripline (see magnified view in (i) along with a scanning electron micrograph of the sample in (ii)), and excited with a 500 MHz RF magnetic field produced by passing a current through the stripline. Magnetic laminography is then performed for a number of different delay times of the RF magnetic field with respect to the X-ray pulses. Scale bar, 2 μm (ii). b , The concept of pump–probe magnetic laminography is illustrated, where the RF magnetic field excitation (red oscillatory waveform) is frequency and phase matched to the incoming X-ray pulses (grey waveforms). By varying the time delay ( δt ) between the continuous RF magnetic field excitation (red) and the X-ray bunches (two temporal measurements, separated by δt , are indicated by the full and dashed grey waveforms), and repeating the laminography measurement for different δt , time resolved maps of the magnetization vector field are obtained. c , d , XMCD projections of the magnetic microdisc are shown for the sample at 0° ( c ) and 45° ( d ), respectively. Scale bars, 1 μm ( c , d ). Full size image The experimental setup is shown schematically in Fig. 1a , where the plane of the sample is tilted at an angle of 29° to the propagation direction of the X-rays. During the measurement the sample is rotated<|im_end|> <|im_start|>assistant Scientists have developed a three-dimensional imaging technique to observe complex behaviours in magnets, including fast-moving waves and 'tornadoes' thousands of times thinner than a human hair. The team, from the Universities of Cambridge and Glasgow in the UK and ETH Zurich and the Paul Scherrer Institute in Switzerland, used their technique to observe how the magnetisation behaves, the first time this has been done in three dimensions. The technique, called time-resolved magnetic laminography, could be used to understand and control the behaviour of new types of magnets for next-generation data storage and processing. The results are reported in the journal Nature Nanotechnology. Magnets are widely used in applications from data storage to energy production and sensors. In order to understand why magnets behave the way they do, it is important to understand the structure of their magnetisation, and how that structure reacts to changing currents or magnetic fields. "Until now, it hasn't been possible to actually measure how magnets respond to changing magnetic fields in three dimensions," said Dr. Claire Donnelly from Cambridge's Cavendish Laboratory, and the study's first author. "We've only really been able to observe these behaviours in thin films, which are essentially two dimensional, and which therefore don't give us a complete picture." Credit: University of Cambridge Moving from two dimensions to three is highly complex, however. Modelling and visualising magnetic behaviour is relatively straightforward in two dimensions, but in three dimensions, the magnetisation can point in any direction and form patterns, which is what makes magnets so powerful. "Not only is it important to know what patterns and structures this magnetisation forms, but it's essential to understand how it reacts to external stimuli," said Donnelly. "These responses are interesting from a fundamental point of view, but they are crucial when it comes to magnetic devices used in technology and applications." One of the main challenges in investigating these responses is tied to the very reason magnetic materials are so relevant for so many applications: changes in the magnetisation typically are extremely small, and happen extremely fast. Magnetic configurations—so-called domain structures—exhibit features on the order of tens to hundreds of nanometres, thousands of times smaller than the width of a human hair, and typically react to magnetic fields and currents in billionths of a second. Now, Donnelly and her collaborators from the Paul Scherrer Institute, the University of Glasgow and ETH Zurich have developed a technique to look inside a magnet, visualise its nanostructure, and how it responds to a changing magnetic field in three dimensions, and at the size and timescales required. Credit: University of Cambridge The technique they developed, time-resolved magnetic laminography, uses powerful X-rays called synchrotron X-rays to probe the magnetic state from different directions at the nanoscale, and how it changes in response to a quickly alternating magnetic field. The resulting seven-dimensional dataset (three dimensions for the position, three for the direction and one for the time) is then obtained using a specially developed reconstruction algorithm, providing a map of the magnetisation dynamics with 70 picosecond temporal resolution, and 50 nanometre spatial resolution. What the researchers saw with their technique was like a nanoscale storm: patterns of waves and tornadoes moving side to side as the magnetic field changed. The movement of these tornadoes, or vortices, had previously only been observed in two dimensions. The researchers tested their technique using conventional magnets, but they say it could also be useful in the development of new types of magnets which exhibit new types of magnetism. These new magnets, such as 3-D-printed nanomagnets, could be useful for new types of high-density, high-efficiency data storage and processing. "We can now investigate the dynamics of new types of systems that could open up new applications we haven't even thought of," said Donnelly. "This new tool will help us to understand, and control, their behaviour." <|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 Magnetic Feshbach resonances allow control of the interactions between ultracold atoms 1 . They are an invaluable tool in studies of few-body and many-body physics 2 , 3 , and can be used to convert pairs of atoms into molecules 4 , 5 by ramping an applied magnetic field across a resonance. Molecules formed from pairs of alkali atoms have been transferred to low-lying states, producing dipolar quantum gases 6 . There is great interest in making molecules formed from an alkali atom and a closed-shell atom such as ground-state Sr or Yb. Such molecules have both a strong electric dipole and an electron spin; they will open up new possibilities for designing quantum many-body systems 7 , 8 , and for tests of fundamental symmetries 9 . The crucial first step is to observe Feshbach resonances in the corresponding atomic mixtures. Very narrow resonances have been predicted theoretically 10 , 11 , 12 , but until now have eluded observation. Here we present the observation of magnetic Feshbach resonances of this type, for an alkali atom, Rb, interacting with ground-state Sr. Main A magnetic Feshbach resonance arises when a pair of ultracold atoms couples to a near-threshold molecular state that is tuned to be close in energy by an applied magnetic field. Magnetoassociation at such a resonance coherently transfers the atoms into the molecular state 13 , 14 . In a few cases, near-threshold molecules formed in this way have been transferred to their absolute ground states 15 , 16 , 17 , allowing exploration of quantum gases with strong dipolar interactions 6 . However, this has so far been achieved only for molecules formed from pairs of alkali atoms. Mixtures of closed-shell alkaline-earth atoms with open-shell alkali atoms have been studied in several laboratories 18 , 19 , 20 , 21 , 22 . No strong coupling mechanism between atomic and molecular states exists in systems of this type, but theoretical work has identified weak coupling mechanisms that should lead to narrow Feshbach resonances, suitable for magnetoassociation 10 , 11 , 12 . In this letter we describe the detection of Feshbach resonances in mixtures of 87 Sr or 88 Sr with 87 Rb. The coupling between atomic and molecular states arises from two mechanisms previously predicted 10 , 11 , 12 and an additional, weaker mechanism that we identify here. The experimental signature of a Feshbach resonance is field-dependent loss of Rb atoms. This may arise from either three-body recombination or inelastic collisions, both of which are enhanced near a resonance. We perform loss spectroscopy using an ultracold Rb–Sr mixture, typically consisting of 5×10 4 Rb atoms mixed with 10 6 87 Sr or 10 7 88 Sr atoms at a temperature of 2 to 5 μK (see Methods ). Figure 1 shows the observed loss features, eleven arising in the 87 Rb– 87 Sr Bose–Fermi mixture and one in the 87 Rb– 88 Sr Bose–Bose mixture. Ten loss features consist of a single, slightly asymmetrical dip with a full-width at half-maximum between 200 and 400 mG. The loss features labelled [1,0]a and [1,1]a each consist of several dips with a width of 20 to 60 mG at a spacing of 80 mG. We fit each dip with a Gaussian and give the resulting positions and widths in Table 1 . None of these Rb loss features arises in the absence of Sr, proving that they depend on Rb–Sr interactions. Fig. 1: Detection of Rb–Sr Feshbach resonances by field-dependent loss of Rb. The fraction of Rb atoms remaining in state ( f , m f ) after loss at each observed Feshbach resonance, normalized to unity far from the loss feature. Eleven loss features are observed in 87 Rb– 87 Sr mixtures and one in 87 Rb– 88 Sr (bottom right panel). The loss features are labelled by [ f , m f ] j , where \$j\\in\$ {a,b,c} is an index used when losses due to several molecular states are observed at the same atomic threshold. Most loss features show a single dip in the atom number, whereas [1,0]a and [1,1]a show several. Each dip is fitted by a Gaussian (black line), with results shown in Table 1 . The colour and shape of symbols indicates the coupling mechanism for the Feshbach resonance: mechanism I (orange triangles), II (blue circles), or III (green squares). The resonance near 521 G also has a contribution from mechanism II. The magnetic field uncertainty is 0.4 G and the noise is less than 40 mG. Error bars represent the standard error of three or more data points. Full size image Table 1 Properties of observed Feshbach resonances Full size table Both the atomic and molecular states are described by the total angular momentum of the Rb atom, f , and its projection m f onto the magnetic field. Where necessary, atomic and molecular quantum numbers are distinguished with the subscripts at and mol. In addition, the molecule has a vibrational quantum number n , counted down from n = −1 for the uppermost level, and a rotational quantum number L , with projection M L . 88 Sr has nuclear spin i Sr = 0, whereas 87 Sr has i Sr = 9/2 and a corresponding projection m i, Sr . The Rb–Sr atom-pair states and the near-threshold molecular states lie almost parallel to the Rb atomic states as a function of magnetic field (see Supplementary Information ). We can therefore use the Breit–Rabi formula of Rb for both the atom-pair states and the molecular states. This allows us to extract zero-field binding energies E b of the molecular states responsible for the resonances, giving the values in Table 2 . The crossing atomic and molecular levels are shown in Figs. 2 and 3 , with filled symbols where we observe loss features. Table 2 Molecular states responsible for Feshbach resonances Full size table Fig. 2: Origin of the 87 Rb– 87 Sr Feshbach resonances. Energies of atomic (red)", "role": "user" }, { "content": "Cooling matter is not easy. Atoms and molecules have the tendency to jump around, to rotate and to vibrate. Freezing these particles by slowing them down is a complicated process. For individual atoms, physicists have figured out over the years how to carry out this cooling process, using techniques like laser cooling, where finely tuned lasers remove energy from the particles. Molecules, on the other hand, are much harder to cool down so that they stand still. These particles consist of two or more atoms that are bound together, and as compound particles they are able to jiggle around in many more ways. First cool, then build Still, physicists would like to have a dense gas of ultracold molecules at their disposal. Since it is not yet possible to directly cool the molecules themselves into this regime, physicists first cool down atoms – a process which is much easier – and then attempt to build molecules. The question is: how does one get these super cold, motionless atoms to 'click together' to form the desired molecules? The answer to this question is a process that exploits a phenomenon known as Feshbach resonance. Molecules of a given type can exist for different configurations of the atoms' internal states, and all of these states have slightly different energies. By applying a magnetic field, the energy of an unbound atom pair can be tuned to exactly the energy of a specific molecular level. Florian Schreck, the research group leader, explains: \"If a coupling mechanism between the atom pair and the molecule exists, one can create a situation in which atom pairs 'resonate' with molecules, thereby clicking together and forming the desired end product.\" New type of ultracold molecules So far, only gases of molecules that consist of two alkali atoms, atoms with a single electron that can form chemical bonds, have been created with the desired high density and ultracold temperature. The group of experimental physicists at the University of Amsterdam, together with theoretical physicists from Nicolaus Copernicus University in Torun, Poland and from Durham University in the UK, have now made an important step towards the creation of a second type of ultracold molecule. More precisely: they have discovered Feshbach resonances between the alkali element rubidium and the alkaline-earth element strontium, which has two electrons to form bonds with. These resonances are suitable to construct ultracold rubidium-strontium molecules, particles with very different properties from the ultracold molecules that have been constructed so far. The main challenge in this work was that the usual strong coupling mechanisms that exist between alkali atoms do not exist for alkaline-earth atoms. Eight years ago, theorists Piotr Zuchowski and Jeremy Hutson predicted very weak and unusual coupling mechanisms that would still lead to Feshbach resonances. However, the theory was unable to predict the value of the magnetic fields at which these resonances would occur. Employing precise molecular spectroscopy, the experimental team was now able to find the magnetic field values and to experimentally confirm the existence of the sought-for Feshbach resonances. Interesting applications There are several reasons why physicists are interested in creating different types of ultracold molecules. First of all, a very low temperature allows researchers to study the properties of the molecules themselves better: anyone who has ever tried to study a fly knows that this is much easier if the fly is motionless on the wall than if it is buzzing around, and the same thing is true for molecules. Precision studies of molecules could uncover fundamental physics going beyond the current standard model of fundamental particle interactions. Secondly, cold molecules can be prepared in very precise states that can then be used for quantum-controlled chemistry: performing delicate chemical reactions with full control over all aspects of the initial components and the reaction conditions. Finally, there are applications to the many-body physics of quantum particles. When molecules are very cold, their quantum fuzziness becomes apparent. Molecules can be at several locations or in several internal states at the same time and the locations or states of several molecules may depend on each other in intricate ways. New quantum phenomena can emerge, which are hard or impossible to describe using even the best supercomputers. By controlling the interactions between the molecules or the potential landscape through which they are moving, physicists hope to learn about these emergent phenomena. Schreck says: \"Gaining insights into the collective behavior of many quantum particles, be it molecules in a gas or electrons in a metal, may open the door to materials with unheard of properties.\" The results expand the set of available tools for the 'quantum LEGO' of building ultracold molecules from atoms. Schreck: \"With this knowledge, it should soon be possible for the first time to make an ultracold, high density gas of rubidium-strontium molecules. Given the number of potential applications that such a gas has, we are very excited about these new possibilities.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Magnetic Feshbach resonances allow control of the interactions between ultracold atoms 1 . They are an invaluable tool in studies of few-body and many-body physics 2 , 3 , and can be used to convert pairs of atoms into molecules 4 , 5 by ramping an applied magnetic field across a resonance. Molecules formed from pairs of alkali atoms have been transferred to low-lying states, producing dipolar quantum gases 6 . There is great interest in making molecules formed from an alkali atom and a closed-shell atom such as ground-state Sr or Yb. Such molecules have both a strong electric dipole and an electron spin; they will open up new possibilities for designing quantum many-body systems 7 , 8 , and for tests of fundamental symmetries 9 . The crucial first step is to observe Feshbach resonances in the corresponding atomic mixtures. Very narrow resonances have been predicted theoretically 10 , 11 , 12 , but until now have eluded observation. Here we present the observation of magnetic Feshbach resonances of this type, for an alkali atom, Rb, interacting with ground-state Sr. Main A magnetic Feshbach resonance arises when a pair of ultracold atoms couples to a near-threshold molecular state that is tuned to be close in energy by an applied magnetic field. Magnetoassociation at such a resonance coherently transfers the atoms into the molecular state 13 , 14 . In a few cases, near-threshold molecules formed in this way have been transferred to their absolute ground states 15 , 16 , 17 , allowing exploration of quantum gases with strong dipolar interactions 6 . However, this has so far been achieved only for molecules formed from pairs of alkali atoms. Mixtures of closed-shell alkaline-earth atoms with open-shell alkali atoms have been studied in several laboratories 18 , 19 , 20 , 21 , 22 . No strong coupling mechanism between atomic and molecular states exists in systems of this type, but theoretical work has identified weak coupling mechanisms that should lead to narrow Feshbach resonances, suitable for magnetoassociation 10 , 11 , 12 . In this letter we describe the detection of Feshbach resonances in mixtures of 87 Sr or 88 Sr with 87 Rb. The coupling between atomic and molecular states arises from two mechanisms previously predicted 10 , 11 , 12 and an additional, weaker mechanism that we identify here. The experimental signature of a Feshbach resonance is field-dependent loss of Rb atoms. This may arise from either three-body recombination or inelastic collisions, both of which are enhanced near a resonance. We perform loss spectroscopy using an ultracold Rb–Sr mixture, typically consisting of 5×10 4 Rb atoms mixed with 10 6 87 Sr or 10 7 88 Sr atoms at a temperature of 2 to 5 μK (see Methods ). Figure 1 shows the observed loss features, eleven arising in the 87 Rb– 87 Sr Bose–Fermi mixture and one in the 87 Rb– 88 Sr Bose–Bose mixture. Ten loss features consist of a single, slightly asymmetrical dip with a full-width at half-maximum between 200 and 400 mG. The loss features labelled [1,0]a and [1,1]a each consist of several dips with a width of 20 to 60 mG at a spacing of 80 mG. We fit each dip with a Gaussian and give the resulting positions and widths in Table 1 . None of these Rb loss features arises in the absence of Sr, proving that they depend on Rb–Sr interactions. Fig. 1: Detection of Rb–Sr Feshbach resonances by field-dependent loss of Rb. The fraction of Rb atoms remaining in state ( f , m f ) after loss at each observed Feshbach resonance, normalized to unity far from the loss feature. Eleven loss features are observed in 87 Rb– 87 Sr mixtures and one in 87 Rb– 88 Sr (bottom right panel). The loss features are labelled by [ f , m f ] j , where $j\in$ {a,b,c} is an index used when losses due to several molecular states are observed at the same atomic threshold. Most loss features show a single dip in the atom number, whereas [1,0]a and [1,1]a show several. Each dip is fitted by a Gaussian (black line), with results shown in Table 1 . The colour and shape of symbols indicates the coupling mechanism for the Feshbach resonance: mechanism I (orange triangles), II (blue circles), or III (green squares). The resonance near 521 G also has a contribution from mechanism II. The magnetic field uncertainty is 0.4 G and the noise is less than 40 mG. Error bars represent the standard error of three or more data points. Full size image Table 1 Properties of observed Feshbach resonances Full size table Both the atomic and molecular states are described by the total angular momentum of the Rb atom, f , and its projection m f onto the magnetic field. Where necessary, atomic and molecular quantum numbers are distinguished with the subscripts at and mol. In addition, the molecule has a vibrational quantum number n , counted down from n = −1 for the uppermost level, and a rotational quantum number L , with projection M L . 88 Sr has nuclear spin i Sr = 0, whereas 87 Sr has i Sr = 9/2 and a corresponding projection m i, Sr . The Rb–Sr atom-pair states and the near-threshold molecular states lie almost parallel to the Rb atomic states as a function of magnetic field (see Supplementary Information ). We can therefore use the Breit–Rabi formula of Rb for both the atom-pair states and the molecular states. This allows us to extract zero-field binding energies E b of the molecular states responsible for the resonances, giving the values in Table 2 . The crossing atomic and molecular levels are shown in Figs. 2 and 3 , with filled symbols where we observe loss features. Table 2 Molecular states responsible for Feshbach resonances Full size table Fig. 2: Origin of the 87 Rb– 87 Sr Feshbach resonances. Energies of atomic (red)<|im_end|> <|im_start|>assistant Cooling matter is not easy. Atoms and molecules have the tendency to jump around, to rotate and to vibrate. Freezing these particles by slowing them down is a complicated process. For individual atoms, physicists have figured out over the years how to carry out this cooling process, using techniques like laser cooling, where finely tuned lasers remove energy from the particles. Molecules, on the other hand, are much harder to cool down so that they stand still. These particles consist of two or more atoms that are bound together, and as compound particles they are able to jiggle around in many more ways. First cool, then build Still, physicists would like to have a dense gas of ultracold molecules at their disposal. Since it is not yet possible to directly cool the molecules themselves into this regime, physicists first cool down atoms – a process which is much easier – and then attempt to build molecules. The question is: how does one get these super cold, motionless atoms to 'click together' to form the desired molecules? The answer to this question is a process that exploits a phenomenon known as Feshbach resonance. Molecules of a given type can exist for different configurations of the atoms' internal states, and all of these states have slightly different energies. By applying a magnetic field, the energy of an unbound atom pair can be tuned to exactly the energy of a specific molecular level. Florian Schreck, the research group leader, explains: "If a coupling mechanism between the atom pair and the molecule exists, one can create a situation in which atom pairs 'resonate' with molecules, thereby clicking together and forming the desired end product." New type of ultracold molecules So far, only gases of molecules that consist of two alkali atoms, atoms with a single electron that can form chemical bonds, have been created with the desired high density and ultracold temperature. The group of experimental physicists at the University of Amsterdam, together with theoretical physicists from Nicolaus Copernicus University in Torun, Poland and from Durham University in the UK, have now made an important step towards the creation of a second type of ultracold molecule. More precisely: they have discovered Feshbach resonances between the alkali element rubidium and the alkaline-earth element strontium, which has two electrons to form bonds with. These resonances are suitable to construct ultracold rubidium-strontium molecules, particles with very different properties from the ultracold molecules that have been constructed so far. The main challenge in this work was that the usual strong coupling mechanisms that exist between alkali atoms do not exist for alkaline-earth atoms. Eight years ago, theorists Piotr Zuchowski and Jeremy Hutson predicted very weak and unusual coupling mechanisms that would still lead to Feshbach resonances. However, the theory was unable to predict the value of the magnetic fields at which these resonances would occur. Employing precise molecular spectroscopy, the experimental team was now able to find the magnetic field values and to experimentally confirm the existence of the sought-for Feshbach resonances. Interesting applications There are several reasons why physicists are interested in creating different types of ultracold molecules. First of all, a very low temperature allows researchers to study the properties of the molecules themselves better: anyone who has ever tried to study a fly knows that this is much easier if the fly is motionless on the wall than if it is buzzing around, and the same thing is true for molecules. Precision studies of molecules could uncover fundamental physics going beyond the current standard model of fundamental particle interactions. Secondly, cold molecules can be prepared in very precise states that can then be used for quantum-controlled chemistry: performing delicate chemical reactions with full control over all aspects of the initial components and the reaction conditions. Finally, there are applications to the many-body physics of quantum particles. When molecules are very cold, their quantum fuzziness becomes apparent. Molecules can be at several locations or in several internal states at the same time and the locations or states of several molecules may depend on each other in intricate ways. New quantum phenomena can emerge, which are hard or impossible to describe using even the best supercomputers. By controlling the interactions between the molecules or the potential landscape through which they are moving, physicists hope to learn about these emergent phenomena. Schreck says: "Gaining insights into the collective behavior of many quantum particles, be it molecules in a gas or electrons in a metal, may open the door to materials with unheard of properties." The results expand the set of available tools for the 'quantum LEGO' of building ultracold molecules from atoms. Schreck: "With this knowledge, it should soon be possible for the first time to make an ultracold, high density gas of rubidium-strontium molecules. Given the number of potential applications that such a gas has, we are very excited about these new possibilities." <|im_end|>

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98417, 617, 25720, 704, 927, 279, 1667, 1268, 311, 6920, 704, 420, 28015, 1920, 11, 1701, 12823, 1093, 21120, 28015, 11, 1405, 61802, 33519, 72475, 4148, 4907, 505, 279, 19252, 13, 386, 82206, 11, 389, 279, 1023, 1450, 11, 527, 1790, 16127, 311, 7155, 1523, 779, 430, 814, 2559, 2103, 13, 4314, 19252, 6824, 315, 1403, 477, 810, 33299, 430, 527, 6965, 3871, 11, 323, 439, 24549, 19252, 814, 527, 3025, 311, 95164, 3491, 2212, 304, 1690, 810, 5627, 13, 5629, 7155, 11, 1243, 1977, 16782, 11, 98417, 1053, 1093, 311, 617, 264, 29050, 6962, 315, 37232, 582, 820, 35715, 520, 872, 34545, 13, 8876, 433, 374, 539, 3686, 3284, 311, 6089, 7155, 279, 35715, 5694, 1139, 420, 17942, 11, 98417, 1176, 7155, 1523, 33299, 1389, 264, 1920, 902, 374, 1790, 8831, 1389, 323, 1243, 4879, 311, 1977, 35715, 13, 578, 3488, 374, 25, 1268, 1587, 832, 636, 1521, 2307, 9439, 11, 11633, 1752, 33299, 311, 364, 3763, 3871, 6, 311, 1376, 279, 12974, 35715, 30, 578, 4320, 311, 420, 3488, 374, 264, 1920, 430, 63488, 264, 25885, 3967, 439, 435, 4385, 35638, 58081, 13, 386, 82206, 315, 264, 2728, 955, 649, 3073, 369, 2204, 33483, 315, 279, 33299, 6, 5419, 5415, 11, 323, 682, 315, 1521, 5415, 617, 10284, 2204, 49969, 13, 3296, 19486, 264, 24924, 2115, 11, 279, 4907, 315, 459, 653, 11130, 19670, 6857, 649, 387, 33519, 311, 7041, 279, 4907, 315, 264, 3230, 31206, 2237, 13, 97156, 5124, 25662, 11, 279, 3495, 1912, 7808, 11, 15100, 25, 330, 2746, 264, 59086, 17383, 1990, 279, 19670, 6857, 323, 279, 43030, 6866, 11, 832, 649, 1893, 264, 6671, 304, 902, 19670, 13840, 364, 417, 263, 349, 6, 449, 35715, 11, 28592, 18965, 3871, 323, 30164, 279, 12974, 842, 2027, 1210, 1561, 955, 315, 37232, 582, 820, 35715, 2100, 3117, 11, 1193, 45612, 315, 35715, 430, 6824, 315, 1403, 58998, 8115, 33299, 11, 33299, 449, 264, 3254, 17130, 430, 649, 1376, 11742, 27460, 11, 617, 1027, 3549, 449, 279, 12974, 1579, 17915, 323, 37232, 582, 820, 9499, 13, 578, 1912, 315, 22772, 98417, 520, 279, 3907, 315, 38841, 11, 3871, 449, 32887, 98417, 505, 79541, 355, 25991, 944, 59344, 3907, 304, 8611, 359, 11, 28702, 323, 505, 58814, 3907, 304, 279, 6560, 11, 617, 1457, 1903, 459, 3062, 3094, 7119, 279, 9886, 315, 264, 2132, 955, 315, 37232, 582, 820, 43030, 13, 4497, 24559, 25, 814, 617, 11352, 435, 4385, 35638, 29280, 3095, 1990, 279, 58998, 8115, 2449, 10485, 307, 2411, 323, 279, 66787, 483, 86187, 2449, 610, 546, 2411, 11, 902, 706, 1403, 57678, 311, 1376, 27460, 449, 13, 4314, 29280, 3095, 527, 14791, 311, 9429, 37232, 582, 820, 10485, 307, 2411, 42728, 546, 2411, 35715, 11, 19252, 449, 1633, 2204, 6012, 505, 279, 37232, 582, 820, 35715, 430, 617, 1027, 20968, 779, 3117, 13, 578, 1925, 8815, 304, 420, 990, 574, 430, 279, 13783, 3831, 59086, 24717, 430, 3073, 1990, 58998, 8115, 33299, 656, 539, 3073, 369, 66787, 483, 86187, 33299, 13, 36944, 1667, 4227, 11, 84062, 393, 11345, 81, 1901, 1412, 29384, 323, 28217, 67413, 942, 19698, 1633, 7621, 323, 19018, 59086, 24717, 430, 1053, 2103, 3063, 311, 435, 4385, 35638, 29280, 3095, 13, 4452, 11, 279, 10334, 574, 12153, 311, 7168, 279, 907, 315, 279, 24924, 5151, 520, 902, 1521, 29280, 3095, 1053, 12446, 13, 21445, 287, 24473, 31206, 66425, 51856, 11, 279, 22772, 2128, 574, 1457, 3025, 311, 1505, 279, 24924, 2115, 2819, 323, 311, 9526, 750, 7838, 279, 14209, 315, 279, 16495, 15548, 435, 4385, 35638, 29280, 3095, 13, 71770, 8522, 2684, 527, 3892, 8125, 3249, 98417, 527, 8173, 304, 6968, 2204, 4595, 315, 37232, 582, 820, 35715, 13, 5629, 315, 682, 11, 264, 1633, 3428, 9499, 6276, 12074, 311, 4007, 279, 6012, 315, 279, 35715, 5694, 2731, 25, 5606, 889, 706, 3596, 6818, 311, 4007, 264, 11722, 8964, 430, 420, 374, 1790, 8831, 422, 279, 11722, 374, 11633, 1752, 389, 279, 7147, 1109, 422, 433, 374, 86424, 2212, 11, 323, 279, 1890, 3245, 374, 837, 369, 35715, 13, 52459, 7978, 315, 35715, 1436, 45063, 16188, 22027, 2133, 7953, 279, 1510, 5410, 1646, 315, 16188, 19320, 22639, 13, 72131, 11, 9439, 35715, 649, 387, 10235, 304, 1633, 24473, 5415, 430, 649, 1243, 387, 1511, 369, 31228, 41370, 30903, 25, 16785, 36301, 11742, 25481, 449, 2539, 2585, 927, 682, 13878, 315, 279, 2926, 6956, 323, 279, 13010, 4787, 13, 17830, 11, 1070, 527, 8522, 311, 279, 1690, 9534, 22027, 315, 31228, 19252, 13, 3277, 35715, 527, 1633, 9439, 11, 872, 31228, 77242, 1918, 9221, 10186, 13, 386, 82206, 649, 387, 520, 3892, 10687, 477, 304, 3892, 5419, 5415, 520, 279, 1890, 892, 323, 279, 10687, 477, 5415, 315, 3892, 35715, 1253, 6904, 389, 1855, 1023, 304, 57216, 5627, 13, 1561, 31228, 44247, 649, 34044, 11, 902, 527, 2653, 477, 12266, 311, 7664, 1701, 1524, 279, 1888, 2307, 66047, 388, 13, 3296, 26991, 279, 22639, 1990, 279, 35715, 477, 279, 4754, 18921, 1555, 902, 814, 527, 7366, 11, 98417, 3987, 311, 4048, 922, 1521, 7425, 306, 44247, 13, 5124, 25662, 2795, 25, 330, 38, 2101, 26793, 1139, 279, 22498, 7865, 315, 1690, 31228, 19252, 11, 387, 433, 35715, 304, 264, 6962, 477, 57678, 304, 264, 9501, 11, 1253, 1825, 279, 6134, 311, 7384, 449, 86560, 315, 6012, 1210, 578, 3135, 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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 Genome sequencing has uncovered a new mutational phenomenon in cancer and congenital disorders called chromothripsis. Chromothripsis is characterized by extensive genomic rearrangements and an oscillating pattern of DNA copy number levels, all curiously restricted to one or a few chromosomes. The mechanism for chromothripsis is unknown, but we previously proposed that it could occur through the physical isolation of chromosomes in aberrant nuclear structures called micronuclei. Here, using a combination of live cell imaging and single-cell genome sequencing, we demonstrate that micronucleus formation can indeed generate a spectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis. These events are restricted to the mis-segregated chromosome and occur within one cell division. We demonstrate that the mechanism for chromothripsis can involve the fragmentation and subsequent reassembly of a single chromatid from a micronucleus. Collectively, these experiments establish a new mutational process of which chromothripsis is one extreme outcome. Main Most cancer genomes are extensively altered by point mutations and chromosome rearrangements. Although mutations are generally thought to accumulate gradually, over many cell division cycles 1 , 2 , recent cancer genome sequencing provides evidence for mutational processes that generate multiple mutations “all-at-once” during a single cell cycle 3 . The most striking example of such an event is “chromothripsis”, where a unique pattern of clustered rearrangements occurs, typically involving only a single chromosome or a few chromosomes 4 , 5 , 6 , 7 . Several models have been proposed to explain the rearrangements in chromothripsis. One proposal is that the affected chromosome is somehow fragmented, with random joining of some segments and loss of others 4 . This model explains the characteristic pattern of DNA copy number in chromothripsis—oscillation between two copy number states, with islands of DNA retention and heterozygosity interspersed with regions of DNA loss. An alternative hypothesis is that chromothripsis is generated by DNA replication errors: collapsed replication forks trigger cycles of microhomology-mediated break-induced replication (MMBIR), where distal sequences are copied to the sites of replication fork collapse by template-switching 8 . Evidence for the latter model comes from templated insertions detected at translocation junctions and sequence triplications 8 , 9 . Both models have only indirect support from genomic sequencing and have not been tested experimentally 10 . We recently proposed that the physical isolation of chromosomes in aberrant nuclear structures called micronuclei might explain the localization of DNA lesions in chromothripsis 11 . Micronuclei are a common outcome of many cell division defects, including mitotic errors that mis-segregate intact chromosomes, and errors in DNA replication or repair that generate acentric chromosome fragments 12 , 13 . We previously found that the partitioning of intact chromosomes into newly formed micronuclei leads to cytological evidence of DNA damage, specifically on the mis-segregated chromosome 11 . After mitosis, chromosomes from micronuclei can be reincorporated into daughter nuclei 11 , potentially integrating mutations from the micronucleus into the genome. Here, using an approach combining live cell imaging with single-cell genomic analysis that we call ‘Look-Seq’, we demonstrate that micronucleus formation can generate a spectrum of complex chromosomal rearrangements, providing the first direct experimental evidence for a mechanism leading to chromothripsis. Damage to micronuclei after S phase entry To determine if micronucleus formation leads to chromosome rearrangements, we first sought to clarify the cell population where rearrangements would most likely occur. Previously, we found that newly-formed micronuclei do not have marked levels of DNA damage in G1, but damaged micronuclei accumulate as cells progress into the S and G2 phases of the cell cycle 11 , suggesting a link between DNA damage and DNA replication. Additionally or alternatively, the nuclear envelopes of micronuclei are prone to irreversible “rupture” as defined by the abrupt loss of soluble nuclear proteins 14 . Nuclear envelope rupture in micronuclei is strongly associated with DNA damage, but occurs at random, not specifically during S phase 14 . To re-examine the timing of DNA damage, micronuclei were generated in synchronized cells by a nocodazole release procedure 11 . As expected 11 , 14 , no significant DNA damage was detected in ruptured micronuclei during G1, but damage was common during S and G2 phases as indicated by fluorescence labelling for γ-H2AX or Gam, a bacteriophage protein that marks double strand breaks 15 ( Extended Data Fig. 1a, b ). Moreover, micronuclei from serum-starved G0 cells showed little detectable DNA damage, despite rupture of the micronuclear envelope during G0 14 ( Extended Data Fig. 1c ). Therefore, DNA damage is not triggered by nuclear envelope rupture alone, but also requires entry into S phase. Consistent with this conclusion, cell labelling with 5-ethynyl-2′-deoxyuridine (EdU) demonstrated that most damaged micronuclei had initiated DNA replication ( Extended Data Fig. 1d ). However, overall EdU incorporation was markedly lower in micronuclei compared to the cell’s primary nucleus, irrespective of whether the micronuclei were ruptured or intact 11 , 14 ( Fig. 1a ). Thus, chromosomes in micronuclei are under-replicated in general, even though the majority of the damaged micronuclei have initiated DNA replication. These results focused the experiments below on micronuclei that rupture after S phase entry. Figure 1: Look-Seq procedure to analyse DNA damage from the under-replicated chromosomes in micronuclei. a , Reduced DNA replication in both intact and ruptured micronuclei. Left, fluorescence intensity measurements after continuous EdU labelling following release from a nocodazole block. EdU intensity is normalized to nuclear area ( N > 100 from two experiments for each category, see Methods). Red bars, mean and standard deviation. b , Look-Seq strategy. Nuclei are labelled with green fluorescent protein-conjugated histone H2B (GFP–H2B). Disruption of the micronuclear envelope is visualized by the loss of a nuclear localized red fluorescent protein (RFP–NLS); reincorporation of the micronucleus is inferred from the absence of micronuclei in either G1 daughter. PowerPoint slide Full size image Look-Seq strategy We designed a procedure to determine the genomic consequences of DNA damage in ruptured micronuclei ( Fig. 1b ). Non-transformed human RPE-1 cells were synchronized by nocodazole release, sorted into 384 well", "role": "user" }, { "content": "Surveys of the genomic terrain of cancer have turned up a curious phenomenon in some tumor cells: a massive rearrangement of DNA in one or a few chromosomes, thought to be produced during a single cell cycle. In a new study, scientists at Dana-Farber Cancer Institute demonstrate how this sudden, isolated shuffling of genetic material - known as chromothripsis - can occur. The discovery was made using live video images of single cells and technology for sequencing the genomes of those cells - a combination researchers dubbed Look-Seq (pronounced \"look-seek\"). The technique makes it possible for scientists to see how changes in specific genes or chromosomes affect cell behavior - critical information for understanding how genes function. \"Only three to five percent of cancer cells show signs of chromothripsis, but the mechanism by which it occurs has been a puzzle,\" said David Pellman, MD, of Dana-Farber, the Broad Institute of Harvard and MIT, and the Howard Hughes Medical Institute, the senior author of the new paper, published in Nature. \"The cells have two distinctive features: a broad disarray in the genetic material of a single chromosome or a few chromosomes, as if the DNA was shredded and haphazardly stitched together; and an odd 'notched' pattern of the amount of DNA in the affected chromosome - where sections containing a full complement of DNA alternate with sections where DNA copies have been lost. \"The question has been whether this could happen in a Darwinian way, with a slow acquisition of changes over a number of cell divisions,\" Pellman continued. \"The evidence, however, points to an all-at-once event.\" In the study Pellman and his colleagues trace chromothripsis to a glitch in cell division that can cause one of the newly formed daughter cells to be short one chromosome, while the other daughter cell inherits an extra one. The surplus chromosome doesn't always join the other chromosomes in the cell nucleus; often, it's stranded elsewhere in the cell and acquires its own tiny membrane, forming a \"micronucleus.\" After cell division, the micronucleus can rupture, potentially exposing the chromosome inside to damage. The chromosome is then absorbed into the nucleus, knitting its imperfect DNA into the cell's genetic programming. In theory, a micronucleus would make a perfect setting for the process of chromothripsis to unfold. The release of a single chromosome from a shattered micronucleus could cause that chromosome - and only that chromosome - to undergo DNA damage. The chromosome might lose some bits of DNA, while the remaining bits are stitched together haphazardly. Such random reassembly could account for the unusual fluctuation in the number of copies of DNA in a single chromosome in the affected cell. \"The formation and breakdown of a micronucleus would seem to satisfy all the conditions by which chromothripsis could occur,\" Pellman said. To see if it in fact explains what happens in cancer cells, he and his colleagues set out to recreate chromothripsis in the lab. The researchers treated cells with a drug that can spur the formation of micronuclei. They collected the ones that actually developed a micronucleus and viewed live images of them under a microscope - the \"Look\" part of Look-Seq. This enabled them to identify cells where the micronucleus ruptured at a key stage of the cell life cycle. After these cells had divided one time, researchers sorted through the pairs of daughter cells to find ones that didn't have a micronucleus. In such cells, the chromosome that had once been quarantined within the micronucleus had presumably escaped as the micronucleus burst, and rejoined its fellow chromosomes in the cell nucleus. The micronucleus-less cells were then genetically sequenced - their strings of DNA read letter by letter. This constitutes the \"Seq\" part of Look-Seq, which was developed in collaboration with Matthew Meyerson, MD, PhD, of Dana-Farber and the Broad Institute. If chromothripsis does arise as a result of the formation and destruction of a micronucleus, as researchers theorized, it should occur in only one of a cell's two daughters - the one that inherits a chromosome formerly wrapped in a micronucleus. The affected daughter cell, therefore, would have more copies of certain DNA sections than its sister cell does. When Pellman's team genetically sequenced pairs of daughter cells from nine cells with micronuclei, they found precisely this imbalance: one member of each pair had at least one chromosome with extra copies of DNA at some locations, while the other member did not. The researchers then tested their prediction that DNA rearrangements would be confined to the chromosome that was once AWOL and had later reunited with its mates. They found that, in eight of the nine pairs of daughter cells whose DNA had been sequenced, such rearrangements were indeed concentrated in that particular chromosome. \"By forcing cells to develop micronuclei, we derived daughter cells that recapitulate all the features seen in chromothripsis,\" said Pellman. \"This is compelling evidence that this process is a major mechanism by which chromothripsis occurs in some cancers. \"The findings support our lab's earlier research showing that the incorrect segregation of intact chromosomes prior to cell division can produce rearrangements of DNA that result in genetic mutations - potentially playing a role in cancer development,\" he continued. \"We also show that the Look-Seq technique is a powerful way of exploring the connection between genetic and molecular change and cell behavior.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 sequencing has uncovered a new mutational phenomenon in cancer and congenital disorders called chromothripsis. Chromothripsis is characterized by extensive genomic rearrangements and an oscillating pattern of DNA copy number levels, all curiously restricted to one or a few chromosomes. The mechanism for chromothripsis is unknown, but we previously proposed that it could occur through the physical isolation of chromosomes in aberrant nuclear structures called micronuclei. Here, using a combination of live cell imaging and single-cell genome sequencing, we demonstrate that micronucleus formation can indeed generate a spectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis. These events are restricted to the mis-segregated chromosome and occur within one cell division. We demonstrate that the mechanism for chromothripsis can involve the fragmentation and subsequent reassembly of a single chromatid from a micronucleus. Collectively, these experiments establish a new mutational process of which chromothripsis is one extreme outcome. Main Most cancer genomes are extensively altered by point mutations and chromosome rearrangements. Although mutations are generally thought to accumulate gradually, over many cell division cycles 1 , 2 , recent cancer genome sequencing provides evidence for mutational processes that generate multiple mutations “all-at-once” during a single cell cycle 3 . The most striking example of such an event is “chromothripsis”, where a unique pattern of clustered rearrangements occurs, typically involving only a single chromosome or a few chromosomes 4 , 5 , 6 , 7 . Several models have been proposed to explain the rearrangements in chromothripsis. One proposal is that the affected chromosome is somehow fragmented, with random joining of some segments and loss of others 4 . This model explains the characteristic pattern of DNA copy number in chromothripsis—oscillation between two copy number states, with islands of DNA retention and heterozygosity interspersed with regions of DNA loss. An alternative hypothesis is that chromothripsis is generated by DNA replication errors: collapsed replication forks trigger cycles of microhomology-mediated break-induced replication (MMBIR), where distal sequences are copied to the sites of replication fork collapse by template-switching 8 . Evidence for the latter model comes from templated insertions detected at translocation junctions and sequence triplications 8 , 9 . Both models have only indirect support from genomic sequencing and have not been tested experimentally 10 . We recently proposed that the physical isolation of chromosomes in aberrant nuclear structures called micronuclei might explain the localization of DNA lesions in chromothripsis 11 . Micronuclei are a common outcome of many cell division defects, including mitotic errors that mis-segregate intact chromosomes, and errors in DNA replication or repair that generate acentric chromosome fragments 12 , 13 . We previously found that the partitioning of intact chromosomes into newly formed micronuclei leads to cytological evidence of DNA damage, specifically on the mis-segregated chromosome 11 . After mitosis, chromosomes from micronuclei can be reincorporated into daughter nuclei 11 , potentially integrating mutations from the micronucleus into the genome. Here, using an approach combining live cell imaging with single-cell genomic analysis that we call ‘Look-Seq’, we demonstrate that micronucleus formation can generate a spectrum of complex chromosomal rearrangements, providing the first direct experimental evidence for a mechanism leading to chromothripsis. Damage to micronuclei after S phase entry To determine if micronucleus formation leads to chromosome rearrangements, we first sought to clarify the cell population where rearrangements would most likely occur. Previously, we found that newly-formed micronuclei do not have marked levels of DNA damage in G1, but damaged micronuclei accumulate as cells progress into the S and G2 phases of the cell cycle 11 , suggesting a link between DNA damage and DNA replication. Additionally or alternatively, the nuclear envelopes of micronuclei are prone to irreversible “rupture” as defined by the abrupt loss of soluble nuclear proteins 14 . Nuclear envelope rupture in micronuclei is strongly associated with DNA damage, but occurs at random, not specifically during S phase 14 . To re-examine the timing of DNA damage, micronuclei were generated in synchronized cells by a nocodazole release procedure 11 . As expected 11 , 14 , no significant DNA damage was detected in ruptured micronuclei during G1, but damage was common during S and G2 phases as indicated by fluorescence labelling for γ-H2AX or Gam, a bacteriophage protein that marks double strand breaks 15 ( Extended Data Fig. 1a, b ). Moreover, micronuclei from serum-starved G0 cells showed little detectable DNA damage, despite rupture of the micronuclear envelope during G0 14 ( Extended Data Fig. 1c ). Therefore, DNA damage is not triggered by nuclear envelope rupture alone, but also requires entry into S phase. Consistent with this conclusion, cell labelling with 5-ethynyl-2′-deoxyuridine (EdU) demonstrated that most damaged micronuclei had initiated DNA replication ( Extended Data Fig. 1d ). However, overall EdU incorporation was markedly lower in micronuclei compared to the cell’s primary nucleus, irrespective of whether the micronuclei were ruptured or intact 11 , 14 ( Fig. 1a ). Thus, chromosomes in micronuclei are under-replicated in general, even though the majority of the damaged micronuclei have initiated DNA replication. These results focused the experiments below on micronuclei that rupture after S phase entry. Figure 1: Look-Seq procedure to analyse DNA damage from the under-replicated chromosomes in micronuclei. a , Reduced DNA replication in both intact and ruptured micronuclei. Left, fluorescence intensity measurements after continuous EdU labelling following release from a nocodazole block. EdU intensity is normalized to nuclear area ( N > 100 from two experiments for each category, see Methods). Red bars, mean and standard deviation. b , Look-Seq strategy. Nuclei are labelled with green fluorescent protein-conjugated histone H2B (GFP–H2B). Disruption of the micronuclear envelope is visualized by the loss of a nuclear localized red fluorescent protein (RFP–NLS); reincorporation of the micronucleus is inferred from the absence of micronuclei in either G1 daughter. PowerPoint slide Full size image Look-Seq strategy We designed a procedure to determine the genomic consequences of DNA damage in ruptured micronuclei ( Fig. 1b ). Non-transformed human RPE-1 cells were synchronized by nocodazole release, sorted into 384 well<|im_end|> <|im_start|>assistant Surveys of the genomic terrain of cancer have turned up a curious phenomenon in some tumor cells: a massive rearrangement of DNA in one or a few chromosomes, thought to be produced during a single cell cycle. In a new study, scientists at Dana-Farber Cancer Institute demonstrate how this sudden, isolated shuffling of genetic material - known as chromothripsis - can occur. The discovery was made using live video images of single cells and technology for sequencing the genomes of those cells - a combination researchers dubbed Look-Seq (pronounced "look-seek"). The technique makes it possible for scientists to see how changes in specific genes or chromosomes affect cell behavior - critical information for understanding how genes function. "Only three to five percent of cancer cells show signs of chromothripsis, but the mechanism by which it occurs has been a puzzle," said David Pellman, MD, of Dana-Farber, the Broad Institute of Harvard and MIT, and the Howard Hughes Medical Institute, the senior author of the new paper, published in Nature. "The cells have two distinctive features: a broad disarray in the genetic material of a single chromosome or a few chromosomes, as if the DNA was shredded and haphazardly stitched together; and an odd 'notched' pattern of the amount of DNA in the affected chromosome - where sections containing a full complement of DNA alternate with sections where DNA copies have been lost. "The question has been whether this could happen in a Darwinian way, with a slow acquisition of changes over a number of cell divisions," Pellman continued. "The evidence, however, points to an all-at-once event." In the study Pellman and his colleagues trace chromothripsis to a glitch in cell division that can cause one of the newly formed daughter cells to be short one chromosome, while the other daughter cell inherits an extra one. The surplus chromosome doesn't always join the other chromosomes in the cell nucleus; often, it's stranded elsewhere in the cell and acquires its own tiny membrane, forming a "micronucleus." After cell division, the micronucleus can rupture, potentially exposing the chromosome inside to damage. The chromosome is then absorbed into the nucleus, knitting its imperfect DNA into the cell's genetic programming. In theory, a micronucleus would make a perfect setting for the process of chromothripsis to unfold. The release of a single chromosome from a shattered micronucleus could cause that chromosome - and only that chromosome - to undergo DNA damage. The chromosome might lose some bits of DNA, while the remaining bits are stitched together haphazardly. Such random reassembly could account for the unusual fluctuation in the number of copies of DNA in a single chromosome in the affected cell. "The formation and breakdown of a micronucleus would seem to satisfy all the conditions by which chromothripsis could occur," Pellman said. To see if it in fact explains what happens in cancer cells, he and his colleagues set out to recreate chromothripsis in the lab. The researchers treated cells with a drug that can spur the formation of micronuclei. They collected the ones that actually developed a micronucleus and viewed live images of them under a microscope - the "Look" part of Look-Seq. This enabled them to identify cells where the micronucleus ruptured at a key stage of the cell life cycle. After these cells had divided one time, researchers sorted through the pairs of daughter cells to find ones that didn't have a micronucleus. In such cells, the chromosome that had once been quarantined within the micronucleus had presumably escaped as the micronucleus burst, and rejoined its fellow chromosomes in the cell nucleus. The micronucleus-less cells were then genetically sequenced - their strings of DNA read letter by letter. This constitutes the "Seq" part of Look-Seq, which was developed in collaboration with Matthew Meyerson, MD, PhD, of Dana-Farber and the Broad Institute. If chromothripsis does arise as a result of the formation and destruction of a micronucleus, as researchers theorized, it should occur in only one of a cell's two daughters - the one that inherits a chromosome formerly wrapped in a micronucleus. The affected daughter cell, therefore, would have more copies of certain DNA sections than its sister cell does. When Pellman's team genetically sequenced pairs of daughter cells from nine cells with micronuclei, they found precisely this imbalance: one member of each pair had at least one chromosome with extra copies of DNA at some locations, while the other member did not. The researchers then tested their prediction that DNA rearrangements would be confined to the chromosome that was once AWOL and had later reunited with its mates. They found that, in eight of the nine pairs of daughter cells whose DNA had been sequenced, such rearrangements were indeed concentrated in that particular chromosome. "By forcing cells to develop micronuclei, we derived daughter cells that recapitulate all the features seen in chromothripsis," said Pellman. "This is compelling evidence that this process is a major mechanism by which chromothripsis occurs in some cancers. "The findings support our lab's earlier research showing that the incorrect segregation of intact chromosomes prior to cell division can produce rearrangements of DNA that result in genetic mutations - potentially playing a role in cancer development," he continued. "We also show that the Look-Seq technique is a powerful way of exploring the connection between genetic and molecular change and cell behavior." <|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 Evidence suggests that spironolactone, a nonselective mineralocorticoid receptor (MR) antagonist, modulates alcohol seeking and consumption. Therefore, spironolactone may represent a novel pharmacotherapy for alcohol use disorder (AUD). In this study, we tested the effects of spironolactone in a mouse model of alcohol drinking (drinking-in-the-dark) and in a rat model of alcohol dependence (vapor exposure). We also investigated the association between spironolactone receipt for at least 60 continuous days and change in self-reported alcohol consumption, using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), in a pharmacoepidemiologic cohort study in the largest integrated healthcare system in the US. Spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in male and female mice. No effects of spironolactone were observed on drinking of a sweet solution without alcohol, food or water intake, motor coordination, alcohol-induced ataxia, or blood alcohol levels. Spironolactone dose-dependently reduced operant alcohol self-administration in dependent and nondependent male and female rats. In humans, a greater reduction in alcohol consumption was observed among those who received spironolactone, compared to propensity score-matched individuals who did not receive spironolactone. The largest effects were among those who reported hazardous/heavy episodic alcohol consumption at baseline (AUDIT-C ≥ 8) and those exposed to ≥ 50 mg/day of spironolactone. These convergent findings across rodent and human studies demonstrate that spironolactone reduces alcohol use and support the hypothesis that this medication may be further studied as a novel pharmacotherapy for AUD. Introduction Alcohol use disorder (AUD) is a chronic relapsing brain disorder leading to high mortality, morbidity, and economic burden [ 1 ]. Compared to other chronic illnesses, currently available medications for AUD are limited. Therefore, there is a critical need to increase the armamentarium of pharmacotherapies to treat individuals with AUD [ 2 ]. Neuroendocrine systems involved in alcohol craving and drinking offer promising pharmacologic targets in this regard [ 3 , 4 ]. The steroid hormone aldosterone and its related mineralocorticoid receptor (MR) regulate fluid and electrolyte homeostasis. In response to decreased blood volume and/or blood pressure, aldosterone is secreted from the cortex of the adrenal gland and binds to MRs located in the principal cells of the kidney. This action facilitates sodium and water reabsorption into the blood and increases blood pressure. MRs are also expressed in brain regions involved in AUD, including the amygdala, prefrontal cortex, and hippocampus [ 5 , 6 , 7 , 8 ], and modulate processes such as memory formation, fear extinction/recall, and stress responses [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Preliminary clinical and preclinical studies suggest that aldosterone and the MR play a role in alcohol seeking and consumption [ 17 ]. We previously reported that blood aldosterone concentrations are significantly decreased in actively drinking individuals with AUD who maintained alcohol abstinence during a 12-week outpatient follow-up [ 18 ]. Aldosterone levels positively correlated with self-reported alcohol craving and anxiety [ 18 ]. More recently, we provided evidence supporting the role of this endocrine system in alcohol use across three species [ 19 ]. In an alcohol self-administration model in monkeys, blood aldosterone levels increased from baseline to 6 and 12 months, and the MR gene ( Nr3c2 ) expression levels in the central nucleus of the amygdala (CeA) were negatively correlated with average alcohol intake. The study also found a negative correlation between Nr3c2 expression in the CeA and measures of anxiety-like behavior and compulsive-like drinking in alcohol-dependent rats. In a second, 12-week clinical study, participants who remained alcohol abstinent, compared to those not abstinent, had lower blood aldosterone concentrations at the endpoint, and aldosterone levels positively correlated with the amount of drinking, alcohol craving, and anxiety in the non-abstinent group [ 19 ]. Collectively, these data suggest that higher MR signaling contributes to increased alcohol consumption, and medications that block MR may represent a novel pharmacotherapeutic approach for AUD. Spironolactone is an FDA-approved MR antagonist medication used to treat essential hypertension, heart failure, edema, primary hyperaldosteronism, and hypokalemia. Spironolactone has been tested in preclinical studies of alcohol drinking and seeking with inconsistent results. Systemic or intracerebroventricular administration of spironolactone, or the MR antagonist RU28318, did not reduce alcohol drinking in male rats [ 20 , 21 ] or mice of both sexes [ 22 ] tested on a continuous (24 h) two-bottle (water vs. alcohol) choice model nor on a limited (1 h) two-bottle choice model following fluid restriction [ 23 ]. Limitations of these studies included low blood alcohol concentration achieved with continuous two-bottle choice models and a “physiological fluid need” (i.e., water restriction) [ 24 ]. However, Kashkin et al. reported that seven days of oral spironolactone treatment decreased alcohol drinking (and blood pressure) in high drinking, but not low drinking, male rats given continuous two-bottle choice access [ 25 ]. More recently, following the renewed interest in the aldosterone/MR pathway in AUD [ 19 ], Makhijani et al. reported that systemic injection of spironolactone reduced operant alcohol self-administration in both male and female rats, and suppressed the persistence of alcohol responding under an extinction condition in female rats [ 26 ]. However, spironolactone decreased general locomotion, especially in males, and this may have affected responding for alcohol. In a follow-up study, Makhijani and colleagues found that MR antagonism with eplerenone or MR knockdown in the CeA transiently reduced alcohol self-administration in female rats [ 27 ]. Given these promising but inconsistent results, additional studies are needed to better understand the pharmacologic potential of spironolactone in reducing alcohol consumption under different experimental settings, including binge-like and alcohol dependence-associated drinking. Additionally, studies are needed to determine to what extent spironolactone, per se or in combination with alcohol, impairs locomotion and motor coordination, and whether there is an interaction between spironolactone and alcohol pharmacokinetics. Finally, initial bench-to-bedside translation of the potential role of spironolactone in AUD is critically needed. We recently conducted a pharmacoepidemiologic study, using electronic health record data from Kaiser Permanente Northern California. Over 500 individuals treated with spironolactone, for any indication,", "role": "user" }, { "content": "A medication for heart problems and high blood pressure may also be effective for treating alcohol use disorder, according to a new study by researchers at the National Institutes of Health and their colleagues. The study presents converging evidence from experiments in mice and rats, as well as a cohort study in humans, suggesting that the medication, spironolactone, may play a role in reducing alcohol drinking. The research was led by scientists at the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA), both parts of NIH, and Yale School of Medicine, New Haven, Connecticut. A report of the new findings is published in Molecular Psychiatry. \"Combining findings across three species and different types of research studies, and then seeing similarities in those data, gives us confidence that we are onto something potentially important scientifically and clinically. These findings support further study of spironolactone as a potential treatment for alcohol use disorder, a medical condition that affects millions of people in the U.S,\" said Lorenzo Leggio, M.D., Ph.D., chief of the Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, a joint laboratory of NIDA and NIAAA, and one of the senior authors. Currently there are three medications approved for alcohol use disorder in the United States, and they are an effective and important aid in the treatment of people with this condition. Given the diverse biological processes that contribute to alcohol use disorder, new medications are needed to provide a broader spectrum of treatment options. Scientists are working to develop a larger menu of pharmaceutical treatments that could be tailored to individual needs. Previous research has shown that mineralocorticoid receptors, which are located throughout the brain and other organs and help regulate fluid and electrolyte balance in the body, might play a role in alcohol use and craving. Preclinical research suggests that higher mineralocorticoid receptor signaling contributes to increased alcohol consumption. The current study sought to expand this line of research by testing spironolactone, a medication with multiple actions, including blocking mineralocorticoid receptors. Spironolactone is used in clinical practice as a diuretic and to treat conditions like heart problems and high blood pressure. In experiments conducted in mouse and rat models of excessive alcohol drinking, NIAAA and NIDA researchers led by co-senior author Leandro Vendruscolo, Pharm.D., Ph.D., from NIDA found that increasing doses of spironolactone decreased alcohol consumption in male and female animals, without causing movement or coordination problems, and without affecting their food or water intake. In a parallel study that was part of this team's collaborative efforts, researchers led by co-senior author Amy C. Justice, M.D., Ph.D., of the Yale School of Medicine, examined health records of a large sample of people from the U.S. Veterans Affairs healthcare system to assess potential changes in alcohol drinking after spironolactone was prescribed for its current clinical indications (e.g., heart problems, high blood pressure). They found a significant association between spironolactone treatment and reduction in self-reported alcohol consumption, as measured by the Alcohol Use Disorders Identification Test-Consumption, a screening tool. Of note, the largest effects were observed among those who reported hazardous/heavy episodic alcohol consumption before starting spironolactone treatment. \"These are very encouraging findings,\" said NIAAA Director George F. Koob, Ph.D., a co-author of the study. \"Taken together, the present study argues for conducting randomized, controlled studies of spironolactone in people with alcohol use disorder to further assess its safety and potential efficacy in this population, as well as additional work to understand how spironolactone may reduce alcohol drinking.\" \"Just like for any other medical condition, people with substance use disorders deserve to have a range of treatment options available to them, and this study is an exciting step in our effort to expand medications for people with alcohol use disorder,\" said Nora Volkow, M.D., director of NIDA. \"In addition, we must address the stigma and other barriers that prevent many people with alcohol use disorder from accessing the treatments we already have available.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Evidence suggests that spironolactone, a nonselective mineralocorticoid receptor (MR) antagonist, modulates alcohol seeking and consumption. Therefore, spironolactone may represent a novel pharmacotherapy for alcohol use disorder (AUD). In this study, we tested the effects of spironolactone in a mouse model of alcohol drinking (drinking-in-the-dark) and in a rat model of alcohol dependence (vapor exposure). We also investigated the association between spironolactone receipt for at least 60 continuous days and change in self-reported alcohol consumption, using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), in a pharmacoepidemiologic cohort study in the largest integrated healthcare system in the US. Spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in male and female mice. No effects of spironolactone were observed on drinking of a sweet solution without alcohol, food or water intake, motor coordination, alcohol-induced ataxia, or blood alcohol levels. Spironolactone dose-dependently reduced operant alcohol self-administration in dependent and nondependent male and female rats. In humans, a greater reduction in alcohol consumption was observed among those who received spironolactone, compared to propensity score-matched individuals who did not receive spironolactone. The largest effects were among those who reported hazardous/heavy episodic alcohol consumption at baseline (AUDIT-C ≥ 8) and those exposed to ≥ 50 mg/day of spironolactone. These convergent findings across rodent and human studies demonstrate that spironolactone reduces alcohol use and support the hypothesis that this medication may be further studied as a novel pharmacotherapy for AUD. Introduction Alcohol use disorder (AUD) is a chronic relapsing brain disorder leading to high mortality, morbidity, and economic burden [ 1 ]. Compared to other chronic illnesses, currently available medications for AUD are limited. Therefore, there is a critical need to increase the armamentarium of pharmacotherapies to treat individuals with AUD [ 2 ]. Neuroendocrine systems involved in alcohol craving and drinking offer promising pharmacologic targets in this regard [ 3 , 4 ]. The steroid hormone aldosterone and its related mineralocorticoid receptor (MR) regulate fluid and electrolyte homeostasis. In response to decreased blood volume and/or blood pressure, aldosterone is secreted from the cortex of the adrenal gland and binds to MRs located in the principal cells of the kidney. This action facilitates sodium and water reabsorption into the blood and increases blood pressure. MRs are also expressed in brain regions involved in AUD, including the amygdala, prefrontal cortex, and hippocampus [ 5 , 6 , 7 , 8 ], and modulate processes such as memory formation, fear extinction/recall, and stress responses [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Preliminary clinical and preclinical studies suggest that aldosterone and the MR play a role in alcohol seeking and consumption [ 17 ]. We previously reported that blood aldosterone concentrations are significantly decreased in actively drinking individuals with AUD who maintained alcohol abstinence during a 12-week outpatient follow-up [ 18 ]. Aldosterone levels positively correlated with self-reported alcohol craving and anxiety [ 18 ]. More recently, we provided evidence supporting the role of this endocrine system in alcohol use across three species [ 19 ]. In an alcohol self-administration model in monkeys, blood aldosterone levels increased from baseline to 6 and 12 months, and the MR gene ( Nr3c2 ) expression levels in the central nucleus of the amygdala (CeA) were negatively correlated with average alcohol intake. The study also found a negative correlation between Nr3c2 expression in the CeA and measures of anxiety-like behavior and compulsive-like drinking in alcohol-dependent rats. In a second, 12-week clinical study, participants who remained alcohol abstinent, compared to those not abstinent, had lower blood aldosterone concentrations at the endpoint, and aldosterone levels positively correlated with the amount of drinking, alcohol craving, and anxiety in the non-abstinent group [ 19 ]. Collectively, these data suggest that higher MR signaling contributes to increased alcohol consumption, and medications that block MR may represent a novel pharmacotherapeutic approach for AUD. Spironolactone is an FDA-approved MR antagonist medication used to treat essential hypertension, heart failure, edema, primary hyperaldosteronism, and hypokalemia. Spironolactone has been tested in preclinical studies of alcohol drinking and seeking with inconsistent results. Systemic or intracerebroventricular administration of spironolactone, or the MR antagonist RU28318, did not reduce alcohol drinking in male rats [ 20 , 21 ] or mice of both sexes [ 22 ] tested on a continuous (24 h) two-bottle (water vs. alcohol) choice model nor on a limited (1 h) two-bottle choice model following fluid restriction [ 23 ]. Limitations of these studies included low blood alcohol concentration achieved with continuous two-bottle choice models and a “physiological fluid need” (i.e., water restriction) [ 24 ]. However, Kashkin et al. reported that seven days of oral spironolactone treatment decreased alcohol drinking (and blood pressure) in high drinking, but not low drinking, male rats given continuous two-bottle choice access [ 25 ]. More recently, following the renewed interest in the aldosterone/MR pathway in AUD [ 19 ], Makhijani et al. reported that systemic injection of spironolactone reduced operant alcohol self-administration in both male and female rats, and suppressed the persistence of alcohol responding under an extinction condition in female rats [ 26 ]. However, spironolactone decreased general locomotion, especially in males, and this may have affected responding for alcohol. In a follow-up study, Makhijani and colleagues found that MR antagonism with eplerenone or MR knockdown in the CeA transiently reduced alcohol self-administration in female rats [ 27 ]. Given these promising but inconsistent results, additional studies are needed to better understand the pharmacologic potential of spironolactone in reducing alcohol consumption under different experimental settings, including binge-like and alcohol dependence-associated drinking. Additionally, studies are needed to determine to what extent spironolactone, per se or in combination with alcohol, impairs locomotion and motor coordination, and whether there is an interaction between spironolactone and alcohol pharmacokinetics. Finally, initial bench-to-bedside translation of the potential role of spironolactone in AUD is critically needed. We recently conducted a pharmacoepidemiologic study, using electronic health record data from Kaiser Permanente Northern California. Over 500 individuals treated with spironolactone, for any indication,<|im_end|> <|im_start|>assistant A medication for heart problems and high blood pressure may also be effective for treating alcohol use disorder, according to a new study by researchers at the National Institutes of Health and their colleagues. The study presents converging evidence from experiments in mice and rats, as well as a cohort study in humans, suggesting that the medication, spironolactone, may play a role in reducing alcohol drinking. The research was led by scientists at the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA), both parts of NIH, and Yale School of Medicine, New Haven, Connecticut. A report of the new findings is published in Molecular Psychiatry. "Combining findings across three species and different types of research studies, and then seeing similarities in those data, gives us confidence that we are onto something potentially important scientifically and clinically. These findings support further study of spironolactone as a potential treatment for alcohol use disorder, a medical condition that affects millions of people in the U.S," said Lorenzo Leggio, M.D., Ph.D., chief of the Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, a joint laboratory of NIDA and NIAAA, and one of the senior authors. Currently there are three medications approved for alcohol use disorder in the United States, and they are an effective and important aid in the treatment of people with this condition. Given the diverse biological processes that contribute to alcohol use disorder, new medications are needed to provide a broader spectrum of treatment options. Scientists are working to develop a larger menu of pharmaceutical treatments that could be tailored to individual needs. Previous research has shown that mineralocorticoid receptors, which are located throughout the brain and other organs and help regulate fluid and electrolyte balance in the body, might play a role in alcohol use and craving. Preclinical research suggests that higher mineralocorticoid receptor signaling contributes to increased alcohol consumption. The current study sought to expand this line of research by testing spironolactone, a medication with multiple actions, including blocking mineralocorticoid receptors. Spironolactone is used in clinical practice as a diuretic and to treat conditions like heart problems and high blood pressure. In experiments conducted in mouse and rat models of excessive alcohol drinking, NIAAA and NIDA researchers led by co-senior author Leandro Vendruscolo, Pharm.D., Ph.D., from NIDA found that increasing doses of spironolactone decreased alcohol consumption in male and female animals, without causing movement or coordination problems, and without affecting their food or water intake. In a parallel study that was part of this team's collaborative efforts, researchers led by co-senior author Amy C. Justice, M.D., Ph.D., of the Yale School of Medicine, examined health records of a large sample of people from the U.S. Veterans Affairs healthcare system to assess potential changes in alcohol drinking after spironolactone was prescribed for its current clinical indications (e.g., heart problems, high blood pressure). They found a significant association between spironolactone treatment and reduction in self-reported alcohol consumption, as measured by the Alcohol Use Disorders Identification Test-Consumption, a screening tool. Of note, the largest effects were observed among those who reported hazardous/heavy episodic alcohol consumption before starting spironolactone treatment. "These are very encouraging findings," said NIAAA Director George F. Koob, Ph.D., a co-author of the study. "Taken together, the present study argues for conducting randomized, controlled studies of spironolactone in people with alcohol use disorder to further assess its safety and potential efficacy in this population, as well as additional work to understand how spironolactone may reduce alcohol drinking." "Just like for any other medical condition, people with substance use disorders deserve to have a range of treatment options available to them, and this study is an exciting step in our effort to expand medications for people with alcohol use disorder," said Nora Volkow, M.D., director of NIDA. "In addition, we must address the stigma and other barriers that prevent many people with alcohol use disorder from accessing the treatments we already have available." <|im_end|>

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304, 2225, 8762, 323, 8954, 32510, 11, 323, 56089, 279, 42056, 315, 13200, 30438, 1234, 459, 52609, 3044, 304, 8954, 32510, 510, 220, 1627, 21087, 4452, 11, 993, 2534, 337, 533, 606, 25983, 4689, 63907, 6082, 11, 5423, 304, 25000, 11, 323, 420, 1253, 617, 11754, 30438, 369, 13200, 13, 763, 264, 1833, 5352, 4007, 11, 386, 22506, 3251, 5676, 323, 18105, 1766, 430, 29433, 43215, 2191, 449, 384, 13206, 268, 606, 477, 29433, 14459, 2996, 304, 279, 24703, 32, 41658, 398, 11293, 13200, 659, 28324, 4138, 304, 8954, 32510, 510, 220, 1544, 21087, 16644, 1521, 26455, 719, 40240, 3135, 11, 5217, 7978, 527, 4460, 311, 2731, 3619, 279, 36449, 39227, 4754, 315, 993, 2534, 337, 533, 606, 304, 18189, 13200, 15652, 1234, 2204, 22772, 5110, 11, 2737, 73922, 12970, 323, 13200, 44393, 75968, 16558, 13, 23212, 11, 7978, 527, 4460, 311, 8417, 311, 1148, 13112, 993, 2534, 337, 533, 606, 11, 824, 513, 477, 304, 10824, 449, 13200, 11, 3242, 4825, 63907, 6082, 323, 9048, 38793, 11, 323, 3508, 1070, 374, 459, 16628, 1990, 993, 2534, 337, 533, 606, 323, 13200, 36449, 79117, 25265, 13, 17830, 11, 2926, 13731, 4791, 49607, 3002, 14807, 315, 279, 4754, 3560, 315, 993, 2534, 337, 533, 606, 304, 58680, 374, 41440, 4460, 13, 1226, 6051, 13375, 264, 15430, 16833, 752, 307, 22530, 39227, 4007, 11, 1701, 14683, 2890, 3335, 828, 505, 68065, 3700, 1543, 6960, 17355, 7188, 13, 6193, 220, 2636, 7931, 12020, 449, 993, 2534, 337, 533, 606, 11, 369, 904, 28137, 11, 128257, 198, 128256, 78191, 198, 32, 24099, 369, 4851, 5435, 323, 1579, 6680, 7410, 1253, 1101, 387, 7524, 369, 27723, 13200, 1005, 19823, 11, 4184, 311, 264, 502, 4007, 555, 12074, 520, 279, 5165, 73828, 315, 6401, 323, 872, 18105, 13, 578, 4007, 18911, 19873, 3252, 6029, 505, 21896, 304, 24548, 323, 32510, 11, 439, 1664, 439, 264, 41944, 4007, 304, 12966, 11, 23377, 430, 279, 24099, 11, 993, 2534, 337, 533, 606, 11, 1253, 1514, 264, 3560, 304, 18189, 13200, 16558, 13, 578, 3495, 574, 6197, 555, 14248, 520, 279, 5165, 10181, 389, 26166, 46784, 320, 45, 52271, 8, 323, 279, 5165, 10181, 389, 45396, 46784, 323, 45396, 2191, 320, 45, 5987, 6157, 705, 2225, 5596, 315, 84370, 11, 323, 44552, 6150, 315, 19152, 11, 1561, 42714, 11, 31461, 13, 362, 1934, 315, 279, 502, 14955, 374, 4756, 304, 60825, 69244, 13, 330, 37292, 5859, 14955, 4028, 2380, 9606, 323, 2204, 4595, 315, 3495, 7978, 11, 323, 1243, 9298, 43874, 304, 1884, 828, 11, 6835, 603, 12410, 430, 584, 527, 8800, 2555, 13893, 3062, 74647, 323, 70432, 13, 4314, 14955, 1862, 4726, 4007, 315, 993, 2534, 337, 533, 606, 439, 264, 4754, 6514, 369, 13200, 1005, 19823, 11, 264, 6593, 3044, 430, 22223, 11990, 315, 1274, 304, 279, 549, 815, 1359, 1071, 74500, 7765, 46245, 11, 386, 920, 2637, 2405, 920, 2637, 10388, 315, 279, 33135, 17680, 606, 2868, 408, 91153, 2508, 323, 45950, 98438, 5237, 72482, 2508, 11360, 11, 264, 10496, 27692, 315, 452, 52271, 323, 452, 5987, 6157, 11, 323, 832, 315, 279, 10195, 12283, 13, 25122, 1070, 527, 2380, 31010, 12054, 369, 13200, 1005, 19823, 304, 279, 3723, 4273, 11, 323, 814, 527, 459, 7524, 323, 3062, 12576, 304, 279, 6514, 315, 1274, 449, 420, 3044, 13, 16644, 279, 17226, 24156, 11618, 430, 17210, 311, 13200, 1005, 19823, 11, 502, 31010, 527, 4460, 311, 3493, 264, 27927, 20326, 315, 6514, 2671, 13, 57116, 527, 3318, 311, 2274, 264, 8294, 5130, 315, 35410, 22972, 430, 1436, 387, 41891, 311, 3927, 3966, 13, 30013, 3495, 706, 6982, 430, 25107, 511, 90438, 590, 44540, 11, 902, 527, 7559, 6957, 279, 8271, 323, 1023, 36853, 323, 1520, 37377, 15962, 323, 73396, 668, 8335, 304, 279, 2547, 11, 2643, 1514, 264, 3560, 304, 13200, 1005, 323, 64804, 13, 5075, 91899, 3495, 13533, 430, 5190, 25107, 511, 90438, 590, 35268, 43080, 44072, 311, 7319, 13200, 15652, 13, 578, 1510, 4007, 16495, 311, 9407, 420, 1584, 315, 3495, 555, 7649, 993, 2534, 337, 533, 606, 11, 264, 24099, 449, 5361, 6299, 11, 2737, 22978, 25107, 511, 90438, 590, 44540, 13, 3165, 2534, 337, 533, 606, 374, 1511, 304, 14830, 6725, 439, 264, 1891, 554, 29150, 323, 311, 4322, 4787, 1093, 4851, 5435, 323, 1579, 6680, 7410, 13, 763, 21896, 13375, 304, 8814, 323, 11494, 4211, 315, 27639, 13200, 16558, 11, 452, 5987, 6157, 323, 452, 52271, 12074, 6197, 555, 1080, 1355, 268, 2521, 3229, 2009, 42824, 85653, 20962, 59348, 11, 25603, 920, 2637, 2405, 920, 2637, 505, 452, 52271, 1766, 430, 7859, 35130, 315, 993, 2534, 337, 533, 606, 25983, 13200, 15652, 304, 8762, 323, 8954, 10099, 11, 2085, 14718, 7351, 477, 38793, 5435, 11, 323, 2085, 28987, 872, 3691, 477, 3090, 23730, 13, 763, 264, 15638, 4007, 430, 574, 961, 315, 420, 2128, 596, 40806, 9045, 11, 12074, 6197, 555, 1080, 1355, 268, 2521, 3229, 29793, 356, 13, 12007, 11, 386, 920, 2637, 2405, 920, 2637, 315, 279, 44552, 6150, 315, 19152, 11, 25078, 2890, 7576, 315, 264, 3544, 6205, 315, 1274, 505, 279, 549, 815, 13, 40432, 23298, 18985, 1887, 311, 8720, 4754, 4442, 304, 13200, 16558, 1306, 993, 2534, 337, 533, 606, 574, 32031, 369, 1202, 1510, 14830, 56190, 320, 68, 1326, 2637, 4851, 5435, 11, 1579, 6680, 7410, 570, 2435, 1766, 264, 5199, 15360, 1990, 993, 2534, 337, 533, 606, 6514, 323, 14278, 304, 659, 85296, 13200, 15652, 11, 439, 17303, 555, 279, 45396, 5560, 73133, 59776, 3475, 12, 43066, 562, 11, 264, 23061, 5507, 13, 5046, 5296, 11, 279, 7928, 6372, 1051, 13468, 4315, 1884, 889, 5068, 51024, 78156, 5781, 67594, 53860, 13200, 15652, 1603, 6041, 993, 2534, 337, 533, 606, 6514, 13, 330, 9673, 527, 1633, 26921, 14955, 1359, 1071, 452, 5987, 6157, 10783, 10058, 435, 13, 30417, 677, 11, 2405, 920, 2637, 264, 1080, 43802, 315, 279, 4007, 13, 330, 66769, 3871, 11, 279, 3118, 4007, 29633, 369, 31474, 47341, 11, 14400, 7978, 315, 993, 2534, 337, 533, 606, 304, 1274, 449, 13200, 1005, 19823, 311, 4726, 8720, 1202, 7296, 323, 4754, 41265, 304, 420, 7187, 11, 439, 1664, 439, 5217, 990, 311, 3619, 1268, 993, 2534, 337, 533, 606, 1253, 8108, 13200, 16558, 1210, 330, 10156, 1093, 369, 904, 1023, 6593, 3044, 11, 1274, 449, 20278, 1005, 24673, 23528, 311, 617, 264, 2134, 315, 6514, 2671, 2561, 311, 1124, 11, 323, 420, 4007, 374, 459, 13548, 3094, 304, 1057, 5149, 311, 9407, 31010, 369, 1274, 449, 13200, 1005, 19823, 1359, 1071, 73645, 43614, 363, 11, 386, 920, 2637, 7690, 315, 452, 52271, 13, 330, 644, 5369, 11, 584, 2011, 2686, 279, 60381, 323, 1023, 30740, 430, 5471, 1690, 1274, 449, 13200, 1005, 19823, 505, 32888, 279, 22972, 584, 2736, 617, 2561, 1210, 220, 128257, 198 ]

2,322

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Patient-derived xenograft and cell line models are popular models for clinical cancer research. However, the inevitable inclusion of a mouse genome in a patient-derived model is a remaining concern in the analysis. Although multiple tools and filtering strategies have been developed to account for this, research has yet to demonstrate the exact impact of the mouse genome and the optimal use of these tools and filtering strategies in an analysis pipeline. Results We construct a benchmark dataset of 5 liver tissues from 3 mouse strains using human whole-exome sequencing kit. Next-generation sequencing reads from mouse tissues are mappable to 49% of the human genome and 409 cancer genes. In total, 1,207,556 mouse-specific alleles are aligned to the human genome reference, including 467,232 (38.7%) alleles with high sensitivity to contamination, which are pervasive causes of false cancer mutations in public databases and are signatures for predicting global contamination. Next, we assess the performance of 8 filtering methods in terms of mouse read filtration and reduction of mouse-specific alleles. All filtering tools generally perform well, although differences in algorithm strictness and efficiency of mouse allele removal are observed. Therefore, we develop a best practice pipeline that contains the estimation of contamination level, mouse read filtration, and variant filtration. Conclusions The inclusion of mouse cells in patient-derived models hinders genomic analysis and should be addressed carefully. Our suggested guidelines improve the robustness and maximize the utility of genomic analysis of these models. Background Patient-derived models (PDMs) serve as a way of preserving and amplifying cancer specimens of patients by providing in vivo or in vitro environments that allow the natural growth of cancer cells. The recent advent of various technologies for PDM construction, including patient-derived xenografts (PDXs), patient-derived tumor cell cultures (PDCs), and patient-derived organoids (PDOrg), has revolutionized translational cancer research by providing useful preclinical models of use in drug development [ 1 , 2 ], drug screening [ 3 , 4 , 5 , 6 ], and a personalized co-clinical trials of cancer patients [ 7 ]. Particularly, next-generation sequencing (NGS) of these amplified primary tumors enabled robust measurement of genomic variants and gene expression changes under various conditions [ 8 , 9 , 10 , 11 ]. Genomic analysis of PDM samples, however, is more complicated than that of original primary tumor samples due to the rise of mouse-originating cells or tissues in the implanted specimen. Indeed, research has shown that resected PDX samples can harbor up to 70–80% murine DNA without a mistake in the separation process, mainly due to the infiltration of murine stromal cells [ 12 , 13 , 14 ]. Additionally, other in vitro models would also contain mouse genome fragments (e.g., fibroblasts in a co-cultured feeder layer or mouse sarcoma-derived Matrigel) [ 15 , 16 ]. Subsequent next-generation sequencing of these samples would inevitably generate short reads of mouse DNA (mouse read, hereafter). Due to the genomic similarity between humans and mice [ 17 ], mouse reads are alignable to the human reference genome, which can cause multiple problems in standard genomic analysis: For example, once aligned, mouse-specific alleles in mouse reads are difficult to distinguish from true variants in human reads, resulting in false mutation calls. In transcriptome sequencing, mapping of cDNA mouse reads leads to aberrant gene expression profiles of cancer cells. Accordingly, researchers have lobbied continuing demands for efficient tools which deconvolute or remove murine effects in genomic analyses of PDM models [ 8 , 14 ]. The removal of mouse reads has been primarily attempted computationally on NGS data. The simplest way to do this is to utilize the differential mappability of mouse reads onto the human and mouse reference genome. Thereby, reads that are mapped only to the mouse reference genome or are mapped better to the mouse than the human reference genome are filtered out. In the last few years, however, at least five computational tools [ 8 , 18 , 19 , 20 , 21 ] have been developed to conduct the same task via different strategies and filtering criteria, and all have reported a satisfactory accuracy (~ 97.84%) in mouse read filtration. While these various solutions have increased the resources available to researchers, there are only a few benchmark studies on the effectiveness of these tools, and conclusions therefrom are inconsistent [ 8 , 22 , 23 ]. More fundamentally, it is still unclear as to whether the use of a filtration tool itself is essential or if steps other than the read filtration (e.g., variant blacklisting) are additionally required. To render an agreeable consensus, benchmark studies providing a comprehensive analysis of the true genome-wide effects of mouse reads, such as alignment landscape and gene- and locus-level vulnerability to contamination, on variant calling using a realistic dataset are needed. Here, we report our benchmark results for the effectiveness of eight currently available mouse read filtering pipelines, reflecting their impact on genome analysis. To construct a realistic benchmark dataset, we directly sequenced mouse tissues that were processed by human exome target enrichment and further mixed with human reads at different rates, which allowed us to identify the quantity, mappability, and alignment landscape of mouse reads at a global level. To measure the impact of mouse reads on variant calling, we listed all mouse-specific alleles that could possibly cause mismatches (and ultimately false variants) in the aligned data and measured their sensitivity to contamination. Deeper analysis of the alleles led to the discovery of additional findings reflective of increased vulnerability in cancer genes and strain specificity, as well as the development of a robust measure for estimating contamination levels. Finally, pipelines were evaluated in terms of their efficiency in read filtering and reducing mouse-specific alleles, and the best practice pipeline was drawn, with additional suggestions for best output. We believe our study provides a basis for developing standards for genomic analysis of PDX and relevant patient-derived models. Results Construction of the benchmark dataset Samples for the benchmark were obtained from fresh liver tissues from 5 mice (2 A/J,", "role": "user" }, { "content": "An analysis of 13,000 tumors highlights two previously overlooked genes as potential new therapeutic targets for cancer treatment. The researchers have also identified potential new therapeutic targets for male infertility. Both findings are the result of the most comprehensive evolutionary analysis of RNA modification proteins to date, published today in the journal Genome Biology. RNA is a fundamental molecule of life involved in coding, decoding, regulating and expressing the genes stored in DNA. Cells often modify RNA's constituent code for a specific purpose, such as tagging the molecule for degradation, or marking it so that the immune system recognizes it and doesn't destroy it. Modifying an RNA molecule can profoundly affect the fate of a living organism, including its development, sex or circadian rhythm. Up to 100 human diseases are linked to defects in the RNA modification process. RNA modification proteins (RMPs) play a key role in this process, adding or removing chemical groups to the sequence and altering the original code copied from DNA. Recent technological advances have made it possible to study how and where RNA is edited and modified, leading to the nascent field of epitranscriptomics. In this study, researchers at the Centre for Genomic Regulation in Barcelona carried out the most comprehensive evolutionary analysis of human RMPs to date, studying how they behave across 32 tissues, 10 species and 13,358 paired tumor-normal human samples. They found that RMP expression hugely varies across different types of tissues, cancer types and cancer stages. Genes that code for RMPs were particularly over-expressed in testicular tissue. The majority of RMPs were expressed at the earliest stages of sperm formation, but a few in more advanced stages, such as the proteins ADAD1 or NSUN7. Depletion of these proteins is known to cause infertility, and thus could be used as future therapeutic targets for infertility. Two RMPs were also found to be highly expressed in the epididymis, the tissue connecting the testes and the ejaculatory duct. One of these is TRDMT1, which has previously been shown to play a major role in the transmission of paternal epigenetic information across generations. According to the researchers, the findings offer clues into how RMPs can transmit environmental information like stress or diet through sperm. The study also looked at the role of RMPs in cancer. The researchers analyzed RMP gene expression across 13,358 samples from 28 different types of human tumors. Twenty-seven percent of all known human RMPs were dysregulated in cancers, significantly more than expected. HENMT1 and LAGE3 were the two most frequently over-expressed genes across a wide variety of cancer types. They were consistently over-expressed in tumors at various stages of progression, particularly at stages III and IV, and could be promising drug targets for anti-tumor therapies. According to Eva Novoa, researcher at the Centre for Genomic Regulation and lead author of the study, some cancer drugs, like the FTO inhibitors, potential drugs to treat glioblastomas, already target RNA modification machinery to treat tumors. These drugs have received a large amount of attention in the last few years because of the abundance and ease of detection of the RNA modifications they target. \"Here, we provide a short-list of RMPs that constitute promising drug targets in specific cancer types. We hope our work will inspire new lines of research in antitumoral therapies,\" says Eva Novoa. \"We already have important drugs like FTO inhibitors that use the machinations of RNA modification to treat cancer. It's exciting to point to several other overlooked pathways that could be future therapeutic targets.\" \"Our next steps are studying the role of RNA modification in transmitting diet-induced metabolic disorders from one generation to the next,\" concludes Eva. \"Understanding how environmental information is converted into molecular information in sperm RNAs, and then transmit across generations, is the next exciting and unanswered question.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 Patient-derived xenograft and cell line models are popular models for clinical cancer research. However, the inevitable inclusion of a mouse genome in a patient-derived model is a remaining concern in the analysis. Although multiple tools and filtering strategies have been developed to account for this, research has yet to demonstrate the exact impact of the mouse genome and the optimal use of these tools and filtering strategies in an analysis pipeline. Results We construct a benchmark dataset of 5 liver tissues from 3 mouse strains using human whole-exome sequencing kit. Next-generation sequencing reads from mouse tissues are mappable to 49% of the human genome and 409 cancer genes. In total, 1,207,556 mouse-specific alleles are aligned to the human genome reference, including 467,232 (38.7%) alleles with high sensitivity to contamination, which are pervasive causes of false cancer mutations in public databases and are signatures for predicting global contamination. Next, we assess the performance of 8 filtering methods in terms of mouse read filtration and reduction of mouse-specific alleles. All filtering tools generally perform well, although differences in algorithm strictness and efficiency of mouse allele removal are observed. Therefore, we develop a best practice pipeline that contains the estimation of contamination level, mouse read filtration, and variant filtration. Conclusions The inclusion of mouse cells in patient-derived models hinders genomic analysis and should be addressed carefully. Our suggested guidelines improve the robustness and maximize the utility of genomic analysis of these models. Background Patient-derived models (PDMs) serve as a way of preserving and amplifying cancer specimens of patients by providing in vivo or in vitro environments that allow the natural growth of cancer cells. The recent advent of various technologies for PDM construction, including patient-derived xenografts (PDXs), patient-derived tumor cell cultures (PDCs), and patient-derived organoids (PDOrg), has revolutionized translational cancer research by providing useful preclinical models of use in drug development [ 1 , 2 ], drug screening [ 3 , 4 , 5 , 6 ], and a personalized co-clinical trials of cancer patients [ 7 ]. Particularly, next-generation sequencing (NGS) of these amplified primary tumors enabled robust measurement of genomic variants and gene expression changes under various conditions [ 8 , 9 , 10 , 11 ]. Genomic analysis of PDM samples, however, is more complicated than that of original primary tumor samples due to the rise of mouse-originating cells or tissues in the implanted specimen. Indeed, research has shown that resected PDX samples can harbor up to 70–80% murine DNA without a mistake in the separation process, mainly due to the infiltration of murine stromal cells [ 12 , 13 , 14 ]. Additionally, other in vitro models would also contain mouse genome fragments (e.g., fibroblasts in a co-cultured feeder layer or mouse sarcoma-derived Matrigel) [ 15 , 16 ]. Subsequent next-generation sequencing of these samples would inevitably generate short reads of mouse DNA (mouse read, hereafter). Due to the genomic similarity between humans and mice [ 17 ], mouse reads are alignable to the human reference genome, which can cause multiple problems in standard genomic analysis: For example, once aligned, mouse-specific alleles in mouse reads are difficult to distinguish from true variants in human reads, resulting in false mutation calls. In transcriptome sequencing, mapping of cDNA mouse reads leads to aberrant gene expression profiles of cancer cells. Accordingly, researchers have lobbied continuing demands for efficient tools which deconvolute or remove murine effects in genomic analyses of PDM models [ 8 , 14 ]. The removal of mouse reads has been primarily attempted computationally on NGS data. The simplest way to do this is to utilize the differential mappability of mouse reads onto the human and mouse reference genome. Thereby, reads that are mapped only to the mouse reference genome or are mapped better to the mouse than the human reference genome are filtered out. In the last few years, however, at least five computational tools [ 8 , 18 , 19 , 20 , 21 ] have been developed to conduct the same task via different strategies and filtering criteria, and all have reported a satisfactory accuracy (~ 97.84%) in mouse read filtration. While these various solutions have increased the resources available to researchers, there are only a few benchmark studies on the effectiveness of these tools, and conclusions therefrom are inconsistent [ 8 , 22 , 23 ]. More fundamentally, it is still unclear as to whether the use of a filtration tool itself is essential or if steps other than the read filtration (e.g., variant blacklisting) are additionally required. To render an agreeable consensus, benchmark studies providing a comprehensive analysis of the true genome-wide effects of mouse reads, such as alignment landscape and gene- and locus-level vulnerability to contamination, on variant calling using a realistic dataset are needed. Here, we report our benchmark results for the effectiveness of eight currently available mouse read filtering pipelines, reflecting their impact on genome analysis. To construct a realistic benchmark dataset, we directly sequenced mouse tissues that were processed by human exome target enrichment and further mixed with human reads at different rates, which allowed us to identify the quantity, mappability, and alignment landscape of mouse reads at a global level. To measure the impact of mouse reads on variant calling, we listed all mouse-specific alleles that could possibly cause mismatches (and ultimately false variants) in the aligned data and measured their sensitivity to contamination. Deeper analysis of the alleles led to the discovery of additional findings reflective of increased vulnerability in cancer genes and strain specificity, as well as the development of a robust measure for estimating contamination levels. Finally, pipelines were evaluated in terms of their efficiency in read filtering and reducing mouse-specific alleles, and the best practice pipeline was drawn, with additional suggestions for best output. We believe our study provides a basis for developing standards for genomic analysis of PDX and relevant patient-derived models. Results Construction of the benchmark dataset Samples for the benchmark were obtained from fresh liver tissues from 5 mice (2 A/J,<|im_end|> <|im_start|>assistant An analysis of 13,000 tumors highlights two previously overlooked genes as potential new therapeutic targets for cancer treatment. The researchers have also identified potential new therapeutic targets for male infertility. Both findings are the result of the most comprehensive evolutionary analysis of RNA modification proteins to date, published today in the journal Genome Biology. RNA is a fundamental molecule of life involved in coding, decoding, regulating and expressing the genes stored in DNA. Cells often modify RNA's constituent code for a specific purpose, such as tagging the molecule for degradation, or marking it so that the immune system recognizes it and doesn't destroy it. Modifying an RNA molecule can profoundly affect the fate of a living organism, including its development, sex or circadian rhythm. Up to 100 human diseases are linked to defects in the RNA modification process. RNA modification proteins (RMPs) play a key role in this process, adding or removing chemical groups to the sequence and altering the original code copied from DNA. Recent technological advances have made it possible to study how and where RNA is edited and modified, leading to the nascent field of epitranscriptomics. In this study, researchers at the Centre for Genomic Regulation in Barcelona carried out the most comprehensive evolutionary analysis of human RMPs to date, studying how they behave across 32 tissues, 10 species and 13,358 paired tumor-normal human samples. They found that RMP expression hugely varies across different types of tissues, cancer types and cancer stages. Genes that code for RMPs were particularly over-expressed in testicular tissue. The majority of RMPs were expressed at the earliest stages of sperm formation, but a few in more advanced stages, such as the proteins ADAD1 or NSUN7. Depletion of these proteins is known to cause infertility, and thus could be used as future therapeutic targets for infertility. Two RMPs were also found to be highly expressed in the epididymis, the tissue connecting the testes and the ejaculatory duct. One of these is TRDMT1, which has previously been shown to play a major role in the transmission of paternal epigenetic information across generations. According to the researchers, the findings offer clues into how RMPs can transmit environmental information like stress or diet through sperm. The study also looked at the role of RMPs in cancer. The researchers analyzed RMP gene expression across 13,358 samples from 28 different types of human tumors. Twenty-seven percent of all known human RMPs were dysregulated in cancers, significantly more than expected. HENMT1 and LAGE3 were the two most frequently over-expressed genes across a wide variety of cancer types. They were consistently over-expressed in tumors at various stages of progression, particularly at stages III and IV, and could be promising drug targets for anti-tumor therapies. According to Eva Novoa, researcher at the Centre for Genomic Regulation and lead author of the study, some cancer drugs, like the FTO inhibitors, potential drugs to treat glioblastomas, already target RNA modification machinery to treat tumors. These drugs have received a large amount of attention in the last few years because of the abundance and ease of detection of the RNA modifications they target. "Here, we provide a short-list of RMPs that constitute promising drug targets in specific cancer types. We hope our work will inspire new lines of research in antitumoral therapies," says Eva Novoa. "We already have important drugs like FTO inhibitors that use the machinations of RNA modification to treat cancer. It's exciting to point to several other overlooked pathways that could be future therapeutic targets." "Our next steps are studying the role of RNA modification in transmitting diet-induced metabolic disorders from one generation to the next," concludes Eva. "Understanding how environmental information is converted into molecular information in sperm RNAs, and then transmit across generations, is the next exciting and unanswered question." <|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 Polydopamine is a biomimetic self-adherent polymer, which can be easily deposited on a wide variety of materials. Despite the rapidly increasing interest in polydopamine-based coatings, the polymerization mechanism and the key intermediate species formed during the deposition process are still controversial. Herein, we report a systematic investigation of polydopamine formation on halloysite nanotubes; the negative charge and high surface area of halloysite nanotubes favour the capture of intermediates that are involved in polydopamine formation and decelerate the kinetics of the process, to unravel the various polymerization steps. Data from X-ray photoelectron and solid-state nuclear magnetic resonance spectroscopies demonstrate that in the initial stage of polydopamine deposition, oxidative coupling reaction of the dopaminechrome molecules is the main reaction pathway that leads to formation of polycatecholamine oligomers as an intermediate and the post cyclization of the linear oligomers occurs subsequently. Furthermore, TRIS molecules are incorporated into the initially formed oligomers. Introduction Natural phenomena have often served as an inspiration for designing new synthetic materials. In recent years, the extraordinary ability of marine mussels to attach to virtually all types of inorganic and organic surfaces has attracted particular attention 1 . Clues for such universal adhesion ability lie in the high content of catechol (L-3,4-dihydroxyphenylalanine, L-Dopa) as well as primary and secondary amines (lysine and histidine) in the mussel’s adhesive proteins, secreted at the mussel-substrate interface 2 . Inspired by this, Lee et al. 3 demonstrated that dopamine, an analog of L-Dopa, is prone to undergo self-polymerization to form a thin, surface-adherent polydopamine (PDA) film on a vast variety of materials. The simplest protocol 4 for coating an object with PDA involves immersing it in an alkaline solution of dopamine and waiting for a PDA layer to form spontaneously on the surface and reach a thickness of typically 1–100 nm. PDA coatings, therefore, overcome the limitations of previous surface modification methods 5 that require specific substrates or harsh chemical conditions. These unique features of a PDA coating in combination with its high biocompatibility and post-functionalization possibilities have triggered an exponentially growing interest for a broad range of applications 6 , 7 , including energy storage, environmental remediation, cell encapsulation, and drug delivery. Understanding how the PDA coating is formed and what is ultimately its structure, is essential for optimizing its performance for tailored applications. However, its insolubility 8 in nearly all aqueous and organic solvents complicates the structural evaluation of PDA. In addition, in most cases, the formation of a PDA film on a surface is associated with the formation of PDA particles in solution and it has been shown 9 that the structure of the film formed on the surface agrees with a process in which particles form in the solution and then adsorb on the surface. These mechanistic complexities as well as the observation that the structural characteristics of PDA films depend on the initial dopamine concentration as well as the type of oxidizing agent used, have led to reports of diverse structures for PDA in literature 10 . The first step of the PDA formation pathway, which comprises oxidation, intermolecular cyclization, and isomerization reactions, has been clearly described by a variety of studies 11 (central circle in Fig. 1 ). However, the following step/s leading to PDA formation are still controversial. The proposed structural models for PDA can be divided into three main categories, namely polymeric, physical and trimer-based models, as sketched in Fig. 1 . Considering the polymeric models, two primary opposite models were proposed: (a) the “Eumelanin model”, which predicts that PDA formation mimics the synthetic pathway of melanin pigments in living organisms, and where the 5,6-dihydroxyindole (DHI) unit is considered the main building block of PDA (Fig. 1(i) ) 3 , and (b) the “open-chain poly(catechol/quinone) model” that views PDA as a linear sequence of catecholamine units bonded through biphenyl-type bonds (Fig. 1(ii) ) 12 . In parallel to these two models, Della Vecchia et al. 13 have proposed a three-component structure of PDA, which comprises uncycled (catecholamine) and cyclized (indole) units, as well as pyrrole dicarboxylic acid moieties with covalent incorporation of tris(hydroxymethyl)aminomethane (TRIS) (Fig. 1(iii) ). Along similar lines, a eumelanin-like polymer chain consisting of DHI units with different degrees of saturation and open-chain dopamine units has also been suggested (Fig. 1(iv) ) 14 . Moreover, Delparastan et al. 8 provided evidence for the high-molecular-weight polymeric nature of PDA films wherein the subunits are covalently connected. In contrast to the above studies supporting the existence of covalent bonds between PDA constituents, several researchers have proposed a supramolecular structure for PDA, assembled by physical interactions rather than covalent bonds. For example, using high-performance liquid chromatography (HPLC) and nuclear magnetic resonance (NMR) analysis, Hong et al. 15 have identified a physical trimer of (dopamine) 2 /DHI formed via self-assembly and stabilized by van der Waals interactions and hydrogen bonds (Fig. 1(v) ). Using solid-state spectroscopic techniques, Dreyer et al. 16 have argued that PDA is a supramolecular aggregate consisting of 5,6-dihydroxyindoline and its quinone derivate, held together by hydrogen-bonding, π-π interaction and charge transfer interactions (Fig. 1(vi) ). This view has been supported by Chan 17 , who investigated the PDA formation process by mass spectrometry coupled with isotope-labeling techniques, and provided evidence for non-covalently bound supramolecular aggregates of dopamine and a cyclized intermediate, dopaminechrome (DAC) being the major components of PDA (Fig. 1(vii) ). However, most of the studies published in recent years have argued that PDA is mainly composed of oligomers, mainly trimers, formed by covalent coupling oxidation, which bind via non-covalent interactions. Reported observations to support this view include the study performed by Ding et al. 18 , who, based on high-resolution mass-spectroscopy, have proposed a covalently bonded trimer of (DHI) 2 /pyrrole dicarboxylic acid, which links up through non-covalent interactions to build the supramolecular structure of PDA (Fig. 1(viii) ). Alfieri et al. 9 have suggested a polycyclic complex as the main constituent involved in PDA formation rather than DHI-based oligomers (Fig. 1(ix) ) and Lyu et al. 19 , also based", "role": "user" }, { "content": "Dopamine is best known as a neurotransmitter. What is rather unknown, however, is that the underwater glue used by mussels contains large amounts of L-Dopa molecules, an analog of dopamine. Inspired by this, polydopamine coatings have recently been described that could be used to activate otherwise inactive surfaces. One problem in the development of these coatings is that their exact structure is unknown. Several models of polydopamine coatings have been put forward, but University of Groningen scientists have now shown through direct measurements what these coatings really look like. Their results were published in Nature Communications on February 7, 2023. Polydopamine coatings show great promise: they don't require any solvents other than water, and are biocompatible. They are versatile coatings that adhere to almost all surfaces and are useful as intermediate layers, for example on inactive surfaces like polyolefins. \"Yet until now, we did not understand their exact composition and the way in which they form,\" explains Hamoon Hemmatpour, postdoc researcher at the Product Technology Group of the University of Groningen Engineering and Technology Institute. Building blocks To remedy this lacuna, Hemmatpour set out to study the formation of the coatings. \"On the macroscopic scale, this coating forms very quickly, too fast to study intermediates that might reveal what is happening,\" he explains. He therefore used nanosized tubes from a clay mineral as a substrate for the coating. A large surface area and negative charges in the mineral attract intermediates from the solution, thereby slowing down the polymerization process. \"This allowed us to take samples of the nanotubes during the polymerization process to identify the intermediates.\" Previous attempts to characterize polydopamine coatings used techniques such as mass spectrometry, which reveal the composition but not the exact chemical structure of the polymer. By studying intermediates on the nanotubes with solid-state NMR and X-ray photoelectron spectroscopy (XPS), Hemmatpour could reconstruct what happens during polymerization. \"These techniques show which chemical bonds are present.\" Once all the information was there, Hemmatpour and his colleagues could uncover the structures of the building blocks in the coatings, and thus resolve their structure. Buffering salt The dopamine starts polymerizing when the buffered solution reaches a pH of 8.5 or higher. \"One thing we noticed is that the buffering salt TRIS became part of the structure, a sizeable part during the first phases of polymerization, and to a lesser degree as the reaction progressed.\" The final analysis of the process reveals auto-oxidation of dopamine, followed by crosslinking, intramolecular cyclization, and isomerization. This study reveals the formation and structure of polydopamine coatings, which allows scientists to adapt the process for different applications. \"We also believe that our use of clay nanotubes could be expanded to the study of other rapid processes,\" says Hemmatpour. \"And adapting the nanotubes to increase surface area would allow us to slow down reactions even further.\" \"There are other interesting observations from this study,\" Hemmatpour adds. \"In neural cells, dopamine is stored in vesicles with a very low pH, but in neurodegenerative diseases, these vesicles somehow become leaky, and the dopamine accumulates in the cytosol where the pH is higher. There, the dopamine polymerizes into toxic clumps, which eventually kill neurons. Our study offers new insights into this mechanism and the intermediates of this process that can be used to find a way to treat neurodegenerative 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 Polydopamine is a biomimetic self-adherent polymer, which can be easily deposited on a wide variety of materials. Despite the rapidly increasing interest in polydopamine-based coatings, the polymerization mechanism and the key intermediate species formed during the deposition process are still controversial. Herein, we report a systematic investigation of polydopamine formation on halloysite nanotubes; the negative charge and high surface area of halloysite nanotubes favour the capture of intermediates that are involved in polydopamine formation and decelerate the kinetics of the process, to unravel the various polymerization steps. Data from X-ray photoelectron and solid-state nuclear magnetic resonance spectroscopies demonstrate that in the initial stage of polydopamine deposition, oxidative coupling reaction of the dopaminechrome molecules is the main reaction pathway that leads to formation of polycatecholamine oligomers as an intermediate and the post cyclization of the linear oligomers occurs subsequently. Furthermore, TRIS molecules are incorporated into the initially formed oligomers. Introduction Natural phenomena have often served as an inspiration for designing new synthetic materials. In recent years, the extraordinary ability of marine mussels to attach to virtually all types of inorganic and organic surfaces has attracted particular attention 1 . Clues for such universal adhesion ability lie in the high content of catechol (L-3,4-dihydroxyphenylalanine, L-Dopa) as well as primary and secondary amines (lysine and histidine) in the mussel’s adhesive proteins, secreted at the mussel-substrate interface 2 . Inspired by this, Lee et al. 3 demonstrated that dopamine, an analog of L-Dopa, is prone to undergo self-polymerization to form a thin, surface-adherent polydopamine (PDA) film on a vast variety of materials. The simplest protocol 4 for coating an object with PDA involves immersing it in an alkaline solution of dopamine and waiting for a PDA layer to form spontaneously on the surface and reach a thickness of typically 1–100 nm. PDA coatings, therefore, overcome the limitations of previous surface modification methods 5 that require specific substrates or harsh chemical conditions. These unique features of a PDA coating in combination with its high biocompatibility and post-functionalization possibilities have triggered an exponentially growing interest for a broad range of applications 6 , 7 , including energy storage, environmental remediation, cell encapsulation, and drug delivery. Understanding how the PDA coating is formed and what is ultimately its structure, is essential for optimizing its performance for tailored applications. However, its insolubility 8 in nearly all aqueous and organic solvents complicates the structural evaluation of PDA. In addition, in most cases, the formation of a PDA film on a surface is associated with the formation of PDA particles in solution and it has been shown 9 that the structure of the film formed on the surface agrees with a process in which particles form in the solution and then adsorb on the surface. These mechanistic complexities as well as the observation that the structural characteristics of PDA films depend on the initial dopamine concentration as well as the type of oxidizing agent used, have led to reports of diverse structures for PDA in literature 10 . The first step of the PDA formation pathway, which comprises oxidation, intermolecular cyclization, and isomerization reactions, has been clearly described by a variety of studies 11 (central circle in Fig. 1 ). However, the following step/s leading to PDA formation are still controversial. The proposed structural models for PDA can be divided into three main categories, namely polymeric, physical and trimer-based models, as sketched in Fig. 1 . Considering the polymeric models, two primary opposite models were proposed: (a) the “Eumelanin model”, which predicts that PDA formation mimics the synthetic pathway of melanin pigments in living organisms, and where the 5,6-dihydroxyindole (DHI) unit is considered the main building block of PDA (Fig. 1(i) ) 3 , and (b) the “open-chain poly(catechol/quinone) model” that views PDA as a linear sequence of catecholamine units bonded through biphenyl-type bonds (Fig. 1(ii) ) 12 . In parallel to these two models, Della Vecchia et al. 13 have proposed a three-component structure of PDA, which comprises uncycled (catecholamine) and cyclized (indole) units, as well as pyrrole dicarboxylic acid moieties with covalent incorporation of tris(hydroxymethyl)aminomethane (TRIS) (Fig. 1(iii) ). Along similar lines, a eumelanin-like polymer chain consisting of DHI units with different degrees of saturation and open-chain dopamine units has also been suggested (Fig. 1(iv) ) 14 . Moreover, Delparastan et al. 8 provided evidence for the high-molecular-weight polymeric nature of PDA films wherein the subunits are covalently connected. In contrast to the above studies supporting the existence of covalent bonds between PDA constituents, several researchers have proposed a supramolecular structure for PDA, assembled by physical interactions rather than covalent bonds. For example, using high-performance liquid chromatography (HPLC) and nuclear magnetic resonance (NMR) analysis, Hong et al. 15 have identified a physical trimer of (dopamine) 2 /DHI formed via self-assembly and stabilized by van der Waals interactions and hydrogen bonds (Fig. 1(v) ). Using solid-state spectroscopic techniques, Dreyer et al. 16 have argued that PDA is a supramolecular aggregate consisting of 5,6-dihydroxyindoline and its quinone derivate, held together by hydrogen-bonding, π-π interaction and charge transfer interactions (Fig. 1(vi) ). This view has been supported by Chan 17 , who investigated the PDA formation process by mass spectrometry coupled with isotope-labeling techniques, and provided evidence for non-covalently bound supramolecular aggregates of dopamine and a cyclized intermediate, dopaminechrome (DAC) being the major components of PDA (Fig. 1(vii) ). However, most of the studies published in recent years have argued that PDA is mainly composed of oligomers, mainly trimers, formed by covalent coupling oxidation, which bind via non-covalent interactions. Reported observations to support this view include the study performed by Ding et al. 18 , who, based on high-resolution mass-spectroscopy, have proposed a covalently bonded trimer of (DHI) 2 /pyrrole dicarboxylic acid, which links up through non-covalent interactions to build the supramolecular structure of PDA (Fig. 1(viii) ). Alfieri et al. 9 have suggested a polycyclic complex as the main constituent involved in PDA formation rather than DHI-based oligomers (Fig. 1(ix) ) and Lyu et al. 19 , also based<|im_end|> <|im_start|>assistant Dopamine is best known as a neurotransmitter. What is rather unknown, however, is that the underwater glue used by mussels contains large amounts of L-Dopa molecules, an analog of dopamine. Inspired by this, polydopamine coatings have recently been described that could be used to activate otherwise inactive surfaces. One problem in the development of these coatings is that their exact structure is unknown. Several models of polydopamine coatings have been put forward, but University of Groningen scientists have now shown through direct measurements what these coatings really look like. Their results were published in Nature Communications on February 7, 2023. Polydopamine coatings show great promise: they don't require any solvents other than water, and are biocompatible. They are versatile coatings that adhere to almost all surfaces and are useful as intermediate layers, for example on inactive surfaces like polyolefins. "Yet until now, we did not understand their exact composition and the way in which they form," explains Hamoon Hemmatpour, postdoc researcher at the Product Technology Group of the University of Groningen Engineering and Technology Institute. Building blocks To remedy this lacuna, Hemmatpour set out to study the formation of the coatings. "On the macroscopic scale, this coating forms very quickly, too fast to study intermediates that might reveal what is happening," he explains. He therefore used nanosized tubes from a clay mineral as a substrate for the coating. A large surface area and negative charges in the mineral attract intermediates from the solution, thereby slowing down the polymerization process. "This allowed us to take samples of the nanotubes during the polymerization process to identify the intermediates." Previous attempts to characterize polydopamine coatings used techniques such as mass spectrometry, which reveal the composition but not the exact chemical structure of the polymer. By studying intermediates on the nanotubes with solid-state NMR and X-ray photoelectron spectroscopy (XPS), Hemmatpour could reconstruct what happens during polymerization. "These techniques show which chemical bonds are present." Once all the information was there, Hemmatpour and his colleagues could uncover the structures of the building blocks in the coatings, and thus resolve their structure. Buffering salt The dopamine starts polymerizing when the buffered solution reaches a pH of 8.5 or higher. "One thing we noticed is that the buffering salt TRIS became part of the structure, a sizeable part during the first phases of polymerization, and to a lesser degree as the reaction progressed." The final analysis of the process reveals auto-oxidation of dopamine, followed by crosslinking, intramolecular cyclization, and isomerization. This study reveals the formation and structure of polydopamine coatings, which allows scientists to adapt the process for different applications. "We also believe that our use of clay nanotubes could be expanded to the study of other rapid processes," says Hemmatpour. "And adapting the nanotubes to increase surface area would allow us to slow down reactions even further." "There are other interesting observations from this study," Hemmatpour adds. "In neural cells, dopamine is stored in vesicles with a very low pH, but in neurodegenerative diseases, these vesicles somehow become leaky, and the dopamine accumulates in the cytosol where the pH is higher. There, the dopamine polymerizes into toxic clumps, which eventually kill neurons. Our study offers new insights into this mechanism and the intermediates of this process that can be used to find a way to treat neurodegenerative 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 Global warming is markedly changing diverse coral reef ecosystems through an increasing frequency and magnitude of mass bleaching events 1 , 2 , 3 . How local impacts scale up across affected regions depends on numerous factors, including patchiness in coral mortality, metabolic effects of extreme temperatures on populations of reef-dwelling species 4 and interactions between taxa. Here we use data from before and after the 2016 mass bleaching event to evaluate ecological changes in corals, algae, fishes and mobile invertebrates at 186 sites along the full latitudinal span of the Great Barrier Reef and western Coral Sea. One year after the bleaching event, reductions in live coral cover of up to 51% were observed on surveyed reefs that experienced extreme temperatures; however, regional patterns of coral mortality were patchy. Consistent declines in coral-feeding fishes were evident at the most heavily affected reefs, whereas few other short-term responses of reef fishes and invertebrates could be attributed directly to changes in coral cover. Nevertheless, substantial region-wide ecological changes occurred that were mostly independent of coral loss, and instead appeared to be linked directly to sea temperatures. Community-wide trophic restructuring was evident, with weakening of strong pre-existing latitudinal gradients in the diversity of fishes, invertebrates and their functional groups. In particular, fishes that scrape algae from reef surfaces, which are considered to be important for recovery after bleaching 2 , declined on northern reefs, whereas other herbivorous groups increased on southern reefs. The full impact of the 2016 bleaching event may not be realized until dead corals erode during the next decade 5 , 6 . However, our short-term observations suggest that the recovery processes, and the ultimate scale of impact, are affected by functional changes in communities, which in turn depend on the thermal affinities of local reef-associated fauna. Such changes will vary geographically, and may be particularly acute at locations where many fishes and invertebrates are close to their thermal distribution limits 7 . Main The 2016 mass bleaching event affected coral reefs world-wide, with catastrophic impacts reported in the Red Sea, central Indian Ocean, across the Pacific Ocean and in the Caribbean 3 , 8 , 9 . The Australian Great Barrier Reef (GBR), the largest coral reef system in the world, experienced the warmest temperatures on record for the region. An estimated 91.1% of reefs along the GBR experienced some bleaching 3 , resulting in an estimated loss of approximately 30% of live coral cover over the following six months 10 . The event was thus comparable to the 1998 mass bleaching event in the Indian Ocean in terms of reported impacts on corals 2 , 11 . We surveyed 186 reef sites along the GBR and at less-studied isolated reefs in the Coral Sea before and after the 2016 bleaching event, and here we report reef- and regional-scale effects of the extreme thermal anomaly and loss of coral cover on the rich reef-associated fish and mobile invertebrate fauna. At each site, globally standardized Reef Life Survey census methods 12 were used to quantify changes to coral cover, reef fishes and mobile macroinvertebrates at multiple depths (overall mean, 6.7 m; range, 0.8–17.0 m). ‘Before’ data were obtained between 2010 and 2015, and ‘after’ data were obtained 8–12 months after bleaching. As reported elsewhere 10 , decreases in live hard coral cover were widespread (Fig. 1 ), although we found that the regional pattern was more spatially heterogeneous than previously described, when field surveys were standardized amongst shallow reef crest habitat 10 . Forty-four of the 186 surveyed sites experienced absolute declines in live coral cover that exceeded 10% (up to 51% loss for one site at Osprey Reef), with the northern Coral Sea reefs suffering the most consistent losses (Fig. 1a, b ). The magnitude of coral-cover change was related to the local sea temperature anomalies (Fig. 1d and Extended Data Fig. 1 ), but coral loss varied considerably, and not all reefs in regions that experienced the greatest temperature anomalies experienced losses in live coral cover. In some cases, such as the central Coral Sea reefs, a history of cyclone damage meant that there was relatively little coral to lose. Thus, geographical patterns in pre-bleaching cover had a critical role in the realized effects of bleaching on corals (Fig. 1d ). Coral-cover losses of the greatest magnitude occurred in disparate locations, including in the northern Coral Sea (Boot and Osprey Reefs; mean, 15% absolute cover loss, or approximately 40% of the pre-bleaching live coral cover), and the southern GBR (most southerly Swain Reefs; 28% loss, or 100% of pre-bleaching cover). The northern reefs in the GBR experienced the most extensive bleaching of those surveyed during the 2016 event 3 , but not all of the reefs in that area suffered the extreme rates of live coral-cover loss that were observed more generally 10 (Fig. 1a, b ). The fate of bleached corals can vary considerably 13 , 14 , and a reasonable proportion of corals on some of these reefs must have regained their zooxanthellae and survived the bleaching event. Algal cover substantially increased across the majority of reefs that experienced coral declines (Fig. 1c and Extended Data Fig. 2 ). Fig. 1: Observed changes in live hard coral cover from the 2016 mass bleaching event across the Coral Sea and GBR. a – c , Reefs in the Coral Sea showed relatively consistent losses of live corals ( a , b ) and gains in algal cover ( c ) in the north, whereas changes along the GBR were highly patchy. Absolute changes in live coral cover are mapped for individual sites ( n = 186), with aggregation of sites at the reef scale shown as plusses ( n = 53). d , Coral-cover loss was related to the local heat anomaly from January to March 2016 regardless of depth, an effect that increased in strength according to pre-bleaching cover of live corals. Average pre-bleaching cover for the region was 26% (middle), whereas low and", "role": "user" }, { "content": "Research published today in Nature describes upheaval among fish and invertebrate communities after a marine heatwave hit Australia's Great Barrier Reef and Coral Sea in early 2016. The IMAS-led study analysed data collected across these areas by the Reef Life Survey (RLS) citizen science program. It identified important changes in reef-animal communities that may affect the resilience of coral reefs, potentially reducing the capacity of corals to rebuild after mass bleaching. Coral reefs are among the most valuable ecosystems on Earth, providing irreplaceable benefits to biodiversity and people. The World Heritage listed Great Barrier Reef is the largest coral reef system and a place of outstanding universal value. \"We know that coral reef ecosystems are changing dramatically in response to global warming, but the focus has usually been on the fate of corals, with clear impacts of mass bleaching observable from aerial images,\" study leader Rick Stuart-Smith said. \"We were interested in how the loss of coral compared with other changes across the full region. \"After reviewing surveys of corals, seaweed, fishes and mobile invertebrates such as sea urchins at 186 sites across the Great Barrier Reef and western Coral Sea—before and after the 2106 heatwave—we realised that coral bleaching was only part of the story. A diver on the Great Barrier Reef conducts a survey for Reef Life Survey (RLS). Credit: Rick Stuart-Smith \"Changes were also happening around the bleached corals, to the fishes and other animals that the reefs support, and which in turn assist coral recovery.\" The study's most important finding was the detection of broad regional ecosystem change that was distinct from the degree of coral loss at each site. An overarching change was consistent across all the surveyed reefs, even those not affected by coral loss due to bleaching. \"While severe declines in live coral cover occurred on northern Great Barrier Reef reefs, losses in the northern Coral Sea were even greater,\" co-author and RLS survey leader, Professor Graham Edgar said. \"However even in the worst hit areas, coral losses varied greatly from reef to reef, with a few sites showing small coral gains. \"The only change in fish or invertebrates that clearly matched this patchy change in coral cover was a decline in coral-feeding fishes such as butterflyfishes. \"Other big changes related more directly to the effect of warmer temperatures on the fishes and invertebrates.\" A Reef Life Survey (RLS) diver conducts a survey. Credit: Rick Stuart-Smith An example of this change in animal populations was seen in parrotfishes, which occurred in fewer surveys across the northern reefs after the bleaching event, but this response was not directly associated with sites of coral cover loss. These herbivorous fishes play an important 'functional' role in preventing algae from taking over and displacing corals on disturbed reefs. They appeared particularly sensitive to the warmer conditions, and their loss may affect the capacity of corals to rebuild. \"Our observations suggest that recovery processes will depend on such functional changes in reef communities, which in turn depend on how temperatures change the makeup of fish and invertebrates that live on the reefs,\" Dr. Stuart-Smith said. \"Although we are lucky that herbivorous fishes are not heavily targeted by fishing in Australia, our results highlight the potential for some ecologically important groups of reef animals to be disproportionately affected by warmer temperatures, particularly near the warm edge of their distributions. \"So as well as considering how to conserve and restore corals in areas affected by bleaching, we also need to consider how to maintain or build the broader fish communities that provide reef resilience. \"This may mean considering where particular species in these important groups are subject to overlapping pressures such as fishing, warming and habitat loss, to better plan protected areas or manage human pressures like fishing for a warmer 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 Global warming is markedly changing diverse coral reef ecosystems through an increasing frequency and magnitude of mass bleaching events 1 , 2 , 3 . How local impacts scale up across affected regions depends on numerous factors, including patchiness in coral mortality, metabolic effects of extreme temperatures on populations of reef-dwelling species 4 and interactions between taxa. Here we use data from before and after the 2016 mass bleaching event to evaluate ecological changes in corals, algae, fishes and mobile invertebrates at 186 sites along the full latitudinal span of the Great Barrier Reef and western Coral Sea. One year after the bleaching event, reductions in live coral cover of up to 51% were observed on surveyed reefs that experienced extreme temperatures; however, regional patterns of coral mortality were patchy. Consistent declines in coral-feeding fishes were evident at the most heavily affected reefs, whereas few other short-term responses of reef fishes and invertebrates could be attributed directly to changes in coral cover. Nevertheless, substantial region-wide ecological changes occurred that were mostly independent of coral loss, and instead appeared to be linked directly to sea temperatures. Community-wide trophic restructuring was evident, with weakening of strong pre-existing latitudinal gradients in the diversity of fishes, invertebrates and their functional groups. In particular, fishes that scrape algae from reef surfaces, which are considered to be important for recovery after bleaching 2 , declined on northern reefs, whereas other herbivorous groups increased on southern reefs. The full impact of the 2016 bleaching event may not be realized until dead corals erode during the next decade 5 , 6 . However, our short-term observations suggest that the recovery processes, and the ultimate scale of impact, are affected by functional changes in communities, which in turn depend on the thermal affinities of local reef-associated fauna. Such changes will vary geographically, and may be particularly acute at locations where many fishes and invertebrates are close to their thermal distribution limits 7 . Main The 2016 mass bleaching event affected coral reefs world-wide, with catastrophic impacts reported in the Red Sea, central Indian Ocean, across the Pacific Ocean and in the Caribbean 3 , 8 , 9 . The Australian Great Barrier Reef (GBR), the largest coral reef system in the world, experienced the warmest temperatures on record for the region. An estimated 91.1% of reefs along the GBR experienced some bleaching 3 , resulting in an estimated loss of approximately 30% of live coral cover over the following six months 10 . The event was thus comparable to the 1998 mass bleaching event in the Indian Ocean in terms of reported impacts on corals 2 , 11 . We surveyed 186 reef sites along the GBR and at less-studied isolated reefs in the Coral Sea before and after the 2016 bleaching event, and here we report reef- and regional-scale effects of the extreme thermal anomaly and loss of coral cover on the rich reef-associated fish and mobile invertebrate fauna. At each site, globally standardized Reef Life Survey census methods 12 were used to quantify changes to coral cover, reef fishes and mobile macroinvertebrates at multiple depths (overall mean, 6.7 m; range, 0.8–17.0 m). ‘Before’ data were obtained between 2010 and 2015, and ‘after’ data were obtained 8–12 months after bleaching. As reported elsewhere 10 , decreases in live hard coral cover were widespread (Fig. 1 ), although we found that the regional pattern was more spatially heterogeneous than previously described, when field surveys were standardized amongst shallow reef crest habitat 10 . Forty-four of the 186 surveyed sites experienced absolute declines in live coral cover that exceeded 10% (up to 51% loss for one site at Osprey Reef), with the northern Coral Sea reefs suffering the most consistent losses (Fig. 1a, b ). The magnitude of coral-cover change was related to the local sea temperature anomalies (Fig. 1d and Extended Data Fig. 1 ), but coral loss varied considerably, and not all reefs in regions that experienced the greatest temperature anomalies experienced losses in live coral cover. In some cases, such as the central Coral Sea reefs, a history of cyclone damage meant that there was relatively little coral to lose. Thus, geographical patterns in pre-bleaching cover had a critical role in the realized effects of bleaching on corals (Fig. 1d ). Coral-cover losses of the greatest magnitude occurred in disparate locations, including in the northern Coral Sea (Boot and Osprey Reefs; mean, 15% absolute cover loss, or approximately 40% of the pre-bleaching live coral cover), and the southern GBR (most southerly Swain Reefs; 28% loss, or 100% of pre-bleaching cover). The northern reefs in the GBR experienced the most extensive bleaching of those surveyed during the 2016 event 3 , but not all of the reefs in that area suffered the extreme rates of live coral-cover loss that were observed more generally 10 (Fig. 1a, b ). The fate of bleached corals can vary considerably 13 , 14 , and a reasonable proportion of corals on some of these reefs must have regained their zooxanthellae and survived the bleaching event. Algal cover substantially increased across the majority of reefs that experienced coral declines (Fig. 1c and Extended Data Fig. 2 ). Fig. 1: Observed changes in live hard coral cover from the 2016 mass bleaching event across the Coral Sea and GBR. a – c , Reefs in the Coral Sea showed relatively consistent losses of live corals ( a , b ) and gains in algal cover ( c ) in the north, whereas changes along the GBR were highly patchy. Absolute changes in live coral cover are mapped for individual sites ( n = 186), with aggregation of sites at the reef scale shown as plusses ( n = 53). d , Coral-cover loss was related to the local heat anomaly from January to March 2016 regardless of depth, an effect that increased in strength according to pre-bleaching cover of live corals. Average pre-bleaching cover for the region was 26% (middle), whereas low and<|im_end|> <|im_start|>assistant Research published today in Nature describes upheaval among fish and invertebrate communities after a marine heatwave hit Australia's Great Barrier Reef and Coral Sea in early 2016. The IMAS-led study analysed data collected across these areas by the Reef Life Survey (RLS) citizen science program. It identified important changes in reef-animal communities that may affect the resilience of coral reefs, potentially reducing the capacity of corals to rebuild after mass bleaching. Coral reefs are among the most valuable ecosystems on Earth, providing irreplaceable benefits to biodiversity and people. The World Heritage listed Great Barrier Reef is the largest coral reef system and a place of outstanding universal value. "We know that coral reef ecosystems are changing dramatically in response to global warming, but the focus has usually been on the fate of corals, with clear impacts of mass bleaching observable from aerial images," study leader Rick Stuart-Smith said. "We were interested in how the loss of coral compared with other changes across the full region. "After reviewing surveys of corals, seaweed, fishes and mobile invertebrates such as sea urchins at 186 sites across the Great Barrier Reef and western Coral Sea—before and after the 2106 heatwave—we realised that coral bleaching was only part of the story. A diver on the Great Barrier Reef conducts a survey for Reef Life Survey (RLS). Credit: Rick Stuart-Smith "Changes were also happening around the bleached corals, to the fishes and other animals that the reefs support, and which in turn assist coral recovery." The study's most important finding was the detection of broad regional ecosystem change that was distinct from the degree of coral loss at each site. An overarching change was consistent across all the surveyed reefs, even those not affected by coral loss due to bleaching. "While severe declines in live coral cover occurred on northern Great Barrier Reef reefs, losses in the northern Coral Sea were even greater," co-author and RLS survey leader, Professor Graham Edgar said. "However even in the worst hit areas, coral losses varied greatly from reef to reef, with a few sites showing small coral gains. "The only change in fish or invertebrates that clearly matched this patchy change in coral cover was a decline in coral-feeding fishes such as butterflyfishes. "Other big changes related more directly to the effect of warmer temperatures on the fishes and invertebrates." A Reef Life Survey (RLS) diver conducts a survey. Credit: Rick Stuart-Smith An example of this change in animal populations was seen in parrotfishes, which occurred in fewer surveys across the northern reefs after the bleaching event, but this response was not directly associated with sites of coral cover loss. These herbivorous fishes play an important 'functional' role in preventing algae from taking over and displacing corals on disturbed reefs. They appeared particularly sensitive to the warmer conditions, and their loss may affect the capacity of corals to rebuild. "Our observations suggest that recovery processes will depend on such functional changes in reef communities, which in turn depend on how temperatures change the makeup of fish and invertebrates that live on the reefs," Dr. Stuart-Smith said. "Although we are lucky that herbivorous fishes are not heavily targeted by fishing in Australia, our results highlight the potential for some ecologically important groups of reef animals to be disproportionately affected by warmer temperatures, particularly near the warm edge of their distributions. "So as well as considering how to conserve and restore corals in areas affected by bleaching, we also need to consider how to maintain or build the broader fish communities that provide reef resilience. "This may mean considering where particular species in these important groups are subject to overlapping pressures such as fishing, warming and habitat loss, to better plan protected areas or manage human pressures like fishing for a warmer future." <|im_end|>

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41665, 2956, 23966, 13, 220, 16, 7026, 719, 53103, 4814, 28830, 33452, 11, 323, 539, 682, 92822, 304, 13918, 430, 10534, 279, 12474, 9499, 75559, 10534, 18151, 304, 3974, 53103, 3504, 13, 763, 1063, 5157, 11, 1778, 439, 279, 8792, 64916, 15379, 92822, 11, 264, 3925, 315, 32343, 606, 5674, 8967, 430, 1070, 574, 12309, 2697, 53103, 311, 9229, 13, 14636, 11, 54001, 12912, 304, 864, 12, 901, 12092, 3504, 1047, 264, 9200, 3560, 304, 279, 15393, 6372, 315, 12704, 12092, 389, 1867, 1147, 320, 30035, 13, 220, 16, 67, 7609, 64916, 76465, 18151, 315, 279, 12474, 26703, 10222, 304, 85129, 10687, 11, 2737, 304, 279, 18671, 64916, 15379, 320, 18402, 323, 15796, 1762, 88, 1050, 45062, 26, 3152, 11, 220, 868, 4, 10973, 3504, 4814, 11, 477, 13489, 220, 1272, 4, 315, 279, 864, 12, 901, 12092, 3974, 53103, 3504, 705, 323, 279, 18561, 480, 13396, 320, 3646, 5945, 700, 398, 4593, 467, 1050, 45062, 26, 220, 1591, 4, 4814, 11, 477, 220, 1041, 4, 315, 864, 12, 901, 12092, 3504, 570, 578, 18671, 92822, 304, 279, 480, 13396, 10534, 279, 1455, 16781, 12704, 12092, 315, 1884, 49098, 2391, 279, 220, 679, 21, 1567, 220, 18, 1174, 719, 539, 682, 315, 279, 92822, 304, 430, 3158, 16654, 279, 14560, 7969, 315, 3974, 53103, 76465, 4814, 430, 1051, 13468, 810, 8965, 220, 605, 320, 30035, 13, 220, 16, 64, 11, 293, 7609, 578, 25382, 315, 12704, 3939, 1867, 1147, 649, 13592, 33452, 220, 1032, 1174, 220, 975, 1174, 323, 264, 13579, 21801, 315, 1867, 1147, 389, 1063, 315, 1521, 92822, 2011, 617, 86025, 872, 42014, 87, 32329, 616, 6043, 323, 26968, 279, 12704, 12092, 1567, 13, 1708, 16876, 3504, 32302, 7319, 4028, 279, 8857, 315, 92822, 430, 10534, 53103, 58054, 320, 30035, 13, 220, 16, 66, 323, 41665, 2956, 23966, 13, 220, 17, 7609, 23966, 13, 220, 16, 25, 51541, 2841, 4442, 304, 3974, 2653, 53103, 3504, 505, 279, 220, 679, 21, 3148, 12704, 12092, 1567, 4028, 279, 64916, 15379, 323, 480, 13396, 13, 264, 1389, 272, 1174, 1050, 45062, 304, 279, 64916, 15379, 8710, 12309, 13263, 18151, 315, 3974, 1867, 1147, 320, 264, 1174, 293, 883, 323, 20192, 304, 453, 16876, 3504, 320, 272, 883, 304, 279, 10411, 11, 20444, 4442, 3235, 279, 480, 13396, 1051, 7701, 11140, 88, 13, 49981, 4442, 304, 3974, 53103, 3504, 527, 24784, 369, 3927, 6732, 320, 308, 284, 220, 9714, 705, 449, 52729, 315, 6732, 520, 279, 71145, 5569, 6982, 439, 628, 83972, 320, 308, 284, 220, 4331, 570, 294, 1174, 64916, 76465, 4814, 574, 5552, 311, 279, 2254, 8798, 64048, 505, 6186, 311, 5587, 220, 679, 21, 15851, 315, 8149, 11, 459, 2515, 430, 7319, 304, 8333, 4184, 311, 864, 12, 901, 12092, 3504, 315, 3974, 1867, 1147, 13, 24478, 864, 12, 901, 12092, 3504, 369, 279, 5654, 574, 220, 1627, 4, 320, 20231, 705, 20444, 3428, 323, 128257, 198, 128256, 78191, 198, 28528, 4756, 3432, 304, 22037, 16964, 96710, 22510, 4315, 7795, 323, 304, 65932, 65216, 10977, 1306, 264, 29691, 8798, 31498, 4295, 8494, 596, 8681, 72087, 77036, 323, 64916, 15379, 304, 4216, 220, 679, 21, 13, 578, 6654, 1950, 35054, 4007, 67458, 828, 14890, 4028, 1521, 5789, 555, 279, 77036, 9601, 24507, 320, 4833, 50, 8, 22618, 8198, 2068, 13, 1102, 11054, 3062, 4442, 304, 71145, 19415, 2931, 10977, 430, 1253, 7958, 279, 56062, 315, 53103, 92822, 11, 13893, 18189, 279, 8824, 315, 1867, 1147, 311, 32593, 1306, 3148, 12704, 12092, 13, 64916, 92822, 527, 4315, 279, 1455, 15525, 61951, 389, 9420, 11, 8405, 6348, 8319, 481, 7720, 311, 73119, 323, 1274, 13, 578, 4435, 34243, 10212, 8681, 72087, 77036, 374, 279, 7928, 53103, 71145, 1887, 323, 264, 2035, 315, 19310, 20789, 907, 13, 330, 1687, 1440, 430, 53103, 71145, 61951, 527, 10223, 29057, 304, 2077, 311, 3728, 24808, 11, 719, 279, 5357, 706, 6118, 1027, 389, 279, 25382, 315, 1867, 1147, 11, 449, 2867, 25949, 315, 3148, 12704, 12092, 40635, 505, 41884, 5448, 1359, 4007, 7808, 23194, 44632, 97338, 1071, 13, 330, 1687, 1051, 8173, 304, 1268, 279, 4814, 315, 53103, 7863, 449, 1023, 4442, 4028, 279, 2539, 5654, 13, 330, 6153, 34988, 32313, 315, 1867, 1147, 11, 67329, 12320, 11, 95461, 323, 6505, 304, 65932, 99868, 1778, 439, 9581, 220, 2639, 1354, 520, 220, 9714, 6732, 4028, 279, 8681, 72087, 77036, 323, 19001, 64916, 15379, 2345, 15145, 323, 1306, 279, 220, 8848, 21, 8798, 31498, 86319, 41193, 430, 53103, 12704, 12092, 574, 1193, 961, 315, 279, 3446, 13, 362, 37441, 389, 279, 8681, 72087, 77036, 74198, 264, 10795, 369, 77036, 9601, 24507, 320, 4833, 50, 570, 16666, 25, 23194, 44632, 97338, 330, 11569, 1051, 1101, 12765, 2212, 279, 12704, 3939, 1867, 1147, 11, 311, 279, 95461, 323, 1023, 10099, 430, 279, 92822, 1862, 11, 323, 902, 304, 2543, 7945, 53103, 13654, 1210, 578, 4007, 596, 1455, 3062, 9455, 574, 279, 18468, 315, 7353, 15481, 26031, 2349, 430, 574, 12742, 505, 279, 8547, 315, 53103, 4814, 520, 1855, 2816, 13, 1556, 98536, 2349, 574, 13263, 4028, 682, 279, 49098, 92822, 11, 1524, 1884, 539, 11754, 555, 53103, 4814, 4245, 311, 12704, 12092, 13, 330, 8142, 15748, 58054, 304, 3974, 53103, 3504, 10222, 389, 18671, 8681, 72087, 77036, 92822, 11, 18151, 304, 279, 18671, 64916, 15379, 1051, 1524, 7191, 1359, 1080, 43802, 323, 432, 7416, 10795, 7808, 11, 17054, 26181, 60091, 1071, 13, 330, 11458, 1524, 304, 279, 12047, 4295, 5789, 11, 53103, 18151, 28830, 19407, 505, 71145, 311, 71145, 11, 449, 264, 2478, 6732, 9204, 2678, 53103, 20192, 13, 330, 791, 1193, 2349, 304, 7795, 477, 304, 65932, 99868, 430, 9539, 18545, 420, 11140, 88, 2349, 304, 53103, 3504, 574, 264, 18174, 304, 53103, 12, 46519, 95461, 1778, 439, 56269, 18668, 288, 13, 330, 11663, 2466, 4442, 5552, 810, 6089, 311, 279, 2515, 315, 46039, 20472, 389, 279, 95461, 323, 304, 65932, 99868, 1210, 362, 77036, 9601, 24507, 320, 4833, 50, 8, 37441, 74198, 264, 10795, 13, 16666, 25, 23194, 44632, 97338, 1556, 3187, 315, 420, 2349, 304, 10065, 22673, 574, 3970, 304, 1370, 4744, 18668, 288, 11, 902, 10222, 304, 17162, 32313, 4028, 279, 18671, 92822, 1306, 279, 12704, 12092, 1567, 11, 719, 420, 2077, 574, 539, 6089, 5938, 449, 6732, 315, 53103, 3504, 4814, 13, 4314, 39999, 344, 20857, 95461, 1514, 459, 3062, 364, 50328, 6, 3560, 304, 27252, 68951, 505, 4737, 927, 323, 13770, 4628, 1867, 1147, 389, 56507, 92822, 13, 2435, 9922, 8104, 16614, 311, 279, 46039, 4787, 11, 323, 872, 4814, 1253, 7958, 279, 8824, 315, 1867, 1147, 311, 32593, 13, 330, 8140, 24654, 4284, 430, 13654, 11618, 690, 6904, 389, 1778, 16003, 4442, 304, 71145, 10977, 11, 902, 304, 2543, 6904, 389, 1268, 20472, 2349, 279, 27649, 315, 7795, 323, 304, 65932, 99868, 430, 3974, 389, 279, 92822, 1359, 2999, 13, 44632, 97338, 1071, 13, 330, 16179, 584, 527, 18069, 430, 39999, 344, 20857, 95461, 527, 539, 17345, 17550, 555, 20543, 304, 8494, 11, 1057, 3135, 11415, 279, 4754, 369, 1063, 12208, 30450, 3062, 5315, 315, 71145, 10099, 311, 387, 73152, 11754, 555, 46039, 20472, 11, 8104, 3221, 279, 8369, 6964, 315, 872, 43785, 13, 330, 4516, 439, 1664, 439, 13126, 1268, 311, 78548, 323, 15301, 1867, 1147, 304, 5789, 11754, 555, 12704, 12092, 11, 584, 1101, 1205, 311, 2980, 1268, 311, 10519, 477, 1977, 279, 27927, 7795, 10977, 430, 3493, 71145, 56062, 13, 330, 2028, 1253, 3152, 13126, 1405, 4040, 9606, 304, 1521, 3062, 5315, 527, 3917, 311, 50917, 40850, 1778, 439, 20543, 11, 24808, 323, 39646, 4814, 11, 311, 2731, 3197, 2682, 5789, 477, 10299, 3823, 40850, 1093, 20543, 369, 264, 46039, 3938, 1210, 220, 128257, 198 ]

2,124

[ { "content": "You are a great 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 evaluate the risk of first trimester exposure to prescription opioids for major congenital malformations, previously reported to be associated with such exposure. Design Population based cohort study. Setting Nationwide sample of publicly and commercially insured pregnant women linked to their liveborn infants, nested in the Medicaid Analytic eXtract (MAX, 2000-14) and the MarketScan Research Database (MarketScan, 2003-15). Participants 1 602 580 publicly insured (MAX) and 1 177 676 commercially insured (MarketScan) pregnant women with eligibility from at least three months before pregnancy to one month after delivery; infants with eligibility for at least three months after birth. Interventions Use of prescription opioids was ascertained by requiring two or more dispensations of any opioid during the first trimester. Main outcomes measures Major malformations overall, cardiac malformations overall, ventricular septal defect, secundum atrial septal defect/patent foramen ovale, neural tube defect, clubfoot, and oral cleft, defined based on validated algorithms. Propensity score stratification was used to adjust for potential confounders and/or proxies for confounders. Estimates from each database were combined using meta-analysis. Results 70 447 (4.4%) of 1 602 580 publicly insured and 12 454 (1.1%) of 1 177 676 commercially insured pregnant women had two or more dispensations of an opioid during the first trimester. Absolute risk of malformations overall was 41.0 (95% confidence interval 39.5 to 42.5) per 1000 pregnancies exposed to opioids versus 32.0 (31.7 to 32.3) per 1000 unexposed pregnancies in the MAX cohort, and 42.6 (39.0 to 46.1) and 37.3 (37.0 to 37.7) per 1000, respectively, in the MarketScan cohort. Pooled unadjusted relative risk estimates were raised for all outcomes but shifted substantially toward the null after adjustment; for malformations overall (relative risk 1.06, 95% confidence interval 1.02 to 1.10), cardiovascular malformations (1.09, 1.00 to 1.18), ventricular septal defect (1.07, 0.95 to 1.21), atrial septal defect/patent foramen ovale (1.04, 0.88 to 1.24), neural tube defect (0.82, 0.53 to 1.27), and clubfoot (1.06, 0.88 to 1.28). The relative risk for oral clefts remained raised after adjustment (1.21, 0.98 to 1.50), with a higher risk of cleft palate (1.62, 1.23 to 2.14). Conclusions Prescription opioids used in early pregnancy are not associated with a substantial increase in risk for most of the malformation types considered, although a small increase in the risk of oral clefts associated with their use is possible. Introduction Pain is common during pregnancy. In addition to the pain that affects women of reproductive age generally, pregnant women undergo a range of physiological changes, including increased ligamentous laxity and weight gain, which can cause or worsen a range of pain inducing conditions. 1 Thus analgesics, including opioids, are drugs often used during pregnancy. 2 Nationwide estimates in the United States suggest that approximately 22% of Medicaid beneficiaries 3 and 14% of commercial insurance beneficiaries 4 receive at least one prescription opioid during pregnancy. The frequency of opioid use during pregnancy in European countries, Canada, and Australia, although lower than in the US, is also substantial (around 5% for most populations studied). 5 6 7 8 9 10 Evidence for the teratogenicity of opioids from epidemiological studies is limited and conflicting. A systematic review from the Centers for Disease Control and Prevention in the US found that previous studies most often reported increases in the risk of congenital malformations overall, cardiovascular malformations overall, ventricular septal defect/atrial septal defect, spina bifida, oral cleft, and clubfoot. 11 In view of the quality of the evidence considerable uncertainty remains about the association between opioids and congenital malformations. 11 A teratogenic effect of opioids is biologically plausible as endogenous opioids are regulators of growth and development, raising concern that use of exogenous opioids at key times might disrupt normal developmental processes, giving rise to congenital malformations. 12 13 The potential increase in the risk of birth defects associated with use of opioids has been highlighted by public health authorities. 14 Understanding this risk is important given the substantial number of women exposed during early pregnancy and the need to appraise the risk-benefit trade-off in the use of opioids for pain control during this period. Additionally, as about half of all pregnancies are unplanned, 15 understanding the risk informs the safety of opioid use in women of reproductive age more generally. 16 17 In this study we assessed the association between exposure to prescription opioids during the first trimester and the risk of congenital malformations. We focused on types of malformation previously suggested to be associated with such exposure, while carefully controlling for confounding and other biases, using nationwide cohorts of publicly and commercially insured pregnant women. Methods Data source and study cohort The study used pregnancy cohorts nested in the Medicaid Analytic eXtract (MAX), which includes data on healthcare use for Medicaid beneficiaries nationwide, for the years 2000 to 2014, and the IBM Health MarketScan Research Database (MarketScan), which includes data on healthcare use from a nationwide sample of commercially insured beneficiaries, for the years 2003 to 2015. The development of the MAX pregnancy cohort by linking maternal and infant claims records has been previously described 18 ; it has been used extensively to study the safety of drugs in pregnancy. 19 20 21 22 23 24 25 26 The MarketScan pregnancy cohort was developed similarly, by linking maternal and infant claims. Both data sources include information on maternal demographics, diagnoses, and procedures received during inpatient, outpatient, or emergency department visits, and dispensed outpatient prescription drugs. The inclusion and exclusion criteria are described in appendix 1 and eFigures 1 and 2. In the primary analysis, pregnancies were considered exposed if the mother filled at least two opioid prescriptions during the first trimester (first 90 days of pregnancy), which is the etiologically relevant exposure window for congenital malformations. eTable 1 lists the specific opioids included. We defined exposure based on two filled prescriptions on the assumption that if a woman refilled her prescription for opioids, she was probably consuming them. Pregnancies were considered unexposed if women did not fill an opioid prescription from 90 days before the date of the", "role": "user" }, { "content": "Two studies published by The BMJ today find no links between prescription opioids or macrolide antibiotics taken during pregnancy and risk of major birth defects. Both opioids (painkillers) and macrolides (antibiotics) are often prescribed during pregnancy. Some previous studies have reported associations between exposure to opioids and macrolides and certain birth defects, but results are inconsistent. Two studies published today set out to address this uncertainty. The first study involved data for more than 82,000 US women who received two or more prescriptions for any opioid during early (first trimester) pregnancy from 2000 to 2015. After taking account of other potential risk factors, the researchers found no clinically meaningful increase in the risk of major birth defects overall, or in heart malformations, club foot or neural tube defects. They did find a small increased risk for cleft palate (four to five additional cases of cleft palate per 10,000 pregnancies exposed to opioids in the first trimester) and say clinicians should advise patients about this potential risk. But overall, they say these findings suggest that prescription opioids used in early pregnancy are not associated with a substantial increase in risk for most of the malformation types considered. In the second study, researchers in Denmark compared data for nearly 1.2 million pregnancies from 1997 to 2016 and found no association between exposure to macrolides in early pregnancy and risk of major birth defects. Infants born with major birth defects occurred in 35 per 1000 pregnancies exposed to macrolides compared with 37 per 1000 pregnancies exposed to penicillin and 33 per 1000 unexposed pregnancies. Results were unchanged after further analysis of individual macrolides and specific birth defects according to organ systems, suggesting that the findings are robust. Both studies are observational, so can't establish cause, and they relied on women taking the drugs as prescribed. What's more, the researchers can't rule out the possibility that they may have missed some birth defects. However, these were large studies using reliable medical insurance and national registry data, respectively, and were able to account for a range of other risk factors that may have influenced the results. As such, both research teams say their findings provide reassurance about the risk of major birth defects when treatment with opioids or macrolide antibiotics are needed during pregnancy. They also help inform clinicians, patients, and drug regulatory authorities about the selection of medications for women who are pregnant and women of reproductive age who may inadvertently become pregnant. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 evaluate the risk of first trimester exposure to prescription opioids for major congenital malformations, previously reported to be associated with such exposure. Design Population based cohort study. Setting Nationwide sample of publicly and commercially insured pregnant women linked to their liveborn infants, nested in the Medicaid Analytic eXtract (MAX, 2000-14) and the MarketScan Research Database (MarketScan, 2003-15). Participants 1 602 580 publicly insured (MAX) and 1 177 676 commercially insured (MarketScan) pregnant women with eligibility from at least three months before pregnancy to one month after delivery; infants with eligibility for at least three months after birth. Interventions Use of prescription opioids was ascertained by requiring two or more dispensations of any opioid during the first trimester. Main outcomes measures Major malformations overall, cardiac malformations overall, ventricular septal defect, secundum atrial septal defect/patent foramen ovale, neural tube defect, clubfoot, and oral cleft, defined based on validated algorithms. Propensity score stratification was used to adjust for potential confounders and/or proxies for confounders. Estimates from each database were combined using meta-analysis. Results 70 447 (4.4%) of 1 602 580 publicly insured and 12 454 (1.1%) of 1 177 676 commercially insured pregnant women had two or more dispensations of an opioid during the first trimester. Absolute risk of malformations overall was 41.0 (95% confidence interval 39.5 to 42.5) per 1000 pregnancies exposed to opioids versus 32.0 (31.7 to 32.3) per 1000 unexposed pregnancies in the MAX cohort, and 42.6 (39.0 to 46.1) and 37.3 (37.0 to 37.7) per 1000, respectively, in the MarketScan cohort. Pooled unadjusted relative risk estimates were raised for all outcomes but shifted substantially toward the null after adjustment; for malformations overall (relative risk 1.06, 95% confidence interval 1.02 to 1.10), cardiovascular malformations (1.09, 1.00 to 1.18), ventricular septal defect (1.07, 0.95 to 1.21), atrial septal defect/patent foramen ovale (1.04, 0.88 to 1.24), neural tube defect (0.82, 0.53 to 1.27), and clubfoot (1.06, 0.88 to 1.28). The relative risk for oral clefts remained raised after adjustment (1.21, 0.98 to 1.50), with a higher risk of cleft palate (1.62, 1.23 to 2.14). Conclusions Prescription opioids used in early pregnancy are not associated with a substantial increase in risk for most of the malformation types considered, although a small increase in the risk of oral clefts associated with their use is possible. Introduction Pain is common during pregnancy. In addition to the pain that affects women of reproductive age generally, pregnant women undergo a range of physiological changes, including increased ligamentous laxity and weight gain, which can cause or worsen a range of pain inducing conditions. 1 Thus analgesics, including opioids, are drugs often used during pregnancy. 2 Nationwide estimates in the United States suggest that approximately 22% of Medicaid beneficiaries 3 and 14% of commercial insurance beneficiaries 4 receive at least one prescription opioid during pregnancy. The frequency of opioid use during pregnancy in European countries, Canada, and Australia, although lower than in the US, is also substantial (around 5% for most populations studied). 5 6 7 8 9 10 Evidence for the teratogenicity of opioids from epidemiological studies is limited and conflicting. A systematic review from the Centers for Disease Control and Prevention in the US found that previous studies most often reported increases in the risk of congenital malformations overall, cardiovascular malformations overall, ventricular septal defect/atrial septal defect, spina bifida, oral cleft, and clubfoot. 11 In view of the quality of the evidence considerable uncertainty remains about the association between opioids and congenital malformations. 11 A teratogenic effect of opioids is biologically plausible as endogenous opioids are regulators of growth and development, raising concern that use of exogenous opioids at key times might disrupt normal developmental processes, giving rise to congenital malformations. 12 13 The potential increase in the risk of birth defects associated with use of opioids has been highlighted by public health authorities. 14 Understanding this risk is important given the substantial number of women exposed during early pregnancy and the need to appraise the risk-benefit trade-off in the use of opioids for pain control during this period. Additionally, as about half of all pregnancies are unplanned, 15 understanding the risk informs the safety of opioid use in women of reproductive age more generally. 16 17 In this study we assessed the association between exposure to prescription opioids during the first trimester and the risk of congenital malformations. We focused on types of malformation previously suggested to be associated with such exposure, while carefully controlling for confounding and other biases, using nationwide cohorts of publicly and commercially insured pregnant women. Methods Data source and study cohort The study used pregnancy cohorts nested in the Medicaid Analytic eXtract (MAX), which includes data on healthcare use for Medicaid beneficiaries nationwide, for the years 2000 to 2014, and the IBM Health MarketScan Research Database (MarketScan), which includes data on healthcare use from a nationwide sample of commercially insured beneficiaries, for the years 2003 to 2015. The development of the MAX pregnancy cohort by linking maternal and infant claims records has been previously described 18 ; it has been used extensively to study the safety of drugs in pregnancy. 19 20 21 22 23 24 25 26 The MarketScan pregnancy cohort was developed similarly, by linking maternal and infant claims. Both data sources include information on maternal demographics, diagnoses, and procedures received during inpatient, outpatient, or emergency department visits, and dispensed outpatient prescription drugs. The inclusion and exclusion criteria are described in appendix 1 and eFigures 1 and 2. In the primary analysis, pregnancies were considered exposed if the mother filled at least two opioid prescriptions during the first trimester (first 90 days of pregnancy), which is the etiologically relevant exposure window for congenital malformations. eTable 1 lists the specific opioids included. We defined exposure based on two filled prescriptions on the assumption that if a woman refilled her prescription for opioids, she was probably consuming them. Pregnancies were considered unexposed if women did not fill an opioid prescription from 90 days before the date of the<|im_end|> <|im_start|>assistant Two studies published by The BMJ today find no links between prescription opioids or macrolide antibiotics taken during pregnancy and risk of major birth defects. Both opioids (painkillers) and macrolides (antibiotics) are often prescribed during pregnancy. Some previous studies have reported associations between exposure to opioids and macrolides and certain birth defects, but results are inconsistent. Two studies published today set out to address this uncertainty. The first study involved data for more than 82,000 US women who received two or more prescriptions for any opioid during early (first trimester) pregnancy from 2000 to 2015. After taking account of other potential risk factors, the researchers found no clinically meaningful increase in the risk of major birth defects overall, or in heart malformations, club foot or neural tube defects. They did find a small increased risk for cleft palate (four to five additional cases of cleft palate per 10,000 pregnancies exposed to opioids in the first trimester) and say clinicians should advise patients about this potential risk. But overall, they say these findings suggest that prescription opioids used in early pregnancy are not associated with a substantial increase in risk for most of the malformation types considered. In the second study, researchers in Denmark compared data for nearly 1.2 million pregnancies from 1997 to 2016 and found no association between exposure to macrolides in early pregnancy and risk of major birth defects. Infants born with major birth defects occurred in 35 per 1000 pregnancies exposed to macrolides compared with 37 per 1000 pregnancies exposed to penicillin and 33 per 1000 unexposed pregnancies. Results were unchanged after further analysis of individual macrolides and specific birth defects according to organ systems, suggesting that the findings are robust. Both studies are observational, so can't establish cause, and they relied on women taking the drugs as prescribed. What's more, the researchers can't rule out the possibility that they may have missed some birth defects. However, these were large studies using reliable medical insurance and national registry data, respectively, and were able to account for a range of other risk factors that may have influenced the results. As such, both research teams say their findings provide reassurance about the risk of major birth defects when treatment with opioids or macrolide antibiotics are needed during pregnancy. They also help inform clinicians, patients, and drug regulatory authorities about the selection of medications for women who are pregnant and women of reproductive age who may inadvertently become pregnant. <|im_end|>

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2,004

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Pneumolysin is a cholesterol-dependent cytolysin (CDC) and virulence factor of Streptococcus pneumoniae . It kills cells by forming pores assembled from oligomeric rings in cholesterol-containing membranes. Cryo-EM has revealed the structures of the membrane-surface bound pre-pore and inserted-pore oligomers, however the molecular contacts that mediate these oligomers are unknown because high-resolution information is not available. Here we have determined the crystal structure of full-length pneumolysin at 1.98 Å resolution. In the structure, crystal contacts demonstrate the likely interactions that enable polymerisation on the cell membrane and the molecular packing of the pre-pore complex. The hemolytic activity is abrogated in mutants that disrupt these intermolecular contacts, highlighting their importance during pore formation. An additional crystal structure of the membrane-binding domain alone suggests that changes in the conformation of a tryptophan rich-loop at the base of the toxin promote monomer-monomer interactions upon membrane binding by creating new contacts. Notably, residues at the interface are conserved in other members of the CDC family, suggesting a common mechanism for pore and pre-pore assembly. Introduction The cholesterol-dependent cytolysin (CDC), pneumolysin 1 is a virulence factor of the human pathogen Streptococcus pneumoniae (pneumococcus) 2 , the leading cause of bacterial pneumonia and a major agent of meningitis and septicaemia as well as debilitating diseases such as otitis media, septic arthritis, keratitis and sinusitis 3 . It is found in virtually all pneumococcal isolates and plays key roles in bacterial colonisation, invasion and inflammation 4 , 5 , 6 . A central feature of the toxin is the formation of transmembrane pores in cholesterol-containing membranes 7 , which lyse or disrupt cell functioning, depending on the concentration 8 , 9 , 10 . Pneumolysin and other CDCs bind to mammalian membranes through a tryptophan-rich loop and a threonine-leucine pair within a membrane-binding domain at the base of the toxin 11 , 12 . The tryptophan-rich loop has been proposed to spring out of the body of the toxin on association with the membrane 12 . All three tryptophans are implicated in membrane binding but Trp433 and Trp435 are particularly important 13 , 14 . Once bound to the membrane, monomers then oligomerise to form a pre-pore complex that subsequently undergoes a complex set of structural transitions to form a transmembrane pore, typically comprising 30–50 subunits. Structures of the pre-pore and inserted-pore oligomers have been determined by cryo-EM at ~28 Å and these structures together with recent analysis of the related CDC, suilysin, show that that pore formation follows the vertical collapse of the pre-pore structure with two extended beta-hairpins penetrating the membrane to form the large beta-barrel pore 7 , 15 . Although high-resolution X-ray structures have been determined for several CDCs, pneumolysin has proved to be elusive. Consequently, structure-function analysis has relied on models based on the structures of the other CDC toxins. Critically, the lack of high-resolution data means that the interactions enabling pneumolysin monomers to pack together to form the pore and pre-pore complexes is not known. In this work, we have determined the structure of pneumolysin at 1.98 Å resolution. The side-by-side packing arrangement in the crystal demonstrates the packing of monomers in the pre-pore complex. Additional structural and mutagenesis data has identified residues that are likely to contribute towards oligomerisation during pre-pore formation. Results The structure of pneumolysin Full-length pneumolysin and a truncated form comprising the membrane-binding domain (domain 4) were produced by expression in E. coli and purified by affinity and gel filtration chromatography. Crystals of the full-length toxin were grown at 4 °C and at pH 8.5. The best crystals were obtained from protein containing substitutions Asp385Asn and Cys432Ala. Neither mutation prevents pore formation 16 , 17 . The asymmetric unit contained a single molecule having the characteristic four domain structure of a CDC, with three non-contiguous domains (domains 1–3) linked to the C-terminal membrane-binding domain ( Fig. 1A ) via the strap-like domain 2. Crystal of the membrane-binding domain were grown at room temperature and contained two molecules in the asymmetric unit. Both refined models have good stereochemistry ( Table 1 ) with 95% and 93% of residues within the Ramachandran favoured regions. Table 1 Data collection and refinement statistics. Full size table Figure 1 Domain structure of pneumolysin and the likely changes upon membrane binding. ( A ) Domains 1, 2 and 3 are contiguous and connected to the C-terminal membrane-binding domain (domain 4) via domain 2. ( B ) overlay of the membrane-binding domains of the full-length pneumolysin (PLY), pneumolysin domain 4 (PLY D4) and perfringolysin O (PFO; PDB: 1PFO 12 ;) structures. The structures reveal the likely changes that occur upon membrane binding. Notably, the tryptophan-rich loop flips outwards and downwards ( arrow ) exposing Trp433, to enable binding to the membrane. Full size image The tryptophan-rich loop, projects from the base of domain 4 in the structure of full-length pneumolysin, reflecting the likely membrane-binding conformation ( Fig. 1B ). Notably, two of the tryptophan residues, Trp433 and Trp435, shown previously to be important for membrane binding and cell lysis 13 , project outwards, so are in position to allow interactions with a lipid bilayer. By contrast, the loop is partially folded back in the structure of domain 4 alone ( Fig. 1B ) and fully bent back against the body of domain 4 in the previously determined structure of perfringolysin O 12 . Together the structures are consistent with previous suggestion that the loop springs outwards and downwards when the toxin binds to the membrane of a mammalian cell ( Fig. 1B ) 12 . In the structure of full-length pneumolysin, domain 4 is offset by ~30° relative to the plane of the long axis of domains 1–3, such that the toxin resembles a bend rod from the side ( Fig. 2A ). The relative position of domain 4 differs in the available structures of CDCs. For example, it is displaced by ∼ 15 Å and twisted by ~25° in the crystal structure of perfrigolysin O (PDB: 1PFO 12 ;), whereas it is offset", "role": "user" }, { "content": "Scientists from the University of Leicester have for the first time created a detailed image of a toxin - called pneumolysin - associated with deadly infections such as bacterial pneumonia, meningitis and septicaemia. The three-year study involving four research groups from across the University has been described as an exciting advance because it points to the possibility of creating therapeutics that block assembly of pneumolysin pores to treat people with pneumococcal disease. The University has recently set up a company Axendos Therapeutics to pursue this aim. Using a technique called X-ray crystallography at Diamond Light Source, the UK's national synchrotron science facility, the Leicester team was able to see the individual atoms of the toxin. The structure not only reveals what the toxin looks like, but also shows how it assembles on the surface of cells to form lethal pores. Funded by the Wellcome Trust and the Medical Research Council, the University of Leicester research published in Scientific Reports was led by Professor Russell Wallis of the Departments of Infection, Immunity and Inflammation and Molecular and Cell Biology and Professor Peter Andrew, Head of Department of Infection, Immunity and Inflammation. Professor Wallis said: \"Our research is about a toxin called pneumolysin produced by a bacterium called pneumococcus (aka Streptococcus pneumoniae). Pneumococcal infections are the leading cause of bacterial pneumonia as well as the cause of a range of other life-threatening diseases such as meningitis and septicaemia. Pneumolysin is instrumental in the ability of pneumococcus to cause disease. The World Health Organization (WHO) estimated that more than 1.6 million people die every year from pneumococcal infections, including more than 800,000 children under 5 years old. \"The aim of the research was to find out how pneumolysin kills our cells, thereby causing tissue damage and contributing to disease. In particular we wanted to find out how multiple copies of the toxin assemble on the surface of cells. \"We managed to determine the structure of pneumolysin using a technique called X-ray crystallography, which enables us to see the individual atoms of the toxin. The structure not only reveals what the toxin looks like, but also shows how it assembles to form lethal pores. \"Ours is the first detailed structure of pneumolysin. This level of detail is important and useful because it enables us to begin to understand how the toxin works. For example, we can see which parts of the toxin come together during pore assembly. When we disrupt these contacts, the toxin becomes inactivated so can no longer kill cells. \"The mode of action of pneumolysin action revealed by our work appears to be conserved in related toxins from other disease-causing bacteria e.g. toxins produced by pathogenic species of Listeria.\" Professor Andrew said: \"The determination of the structure of pneumolysin is a thrilling achievement that, worldwide, scientists have been pursuing for more than twenty years. It also offers the real prospect of enhancing our ability to find new drugs for treatment of pneumococcal diseases. Because of fears of antibiotic resistance, researchers have been trying for decades to find new antimicrobial drugs but with little success. A new approach is to identify new targets for therapy and our work over a long period shows that pneumolysin is an excellent target for new treatments. The University of Leicester set up a spin-out company to find drugs that target the toxin. Now the determination of the toxin's structure is an important advance towards achieving this objective.\" Professor Wallis said: \"The work is especially exciting because of the importance of pneumolysin towards pneumococcal disease and the devastating consequences of pneumococcal infections. Our work has provided new insight into how the toxin kills cells. Much of the experimental work was carried out by two PhD students: Jamie Marshall, who has just completed his PhD and Bayan Faraj, who is in the final year of her project. Overall it has been a real collaborative effort between four research groups across the College of Medicine, Biological Sciences and Psychology involving the groups in the Department of Infection, Immunity and Inflammation as well as the groups of Prof Peter Moody and Dr El-Mezgueldi in the Department of Molecular and Cell Biology.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Pneumolysin is a cholesterol-dependent cytolysin (CDC) and virulence factor of Streptococcus pneumoniae . It kills cells by forming pores assembled from oligomeric rings in cholesterol-containing membranes. Cryo-EM has revealed the structures of the membrane-surface bound pre-pore and inserted-pore oligomers, however the molecular contacts that mediate these oligomers are unknown because high-resolution information is not available. Here we have determined the crystal structure of full-length pneumolysin at 1.98 Å resolution. In the structure, crystal contacts demonstrate the likely interactions that enable polymerisation on the cell membrane and the molecular packing of the pre-pore complex. The hemolytic activity is abrogated in mutants that disrupt these intermolecular contacts, highlighting their importance during pore formation. An additional crystal structure of the membrane-binding domain alone suggests that changes in the conformation of a tryptophan rich-loop at the base of the toxin promote monomer-monomer interactions upon membrane binding by creating new contacts. Notably, residues at the interface are conserved in other members of the CDC family, suggesting a common mechanism for pore and pre-pore assembly. Introduction The cholesterol-dependent cytolysin (CDC), pneumolysin 1 is a virulence factor of the human pathogen Streptococcus pneumoniae (pneumococcus) 2 , the leading cause of bacterial pneumonia and a major agent of meningitis and septicaemia as well as debilitating diseases such as otitis media, septic arthritis, keratitis and sinusitis 3 . It is found in virtually all pneumococcal isolates and plays key roles in bacterial colonisation, invasion and inflammation 4 , 5 , 6 . A central feature of the toxin is the formation of transmembrane pores in cholesterol-containing membranes 7 , which lyse or disrupt cell functioning, depending on the concentration 8 , 9 , 10 . Pneumolysin and other CDCs bind to mammalian membranes through a tryptophan-rich loop and a threonine-leucine pair within a membrane-binding domain at the base of the toxin 11 , 12 . The tryptophan-rich loop has been proposed to spring out of the body of the toxin on association with the membrane 12 . All three tryptophans are implicated in membrane binding but Trp433 and Trp435 are particularly important 13 , 14 . Once bound to the membrane, monomers then oligomerise to form a pre-pore complex that subsequently undergoes a complex set of structural transitions to form a transmembrane pore, typically comprising 30–50 subunits. Structures of the pre-pore and inserted-pore oligomers have been determined by cryo-EM at ~28 Å and these structures together with recent analysis of the related CDC, suilysin, show that that pore formation follows the vertical collapse of the pre-pore structure with two extended beta-hairpins penetrating the membrane to form the large beta-barrel pore 7 , 15 . Although high-resolution X-ray structures have been determined for several CDCs, pneumolysin has proved to be elusive. Consequently, structure-function analysis has relied on models based on the structures of the other CDC toxins. Critically, the lack of high-resolution data means that the interactions enabling pneumolysin monomers to pack together to form the pore and pre-pore complexes is not known. In this work, we have determined the structure of pneumolysin at 1.98 Å resolution. The side-by-side packing arrangement in the crystal demonstrates the packing of monomers in the pre-pore complex. Additional structural and mutagenesis data has identified residues that are likely to contribute towards oligomerisation during pre-pore formation. Results The structure of pneumolysin Full-length pneumolysin and a truncated form comprising the membrane-binding domain (domain 4) were produced by expression in E. coli and purified by affinity and gel filtration chromatography. Crystals of the full-length toxin were grown at 4 °C and at pH 8.5. The best crystals were obtained from protein containing substitutions Asp385Asn and Cys432Ala. Neither mutation prevents pore formation 16 , 17 . The asymmetric unit contained a single molecule having the characteristic four domain structure of a CDC, with three non-contiguous domains (domains 1–3) linked to the C-terminal membrane-binding domain ( Fig. 1A ) via the strap-like domain 2. Crystal of the membrane-binding domain were grown at room temperature and contained two molecules in the asymmetric unit. Both refined models have good stereochemistry ( Table 1 ) with 95% and 93% of residues within the Ramachandran favoured regions. Table 1 Data collection and refinement statistics. Full size table Figure 1 Domain structure of pneumolysin and the likely changes upon membrane binding. ( A ) Domains 1, 2 and 3 are contiguous and connected to the C-terminal membrane-binding domain (domain 4) via domain 2. ( B ) overlay of the membrane-binding domains of the full-length pneumolysin (PLY), pneumolysin domain 4 (PLY D4) and perfringolysin O (PFO; PDB: 1PFO 12 ;) structures. The structures reveal the likely changes that occur upon membrane binding. Notably, the tryptophan-rich loop flips outwards and downwards ( arrow ) exposing Trp433, to enable binding to the membrane. Full size image The tryptophan-rich loop, projects from the base of domain 4 in the structure of full-length pneumolysin, reflecting the likely membrane-binding conformation ( Fig. 1B ). Notably, two of the tryptophan residues, Trp433 and Trp435, shown previously to be important for membrane binding and cell lysis 13 , project outwards, so are in position to allow interactions with a lipid bilayer. By contrast, the loop is partially folded back in the structure of domain 4 alone ( Fig. 1B ) and fully bent back against the body of domain 4 in the previously determined structure of perfringolysin O 12 . Together the structures are consistent with previous suggestion that the loop springs outwards and downwards when the toxin binds to the membrane of a mammalian cell ( Fig. 1B ) 12 . In the structure of full-length pneumolysin, domain 4 is offset by ~30° relative to the plane of the long axis of domains 1–3, such that the toxin resembles a bend rod from the side ( Fig. 2A ). The relative position of domain 4 differs in the available structures of CDCs. For example, it is displaced by ∼ 15 Å and twisted by ~25° in the crystal structure of perfrigolysin O (PDB: 1PFO 12 ;), whereas it is offset<|im_end|> <|im_start|>assistant Scientists from the University of Leicester have for the first time created a detailed image of a toxin - called pneumolysin - associated with deadly infections such as bacterial pneumonia, meningitis and septicaemia. The three-year study involving four research groups from across the University has been described as an exciting advance because it points to the possibility of creating therapeutics that block assembly of pneumolysin pores to treat people with pneumococcal disease. The University has recently set up a company Axendos Therapeutics to pursue this aim. Using a technique called X-ray crystallography at Diamond Light Source, the UK's national synchrotron science facility, the Leicester team was able to see the individual atoms of the toxin. The structure not only reveals what the toxin looks like, but also shows how it assembles on the surface of cells to form lethal pores. Funded by the Wellcome Trust and the Medical Research Council, the University of Leicester research published in Scientific Reports was led by Professor Russell Wallis of the Departments of Infection, Immunity and Inflammation and Molecular and Cell Biology and Professor Peter Andrew, Head of Department of Infection, Immunity and Inflammation. Professor Wallis said: "Our research is about a toxin called pneumolysin produced by a bacterium called pneumococcus (aka Streptococcus pneumoniae). Pneumococcal infections are the leading cause of bacterial pneumonia as well as the cause of a range of other life-threatening diseases such as meningitis and septicaemia. Pneumolysin is instrumental in the ability of pneumococcus to cause disease. The World Health Organization (WHO) estimated that more than 1.6 million people die every year from pneumococcal infections, including more than 800,000 children under 5 years old. "The aim of the research was to find out how pneumolysin kills our cells, thereby causing tissue damage and contributing to disease. In particular we wanted to find out how multiple copies of the toxin assemble on the surface of cells. "We managed to determine the structure of pneumolysin using a technique called X-ray crystallography, which enables us to see the individual atoms of the toxin. The structure not only reveals what the toxin looks like, but also shows how it assembles to form lethal pores. "Ours is the first detailed structure of pneumolysin. This level of detail is important and useful because it enables us to begin to understand how the toxin works. For example, we can see which parts of the toxin come together during pore assembly. When we disrupt these contacts, the toxin becomes inactivated so can no longer kill cells. "The mode of action of pneumolysin action revealed by our work appears to be conserved in related toxins from other disease-causing bacteria e.g. toxins produced by pathogenic species of Listeria." Professor Andrew said: "The determination of the structure of pneumolysin is a thrilling achievement that, worldwide, scientists have been pursuing for more than twenty years. It also offers the real prospect of enhancing our ability to find new drugs for treatment of pneumococcal diseases. Because of fears of antibiotic resistance, researchers have been trying for decades to find new antimicrobial drugs but with little success. A new approach is to identify new targets for therapy and our work over a long period shows that pneumolysin is an excellent target for new treatments. The University of Leicester set up a spin-out company to find drugs that target the toxin. Now the determination of the toxin's structure is an important advance towards achieving this objective." Professor Wallis said: "The work is especially exciting because of the importance of pneumolysin towards pneumococcal disease and the devastating consequences of pneumococcal infections. Our work has provided new insight into how the toxin kills cells. Much of the experimental work was carried out by two PhD students: Jamie Marshall, who has just completed his PhD and Bayan Faraj, who is in the final year of her project. Overall it has been a real collaborative effort between four research groups across the College of Medicine, Biological Sciences and Psychology involving the groups in the Department of Infection, Immunity and Inflammation as well as the groups of Prof Peter Moody and Dr El-Mezgueldi in the Department of Molecular and Cell Biology." <|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 Cellular mechanisms underlying the development of left–right asymmetry in tissues and embryos remain obscure. Here, the development of a chiral pattern of actomyosin was revealed by studying actin cytoskeleton self-organization in cells with isotropic circular shape. A radially symmetrical system of actin bundles consisting of α-actinin-enriched radial fibres (RFs) and myosin-IIA-enriched transverse fibres (TFs) evolved spontaneously into the chiral system as a result of the unidirectional tilting of all RFs, which was accompanied by a tangential shift in the retrograde movement of TFs. We showed that myosin-IIA-dependent contractile stresses within TFs drive their movement along RFs, which grow centripetally in a formin-dependent fashion. The handedness of the chiral pattern was shown to be regulated by α-actinin-1. Computational modelling demonstrated that the dynamics of the RF–TF system can explain the pattern transition from radial to chiral. Thus, actin cytoskeleton self-organization provides built-in machinery that potentially allows cells to develop left–right asymmetry. Main Processes that establish left–right asymmetry are among the most intriguing biological phenomena. Even though the mechanisms of establishment of left–right asymmetry in embryonic development are complex and involve the coordinated activity of many cells 1 , 2 , 3 , the ability of cells to distinguish between left and right is evident in relatively simple systems, such as the collective movement of identical cells cultured on ring-shaped or stripe-shaped micropatterns 4 , 5 , 6 , or in individual cells grown in isotropic conditions. Examples include neutrophil-like cells 7 , some types of nerve cell 8 , 9 , spreading platelets 10 and zebrafish melanophores 11 . Helical cytoskeletal polymers, such as actin filaments and microtubules, are natural candidates for initiating cellular left–right asymmetry as they are characterized by both longitudinal polarity and handedness 12 , 13 . Indeed, the left–right asymmetry in neutrophil polarization seems to depend on microtubules 7 , whereas the chiral movement of cells on micropatterns 5 , 6 and the nuclear rotation in pigment cells 11 are mediated by the actin cytoskeleton. However, the specific cytoskeletal mechanisms leading to the establishment of a cellular asymmetry have yet to be deciphered. Understanding how the intrinsic asymmetry of individual actin filaments can be translated into asymmetric behaviour of the entire actin cytoskeleton, and consequently of the entire cell, requires an exploration of actin cytoskeleton self-organization. In cultured fibroblasts, spreading and polarization are accompanied by self-organization of the array of actin filament bundles (known also as actin cables, actin fibres or stress fibres) 14 , 15 , 16 , 17 . A closer look at the actin cytoskeleton revealed several classes of actin filament bundles that differ in protein composition, dynamics and mode of development 15 , 16 , 18 , 19 , 20 , 21 . In well-spread, elongated, but weakly motile cells, the predominant type of bundle is the ‘ventral’ stress fibre. These are anchored at each end to focal adhesions and are characterized by a striated morphology with alternating bands of α-actinin and myosin II (refs 16 , 17 , 19 ). Motile and spreading cells often form ‘dorsal’ fibres that grow from the focal adhesion towards the cell centre, presumably in a formin-dependent manner 19 , 22 . These fibres are enriched in α-actinin, palladin and VASP, and are largely devoid of myosin 19 , 23 , 24 , 25 . In addition, TFs, or arcs, are formed at the boundary between the lamellipodium and lamellum 18 , 26 , 27 , 28 . These fibres are characterized by the presence of tropomyosin 4 and myosin IIA (refs 23 , 27 , 28 ), and move from the cell periphery in a centripetal direction. It seems that the system of actin fibres is dynamically richer than one would expect. By studying cells confined to circular adhesive islands, we demonstrate that dynamic actin fibres associated with focal adhesions can generate a chiral pattern with uniform handedness. The handedness of the chiral pattern was shown to be regulated by the actin crosslinking protein α-actinin. We studied in detail the dynamics of the actin fibres and the mode of their interaction and proposed a physical model accounting for the observed phenomena. Thus, our results suggest a basic cytoskeletal mechanism for the establishment of left–right asymmetry in cells. RESULTS Types of pattern formed by the actin cytoskeleton in cells plated on circular adhesive islands To dissect the process of actin cytoskeleton self-organization from cell shape change, we studied cell behaviour using circular adhesive islands. Analysis of 100 videos, recorded over a period of up to 12 h, revealed the formation of several distinct arrays. These were characterized by the actin structures from which they were composed, as well as the typical transitions observed between them ( Fig. 1a and Supplementary Videos 1 and 2 ). Figure 1: Distinct patterns of actin cytoskeleton self-organization. ( a ) A flow diagram of actin cytoskeleton transformations in cells plated on circular fibronectin islands of area 1,800 μm 2 . Actin and focal adhesions were visualized with either co-transfection of LifeAct–GFP and mCherry–paxillin, or labelled with phalloidin and anti-paxillin antibodies. Maximum-projection images of actin, as viewed from above (see schematic diagram in top right corner), are shown. Actin cytoskeleton self-organizes into five characteristic patterns—circular, radial, chiral, chordal and linear. The flow diagram is derived from live observations of actin dynamics in 59 cells pooled from five experiments. Thick arrows show prevalent transitions. Thin arrows show rarely observed transitions (2–3 observations). ( b ) A typical example of the dynamic self-organization of the actin cytoskeleton. The actin cytoskeleton first organized into the radial pattern (100 min). The RFs began to tilt (198 min), leading to the chiral pattern organization (260 min). The actin cytoskeleton can break the chiral symmetry by self-organizing into the linear array (646 min). The actin cytoskeleton was visualized by transfection with LifeAct–GFP. Full-length sequence is shown in Supplementary Video 1 . Scale bar, 10 μm. Full size image At the early stages of actin network self-organization, a circumferential actin bundle underlying the circular cell boundary was formed", "role": "user" }, { "content": "Researchers at the Mechanobiology Institute, National University of Singapore, have made significant advances in our understanding of cellular biology; providing evidence that the inherent 'handedness' of molecular structures directs the behavior of individual cells and confers them the ability to sense the difference between left and right. This work is published in Nature Cell Biology. Cellular decision making Our bodies are made up of hundreds of different types of cells, each of which performs a unique and highly specialized task. Traditionally, the ability of cells to specialize in a given function was attributed to its genetic code. However, it is becoming increasingly clear that cells do not simply live by a set of inherited or pre-determined instructions. Instead, 'cellular decisions' are made dynamically, much like humans make decisions based on the information provided to us by our senses. Although cells do not have the ability to see or hear, they do possess sensory structures that allow them to detect and measure various environmental stimuli. The application of mechanical force to the cell, for example, will be felt and the cell will respond accordingly. One of the most prominent cellular responses is to change shape and this property is reflected in the varying shapes of specialised cells. Cellular senses have been attributed to various force-sensing cellular structures such as the cytoskeleton. This structure differs significantly from its namesake, the human skeleton, by being highly dynamic and playing roles in addition to the provision of structural support. For example, this network of molecular filaments or cables also generates internal forces that drive shape changes and even motility. As the cytoskeleton develops, individual protein filaments grow and shrink. They bundle together to form thicker fibres, and they move or contract. Each of these processes is collectively known as 'cytoskeleton dynamics'. Figure 2: The cytoskeleton (yellow) surrounds the nucleus (purple), displaying L-R asymmetry during cytoskeletal organization. Credit: Mechanobiology Institute, National University of Singapore The question that has long intrigued scientists is how cytoskeleton dynamics can direct the behaviour of different cell types. To investigate this, MBI researchers Professor Alexander Bershadsky and Dr Tee Yee Han, in collaboration with researchers from the USA and Israel, observed the cytoskeleton in cells that were confined to a small circular area, using a technique known as \"micro-patterning\". This prevented the cells from changing shape and thus provided the researchers an unhindered view of cytoskeleton dynamics. A surprising find What was detected came as a surprise to the researchers. A pronounced left-right asymmetry was observed during cytoskeletal organisation. This asymmetry, which appeared as a whirlpool, with filaments moving anticlockwise inside the cell, was found to originate from the inherent twist that is present in individual actin filaments. This helical twist occurs naturally as individual actin proteins join together to form the long actin cables that make up overall structure. This seemingly simple property has profound consequences as it suggests that the asymmetry of a single protein is translated to the asymmetric behaviour of a whole cell. This is akin to the twist of a screw or bolt directing the function or behaviour of the machine in which it is placed. The ability of cells to distinguish between left and right is a phenomenon that continues to fascinate scientists. It is clear from this study that the asymmetry inherent in molecular structures can define the behaviour of whole cells, and this provides new insight into the ability of cells to 'make decisions' based on the mechanical properties of its environment. However, these findings also raise fascinating questions as to whether the same phenomenon can influence the formation and function of our organs, or even affect organism behaviour. Indeed relatively simple biological systems, such as cells grown on defined patterns, display a pronounced asymmetry in their movement. At the other extreme, brain function and human cognition is dependent on the asymmetric behaviour of nerve cells. The possibility that the inherent asymmetry of molecular structures can define cell, tissue or even organism behaviour will undoubtedly drive further studies for years to come. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Cellular mechanisms underlying the development of left–right asymmetry in tissues and embryos remain obscure. Here, the development of a chiral pattern of actomyosin was revealed by studying actin cytoskeleton self-organization in cells with isotropic circular shape. A radially symmetrical system of actin bundles consisting of α-actinin-enriched radial fibres (RFs) and myosin-IIA-enriched transverse fibres (TFs) evolved spontaneously into the chiral system as a result of the unidirectional tilting of all RFs, which was accompanied by a tangential shift in the retrograde movement of TFs. We showed that myosin-IIA-dependent contractile stresses within TFs drive their movement along RFs, which grow centripetally in a formin-dependent fashion. The handedness of the chiral pattern was shown to be regulated by α-actinin-1. Computational modelling demonstrated that the dynamics of the RF–TF system can explain the pattern transition from radial to chiral. Thus, actin cytoskeleton self-organization provides built-in machinery that potentially allows cells to develop left–right asymmetry. Main Processes that establish left–right asymmetry are among the most intriguing biological phenomena. Even though the mechanisms of establishment of left–right asymmetry in embryonic development are complex and involve the coordinated activity of many cells 1 , 2 , 3 , the ability of cells to distinguish between left and right is evident in relatively simple systems, such as the collective movement of identical cells cultured on ring-shaped or stripe-shaped micropatterns 4 , 5 , 6 , or in individual cells grown in isotropic conditions. Examples include neutrophil-like cells 7 , some types of nerve cell 8 , 9 , spreading platelets 10 and zebrafish melanophores 11 . Helical cytoskeletal polymers, such as actin filaments and microtubules, are natural candidates for initiating cellular left–right asymmetry as they are characterized by both longitudinal polarity and handedness 12 , 13 . Indeed, the left–right asymmetry in neutrophil polarization seems to depend on microtubules 7 , whereas the chiral movement of cells on micropatterns 5 , 6 and the nuclear rotation in pigment cells 11 are mediated by the actin cytoskeleton. However, the specific cytoskeletal mechanisms leading to the establishment of a cellular asymmetry have yet to be deciphered. Understanding how the intrinsic asymmetry of individual actin filaments can be translated into asymmetric behaviour of the entire actin cytoskeleton, and consequently of the entire cell, requires an exploration of actin cytoskeleton self-organization. In cultured fibroblasts, spreading and polarization are accompanied by self-organization of the array of actin filament bundles (known also as actin cables, actin fibres or stress fibres) 14 , 15 , 16 , 17 . A closer look at the actin cytoskeleton revealed several classes of actin filament bundles that differ in protein composition, dynamics and mode of development 15 , 16 , 18 , 19 , 20 , 21 . In well-spread, elongated, but weakly motile cells, the predominant type of bundle is the ‘ventral’ stress fibre. These are anchored at each end to focal adhesions and are characterized by a striated morphology with alternating bands of α-actinin and myosin II (refs 16 , 17 , 19 ). Motile and spreading cells often form ‘dorsal’ fibres that grow from the focal adhesion towards the cell centre, presumably in a formin-dependent manner 19 , 22 . These fibres are enriched in α-actinin, palladin and VASP, and are largely devoid of myosin 19 , 23 , 24 , 25 . In addition, TFs, or arcs, are formed at the boundary between the lamellipodium and lamellum 18 , 26 , 27 , 28 . These fibres are characterized by the presence of tropomyosin 4 and myosin IIA (refs 23 , 27 , 28 ), and move from the cell periphery in a centripetal direction. It seems that the system of actin fibres is dynamically richer than one would expect. By studying cells confined to circular adhesive islands, we demonstrate that dynamic actin fibres associated with focal adhesions can generate a chiral pattern with uniform handedness. The handedness of the chiral pattern was shown to be regulated by the actin crosslinking protein α-actinin. We studied in detail the dynamics of the actin fibres and the mode of their interaction and proposed a physical model accounting for the observed phenomena. Thus, our results suggest a basic cytoskeletal mechanism for the establishment of left–right asymmetry in cells. RESULTS Types of pattern formed by the actin cytoskeleton in cells plated on circular adhesive islands To dissect the process of actin cytoskeleton self-organization from cell shape change, we studied cell behaviour using circular adhesive islands. Analysis of 100 videos, recorded over a period of up to 12 h, revealed the formation of several distinct arrays. These were characterized by the actin structures from which they were composed, as well as the typical transitions observed between them ( Fig. 1a and Supplementary Videos 1 and 2 ). Figure 1: Distinct patterns of actin cytoskeleton self-organization. ( a ) A flow diagram of actin cytoskeleton transformations in cells plated on circular fibronectin islands of area 1,800 μm 2 . Actin and focal adhesions were visualized with either co-transfection of LifeAct–GFP and mCherry–paxillin, or labelled with phalloidin and anti-paxillin antibodies. Maximum-projection images of actin, as viewed from above (see schematic diagram in top right corner), are shown. Actin cytoskeleton self-organizes into five characteristic patterns—circular, radial, chiral, chordal and linear. The flow diagram is derived from live observations of actin dynamics in 59 cells pooled from five experiments. Thick arrows show prevalent transitions. Thin arrows show rarely observed transitions (2–3 observations). ( b ) A typical example of the dynamic self-organization of the actin cytoskeleton. The actin cytoskeleton first organized into the radial pattern (100 min). The RFs began to tilt (198 min), leading to the chiral pattern organization (260 min). The actin cytoskeleton can break the chiral symmetry by self-organizing into the linear array (646 min). The actin cytoskeleton was visualized by transfection with LifeAct–GFP. Full-length sequence is shown in Supplementary Video 1 . Scale bar, 10 μm. Full size image At the early stages of actin network self-organization, a circumferential actin bundle underlying the circular cell boundary was formed<|im_end|> <|im_start|>assistant Researchers at the Mechanobiology Institute, National University of Singapore, have made significant advances in our understanding of cellular biology; providing evidence that the inherent 'handedness' of molecular structures directs the behavior of individual cells and confers them the ability to sense the difference between left and right. This work is published in Nature Cell Biology. Cellular decision making Our bodies are made up of hundreds of different types of cells, each of which performs a unique and highly specialized task. Traditionally, the ability of cells to specialize in a given function was attributed to its genetic code. However, it is becoming increasingly clear that cells do not simply live by a set of inherited or pre-determined instructions. Instead, 'cellular decisions' are made dynamically, much like humans make decisions based on the information provided to us by our senses. Although cells do not have the ability to see or hear, they do possess sensory structures that allow them to detect and measure various environmental stimuli. The application of mechanical force to the cell, for example, will be felt and the cell will respond accordingly. One of the most prominent cellular responses is to change shape and this property is reflected in the varying shapes of specialised cells. Cellular senses have been attributed to various force-sensing cellular structures such as the cytoskeleton. This structure differs significantly from its namesake, the human skeleton, by being highly dynamic and playing roles in addition to the provision of structural support. For example, this network of molecular filaments or cables also generates internal forces that drive shape changes and even motility. As the cytoskeleton develops, individual protein filaments grow and shrink. They bundle together to form thicker fibres, and they move or contract. Each of these processes is collectively known as 'cytoskeleton dynamics'. Figure 2: The cytoskeleton (yellow) surrounds the nucleus (purple), displaying L-R asymmetry during cytoskeletal organization. Credit: Mechanobiology Institute, National University of Singapore The question that has long intrigued scientists is how cytoskeleton dynamics can direct the behaviour of different cell types. To investigate this, MBI researchers Professor Alexander Bershadsky and Dr Tee Yee Han, in collaboration with researchers from the USA and Israel, observed the cytoskeleton in cells that were confined to a small circular area, using a technique known as "micro-patterning". This prevented the cells from changing shape and thus provided the researchers an unhindered view of cytoskeleton dynamics. A surprising find What was detected came as a surprise to the researchers. A pronounced left-right asymmetry was observed during cytoskeletal organisation. This asymmetry, which appeared as a whirlpool, with filaments moving anticlockwise inside the cell, was found to originate from the inherent twist that is present in individual actin filaments. This helical twist occurs naturally as individual actin proteins join together to form the long actin cables that make up overall structure. This seemingly simple property has profound consequences as it suggests that the asymmetry of a single protein is translated to the asymmetric behaviour of a whole cell. This is akin to the twist of a screw or bolt directing the function or behaviour of the machine in which it is placed. The ability of cells to distinguish between left and right is a phenomenon that continues to fascinate scientists. It is clear from this study that the asymmetry inherent in molecular structures can define the behaviour of whole cells, and this provides new insight into the ability of cells to 'make decisions' based on the mechanical properties of its environment. However, these findings also raise fascinating questions as to whether the same phenomenon can influence the formation and function of our organs, or even affect organism behaviour. Indeed relatively simple biological systems, such as cells grown on defined patterns, display a pronounced asymmetry in their movement. At the other extreme, brain function and human cognition is dependent on the asymmetric behaviour of nerve cells. The possibility that the inherent asymmetry of molecular structures can define cell, tissue or even organism behaviour will undoubtedly drive further studies for years to come. <|im_end|>

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1664, 1355, 21376, 11, 74595, 660, 11, 719, 7621, 398, 3937, 458, 7917, 11, 279, 96531, 955, 315, 13190, 374, 279, 3451, 688, 3545, 529, 8631, 57525, 13, 4314, 527, 78219, 520, 1855, 842, 311, 42199, 1008, 17082, 919, 323, 527, 32971, 555, 264, 6076, 660, 79612, 449, 73462, 21562, 315, 19581, 12, 533, 65544, 323, 856, 437, 258, 8105, 320, 16541, 220, 845, 1174, 220, 1114, 1174, 220, 777, 7609, 19514, 458, 323, 31135, 7917, 3629, 1376, 3451, 67, 1105, 278, 529, 16178, 417, 430, 3139, 505, 279, 42199, 1008, 59738, 7119, 279, 2849, 12541, 11, 36548, 304, 264, 369, 1083, 43918, 11827, 220, 777, 1174, 220, 1313, 662, 4314, 16178, 417, 527, 69671, 304, 19581, 12, 533, 65544, 11, 67597, 32084, 323, 650, 66204, 11, 323, 527, 14090, 76939, 315, 856, 437, 258, 220, 777, 1174, 220, 1419, 1174, 220, 1187, 1174, 220, 914, 662, 763, 5369, 11, 30245, 82, 11, 477, 67850, 11, 527, 14454, 520, 279, 19254, 1990, 279, 32703, 616, 575, 47876, 323, 32703, 616, 372, 220, 972, 1174, 220, 1627, 1174, 220, 1544, 1174, 220, 1591, 662, 4314, 16178, 417, 527, 32971, 555, 279, 9546, 315, 21965, 5650, 437, 258, 220, 19, 323, 856, 437, 258, 358, 5987, 320, 16541, 220, 1419, 1174, 220, 1544, 1174, 220, 1591, 7026, 323, 3351, 505, 279, 2849, 824, 94648, 304, 264, 2960, 4664, 22029, 5216, 13, 1102, 5084, 430, 279, 1887, 315, 1180, 258, 16178, 417, 374, 43111, 59774, 1109, 832, 1053, 1755, 13, 3296, 21630, 7917, 45408, 311, 28029, 65558, 30100, 11, 584, 20461, 430, 8915, 1180, 258, 16178, 417, 5938, 449, 42199, 1008, 17082, 919, 649, 7068, 264, 523, 37478, 5497, 449, 14113, 23415, 2136, 13, 578, 23415, 2136, 315, 279, 523, 37478, 5497, 574, 6982, 311, 387, 35319, 555, 279, 1180, 258, 5425, 2125, 287, 13128, 19581, 12, 533, 65544, 13, 1226, 20041, 304, 7872, 279, 30295, 315, 279, 1180, 258, 16178, 417, 323, 279, 3941, 315, 872, 16628, 323, 11223, 264, 7106, 1646, 24043, 369, 279, 13468, 44247, 13, 14636, 11, 1057, 3135, 4284, 264, 6913, 9693, 43681, 86255, 17383, 369, 279, 21967, 315, 2163, 4235, 1315, 54395, 33342, 304, 7917, 13, 54128, 21431, 315, 5497, 14454, 555, 279, 1180, 258, 9693, 43681, 28193, 304, 7917, 88233, 389, 28029, 65558, 30100, 2057, 75050, 279, 1920, 315, 1180, 258, 9693, 43681, 28193, 659, 12, 24844, 505, 2849, 6211, 2349, 11, 584, 20041, 2849, 17432, 1701, 28029, 65558, 30100, 13, 18825, 315, 220, 1041, 6946, 11, 12715, 927, 264, 4261, 315, 709, 311, 220, 717, 305, 11, 10675, 279, 18488, 315, 3892, 12742, 18893, 13, 4314, 1051, 32971, 555, 279, 1180, 258, 14726, 505, 902, 814, 1051, 24306, 11, 439, 1664, 439, 279, 14595, 34692, 13468, 1990, 1124, 320, 23966, 13, 220, 16, 64, 323, 99371, 20114, 220, 16, 323, 220, 17, 7609, 19575, 220, 16, 25, 28704, 7956, 12912, 315, 1180, 258, 9693, 43681, 28193, 659, 12, 24844, 13, 320, 264, 883, 362, 6530, 13861, 315, 1180, 258, 9693, 43681, 28193, 54070, 304, 7917, 88233, 389, 28029, 16178, 2298, 440, 258, 30100, 315, 3158, 220, 16, 11, 4728, 33983, 76, 220, 17, 662, 3298, 258, 323, 42199, 1008, 17082, 919, 1051, 9302, 1534, 449, 3060, 1080, 39160, 13421, 315, 9601, 2471, 4235, 38, 11960, 323, 296, 1163, 5515, 4235, 79, 710, 61597, 11, 477, 61336, 449, 1343, 37037, 307, 258, 323, 7294, 2320, 710, 61597, 59854, 13, 27697, 10039, 7761, 5448, 315, 1180, 258, 11, 439, 19894, 505, 3485, 320, 4151, 68144, 13861, 304, 1948, 1314, 9309, 705, 527, 6982, 13, 3298, 258, 9693, 43681, 28193, 659, 12, 8629, 4861, 1139, 4330, 29683, 12912, 2345, 66, 22190, 11, 57936, 11, 523, 37478, 11, 44321, 278, 323, 13790, 13, 578, 6530, 13861, 374, 14592, 505, 3974, 24654, 315, 1180, 258, 30295, 304, 220, 2946, 7917, 76476, 505, 4330, 21896, 13, 82377, 38057, 1501, 46941, 34692, 13, 70722, 38057, 1501, 19029, 13468, 34692, 320, 17, 4235, 18, 24654, 570, 320, 293, 883, 362, 14595, 3187, 315, 279, 8915, 659, 12, 24844, 315, 279, 1180, 258, 9693, 43681, 28193, 13, 578, 1180, 258, 9693, 43681, 28193, 1176, 17057, 1139, 279, 57936, 5497, 320, 1041, 1332, 570, 578, 22835, 82, 6137, 311, 37300, 320, 3753, 1332, 705, 6522, 311, 279, 523, 37478, 5497, 7471, 320, 11387, 1332, 570, 578, 1180, 258, 9693, 43681, 28193, 649, 1464, 279, 523, 37478, 46220, 555, 659, 12, 8629, 4954, 1139, 279, 13790, 1358, 320, 22642, 1332, 570, 578, 1180, 258, 9693, 43681, 28193, 574, 9302, 1534, 555, 1380, 13421, 449, 9601, 2471, 4235, 38, 11960, 13, 8797, 30425, 8668, 374, 6982, 304, 99371, 8519, 220, 16, 662, 25635, 3703, 11, 220, 605, 33983, 76, 13, 8797, 1404, 2217, 2468, 279, 4216, 18094, 315, 1180, 258, 4009, 659, 12, 24844, 11, 264, 10408, 809, 2335, 1180, 258, 13190, 16940, 279, 28029, 2849, 19254, 574, 14454, 128257, 198, 128256, 78191, 198, 60210, 520, 279, 28901, 18843, 2508, 10181, 11, 5165, 3907, 315, 21181, 11, 617, 1903, 5199, 31003, 304, 1057, 8830, 315, 35693, 34458, 26, 8405, 6029, 430, 279, 38088, 364, 71, 6601, 2136, 6, 315, 31206, 14726, 67146, 279, 7865, 315, 3927, 7917, 323, 2389, 388, 1124, 279, 5845, 311, 5647, 279, 6811, 1990, 2163, 323, 1314, 13, 1115, 990, 374, 4756, 304, 22037, 14299, 40023, 13, 88207, 5597, 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5457, 1355, 49205, 35693, 14726, 1778, 439, 279, 9693, 43681, 28193, 13, 1115, 6070, 44642, 12207, 505, 1202, 5144, 731, 11, 279, 3823, 30535, 11, 555, 1694, 7701, 8915, 323, 5737, 13073, 304, 5369, 311, 279, 17575, 315, 24693, 1862, 13, 1789, 3187, 11, 420, 4009, 315, 31206, 1488, 24469, 477, 37172, 1101, 27983, 5419, 8603, 430, 6678, 6211, 4442, 323, 1524, 3937, 1429, 13, 1666, 279, 9693, 43681, 28193, 39671, 11, 3927, 13128, 1488, 24469, 3139, 323, 30000, 13, 2435, 13190, 3871, 311, 1376, 59884, 16178, 417, 11, 323, 814, 3351, 477, 5226, 13, 9062, 315, 1521, 11618, 374, 45925, 3967, 439, 364, 11377, 43681, 28193, 30295, 4527, 19575, 220, 17, 25, 578, 9693, 43681, 28193, 320, 28969, 8, 71374, 279, 62607, 320, 57607, 705, 29040, 445, 11151, 54395, 33342, 2391, 9693, 43681, 86255, 7471, 13, 16666, 25, 28901, 18843, 2508, 10181, 11, 5165, 3907, 315, 21181, 578, 3488, 430, 706, 1317, 69118, 14248, 374, 1268, 9693, 43681, 28193, 30295, 649, 2167, 279, 17432, 315, 2204, 2849, 4595, 13, 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6070, 13, 1115, 23490, 4382, 3424, 706, 28254, 16296, 439, 433, 13533, 430, 279, 54395, 33342, 315, 264, 3254, 13128, 374, 25548, 311, 279, 97929, 17432, 315, 264, 4459, 2849, 13, 1115, 374, 53007, 311, 279, 27744, 315, 264, 22733, 477, 32942, 46090, 279, 734, 477, 17432, 315, 279, 5780, 304, 902, 433, 374, 9277, 13, 578, 5845, 315, 7917, 311, 33137, 1990, 2163, 323, 1314, 374, 264, 25885, 430, 9731, 311, 15550, 3357, 14248, 13, 1102, 374, 2867, 505, 420, 4007, 430, 279, 54395, 33342, 38088, 304, 31206, 14726, 649, 7124, 279, 17432, 315, 4459, 7917, 11, 323, 420, 5825, 502, 20616, 1139, 279, 5845, 315, 7917, 311, 364, 7072, 11429, 6, 3196, 389, 279, 22936, 6012, 315, 1202, 4676, 13, 4452, 11, 1521, 14955, 1101, 4933, 27387, 4860, 439, 311, 3508, 279, 1890, 25885, 649, 10383, 279, 18488, 323, 734, 315, 1057, 36853, 11, 477, 1524, 7958, 47120, 17432, 13, 23150, 12309, 4382, 24156, 6067, 11, 1778, 439, 7917, 15042, 389, 4613, 12912, 11, 3113, 264, 38617, 54395, 33342, 304, 872, 7351, 13, 2468, 279, 1023, 14560, 11, 8271, 734, 323, 3823, 75310, 374, 18222, 389, 279, 97929, 17432, 315, 32015, 7917, 13, 578, 13336, 430, 279, 38088, 54395, 33342, 315, 31206, 14726, 649, 7124, 2849, 11, 20438, 477, 1524, 47120, 17432, 690, 38048, 6678, 4726, 7978, 369, 1667, 311, 2586, 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 Metal oxides with a tunnelled structure are attractive as charge storage materials for rechargeable batteries and supercapacitors, since the tunnels enable fast reversible insertion/extraction of charge carriers (for example, lithium ions). Common synthesis methods can introduce large cations such as potassium, barium and ammonium ions into the tunnels, but how these cations affect charge storage performance is not fully understood. Here, we report the role of tunnel cations in governing the electrochemical properties of electrode materials by focusing on potassium ions in α-MnO 2 . We show that the presence of cations inside 2 × 2 tunnels of manganese dioxide increases the electronic conductivity, and improves lithium ion diffusivity. In addition, transmission electron microscopy analysis indicates that the tunnels remain intact whether cations are present in the tunnels or not. Our systematic study shows that cation addition to α-MnO 2 has a strong beneficial effect on the electrochemical performance of this material. Introduction Metal oxides with an internal tunnel structure such as α-MnO 2 , TiO 2 and β-FeOOH are widely used for charge storage in rechargeable batteries and supercapacitors where charge carriers such as Li + , Na + and Mg 2+ can be reversibly inserted and extracted 1 , 2 , 3 , 4 . Of these oxides, α-MnO 2 , which possesses the typical octahedral molecular sieve structure, is characterized by well-ordered one-dimensional 1 × 1 and 2 × 2 tunnels 5 , as illustrated in Supplementary Fig. 1 . The 2 × 2 tunnel (4.6 × 4.6 Å) is large enough to accommodate charge carriers such as Li + , Na + and Mg 2+ , enabling fast ion diffusion inside the tunnel cavity 6 . In addition, Mn-based oxides are low cost, environmentally friendly and safer with respect to over-charge conditions compared with Co-based oxide electrodes 7 . Consequently, α-MnO 2 has been extensively studied as a promising cathode material for lithium (sodium and magnesium) ion batteries 8 , 9 , 10 , 11 , lithium air batteries 12 , 13 and supercapacitors 14 , 15 , 16 . Recent research shows that large cations such as K + , Ba 2+ and NH 4 + can be introduced during synthesis of α-MnO 2 (refs 17 , 18 ). These cations, which partially occupy the tunnel cavities at certain stabilized lattice sites, are expected to interact with the charge carrier (Li + , Na + and Mg 2+ ) and thus affect the charge storage performance of α-MnO 2 where tunnel-driven (de)intercalation contributes to the overall capacity 16 , 18 , 19 , 20 . Despite considerable research devoted to improving the charge storage performance of α-MnO 2 , the underlying mechanism by which tunnel cations affect the insertion/extraction of charge carriers is poorly understood. In the case of Li + being the charge carrier, many researchers believe that the presence of large cations (K + , Ba 2+ ) inside the 2 × 2 tunnels impedes the diffusion of Li + by physical blocking and repulsive electrostatic forces 18 , 21 , 22 , 23 . Others have pointed out that fast (de)intercalation of Li + requires a stable tunnel structure, and the existence of cations helps to prevent the collapse of the tunnels 24 , 25 . As yet, no conclusive evidence has been provided to clarify whether the tunnel cations promote or impede rapid migration of Li ions. An important factor that contributes to this ambiguity is the difficulty of visualizing these cations and determining their content and position, given the spatial resolution limits of most non-aberration-corrected electron microscopes. It is apparent that there is a pressing need to understand the effect of tunnel cations on charge storage behaviour of materials such as α-MnO 2 to allow the synthesis methods and properties of such tunnel-structured oxides to be optimized. In this report, nanowires of K + -doped α-MnO 2 are hydrothermally synthesized and the K + concentration is controlled and differentiated by acid solution treatment. The effect of varying K + concentration on the rate performance of a Li/α-MnO 2 battery is studied systematically by measuring the electronic conductivity and Li + diffusivity in the α-MnO 2 cathode. The underlying mechanism is revealed using a powerful combination of aberration-corrected scanning transmission electron microscopy (ACSTEM), transmission electron microscopy (TEM), electrical response measurements of single α-MnO 2 nanowires, electrochemical impedance spectroscopy (EIS) and density functional theory (DFT) simulations. Results Structural characterization of α-K x MnO 2 Hydrothermally synthesized α-MnO 2 nanowires were characterized using ACSTEM, and the results are shown in Fig. 1 . It can be seen from Fig. 1a,b that the α-MnO 2 nanowire is monocrystalline, growing in the [001] direction with a uniform diameter. The [100] atomic resolution high-angle annular dark field (HAADF) image in Fig. 1c shows the 2 × 2 tunnels (dark stripes) surrounded by two Mn atomic columns (yellow spheres) corresponding to the tunnel walls on each side. It can also be seen that the 2 × 2 tunnels are decorated with ordered K atomic columns (pink spheres) around their centre positions, based on which the [100] atomic model is provided in Fig. 1d . K + ions are successfully introduced during synthesis because excess K + are present in solution to support the 2 × 2 tunnels during their initial formation. The down-tunnel image of one α-MnO 2 nanowire ( Fig. 1e ) shows that the nanowire has a square shaped cross-section with four {100} lateral surfaces. The corresponding crystal structure is shown in Fig. 1f , in which 1 × 1 and 2 × 2 tunnels are clearly observed. 1 × 1 tunnels are essentially empty while each 2 × 2 tunnel is found to contain one atomic column, in good agreement with the lateral HAADF image in Fig. 1c . The energy-dispersive spectroscopy (EDS) along the [110] direction shown in Fig. 1f confirmed the tunnel walls to be Mn and the central atoms inside the 2 × 2 tunnels to be K + (Wyckoff", "role": "user" }, { "content": "Battery researchers seeking improved electrode materials have focused on \"tunneled\" structures that make it easier for charge-carrying ions to move in and out of the electrode. Now a team led by a researcher at the University of Illinois at Chicago has used a special electron microscope with atomic-level resolution to show that certain large ions can hold the tunnels open so that the charge-carrying ions can enter and exit the electrode easily and quickly. The finding is reported in Nature Communications. \"Significant research has been done to increase the energy density and power density of lithium ion battery systems,\" says Reza Shahbazian-Yassar, associate professor of mechanical and industrial engineering at UIC. The current generation, he said, is useful enough for portable devices, but the maximum energy and power that can be extracted is limiting. \"So for an electric car, we need to increase the energy and power of the battery—and decrease the cost as well,\" he said. His team, which includes coworkers at Argonne National Laboratory, Michigan Technological Institute and the University of Bath in the U.K., has focused on developing a cathode based on manganese dioxide, a very low cost and environmentally-friendly material with high storage capacity. Manganese dioxide has a lattice structure with regularly spaced tunnels that allow charge carriers—like lithium ions—to move in and out freely. \"But for the tunnels to survive for long-lasting function, they need support structures at the atomic scale,\" Shahbazian-Yassar said. \"We call them tunnel stabilizers, and they are generally big, positive ions, like potassium or barium.\" 3-D schematic shows how doping with potassium may facilitate the insertion of lithium ions into manganese dioxide coated on a current collector. Credit: Reza Shahbazian-Yassar/UIC But the tunnel stabilizers, being positively charged like the lithium ions, should repel each other. \"If lithium goes in, will the tunnel stabilizer come out?\" Shahbazian-Yassar shrugged. \"The research community was in disagreement about the role of tunnel stabilizers during the transfer of lithium into tunnels. Does it help, or hurt?\" The new study represents the first use of electron microscopy to visualize the atomic structure of tunnels in a one-dimensional electrode material—which the researchers say had not previously been possible due to the difficulty of preparing samples. It took them two years to establish the procedure to look for tunnels in potassium-doped nanowires of manganese dioxide down to the single-atom level. Yifei Yuan, a postdoctoral researcher working jointly at Argonne National Laboratory and UIC and the lead author on the study, was then able to use a powerful technique called aberration-corrected scanning transmission electron microscopy to image the tunnels at sub-ångstrom resolution so he could clearly see inside them—and he saw they do change in the presence of a stabilizer ion. \"It's a direct way to see the tunnels,\" Yuan said. \"And we saw that when you add a tunnel stabilizer, the tunnels expand, their electronic structures also change, and such changes allow the lithium ions to move in and out, around the stabilizer.\" The finding shows that tunnel stabilizers can help in the transfer of ions into tunnels and the rate of charge and discharge, Shahbazian-Yassar said. The presence of potassium ions in the tunnels improves the electronic conductivity of manganese dioxide and the ability of lithium ions to diffuse quickly in and out of the nanowires. \"With potassium ions staying in the center of the tunnels, the capacity retention improves by half under high cycling current, which means the battery can hold on to its capacity for a longer time,\" he 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 Metal oxides with a tunnelled structure are attractive as charge storage materials for rechargeable batteries and supercapacitors, since the tunnels enable fast reversible insertion/extraction of charge carriers (for example, lithium ions). Common synthesis methods can introduce large cations such as potassium, barium and ammonium ions into the tunnels, but how these cations affect charge storage performance is not fully understood. Here, we report the role of tunnel cations in governing the electrochemical properties of electrode materials by focusing on potassium ions in α-MnO 2 . We show that the presence of cations inside 2 × 2 tunnels of manganese dioxide increases the electronic conductivity, and improves lithium ion diffusivity. In addition, transmission electron microscopy analysis indicates that the tunnels remain intact whether cations are present in the tunnels or not. Our systematic study shows that cation addition to α-MnO 2 has a strong beneficial effect on the electrochemical performance of this material. Introduction Metal oxides with an internal tunnel structure such as α-MnO 2 , TiO 2 and β-FeOOH are widely used for charge storage in rechargeable batteries and supercapacitors where charge carriers such as Li + , Na + and Mg 2+ can be reversibly inserted and extracted 1 , 2 , 3 , 4 . Of these oxides, α-MnO 2 , which possesses the typical octahedral molecular sieve structure, is characterized by well-ordered one-dimensional 1 × 1 and 2 × 2 tunnels 5 , as illustrated in Supplementary Fig. 1 . The 2 × 2 tunnel (4.6 × 4.6 Å) is large enough to accommodate charge carriers such as Li + , Na + and Mg 2+ , enabling fast ion diffusion inside the tunnel cavity 6 . In addition, Mn-based oxides are low cost, environmentally friendly and safer with respect to over-charge conditions compared with Co-based oxide electrodes 7 . Consequently, α-MnO 2 has been extensively studied as a promising cathode material for lithium (sodium and magnesium) ion batteries 8 , 9 , 10 , 11 , lithium air batteries 12 , 13 and supercapacitors 14 , 15 , 16 . Recent research shows that large cations such as K + , Ba 2+ and NH 4 + can be introduced during synthesis of α-MnO 2 (refs 17 , 18 ). These cations, which partially occupy the tunnel cavities at certain stabilized lattice sites, are expected to interact with the charge carrier (Li + , Na + and Mg 2+ ) and thus affect the charge storage performance of α-MnO 2 where tunnel-driven (de)intercalation contributes to the overall capacity 16 , 18 , 19 , 20 . Despite considerable research devoted to improving the charge storage performance of α-MnO 2 , the underlying mechanism by which tunnel cations affect the insertion/extraction of charge carriers is poorly understood. In the case of Li + being the charge carrier, many researchers believe that the presence of large cations (K + , Ba 2+ ) inside the 2 × 2 tunnels impedes the diffusion of Li + by physical blocking and repulsive electrostatic forces 18 , 21 , 22 , 23 . Others have pointed out that fast (de)intercalation of Li + requires a stable tunnel structure, and the existence of cations helps to prevent the collapse of the tunnels 24 , 25 . As yet, no conclusive evidence has been provided to clarify whether the tunnel cations promote or impede rapid migration of Li ions. An important factor that contributes to this ambiguity is the difficulty of visualizing these cations and determining their content and position, given the spatial resolution limits of most non-aberration-corrected electron microscopes. It is apparent that there is a pressing need to understand the effect of tunnel cations on charge storage behaviour of materials such as α-MnO 2 to allow the synthesis methods and properties of such tunnel-structured oxides to be optimized. In this report, nanowires of K + -doped α-MnO 2 are hydrothermally synthesized and the K + concentration is controlled and differentiated by acid solution treatment. The effect of varying K + concentration on the rate performance of a Li/α-MnO 2 battery is studied systematically by measuring the electronic conductivity and Li + diffusivity in the α-MnO 2 cathode. The underlying mechanism is revealed using a powerful combination of aberration-corrected scanning transmission electron microscopy (ACSTEM), transmission electron microscopy (TEM), electrical response measurements of single α-MnO 2 nanowires, electrochemical impedance spectroscopy (EIS) and density functional theory (DFT) simulations. Results Structural characterization of α-K x MnO 2 Hydrothermally synthesized α-MnO 2 nanowires were characterized using ACSTEM, and the results are shown in Fig. 1 . It can be seen from Fig. 1a,b that the α-MnO 2 nanowire is monocrystalline, growing in the [001] direction with a uniform diameter. The [100] atomic resolution high-angle annular dark field (HAADF) image in Fig. 1c shows the 2 × 2 tunnels (dark stripes) surrounded by two Mn atomic columns (yellow spheres) corresponding to the tunnel walls on each side. It can also be seen that the 2 × 2 tunnels are decorated with ordered K atomic columns (pink spheres) around their centre positions, based on which the [100] atomic model is provided in Fig. 1d . K + ions are successfully introduced during synthesis because excess K + are present in solution to support the 2 × 2 tunnels during their initial formation. The down-tunnel image of one α-MnO 2 nanowire ( Fig. 1e ) shows that the nanowire has a square shaped cross-section with four {100} lateral surfaces. The corresponding crystal structure is shown in Fig. 1f , in which 1 × 1 and 2 × 2 tunnels are clearly observed. 1 × 1 tunnels are essentially empty while each 2 × 2 tunnel is found to contain one atomic column, in good agreement with the lateral HAADF image in Fig. 1c . The energy-dispersive spectroscopy (EDS) along the [110] direction shown in Fig. 1f confirmed the tunnel walls to be Mn and the central atoms inside the 2 × 2 tunnels to be K + (Wyckoff<|im_end|> <|im_start|>assistant Battery researchers seeking improved electrode materials have focused on "tunneled" structures that make it easier for charge-carrying ions to move in and out of the electrode. Now a team led by a researcher at the University of Illinois at Chicago has used a special electron microscope with atomic-level resolution to show that certain large ions can hold the tunnels open so that the charge-carrying ions can enter and exit the electrode easily and quickly. The finding is reported in Nature Communications. "Significant research has been done to increase the energy density and power density of lithium ion battery systems," says Reza Shahbazian-Yassar, associate professor of mechanical and industrial engineering at UIC. The current generation, he said, is useful enough for portable devices, but the maximum energy and power that can be extracted is limiting. "So for an electric car, we need to increase the energy and power of the battery—and decrease the cost as well," he said. His team, which includes coworkers at Argonne National Laboratory, Michigan Technological Institute and the University of Bath in the U.K., has focused on developing a cathode based on manganese dioxide, a very low cost and environmentally-friendly material with high storage capacity. Manganese dioxide has a lattice structure with regularly spaced tunnels that allow charge carriers—like lithium ions—to move in and out freely. "But for the tunnels to survive for long-lasting function, they need support structures at the atomic scale," Shahbazian-Yassar said. "We call them tunnel stabilizers, and they are generally big, positive ions, like potassium or barium." 3-D schematic shows how doping with potassium may facilitate the insertion of lithium ions into manganese dioxide coated on a current collector. Credit: Reza Shahbazian-Yassar/UIC But the tunnel stabilizers, being positively charged like the lithium ions, should repel each other. "If lithium goes in, will the tunnel stabilizer come out?" Shahbazian-Yassar shrugged. "The research community was in disagreement about the role of tunnel stabilizers during the transfer of lithium into tunnels. Does it help, or hurt?" The new study represents the first use of electron microscopy to visualize the atomic structure of tunnels in a one-dimensional electrode material—which the researchers say had not previously been possible due to the difficulty of preparing samples. It took them two years to establish the procedure to look for tunnels in potassium-doped nanowires of manganese dioxide down to the single-atom level. Yifei Yuan, a postdoctoral researcher working jointly at Argonne National Laboratory and UIC and the lead author on the study, was then able to use a powerful technique called aberration-corrected scanning transmission electron microscopy to image the tunnels at sub-ångstrom resolution so he could clearly see inside them—and he saw they do change in the presence of a stabilizer ion. "It's a direct way to see the tunnels," Yuan said. "And we saw that when you add a tunnel stabilizer, the tunnels expand, their electronic structures also change, and such changes allow the lithium ions to move in and out, around the stabilizer." The finding shows that tunnel stabilizers can help in the transfer of ions into tunnels and the rate of charge and discharge, Shahbazian-Yassar said. The presence of potassium ions in the tunnels improves the electronic conductivity of manganese dioxide and the ability of lithium ions to diffuse quickly in and out of the nanowires. "With potassium ions staying in the center of the tunnels, the capacity retention improves by half under high cycling current, which means the battery can hold on to its capacity for a longer time," he 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 Objective To describe postpartum depression and associated risk factors among postpartum patients in the United States (US) between February and July 2020. This study used a cross-sectional descriptive design to collect survey data from a convenience sample of postpartum patients who lived in the US and delivered a live infant after the US declared COVID-19 a public health emergency. Results Our sample included 670 postpartum patients who completed an online survey inclusive of the Edinburgh Postnatal Depression Scale (EPDS) and selected demographic items (e.g. NICU admission status, infant gestational age, infant feeding method). In our sample, 1 in 3 participants screened positive for postpartum depression and 1 in 5 had major depressive symptoms. Participants who fed their infants formula had 92% greater odds of screening positive for postpartum depression and were 73% more likely to screen positive for major depressive symptoms compared to those who breastfed or bottle-fed with their own human milk. Participants with infants admitted to a NICU had 74% greater odds of screening positive. Each 1 week increase in weeks postpartum increased the odds of screening positive by 4%. Participants who worried about themselves and their infants contracting COVID-19 had 71% greater odds of screening positive. Introduction Patients who delivered an infant during the coronavirus (COVID-19) pandemic have reported higher levels of stress during childbirth [ 1 ]. Additionally, 29.6% of pregnant patients assessed during the pandemic experience depressive symptoms [ 2 ]. Subsequently, COVID-19 has had a significant effect on peripartum mental health outcomes. COVID-19 continues to threaten public health, as infection rates in the United States increase dramatically and new variants emerge [ 3 ]. Accordingly, many cities, counties, and states within the United States have implemented or upheld mandates for the public to wear face masks to prevent the spread of COVID-19 [ 4 ]. Pregnant and postpartum patients are considered an at-risk population for severe COVID-19 infection and symptoms [ 5 ]. The emotional, social, and physical consequences associated with increased anxiety and confusion surrounding infection risk can adversely affect maternal mental health [ 6 , 7 , 8 ], placing postpartum patients at greater risk for postpartum depression [ 7 , 8 , 9 ]. Emerging research has begun to describe how the stressors associated with COVID-19 affect postpartum mental health [ 9 , 10 , 11 , 12 , 13 ]; however, few studies have been conducted in the United States which describe factors associated with postpartum depression during the COVID-19 pandemic. As the COVID-19 pandemic and the public health response to it evolves, it is critical for clinicians and researchers to understand postpartum depression within the context of a global pandemic. Peripartum patients during the pandemic may have different experiences than those who delivered prior to the pandemic. Consequently, describing and understanding the risk factors for postpartum depression during this unprecedented time can inform clinical practice and policy. Accordingly, our report describes postpartum depression and associated risk factors of postpartum patients in the United Sates between February and July 2020. Main text Methods This report is associated with the COVID-19 M.A.M.A.S. (Maternal Attachment, Mood, Ability, and Support) study which used a cross-sectional descriptive design to collect survey data from a convenience sample of postpartum patients who were at least 18 years of age , lived in the United States, and delivered a live infant after the United States declared COVID-19 a public health emergency (January 31, 2020) [ 14 ]. The study collected data on maternal mental health outcomes and related demographics and received ethics approval and a waiver of documentation of informed consent from the University of Michigan Institutional Review Board. All participants were provided with study information and informed that completing the survey signified their consent. Participants were recruited through group and individual accounts targeting peripartum women on major social media outlets. The web-based survey was developed specifically for this study, was available June 4-July 8, 2020, and included items to assess maternal mental health, self-efficacy, social support, and breastfeeding (see Additional file 1 ). This analysis describes results of the Edinburgh Postnatal Depression Scale (EPDS) [ 15 ] and associations among positive screens with potential demographic factors using logistic regression. Significance level was set at α = 0.05 for all analyses. The EPDS is a valid and reliable screening tool that is widely used to identify depression symptoms in postpartum patients (in this study, Cronbach’s α = 0.88). Participants rate their agreement on 10 items using a 0–3 Likert scale. Total scores are calculated by summing scores across all items. A score of 10 or greater is considered a positive screen for postpartum depression and suggests further follow up is needed. A score of 13 or greater suggests presence of major depressive symptoms. Regardless of score, a positive response to the item about self-harm ideation results in a positive screen at both cut-off points [ 10 , 13 ]. Explanatory factors included in the analyses were selected from available data in the survey demographic item section, including infant feeding (breastfeeding and/or pumping versus formula feeding), infant admission to a neonatal intensive care unit (NICU), gestational age of infant at birth, maternal age, number of weeks postpartum at time of survey completion, and three COVID-19 related items developed for this study. The COVID-19 items measured peripartum self-quarantining behaviors, worry of becoming infected with COVID-19 for self-and/or infant, and COVID-19 exposure (confirmed or suspected infection of self or family member). Results and discussion The sample of those who completed the EPDS and all explanatory factors included 670 postpartum patients residing in 46 States. The sample was predominantly white and married (Table 1 ). Of participants, 38% (n = 256) screened positive for postpartum depression (score ≥ 10 or affirmative response to self-harm item) and, of these, 57% (n = 146; 21.8% of total sample) screened positive for major depressive symptoms (score ≥ 13 or affirmative response to self-harm item). Fifty-one participants (7.6% of total sample) provided an affirmative response to the self-harm item with most also scoring ≥", "role": "user" }, { "content": "One in three new mothers during early COVID-19 screened positive for postpartum depression––nearly triple pre-pandemic levels––and one in five had major depressive symptoms, say University of Michigan researchers. New research from the U-M School of Nursing found that depression in new mothers rose considerably during the pandemic. Before COVID, the Centers for Disease Control and Prevention estimated that one in eight women experienced postpartum depression, and about 5-7% experienced major depressive symptoms, said lead author Clayton Shuman, U-M assistant professor of nursing. The study, \"Postpartum depression and associated risk factors during the COVID-19 pandemic\" appears in BMC Research Notes. It comes from a larger study called \"COVID-19 MAMAS (Maternal Attachment, Mood, Ability, and Support),\" which gave rise to several papers about pregnancy and postpartum experiences during COVID. For this paper, researchers collected survey data between February and July 2020 from 670 U.S. postpartum patients who completed the Edinburgh Postnatal Depression Scale online and provided demographic information. Their research found that: Moms who fed infants formula had 92% greater odds of screening positive for postpartum depression and were 73% more likely to screen positive for major depressive symptoms, compared to those who breastfed or bottle-fed with their own human milk. Moms with infants in neonatal intensive care units had 74% greater odds of screening positive, and each one-week increase in weeks postpartum increased the odds of screening positive by 4%. Moms worried about contracting COVID-19 had 71% greater odds of screening positive for postpartum depression. Shuman says he was surprised by how many women screened positive for depression and major depression. \"We also found that almost one in five participants who screened positive for postpartum depression reported having thoughts of harming themselves. This is very concerning given that prior to the pandemic, Dr. Lindsay Admon and colleagues from U-M found the rate of suicidality among prenatal and postpartum patients is on the rise in the U.S.\" There are several possible reasons for the breastfeeding finding, Shuman said. Previous research found that breastfeeding support resources such as lactation consults were limited during early COVID and may have increased distress or caused people to switch to formula. Stress from supply chain problems that resulted in formula shortages could have also contributed to depression. Finally, studies suggest that breastfeeding may help to protect postpartum patients from postpartum depression, helping to minimize the severity of depressive symptoms and improving recovery time. This increase highlights the need to identify depressive symptoms in postpartum patients, but screening is only a first step, Shuman said. \"Treatment is pivotal to recovery,\" he said. \"Resources and education about postpartum depression must be better disseminated and implemented. These resources should be shared with the general public to reduce stigma, and shared with those who provide social and emotional support to postpartum patients, such as partners and family members. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 describe postpartum depression and associated risk factors among postpartum patients in the United States (US) between February and July 2020. This study used a cross-sectional descriptive design to collect survey data from a convenience sample of postpartum patients who lived in the US and delivered a live infant after the US declared COVID-19 a public health emergency. Results Our sample included 670 postpartum patients who completed an online survey inclusive of the Edinburgh Postnatal Depression Scale (EPDS) and selected demographic items (e.g. NICU admission status, infant gestational age, infant feeding method). In our sample, 1 in 3 participants screened positive for postpartum depression and 1 in 5 had major depressive symptoms. Participants who fed their infants formula had 92% greater odds of screening positive for postpartum depression and were 73% more likely to screen positive for major depressive symptoms compared to those who breastfed or bottle-fed with their own human milk. Participants with infants admitted to a NICU had 74% greater odds of screening positive. Each 1 week increase in weeks postpartum increased the odds of screening positive by 4%. Participants who worried about themselves and their infants contracting COVID-19 had 71% greater odds of screening positive. Introduction Patients who delivered an infant during the coronavirus (COVID-19) pandemic have reported higher levels of stress during childbirth [ 1 ]. Additionally, 29.6% of pregnant patients assessed during the pandemic experience depressive symptoms [ 2 ]. Subsequently, COVID-19 has had a significant effect on peripartum mental health outcomes. COVID-19 continues to threaten public health, as infection rates in the United States increase dramatically and new variants emerge [ 3 ]. Accordingly, many cities, counties, and states within the United States have implemented or upheld mandates for the public to wear face masks to prevent the spread of COVID-19 [ 4 ]. Pregnant and postpartum patients are considered an at-risk population for severe COVID-19 infection and symptoms [ 5 ]. The emotional, social, and physical consequences associated with increased anxiety and confusion surrounding infection risk can adversely affect maternal mental health [ 6 , 7 , 8 ], placing postpartum patients at greater risk for postpartum depression [ 7 , 8 , 9 ]. Emerging research has begun to describe how the stressors associated with COVID-19 affect postpartum mental health [ 9 , 10 , 11 , 12 , 13 ]; however, few studies have been conducted in the United States which describe factors associated with postpartum depression during the COVID-19 pandemic. As the COVID-19 pandemic and the public health response to it evolves, it is critical for clinicians and researchers to understand postpartum depression within the context of a global pandemic. Peripartum patients during the pandemic may have different experiences than those who delivered prior to the pandemic. Consequently, describing and understanding the risk factors for postpartum depression during this unprecedented time can inform clinical practice and policy. Accordingly, our report describes postpartum depression and associated risk factors of postpartum patients in the United Sates between February and July 2020. Main text Methods This report is associated with the COVID-19 M.A.M.A.S. (Maternal Attachment, Mood, Ability, and Support) study which used a cross-sectional descriptive design to collect survey data from a convenience sample of postpartum patients who were at least 18 years of age , lived in the United States, and delivered a live infant after the United States declared COVID-19 a public health emergency (January 31, 2020) [ 14 ]. The study collected data on maternal mental health outcomes and related demographics and received ethics approval and a waiver of documentation of informed consent from the University of Michigan Institutional Review Board. All participants were provided with study information and informed that completing the survey signified their consent. Participants were recruited through group and individual accounts targeting peripartum women on major social media outlets. The web-based survey was developed specifically for this study, was available June 4-July 8, 2020, and included items to assess maternal mental health, self-efficacy, social support, and breastfeeding (see Additional file 1 ). This analysis describes results of the Edinburgh Postnatal Depression Scale (EPDS) [ 15 ] and associations among positive screens with potential demographic factors using logistic regression. Significance level was set at α = 0.05 for all analyses. The EPDS is a valid and reliable screening tool that is widely used to identify depression symptoms in postpartum patients (in this study, Cronbach’s α = 0.88). Participants rate their agreement on 10 items using a 0–3 Likert scale. Total scores are calculated by summing scores across all items. A score of 10 or greater is considered a positive screen for postpartum depression and suggests further follow up is needed. A score of 13 or greater suggests presence of major depressive symptoms. Regardless of score, a positive response to the item about self-harm ideation results in a positive screen at both cut-off points [ 10 , 13 ]. Explanatory factors included in the analyses were selected from available data in the survey demographic item section, including infant feeding (breastfeeding and/or pumping versus formula feeding), infant admission to a neonatal intensive care unit (NICU), gestational age of infant at birth, maternal age, number of weeks postpartum at time of survey completion, and three COVID-19 related items developed for this study. The COVID-19 items measured peripartum self-quarantining behaviors, worry of becoming infected with COVID-19 for self-and/or infant, and COVID-19 exposure (confirmed or suspected infection of self or family member). Results and discussion The sample of those who completed the EPDS and all explanatory factors included 670 postpartum patients residing in 46 States. The sample was predominantly white and married (Table 1 ). Of participants, 38% (n = 256) screened positive for postpartum depression (score ≥ 10 or affirmative response to self-harm item) and, of these, 57% (n = 146; 21.8% of total sample) screened positive for major depressive symptoms (score ≥ 13 or affirmative response to self-harm item). Fifty-one participants (7.6% of total sample) provided an affirmative response to the self-harm item with most also scoring ≥<|im_end|> <|im_start|>assistant One in three new mothers during early COVID-19 screened positive for postpartum depression––nearly triple pre-pandemic levels––and one in five had major depressive symptoms, say University of Michigan researchers. New research from the U-M School of Nursing found that depression in new mothers rose considerably during the pandemic. Before COVID, the Centers for Disease Control and Prevention estimated that one in eight women experienced postpartum depression, and about 5-7% experienced major depressive symptoms, said lead author Clayton Shuman, U-M assistant professor of nursing. The study, "Postpartum depression and associated risk factors during the COVID-19 pandemic" appears in BMC Research Notes. It comes from a larger study called "COVID-19 MAMAS (Maternal Attachment, Mood, Ability, and Support)," which gave rise to several papers about pregnancy and postpartum experiences during COVID. For this paper, researchers collected survey data between February and July 2020 from 670 U.S. postpartum patients who completed the Edinburgh Postnatal Depression Scale online and provided demographic information. Their research found that: Moms who fed infants formula had 92% greater odds of screening positive for postpartum depression and were 73% more likely to screen positive for major depressive symptoms, compared to those who breastfed or bottle-fed with their own human milk. Moms with infants in neonatal intensive care units had 74% greater odds of screening positive, and each one-week increase in weeks postpartum increased the odds of screening positive by 4%. Moms worried about contracting COVID-19 had 71% greater odds of screening positive for postpartum depression. Shuman says he was surprised by how many women screened positive for depression and major depression. "We also found that almost one in five participants who screened positive for postpartum depression reported having thoughts of harming themselves. This is very concerning given that prior to the pandemic, Dr. Lindsay Admon and colleagues from U-M found the rate of suicidality among prenatal and postpartum patients is on the rise in the U.S." There are several possible reasons for the breastfeeding finding, Shuman said. Previous research found that breastfeeding support resources such as lactation consults were limited during early COVID and may have increased distress or caused people to switch to formula. Stress from supply chain problems that resulted in formula shortages could have also contributed to depression. Finally, studies suggest that breastfeeding may help to protect postpartum patients from postpartum depression, helping to minimize the severity of depressive symptoms and improving recovery time. This increase highlights the need to identify depressive symptoms in postpartum patients, but screening is only a first step, Shuman said. "Treatment is pivotal to recovery," he said. "Resources and education about postpartum depression must be better disseminated and implemented. These resources should be shared with the general public to reduce stigma, and shared with those who provide social and emotional support to postpartum patients, such as partners and family members. <|im_end|>

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1,974

[ { "content": "You are a great 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 fossil record provides striking case studies of biodiversity loss and global ecosystem upheaval. Because of this, many studies have sought to assess the magnitude of the current biodiversity crisis relative to past crises—a task greatly complicated by the need to extrapolate extinction rates. Here we challenge this approach by showing that the rarity of previously abundant taxa may be more important than extinction in the cascade of events leading to global changes in the biosphere. Mass rarity may provide the most robust measure of our current biodiversity crisis relative to those past, and new insights into the dynamics of mass extinction. Main It has become commonplace to refer to the modern biodiversity crisis as the ‘sixth mass extinction’ 1 , 2 . With three short words, we place the biotic and environmental disturbance created by mankind on par with the greatest biodiversity crises of the past half billion years. This is a comparison that demands close attention as the ‘Big Five’ mass extinctions include truly catastrophic events 3 , 4 , the biggest of which resulted in the inferred extinction of >75% of species alive at the time 1 , 4 . In addition, mass extinctions have shaped the evolutionary history of the planet 5 , 6 , 7 . Organisms that were ecologically dominant before a mass extinction frequently do not survive, and rarely enjoy the same levels of dominance in the aftermath 6 , 8 . However, there are fundamental differences between the types of data upon which past mass extinctions have been identified, and those upon which the current biodiversity crisis is being assessed. That is, abundant marine fossil genera on multi-million year timescales for the former 9 , 10 , and (often rare) terrestrial species on decadal to centennial timescales for the latter 1 . So the question is critical: are we currently in the midst of the ‘sixth’ mass extinction, and can we develop an appropriate metric for the comparison of ancient and modern biotic crises? The Big Five mass extinctions were profoundly disruptive events with effects extending far beyond the loss of taxonomic diversity 11 , 12 , 13 , 14 , 15 . In addition to extinction, all major mass extinctions are also characterized by prolonged intervals of ecological change 12 , 16 . Ecosystems are comprised of interacting networks of biotic and biophysical components, including taxa, nutrients, and their trophic and non-trophic interactions 17 . Species loss and ecosystem reassembly during mass extinction is unsurprising given the disruption of ecological networks 18 . For hundreds of thousands to millions of years after mass extinctions, a series of short-lived, low-diversity and (at times) low productivity ecosystems dominate 16 , 19 , 20 . Large-bodied taxa often become dwarfed, or are replaced by small-bodied taxa 21 , 22 . Previously dominant groups may be supplanted in the evolutionary diversifications that follow 23 , 24 , 25 , as new, diverse ecosystems are built 26 . The largest extinction intervals result in permanent state changes in the structure of ecosystems, as well as the character of the flora and fauna that dominate them 5 , 25 , 27 . Mass extinctions, therefore, not only punctuate the history of life, they also forever alter its trajectory. In this light, the fossil record of mass extinctions is an important laboratory for understanding the effects of current environmental change on global ecosystem structure and function 28 . A key question is: how do minor biodiversity crises become mass extinctions? And, why do mass extinctions tend to coincide with permanent state changes in global ecosystems? To date, studies have considered these issues by comparing projected rates of modern species loss and rates estimated from the fossil record 1 , 11 , 29 —a method complicated by the need to extrapolate across temporal scales and abrupt state changes. Here, we propose a different approach, and consider whether the loss of species abundance—mass rarity—might have characterized past mass extinctions as they were occurring. Rarity is important for two reasons: first, because it more accurately reflects function in ecological networks 30 and thus mass rarity (rather than mass extinction) may be a primary driver of the events and patterns associated with the mass disappearance of fossils from the fossil record. Second, the extent to which previously common taxa have become rare offers a direct metric of the size of the present biotic crisis. There may be no need to project current extinction rates in order to get a sense of the future of ecosystems. Mass rarity may be all that is needed to forever change the biosphere. From past abundance to current rarity Humans have reduced the abundance of many historically common species. This increased rarity has been achieved through wholesale reduction in geographic ranges and/or population sizes, through modification of terrestrial habitats, appropriation of primary productivity for humanity, overexploitation and pollution, among other factors 31 , 32 , 33 . On land, widespread evidence exists for ongoing habitat loss and population declines globally 31 , 34 . This includes, for instance, a 20% decline in habitat specialist populations monitored by the Wild Bird Index since the 1980s, and continuing declines in the IUCN Red List Index of species survival aggregated across birds, mammals, amphibians and corals 31 . Likewise, most fished coral reefs support less than half the expected fish biomass 35 , with long-term declines in the abundance of reef taxa since first human contact 36 . Among subsets of mammals, birds, butterflies, and highly mobile pelagic predators, more than 50% of the taxa studied have experienced range contractions in the last decades to centuries 37 , 38 , 39 . Yet to date, the absolute number of recorded species extinctions is dwarfed by those inferred for mass extinctions in the geological past 1 , 11 and local declines in species richness are equivocal 33 , 40 . However, the extent of abundance loss is not equivocal, nor is the effect of land use 34 . Mass rarity,", "role": "user" }, { "content": "A Yale-led study urges scientists to move their focus from species extinction to species rarity in order to recognize, and avoid, a mass extinction in the modern world. Writing in the journal Nature the week of Dec. 16, Yale's Pincelli Hull and colleagues from the Smithsonian Institution argue that modern extinction rates may be a poor measure of whether we're in the midst of a mass extinction event today—something many scientists suspect may be happening. Instead, Hull and her co-authors contend, the best way to see a mass extinction in real time is by studying changes in species and ecosystems. Earth has experienced more than a dozen mass extinction events, when the great diversity of life on Earth disappeared and was replaced by a flora or fauna often entirely unlike what had come before. The largest of these events (the most recent, which wiped out the dinosaurs, was 66 million years ago) have collectively become known as the \"Five Mass Extinctions.\" In recent years, Hull says, some have argued that Earth is entering a sixth mass extinction event. It also was the topic of Elizabeth Kolbert's Pulitzer Prize-winning book, \"The Sixth Extinction.\" \"I am an extinction scientist. In my research I dissect past extinctions to work out what occurred and why. The idea of being able to pin down whether we are in a sixth mass extinction, based on extinction rates measured today, was absolutely astounding to me,\" said Hull, who is lead author of the study and an assistant professor of geology and geophysics. \"It implied a deep mechanistic and predictive understanding of how mass extinctions unfold that I wasn't sure we actually had.\" Hull and her co-authors, Simon Darroch and Douglas Erwin, contend that long before species become extinct, their rarity may cause far-reaching changes in global ecosystems. In fact, the researchers explain, the rarity of previously abundant species and ecosystems alone may be enough to drive permanent shifts in the biosphere. A review of the fossil record, they said, shows that rarity of previously abundant organisms is the only factor tied with certainty to the widespread ecological change observed across extinction boundaries, and because of this, the magnitude and extent of rarity may provide the best comparison of the current biotic crisis to those of the past. \"Ecology tells us that ecosystems can collapse completely on timescales ranging from 100 to 10,000 years, which is a process that typically isn't preserved in the fossil record, so we simply don't have a good idea of what these transitional ecosystems look like,\" Darroch said. \"Figuring out how mass rarity in a wide range of species in today's oceans may scale up to a mass extinction on longer timescales is one of the great scientific challenges of our generation.\" The researchers note, for example, that the modern ocean is full of ecological \"ghosts\"—species that are now so rare that they no longer fill the ecological roles they did previously, when they were more abundant. In other words, species rarity itself, rather than extinction, can lead to a cascade of changes within ecosystems, long before the species goes extinct, the scientists explain. \"The ecological ghosts of oceans past already swim in emptied seas,\" the authors said in the paper. But they also noted that today's fossil record has yet to be written. \"There are steps to take to avoid a mass extinction-like record, even if there are signs of it,\" Hull said. \"This makes it all the more urgent to act early to protect ecosystems and restore once-abundant species.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The fossil record provides striking case studies of biodiversity loss and global ecosystem upheaval. Because of this, many studies have sought to assess the magnitude of the current biodiversity crisis relative to past crises—a task greatly complicated by the need to extrapolate extinction rates. Here we challenge this approach by showing that the rarity of previously abundant taxa may be more important than extinction in the cascade of events leading to global changes in the biosphere. Mass rarity may provide the most robust measure of our current biodiversity crisis relative to those past, and new insights into the dynamics of mass extinction. Main It has become commonplace to refer to the modern biodiversity crisis as the ‘sixth mass extinction’ 1 , 2 . With three short words, we place the biotic and environmental disturbance created by mankind on par with the greatest biodiversity crises of the past half billion years. This is a comparison that demands close attention as the ‘Big Five’ mass extinctions include truly catastrophic events 3 , 4 , the biggest of which resulted in the inferred extinction of >75% of species alive at the time 1 , 4 . In addition, mass extinctions have shaped the evolutionary history of the planet 5 , 6 , 7 . Organisms that were ecologically dominant before a mass extinction frequently do not survive, and rarely enjoy the same levels of dominance in the aftermath 6 , 8 . However, there are fundamental differences between the types of data upon which past mass extinctions have been identified, and those upon which the current biodiversity crisis is being assessed. That is, abundant marine fossil genera on multi-million year timescales for the former 9 , 10 , and (often rare) terrestrial species on decadal to centennial timescales for the latter 1 . So the question is critical: are we currently in the midst of the ‘sixth’ mass extinction, and can we develop an appropriate metric for the comparison of ancient and modern biotic crises? The Big Five mass extinctions were profoundly disruptive events with effects extending far beyond the loss of taxonomic diversity 11 , 12 , 13 , 14 , 15 . In addition to extinction, all major mass extinctions are also characterized by prolonged intervals of ecological change 12 , 16 . Ecosystems are comprised of interacting networks of biotic and biophysical components, including taxa, nutrients, and their trophic and non-trophic interactions 17 . Species loss and ecosystem reassembly during mass extinction is unsurprising given the disruption of ecological networks 18 . For hundreds of thousands to millions of years after mass extinctions, a series of short-lived, low-diversity and (at times) low productivity ecosystems dominate 16 , 19 , 20 . Large-bodied taxa often become dwarfed, or are replaced by small-bodied taxa 21 , 22 . Previously dominant groups may be supplanted in the evolutionary diversifications that follow 23 , 24 , 25 , as new, diverse ecosystems are built 26 . The largest extinction intervals result in permanent state changes in the structure of ecosystems, as well as the character of the flora and fauna that dominate them 5 , 25 , 27 . Mass extinctions, therefore, not only punctuate the history of life, they also forever alter its trajectory. In this light, the fossil record of mass extinctions is an important laboratory for understanding the effects of current environmental change on global ecosystem structure and function 28 . A key question is: how do minor biodiversity crises become mass extinctions? And, why do mass extinctions tend to coincide with permanent state changes in global ecosystems? To date, studies have considered these issues by comparing projected rates of modern species loss and rates estimated from the fossil record 1 , 11 , 29 —a method complicated by the need to extrapolate across temporal scales and abrupt state changes. Here, we propose a different approach, and consider whether the loss of species abundance—mass rarity—might have characterized past mass extinctions as they were occurring. Rarity is important for two reasons: first, because it more accurately reflects function in ecological networks 30 and thus mass rarity (rather than mass extinction) may be a primary driver of the events and patterns associated with the mass disappearance of fossils from the fossil record. Second, the extent to which previously common taxa have become rare offers a direct metric of the size of the present biotic crisis. There may be no need to project current extinction rates in order to get a sense of the future of ecosystems. Mass rarity may be all that is needed to forever change the biosphere. From past abundance to current rarity Humans have reduced the abundance of many historically common species. This increased rarity has been achieved through wholesale reduction in geographic ranges and/or population sizes, through modification of terrestrial habitats, appropriation of primary productivity for humanity, overexploitation and pollution, among other factors 31 , 32 , 33 . On land, widespread evidence exists for ongoing habitat loss and population declines globally 31 , 34 . This includes, for instance, a 20% decline in habitat specialist populations monitored by the Wild Bird Index since the 1980s, and continuing declines in the IUCN Red List Index of species survival aggregated across birds, mammals, amphibians and corals 31 . Likewise, most fished coral reefs support less than half the expected fish biomass 35 , with long-term declines in the abundance of reef taxa since first human contact 36 . Among subsets of mammals, birds, butterflies, and highly mobile pelagic predators, more than 50% of the taxa studied have experienced range contractions in the last decades to centuries 37 , 38 , 39 . Yet to date, the absolute number of recorded species extinctions is dwarfed by those inferred for mass extinctions in the geological past 1 , 11 and local declines in species richness are equivocal 33 , 40 . However, the extent of abundance loss is not equivocal, nor is the effect of land use 34 . Mass rarity,<|im_end|> <|im_start|>assistant A Yale-led study urges scientists to move their focus from species extinction to species rarity in order to recognize, and avoid, a mass extinction in the modern world. Writing in the journal Nature the week of Dec. 16, Yale's Pincelli Hull and colleagues from the Smithsonian Institution argue that modern extinction rates may be a poor measure of whether we're in the midst of a mass extinction event today—something many scientists suspect may be happening. Instead, Hull and her co-authors contend, the best way to see a mass extinction in real time is by studying changes in species and ecosystems. Earth has experienced more than a dozen mass extinction events, when the great diversity of life on Earth disappeared and was replaced by a flora or fauna often entirely unlike what had come before. The largest of these events (the most recent, which wiped out the dinosaurs, was 66 million years ago) have collectively become known as the "Five Mass Extinctions." In recent years, Hull says, some have argued that Earth is entering a sixth mass extinction event. It also was the topic of Elizabeth Kolbert's Pulitzer Prize-winning book, "The Sixth Extinction." "I am an extinction scientist. In my research I dissect past extinctions to work out what occurred and why. The idea of being able to pin down whether we are in a sixth mass extinction, based on extinction rates measured today, was absolutely astounding to me," said Hull, who is lead author of the study and an assistant professor of geology and geophysics. "It implied a deep mechanistic and predictive understanding of how mass extinctions unfold that I wasn't sure we actually had." Hull and her co-authors, Simon Darroch and Douglas Erwin, contend that long before species become extinct, their rarity may cause far-reaching changes in global ecosystems. In fact, the researchers explain, the rarity of previously abundant species and ecosystems alone may be enough to drive permanent shifts in the biosphere. A review of the fossil record, they said, shows that rarity of previously abundant organisms is the only factor tied with certainty to the widespread ecological change observed across extinction boundaries, and because of this, the magnitude and extent of rarity may provide the best comparison of the current biotic crisis to those of the past. "Ecology tells us that ecosystems can collapse completely on timescales ranging from 100 to 10,000 years, which is a process that typically isn't preserved in the fossil record, so we simply don't have a good idea of what these transitional ecosystems look like," Darroch said. "Figuring out how mass rarity in a wide range of species in today's oceans may scale up to a mass extinction on longer timescales is one of the great scientific challenges of our generation." The researchers note, for example, that the modern ocean is full of ecological "ghosts"—species that are now so rare that they no longer fill the ecological roles they did previously, when they were more abundant. In other words, species rarity itself, rather than extinction, can lead to a cascade of changes within ecosystems, long before the species goes extinct, the scientists explain. "The ecological ghosts of oceans past already swim in emptied seas," the authors said in the paper. But they also noted that today's fossil record has yet to be written. "There are steps to take to avoid a mass extinction-like record, even if there are signs of it," Hull said. "This makes it all the more urgent to act early to protect ecosystems and restore once-abundant species." <|im_end|>

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1,969

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Chirality is a manifestation of the asymmetry inherent in nature. It has been defined as the symmetry breaking of the parity of static objects, and the definition was extended to dynamic motion such that true and false chiralities were distinguished. Recently, rotating, yet not propagating, atomic motions were predicted and observed in two-dimensional materials, and they were referred to as ‘chiral phonons’. A natural development would be the discovery of truly chiral phonons that propagate while rotating in three-dimensional materials. Here we used circularly polarized Raman scattering and first-principles calculations to identify truly chiral phonons in chiral bulk crystals. This approach enabled us to determine the chirality of a crystal in a non-contact and non-destructive manner. In addition, we demonstrated that the law of the conservation of pseudo-angular momentum holds between circularly polarized photons and chiral phonons. These findings are expected to help develop ways for transferring the pseudo-angular momentum from photons to electron spins via propagating chiral phonons in opto-phononic-spintronic devices. Main Chirality, the breaking of reflection and inversion symmetries 1 , appears at all levels of nature and has been studied in many fields of research 2 . Barron extended the concept of chirality to the dynamic regime by classifying into true and false chiralities 3 . True chirality is demonstrated by systems that exist in two different enantiomeric states that are interconverted by spatial inversion \$({{{\\mathcal{P}}}})\$ , rather than by time inversion \$({{{\\mathcal{T}}}})\$ combined with appropriate spatial rotation \$({{{\\mathcal{R}}}})\$ (ref. 3 ). This concept contrasts with false chirality, where the two states are interconverted by \${{{\\mathcal{P}}}}\$ and by \${{{\\mathcal{T}}}}\$ , for example, magneto-optical Faraday rotation. Chirality was further extended to the dynamics of quasi-particles. Possible band structure shapes have been classified in terms of pseudo-momentum and pseudo-angular momentum (PAM) 4 , which originate from the phase factors acquired by discrete translation and rotation symmetry operations on wave functions, respectively. In crystals, these are different from the momentum and angular momentum (AM), which are continuous linear and circular motions of an object in real space, respectively. Recently, circularly rotating atomic motion with non-zero PAM and AM at high-symmetry points in the Brillouin zone in monolayer hexagonal lattices was theoretically predicted and named ‘chiral phonons, 5 , 6 . This prediction was verified experimentally in the transition-metal dichalcogenide WSe 2 via transient infrared spectroscopy 7 . Employing Barron’s true chirality, one can extend the concept of a chiral phonon to ‘truly chiral phonons’, which have two enantiomeric chiral modes that propagate with finite group velocity while circularly rotating in three-dimensional materials wherein PAM and AM have opposite signs. These modes should be interconverted by \${{{\\mathcal{P}}}}\$ but not by \${{{\\mathcal{RT}}}}\$ . The observation of truly chiral phonons would require the use of chiral materials, as has been proposed theoretically 8 . Several Raman experiments designed to identify phonon symmetry in chiral crystals have been conducted 9 , 10 , 11 , 12 , 13 , 14 , 15 . Frequency-degenerated phonon modes were observed to undergo splitting at the centre of the Brillouin zone (Γ 3 doublets) in α-quartz and trigonal tellurium 9 , 11 . Moreover, theoretical work on phonon band dispersion has been reported on α-HgS (cinnabar), where the splitting was attributed to the linear wave vector shifts caused by chirality 16 . Nonetheless, previous studies have mostly focused on examining the phonon symmetry without considering PAM and AM. Here we used circularly polarized Raman spectroscopy ( Methods ) to observe the phonon modes and their splitting in chiral crystals of α-HgS. Moreover, we performed first-principles calculations ( Methods ) to compute the dispersion, PAM and AM of phonons in α-HgS. A comparison between the experiment and calculation shows that the split phonons were indeed truly chiral phonons. We also confirmed that the conservation law of PAM holds in circularly polarized Raman scattering by taking into account the three-fold rotational symmetry. Trigonal α-HgS crystals contain two enantiomeric cinnabar structures with right- and left-handed helices (R- and L-HgS), which belong to the space groups P 3 1 21 (translation by c /3 in three-fold rotation) and P 3 2 21 (translation by 2 c /3 in three-fold rotation), respectively 17 . This crystal has a three-fold helical axis along the c direction (Fig. 1a ), with large optical activity 18 . Our samples were single crystals of naturally grown α-HgS with lateral dimensions of 3 mm. We selected a c -axis-oriented as-grown surface of R-HgS, which was confirmed by X-ray analysis. Fig. 1: Chiral properties of α-HgS. a , Right-handed helical chain along the c axis of R-HgS. Each Hg atom (red sphere) is bonded with two S atoms (blue spheres). Chemical bonds are denoted by green lines. b , Brillouin zone of α-HgS. The blue lines indicate the reciprocal lattice vectors. The green lines and dots represent the high-symmetry paths and points, respectively. c , Schematic diagram of phonon dispersion from the Γ to A point. Filled red, blue and black circles at the N point correspond to the phonon modes of d , e and f , respectively. d – f , Two-dimensional projections of schematic atomic motions (Hg, gold arrows; S, blue arrows) in R-HgS at point N for a Δ 2 mode with \${m}_{{{{\\rm{PAM}}}}}^{{{{\\rm{s}}}}}=+1\$ and m AM > 0 ( d ), a Δ 3 mode with \${m}_{{{{\\rm{PAM}}}}}^{{{{\\rm{s}}}}}=-1\$ and m AM < 0 ( e ) and a Δ 1 mode with \${m}_{{{{\\rm{PAM}}}}}^{{{{\\rm{s}}}}}=0\$ and m AM ≃ 0 ( f ). The black lines indicate the lattice vectors. Counter-clockwise, clockwise circular and linear motions indicate that m AM is positive, negative and zero, respectively. The three-fold rotation symmetry operation generates phase factors of atomic motions, namely PAM \${m}_{{{{\\rm{PAM}}}}}^{{{{\\rm{s}}}}}\$ . The phase difference at the position of each atom after the operation is shown. Full size image The phonon modes at the centre of the Brillouin zone (Γ point) of α-HgS are classified into two \${\\Gamma }_{1}^{(1,2)}\$ singlets (Raman active), three \${\\Gamma }_{2}^{(1-3)}\$ singlets (infrared active) and five \${\\Gamma }_{3}^{(1-5)}\$ doublets (Raman and infrared active).", "role": "user" }, { "content": "Chirality is the breaking of reflection and inversion symmetries. Simply put, it is when an object's mirror images cannot be superimposed over each other. A common example are your two hands—while mirror images of each other, they can never overlap. Chirality appears at all levels in nature and is ubiquitous. In addition to static chirality, chirality can also occur due to dynamic motion including rotation. With this in mind, we can distinguish true and false chirality. A system is truly chiral if—when translating—space inversion does not equate to time reversal combined with a proper spatial rotation. Phonons are quanta (or small packets) of energy associated with the vibration of atoms in a crystal lattice. Recently, phonons with chiral properties have been theorized and experimentally discovered in two-dimensional (2D) materials such as tungsten diselenide. The discovered chiral phonons are rotating—yet not propagating—atomic motions. But, truly chiral phonons would be atomic motions that are both rotating and propagating, and these have never been observed in three-dimensional (3D) bulk systems. Now, a team of researchers led by scientists from Tokyo Institute of Technology (Tokyo Tech) has identified truly chiral phonons, both theoretically and experimentally. Their work is published in Nature Physics. The team, led by Professor Takuya Satoh of the Department of Physics at Tokyo Tech, observed the chiral phonons in cinnabar (α-HgS). This was achieved using a combination of first-principles calculations and an experimental technique called circularly polarized Raman scattering. \"Chiral structures can be probed using chiral techniques. So, using circularly polarized light, which has its own handedness (i.e., right-handed or left-handedness), is critical. Dynamic chiral structures can be mapped using pseudo-angular momentum (PAM). Pseudo-momentum and PAM originate from the phase factors acquired by discrete translation and rotation symmetry operations, respectively,\" explains Professor Satoh. The researchers' novel experimental approach also allowed them to probe the fundamental traits of PAM. They found that the law of the conservation of PAM—one of the key laws of physics—holds between circularly polarized photons and chiral phonons. \"Our work also provides an optical method to identify the handedness of chiral materials using PAM. Namely, we can determine the handedness of materials with better resolution than X-ray diffraction (XRD) can achieve. Moreover, XRD requires a large-enough crystal, is invasive, and can be destructive. Circularly polarized Raman scattering, on the other hand, allowed us to determine the chirality of structures XRD could not, in a non-contact and non-destructive manner,\" concludes Professor Satoh. This study is the first to identify truly chiral phonons in 3D materials, which are clearly distinct from those seen previously in 2D hexagonal systems. The knowledge gained here could drive new research into developing ways for transferring the PAM from photons to electron spins via propagating chiral phonons in future devices. Furthermore, this approach enables the determination of the true chirality of a crystal in an improved manner, providing a new critical tool for experimentalists' and researchers. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Chirality is a manifestation of the asymmetry inherent in nature. It has been defined as the symmetry breaking of the parity of static objects, and the definition was extended to dynamic motion such that true and false chiralities were distinguished. Recently, rotating, yet not propagating, atomic motions were predicted and observed in two-dimensional materials, and they were referred to as ‘chiral phonons’. A natural development would be the discovery of truly chiral phonons that propagate while rotating in three-dimensional materials. Here we used circularly polarized Raman scattering and first-principles calculations to identify truly chiral phonons in chiral bulk crystals. This approach enabled us to determine the chirality of a crystal in a non-contact and non-destructive manner. In addition, we demonstrated that the law of the conservation of pseudo-angular momentum holds between circularly polarized photons and chiral phonons. These findings are expected to help develop ways for transferring the pseudo-angular momentum from photons to electron spins via propagating chiral phonons in opto-phononic-spintronic devices. Main Chirality, the breaking of reflection and inversion symmetries 1 , appears at all levels of nature and has been studied in many fields of research 2 . Barron extended the concept of chirality to the dynamic regime by classifying into true and false chiralities 3 . True chirality is demonstrated by systems that exist in two different enantiomeric states that are interconverted by spatial inversion $({{{\mathcal{P}}}})$ , rather than by time inversion $({{{\mathcal{T}}}})$ combined with appropriate spatial rotation $({{{\mathcal{R}}}})$ (ref. 3 ). This concept contrasts with false chirality, where the two states are interconverted by ${{{\mathcal{P}}}}$ and by ${{{\mathcal{T}}}}$ , for example, magneto-optical Faraday rotation. Chirality was further extended to the dynamics of quasi-particles. Possible band structure shapes have been classified in terms of pseudo-momentum and pseudo-angular momentum (PAM) 4 , which originate from the phase factors acquired by discrete translation and rotation symmetry operations on wave functions, respectively. In crystals, these are different from the momentum and angular momentum (AM), which are continuous linear and circular motions of an object in real space, respectively. Recently, circularly rotating atomic motion with non-zero PAM and AM at high-symmetry points in the Brillouin zone in monolayer hexagonal lattices was theoretically predicted and named ‘chiral phonons, 5 , 6 . This prediction was verified experimentally in the transition-metal dichalcogenide WSe 2 via transient infrared spectroscopy 7 . Employing Barron’s true chirality, one can extend the concept of a chiral phonon to ‘truly chiral phonons’, which have two enantiomeric chiral modes that propagate with finite group velocity while circularly rotating in three-dimensional materials wherein PAM and AM have opposite signs. These modes should be interconverted by ${{{\mathcal{P}}}}$ but not by ${{{\mathcal{RT}}}}$ . The observation of truly chiral phonons would require the use of chiral materials, as has been proposed theoretically 8 . Several Raman experiments designed to identify phonon symmetry in chiral crystals have been conducted 9 , 10 , 11 , 12 , 13 , 14 , 15 . Frequency-degenerated phonon modes were observed to undergo splitting at the centre of the Brillouin zone (Γ 3 doublets) in α-quartz and trigonal tellurium 9 , 11 . Moreover, theoretical work on phonon band dispersion has been reported on α-HgS (cinnabar), where the splitting was attributed to the linear wave vector shifts caused by chirality 16 . Nonetheless, previous studies have mostly focused on examining the phonon symmetry without considering PAM and AM. Here we used circularly polarized Raman spectroscopy ( Methods ) to observe the phonon modes and their splitting in chiral crystals of α-HgS. Moreover, we performed first-principles calculations ( Methods ) to compute the dispersion, PAM and AM of phonons in α-HgS. A comparison between the experiment and calculation shows that the split phonons were indeed truly chiral phonons. We also confirmed that the conservation law of PAM holds in circularly polarized Raman scattering by taking into account the three-fold rotational symmetry. Trigonal α-HgS crystals contain two enantiomeric cinnabar structures with right- and left-handed helices (R- and L-HgS), which belong to the space groups P 3 1 21 (translation by c /3 in three-fold rotation) and P 3 2 21 (translation by 2 c /3 in three-fold rotation), respectively 17 . This crystal has a three-fold helical axis along the c direction (Fig. 1a ), with large optical activity 18 . Our samples were single crystals of naturally grown α-HgS with lateral dimensions of 3 mm. We selected a c -axis-oriented as-grown surface of R-HgS, which was confirmed by X-ray analysis. Fig. 1: Chiral properties of α-HgS. a , Right-handed helical chain along the c axis of R-HgS. Each Hg atom (red sphere) is bonded with two S atoms (blue spheres). Chemical bonds are denoted by green lines. b , Brillouin zone of α-HgS. The blue lines indicate the reciprocal lattice vectors. The green lines and dots represent the high-symmetry paths and points, respectively. c , Schematic diagram of phonon dispersion from the Γ to A point. Filled red, blue and black circles at the N point correspond to the phonon modes of d , e and f , respectively. d – f , Two-dimensional projections of schematic atomic motions (Hg, gold arrows; S, blue arrows) in R-HgS at point N for a Δ 2 mode with ${m}_{{{{\rm{PAM}}}}}^{{{{\rm{s}}}}}=+1$ and m AM > 0 ( d ), a Δ 3 mode with ${m}_{{{{\rm{PAM}}}}}^{{{{\rm{s}}}}}=-1$ and m AM < 0 ( e ) and a Δ 1 mode with ${m}_{{{{\rm{PAM}}}}}^{{{{\rm{s}}}}}=0$ and m AM ≃ 0 ( f ). The black lines indicate the lattice vectors. Counter-clockwise, clockwise circular and linear motions indicate that m AM is positive, negative and zero, respectively. The three-fold rotation symmetry operation generates phase factors of atomic motions, namely PAM ${m}_{{{{\rm{PAM}}}}}^{{{{\rm{s}}}}}$ . The phase difference at the position of each atom after the operation is shown. Full size image The phonon modes at the centre of the Brillouin zone (Γ point) of α-HgS are classified into two ${\Gamma }_{1}^{(1,2)}$ singlets (Raman active), three ${\Gamma }_{2}^{(1-3)}$ singlets (infrared active) and five ${\Gamma }_{3}^{(1-5)}$ doublets (Raman and infrared active).<|im_end|> <|im_start|>assistant Chirality is the breaking of reflection and inversion symmetries. Simply put, it is when an object's mirror images cannot be superimposed over each other. A common example are your two hands—while mirror images of each other, they can never overlap. Chirality appears at all levels in nature and is ubiquitous. In addition to static chirality, chirality can also occur due to dynamic motion including rotation. With this in mind, we can distinguish true and false chirality. A system is truly chiral if—when translating—space inversion does not equate to time reversal combined with a proper spatial rotation. Phonons are quanta (or small packets) of energy associated with the vibration of atoms in a crystal lattice. Recently, phonons with chiral properties have been theorized and experimentally discovered in two-dimensional (2D) materials such as tungsten diselenide. The discovered chiral phonons are rotating—yet not propagating—atomic motions. But, truly chiral phonons would be atomic motions that are both rotating and propagating, and these have never been observed in three-dimensional (3D) bulk systems. Now, a team of researchers led by scientists from Tokyo Institute of Technology (Tokyo Tech) has identified truly chiral phonons, both theoretically and experimentally. Their work is published in Nature Physics. The team, led by Professor Takuya Satoh of the Department of Physics at Tokyo Tech, observed the chiral phonons in cinnabar (α-HgS). This was achieved using a combination of first-principles calculations and an experimental technique called circularly polarized Raman scattering. "Chiral structures can be probed using chiral techniques. So, using circularly polarized light, which has its own handedness (i.e., right-handed or left-handedness), is critical. Dynamic chiral structures can be mapped using pseudo-angular momentum (PAM). Pseudo-momentum and PAM originate from the phase factors acquired by discrete translation and rotation symmetry operations, respectively," explains Professor Satoh. The researchers' novel experimental approach also allowed them to probe the fundamental traits of PAM. They found that the law of the conservation of PAM—one of the key laws of physics—holds between circularly polarized photons and chiral phonons. "Our work also provides an optical method to identify the handedness of chiral materials using PAM. Namely, we can determine the handedness of materials with better resolution than X-ray diffraction (XRD) can achieve. Moreover, XRD requires a large-enough crystal, is invasive, and can be destructive. Circularly polarized Raman scattering, on the other hand, allowed us to determine the chirality of structures XRD could not, in a non-contact and non-destructive manner," concludes Professor Satoh. This study is the first to identify truly chiral phonons in 3D materials, which are clearly distinct from those seen previously in 2D hexagonal systems. The knowledge gained here could drive new research into developing ways for transferring the PAM from photons to electron spins via propagating chiral phonons in future devices. Furthermore, this approach enables the determination of the true chirality of a crystal in an improved manner, providing a new critical tool for experimentalists' and researchers. <|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 Squamous cell carcinoma of the head and neck (SCCHN) is a common, aggressive, treatment-resistant cancer with a high recurrence rate and mortality, but the mechanism of treatment resistance remains unclear. Here we describe a mechanism where the AAA-ATPase TRIP13 promotes treatment resistance. Overexpression of TRIP13 in non-malignant cells results in malignant transformation. High expression of TRIP13 in SCCHN leads to aggressive, treatment-resistant tumors and enhanced repair of DNA damage. Using mass spectrometry, we identify DNA-PKcs complex proteins that mediate nonhomologous end joining (NHEJ), as TRIP13-binding partners. Using repair-deficient reporter systems, we show that TRIP13 promotes NHEJ, even when homologous recombination is intact. Importantly, overexpression of TRIP13 sensitizes SCCHN to an inhibitor of DNA-PKcs. Thus, this study defines a new mechanism of treatment resistance in SCCHN and underscores the importance of targeting NHEJ to overcome treatment failure in SCCHN and potentially in other cancers that overexpress TRIP13. Introduction Squamous cell carcinoma is a common cancer occurring in the head and neck, skin, oesophagus, lung and cervix. Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer globally 1 . Half of the 600,000 patients diagnosed annually will die in 5 years 1 , 2 . The morbidity is worse than breast cancer or melanoma 2 because of late diagnosis and tumor relapse. Late-stage lesions are treated by chemotherapy and radiation, which have changed little in 50 years, emphasizing the need for new treatment 1 . Characterization of the mechanism that promotes treatment resistance will provide novel treatment targets. Although the mechanism is unclear, pathways that promote DNA repair induce treatment resistance 3 , underscoring the importance of characterizing these proteins in SCCHN. Double-strand breaks (DSBs), the most dangerous type of DNA damage, are induced by radiation and chemotherapy 4 and DSBs are repaired primarily by homologous recombination (HR) or nonhomologous end joining (NHEJ) 3 . HR requires a DNA template, normally a homologous chromosome in germ cells or a sister chromatid in somatic cells. HR is essential for genetic diversity and transmission of genetic information between generations of cells and organisms. NHEJ occurs throughout the cell cycle and is required for physiologic processes including antigen receptor diversity and generation of antigen-specific antibodies 5 . NHEJ is usually inaccurate since DNA ends join without a template 6 . Error-prone or excessive repair promotes mutations, chromosome instability and cancer, whereas unrepaired DNA leads to cell death. In cancer, efficient repair of radiation- and chemotherapy-induced DSBs promotes treatment resistance with subsequent relapse. Therefore, inhibition of NHEJ would improve response to treatment. On the basis of meta-analyses of multiple SCCHN data sets, we nominated Thyroid hormone Receptor Interactor 13 (TRIP13 or HPV16E1BP) as an oncogene. TRIP13 is the mouse orthologue of pachytene checkpoint 2 (Pch2), a checkpoint for synapsis before DSB repair and recombination in yeast and Caenorhabditis elegans 7 , 8 . In mice, TRIP13 mediates DSB repair 9 , 10 ; however, the role of TRIP13 in humans has not been investigated. In this study, we investigated a mechanism by which TRIP13 promotes treatment resistance. Overexpression of TRIP13 in non-malignant cells leads to malignant transformation. High expression of TRIP13 in SCCHN promoted aggressive tumor growth, treatment resistance and enhanced repair of DNA damage. TRIP13-binding partners, including DNA-PKcs complex proteins mediating NHEJ, were identified using mass spectrometry. Repair-deficient reporter systems revealed that TRIP13 promotes NHEJ. Overexpression of TRIP13 sensitized SCCHN to an inhibitor of DNA-PKcs and impairment of TRIP13 ATPase activity diminishes its DSB repair efficiency. These findings define a mechanism of treatment resistance in SCCHN and emphasize the importance of targeting NHEJ to overcome treatment failure. Results TRIP13 is overexpressed in SCCHN Recent sequencing studies emphasized the limited number of mutations present in SCCHN 11 . Therefore, we performed meta-analysis of multiple SCCHN data sets ( Fig. 1a , left to right: Cromer Head-Neck, accession GSE2379 (ref. 12 ), Estilo Head-Neck, accession GSE13601 (ref. 13 ), Ye Head-Neck, accession GSE9844 (ref. 14 ), Kuriakose Head-Neck, accession GDS2520 (ref. 15 ), Ginos Head-Neck 16 , Toruner Head-Neck, accession GSE3524 (ref. 17 ), all available from Oncomine, Compendia Bioscience, Ann Arbor, MI, USA), to nominate potential novel oncogenes. TRIP13 was significantly upregulated in all six data sets interrogated ( Fig. 1a ). The Cancer Genome Atlas data set showed highly increased TRIP13 copy number (approximately four copies) in ~14% (40/290) of SCCHN patients ( Fig. 1b ). TRIP13 was nominated as an oncogene and is not mutated in SCCHN ( Supplementary Fig. 1A , left panel). TRIP13 copy number and gene expression frequency are increased in multiple cancers ( Supplementary Fig. 1A , middle and right panels). Compared with immortalized non-malignant keratinocytes, fluorescence in situ hybridization (FISH) showed increased TRIP13 copy number in SCCHN cells and tissue ( Fig. 1c , Supplementary Fig. 1B,C ). Figure 1: TRIP13 is upregulated in SCCHN. ( a ) Meta-analysis showing TRIP13 upregulation in cancer compared with normal tissue. Left to right: Cromer-Head-Neck, Estilo-Head-Neck, Ye-Head-Neck, Kuriakose-Head-Neck, Ginos-Head-Neck, Toruner-Head-Neck (accession numbers are in Results section). ( b ) Analysis of 35 normal and 37 SCCHN cases showing TRIP13 DNA copy number increase in The Cancer Genome Atlas data set. ( c ) FISH detection of TRIP13 amplification in SCCHN cell line UM-SCC-22B compared with normal keratinocyte HOK16B. The 5′ (green) and 3′ (red) ends of TRIP13 were labelled. Colocalization of 5′ and 3′ ends (yellow) indicates a full copy of TRIP13 (white arrow; bar=2 μm). ( d ) Matched normal and tumour tissue lysates from SCCHN patients ( n =18, 9 normal, 9 tumor) were immunoblotted with anti-TRIP13 and anti-actin antibodies. Signal intensity was quantified (arbitrary-densitometric-units, DU), normalized to actin and expressed and plotted as percent of its corresponding control (lower panel). ( e ) A TMA with SCCHN and normal tissue ( n =72 cases, 12 normal, 60 SCCHN patients) was stained for TRIP13 with DAB detection (bar=30 μm). Staining proportion was scored and plotted (lower panel). Forward and stepwise variable selection procedures and the Likelihood Ration test were used for statistical analysis", "role": "user" }, { "content": "Imagine you're fighting for your life but no matter how hard you hit, your opponent won't go down. The same can be said of highly treatment-resistant cancers, such as head and neck cancer, where during radiation and chemotherapy some cancer cells repair themselves, survive and thrive. Head and neck cancer is the sixth most common cancer in the world, but the late detection and treatment resistance result in a high mortality rate. Now, University of Michigan researchers have found that a particular protein—TRIP13—encourages those cancer cells to repair themselves. And they have identified an existing chemical that blocks this mechanism for cell repair. \"This is a very significant advance, because identifying the function of the protein that fuels the repair of cancer cells and having an existing chemical that blocks the process, could speed the process of moving to clinical trials,\" said principal investigator Nisha D'Silva, U-M professor of dentistry and associate professor of pathology. Typically, if scientists discover a promising drug therapy target, it takes years to develop drug compounds from scratch and move these into clinical trials. If cell DNA is damaged and the cell cannot repair the damage, the cell dies. In head and neck cancers, D'Silva and colleagues showed that cancer cells that overexpress TRIP13 were able to repair their DNA enough to survive and continue to grow as cancer. \"Targeting this repair mechanism with specific drugs could increase effectiveness of treatment and improve survival of cancer patients,\" D'Silva said. \"And given the overexpression of TRIP13 in several treatment-resistant cancers, this strategy will likely be important for multiple cancers.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Squamous cell carcinoma of the head and neck (SCCHN) is a common, aggressive, treatment-resistant cancer with a high recurrence rate and mortality, but the mechanism of treatment resistance remains unclear. Here we describe a mechanism where the AAA-ATPase TRIP13 promotes treatment resistance. Overexpression of TRIP13 in non-malignant cells results in malignant transformation. High expression of TRIP13 in SCCHN leads to aggressive, treatment-resistant tumors and enhanced repair of DNA damage. Using mass spectrometry, we identify DNA-PKcs complex proteins that mediate nonhomologous end joining (NHEJ), as TRIP13-binding partners. Using repair-deficient reporter systems, we show that TRIP13 promotes NHEJ, even when homologous recombination is intact. Importantly, overexpression of TRIP13 sensitizes SCCHN to an inhibitor of DNA-PKcs. Thus, this study defines a new mechanism of treatment resistance in SCCHN and underscores the importance of targeting NHEJ to overcome treatment failure in SCCHN and potentially in other cancers that overexpress TRIP13. Introduction Squamous cell carcinoma is a common cancer occurring in the head and neck, skin, oesophagus, lung and cervix. Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer globally 1 . Half of the 600,000 patients diagnosed annually will die in 5 years 1 , 2 . The morbidity is worse than breast cancer or melanoma 2 because of late diagnosis and tumor relapse. Late-stage lesions are treated by chemotherapy and radiation, which have changed little in 50 years, emphasizing the need for new treatment 1 . Characterization of the mechanism that promotes treatment resistance will provide novel treatment targets. Although the mechanism is unclear, pathways that promote DNA repair induce treatment resistance 3 , underscoring the importance of characterizing these proteins in SCCHN. Double-strand breaks (DSBs), the most dangerous type of DNA damage, are induced by radiation and chemotherapy 4 and DSBs are repaired primarily by homologous recombination (HR) or nonhomologous end joining (NHEJ) 3 . HR requires a DNA template, normally a homologous chromosome in germ cells or a sister chromatid in somatic cells. HR is essential for genetic diversity and transmission of genetic information between generations of cells and organisms. NHEJ occurs throughout the cell cycle and is required for physiologic processes including antigen receptor diversity and generation of antigen-specific antibodies 5 . NHEJ is usually inaccurate since DNA ends join without a template 6 . Error-prone or excessive repair promotes mutations, chromosome instability and cancer, whereas unrepaired DNA leads to cell death. In cancer, efficient repair of radiation- and chemotherapy-induced DSBs promotes treatment resistance with subsequent relapse. Therefore, inhibition of NHEJ would improve response to treatment. On the basis of meta-analyses of multiple SCCHN data sets, we nominated Thyroid hormone Receptor Interactor 13 (TRIP13 or HPV16E1BP) as an oncogene. TRIP13 is the mouse orthologue of pachytene checkpoint 2 (Pch2), a checkpoint for synapsis before DSB repair and recombination in yeast and Caenorhabditis elegans 7 , 8 . In mice, TRIP13 mediates DSB repair 9 , 10 ; however, the role of TRIP13 in humans has not been investigated. In this study, we investigated a mechanism by which TRIP13 promotes treatment resistance. Overexpression of TRIP13 in non-malignant cells leads to malignant transformation. High expression of TRIP13 in SCCHN promoted aggressive tumor growth, treatment resistance and enhanced repair of DNA damage. TRIP13-binding partners, including DNA-PKcs complex proteins mediating NHEJ, were identified using mass spectrometry. Repair-deficient reporter systems revealed that TRIP13 promotes NHEJ. Overexpression of TRIP13 sensitized SCCHN to an inhibitor of DNA-PKcs and impairment of TRIP13 ATPase activity diminishes its DSB repair efficiency. These findings define a mechanism of treatment resistance in SCCHN and emphasize the importance of targeting NHEJ to overcome treatment failure. Results TRIP13 is overexpressed in SCCHN Recent sequencing studies emphasized the limited number of mutations present in SCCHN 11 . Therefore, we performed meta-analysis of multiple SCCHN data sets ( Fig. 1a , left to right: Cromer Head-Neck, accession GSE2379 (ref. 12 ), Estilo Head-Neck, accession GSE13601 (ref. 13 ), Ye Head-Neck, accession GSE9844 (ref. 14 ), Kuriakose Head-Neck, accession GDS2520 (ref. 15 ), Ginos Head-Neck 16 , Toruner Head-Neck, accession GSE3524 (ref. 17 ), all available from Oncomine, Compendia Bioscience, Ann Arbor, MI, USA), to nominate potential novel oncogenes. TRIP13 was significantly upregulated in all six data sets interrogated ( Fig. 1a ). The Cancer Genome Atlas data set showed highly increased TRIP13 copy number (approximately four copies) in ~14% (40/290) of SCCHN patients ( Fig. 1b ). TRIP13 was nominated as an oncogene and is not mutated in SCCHN ( Supplementary Fig. 1A , left panel). TRIP13 copy number and gene expression frequency are increased in multiple cancers ( Supplementary Fig. 1A , middle and right panels). Compared with immortalized non-malignant keratinocytes, fluorescence in situ hybridization (FISH) showed increased TRIP13 copy number in SCCHN cells and tissue ( Fig. 1c , Supplementary Fig. 1B,C ). Figure 1: TRIP13 is upregulated in SCCHN. ( a ) Meta-analysis showing TRIP13 upregulation in cancer compared with normal tissue. Left to right: Cromer-Head-Neck, Estilo-Head-Neck, Ye-Head-Neck, Kuriakose-Head-Neck, Ginos-Head-Neck, Toruner-Head-Neck (accession numbers are in Results section). ( b ) Analysis of 35 normal and 37 SCCHN cases showing TRIP13 DNA copy number increase in The Cancer Genome Atlas data set. ( c ) FISH detection of TRIP13 amplification in SCCHN cell line UM-SCC-22B compared with normal keratinocyte HOK16B. The 5′ (green) and 3′ (red) ends of TRIP13 were labelled. Colocalization of 5′ and 3′ ends (yellow) indicates a full copy of TRIP13 (white arrow; bar=2 μm). ( d ) Matched normal and tumour tissue lysates from SCCHN patients ( n =18, 9 normal, 9 tumor) were immunoblotted with anti-TRIP13 and anti-actin antibodies. Signal intensity was quantified (arbitrary-densitometric-units, DU), normalized to actin and expressed and plotted as percent of its corresponding control (lower panel). ( e ) A TMA with SCCHN and normal tissue ( n =72 cases, 12 normal, 60 SCCHN patients) was stained for TRIP13 with DAB detection (bar=30 μm). Staining proportion was scored and plotted (lower panel). Forward and stepwise variable selection procedures and the Likelihood Ration test were used for statistical analysis<|im_end|> <|im_start|>assistant Imagine you're fighting for your life but no matter how hard you hit, your opponent won't go down. The same can be said of highly treatment-resistant cancers, such as head and neck cancer, where during radiation and chemotherapy some cancer cells repair themselves, survive and thrive. Head and neck cancer is the sixth most common cancer in the world, but the late detection and treatment resistance result in a high mortality rate. Now, University of Michigan researchers have found that a particular protein—TRIP13—encourages those cancer cells to repair themselves. And they have identified an existing chemical that blocks this mechanism for cell repair. "This is a very significant advance, because identifying the function of the protein that fuels the repair of cancer cells and having an existing chemical that blocks the process, could speed the process of moving to clinical trials," said principal investigator Nisha D'Silva, U-M professor of dentistry and associate professor of pathology. Typically, if scientists discover a promising drug therapy target, it takes years to develop drug compounds from scratch and move these into clinical trials. If cell DNA is damaged and the cell cannot repair the damage, the cell dies. In head and neck cancers, D'Silva and colleagues showed that cancer cells that overexpress TRIP13 were able to repair their DNA enough to survive and continue to grow as cancer. "Targeting this repair mechanism with specific drugs could increase effectiveness of treatment and improve survival of cancer patients," D'Silva said. "And given the overexpression of TRIP13 in several treatment-resistant cancers, this strategy will likely be important for multiple cancers." <|im_end|>

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1,979

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Purpose The study was designed to assess the capacity of human sperm RNA-seq data to gauge the diversity of the associated microbiome within the ejaculate. Methods Semen samples were collected, and semen parameters evaluated at time of collection. Sperm RNA was isolated and subjected to RNA-seq. Microbial composition was determined by aligning sequencing reads not mapped to the human genome to the NCBI RefSeq bacterial, viral and archaeal genomes following RNA-Seq. Analysis of microbial assignments utilized phyloseq and vegan. Results Microbial composition within each sample was characterized as a function of microbial associated RNAs. Bacteria known to be associated with the male reproductive tract were present at similar levels in all samples representing 11 genera from four phyla with one exception, an outlier. Shannon diversity index ( p < 0.001) and beta diversity (unweighted UniFrac distances, p = 9.99e-4; beta dispersion, p = 0.006) indicated the outlier was significantly different from all other samples. The outlier sample exhibited a dramatic increase in Streptococcus . Multiple testing indicated two operational taxonomic units, S. agalactiae and S. dysgalactiae ( p = 0.009), were present. Conclusion These results provide a first look at the microbiome as a component of human sperm RNA sequencing that has sufficient sensitivity to identify contamination or potential pathogenic bacterial colonization at least among the known contributors. Access provided by DEAL DE / Springer Compact Clearingstelle Uni Freiburg _ Working on a manuscript? Avoid the common mistakes Introduction The current accepted standard for evaluating the male reproductive tract microbiome employs culturing techniques. These can be limiting [ 1 , 2 ] as the majority of pathogens cannot be cultured [ 3 ]. To provide an overview, metagenomic/targeted DNA sequencing of 16S ribosomal RNA (rDNA) hypervariable regions and RNA sequencing of the 16S rRNA hypervariable regions using PCR or next-generation sequencing (NGS) has been performed on seminal fluid, semen, and urine [ 1 , 2 , 4 , 5 , 6 ]. These strategies are capable of genus and species identification [ 2 ], but are generally targeted to one or a group of bacteria [ 1 ]. Despite an increased sensitivity by 16S rRNA/rDNA sequencing, technical considerations and cost may be perceived as a limiting factor in some clinical laboratories [ 7 ]. Similarly, virus detection must be performed separately and relies on targeted viral culture or virus specific DNA/RNA sequencing strategies [ 8 , 9 , 10 ]. However, sequencing costs have decreased dramatically from the ~ 3.5 billion dollars for the first human genomes to less than 1000 dollars and are still declining with a non-targeted approach providing a more complete and picture. Male genital tract bacteria are primarily introduced by direct contact to the source, e.g., sexual transmission [ 6 ]. Escherichia coli is the most frequently noted bacteria in males, associated with genital tract infection or urethral/post-urethral contamination upon semen collection [ 6 , 11 ]. Comparative 16S rDNA sequencing between male and female partners indicates that 85% of the phylotypes are shared, primarily within the genera Lactobacillus , Veillonella , Streptococcus , Porphyromonas , and Atopobium [ 4 ]. Compared to vaginal bacterial communities, the male seminal fluid has a less concentrated, more diverse (alpha diversity) bacterial community [ 4 ]. We sought to determine if human sperm RNA-seq data could provide a sensitive method of detection. To accomplish this objective, the microbial composition among 85 individuals was compared to previously published reports of the male reproductive tract microbiome [ 1 , 6 , 12 , 13 , 14 , 15 ]. Here, we report that human sperm RNA-seq is a viable method for the evaluation of the seminal microbiome. By RNA-seq, we have identified a male that may present with Streptococcus agalactiae bacterial colonization. Materials and methods Study population, sperm RNA isolation, sequencing, and alignment A total of 85 informed consented deidentified biobanked semen samples from idiopathic infertile couples were obtained from two independent groups of sites within the USA and a single site in Canada. Males ranged in age from 24 to 44 years old (mean age = 34.73). Each couple had undergone at least one cycle of timed intercourse (TIC), intrauterine insemination (IUI), intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF). By study completion, 48 couples achieved live birth (LB) and 37 couples failed to achieve a birth (NLB). The corresponding deidentified frozen semen samples were processed and analyzed as summarized in Fig. 1 in accord with IRB protocol 095701MP2E(5R). Sperm RNA was isolated as previously described [ 16 , 17 , 18 , 19 ] and sequenced on an Illumina Next-seq 500 to assess library quality and then an Illumina Hi-seq 4000 to increase sequencing depth. Sequences aligned to the human genome [ 20 ] were removed from further analysis. Sequences not mapped to the human genome by HISAT2 [ 21 ] were aligned to the bacterial/viral/archaeal genomes (NCBI RefSeq release 95—all bacterial genomes, as well as NCBI RefSeq release 76—all bacterial, viral, archaeal genomes) with the 98% similarity taxonomic profiling method of Kraken v1 [ 22 ]. Using the Kraken-filter command, the threshold for calling a sequence was set at 0.15. The percentage of microbial sequencing reads was determined as a function of total sequence reads. For each sample, the percentage of microbial assigned reads from the total sequencing reads was calculated for total microbial assignments after removing internal controls, Enterobacteria phage phiX174 sensu lato (phiX) and Escherichia virus MS2 (MS2). Within each sample, the percentage of species-specific microbial sequences was calculated for each sequencing run. One sample presented an abnormally high number of microbial-assigned sequencing reads (outlier) and was considered separately from the remaining group of 84 samples which provided a background distribution. A subset of these samples including the outlier were also assessed using the Greengenes v13_8 reference database aligning sequences based on a 99% percent similarity to the 16S rRNA. Fig. 1 Study design. Sample collection and processing is outlined. Sperm RNA from 85 semen samples was isolated and sequenced using a Next-seq 500", "role": "user" }, { "content": "A new collaborative study published by a research team from the Wayne State University School of Medicine, the CReATe Fertility Centre and the University of Massachusetts Amherst provides the first in-depth look at the microbiome of human sperm utilizing RNA sequencing with sufficient sensitivity to identify contamination and pathogenic bacterial colonization. \"We show that non-targeted sequencing of human sperm RNA has the potential to provide a profile of micro-organisms (bacteria, viruses, archaea),\" said Stephen Krawetz, Ph.D., associate director of the C.S. Mott Center for Human Growth and Development at WSU and the Charlotte B. Failing Professor of Fetal Therapy and Diagnosis in the Department of Obstetrics and Gynecology, and the Center for Molecular Medicine and Genetics. \"This information was recovered from the data typically cast aside as part of routine nucleic acid sequencing. The enhanced sensitivity and specificity of the sequencing technology as compared to current approaches may prove useful as a diagnostic tool for microbial status as part of the routine assessment as we move toward personalized care.\" The study, \"What human sperm RNA-Seq tells us about the microbiome\" published in the Journal of Assisted Reproduction and Genetics, sought to determine if human sperm RNA sequencing data could provide a sensitive method of detection of micro-organisms, including bacteria, viruses and archaea compared to current methods of targeted culturing. The researchers collected 85 semen samples, isolated the sperm RNA and subjected it to RNA sequencing. Grace Swanson, Ph.D., a postdoctoral fellow working with Dr. Krawetz, discovered a sample with an abnormally high level of microbial sequences. After taking a closer look, the sample was found to contain a considerable amount of Streptococcus agalactiae bacteria. A leading cause of neonatal infection during pregnancy and post-delivery linked to significant mortality rates in premature births, this bacteria can also be life-threatening in adults, particularly the elderly. The current method for testing the male reproductive tract microbiome relies on culturing samples. This, the study reported, can be limiting because the majority of pathogens cannot be cultured. The costs of RNA sequencing have dropped dramatically and continue to decrease, providing a more complete picture of the human biome. \"Given the recent increase and severity of Streptococcus (agalactiae) infection, as well as others in adults, neonates and newborns, non-targeted human sperm RNA sequencing data may, in addition to providing fertility status, prove useful as a diagnostic for microbial status,\" Dr. Krawetz 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 Purpose The study was designed to assess the capacity of human sperm RNA-seq data to gauge the diversity of the associated microbiome within the ejaculate. Methods Semen samples were collected, and semen parameters evaluated at time of collection. Sperm RNA was isolated and subjected to RNA-seq. Microbial composition was determined by aligning sequencing reads not mapped to the human genome to the NCBI RefSeq bacterial, viral and archaeal genomes following RNA-Seq. Analysis of microbial assignments utilized phyloseq and vegan. Results Microbial composition within each sample was characterized as a function of microbial associated RNAs. Bacteria known to be associated with the male reproductive tract were present at similar levels in all samples representing 11 genera from four phyla with one exception, an outlier. Shannon diversity index ( p < 0.001) and beta diversity (unweighted UniFrac distances, p = 9.99e-4; beta dispersion, p = 0.006) indicated the outlier was significantly different from all other samples. The outlier sample exhibited a dramatic increase in Streptococcus . Multiple testing indicated two operational taxonomic units, S. agalactiae and S. dysgalactiae ( p = 0.009), were present. Conclusion These results provide a first look at the microbiome as a component of human sperm RNA sequencing that has sufficient sensitivity to identify contamination or potential pathogenic bacterial colonization at least among the known contributors. Access provided by DEAL DE / Springer Compact Clearingstelle Uni Freiburg _ Working on a manuscript? Avoid the common mistakes Introduction The current accepted standard for evaluating the male reproductive tract microbiome employs culturing techniques. These can be limiting [ 1 , 2 ] as the majority of pathogens cannot be cultured [ 3 ]. To provide an overview, metagenomic/targeted DNA sequencing of 16S ribosomal RNA (rDNA) hypervariable regions and RNA sequencing of the 16S rRNA hypervariable regions using PCR or next-generation sequencing (NGS) has been performed on seminal fluid, semen, and urine [ 1 , 2 , 4 , 5 , 6 ]. These strategies are capable of genus and species identification [ 2 ], but are generally targeted to one or a group of bacteria [ 1 ]. Despite an increased sensitivity by 16S rRNA/rDNA sequencing, technical considerations and cost may be perceived as a limiting factor in some clinical laboratories [ 7 ]. Similarly, virus detection must be performed separately and relies on targeted viral culture or virus specific DNA/RNA sequencing strategies [ 8 , 9 , 10 ]. However, sequencing costs have decreased dramatically from the ~ 3.5 billion dollars for the first human genomes to less than 1000 dollars and are still declining with a non-targeted approach providing a more complete and picture. Male genital tract bacteria are primarily introduced by direct contact to the source, e.g., sexual transmission [ 6 ]. Escherichia coli is the most frequently noted bacteria in males, associated with genital tract infection or urethral/post-urethral contamination upon semen collection [ 6 , 11 ]. Comparative 16S rDNA sequencing between male and female partners indicates that 85% of the phylotypes are shared, primarily within the genera Lactobacillus , Veillonella , Streptococcus , Porphyromonas , and Atopobium [ 4 ]. Compared to vaginal bacterial communities, the male seminal fluid has a less concentrated, more diverse (alpha diversity) bacterial community [ 4 ]. We sought to determine if human sperm RNA-seq data could provide a sensitive method of detection. To accomplish this objective, the microbial composition among 85 individuals was compared to previously published reports of the male reproductive tract microbiome [ 1 , 6 , 12 , 13 , 14 , 15 ]. Here, we report that human sperm RNA-seq is a viable method for the evaluation of the seminal microbiome. By RNA-seq, we have identified a male that may present with Streptococcus agalactiae bacterial colonization. Materials and methods Study population, sperm RNA isolation, sequencing, and alignment A total of 85 informed consented deidentified biobanked semen samples from idiopathic infertile couples were obtained from two independent groups of sites within the USA and a single site in Canada. Males ranged in age from 24 to 44 years old (mean age = 34.73). Each couple had undergone at least one cycle of timed intercourse (TIC), intrauterine insemination (IUI), intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF). By study completion, 48 couples achieved live birth (LB) and 37 couples failed to achieve a birth (NLB). The corresponding deidentified frozen semen samples were processed and analyzed as summarized in Fig. 1 in accord with IRB protocol 095701MP2E(5R). Sperm RNA was isolated as previously described [ 16 , 17 , 18 , 19 ] and sequenced on an Illumina Next-seq 500 to assess library quality and then an Illumina Hi-seq 4000 to increase sequencing depth. Sequences aligned to the human genome [ 20 ] were removed from further analysis. Sequences not mapped to the human genome by HISAT2 [ 21 ] were aligned to the bacterial/viral/archaeal genomes (NCBI RefSeq release 95—all bacterial genomes, as well as NCBI RefSeq release 76—all bacterial, viral, archaeal genomes) with the 98% similarity taxonomic profiling method of Kraken v1 [ 22 ]. Using the Kraken-filter command, the threshold for calling a sequence was set at 0.15. The percentage of microbial sequencing reads was determined as a function of total sequence reads. For each sample, the percentage of microbial assigned reads from the total sequencing reads was calculated for total microbial assignments after removing internal controls, Enterobacteria phage phiX174 sensu lato (phiX) and Escherichia virus MS2 (MS2). Within each sample, the percentage of species-specific microbial sequences was calculated for each sequencing run. One sample presented an abnormally high number of microbial-assigned sequencing reads (outlier) and was considered separately from the remaining group of 84 samples which provided a background distribution. A subset of these samples including the outlier were also assessed using the Greengenes v13_8 reference database aligning sequences based on a 99% percent similarity to the 16S rRNA. Fig. 1 Study design. Sample collection and processing is outlined. Sperm RNA from 85 semen samples was isolated and sequenced using a Next-seq 500<|im_end|> <|im_start|>assistant A new collaborative study published by a research team from the Wayne State University School of Medicine, the CReATe Fertility Centre and the University of Massachusetts Amherst provides the first in-depth look at the microbiome of human sperm utilizing RNA sequencing with sufficient sensitivity to identify contamination and pathogenic bacterial colonization. "We show that non-targeted sequencing of human sperm RNA has the potential to provide a profile of micro-organisms (bacteria, viruses, archaea)," said Stephen Krawetz, Ph.D., associate director of the C.S. Mott Center for Human Growth and Development at WSU and the Charlotte B. Failing Professor of Fetal Therapy and Diagnosis in the Department of Obstetrics and Gynecology, and the Center for Molecular Medicine and Genetics. "This information was recovered from the data typically cast aside as part of routine nucleic acid sequencing. The enhanced sensitivity and specificity of the sequencing technology as compared to current approaches may prove useful as a diagnostic tool for microbial status as part of the routine assessment as we move toward personalized care." The study, "What human sperm RNA-Seq tells us about the microbiome" published in the Journal of Assisted Reproduction and Genetics, sought to determine if human sperm RNA sequencing data could provide a sensitive method of detection of micro-organisms, including bacteria, viruses and archaea compared to current methods of targeted culturing. The researchers collected 85 semen samples, isolated the sperm RNA and subjected it to RNA sequencing. Grace Swanson, Ph.D., a postdoctoral fellow working with Dr. Krawetz, discovered a sample with an abnormally high level of microbial sequences. After taking a closer look, the sample was found to contain a considerable amount of Streptococcus agalactiae bacteria. A leading cause of neonatal infection during pregnancy and post-delivery linked to significant mortality rates in premature births, this bacteria can also be life-threatening in adults, particularly the elderly. The current method for testing the male reproductive tract microbiome relies on culturing samples. This, the study reported, can be limiting because the majority of pathogens cannot be cultured. The costs of RNA sequencing have dropped dramatically and continue to decrease, providing a more complete picture of the human biome. "Given the recent increase and severity of Streptococcus (agalactiae) infection, as well as others in adults, neonates and newborns, non-targeted human sperm RNA sequencing data may, in addition to providing fertility status, prove useful as a diagnostic for microbial status," Dr. Krawetz said. <|im_end|>

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1,940

[ { "content": "You are a great 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 emerging oxide–zeolite bifunctional catalysis for direct syngas conversion has drawn extensive interest, both academically and industrially, with further exploration urging a clear mechanistic understanding of this complex catalytic network. Herein, using a specially designed quasi-in situ, solid-state nuclear magnetic resonance-gas chromatography/gas chromatography-mass spectrometry analysis strategy, this reaction is fully monitored from the very early induction period to steady-state conversion under high-pressure flow-reaction conditions, using ZnAlO x /H-ZSM-5 composites as model catalysts. We identify abundant critical and/or transient intermediates in dynamic evolution, including carboxylates, alkoxyls, acid-bounded methyl-cyclopentenones and methyl-cyclopentenyl carbocations, providing direct evidence of vigorous regulation by unique, oxygenate-based pathways of the reaction network. This proposed mechanism overturns the general cognition of oxide–zeolite reactions as simple tandem catalysis, and highlights the many roles (both positive and negative) of CO and H 2 molecules via oxygenate-based routes, thus dictating the final product. The current characterization technology and its mechanistic understanding would benefit further exploration in bifunctional catalysis. Main Over the years, Fischer–Tropsch synthesis (FTS) has been the core technology for the direct conversion of syngas (CO/H 2 ) into high-value-added hydrocarbons to substitute petroleum products, despite the well-recognized limited product selectivity that follows a statistical Anderson–Schulz–Flory (ASF) distribution 1 . In spite of the continuous developments of alternative strategies such as functionalized FTS 2 , 3 , 4 , 5 , selectivity control in FTS remains challenging. Meanwhile, the recently discovered oxide–zeolite-based bifunctional catalysis, namely OXZEO, has grown into another flourishing process and profoundly rekindled interest in this field 6 , 7 , 8 . This particular method describes the use of selected OXZEO composite catalysts for the direct transformation of syngas into target hydrocarbons—for example, C 2–4 olefins 9 , 10 , 11 , 12 , gasoline 13 and aromatics 14 , 15 , 16 , attaining a surprisingly high selectivity far beyond the limits predicted by the ASF model in FTS. Industrial exploration of OXZEO catalysis is progressing smoothly, and the first 1,000 ton yr –1 pilot plant testing of syngas to olefins via OXZEO was recently accomplished in Shaanxi, China 8 . In regard to the mechanism, this reaction is generally regarded as tandem catalysis where the oxide component is responsible for the initial activation of CO and H 2 to C 1 intermediates, while subsequent C–C coupling of the C 1 intermediates take place in the micropores of zeolites for shape-selective synthesis 6 , 7 , 17 . To date, except for some oxide catalysts reported to produce ketene as the intermediate 9 , 11 , 18 , 19 , many other studies adopted conventional methanol-synthesis oxides in composite catalysts 6 , 7 , 10 , 15 , 17 . Thus, the OXZEO catalytic network is generally regarded as a simple relay reaction comprising methanol synthesis (on oxide) and a methanol-to-hydrocarbon (MTH) reaction under a hydrocarbon pool (HCP) mechanism (on zeolite) 20 , 21 , 22 , 23 , 24 , 25 . However, the adoption of HCP in the OXZEO bifunctional system has never been verified to the best of our knowledge. At least two major concerns are raised, regarding the complexity of this system. First, unlike conventional tandem catalysis, the active sites on both components (oxides and zeolites) of hybrid OXZEO catalysts have the ability to transform secondary intermediates before formation of the final products, leading to a different reaction network than that catalysed separately by zeolite and oxide. For instance, a shuttle-mode reaction between oxide and zeolite components has recently been revealed for ZnAl 2 O 4 /H-MOR 12 . Second, highly reactive CO and H 2 (often fed at high pressures of up to tens of bars) may interfere/react at any step of the secondary reaction network and alter the mechanism. Therefore, direct adoption of the classical HCP mechanism will be carefully reconsidered although it has been extended to cover wider research domains 26 , 27 . In fact, the participation of CO and H 2 in MTH reactions has been investigated experimentally 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 . Among those studies, CO was suggested to be responsible for the formation of the initial C–C bond 28 , 29 , 30 , 31 , 32 and was also reported to facilitate the production of aromatics 32 , 35 . Moreover, high-pressure H 2 co-feeding can intercept the formation of deactivation-inducing polycyclic aromatics 33 , 34 . Recently, the additional modulation effect of CO and H 2 on syngas conversion has gained increasing attention in OXZEO-catalysed syngas conversion reactions 10 , 15 . These studies indicate a more complicated catalytic network of practical OXZEO catalysis. During the progress of this work, phenolics, ketones and furans were also identified for OXZEO catalysts (ZnCr 2 O 4 /H-ZSM-5 and MnO/H-ZSM-5) and are suggested as intermediates 36 , 37 , but the catalytic mechanism that is different from HCP remains elusive. In this work, syngas conversion for ZnAlO x /H-ZSM-5 was investigated as a model reaction to elucidate the mechanisms involved in bifunctional catalytic systems. The reaction process, from the induction period to steady-state conversion, was monitored by combining quasi-in situ, solid-state nuclear magnetic resonance (ssNMR) and online gas chromatography/gas chromatography-mass spectrometry (GC/GC-MS) analysis, which allowed us to unambiguously identify a large variety of highly reactive intermediates in activated states, including multiple carboxylates, alkoxy groups, methyl-cyclopentenones (MCPenones) and abundant carbocations, including methyl-cyclopentenyl carbocations (MCPenes + ) adsorbed on the catalysts. Such observations validate the pivotal role of highly vigorous oxygenate-based routes during the reaction. Moreover, the reactivity and evolution of different intermediates have been explored in detail. Accordingly, a full reaction network comprising highly active oxygenate-based catalytic routes, along with the conventional dual-cycle HCP mechanism, was proposed. Furthermore, the universality of this mechanism in syngas conversion has been unveiled for different OXZEO bifunctional catalysts. Results Syngas conversion tests for ZnAlO x /H-ZSM-5 catalysts Two commerical H-ZSM-5 zeolites, with Si/Al ratios (SARs) of 82.4 and 16.4, were physically mixed with synthesized ZnAlO x oxide (spinel structure; Supplementary", "role": "user" }, { "content": "A research team led by Prof. Hou Guangjin and Prof. Bao Xinhe from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences (CAS) has revealed the oxygenate-based routes in syngas conversion over oxide–zeolite (OXZEO) bifunctional catalysts by solid-state Nuclear Magnetic Resonance (NMR). This study was published in Nature Catalysis on June 23. OXZEO catalysis was proposed in 2016 by Prof. Bao Xinhe and Prof. Pan Xiulian from DICP. It provides a platform for the efficient utilization of coal and other carbon resources. However, the reaction mechanism in OXZEO catalysis still remains unclear. In this study, the researchers chose the syngas conversion over the ZnAlOx/H-ZSM-5 bifunctional catalyst as a model system to highlight the mechanistic difference in the OXZEO-based syngas direct conversion. ZnAlOx is a typical metal oxide for syngas to methanol process while H-ZSM-5 is a typical zeolite for methanol to hydrocarbons (MTH) reaction. They used the quasi-in situ solid-state NMR (ssNMR)-Gas Chromatography (GC) analysis strategy to reveal the dynamic evolution of abundant critical and/or transient intermediates, including multi-carbon carboxylates, alkoxyls, acid-bounded methyl-cyclopentenones, and methyl-cyclopentenyl carbocations, from the very early induction period to the steady-state conversion under high-pressure flow-reaction conditions. Oxygenate-based routes were proved to be contributed to the outlet olefins and aromatics, where the feed, i.e., CO and H2, was also a vigorous participant in these secondary reactions. In addition to the ZnAlOx/H-ZSM-5 catalyst, the researchers also discovered that the key intermediates exist in multiple OXZEO catalysts, proving the universality of oxygenate-based routes in OXZEO-based syngas conversion. \"Our findings provide new insights into the reaction mechanism of syngas conversion on bifunctional catalysts, and may also help to better understand the mechanism of CO2 and biomass conversion,\" said Prof. Hou. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 emerging oxide–zeolite bifunctional catalysis for direct syngas conversion has drawn extensive interest, both academically and industrially, with further exploration urging a clear mechanistic understanding of this complex catalytic network. Herein, using a specially designed quasi-in situ, solid-state nuclear magnetic resonance-gas chromatography/gas chromatography-mass spectrometry analysis strategy, this reaction is fully monitored from the very early induction period to steady-state conversion under high-pressure flow-reaction conditions, using ZnAlO x /H-ZSM-5 composites as model catalysts. We identify abundant critical and/or transient intermediates in dynamic evolution, including carboxylates, alkoxyls, acid-bounded methyl-cyclopentenones and methyl-cyclopentenyl carbocations, providing direct evidence of vigorous regulation by unique, oxygenate-based pathways of the reaction network. This proposed mechanism overturns the general cognition of oxide–zeolite reactions as simple tandem catalysis, and highlights the many roles (both positive and negative) of CO and H 2 molecules via oxygenate-based routes, thus dictating the final product. The current characterization technology and its mechanistic understanding would benefit further exploration in bifunctional catalysis. Main Over the years, Fischer–Tropsch synthesis (FTS) has been the core technology for the direct conversion of syngas (CO/H 2 ) into high-value-added hydrocarbons to substitute petroleum products, despite the well-recognized limited product selectivity that follows a statistical Anderson–Schulz–Flory (ASF) distribution 1 . In spite of the continuous developments of alternative strategies such as functionalized FTS 2 , 3 , 4 , 5 , selectivity control in FTS remains challenging. Meanwhile, the recently discovered oxide–zeolite-based bifunctional catalysis, namely OXZEO, has grown into another flourishing process and profoundly rekindled interest in this field 6 , 7 , 8 . This particular method describes the use of selected OXZEO composite catalysts for the direct transformation of syngas into target hydrocarbons—for example, C 2–4 olefins 9 , 10 , 11 , 12 , gasoline 13 and aromatics 14 , 15 , 16 , attaining a surprisingly high selectivity far beyond the limits predicted by the ASF model in FTS. Industrial exploration of OXZEO catalysis is progressing smoothly, and the first 1,000 ton yr –1 pilot plant testing of syngas to olefins via OXZEO was recently accomplished in Shaanxi, China 8 . In regard to the mechanism, this reaction is generally regarded as tandem catalysis where the oxide component is responsible for the initial activation of CO and H 2 to C 1 intermediates, while subsequent C–C coupling of the C 1 intermediates take place in the micropores of zeolites for shape-selective synthesis 6 , 7 , 17 . To date, except for some oxide catalysts reported to produce ketene as the intermediate 9 , 11 , 18 , 19 , many other studies adopted conventional methanol-synthesis oxides in composite catalysts 6 , 7 , 10 , 15 , 17 . Thus, the OXZEO catalytic network is generally regarded as a simple relay reaction comprising methanol synthesis (on oxide) and a methanol-to-hydrocarbon (MTH) reaction under a hydrocarbon pool (HCP) mechanism (on zeolite) 20 , 21 , 22 , 23 , 24 , 25 . However, the adoption of HCP in the OXZEO bifunctional system has never been verified to the best of our knowledge. At least two major concerns are raised, regarding the complexity of this system. First, unlike conventional tandem catalysis, the active sites on both components (oxides and zeolites) of hybrid OXZEO catalysts have the ability to transform secondary intermediates before formation of the final products, leading to a different reaction network than that catalysed separately by zeolite and oxide. For instance, a shuttle-mode reaction between oxide and zeolite components has recently been revealed for ZnAl 2 O 4 /H-MOR 12 . Second, highly reactive CO and H 2 (often fed at high pressures of up to tens of bars) may interfere/react at any step of the secondary reaction network and alter the mechanism. Therefore, direct adoption of the classical HCP mechanism will be carefully reconsidered although it has been extended to cover wider research domains 26 , 27 . In fact, the participation of CO and H 2 in MTH reactions has been investigated experimentally 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 . Among those studies, CO was suggested to be responsible for the formation of the initial C–C bond 28 , 29 , 30 , 31 , 32 and was also reported to facilitate the production of aromatics 32 , 35 . Moreover, high-pressure H 2 co-feeding can intercept the formation of deactivation-inducing polycyclic aromatics 33 , 34 . Recently, the additional modulation effect of CO and H 2 on syngas conversion has gained increasing attention in OXZEO-catalysed syngas conversion reactions 10 , 15 . These studies indicate a more complicated catalytic network of practical OXZEO catalysis. During the progress of this work, phenolics, ketones and furans were also identified for OXZEO catalysts (ZnCr 2 O 4 /H-ZSM-5 and MnO/H-ZSM-5) and are suggested as intermediates 36 , 37 , but the catalytic mechanism that is different from HCP remains elusive. In this work, syngas conversion for ZnAlO x /H-ZSM-5 was investigated as a model reaction to elucidate the mechanisms involved in bifunctional catalytic systems. The reaction process, from the induction period to steady-state conversion, was monitored by combining quasi-in situ, solid-state nuclear magnetic resonance (ssNMR) and online gas chromatography/gas chromatography-mass spectrometry (GC/GC-MS) analysis, which allowed us to unambiguously identify a large variety of highly reactive intermediates in activated states, including multiple carboxylates, alkoxy groups, methyl-cyclopentenones (MCPenones) and abundant carbocations, including methyl-cyclopentenyl carbocations (MCPenes + ) adsorbed on the catalysts. Such observations validate the pivotal role of highly vigorous oxygenate-based routes during the reaction. Moreover, the reactivity and evolution of different intermediates have been explored in detail. Accordingly, a full reaction network comprising highly active oxygenate-based catalytic routes, along with the conventional dual-cycle HCP mechanism, was proposed. Furthermore, the universality of this mechanism in syngas conversion has been unveiled for different OXZEO bifunctional catalysts. Results Syngas conversion tests for ZnAlO x /H-ZSM-5 catalysts Two commerical H-ZSM-5 zeolites, with Si/Al ratios (SARs) of 82.4 and 16.4, were physically mixed with synthesized ZnAlO x oxide (spinel structure; Supplementary<|im_end|> <|im_start|>assistant A research team led by Prof. Hou Guangjin and Prof. Bao Xinhe from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences (CAS) has revealed the oxygenate-based routes in syngas conversion over oxide–zeolite (OXZEO) bifunctional catalysts by solid-state Nuclear Magnetic Resonance (NMR). This study was published in Nature Catalysis on June 23. OXZEO catalysis was proposed in 2016 by Prof. Bao Xinhe and Prof. Pan Xiulian from DICP. It provides a platform for the efficient utilization of coal and other carbon resources. However, the reaction mechanism in OXZEO catalysis still remains unclear. In this study, the researchers chose the syngas conversion over the ZnAlOx/H-ZSM-5 bifunctional catalyst as a model system to highlight the mechanistic difference in the OXZEO-based syngas direct conversion. ZnAlOx is a typical metal oxide for syngas to methanol process while H-ZSM-5 is a typical zeolite for methanol to hydrocarbons (MTH) reaction. They used the quasi-in situ solid-state NMR (ssNMR)-Gas Chromatography (GC) analysis strategy to reveal the dynamic evolution of abundant critical and/or transient intermediates, including multi-carbon carboxylates, alkoxyls, acid-bounded methyl-cyclopentenones, and methyl-cyclopentenyl carbocations, from the very early induction period to the steady-state conversion under high-pressure flow-reaction conditions. Oxygenate-based routes were proved to be contributed to the outlet olefins and aromatics, where the feed, i.e., CO and H2, was also a vigorous participant in these secondary reactions. In addition to the ZnAlOx/H-ZSM-5 catalyst, the researchers also discovered that the key intermediates exist in multiple OXZEO catalysts, proving the universality of oxygenate-based routes in OXZEO-based syngas conversion. "Our findings provide new insights into the reaction mechanism of syngas conversion on bifunctional catalysts, and may also help to better understand the mechanism of CO2 and biomass conversion," said Prof. Hou. <|im_end|>

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51483, 82, 220, 21, 1174, 220, 22, 1174, 220, 605, 1174, 220, 868, 1174, 220, 1114, 662, 14636, 11, 279, 507, 55, 57, 6903, 34454, 70504, 4009, 374, 8965, 27458, 439, 264, 4382, 32951, 13010, 46338, 21747, 39710, 39975, 320, 263, 51180, 8, 323, 264, 21747, 39710, 4791, 2902, 68107, 74441, 320, 44, 3701, 8, 13010, 1234, 264, 17055, 74441, 7463, 320, 39, 7269, 8, 17383, 320, 263, 14017, 337, 635, 8, 220, 508, 1174, 220, 1691, 1174, 220, 1313, 1174, 220, 1419, 1174, 220, 1187, 1174, 220, 914, 662, 4452, 11, 279, 25375, 315, 473, 7269, 304, 279, 507, 55, 57, 6903, 92640, 600, 278, 1887, 706, 2646, 1027, 24884, 311, 279, 1888, 315, 1057, 6677, 13, 2468, 3325, 1403, 3682, 10742, 527, 9408, 11, 9002, 279, 23965, 315, 420, 1887, 13, 5629, 11, 20426, 21349, 67042, 34454, 4548, 11, 279, 4642, 6732, 389, 2225, 6956, 320, 5241, 3422, 323, 14017, 337, 3695, 8, 315, 26038, 507, 55, 57, 6903, 51483, 82, 617, 279, 5845, 311, 5276, 14580, 55275, 988, 1603, 18488, 315, 279, 1620, 3956, 11, 6522, 311, 264, 2204, 13010, 4009, 1109, 430, 34454, 1065, 291, 26214, 555, 14017, 337, 635, 323, 51180, 13, 1789, 2937, 11, 264, 45641, 15331, 13010, 1990, 51180, 323, 14017, 337, 635, 6956, 706, 6051, 1027, 10675, 369, 127265, 2149, 220, 17, 507, 220, 19, 611, 39, 5364, 878, 220, 717, 662, 10657, 11, 7701, 56563, 7432, 323, 473, 220, 17, 320, 61917, 23114, 520, 1579, 40850, 315, 709, 311, 22781, 315, 16283, 8, 1253, 40978, 28517, 520, 904, 3094, 315, 279, 14580, 13010, 4009, 323, 11857, 279, 17383, 13, 15636, 11, 2167, 25375, 315, 279, 29924, 473, 7269, 17383, 690, 387, 15884, 40175, 291, 8051, 433, 706, 1027, 11838, 311, 3504, 22622, 3495, 31576, 220, 1627, 1174, 220, 1544, 662, 763, 2144, 11, 279, 20852, 315, 7432, 323, 473, 220, 17, 304, 386, 3701, 25481, 706, 1027, 27313, 9526, 750, 220, 1591, 1174, 220, 1682, 1174, 220, 966, 1174, 220, 2148, 1174, 220, 843, 1174, 220, 1644, 1174, 220, 1958, 1174, 220, 1758, 662, 22395, 1884, 7978, 11, 7432, 574, 12090, 311, 387, 8647, 369, 279, 18488, 315, 279, 2926, 356, 4235, 34, 11049, 220, 1591, 1174, 220, 1682, 1174, 220, 966, 1174, 220, 2148, 1174, 220, 843, 323, 574, 1101, 5068, 311, 28696, 279, 5788, 315, 32369, 29470, 220, 843, 1174, 220, 1758, 662, 23674, 11, 1579, 89561, 473, 220, 17, 1080, 12, 46519, 649, 29739, 279, 18488, 315, 409, 23863, 18251, 59144, 1499, 3418, 66404, 32369, 29470, 220, 1644, 1174, 220, 1958, 662, 42096, 11, 279, 5217, 67547, 2515, 315, 7432, 323, 473, 220, 17, 389, 6705, 983, 300, 14747, 706, 18661, 7859, 6666, 304, 507, 55, 57, 6903, 1824, 4306, 1065, 291, 6705, 983, 300, 14747, 25481, 220, 605, 1174, 220, 868, 662, 4314, 7978, 13519, 264, 810, 17395, 34454, 70504, 4009, 315, 15325, 507, 55, 57, 6903, 34454, 4548, 13, 12220, 279, 5208, 315, 420, 990, 11, 14345, 47007, 11, 32381, 3233, 323, 18742, 598, 1051, 1101, 11054, 369, 507, 55, 57, 6903, 51483, 82, 320, 57, 77, 16384, 220, 17, 507, 220, 19, 611, 39, 11419, 9691, 12, 20, 323, 57831, 46, 24240, 11419, 9691, 12, 20, 8, 323, 527, 12090, 439, 55275, 988, 220, 1927, 1174, 220, 1806, 1174, 719, 279, 34454, 70504, 17383, 430, 374, 2204, 505, 473, 7269, 8625, 66684, 13, 763, 420, 990, 11, 6705, 983, 300, 14747, 369, 127265, 2149, 46, 865, 611, 39, 11419, 9691, 12, 20, 574, 27313, 439, 264, 1646, 13010, 311, 97298, 349, 279, 24717, 6532, 304, 92640, 600, 278, 34454, 70504, 6067, 13, 578, 13010, 1920, 11, 505, 279, 38156, 4261, 311, 24981, 21395, 14747, 11, 574, 41223, 555, 35271, 48844, 3502, 10109, 11, 6573, 21395, 11499, 24924, 58081, 320, 784, 45, 18953, 8, 323, 2930, 6962, 98284, 5814, 4951, 300, 98284, 5814, 1474, 395, 9618, 442, 15501, 320, 23710, 16169, 34, 12, 4931, 8, 6492, 11, 902, 5535, 603, 311, 653, 3042, 27843, 7162, 10765, 264, 3544, 8205, 315, 7701, 56563, 55275, 988, 304, 22756, 5415, 11, 2737, 5361, 1841, 2054, 4010, 988, 11, 453, 9509, 4223, 5315, 11, 79574, 1824, 3418, 23085, 306, 268, 3233, 320, 44, 7269, 268, 3233, 8, 323, 44611, 35872, 56299, 11, 2737, 79574, 1824, 3418, 23085, 306, 268, 4010, 35872, 56299, 320, 44, 7269, 22383, 489, 883, 14058, 269, 2788, 389, 279, 51483, 82, 13, 15483, 24654, 9788, 279, 60850, 3560, 315, 7701, 71920, 24463, 349, 6108, 11543, 2391, 279, 13010, 13, 23674, 11, 279, 312, 7323, 323, 15740, 315, 2204, 55275, 988, 617, 1027, 36131, 304, 7872, 13, 63909, 11, 264, 2539, 13010, 4009, 46338, 7701, 4642, 24463, 349, 6108, 34454, 70504, 11543, 11, 3235, 449, 279, 21349, 19091, 78790, 473, 7269, 17383, 11, 574, 11223, 13, 24296, 11, 279, 11159, 2786, 315, 420, 17383, 304, 6705, 983, 300, 14747, 706, 1027, 39297, 369, 2204, 507, 55, 57, 6903, 92640, 600, 278, 51483, 82, 13, 18591, 5837, 983, 300, 14747, 7177, 369, 127265, 2149, 46, 865, 611, 39, 11419, 9691, 12, 20, 51483, 82, 9220, 1081, 261, 950, 473, 11419, 9691, 12, 20, 14017, 337, 3695, 11, 449, 12095, 14, 2149, 42338, 320, 50, 946, 82, 8, 315, 220, 6086, 13, 19, 323, 220, 845, 13, 19, 11, 1051, 22655, 9709, 449, 92106, 127265, 2149, 46, 865, 51180, 320, 2203, 30808, 6070, 26, 99371, 128257, 198, 128256, 78191, 198, 32, 3495, 2128, 6197, 555, 8626, 13, 60700, 65537, 50900, 323, 8626, 13, 426, 3524, 70761, 383, 505, 279, 423, 10700, 10181, 315, 36424, 28415, 320, 94261, 47, 8, 315, 279, 8620, 16192, 315, 23199, 320, 88616, 8, 706, 10675, 279, 24463, 349, 6108, 11543, 304, 6705, 983, 300, 14747, 927, 51180, 4235, 3059, 337, 635, 320, 61255, 57, 6903, 8, 92640, 600, 278, 51483, 82, 555, 6573, 21395, 38544, 63755, 1838, 263, 685, 320, 45, 18953, 570, 1115, 4007, 574, 4756, 304, 22037, 32544, 4548, 389, 5651, 220, 1419, 13, 507, 55, 57, 6903, 34454, 4548, 574, 11223, 304, 220, 679, 21, 555, 8626, 13, 426, 3524, 70761, 383, 323, 8626, 13, 11233, 43526, 360, 1122, 505, 98860, 47, 13, 1102, 5825, 264, 5452, 369, 279, 11297, 50549, 315, 11756, 323, 1023, 12782, 5070, 13, 4452, 11, 279, 13010, 17383, 304, 507, 55, 57, 6903, 34454, 4548, 2103, 8625, 25420, 13, 763, 420, 4007, 11, 279, 12074, 14896, 279, 6705, 983, 300, 14747, 927, 279, 127265, 2149, 46, 87, 24240, 11419, 9691, 12, 20, 92640, 600, 278, 51483, 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323, 32369, 29470, 11, 1405, 279, 5510, 11, 602, 1770, 2637, 7432, 323, 473, 17, 11, 574, 1101, 264, 71920, 25923, 304, 1521, 14580, 25481, 13, 763, 5369, 311, 279, 127265, 2149, 46, 87, 24240, 11419, 9691, 12, 20, 51483, 11, 279, 12074, 1101, 11352, 430, 279, 1401, 55275, 988, 3073, 304, 5361, 507, 55, 57, 6903, 51483, 82, 11, 39858, 279, 11159, 2786, 315, 24463, 349, 6108, 11543, 304, 507, 55, 57, 6903, 6108, 6705, 983, 300, 14747, 13, 330, 8140, 14955, 3493, 502, 26793, 1139, 279, 13010, 17383, 315, 6705, 983, 300, 14747, 389, 92640, 600, 278, 51483, 82, 11, 323, 1253, 1101, 1520, 311, 2731, 3619, 279, 17383, 315, 7432, 17, 323, 58758, 14747, 1359, 1071, 8626, 13, 60700, 13, 220, 128257, 198 ]

2,071

[ { "content": "You are a great 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 Abnormal activation of endochondral bone formation in soft tissues causes significant medical diseases associated with disability and pain. Hyperactive mutations in the bone morphogenetic protein (BMP) type 1 receptor ACVR1 lead to fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder characterized by progressive ossification in soft tissues. However, the specific cellular mechanisms are unclear. In addition, the difficulty obtaining tissue samples from FOP patients and the limitations in mouse models of FOP hamper our ability to dissect the pathogenesis of FOP. Methods To address these challenges and develop a “disease model in a dish”, we created human induced pluripotent stem cells (iPS cells) derived from normal and FOP dermal fibroblasts by two separate methods, retroviral integration or integration-free episomal vectors. We tested if the ability to contribute to different steps of endochondral bone formation was different in FOP vs. control iPS cells. Results Remarkably, FOP iPS cells showed increased mineralization and enhanced chondrogenesis in vitro . The mineralization phenotypes could be suppressed with a small-molecule inhibitor of BMP signaling, DMH1. Our results indicate that the FOP ACVR1 R206H mutation favors chondrogenesis and increases mineral deposition in vitro . Conclusions Our findings establish a FOP disease cell model for in vitro experimentation and provide a proof-of-concept for using human iPS cell models to understand human skeletal disorders. Background Tissue mineralization is one of the most dramatic transitions in normal development and disease. Hard tissues, such as bone and teeth, maintain body structure, protect vital organs, and facilitate eating. Abnormal activation of endochondral bone formation in soft tissues from congenital disorders, such as fibrodysplasia ossificans progressiva (FOP; OMIM #135100) or from trauma or central nervous system injury [ 1 ] cause severe disability and pain. Although bone morphogenetic proteins (BMPs) are key regulators of osteogenesis [ 2 ] and are implicated in pathologic calcification [ 3 ], their specific functions in humans are not well understood. Human induced pluripotent stem cells (iPS cells) derived from patients with genetic mutations affecting key signaling pathways provide a unique opportunity to dissect human development and disease pathogenesis in models amenable to experimental manipulation [ 4 ]. FOP is a rare but debilitating disease of heterotopic bone formation associated with mutations in the Activin A Type I receptor (ACVR1) [ 5 ], which is activated by BMPs. A single amino acid change (R206H) commonly resulting from a single base mutation (617G > A) is found in the majority of FOP patients and can increase sensitivity of the receptor to BMP ligands [ 6 ]. Patients are born without heterotopic ossification yet characteristically form large amounts of bone either spontaneously or after trauma [ 7 ]. The heterotopic ossification follows an endochondral bone formation pathway that starts with a pre-cartilaginous fibro-proliferative anlage and eventually mineralizes. The ferocity of these episodes makes it nearly impossible to obtain tissue samples prospectively and significantly complicates surgical management. Here, we created a series of iPS cells from dermal fibroblasts of donors with FOP by either DNA-integrating retroviral or integration-free episomal plasmid methods [ 4 , 8 ]. The FOP iPS cells showed increased mineral deposition and chondrogenesis, potentially reflecting a predisposition towards endochondral bone formation in FOP. Our findings provide a valuable foundation for human stem cell-based systems to delineate the mechanisms of normal and pathologic skeletal formation. Materials and methods Cell culture Primary human dermal fibroblasts (HDFs) from commercial sources or from 3-mm skin biopsies carefully obtained from donors (without causing deep tissue injury) or from surgical excess were cultured [ 9 ] and are described in Table 1 and Additional file 1 : Table S1. HDFs less than five passages old were used for iPS cell reprogramming. Presence or absence of the ACVR1 mutation was sequenced and verified as described [ 5 ]. Primary human mesenchymal stem cells (hMSCs) were prepared from iliac bone as described previously [ 10 ] and expanded as a monolayer. Table 1 Cell lines used in this study Full size table Retroviral [ 4 ] and episomal integration-free [ 8 ] iPS cells were derived as described. H9 human embryonic stem (ES) cells were from WiCell Research Institute (Madison, WI). All pluripotent cell lines were maintained in mTeSR1 medium (StemCell Technologies, Vancouver, Canada) on growth-factor-reduced Matrigel (BD Biosciences)-coated plates (150–300 μg/ml, 30 min coating) or in primate ES cell medium (ReproCELL, Tokyo, Japan) on mitomycin C-treated or irradiated SNL feeder cells [ 11 ]. SNLs were carefully removed by at least one passage in feeder-free conditions before use in differentiation assays. The ROCK inhibitor Y-27632 (10 μM, Tocris Bioscience, Minneapolis, MN) dissolved in DMSO was added to mTeSR1 at passaging and removed the following day. Karyotyping was done by Cell Line Genetics (Madison, WI) or Nihon Gene Research Laboratories (Sendai, Japan). Cells exposed to recombinant BMP4 protein (R&D Systems, Minneapolis, MN) were treated for 45 minutes. All human tissue collection, human stem cell studies, procedures, and written consents were approved by the UCSF Committee on Human Research, the UCSF Gamete and Embryonic Stem Cell Research Committee, or by the Ethics Committee of the Department of Medicine and Graduate School of Medicine, Kyoto University. Embryoid body formation Embryoid bodies (EBs) were formed from iPS cells or human ES cells once their cultures reached 80% confluence. After washing with PBS, Accutase (StemCell Technologies, Vancouver, Canada) was applied for two minutes to remove cells from the plate. Cells were centrifuged at 175 × g for two minutes and then resuspended in a 4:1 mix of EB differentiation medium (80% Knockout DMEM, 20% FBS, 1% Glutamax, 1% non-essential amino acids, and 0.1 mM 2-mercaptoethanol) and mTeSR1, and supplemented with 10 μM Y-27632. Cells were plated onto ultra-low attachment plates without medium changes for seven days. On day eight, EBs were collected and allowed to settle in a conical tube for 30 minutes. The mixed medium was removed and replaced with 100% EB differentiation medium (Knockout DMEM supplemented with 20% FBS, 1% Glutamax, 1% non-essential amino acids, and 0.1 mM 2-mercaptoethanol) changed every three to four days.", "role": "user" }, { "content": "(Medical Xpress)—Researchers have developed a new way to study bone disorders and bone growth, using stem cells from patients afflicted with a rare, genetic bone disease. The approach, based on Nobel-Prize winning techniques, could illuminate the illness, in which muscles and tendons progressively turn into bone, and addresses the similar destructive process that afflicts a growing number of veterans who have suffered blast injuries—including traumatic amputations or injuries to the brain and nervous system. This insidious hardening of tissues also grips some patients following joint replacement or severe bone injuries. The disease model, described in a new study by a UC San Francisco-led team, involves taking skin cells from patients with the bone disease, reprogramming them in a lab dish to their embryonic state, and deriving stem cells from them. Once the team derived the stem cells, they identified a cellular mechanism that drives abnormal bone growth in the thus-far untreatable bone disease, called fibrodysplasiaossificans progressiva (FOP). Furthermore, they found that certain chemicals could slow abnormal bone growth in the stem cells, a discovery that might help guide future drug development. Clinically, the genetic and trauma-caused conditions are very similar, with bone formation in muscle leading to pain and restricted movement, according to the leader of the new study, Edward Hsiao, MD, PhD, an endocrinologist who cares for patients with rare and unusual bone diseases at the UCSF Metabolic Bone Clinic in the Division of Endocrinology and Metabolism. The human cell-based disease model is expected to lead to a better understanding of these disorders and other illnesses, Hsiao said. \"The new FOP model already has shed light on the disease process in FOP by showing that the mutated gene can affect different steps of bone formation,\" Hsiao said. \"These different stages represent potential targets for limiting or stopping the progression of the disease, and may also be useful for blocking abnormal bone formation in other conditions besides FOP. The human stem-cell lines we developed will be useful for identifying drugs that target the bone-formation process in humans.\" The team's development of, and experimentation with, the human stem-cell disease model for FOP, published in the December issue of the Orphanet Journal of Rare Diseases, is a realization of the promise of research using stem cells of the type known as induced pluripotent stem (iPS) cells, immortal cells of nearly limitless potential, derived not from embryos, but from adult tissues. Shinya Yamanaka, MD, PhD, a UCSF professor of anatomy and a senior investigator with the UCSF-affiliated Gladstone Institutes, as well as the director of the Center for iPSCell Research and Application (CiRA) and a principal investigator at Kyoto University, shared the Nobel Prize in 2012 for discovering how to make iPS cells from skin cells using a handful of protein \"factors.\" These factors guide a reprogramming process that reverts the cells to an embryonic state, in which they have the potential to become virtually any type of cell. Because injuries and surgeries can trigger rapid bone formation in FOP patients, obtaining tissue samples for extensive lab study is extremely difficult. Human iPS cells provide a unique solution by allowing the creation of the needed tissues in the lab. Hsiao and colleagues carefully gathered skin samples from donors, and then grew the skin cells in culture before converting them into iPS cells using the methods created by Yamanaka. In addition to providing an alternative to embryonic stem cells for potential use in regenerating diseased tissues, iPS cells are being used to learn more about diseases, especially diseases driven by mutated genes. Unlike the skin cells from which they originated, the human iPS cells created from FOP patients show increased cartilage formation and increased bone mineralization, two critical steps that are necessary to form mature bone. Bone morphogenetic proteins (BMPs) play a central role in the bone formation within muscle. FOP results from a gene mutation that causes a defect in the receptor protein to which BMPs bind, thereby increasing bone formation. \"These cells will be a key tool for finding ways to stimulate and control human bone growth for regenerative medicine or bone repair,\" Hsiao said. \"The iPS cells may also help us identify treatments for more common diseases, such as atherosclerosis and vascular calcification, because the same bone morphogenetic protein pathways are involved in these medical conditions.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Abnormal activation of endochondral bone formation in soft tissues causes significant medical diseases associated with disability and pain. Hyperactive mutations in the bone morphogenetic protein (BMP) type 1 receptor ACVR1 lead to fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder characterized by progressive ossification in soft tissues. However, the specific cellular mechanisms are unclear. In addition, the difficulty obtaining tissue samples from FOP patients and the limitations in mouse models of FOP hamper our ability to dissect the pathogenesis of FOP. Methods To address these challenges and develop a “disease model in a dish”, we created human induced pluripotent stem cells (iPS cells) derived from normal and FOP dermal fibroblasts by two separate methods, retroviral integration or integration-free episomal vectors. We tested if the ability to contribute to different steps of endochondral bone formation was different in FOP vs. control iPS cells. Results Remarkably, FOP iPS cells showed increased mineralization and enhanced chondrogenesis in vitro . The mineralization phenotypes could be suppressed with a small-molecule inhibitor of BMP signaling, DMH1. Our results indicate that the FOP ACVR1 R206H mutation favors chondrogenesis and increases mineral deposition in vitro . Conclusions Our findings establish a FOP disease cell model for in vitro experimentation and provide a proof-of-concept for using human iPS cell models to understand human skeletal disorders. Background Tissue mineralization is one of the most dramatic transitions in normal development and disease. Hard tissues, such as bone and teeth, maintain body structure, protect vital organs, and facilitate eating. Abnormal activation of endochondral bone formation in soft tissues from congenital disorders, such as fibrodysplasia ossificans progressiva (FOP; OMIM #135100) or from trauma or central nervous system injury [ 1 ] cause severe disability and pain. Although bone morphogenetic proteins (BMPs) are key regulators of osteogenesis [ 2 ] and are implicated in pathologic calcification [ 3 ], their specific functions in humans are not well understood. Human induced pluripotent stem cells (iPS cells) derived from patients with genetic mutations affecting key signaling pathways provide a unique opportunity to dissect human development and disease pathogenesis in models amenable to experimental manipulation [ 4 ]. FOP is a rare but debilitating disease of heterotopic bone formation associated with mutations in the Activin A Type I receptor (ACVR1) [ 5 ], which is activated by BMPs. A single amino acid change (R206H) commonly resulting from a single base mutation (617G > A) is found in the majority of FOP patients and can increase sensitivity of the receptor to BMP ligands [ 6 ]. Patients are born without heterotopic ossification yet characteristically form large amounts of bone either spontaneously or after trauma [ 7 ]. The heterotopic ossification follows an endochondral bone formation pathway that starts with a pre-cartilaginous fibro-proliferative anlage and eventually mineralizes. The ferocity of these episodes makes it nearly impossible to obtain tissue samples prospectively and significantly complicates surgical management. Here, we created a series of iPS cells from dermal fibroblasts of donors with FOP by either DNA-integrating retroviral or integration-free episomal plasmid methods [ 4 , 8 ]. The FOP iPS cells showed increased mineral deposition and chondrogenesis, potentially reflecting a predisposition towards endochondral bone formation in FOP. Our findings provide a valuable foundation for human stem cell-based systems to delineate the mechanisms of normal and pathologic skeletal formation. Materials and methods Cell culture Primary human dermal fibroblasts (HDFs) from commercial sources or from 3-mm skin biopsies carefully obtained from donors (without causing deep tissue injury) or from surgical excess were cultured [ 9 ] and are described in Table 1 and Additional file 1 : Table S1. HDFs less than five passages old were used for iPS cell reprogramming. Presence or absence of the ACVR1 mutation was sequenced and verified as described [ 5 ]. Primary human mesenchymal stem cells (hMSCs) were prepared from iliac bone as described previously [ 10 ] and expanded as a monolayer. Table 1 Cell lines used in this study Full size table Retroviral [ 4 ] and episomal integration-free [ 8 ] iPS cells were derived as described. H9 human embryonic stem (ES) cells were from WiCell Research Institute (Madison, WI). All pluripotent cell lines were maintained in mTeSR1 medium (StemCell Technologies, Vancouver, Canada) on growth-factor-reduced Matrigel (BD Biosciences)-coated plates (150–300 μg/ml, 30 min coating) or in primate ES cell medium (ReproCELL, Tokyo, Japan) on mitomycin C-treated or irradiated SNL feeder cells [ 11 ]. SNLs were carefully removed by at least one passage in feeder-free conditions before use in differentiation assays. The ROCK inhibitor Y-27632 (10 μM, Tocris Bioscience, Minneapolis, MN) dissolved in DMSO was added to mTeSR1 at passaging and removed the following day. Karyotyping was done by Cell Line Genetics (Madison, WI) or Nihon Gene Research Laboratories (Sendai, Japan). Cells exposed to recombinant BMP4 protein (R&D Systems, Minneapolis, MN) were treated for 45 minutes. All human tissue collection, human stem cell studies, procedures, and written consents were approved by the UCSF Committee on Human Research, the UCSF Gamete and Embryonic Stem Cell Research Committee, or by the Ethics Committee of the Department of Medicine and Graduate School of Medicine, Kyoto University. Embryoid body formation Embryoid bodies (EBs) were formed from iPS cells or human ES cells once their cultures reached 80% confluence. After washing with PBS, Accutase (StemCell Technologies, Vancouver, Canada) was applied for two minutes to remove cells from the plate. Cells were centrifuged at 175 × g for two minutes and then resuspended in a 4:1 mix of EB differentiation medium (80% Knockout DMEM, 20% FBS, 1% Glutamax, 1% non-essential amino acids, and 0.1 mM 2-mercaptoethanol) and mTeSR1, and supplemented with 10 μM Y-27632. Cells were plated onto ultra-low attachment plates without medium changes for seven days. On day eight, EBs were collected and allowed to settle in a conical tube for 30 minutes. The mixed medium was removed and replaced with 100% EB differentiation medium (Knockout DMEM supplemented with 20% FBS, 1% Glutamax, 1% non-essential amino acids, and 0.1 mM 2-mercaptoethanol) changed every three to four days.<|im_end|> <|im_start|>assistant (Medical Xpress)—Researchers have developed a new way to study bone disorders and bone growth, using stem cells from patients afflicted with a rare, genetic bone disease. The approach, based on Nobel-Prize winning techniques, could illuminate the illness, in which muscles and tendons progressively turn into bone, and addresses the similar destructive process that afflicts a growing number of veterans who have suffered blast injuries—including traumatic amputations or injuries to the brain and nervous system. This insidious hardening of tissues also grips some patients following joint replacement or severe bone injuries. The disease model, described in a new study by a UC San Francisco-led team, involves taking skin cells from patients with the bone disease, reprogramming them in a lab dish to their embryonic state, and deriving stem cells from them. Once the team derived the stem cells, they identified a cellular mechanism that drives abnormal bone growth in the thus-far untreatable bone disease, called fibrodysplasiaossificans progressiva (FOP). Furthermore, they found that certain chemicals could slow abnormal bone growth in the stem cells, a discovery that might help guide future drug development. Clinically, the genetic and trauma-caused conditions are very similar, with bone formation in muscle leading to pain and restricted movement, according to the leader of the new study, Edward Hsiao, MD, PhD, an endocrinologist who cares for patients with rare and unusual bone diseases at the UCSF Metabolic Bone Clinic in the Division of Endocrinology and Metabolism. The human cell-based disease model is expected to lead to a better understanding of these disorders and other illnesses, Hsiao said. "The new FOP model already has shed light on the disease process in FOP by showing that the mutated gene can affect different steps of bone formation," Hsiao said. "These different stages represent potential targets for limiting or stopping the progression of the disease, and may also be useful for blocking abnormal bone formation in other conditions besides FOP. The human stem-cell lines we developed will be useful for identifying drugs that target the bone-formation process in humans." The team's development of, and experimentation with, the human stem-cell disease model for FOP, published in the December issue of the Orphanet Journal of Rare Diseases, is a realization of the promise of research using stem cells of the type known as induced pluripotent stem (iPS) cells, immortal cells of nearly limitless potential, derived not from embryos, but from adult tissues. Shinya Yamanaka, MD, PhD, a UCSF professor of anatomy and a senior investigator with the UCSF-affiliated Gladstone Institutes, as well as the director of the Center for iPSCell Research and Application (CiRA) and a principal investigator at Kyoto University, shared the Nobel Prize in 2012 for discovering how to make iPS cells from skin cells using a handful of protein "factors." These factors guide a reprogramming process that reverts the cells to an embryonic state, in which they have the potential to become virtually any type of cell. Because injuries and surgeries can trigger rapid bone formation in FOP patients, obtaining tissue samples for extensive lab study is extremely difficult. Human iPS cells provide a unique solution by allowing the creation of the needed tissues in the lab. Hsiao and colleagues carefully gathered skin samples from donors, and then grew the skin cells in culture before converting them into iPS cells using the methods created by Yamanaka. In addition to providing an alternative to embryonic stem cells for potential use in regenerating diseased tissues, iPS cells are being used to learn more about diseases, especially diseases driven by mutated genes. Unlike the skin cells from which they originated, the human iPS cells created from FOP patients show increased cartilage formation and increased bone mineralization, two critical steps that are necessary to form mature bone. Bone morphogenetic proteins (BMPs) play a central role in the bone formation within muscle. FOP results from a gene mutation that causes a defect in the receptor protein to which BMPs bind, thereby increasing bone formation. "These cells will be a key tool for finding ways to stimulate and control human bone growth for regenerative medicine or bone repair," Hsiao said. "The iPS cells may also help us identify treatments for more common diseases, such as atherosclerosis and vascular calcification, because the same bone morphogenetic protein pathways are involved in these medical conditions." <|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 Positive selection of diverse yet self-tolerant thymocytes is vital to immunity and requires a limited degree of T cell antigen receptor (TCR) signaling in response to self peptide–major histocompatibility complexes (self peptide–MHCs). Affinity of newly generated TCR for peptide-MHC primarily sets the boundaries for positive selection. We report that N-glycan branching of TCR and the CD4 and CD8 coreceptors separately altered the upper and lower affinity boundaries from which interactions between peptide-MHC and TCR positively select T cells. During thymocyte development, N-glycan branching varied approximately 15-fold. N-glycan branching was required for positive selection and decoupled Lck signaling from TCR-driven Ca 2+ flux to simultaneously promote low-affinity peptide-MHC responses while inhibiting high-affinity ones. Therefore, N-glycan branching imposes a sliding scale on interactions between peptide-MHC and TCR that bidirectionally expands the affinity range for positive selection. Main The production of functional and self-tolerant T lymphocytes is vital for adaptive immunity and prevention of autoimmunity. Development of thymocytes progresses through four CD4 − CD8 − double-negative (DN) stages (DN1–DN4), a CD4 + CD8 + double-positive (DP) stage and a CD4 + or CD8 + single-positive (SP) stage 1 . Thymocytes must be surveyed for responsiveness and self-tolerance before exiting the thymus, where TCR interactions with self peptide–MHC have a crucial role 1 . Only intermediate TCR signals positively select self-tolerant SP thymocytes (positive selection) 1 . Thymocytes that do not receive sufficient basal TCR signaling die by neglect, whereas cells that encounter strong TCR signaling die by negative selection 1 . Positive selection of conventional MHC-restricted thymocytes is initiated by the binding of newly rearranged TCRαβ to peptide-MHC 1 . The strength of this interaction is a primary control point for positive selection and is often viewed as a static and linear function of differences in binding affinity between newly rearranged TCRαβ and peptide-MHC 2 . Thus, investigations seeking dynamic mechanisms controlling positive selection have focused primarily on downstream signaling pathways. Indeed, the upper and lower affinity boundaries for peptide-MHC binding to TCR that encapsulate positively selecting TCRαβ signals are modulated by several downstream signaling mechanisms 3 , 4 , 5 , 6 , 7 , 8 , 9 . For example, the lower affinity boundary is regulated by Ca 2+ -mediated activation of calcineurin and the transcription factor NFAT 3 , 4 , and the upper boundary depends on the phosphorylation and subcellular localization of the kinase Erk 7 , 10 , Themis-mediated suppression of low-affinity peptide-MHC–TCR signals 11 and calcineurin-independent Ca 2+ flux 4 . CD4 or CD8 coreceptor-mediated delivery of the tyrosine kinase Lck to TCRαβ regulates both boundaries and is required for both positive and negative selection 12 , 13 , 14 . Post-translational modifications of the TCR complex provide an alternative mechanism to control positive selection by directly affecting binding of peptide-MHC and TCR and/or their interaction with coreceptors. The most common post-translational modification at the cell surface is glycosylation, but the functional role of this modification has not been explored in thymocyte selection. In peripheral T cells, the interaction of galectins with N-glycans attached to TCR, CD4 and CD8 forms a molecular lattice that negatively regulates agonist-induced TCR clustering at the immune synapse, thereby inhibiting Erk signaling induced by Lck, calcium flux and autoimmunity 15 , 16 , 17 , 18 , 19 . More generally, the degree of N-glycan branching (0–4 branches) and the number of N-glycans per protein molecule cooperate to regulate binding to galectins, thereby differentially controlling the clustering, concentration and endocytosis of multiple surface glycoproteins simultaneously 20 , 21 . Deletion of the Golgi branching enzyme N -acetylglucosaminyltranferase V (GlcNAcT-V, here referred to as Mgat5) weakens the galectin lattice and markedly increases TCR clustering and signaling at the immune synapse but does not alter thymocyte development 15 . Here we investigate this apparent paradox and report that N-glycan branching differentially controls TCR and the CD4 and CD8 coreceptors, thereby decoupling Lck-induced Erk signaling from Ca 2+ flux to simultaneously extend both the lower and upper affinity boundaries defining positive selection. In this manner, N-glycan branching bidirectionally expands the affinity range of interactions between peptide-MHC and TCR that result in positive selection. Results N-glycan branching during T cell development To first examine a potential regulatory role for N-glycan branching during thymocyte selection, we stained thymocytes with the plant lectin L-PHA, which binds specifically to β-1,6- N -acetylglucosamine (GlcNAc)-branched tri- and tetra-antennary N-glycans produced by the Mgat5 enzyme, and more generally, serves as a gauge of overall branching 15 , 22 ( Supplementary Fig. 1a ). Remarkable variation in L-PHA binding was present, oscillating by up to ∼ 15-fold in DN1–DN4 cells, increasing by ∼ 12-fold from DN4 to DP cells, then declining by approximately three- and sixfold in SP thymocytes and peripheral T cells, respectively ( Fig. 1a ). In contrast, using the plant lectin concanavalin A to evaluate expression of high-mannose N-glycans revealed little variability during thymocyte development ( Supplementary Fig. 1b ), which indicated that changes in branching are occurring largely without concomitant increases in high-mannose N-glycans. A ∼ 15–20% change in L-PHA binding is sufficient to alter peripheral TCR clustering and signaling, T cell growth and autoimmune risk 18 , 23 . Thus, the changes in branching are profound and suggest highly dynamic regulation of TCR clustering by branching throughout thymocyte development. Figure 1: N-glycan branching is required for T cell development. ( a ) Flow cytometric analysis of cell surface L-PHA binding on thymic subpopulations and splenic CD4 + and CD8 + T cells, normalized to SP CD4 thymocytes (left, histogram of a single mouse; right, average of 10 mice). DN thymocytes were gated as CD4 − CD8 − ; DN1 as CD25 lo CD44 hi ; DN2 as CD25 hi CD44 hi ; DN3 as CD25 hi CD44 lo ; and DN4 as CD25 lo CD44 lo ; n = 10 mice. Each symbol represents one mouse; small horizontal lines indicate the mean. ( b ) Histology of the thymus (cortex (C) and medulla (M)). ( c )", "role": "user" }, { "content": "Research by UC Irvine immunologists reveals new information about how our immune system functions, shedding light on a vital process that determines how the body's ability to fight infection develops. In the online version of Nature Immunology, neurology professor Dr. Michael Demetriou, postdoctoral scholar Raymond Zhou and other Institute for Immunology colleagues describe a critical mechanism underlying how T cells are created, selected and released into the bloodstream. A T cell is a type of blood cell called a lymphocyte that protects the body from infection. T cell precursors called thymocytes are created in the bone marrow and migrate to the thymus – a walnut-sized organ at the base of the neck – where they turn into T cells. However, very few thymocytes become fully functional T cells, and in the current study, the Demetriou team gained important new insights into why. As they transform into T cells, thymocytes grow receptors that react to an antigen (any substance provoking an immune response) that's bound to a small molecule called MHC. If this reaction is too strong or too weak, the thymocyte does not mature into a T cell. Demetriou and the others found that the delicate balance determining the proper reactive ability is controlled by glycosylation, a process in which a sugar attaches to a target protein to give the protein stability and form. They saw that changes in the addition of sugars to receptors – including the blocking of glycosylation – during T cell development profoundly influenced how thymocytes reacted to the MHC-bound antigens and whether they became mature T cells. Glycosylation also may help explain the creation of self-reactive T cells that escape from the thymus and can go on to attack the body's own antigens, a process called autoimmunity that's the basis of immune system disorders such as multiple sclerosis. \"Understanding how T cells are selected for antigen reactivity has been an enigma, and here we have made a major advance in understanding how this selection works,\" Demetriou said. The work, he added, represents a breakthrough in basic research and facilitates further discoveries about T cell processes that could someday yield new therapeutic approaches to infection and autoimmune 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 Positive selection of diverse yet self-tolerant thymocytes is vital to immunity and requires a limited degree of T cell antigen receptor (TCR) signaling in response to self peptide–major histocompatibility complexes (self peptide–MHCs). Affinity of newly generated TCR for peptide-MHC primarily sets the boundaries for positive selection. We report that N-glycan branching of TCR and the CD4 and CD8 coreceptors separately altered the upper and lower affinity boundaries from which interactions between peptide-MHC and TCR positively select T cells. During thymocyte development, N-glycan branching varied approximately 15-fold. N-glycan branching was required for positive selection and decoupled Lck signaling from TCR-driven Ca 2+ flux to simultaneously promote low-affinity peptide-MHC responses while inhibiting high-affinity ones. Therefore, N-glycan branching imposes a sliding scale on interactions between peptide-MHC and TCR that bidirectionally expands the affinity range for positive selection. Main The production of functional and self-tolerant T lymphocytes is vital for adaptive immunity and prevention of autoimmunity. Development of thymocytes progresses through four CD4 − CD8 − double-negative (DN) stages (DN1–DN4), a CD4 + CD8 + double-positive (DP) stage and a CD4 + or CD8 + single-positive (SP) stage 1 . Thymocytes must be surveyed for responsiveness and self-tolerance before exiting the thymus, where TCR interactions with self peptide–MHC have a crucial role 1 . Only intermediate TCR signals positively select self-tolerant SP thymocytes (positive selection) 1 . Thymocytes that do not receive sufficient basal TCR signaling die by neglect, whereas cells that encounter strong TCR signaling die by negative selection 1 . Positive selection of conventional MHC-restricted thymocytes is initiated by the binding of newly rearranged TCRαβ to peptide-MHC 1 . The strength of this interaction is a primary control point for positive selection and is often viewed as a static and linear function of differences in binding affinity between newly rearranged TCRαβ and peptide-MHC 2 . Thus, investigations seeking dynamic mechanisms controlling positive selection have focused primarily on downstream signaling pathways. Indeed, the upper and lower affinity boundaries for peptide-MHC binding to TCR that encapsulate positively selecting TCRαβ signals are modulated by several downstream signaling mechanisms 3 , 4 , 5 , 6 , 7 , 8 , 9 . For example, the lower affinity boundary is regulated by Ca 2+ -mediated activation of calcineurin and the transcription factor NFAT 3 , 4 , and the upper boundary depends on the phosphorylation and subcellular localization of the kinase Erk 7 , 10 , Themis-mediated suppression of low-affinity peptide-MHC–TCR signals 11 and calcineurin-independent Ca 2+ flux 4 . CD4 or CD8 coreceptor-mediated delivery of the tyrosine kinase Lck to TCRαβ regulates both boundaries and is required for both positive and negative selection 12 , 13 , 14 . Post-translational modifications of the TCR complex provide an alternative mechanism to control positive selection by directly affecting binding of peptide-MHC and TCR and/or their interaction with coreceptors. The most common post-translational modification at the cell surface is glycosylation, but the functional role of this modification has not been explored in thymocyte selection. In peripheral T cells, the interaction of galectins with N-glycans attached to TCR, CD4 and CD8 forms a molecular lattice that negatively regulates agonist-induced TCR clustering at the immune synapse, thereby inhibiting Erk signaling induced by Lck, calcium flux and autoimmunity 15 , 16 , 17 , 18 , 19 . More generally, the degree of N-glycan branching (0–4 branches) and the number of N-glycans per protein molecule cooperate to regulate binding to galectins, thereby differentially controlling the clustering, concentration and endocytosis of multiple surface glycoproteins simultaneously 20 , 21 . Deletion of the Golgi branching enzyme N -acetylglucosaminyltranferase V (GlcNAcT-V, here referred to as Mgat5) weakens the galectin lattice and markedly increases TCR clustering and signaling at the immune synapse but does not alter thymocyte development 15 . Here we investigate this apparent paradox and report that N-glycan branching differentially controls TCR and the CD4 and CD8 coreceptors, thereby decoupling Lck-induced Erk signaling from Ca 2+ flux to simultaneously extend both the lower and upper affinity boundaries defining positive selection. In this manner, N-glycan branching bidirectionally expands the affinity range of interactions between peptide-MHC and TCR that result in positive selection. Results N-glycan branching during T cell development To first examine a potential regulatory role for N-glycan branching during thymocyte selection, we stained thymocytes with the plant lectin L-PHA, which binds specifically to β-1,6- N -acetylglucosamine (GlcNAc)-branched tri- and tetra-antennary N-glycans produced by the Mgat5 enzyme, and more generally, serves as a gauge of overall branching 15 , 22 ( Supplementary Fig. 1a ). Remarkable variation in L-PHA binding was present, oscillating by up to ∼ 15-fold in DN1–DN4 cells, increasing by ∼ 12-fold from DN4 to DP cells, then declining by approximately three- and sixfold in SP thymocytes and peripheral T cells, respectively ( Fig. 1a ). In contrast, using the plant lectin concanavalin A to evaluate expression of high-mannose N-glycans revealed little variability during thymocyte development ( Supplementary Fig. 1b ), which indicated that changes in branching are occurring largely without concomitant increases in high-mannose N-glycans. A ∼ 15–20% change in L-PHA binding is sufficient to alter peripheral TCR clustering and signaling, T cell growth and autoimmune risk 18 , 23 . Thus, the changes in branching are profound and suggest highly dynamic regulation of TCR clustering by branching throughout thymocyte development. Figure 1: N-glycan branching is required for T cell development. ( a ) Flow cytometric analysis of cell surface L-PHA binding on thymic subpopulations and splenic CD4 + and CD8 + T cells, normalized to SP CD4 thymocytes (left, histogram of a single mouse; right, average of 10 mice). DN thymocytes were gated as CD4 − CD8 − ; DN1 as CD25 lo CD44 hi ; DN2 as CD25 hi CD44 hi ; DN3 as CD25 hi CD44 lo ; and DN4 as CD25 lo CD44 lo ; n = 10 mice. Each symbol represents one mouse; small horizontal lines indicate the mean. ( b ) Histology of the thymus (cortex (C) and medulla (M)). ( c )<|im_end|> <|im_start|>assistant Research by UC Irvine immunologists reveals new information about how our immune system functions, shedding light on a vital process that determines how the body's ability to fight infection develops. In the online version of Nature Immunology, neurology professor Dr. Michael Demetriou, postdoctoral scholar Raymond Zhou and other Institute for Immunology colleagues describe a critical mechanism underlying how T cells are created, selected and released into the bloodstream. A T cell is a type of blood cell called a lymphocyte that protects the body from infection. T cell precursors called thymocytes are created in the bone marrow and migrate to the thymus – a walnut-sized organ at the base of the neck – where they turn into T cells. However, very few thymocytes become fully functional T cells, and in the current study, the Demetriou team gained important new insights into why. As they transform into T cells, thymocytes grow receptors that react to an antigen (any substance provoking an immune response) that's bound to a small molecule called MHC. If this reaction is too strong or too weak, the thymocyte does not mature into a T cell. Demetriou and the others found that the delicate balance determining the proper reactive ability is controlled by glycosylation, a process in which a sugar attaches to a target protein to give the protein stability and form. They saw that changes in the addition of sugars to receptors – including the blocking of glycosylation – during T cell development profoundly influenced how thymocytes reacted to the MHC-bound antigens and whether they became mature T cells. Glycosylation also may help explain the creation of self-reactive T cells that escape from the thymus and can go on to attack the body's own antigens, a process called autoimmunity that's the basis of immune system disorders such as multiple sclerosis. "Understanding how T cells are selected for antigen reactivity has been an enigma, and here we have made a major advance in understanding how this selection works," Demetriou said. The work, he added, represents a breakthrough in basic research and facilitates further discoveries about T cell processes that could someday yield new therapeutic approaches to infection and autoimmune diseases. <|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 Freshwater lakes represent large methane sources that, in contrast to the Ocean, significantly contribute to non-anthropogenic methane emissions to the atmosphere. Particularly mixed lakes are major methane emitters, while permanently and seasonally stratified lakes with anoxic bottom waters are often characterized by strongly reduced methane emissions. The causes for this reduced methane flux from anoxic lake waters are not fully understood. Here we identified the microorganisms and processes responsible for the near complete consumption of methane in the anoxic waters of a permanently stratified lake, Lago di Cadagno. Interestingly, known anaerobic methanotrophs could not be detected in these waters. Instead, we found abundant gamma-proteobacterial aerobic methane-oxidizing bacteria active in the anoxic waters. In vitro incubations revealed that, among all the tested potential electron acceptors, only the addition of oxygen enhanced the rates of methane oxidation. An equally pronounced stimulation was also observed when the anoxic water samples were incubated in the light. Our combined results from molecular, biogeochemical and single-cell analyses indicate that methane removal at the anoxic chemocline of Lago di Cadagno is due to true aerobic oxidation of methane fuelled by in situ oxygen production by photosynthetic algae. A similar mechanism could be active in seasonally stratified lakes and marine basins such as the Black Sea, where light penetrates to the anoxic chemocline. Given the widespread occurrence of seasonally stratified anoxic lakes, aerobic methane oxidation coupled to oxygenic photosynthesis might have an important but so far neglected role in methane emissions from lakes. Introduction Freshwater lakes occupy only a small portion of the Earth’s surface and yet they contribute more non-anthropogenic methane to the atmosphere (up to 16%; Bastviken et al., 2004 ) than the Ocean (<1%; Rhee et al., 2009 ). The lower concentrations of sulphate in lake waters (mostly <0.2 m M ) compared with ocean waters (28 m M ) lead to enhanced degradation of organic material by methanogenesis, which is one of the main causes for higher methane emission from continental compared with marine aquatic systems. Additionally, aerobic and anaerobic methane oxidation processes act as a very efficient methane filter in marine sediments and water column (for example, Hinrichs and Boetius, 2002 ; Reeburgh, 2007 ). In contrast, the full variety of processes responsible for methane removal in lacustrine environments is not understood nor are the key microbial players known. Mixed lakes with oxygenated water columns exhibit high rates of methane oxidation at the sediment/water interface (for example, Lidstrom and Somers, 1984 ). Permanently or seasonally stratified lakes, on the other hand, show the highest rates of methane oxidation at and around the oxic/anoxic transition zone in the water column (for example, Blees et al., 2014 ). In all cases, the main methane-removing process from limnic systems is considered aerobic methane oxidation, fuelled by oxygen diffusion or intrusion events from the oxic water column. Methanotrophic microorganisms have a key role in reducing methane fluxes in oxic as well as in anoxic aquatic systems. Both bacteria and archaea possess the capacity to oxidize methane. At circumneutral pH, aerobic oxidation of methane is performed by methane-oxidizing bacteria (MOB) belonging to alpha- and gamma-proteobacteria (for a review, see Hanson and Hanson, 1996 and Trotsenko and Murrell, 2008 ). The biochemical pathway for methane oxidation employed by all known MOB involves soluble and/or particulate methane monooxygenase enzymes (sMMO and pMMO, respectively). This pathway is also utilized by the bacterium Candidatus Methylomirabilis oxyfera that can couple aerobic oxidation of methane to nitrite reduction to N 2 ( Raghoebarsing et al., 2006 ; Ettwig et al., 2008 ). Interestingly, this bacterium is found in anoxic habitats, because it has the capacity to generate oxygen intracellularly from NO x ( Ettwig et al., 2010 ). True anaerobic oxidation of methane (AOM) is performed by anaerobic methanotrophic archaea of which three different clades are known to date (ANME-1, -2 and -3). Most commonly reported AOM in the environment is directly coupled to reduction of sulphate and occurs in sulphate-rich marine sediments ( Hinrichs and Boetius, 2002 ; Knittel and Boetius, 2009 ; Milucka et al., 2012 ). Recently, it has been proposed that ANME-2 archaea belonging to a new family Candidatus ‘ Methanoperedenaceae ’ might also be capable of linking AOM to nitrate reduction to nitrite ( Haroon et al., 2013 ). The biochemical pathway of anaerobic oxidation of methane utilized by the ANME is fundamentally different from the aerobic one and employs a set of nine enzymes, with methyl-coenzyme M reductase (MCR) being the key enzyme-activating methane ( Scheller et al., 2010 ). AOM coupled to reduction of metal oxides (iron and manganese) was also proposed to occur in the ocean ( Beal et al., 2009 ; Wankel et al., 2012 ) and in lakes ( Sivan et al., 2011 ), but the mechanisms behind these processes and the responsible microorganisms have not yet been conclusively identified. We investigated methane oxidation in the permanently stratified water column of Lago di Cadagno. This meromictic lake, unlike non-stratified lakes, hosts a very efficient methane filter and high methane fluxes from the anoxic hypolimnion are nearly completely consumed just below the oxycline. The aim of our study was to identify the biogeochemical processes and microorganisms responsible for the methane consumption. Materials and methods Study site Lago di Cadagno is a meromictic lake located in the Piora valley in the southern Alps of Switzerland (1923 m altitude). Further lake and water characteristics are listed in Supplementary Material and Methods . Sampling Sampling was performed from a fixed platform. A SBE 19 CTD probe (Sea-Bird Electronics, Bellevue, WA, USA) equipped with oxygen and pH sensor (SBE 18 pH sensor, Sea-Bird Electronics, measurement range 0–14, accuracy 0.1 pH units) was used to measure conductivity, temperature, light transmission, pH, dissolved oxygen and turbidity. Additionally, micro-optodes (types PSt1 and TOS7 with 50- and 140-μm tip diameter, respectively, white optical isolation, PreSens, Regensburg, Germany) were used for online measurements of oxygen down to ca. 300 nmol l −1 (2009) and ca. 20 nmol l −1 (2011, 2013) to determine", "role": "user" }, { "content": "Methane emissions are strongly reduced in lakes with anoxic bottom waters. But here – contrary to what has previously been assumed – methane removal is not due to archaea or anaerobic bacteria. A new study on Lake Cadagno in Canton Ticino shows that the microorganisms responsible are aerobic proteobacteria. The oxygen they require is produced in situ by photosynthetic algae. In contrast to oceans, freshwater lakes – and tropical reservoirs – are significant sources of methane emissions. Methane, a greenhouse gas, arises from the degradation of organic material settling on the bottom. Although lakes occupy a much smaller proportion of the Earth's surface than oceans, they account for a much larger proportion of methane emissions. Well-mixed lakes, in turn, are the main contributors, while emissions from seasonally or permanently stratified lakes with anoxic bottom waters are greatly reduced. It has been assumed to date that the methane-removing processes occurring in such lakes are the same as those in marine systems. But a new study carried out on Lake Cadagno (Canton Ticino) by researchers from Eawag and the Max Planck Institute for Marine Microbiology (Bremen, Germany) shows that this is not the case. The scientists demonstrated that methane is almost completely consumed in the anoxic waters of Lake Cadagno, but they did not detect any known anaerobic methane-oxidizing bacteria – or archaea, which are responsible for marine methane oxidation. Instead, water samples collected from a depth of around 12 metres were found to contain abundant aerobic proteobacteria – up to 240,000 cells per millilitre. \"We wondered, of course, how these aerobic bacteria can survive in anoxic waters,\" says first author Jana Milucka of the Max Planck Institute for Marine Microbiology. To answer this question, the behaviour of the bacteria was investigated in laboratory experiments: methane oxidation was found to be stimulated only when oxygen was added to the samples incubated in vitro, or when they were exposed to light. The scientists concluded that the oxygen required by the bacteria is produced by photosynthesis in neighbouring diatoms. Analysis by fluorescence microscopy showed that methane-oxidizing bacteria belonging to the family Methylococcaceae occur in close proximity to diatoms and can thus utilize the oxygen they generate. Thanks to the combined activity of bacteria and diatoms, methane is thus consumed in the lake rather than being released into the atmosphere. This type of methane removal has not previously been described in freshwater systems. Project leader Carsten Schubert of Eawag comments: \"For lakes with anoxic layers, and also for certain marine zones, it looks as if the textbooks will have to be rewritten.\" Aerobic methane-oxidizing bacteria may play a significant role wherever sufficient light penetrates to anoxic water layers; according to Schubert, this is the case in most Swiss lakes. Similar observations have already been made in Lake Rotsee near Lucerne, in studies not yet published. Research will now focus on deeper lakes, where initial investigations suggest that different processes occur. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Freshwater lakes represent large methane sources that, in contrast to the Ocean, significantly contribute to non-anthropogenic methane emissions to the atmosphere. Particularly mixed lakes are major methane emitters, while permanently and seasonally stratified lakes with anoxic bottom waters are often characterized by strongly reduced methane emissions. The causes for this reduced methane flux from anoxic lake waters are not fully understood. Here we identified the microorganisms and processes responsible for the near complete consumption of methane in the anoxic waters of a permanently stratified lake, Lago di Cadagno. Interestingly, known anaerobic methanotrophs could not be detected in these waters. Instead, we found abundant gamma-proteobacterial aerobic methane-oxidizing bacteria active in the anoxic waters. In vitro incubations revealed that, among all the tested potential electron acceptors, only the addition of oxygen enhanced the rates of methane oxidation. An equally pronounced stimulation was also observed when the anoxic water samples were incubated in the light. Our combined results from molecular, biogeochemical and single-cell analyses indicate that methane removal at the anoxic chemocline of Lago di Cadagno is due to true aerobic oxidation of methane fuelled by in situ oxygen production by photosynthetic algae. A similar mechanism could be active in seasonally stratified lakes and marine basins such as the Black Sea, where light penetrates to the anoxic chemocline. Given the widespread occurrence of seasonally stratified anoxic lakes, aerobic methane oxidation coupled to oxygenic photosynthesis might have an important but so far neglected role in methane emissions from lakes. Introduction Freshwater lakes occupy only a small portion of the Earth’s surface and yet they contribute more non-anthropogenic methane to the atmosphere (up to 16%; Bastviken et al., 2004 ) than the Ocean (<1%; Rhee et al., 2009 ). The lower concentrations of sulphate in lake waters (mostly <0.2 m M ) compared with ocean waters (28 m M ) lead to enhanced degradation of organic material by methanogenesis, which is one of the main causes for higher methane emission from continental compared with marine aquatic systems. Additionally, aerobic and anaerobic methane oxidation processes act as a very efficient methane filter in marine sediments and water column (for example, Hinrichs and Boetius, 2002 ; Reeburgh, 2007 ). In contrast, the full variety of processes responsible for methane removal in lacustrine environments is not understood nor are the key microbial players known. Mixed lakes with oxygenated water columns exhibit high rates of methane oxidation at the sediment/water interface (for example, Lidstrom and Somers, 1984 ). Permanently or seasonally stratified lakes, on the other hand, show the highest rates of methane oxidation at and around the oxic/anoxic transition zone in the water column (for example, Blees et al., 2014 ). In all cases, the main methane-removing process from limnic systems is considered aerobic methane oxidation, fuelled by oxygen diffusion or intrusion events from the oxic water column. Methanotrophic microorganisms have a key role in reducing methane fluxes in oxic as well as in anoxic aquatic systems. Both bacteria and archaea possess the capacity to oxidize methane. At circumneutral pH, aerobic oxidation of methane is performed by methane-oxidizing bacteria (MOB) belonging to alpha- and gamma-proteobacteria (for a review, see Hanson and Hanson, 1996 and Trotsenko and Murrell, 2008 ). The biochemical pathway for methane oxidation employed by all known MOB involves soluble and/or particulate methane monooxygenase enzymes (sMMO and pMMO, respectively). This pathway is also utilized by the bacterium Candidatus Methylomirabilis oxyfera that can couple aerobic oxidation of methane to nitrite reduction to N 2 ( Raghoebarsing et al., 2006 ; Ettwig et al., 2008 ). Interestingly, this bacterium is found in anoxic habitats, because it has the capacity to generate oxygen intracellularly from NO x ( Ettwig et al., 2010 ). True anaerobic oxidation of methane (AOM) is performed by anaerobic methanotrophic archaea of which three different clades are known to date (ANME-1, -2 and -3). Most commonly reported AOM in the environment is directly coupled to reduction of sulphate and occurs in sulphate-rich marine sediments ( Hinrichs and Boetius, 2002 ; Knittel and Boetius, 2009 ; Milucka et al., 2012 ). Recently, it has been proposed that ANME-2 archaea belonging to a new family Candidatus ‘ Methanoperedenaceae ’ might also be capable of linking AOM to nitrate reduction to nitrite ( Haroon et al., 2013 ). The biochemical pathway of anaerobic oxidation of methane utilized by the ANME is fundamentally different from the aerobic one and employs a set of nine enzymes, with methyl-coenzyme M reductase (MCR) being the key enzyme-activating methane ( Scheller et al., 2010 ). AOM coupled to reduction of metal oxides (iron and manganese) was also proposed to occur in the ocean ( Beal et al., 2009 ; Wankel et al., 2012 ) and in lakes ( Sivan et al., 2011 ), but the mechanisms behind these processes and the responsible microorganisms have not yet been conclusively identified. We investigated methane oxidation in the permanently stratified water column of Lago di Cadagno. This meromictic lake, unlike non-stratified lakes, hosts a very efficient methane filter and high methane fluxes from the anoxic hypolimnion are nearly completely consumed just below the oxycline. The aim of our study was to identify the biogeochemical processes and microorganisms responsible for the methane consumption. Materials and methods Study site Lago di Cadagno is a meromictic lake located in the Piora valley in the southern Alps of Switzerland (1923 m altitude). Further lake and water characteristics are listed in Supplementary Material and Methods . Sampling Sampling was performed from a fixed platform. A SBE 19 CTD probe (Sea-Bird Electronics, Bellevue, WA, USA) equipped with oxygen and pH sensor (SBE 18 pH sensor, Sea-Bird Electronics, measurement range 0–14, accuracy 0.1 pH units) was used to measure conductivity, temperature, light transmission, pH, dissolved oxygen and turbidity. Additionally, micro-optodes (types PSt1 and TOS7 with 50- and 140-μm tip diameter, respectively, white optical isolation, PreSens, Regensburg, Germany) were used for online measurements of oxygen down to ca. 300 nmol l −1 (2009) and ca. 20 nmol l −1 (2011, 2013) to determine<|im_end|> <|im_start|>assistant Methane emissions are strongly reduced in lakes with anoxic bottom waters. But here – contrary to what has previously been assumed – methane removal is not due to archaea or anaerobic bacteria. A new study on Lake Cadagno in Canton Ticino shows that the microorganisms responsible are aerobic proteobacteria. The oxygen they require is produced in situ by photosynthetic algae. In contrast to oceans, freshwater lakes – and tropical reservoirs – are significant sources of methane emissions. Methane, a greenhouse gas, arises from the degradation of organic material settling on the bottom. Although lakes occupy a much smaller proportion of the Earth's surface than oceans, they account for a much larger proportion of methane emissions. Well-mixed lakes, in turn, are the main contributors, while emissions from seasonally or permanently stratified lakes with anoxic bottom waters are greatly reduced. It has been assumed to date that the methane-removing processes occurring in such lakes are the same as those in marine systems. But a new study carried out on Lake Cadagno (Canton Ticino) by researchers from Eawag and the Max Planck Institute for Marine Microbiology (Bremen, Germany) shows that this is not the case. The scientists demonstrated that methane is almost completely consumed in the anoxic waters of Lake Cadagno, but they did not detect any known anaerobic methane-oxidizing bacteria – or archaea, which are responsible for marine methane oxidation. Instead, water samples collected from a depth of around 12 metres were found to contain abundant aerobic proteobacteria – up to 240,000 cells per millilitre. "We wondered, of course, how these aerobic bacteria can survive in anoxic waters," says first author Jana Milucka of the Max Planck Institute for Marine Microbiology. To answer this question, the behaviour of the bacteria was investigated in laboratory experiments: methane oxidation was found to be stimulated only when oxygen was added to the samples incubated in vitro, or when they were exposed to light. The scientists concluded that the oxygen required by the bacteria is produced by photosynthesis in neighbouring diatoms. Analysis by fluorescence microscopy showed that methane-oxidizing bacteria belonging to the family Methylococcaceae occur in close proximity to diatoms and can thus utilize the oxygen they generate. Thanks to the combined activity of bacteria and diatoms, methane is thus consumed in the lake rather than being released into the atmosphere. This type of methane removal has not previously been described in freshwater systems. Project leader Carsten Schubert of Eawag comments: "For lakes with anoxic layers, and also for certain marine zones, it looks as if the textbooks will have to be rewritten." Aerobic methane-oxidizing bacteria may play a significant role wherever sufficient light penetrates to anoxic water layers; according to Schubert, this is the case in most Swiss lakes. Similar observations have already been made in Lake Rotsee near Lucerne, in studies not yet published. Research will now focus on deeper lakes, where initial investigations suggest that different processes occur. <|im_end|>

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304, 297, 14668, 439, 1664, 439, 304, 459, 82329, 72491, 6067, 13, 11995, 24032, 323, 39211, 64, 15575, 279, 8824, 311, 36172, 553, 61083, 13, 2468, 10408, 60668, 37143, 11, 91490, 71162, 315, 61083, 374, 10887, 555, 61083, 12, 85078, 4954, 24032, 320, 10754, 33, 8, 33152, 311, 8451, 12, 323, 22350, 10039, 668, 677, 78852, 320, 2000, 264, 3477, 11, 1518, 76313, 323, 76313, 11, 220, 2550, 21, 323, 19881, 2641, 56155, 323, 386, 852, 657, 11, 220, 1049, 23, 7609, 578, 93532, 38970, 369, 61083, 71162, 20011, 555, 682, 3967, 11672, 33, 18065, 88045, 323, 5255, 2598, 6468, 61083, 1647, 2689, 19472, 521, 56067, 320, 82, 8195, 46, 323, 281, 8195, 46, 11, 15947, 570, 1115, 38970, 374, 1101, 34716, 555, 279, 17854, 2411, 94916, 1015, 386, 42972, 316, 404, 13052, 285, 99690, 809, 64, 430, 649, 5743, 91490, 71162, 315, 61083, 311, 25719, 1269, 14278, 311, 452, 220, 17, 320, 51359, 6292, 3141, 29698, 1880, 453, 2637, 220, 1049, 21, 2652, 469, 5683, 38022, 1880, 453, 2637, 220, 1049, 23, 7609, 58603, 11, 420, 17854, 2411, 374, 1766, 304, 459, 82329, 71699, 11, 1606, 433, 706, 279, 8824, 311, 7068, 24463, 10805, 65441, 398, 505, 5782, 865, 320, 469, 5683, 38022, 1880, 453, 2637, 220, 679, 15, 7609, 3082, 41390, 261, 31906, 71162, 315, 61083, 320, 32, 1937, 8, 374, 10887, 555, 41390, 261, 31906, 21747, 276, 354, 42810, 39211, 64, 315, 902, 2380, 2204, 1206, 3536, 527, 3967, 311, 2457, 320, 1111, 7614, 12, 16, 11, 482, 17, 323, 482, 18, 570, 7648, 17037, 5068, 362, 1937, 304, 279, 4676, 374, 6089, 34356, 311, 14278, 315, 83778, 349, 323, 13980, 304, 83778, 349, 41947, 29691, 11163, 12843, 320, 50733, 14172, 82, 323, 2577, 295, 9334, 11, 220, 1049, 17, 2652, 13934, 96383, 323, 2577, 295, 9334, 11, 220, 1049, 24, 2652, 10357, 1983, 64, 1880, 453, 2637, 220, 679, 17, 7609, 42096, 11, 433, 706, 1027, 11223, 430, 2147, 7614, 12, 17, 39211, 64, 33152, 311, 264, 502, 3070, 94916, 1015, 3451, 57175, 276, 3376, 14466, 114785, 18217, 2643, 1101, 387, 13171, 315, 31799, 362, 1937, 311, 25719, 7853, 14278, 311, 25719, 1269, 320, 5340, 9186, 1880, 453, 2637, 220, 679, 18, 7609, 578, 93532, 38970, 315, 41390, 261, 31906, 71162, 315, 61083, 34716, 555, 279, 2147, 7614, 374, 43593, 2204, 505, 279, 91490, 832, 323, 51242, 264, 743, 315, 11888, 56067, 11, 449, 79574, 23283, 65728, 386, 312, 1076, 521, 320, 44, 9150, 8, 1694, 279, 1401, 49242, 12, 9035, 1113, 61083, 320, 5124, 7218, 1880, 453, 2637, 220, 679, 15, 7609, 362, 1937, 34356, 311, 14278, 315, 9501, 19488, 3422, 320, 2534, 323, 87934, 8, 574, 1101, 11223, 311, 12446, 304, 279, 18435, 320, 2893, 278, 1880, 453, 2637, 220, 1049, 24, 2652, 468, 1201, 301, 1880, 453, 2637, 220, 679, 17, 883, 323, 304, 44236, 320, 328, 28422, 1880, 453, 2637, 220, 679, 16, 7026, 719, 279, 24717, 4920, 1521, 11618, 323, 279, 8647, 8162, 76991, 617, 539, 3686, 1027, 84082, 3210, 11054, 13, 1226, 27313, 61083, 71162, 304, 279, 31859, 44397, 1908, 3090, 3330, 315, 445, 6438, 1891, 33160, 351, 2201, 13, 1115, 4809, 316, 858, 292, 22553, 11, 20426, 2536, 42728, 266, 1908, 44236, 11, 18939, 264, 1633, 11297, 61083, 4141, 323, 1579, 61083, 31405, 288, 505, 279, 459, 82329, 9950, 337, 318, 77, 290, 527, 7154, 6724, 27073, 1120, 3770, 279, 99690, 89034, 13, 578, 9395, 315, 1057, 4007, 574, 311, 10765, 279, 6160, 540, 25634, 32056, 11618, 323, 8162, 76991, 8647, 369, 279, 61083, 15652, 13, 32009, 323, 5528, 19723, 2816, 445, 6438, 1891, 33160, 351, 2201, 374, 264, 4809, 316, 858, 292, 22553, 7559, 304, 279, 393, 2521, 64, 34681, 304, 279, 18561, 94000, 315, 30221, 320, 5926, 18, 296, 36958, 570, 15903, 22553, 323, 3090, 17910, 527, 10212, 304, 99371, 10441, 323, 19331, 662, 96409, 96409, 574, 10887, 505, 264, 8521, 5452, 13, 362, 328, 11855, 220, 777, 356, 17417, 22477, 320, 60261, 7826, 2668, 38784, 11, 86705, 361, 11, 29666, 11, 7427, 8, 19167, 449, 24463, 323, 37143, 12271, 320, 50, 11855, 220, 972, 37143, 12271, 11, 15379, 7826, 2668, 38784, 11, 19179, 2134, 220, 15, 4235, 975, 11, 13708, 220, 15, 13, 16, 37143, 8316, 8, 574, 1511, 311, 6767, 98971, 11, 9499, 11, 3177, 18874, 11, 37143, 11, 56767, 24463, 323, 29112, 19025, 13, 23212, 11, 8162, 57212, 2601, 320, 9426, 393, 626, 16, 323, 350, 3204, 22, 449, 220, 1135, 12, 323, 220, 6860, 12, 44223, 76, 11813, 23899, 11, 15947, 11, 4251, 29393, 31398, 11, 5075, 50, 729, 11, 3263, 78029, 11, 10057, 8, 1051, 1511, 369, 2930, 22323, 315, 24463, 1523, 311, 2211, 13, 220, 3101, 26807, 337, 326, 25173, 16, 320, 1049, 24, 8, 323, 2211, 13, 220, 508, 26807, 337, 326, 25173, 16, 320, 679, 16, 11, 220, 679, 18, 8, 311, 8417, 128257, 198, 128256, 78191, 198, 44, 774, 2194, 20748, 527, 16917, 11293, 304, 44236, 449, 459, 82329, 5740, 21160, 13, 2030, 1618, 1389, 26102, 311, 1148, 706, 8767, 1027, 19655, 1389, 61083, 17065, 374, 539, 4245, 311, 39211, 64, 477, 41390, 261, 31906, 24032, 13, 362, 502, 4007, 389, 11940, 33160, 351, 2201, 304, 73466, 79526, 3394, 5039, 430, 279, 8162, 76991, 8647, 527, 91490, 5541, 677, 78852, 13, 578, 24463, 814, 1397, 374, 9124, 304, 10109, 555, 7397, 1910, 18015, 68951, 13, 763, 13168, 311, 54280, 11, 80744, 44236, 1389, 323, 35148, 45512, 82, 1389, 527, 5199, 8336, 315, 61083, 20748, 13, 57175, 2194, 11, 264, 37647, 6962, 11, 48282, 505, 279, 53568, 315, 17808, 3769, 52945, 389, 279, 5740, 13, 10541, 44236, 48678, 264, 1790, 9333, 21801, 315, 279, 9420, 596, 7479, 1109, 54280, 11, 814, 2759, 369, 264, 1790, 8294, 21801, 315, 61083, 20748, 13, 8489, 1474, 3366, 44236, 11, 304, 2543, 11, 527, 279, 1925, 20965, 11, 1418, 20748, 505, 3280, 750, 477, 31859, 44397, 1908, 44236, 449, 459, 82329, 5740, 21160, 527, 19407, 11293, 13, 1102, 706, 1027, 19655, 311, 2457, 430, 279, 61083, 12, 1864, 9308, 11618, 31965, 304, 1778, 44236, 527, 279, 1890, 439, 1884, 304, 29691, 6067, 13, 2030, 264, 502, 4007, 11953, 704, 389, 11940, 33160, 351, 2201, 320, 34, 32054, 79526, 3394, 8, 555, 12074, 505, 469, 675, 351, 323, 279, 7639, 9878, 377, 10181, 369, 23820, 18654, 81162, 320, 33, 62969, 11, 10057, 8, 5039, 430, 420, 374, 539, 279, 1162, 13, 578, 14248, 21091, 430, 61083, 374, 4661, 6724, 27073, 304, 279, 459, 82329, 21160, 315, 11940, 33160, 351, 2201, 11, 719, 814, 1550, 539, 11388, 904, 3967, 41390, 261, 31906, 61083, 12, 85078, 4954, 24032, 1389, 477, 39211, 64, 11, 902, 527, 8647, 369, 29691, 61083, 71162, 13, 12361, 11, 3090, 10688, 14890, 505, 264, 8149, 315, 2212, 220, 717, 37356, 1051, 1766, 311, 6782, 44611, 91490, 5541, 677, 78852, 1389, 709, 311, 220, 8273, 11, 931, 7917, 824, 2606, 3748, 265, 13, 330, 1687, 31156, 11, 315, 3388, 11, 1268, 1521, 91490, 24032, 649, 18167, 304, 459, 82329, 21160, 1359, 2795, 1176, 3229, 118870, 10357, 1983, 64, 315, 279, 7639, 9878, 377, 10181, 369, 23820, 18654, 81162, 13, 2057, 4320, 420, 3488, 11, 279, 17432, 315, 279, 24032, 574, 27313, 304, 27692, 21896, 25, 61083, 71162, 574, 1766, 311, 387, 81471, 1193, 994, 24463, 574, 3779, 311, 279, 10688, 49727, 660, 304, 55004, 11, 477, 994, 814, 1051, 15246, 311, 3177, 13, 578, 14248, 20536, 430, 279, 24463, 2631, 555, 279, 24032, 374, 9124, 555, 7397, 74767, 304, 62027, 1891, 66650, 13, 18825, 555, 97332, 92914, 8710, 430, 61083, 12, 85078, 4954, 24032, 33152, 311, 279, 3070, 57175, 88, 1092, 14310, 114785, 12446, 304, 3345, 37843, 311, 1891, 66650, 323, 649, 8617, 29166, 279, 24463, 814, 7068, 13, 11361, 311, 279, 11093, 5820, 315, 24032, 323, 1891, 66650, 11, 61083, 374, 8617, 27073, 304, 279, 22553, 4856, 1109, 1694, 6004, 1139, 279, 16975, 13, 1115, 955, 315, 61083, 17065, 706, 539, 8767, 1027, 7633, 304, 80744, 6067, 13, 5907, 7808, 3341, 16172, 5124, 392, 531, 315, 469, 675, 351, 6170, 25, 330, 2520, 44236, 449, 459, 82329, 13931, 11, 323, 1101, 369, 3738, 29691, 26467, 11, 433, 5992, 439, 422, 279, 65303, 690, 617, 311, 387, 59624, 1210, 64150, 31906, 61083, 12, 85078, 4954, 24032, 1253, 1514, 264, 5199, 3560, 28578, 14343, 3177, 44805, 988, 311, 459, 82329, 3090, 13931, 26, 4184, 311, 5124, 392, 531, 11, 420, 374, 279, 1162, 304, 1455, 30791, 44236, 13, 22196, 24654, 617, 2736, 1027, 1903, 304, 11940, 28460, 4151, 3221, 14103, 68495, 11, 304, 7978, 539, 3686, 4756, 13, 8483, 690, 1457, 5357, 389, 19662, 44236, 11, 1405, 2926, 26969, 4284, 430, 2204, 11618, 12446, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The origin of motility in bilaterian animals represents an evolutionary innovation that transformed the Earth system. This innovation probably occurred in the late Ediacaran period—as evidenced by an abundance of trace fossils (ichnofossils) dating to this time, which include trails, trackways and burrows 1 , 2 , 3 . However, with few exceptions 4 , 5 , 6 , 7 , 8 , the producers of most of the late Ediacaran ichnofossils are unknown, which has resulted in a disconnection between the body- and trace-fossil records. Here we describe the fossil of a bilaterian of the terminal Ediacaran period (dating to 551–539 million years ago), which we name Yilingia spiciformis (gen. et sp. nov). This body fossil is preserved along with the trail that the animal produced during a death march. Yilingia is an elongate and segmented bilaterian with repetitive and trilobate body units, each of which consists of a central lobe and two posteriorly pointing lateral lobes, indicating body and segment polarity. Yilingia is possibly related to panarthropods or annelids, and sheds light on the origin of segmentation in bilaterians. As one of the few Ediacaran animals demonstrated to have produced long and continuous trails, Yilingia provides insights into the identity of the animals that were responsible for Ediacaran trace fossils. Main Molecular clock estimates predict that bilaterian animals diverged in the Cryogenian or Ediacaran period, and many bilaterian clades had diverged before the close of the Ediacaran period 9 , 10 . If correct, these estimates mandate the existence of motile bilaterians in the Ediacaran period. In part, this prediction is met by trace fossils from the late Ediacaran period, which include many tracks, trails and burrows 1 , 2 , 3 . However, the phylogenetic importance of these ichnofossils is limited by the dearth of morphological details regarding the animals that produced them. To date, only a few Ediacaran taxa— Dickinsonia 4 , 5 , Kimberella 6 , 7 and Yorgia 8 —have been demonstrated to be capable of movement and producing trace fossils. For these genera, evidence for motility comes from trace fossils (known as mortichnia) that are produced shortly before death and are preserved together with the producers of the traces 11 . However, these Ediacaran organisms mostly produced discrete and isolated footprints or radula marks; so far, only Kimberella is known to be capable of producing continuous trails 12 . Thus, the identity of the producer(s) of most of the long and continuous trails that date to the Ediacaran period remains unknown. This limited knowledge about motile Ediacaran bilaterians greatly undermines our efforts to grasp the biological basis for a transformative evolutionary innovation that ultimately led to the Cambrian substrate and agronomic revolutions 13 , 14 , which has had lasting effects on the evolution of the Earth surface system 15 , 16 . Here we report Yilingia spiciformis (gen. et sp. nov), an animal fossil from the terminal Ediacaran Shibantan Member of the Dengying Formation (dated to 551–539 million years ago) 17 , 18 (Extended Data Fig. 1 ) of the Yangtze Gorges area (South China). Y. spiciformis is preserved with its locomotion traces, including a mortichnium. It is an elongate bilaterian animal that shows evidence of body segmentation, segment polarity and directional locomotion. Yilingia offers critical insights into the identity of Ediacaran trace makers as well as the early evolution of body segmentation and bilaterian motility. Yilingia gen. nov. Etymology . Yilinigia is derived from the Yiling district, in which the fossil locality is located. Diagnosis . Diagnosis is as for the type species. Yilingia spiciformis gen. et sp. nov. (Fig. 1 , Extended Data Figs. 4 , 5 , 7 ) Fig. 1: Body fossils and associated mortichnium of Y. spiciformis . a – c , Holotype body fossil (specimen NIGP-166252). Panels a and b are the part and counterpart (matching by yellow brackets) on bed top and bed sole, respectively. c , Enlargement of area in white rectangle in a , showing segmentation, trilobation and polarity. Note the lateral lobes with podomere-like segments (white arrows). d , Incomplete body fossil of the posterior end, convex preservation on bed sole (specimen NIGP-166258). e , Thin section perpendicular to bedding surface and along dotted yellow line in d . Note the biconvex transverse cross-section of the fossil (outlined by dotted line). f , Body fossil (convex preservation, blue bracket) and associated mortichnium (white bracket) on bed sole (specimen NIGP-166253). Note the mortichnium with lateral grooves (arrows) that truncate primary bedding-surface structures and smaller trace fossils (white arrowhead, probably Helminthoidichnites ). g , Thin section perpendicular to bedding surface and along dotted line in f . The illustrated specimens were selected from a total of 48 specimens in the collection. Red symbols denote stratigraphic orientation: inverted ‘T’ denotes the bed sole; ‘T’ denotes the bed top; and the upward-pointing arrow denotes the stratigraphic up-direction. Scale bars, 2 cm ( a , b , d ), 1 cm ( c , e ), 5 cm ( f ), 0.5 cm ( g ). Full size image Etymology . Spiciformis is derived from spiciform, with reference to the spiky appearance of the fossil, which resembles ears of wheat. Holotype . NIGP-166252 (Fig. 1a–c ) body fossil, deposited in the Nanjing Institute of Geology and Palaeontology (Nanjing, China). Referred material . In addition to the holotype, 34 body fossils and 13 trace fossils were examined (Supplementary Table 1 ), of which the body fossils are referred to this species. Illustrated fossils are deposited in the Nanjing Institute of Geology and Palaeontology (accession numbers NIGP-166253 to NIGP-166258, NIGP-169870), but NIGP-169869 is currently left on the outcrop at Wuhe village (Yichang, Hubei province, China). Locality and horizon . Terminal Ediacaran Shibantan Member, Dengying Formation, Yangtze Gorges area (South China). Diagnosis . An elongate, segmented and soft-bodied bilaterian animal with repetitive trilobate body units, each of which consists of a rhomboidal central lobe and two subtriangular lateral lobes that are consistently directed towards one end of the body", "role": "user" }, { "content": "In a remarkable evolutionary discovery, a team of scientists co-led by a Virginia Tech geoscientist has discovered what could be among the first trails made by animals on the surface of the Earth roughly a half-billion years ago. Shuhai Xiao, a professor of geosciences with the Virginia Tech College of Science, calls the unearthed fossils, including the bodies and trails left by an ancient animal species, the most convincing sign of ancient animal mobility, dating back about 550 million years. Named Yilingia spiciformis—that translates to spiky Yiling bug, Yiling being the Chinese city near the discovery site—the animal was found in multiple layers of rock by Xiao and Zhe Chen, Chuanming Zhou, and Xunlai Yuan from the Chinese Academy of Sciences' Nanjing Institute of Geology and Palaeontology. The findings are published in the latest issue of Nature. The trials are from the same rock unit and are roughly the same age as bug-like footprints found by Xiao and his team in a series of digs from 2013 to 2018 in the Yangtze Gorges area of southern China, and date back to the Ediacaran Period, well before the age of dinosaurs or even the Pangea supercontinent. What sets this find apart: The preserved fossil of the animal that made the trail versus the unknowable guesswork where the body has not been preserved. \"This discovery shows that segmented and mobile animals evolved by 550 million years ago,\" Xiao said. \"Mobility made it possible for animals to make an unmistakable footprint on Earth, both literally and metaphorically. Those are the kind of features you find in a group of animals called bilaterans. This group includes us humans and most animals. Animals and particularly humans are movers and shakers on Earth. Their ability to shape the face of the planet is ultimately tied to the origin of animal motility.\" Animation of the 550-million-year-old animal Yilingia spiciformis and its locomotion trails. These fossils shed new light on the evolution of animal mobility and body segmentation. Credit: Dr. Zhe Chen at Nanjing Institute of Geology and Paleontology The animal was a millipede-like creature a quarter-inch to an inch wide and up to 4 inches long that alternately dragged its body across the muddy ocean floor and rested along the way, leaving trails as loing as 23 inches. The animal was an elongated narrow creature, with 50 or so body segments, a left and right side, a back and belly, and a head and a tail. The origin of bilaterally symmetric animals—known as bilaterians—with segmented bodies and directional mobility is a monumental event in early animal evolution, and is estimated to have occurred the Ediacaran Period, between 635 and 539 million years ago. But until this finding by Xiao and his team, there was no convincing fossil evidence to substantiate those estimates. One of the recovered specimens is particularly vital because the animal and the trail it produced just before its death are preserved together. A fossilized trail of the animal Yilingia spiciformis, dating back 550 million years. The trail was found in China by a team of scientists including Shuhai Xiao of the Virginia Tech College of Science. Credit: Virginia Tech College of Science Remarkably, the find also marks what may be the first sign of decision making among animals—the trails suggest an effort to move toward or away from something, perhaps under the direction of a sophisticated central nerve system, Xiao said. The mobility of animals led to environmental and ecological impacts on the Earth surface system and ultimately led to the Cambrian substrate and agronomic revolutions, he said. \"We are the most impactful animal on Earth,\" added Xiao, also an affiliated member of the Global Change Center at Virginia Tech. \"We make a huge footprint, not only from locomotion, but in many other and more impactful activities related to our ability to move. When and how animal locomotion evolved defines an important geological and evolutionary context of anthropogenic impact on the surface of the Earth.\" Rachel Wood, a professor in the School of GeoSciences at University of Edinburgh in Scotland, who was not involved with the study, said, \"This is a remarkable finding of highly significant fossils. We now have evidence that segmented animals were present and had gained an ability to move across the sea floor before the Cambrian, and more notably we can tie the actual trace-maker to the trace. Such preservation is unusual and provides considerable insight into a major step in the evolution of 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 The origin of motility in bilaterian animals represents an evolutionary innovation that transformed the Earth system. This innovation probably occurred in the late Ediacaran period—as evidenced by an abundance of trace fossils (ichnofossils) dating to this time, which include trails, trackways and burrows 1 , 2 , 3 . However, with few exceptions 4 , 5 , 6 , 7 , 8 , the producers of most of the late Ediacaran ichnofossils are unknown, which has resulted in a disconnection between the body- and trace-fossil records. Here we describe the fossil of a bilaterian of the terminal Ediacaran period (dating to 551–539 million years ago), which we name Yilingia spiciformis (gen. et sp. nov). This body fossil is preserved along with the trail that the animal produced during a death march. Yilingia is an elongate and segmented bilaterian with repetitive and trilobate body units, each of which consists of a central lobe and two posteriorly pointing lateral lobes, indicating body and segment polarity. Yilingia is possibly related to panarthropods or annelids, and sheds light on the origin of segmentation in bilaterians. As one of the few Ediacaran animals demonstrated to have produced long and continuous trails, Yilingia provides insights into the identity of the animals that were responsible for Ediacaran trace fossils. Main Molecular clock estimates predict that bilaterian animals diverged in the Cryogenian or Ediacaran period, and many bilaterian clades had diverged before the close of the Ediacaran period 9 , 10 . If correct, these estimates mandate the existence of motile bilaterians in the Ediacaran period. In part, this prediction is met by trace fossils from the late Ediacaran period, which include many tracks, trails and burrows 1 , 2 , 3 . However, the phylogenetic importance of these ichnofossils is limited by the dearth of morphological details regarding the animals that produced them. To date, only a few Ediacaran taxa— Dickinsonia 4 , 5 , Kimberella 6 , 7 and Yorgia 8 —have been demonstrated to be capable of movement and producing trace fossils. For these genera, evidence for motility comes from trace fossils (known as mortichnia) that are produced shortly before death and are preserved together with the producers of the traces 11 . However, these Ediacaran organisms mostly produced discrete and isolated footprints or radula marks; so far, only Kimberella is known to be capable of producing continuous trails 12 . Thus, the identity of the producer(s) of most of the long and continuous trails that date to the Ediacaran period remains unknown. This limited knowledge about motile Ediacaran bilaterians greatly undermines our efforts to grasp the biological basis for a transformative evolutionary innovation that ultimately led to the Cambrian substrate and agronomic revolutions 13 , 14 , which has had lasting effects on the evolution of the Earth surface system 15 , 16 . Here we report Yilingia spiciformis (gen. et sp. nov), an animal fossil from the terminal Ediacaran Shibantan Member of the Dengying Formation (dated to 551–539 million years ago) 17 , 18 (Extended Data Fig. 1 ) of the Yangtze Gorges area (South China). Y. spiciformis is preserved with its locomotion traces, including a mortichnium. It is an elongate bilaterian animal that shows evidence of body segmentation, segment polarity and directional locomotion. Yilingia offers critical insights into the identity of Ediacaran trace makers as well as the early evolution of body segmentation and bilaterian motility. Yilingia gen. nov. Etymology . Yilinigia is derived from the Yiling district, in which the fossil locality is located. Diagnosis . Diagnosis is as for the type species. Yilingia spiciformis gen. et sp. nov. (Fig. 1 , Extended Data Figs. 4 , 5 , 7 ) Fig. 1: Body fossils and associated mortichnium of Y. spiciformis . a – c , Holotype body fossil (specimen NIGP-166252). Panels a and b are the part and counterpart (matching by yellow brackets) on bed top and bed sole, respectively. c , Enlargement of area in white rectangle in a , showing segmentation, trilobation and polarity. Note the lateral lobes with podomere-like segments (white arrows). d , Incomplete body fossil of the posterior end, convex preservation on bed sole (specimen NIGP-166258). e , Thin section perpendicular to bedding surface and along dotted yellow line in d . Note the biconvex transverse cross-section of the fossil (outlined by dotted line). f , Body fossil (convex preservation, blue bracket) and associated mortichnium (white bracket) on bed sole (specimen NIGP-166253). Note the mortichnium with lateral grooves (arrows) that truncate primary bedding-surface structures and smaller trace fossils (white arrowhead, probably Helminthoidichnites ). g , Thin section perpendicular to bedding surface and along dotted line in f . The illustrated specimens were selected from a total of 48 specimens in the collection. Red symbols denote stratigraphic orientation: inverted ‘T’ denotes the bed sole; ‘T’ denotes the bed top; and the upward-pointing arrow denotes the stratigraphic up-direction. Scale bars, 2 cm ( a , b , d ), 1 cm ( c , e ), 5 cm ( f ), 0.5 cm ( g ). Full size image Etymology . Spiciformis is derived from spiciform, with reference to the spiky appearance of the fossil, which resembles ears of wheat. Holotype . NIGP-166252 (Fig. 1a–c ) body fossil, deposited in the Nanjing Institute of Geology and Palaeontology (Nanjing, China). Referred material . In addition to the holotype, 34 body fossils and 13 trace fossils were examined (Supplementary Table 1 ), of which the body fossils are referred to this species. Illustrated fossils are deposited in the Nanjing Institute of Geology and Palaeontology (accession numbers NIGP-166253 to NIGP-166258, NIGP-169870), but NIGP-169869 is currently left on the outcrop at Wuhe village (Yichang, Hubei province, China). Locality and horizon . Terminal Ediacaran Shibantan Member, Dengying Formation, Yangtze Gorges area (South China). Diagnosis . An elongate, segmented and soft-bodied bilaterian animal with repetitive trilobate body units, each of which consists of a rhomboidal central lobe and two subtriangular lateral lobes that are consistently directed towards one end of the body<|im_end|> <|im_start|>assistant In a remarkable evolutionary discovery, a team of scientists co-led by a Virginia Tech geoscientist has discovered what could be among the first trails made by animals on the surface of the Earth roughly a half-billion years ago. Shuhai Xiao, a professor of geosciences with the Virginia Tech College of Science, calls the unearthed fossils, including the bodies and trails left by an ancient animal species, the most convincing sign of ancient animal mobility, dating back about 550 million years. Named Yilingia spiciformis—that translates to spiky Yiling bug, Yiling being the Chinese city near the discovery site—the animal was found in multiple layers of rock by Xiao and Zhe Chen, Chuanming Zhou, and Xunlai Yuan from the Chinese Academy of Sciences' Nanjing Institute of Geology and Palaeontology. The findings are published in the latest issue of Nature. The trials are from the same rock unit and are roughly the same age as bug-like footprints found by Xiao and his team in a series of digs from 2013 to 2018 in the Yangtze Gorges area of southern China, and date back to the Ediacaran Period, well before the age of dinosaurs or even the Pangea supercontinent. What sets this find apart: The preserved fossil of the animal that made the trail versus the unknowable guesswork where the body has not been preserved. "This discovery shows that segmented and mobile animals evolved by 550 million years ago," Xiao said. "Mobility made it possible for animals to make an unmistakable footprint on Earth, both literally and metaphorically. Those are the kind of features you find in a group of animals called bilaterans. This group includes us humans and most animals. Animals and particularly humans are movers and shakers on Earth. Their ability to shape the face of the planet is ultimately tied to the origin of animal motility." Animation of the 550-million-year-old animal Yilingia spiciformis and its locomotion trails. These fossils shed new light on the evolution of animal mobility and body segmentation. Credit: Dr. Zhe Chen at Nanjing Institute of Geology and Paleontology The animal was a millipede-like creature a quarter-inch to an inch wide and up to 4 inches long that alternately dragged its body across the muddy ocean floor and rested along the way, leaving trails as loing as 23 inches. The animal was an elongated narrow creature, with 50 or so body segments, a left and right side, a back and belly, and a head and a tail. The origin of bilaterally symmetric animals—known as bilaterians—with segmented bodies and directional mobility is a monumental event in early animal evolution, and is estimated to have occurred the Ediacaran Period, between 635 and 539 million years ago. But until this finding by Xiao and his team, there was no convincing fossil evidence to substantiate those estimates. One of the recovered specimens is particularly vital because the animal and the trail it produced just before its death are preserved together. A fossilized trail of the animal Yilingia spiciformis, dating back 550 million years. The trail was found in China by a team of scientists including Shuhai Xiao of the Virginia Tech College of Science. Credit: Virginia Tech College of Science Remarkably, the find also marks what may be the first sign of decision making among animals—the trails suggest an effort to move toward or away from something, perhaps under the direction of a sophisticated central nerve system, Xiao said. The mobility of animals led to environmental and ecological impacts on the Earth surface system and ultimately led to the Cambrian substrate and agronomic revolutions, he said. "We are the most impactful animal on Earth," added Xiao, also an affiliated member of the Global Change Center at Virginia Tech. "We make a huge footprint, not only from locomotion, but in many other and more impactful activities related to our ability to move. When and how animal locomotion evolved defines an important geological and evolutionary context of anthropogenic impact on the surface of the Earth." Rachel Wood, a professor in the School of GeoSciences at University of Edinburgh in Scotland, who was not involved with the study, said, "This is a remarkable finding of highly significant fossils. We now have evidence that segmented animals were present and had gained an ability to move across the sea floor before the Cambrian, and more notably we can tie the actual trace-maker to the trace. Such preservation is unusual and provides considerable insight into a major step in the evolution of animals." <|im_end|>

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2,445

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Living in a group allows individuals to decrease their defenses, enabling other beneficial behaviors such as foraging. The detection of a threat through social cues is widely reported, however, the safety cues that guide animals to break away from a defensive behavior and resume alternate activities remain elusive. Here we show that fruit flies display a graded decrease in freezing behavior, triggered by an inescapable threat, with increasing group sizes. Furthermore, flies use the cessation of movement of other flies as a cue of threat and its resumption as a cue of safety. Finally, we find that lobula columnar neurons, LC11, mediate the propensity for freezing flies to resume moving in response to the movement of others. By identifying visual motion cues, and the neurons involved in their processing, as the basis of a social safety cue this study brings new insights into the neuronal basis of safety in numbers. Introduction Predation is thought to be a key factor driving group formation and social behavior (reviewed in ref. 1 ). It has long been established that being in a group can constitute an anti-predatory strategy 2 , 3 , as it affords the use of social cues to detect predators 4 , 5 , 6 , 7 , enables coordinated defensive responses 8 or simply dilutes the probability of each individual to be predated 3 . A major consequence of this safety in numbers effect, reported in taxa throughout the animal kingdom, is that animals tend to decrease their individual vigilance 9 , stress levels 10 , or defensive behaviors 11 when in a social setting. One of the most studied benefits of being in a group is the facilitated detection of behaviorally significant cues in the environment, as information about their presence can quickly spread across a large group of individuals 12 . In the context of threat detection, most research has focused on actively emitted signals, such as alarm calls and foot stamping (reviewed in refs. 13 , 14 ). However, cues generated by movement patterns produced by defensive responses of surrounding prey can play a crucial role in predator detection. For example, crested pigeons use distinct wing whistles produced by conspecific escape flights 5 and rats use silence resulting from freezing, as alarm cues 4 . Recently, it has also been suggested that seismic waves produced by fast running in elephants promote vigilance in conspecifics 15 . This form of social detection of threat may be advantageous as it does not require the active production of a signal that may render the emitter more conspicuous and thus vulnerable. Although few studies demonstrated this phenomenon, it is described in distant vertebrate species. Because living in a group allows individuals to decrease their defenses, it also enables other globally beneficial behaviors such as foraging. These selective forces on the evolution of social behavior have been demonstrated in a wide range of animals, from invertebrates to mammals 1 , 2 . Despite its wide prevalence, the mechanisms that lead to a decrease in defensive behaviors are largely unknown. Hence, in order to gain mechanistic insight into how increasing group size impacts defense behaviors, we decided to use Drosophila melanogaster since it allows the use of groups of varying size, the large number of replicates required for detailed behavioral analysis and genetic access to specific neuronal subtypes. Importantly, fruit flies display social behaviors in different contexts 16 , 17 , 18 , 19 , 20 , 21 , namely social regulation of anti-predation strategies, such as the socially transmitted suppression of egg laying in the presence of predatory wasps 17 or the reduction in erratic turns during evasive flights when in a group, compared to when alone, in the presence of dragonflies 21 . In this study, we show that Drosophila melanogaster regulate their freezing behavior in response to threat as a function of group size. We identify the motion of others as a key regulator of freezing, with its cessation acting as a signal of danger and its presence constituting a safety signal. We further identify lobula columnar neurons 11 as major mediators of the usage of the movement of others as a safety cue. The identification of the sensory neurons responsible for social regulation of freezing opens up the possibility to gain mechanistic insight into the safety in numbers effect. Results Flies in groups display lower sustained freezing responses To simulate a predator’s attack, we used a looming stimulus (Fig. 1a ), an expanding dark disc, that mimics an object on collision course and elicits defense responses in visual animals, including humans (reviewed in refs. 22 , 23 , 24 ). Individually tested fruit flies respond to looming stimuli with escapes in the form of jumps 25 , 26 , in flight evasive maneuvers 27 or running as well as with freezing 28 , 29 when in an enclosed environment. In our setup, the presentation of 20 looming stimuli (Fig. 1a ) elicited reliable freezing responses for flies tested individually and in groups of up to 10 individuals (Fig. 1b–e , Supplementary Fig. 1 shows that running and jumps are less prominent in these arenas). The fraction of flies freezing increased as the stimulation period progressed for flies tested individually and in groups of up to five flies; in groups of 6–10 individuals, the fraction of flies freezing only transiently increased with each looming stimulus (Fig. 1b ). The fraction of flies freezing was maximal for individuals and minimal for groups of 6–10, while groups of 2–5 flies showed intermediate responses (Fig. 1b ). The step-wise decrease between groups of five and six flies, does not seem to depend on fly density, as testing groups of five flies in a chamber that is 1-cm smaller, creating a density similar to that in groups of 7, did not impact freezing responses (Supplementary Fig. 2 ). At the level of each individual fly’s behavior, flies tested alone spent more time freezing, 76.67%, interquartile range (IQR) 39.75–90.42%, during the stimulation period", "role": "user" }, { "content": "For schools of fish, herds of antelope, and even human societies, inherent safety is one of many advantages of cooperative groups. Surrounded by their peers, individuals can lower their vigilance and calmly engage in other activities, such as foraging or watching YouTube videos. But the \"safety in numbers\" rule relies on more than just being together. In many cases, communication also plays a big role. Social cues of danger are fairly well known. Just think about the many ways that animals convey the presence of a threat: Shrieks, yelps and barks immediately come to mind. But what about examples of social cues of safety? After all, knowing that the danger has passed is important for lowering defenses and resuming other activities. This task is more challenging because it's actually a trick question—no social safety cues have been identified until now. However, researchers have now reported the discovery of the first social safety cue, thanks to a tiny insect: the fruit fly. The results of their study, published today (August 21) in the scientific journal Nature Communications, mark a new phase in our understanding of how social communication works. A silent sign of danger \"When people think about social communication of danger, they normally think about alarm calls,\" says Marta Moita, a principal investigator at the Champalimaud Center for the Unknown in Portugal. \"But we are interested in a different type of threat cue, the expression of the defensive behaviors themselves.\" Freezing is one of the three universal defense responses, together with fight and flight. This response is the best course of action in situations where escape is either impossible or less advantageous than just staying still with the hope of remaining unnoticed. \"Freezing may actually be a safer way of conveying the existence of danger to others,\" Moita points out. \"This manner of social communication does not require the active production of a signal that may result in drawing unwelcome attention. Also, freezing may constitute a public cue that can be used by any surrounding animal regardless of species,\" she explains. Moita's team has recently demonstrated that individual fruit flies freeze in response to an inescapable threat. The researchers wondered if this behavior would change if there other flies were around. Safety in (exactly how many) numbers To answer this question, Clara Ferreira, the lead author of the study, proceeded with a systematic set of experiments, beginning with one fly, then two, three, and so forth, up to groups of 10. \"We placed the flies in a transparent closed chamber and repeatedly exposed them to an expanding dark disk, which mimics an object on a collision course. Just imagine the visual effect of an approaching open palm,\" Ferreira explains. \"Many visual animals that are exposed to such a stimulus respond defensively, including humans. If they freeze, they often stay motionless for quite some time, even after the threat is gone.\" Their results revealed that group size matters. \"All groups—from two to 10—froze less than individual flies. However, we were surprised to find a complex effect of group size on the flies' behavior,\" says Ferreira. In groups of six and more, the flies froze transiently when the threat appeared and then resumed movement once it was gone. On the other hand, the flies' response pattern in groups of five or less was more similar to that of individual flies. \"Flies in those groups still froze less than single flies. However, their freezing time increased as the experiment progressed. The more repetitions of the threatening stimulus they experienced, the longer they would remain motionless when it reappeared,\" Ferreira explains. \"These results were very intriguing,\" she adds. \"This was the first time the effect of group size on freezing was systematically characterized in any species, and it revealed a fascinating and intricate relation.\" Should I stay or should I go? These findings clearly demonstrated that flies change their defensive responses when others are present. This novel observation raised a pressing question—what social cues were the flies responding to? To find the answer, Ferreira and Moita meticulously analyzed their previous results and conducted additional experiments using blind flies and controllable magnetic \"dummy flies.\" The results revealed a two-part answer. \"The first part describes the flies' response to the appearance of the threat,\" Ferreira recounts. \"We learned that an individual fly was more likely to enter freezing if its peers (magnetic or otherwise) froze in response to the threat. We were somewhat expecting to see this. Previous studies in the lab showed that in specific situations, freezing is a social cue of danger in rats. Here, we witnessed a similar behavior in flies.\" The second part of the answer, however, caught the researchers by surprise: Flies were more likely to stop freezing if others began to move. \"This means that flies were using the resumption of movement as a social cue of safety,\" Ferreira says. \"This is a completely novel phenomenon,\" Moita says. \"There are many types of recorded social alarm cues, but this is the first social safety cue to be identified in any animal species. It also pins down movement as the social cue we were searching for. In a sense, this cue kills two birds with one stone: The sudden cessation of movement signifies danger, whereas its resumption signifies safety.\" Next stop—the brain Moita and Ferreira's series of striking discoveries opens a unique opportunity to learn how the brain perceives and responds to social cues. \"The fruit fly is one of the most powerful animal models used in scientific research nowadays,\" says Ferreira. \"It offers specialized tools to study neurobiology in a very specific and targeted manner.\" The authors have already begun unraveling the neural basis of this behavior. \"In this project, we identified a set of visual neurons that are crucial for perceiving the movement of others as a safety cue,\" Ferreira explains. \"And we are planning to continue investigating the neural circuits involved.\" As Moita points out, even though flies and humans are different, there are parallels across these and other species that may make findings in the fly relevant for revealing general principles. \"Since we are studying a fundamental behavior spanning almost all of animal life—the tendency to seek safety in numbers—we believe that our work paves the way for understanding conserved mechanisms in other animals,\" she concludes. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Living in a group allows individuals to decrease their defenses, enabling other beneficial behaviors such as foraging. The detection of a threat through social cues is widely reported, however, the safety cues that guide animals to break away from a defensive behavior and resume alternate activities remain elusive. Here we show that fruit flies display a graded decrease in freezing behavior, triggered by an inescapable threat, with increasing group sizes. Furthermore, flies use the cessation of movement of other flies as a cue of threat and its resumption as a cue of safety. Finally, we find that lobula columnar neurons, LC11, mediate the propensity for freezing flies to resume moving in response to the movement of others. By identifying visual motion cues, and the neurons involved in their processing, as the basis of a social safety cue this study brings new insights into the neuronal basis of safety in numbers. Introduction Predation is thought to be a key factor driving group formation and social behavior (reviewed in ref. 1 ). It has long been established that being in a group can constitute an anti-predatory strategy 2 , 3 , as it affords the use of social cues to detect predators 4 , 5 , 6 , 7 , enables coordinated defensive responses 8 or simply dilutes the probability of each individual to be predated 3 . A major consequence of this safety in numbers effect, reported in taxa throughout the animal kingdom, is that animals tend to decrease their individual vigilance 9 , stress levels 10 , or defensive behaviors 11 when in a social setting. One of the most studied benefits of being in a group is the facilitated detection of behaviorally significant cues in the environment, as information about their presence can quickly spread across a large group of individuals 12 . In the context of threat detection, most research has focused on actively emitted signals, such as alarm calls and foot stamping (reviewed in refs. 13 , 14 ). However, cues generated by movement patterns produced by defensive responses of surrounding prey can play a crucial role in predator detection. For example, crested pigeons use distinct wing whistles produced by conspecific escape flights 5 and rats use silence resulting from freezing, as alarm cues 4 . Recently, it has also been suggested that seismic waves produced by fast running in elephants promote vigilance in conspecifics 15 . This form of social detection of threat may be advantageous as it does not require the active production of a signal that may render the emitter more conspicuous and thus vulnerable. Although few studies demonstrated this phenomenon, it is described in distant vertebrate species. Because living in a group allows individuals to decrease their defenses, it also enables other globally beneficial behaviors such as foraging. These selective forces on the evolution of social behavior have been demonstrated in a wide range of animals, from invertebrates to mammals 1 , 2 . Despite its wide prevalence, the mechanisms that lead to a decrease in defensive behaviors are largely unknown. Hence, in order to gain mechanistic insight into how increasing group size impacts defense behaviors, we decided to use Drosophila melanogaster since it allows the use of groups of varying size, the large number of replicates required for detailed behavioral analysis and genetic access to specific neuronal subtypes. Importantly, fruit flies display social behaviors in different contexts 16 , 17 , 18 , 19 , 20 , 21 , namely social regulation of anti-predation strategies, such as the socially transmitted suppression of egg laying in the presence of predatory wasps 17 or the reduction in erratic turns during evasive flights when in a group, compared to when alone, in the presence of dragonflies 21 . In this study, we show that Drosophila melanogaster regulate their freezing behavior in response to threat as a function of group size. We identify the motion of others as a key regulator of freezing, with its cessation acting as a signal of danger and its presence constituting a safety signal. We further identify lobula columnar neurons 11 as major mediators of the usage of the movement of others as a safety cue. The identification of the sensory neurons responsible for social regulation of freezing opens up the possibility to gain mechanistic insight into the safety in numbers effect. Results Flies in groups display lower sustained freezing responses To simulate a predator’s attack, we used a looming stimulus (Fig. 1a ), an expanding dark disc, that mimics an object on collision course and elicits defense responses in visual animals, including humans (reviewed in refs. 22 , 23 , 24 ). Individually tested fruit flies respond to looming stimuli with escapes in the form of jumps 25 , 26 , in flight evasive maneuvers 27 or running as well as with freezing 28 , 29 when in an enclosed environment. In our setup, the presentation of 20 looming stimuli (Fig. 1a ) elicited reliable freezing responses for flies tested individually and in groups of up to 10 individuals (Fig. 1b–e , Supplementary Fig. 1 shows that running and jumps are less prominent in these arenas). The fraction of flies freezing increased as the stimulation period progressed for flies tested individually and in groups of up to five flies; in groups of 6–10 individuals, the fraction of flies freezing only transiently increased with each looming stimulus (Fig. 1b ). The fraction of flies freezing was maximal for individuals and minimal for groups of 6–10, while groups of 2–5 flies showed intermediate responses (Fig. 1b ). The step-wise decrease between groups of five and six flies, does not seem to depend on fly density, as testing groups of five flies in a chamber that is 1-cm smaller, creating a density similar to that in groups of 7, did not impact freezing responses (Supplementary Fig. 2 ). At the level of each individual fly’s behavior, flies tested alone spent more time freezing, 76.67%, interquartile range (IQR) 39.75–90.42%, during the stimulation period<|im_end|> <|im_start|>assistant For schools of fish, herds of antelope, and even human societies, inherent safety is one of many advantages of cooperative groups. Surrounded by their peers, individuals can lower their vigilance and calmly engage in other activities, such as foraging or watching YouTube videos. But the "safety in numbers" rule relies on more than just being together. In many cases, communication also plays a big role. Social cues of danger are fairly well known. Just think about the many ways that animals convey the presence of a threat: Shrieks, yelps and barks immediately come to mind. But what about examples of social cues of safety? After all, knowing that the danger has passed is important for lowering defenses and resuming other activities. This task is more challenging because it's actually a trick question—no social safety cues have been identified until now. However, researchers have now reported the discovery of the first social safety cue, thanks to a tiny insect: the fruit fly. The results of their study, published today (August 21) in the scientific journal Nature Communications, mark a new phase in our understanding of how social communication works. A silent sign of danger "When people think about social communication of danger, they normally think about alarm calls," says Marta Moita, a principal investigator at the Champalimaud Center for the Unknown in Portugal. "But we are interested in a different type of threat cue, the expression of the defensive behaviors themselves." Freezing is one of the three universal defense responses, together with fight and flight. This response is the best course of action in situations where escape is either impossible or less advantageous than just staying still with the hope of remaining unnoticed. "Freezing may actually be a safer way of conveying the existence of danger to others," Moita points out. "This manner of social communication does not require the active production of a signal that may result in drawing unwelcome attention. Also, freezing may constitute a public cue that can be used by any surrounding animal regardless of species," she explains. Moita's team has recently demonstrated that individual fruit flies freeze in response to an inescapable threat. The researchers wondered if this behavior would change if there other flies were around. Safety in (exactly how many) numbers To answer this question, Clara Ferreira, the lead author of the study, proceeded with a systematic set of experiments, beginning with one fly, then two, three, and so forth, up to groups of 10. "We placed the flies in a transparent closed chamber and repeatedly exposed them to an expanding dark disk, which mimics an object on a collision course. Just imagine the visual effect of an approaching open palm," Ferreira explains. "Many visual animals that are exposed to such a stimulus respond defensively, including humans. If they freeze, they often stay motionless for quite some time, even after the threat is gone." Their results revealed that group size matters. "All groups—from two to 10—froze less than individual flies. However, we were surprised to find a complex effect of group size on the flies' behavior," says Ferreira. In groups of six and more, the flies froze transiently when the threat appeared and then resumed movement once it was gone. On the other hand, the flies' response pattern in groups of five or less was more similar to that of individual flies. "Flies in those groups still froze less than single flies. However, their freezing time increased as the experiment progressed. The more repetitions of the threatening stimulus they experienced, the longer they would remain motionless when it reappeared," Ferreira explains. "These results were very intriguing," she adds. "This was the first time the effect of group size on freezing was systematically characterized in any species, and it revealed a fascinating and intricate relation." Should I stay or should I go? These findings clearly demonstrated that flies change their defensive responses when others are present. This novel observation raised a pressing question—what social cues were the flies responding to? To find the answer, Ferreira and Moita meticulously analyzed their previous results and conducted additional experiments using blind flies and controllable magnetic "dummy flies." The results revealed a two-part answer. "The first part describes the flies' response to the appearance of the threat," Ferreira recounts. "We learned that an individual fly was more likely to enter freezing if its peers (magnetic or otherwise) froze in response to the threat. We were somewhat expecting to see this. Previous studies in the lab showed that in specific situations, freezing is a social cue of danger in rats. Here, we witnessed a similar behavior in flies." The second part of the answer, however, caught the researchers by surprise: Flies were more likely to stop freezing if others began to move. "This means that flies were using the resumption of movement as a social cue of safety," Ferreira says. "This is a completely novel phenomenon," Moita says. "There are many types of recorded social alarm cues, but this is the first social safety cue to be identified in any animal species. It also pins down movement as the social cue we were searching for. In a sense, this cue kills two birds with one stone: The sudden cessation of movement signifies danger, whereas its resumption signifies safety." Next stop—the brain Moita and Ferreira's series of striking discoveries opens a unique opportunity to learn how the brain perceives and responds to social cues. "The fruit fly is one of the most powerful animal models used in scientific research nowadays," says Ferreira. "It offers specialized tools to study neurobiology in a very specific and targeted manner." The authors have already begun unraveling the neural basis of this behavior. "In this project, we identified a set of visual neurons that are crucial for perceiving the movement of others as a safety cue," Ferreira explains. "And we are planning to continue investigating the neural circuits involved." As Moita points out, even though flies and humans are different, there are parallels across these and other species that may make findings in the fly relevant for revealing general principles. "Since we are studying a fundamental behavior spanning almost all of animal life—the tendency to seek safety in numbers—we believe that our work paves the way for understanding conserved mechanisms in other animals," she concludes. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Superconducting circuits can operate at higher energy efficiencies than their room-temperature counterparts and have the potential to enable large-scale control and readout of quantum computers. However, the required interface with room-temperature electronics creates difficulties in scaling up such cryogenic systems. One option is to use optical fibres as a medium in conjunction with fast optical modulators that can be efficiently driven by electrical signals at low temperatures. However, as superconducting circuits are current operated with low impedances, they interface poorly with conventional electro-optical modulators. Here we report an integrated current-driven modulator that is based on the magneto-optic effect and can operate at temperatures as low as 4 K. The device combines a magneto-optic garnet crystal with a silicon waveguide resonator and integrates an electromagnet to modulate the refractive index of the garnet. The modulator offers data rates of up to 2 Gbps with an energy consumption below 4 pJ per bit of transferred information, which could be reduced to less than 50 fJ per bit by replacing dissipative electrodes with superconductors and optimizing the geometric parameters. Main In classical and quantum cryogenic computing systems, there is a need to transfer massive amounts of information from cryogenic circuitry to room temperature, as well as minimizing the hardware complexity and heat load. This becomes particularly challenging as systems are scaled up given the limited physical space and cooling power available in cryogenic systems. The issue can be addressed with photonic integrated circuits operating at low temperatures and the use of optical fibres to connect different temperature stages, thus enabling scalable, low-cost and power-efficient optical interconnections for large data transfer rates 1 , 2 , 3 . Silicon photonics is arguably the most promising technology platform for the development of cryogenic photonic integrated circuit components, due to its high scalability, excellent optical performance and compatibility with complementary metal–oxide–semiconductor and superconducting electronics fabrication 4 . However, low temperatures (for example, below 4 K) create important limitations for conventional silicon modulators and switches. Thermo-optic (TO) switches become non-functional due to a considerable drop in TO coefficient 5 , and modulators based on plasma dispersion suffer from free-carrier freeze-out, which reduces their efficiency 6 . The carrier freeze-out effect can be compensated by augmenting the doping concentration, but only at the cost of increased optical absorption 7 . To date, only electro-optic modulators have been shown to work at low temperatures 2 , 7 , 8 , 9 , 10 , 11 , and the use of magneto-optical (MO) effects in integrated optics has been limited to optical isolators and circulators 12 , 13 , although there are a few theoretical proposals existing for MO modulation 14 , 15 , 16 . This is largely due to the difficulties in manufacturing integrated MO devices, the challenges involved in applying fast time-variant magnetic fields and the generally slower response of the MO effect compared with the electro-optic effect. In this Article, we report a high-speed MO modulator operating at temperatures as low as 4 K. The device is created by combining an MO garnet crystal with a silicon waveguide resonator and integrating an electromagnet to modulate the refractive index of the garnet. The device is particularly efficient at cryogenic temperatures, where the MO effect becomes stronger 17 and the power consumption in the electromagnet decreases drastically compared with room temperature due to the reduced ohmic loss. We show that the modulator can offer data rates of up to 2 Gbps with an energy consumption as low as 4 pJ per bit of transferred information, which could be reduced to below 50 fJ per bit if the electrodes are replaced by superconductors and the fabrication process is further optimized. Our current-driven MO modulator can be of use in the development of power-efficient data links for the next generation of superconducting supercomputers and interface circuits for quantum computers 18 , 19 , 20 , 21 , 22 , 23 . Integrated MO modulator Our modulator is based on an all-pass silicon microring resonator with a cerium-substituted yttrium iron garnet (Ce:YIG) bonded on top (Fig. 1a ). The light that circulates in the microring resonator interacts evanescently with the garnet, and is affected by its MO properties. A gold coil, aligned with the silicon microring, serves as an integrated electromagnet and is used to control the MO properties of Ce:YIG, whereas a silicon waveguide is used to couple light in and out of the resonator. Fig. 1: Integrated MO modulator. a , Perspective view of the device (not to scale). The top gold coil is used to apply a radial magnetic field to Ce:YIG underneath, making it non-reciprocal. The silicon microring and silicon waveguide, in the all-pass filter configuration, are visible through the transparent top cladding. b , Cross-section of the microring and electromagnet (not to scale) where the direction of the electrical current and magnetic field are highlighted. c , Optical micrograph of the fabricated sample (top view). Full size image The main idea of our work is to exploit the refractive-index variation induced by an applied magnetic field to control the resonant wavelength of the microring and hence modulate the light passing through the waveguide. When an electrical current flows through the coil, Ce:YIG is magnetized by a in-plane transverse-magnetic field (Fig. 1b ), changing the effective refractive index of the optical mode 24 (Supplementary Section 1 ). For the microring, a variation in the effective index, Δ n eff , causes a proportional shift in the optical spectrum of the resonator: $${\\Delta}\\lambda _{{\\mathrm{MO}}} = \\lambda \\frac{{{\\Delta}n_{{\\mathrm{eff}}}}}{{n_{\\mathrm{g}}}},$$ (1) where λ is the optical wavelength and n g is the group refractive index of the optical mode 25 . If an applied current causes the resonant wavelength of the microring to tune towards the wavelength of the optical input signal, light is dissipated in the microring and transmission through the waveguide decreases. When the direction of the current is reversed, the microring resonance tunes away from the wavelength of the incoming light, which can then propagate through the", "role": "user" }, { "content": "In the future, many computers will most likely be based on electronic circuits made of superconductors. These are materials through which an electrical current can flow without energy losses, could be very promising for the development of high-performance supercomputers and quantum computers. Researchers at University of California Santa Barbara, Raytheon BBN Technologies, University of Cagliari, Microsoft Research, and the Tokyo Institute of Technology have recently developed a magneto-optic modulator—a device that control the properties of a light beam through a magnetic field. This device, introduced in a paper published in Nature Electronics, could contribute to the implementation of large-scale electronics and computers based on superconductors. \"We are working on a new technology that can speed up high-performance supercomputers and quantum computers based on superconductor technology,\" Paolo Pintus, the researcher who led the study, told TechXplore. \"Superconductors work properly only at low temperatures, generally just above absolute zero (-273.15° Celsius). Because of this, circuits made of these materials must be kept inside a dedicated refrigerator.\" Circuits made of superconductors are typically connected to their external surroundings using metal cables. These cables have a limited communication speed and can transfer heat into a cold circuit. A promising alternative would be to use optical fibers, thin and flexible glass wires that can convey light signals and are currently used to bring internet data over long distances. These fibers offer two main advantages over metal cables: they can transmit 1,000 times more data within the same period of time without transferring heat, since glass is a good thermal insulator. \"As part of our work, we designed and fabricated a device (known as 'optical modulator') that converts information carried by an electrical current in an electromagnet into light,\" Pintus explained. \"This is thanks to a physical mechanism called 'magneto-optic effect.' This light can travel through an optical fiber and carry information out of the cold environment, without altering the functionality of the cold circuit.\" Optical modulators such as the device created by Pintus and his colleagues allow researchers to control the properties of light beams, so that they can transfer information in the form of optical signals. These modulators have numerous potential applications, for instance allowing the transmission of binary (one and zero) codes over long distances. The magneto-optic modulator created by the researchers uses an electrical current to generate a magnetic field. This magnetic field in turn induces a change in the optical properties of a synthetic garnet where light is propagating. \"The mechanism underpinning our modulator is analogous to a guitar player who changes the stiffness of the strings to play a different sound,\" Pintus said. \"In our case, the magnetic field controls the optical density of the medium where the light is traveling, such that when the light can propagate, we get a '1,' and when the light is attenuated, we have a '0.'\" In initial evaluations, the magneto-optic modulator created by Pintus and his colleagues achieved highly promising results. Most notably, it reached a relatively fast modulation speed (a few Gigabits per second) and could operate at temperatures as low as 4 K (-269.15° Celsius). Electricity flowing through a metal coil generates electric (purple) and magnetic (faint green) fields. This changes the properties of the substrate, which tunes the resonance ring (red) to different frequencies. The whole setup enables the scientists to convert a continuous beam of light (red on left) into pulses that can carry data through a fiber-optic cable. Credit: Brian Long, Senior Artist, Marketing and Communications of the University of California Santa Barbara \"This is the key component to enable energy-efficient large data transfer rate from superconducting circuits, operating inside a cryostat at low temperature, and room temperature,\" Pintus said. \"Normally, optical modulators are based on a few electro-optic effects, where an electric field changes the optical property of the material where the light is propagating. The magneto-optic effect that we used, on the other hand, is a dual effect, where a magnetic field changes the optical property of a medium.\" Although the magneto-optic effect is well-known and extensively studied, Pintus and his colleagues were among the few who investigated its potential value for creating modulators. This area had not been explored much before because manufacturing integrated magneto-optic devices and applying fast time-variant magnetic fields can be very challenging. In addition, the magneto-optic effect tends to be associated with significantly slower response times than electro-optic effects. \"Ours is the first proof of concept of a high-speed modulator based on a magneto-optic effect,\" Pintus said. \"With this modulator, we demonstrate a key building block to enable effective communication between cryogenic environment and room-temperature electronics using optical fibers. Compared to previous cryogenic (electro-optic) modulators, our proposed solution has a very simple structure and it is compatible with superconducting circuits, since the input electrical impedance is very small.\" The promising performance and cryogenic nature of the researchers' modulator make it suitable for connecting standard electronics (at room temperature) with cryogenic superconducting and quantum computing architecture. In the future, this recent study could pave the way for new research focusing on magneto-optic materials for optical modulation and on their potential computing applications. \"In our work, we demonstrated a modulation rate of 2 Gigabit-per-second with energy consumption below 4 picojoule-per-bit of transferred information, which could be reduced by 80 times (below 50 femtojoule-per-bit) by optimizing the fabrication process in the same material system,\" Pintus added. \"Although this performance is impressive, we believe there is a lot of room for further improvements. In our next works, we would like to explore other materials to achieve higher modulation rate and lower power consumption. The field of cryogenic magneto-optic material is an unexplored area and it will take more investigation to narrow down the most promising materials.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Superconducting circuits can operate at higher energy efficiencies than their room-temperature counterparts and have the potential to enable large-scale control and readout of quantum computers. However, the required interface with room-temperature electronics creates difficulties in scaling up such cryogenic systems. One option is to use optical fibres as a medium in conjunction with fast optical modulators that can be efficiently driven by electrical signals at low temperatures. However, as superconducting circuits are current operated with low impedances, they interface poorly with conventional electro-optical modulators. Here we report an integrated current-driven modulator that is based on the magneto-optic effect and can operate at temperatures as low as 4 K. The device combines a magneto-optic garnet crystal with a silicon waveguide resonator and integrates an electromagnet to modulate the refractive index of the garnet. The modulator offers data rates of up to 2 Gbps with an energy consumption below 4 pJ per bit of transferred information, which could be reduced to less than 50 fJ per bit by replacing dissipative electrodes with superconductors and optimizing the geometric parameters. Main In classical and quantum cryogenic computing systems, there is a need to transfer massive amounts of information from cryogenic circuitry to room temperature, as well as minimizing the hardware complexity and heat load. This becomes particularly challenging as systems are scaled up given the limited physical space and cooling power available in cryogenic systems. The issue can be addressed with photonic integrated circuits operating at low temperatures and the use of optical fibres to connect different temperature stages, thus enabling scalable, low-cost and power-efficient optical interconnections for large data transfer rates 1 , 2 , 3 . Silicon photonics is arguably the most promising technology platform for the development of cryogenic photonic integrated circuit components, due to its high scalability, excellent optical performance and compatibility with complementary metal–oxide–semiconductor and superconducting electronics fabrication 4 . However, low temperatures (for example, below 4 K) create important limitations for conventional silicon modulators and switches. Thermo-optic (TO) switches become non-functional due to a considerable drop in TO coefficient 5 , and modulators based on plasma dispersion suffer from free-carrier freeze-out, which reduces their efficiency 6 . The carrier freeze-out effect can be compensated by augmenting the doping concentration, but only at the cost of increased optical absorption 7 . To date, only electro-optic modulators have been shown to work at low temperatures 2 , 7 , 8 , 9 , 10 , 11 , and the use of magneto-optical (MO) effects in integrated optics has been limited to optical isolators and circulators 12 , 13 , although there are a few theoretical proposals existing for MO modulation 14 , 15 , 16 . This is largely due to the difficulties in manufacturing integrated MO devices, the challenges involved in applying fast time-variant magnetic fields and the generally slower response of the MO effect compared with the electro-optic effect. In this Article, we report a high-speed MO modulator operating at temperatures as low as 4 K. The device is created by combining an MO garnet crystal with a silicon waveguide resonator and integrating an electromagnet to modulate the refractive index of the garnet. The device is particularly efficient at cryogenic temperatures, where the MO effect becomes stronger 17 and the power consumption in the electromagnet decreases drastically compared with room temperature due to the reduced ohmic loss. We show that the modulator can offer data rates of up to 2 Gbps with an energy consumption as low as 4 pJ per bit of transferred information, which could be reduced to below 50 fJ per bit if the electrodes are replaced by superconductors and the fabrication process is further optimized. Our current-driven MO modulator can be of use in the development of power-efficient data links for the next generation of superconducting supercomputers and interface circuits for quantum computers 18 , 19 , 20 , 21 , 22 , 23 . Integrated MO modulator Our modulator is based on an all-pass silicon microring resonator with a cerium-substituted yttrium iron garnet (Ce:YIG) bonded on top (Fig. 1a ). The light that circulates in the microring resonator interacts evanescently with the garnet, and is affected by its MO properties. A gold coil, aligned with the silicon microring, serves as an integrated electromagnet and is used to control the MO properties of Ce:YIG, whereas a silicon waveguide is used to couple light in and out of the resonator. Fig. 1: Integrated MO modulator. a , Perspective view of the device (not to scale). The top gold coil is used to apply a radial magnetic field to Ce:YIG underneath, making it non-reciprocal. The silicon microring and silicon waveguide, in the all-pass filter configuration, are visible through the transparent top cladding. b , Cross-section of the microring and electromagnet (not to scale) where the direction of the electrical current and magnetic field are highlighted. c , Optical micrograph of the fabricated sample (top view). Full size image The main idea of our work is to exploit the refractive-index variation induced by an applied magnetic field to control the resonant wavelength of the microring and hence modulate the light passing through the waveguide. When an electrical current flows through the coil, Ce:YIG is magnetized by a in-plane transverse-magnetic field (Fig. 1b ), changing the effective refractive index of the optical mode 24 (Supplementary Section 1 ). For the microring, a variation in the effective index, Δ n eff , causes a proportional shift in the optical spectrum of the resonator: $${\Delta}\lambda _{{\mathrm{MO}}} = \lambda \frac{{{\Delta}n_{{\mathrm{eff}}}}}{{n_{\mathrm{g}}}},$$ (1) where λ is the optical wavelength and n g is the group refractive index of the optical mode 25 . If an applied current causes the resonant wavelength of the microring to tune towards the wavelength of the optical input signal, light is dissipated in the microring and transmission through the waveguide decreases. When the direction of the current is reversed, the microring resonance tunes away from the wavelength of the incoming light, which can then propagate through the<|im_end|> <|im_start|>assistant In the future, many computers will most likely be based on electronic circuits made of superconductors. These are materials through which an electrical current can flow without energy losses, could be very promising for the development of high-performance supercomputers and quantum computers. Researchers at University of California Santa Barbara, Raytheon BBN Technologies, University of Cagliari, Microsoft Research, and the Tokyo Institute of Technology have recently developed a magneto-optic modulator—a device that control the properties of a light beam through a magnetic field. This device, introduced in a paper published in Nature Electronics, could contribute to the implementation of large-scale electronics and computers based on superconductors. "We are working on a new technology that can speed up high-performance supercomputers and quantum computers based on superconductor technology," Paolo Pintus, the researcher who led the study, told TechXplore. "Superconductors work properly only at low temperatures, generally just above absolute zero (-273.15° Celsius). Because of this, circuits made of these materials must be kept inside a dedicated refrigerator." Circuits made of superconductors are typically connected to their external surroundings using metal cables. These cables have a limited communication speed and can transfer heat into a cold circuit. A promising alternative would be to use optical fibers, thin and flexible glass wires that can convey light signals and are currently used to bring internet data over long distances. These fibers offer two main advantages over metal cables: they can transmit 1,000 times more data within the same period of time without transferring heat, since glass is a good thermal insulator. "As part of our work, we designed and fabricated a device (known as 'optical modulator') that converts information carried by an electrical current in an electromagnet into light," Pintus explained. "This is thanks to a physical mechanism called 'magneto-optic effect.' This light can travel through an optical fiber and carry information out of the cold environment, without altering the functionality of the cold circuit." Optical modulators such as the device created by Pintus and his colleagues allow researchers to control the properties of light beams, so that they can transfer information in the form of optical signals. These modulators have numerous potential applications, for instance allowing the transmission of binary (one and zero) codes over long distances. The magneto-optic modulator created by the researchers uses an electrical current to generate a magnetic field. This magnetic field in turn induces a change in the optical properties of a synthetic garnet where light is propagating. "The mechanism underpinning our modulator is analogous to a guitar player who changes the stiffness of the strings to play a different sound," Pintus said. "In our case, the magnetic field controls the optical density of the medium where the light is traveling, such that when the light can propagate, we get a '1,' and when the light is attenuated, we have a '0.'" In initial evaluations, the magneto-optic modulator created by Pintus and his colleagues achieved highly promising results. Most notably, it reached a relatively fast modulation speed (a few Gigabits per second) and could operate at temperatures as low as 4 K (-269.15° Celsius). Electricity flowing through a metal coil generates electric (purple) and magnetic (faint green) fields. This changes the properties of the substrate, which tunes the resonance ring (red) to different frequencies. The whole setup enables the scientists to convert a continuous beam of light (red on left) into pulses that can carry data through a fiber-optic cable. Credit: Brian Long, Senior Artist, Marketing and Communications of the University of California Santa Barbara "This is the key component to enable energy-efficient large data transfer rate from superconducting circuits, operating inside a cryostat at low temperature, and room temperature," Pintus said. "Normally, optical modulators are based on a few electro-optic effects, where an electric field changes the optical property of the material where the light is propagating. The magneto-optic effect that we used, on the other hand, is a dual effect, where a magnetic field changes the optical property of a medium." Although the magneto-optic effect is well-known and extensively studied, Pintus and his colleagues were among the few who investigated its potential value for creating modulators. This area had not been explored much before because manufacturing integrated magneto-optic devices and applying fast time-variant magnetic fields can be very challenging. In addition, the magneto-optic effect tends to be associated with significantly slower response times than electro-optic effects. "Ours is the first proof of concept of a high-speed modulator based on a magneto-optic effect," Pintus said. "With this modulator, we demonstrate a key building block to enable effective communication between cryogenic environment and room-temperature electronics using optical fibers. Compared to previous cryogenic (electro-optic) modulators, our proposed solution has a very simple structure and it is compatible with superconducting circuits, since the input electrical impedance is very small." The promising performance and cryogenic nature of the researchers' modulator make it suitable for connecting standard electronics (at room temperature) with cryogenic superconducting and quantum computing architecture. In the future, this recent study could pave the way for new research focusing on magneto-optic materials for optical modulation and on their potential computing applications. "In our work, we demonstrated a modulation rate of 2 Gigabit-per-second with energy consumption below 4 picojoule-per-bit of transferred information, which could be reduced by 80 times (below 50 femtojoule-per-bit) by optimizing the fabrication process in the same material system," Pintus added. "Although this performance is impressive, we believe there is a lot of room for further improvements. In our next works, we would like to explore other materials to achieve higher modulation rate and lower power consumption. The field of cryogenic magneto-optic material is an unexplored area and it will take more investigation to narrow down the most promising materials." <|im_end|>

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15376, 1523, 279, 1455, 26455, 7384, 1210, 220, 128257, 198 ]

2,619

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Intraspecific competition is a major force in mediating population dynamics, fuelling adaptation, and potentially leading to evolutionary diversification. Among the evolutionary arms races between parasites, one of the most fundamental and intriguing behavioural adaptations and counter-adaptations are superparasitism and superparasitism avoidance. However, the underlying mechanisms and ecological contexts of these phenomena remain underexplored. Here, we apply the Drosophila parasite Leptopilina boulardi as a study system and find that this solitary endoparasitic wasp provokes a host escape response for superparasitism avoidance. We combine multi-omics and in vivo functional studies to characterize a small set of RhoGAP domain-containing genes that mediate the parasite’s manipulation of host escape behaviour by inducing reactive oxygen species in the host central nervous system. We further uncover an evolutionary scenario in which neofunctionalization and specialization gave rise to the novel role of RhoGAP domain in avoiding superparasitism, with an ancestral origin prior to the divergence between Leptopilina specialist and generalist species. Our study suggests that superparasitism avoidance is adaptive for a parasite and adds to our understanding of how the molecular manipulation of host behaviour has evolved in this system. Introduction How competition shapes the communities of animals and plants has been one of the central topics in ecology and evolution for decades 1 , 2 , 3 , 4 , 5 . Under limited resources, intraspecific competition limits the increase in population size and potentially lowers genetic diversity due to genetic drift; hence, the population is more likely to become extinct when exposed to new environments 4 , 6 , 7 . On the other hand, competition induces natural selection that might enable rapid adaptation to novel conditions and niche expansion for the populations at longer timescales 5 , 8 , 9 . Intraspecific competition is widespread and particularly important in communities of parasitoid wasps and other parasites, whose development closely relies on the condition of hosts 10 . Furthermore, the offspring of parasitic wasps are typically confined to the host that was parasitized, so the strategies of the ovipositing female therefore largely determine her reproductive outputs; her strategy is therefore under strong natural selection. 11 . Superparasitism, i.e. two or more eggs being laid into a single host by one or more parasitoid females, and superparasitism avoidance are among the most fundamental intraspecific competition behaviours of solitary wasps 12 , 13 , 14 . However, issues regarding their evolutionary consequences and fitness costs have long been debated 12 , 15 , 16 , 17 . In most conditions, parasitoid females refuse to lay additional eggs into already parasitized hosts (superparasitism avoidance), since superparasitism would introduce intense competition between wasps in a narrow niche 12 , 18 . Superparasitism seriously lowers the reproductive efficiency of parasitoids by affecting the body size or weight of parasitoid offspring, extending the developmental time of wasp progeny, and increasing premature mortality of both developing hosts and parasitoids 19 , 20 , 21 , 22 , 23 . Despite being considered disadvantageous, female parasitoids superparasitize on some occasions. This paradoxical decision was first interpreted as being the consequence of ‘errors’ on the part of the egg-laying females but was later re-interpreted as an adaptive decision when females have no better solution, i.e. when the overall environmental quality is low 12 , 24 , 25 . Furthermore, recent studies discovered an inheritable filamentous virus (FV) that can manipulate superparasitism in wasps, suggesting that superparasitism is likely to be manipulated by symbionts as an adaptive strategy for virus transmission 13 , 26 , 27 . Despite long being of interest and the topic of debate, the detailed mechanism underlying superparasitism avoidance remains largely underexplored, which limits further addressing its enigmatic ecological context. Drosophila parasitoids have been widely utilised as both experimental and theoretical models to study the mechanisms underpinning the host response to parasite infection 28 , 29 , 30 , 31 , 32 , 33 , 34 . In this study, we use the solitary endoparasitoid Leptopilina boulardi (Lb) as the study system to characterise the molecular basis underlying the avoidance of parasitoid superparasitism. We find that Lb avoids superparasitism by manipulating the host escape behaviour via inducing reactive oxygen species in the host central nervous system. By tracing the evolutionary scenario of this mechanism, we find that the neofunctionalization and expression specialisation gave rise to the novel role of an ancient RhoGAP domain which allows parasitoids to manipulating the host behaviour. Results Parasitisation of Lb induces host escape behaviour Solitary parasitoids usually lay a single egg inside the host per each oviposition. Even when multiple ovipositions occur, at most one of the laid offsprings can successfully develop into the adult and emerge from a single host (if survived) 10 , 11 , 12 . Thus, behavioural qualification of “superparasitism” in solitary parasitoids is unambiguous, i.e., the appearance of more than one egg in a single host. This strictly exclusive pattern makes this type of parasitoids as an ideal model to study superparasitism. Lb is a classic solitary parasitoid of Drosophila that mainly attacks 2nd instar larvae of D. melanogaster , and adult wasps emerge when hosts are at the pupal stage 28 . The Lb line in this study was checked to verify the absence of LbFV infection ('Methods'), and its parasitisation strategy was observed under different parasite to host ratios. When fly larvae were exposed to 3-day-old Lb females with a parasite to host ratio of 1:10 in standard fly food bottles, we found that most larvae contained a single (parasitoid) egg after 60 min, while the prevalence of hosts with two or more eggs increased substantially thereafter to become almost universal by 240 min (Fig. 1a ). Similarly, the parasitized Drosophila hosts generally had only one Lb egg during the early phase of parasitism, but two or more eggs per host were often observed when wasps were present for a long time when there was a 1:20 parasite:host ratio (Fig. 1b ). These results confirm that Lb usually has a tendency to avoid superparasitism when there are sufficient", "role": "user" }, { "content": "Parasitic wasps are natural enemies for effective control over the population of pests in nature. Hence, they are extensively used as green agents of pest control in agriculture and forestry. There are a diversity of parasitic wasps, which have assorted parasitic habits. In general, parasitism can be divided into three types: solitary parasitism, gregarious parasitism and synparasitism. Superparasitism—two or more eggs being laid into a single host by one or more parasitoid females—usually leads to intraspecific or interspecific competition, which is thus a waste of parasitic resource. Superparasitism avoidance has captured immense attention among biologists both at home and abroad, but the underlying mechanism remains obscure. The team led by Prof. Chen Xuexin and Prof. Huang Jianhua from the Zhejiang University College of Agriculture and Biotechnology worked in partnership with the team led by researcher Zhan Shuai from the CAS Center for Excellence in Molecular Plant Sciences to conduct research into how parasitic wasps manipulate their host behavior to avoid intraspecific competition. Their research findings were published in an article titled \"Neofunctionalization of an ancient domain allows parasites to avoid intraspecific competition by manipulating host behavior\" in the journal Nature Communications on September 16. Leptopilina genus has some important parasitoid wasps of soft fruit pests, including some Drosophila species. Researchers discovered that two closely related species of Leptopilina—L. boulardi and L. heterotoma—are characterized by superparasitism avoidance. Therefore, these two parasitic systems are the ideal model for exploring the avoidance of intraspecific competition among parasitoid wasps. They first found that Leptopilina parasitism is often accompanied by the host escape response. By comparing escaped and non-escaped hosts, they detected noticeable superparasitism among non-escaped, i.e. they often had multiple parasitic eggs in their bodies, suggesting that host escape is a strategy that helps parasitoid wasps avoid intraspecific competition. It was further found that all escaped hosts had eggs laid and venom protein injected by the parasitoid wasps. By combining multi-omics data, researchers characterized a small set of RhoGAP genes (termed as Escape-related genes with a GtPase Activating Protein domain—EsGAP) that mediate the parasite's manipulation of host escape by inducing reactive oxygen species in the host central nervous system. Functional studies revealed that this family of proteins can cause elevated levels of reactive oxygen species (ROS) in the central nervous system of the host larvae, thereby leading to the host escape behavior. The study finally traced the origin and evolution of such EsGAP genes and found that the RhoGAP structural domain, which is pervasive in eukaryotes, has evolved in a large number of independent replication events, and one of its branches is recruited and eventually specialized into a venom gland-specific expression gene by Leptopilina, fulfilling a new function in regulating host behavior. \"We have identified a parasitic strategy of Leptopilina in regulating host behavior, thus avoiding intraspecific competition and elucidating the involvement of EsGAP in manipulating host escape behavior at the molecular level,\" said Prof. Chen. \"We have also proposed a new theory regarding how avoidance of superparasitism and intraspecific competition promotes population differentiation and host expansion among parasitoid wasps. These research findings contribute to a perspicacious understanding of the molecular mechanism of superparasitism avoidance in parasitoid wasps and provide a theoretical basis for enhancing the potential effect of parasitoid wasps in biological control.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Intraspecific competition is a major force in mediating population dynamics, fuelling adaptation, and potentially leading to evolutionary diversification. Among the evolutionary arms races between parasites, one of the most fundamental and intriguing behavioural adaptations and counter-adaptations are superparasitism and superparasitism avoidance. However, the underlying mechanisms and ecological contexts of these phenomena remain underexplored. Here, we apply the Drosophila parasite Leptopilina boulardi as a study system and find that this solitary endoparasitic wasp provokes a host escape response for superparasitism avoidance. We combine multi-omics and in vivo functional studies to characterize a small set of RhoGAP domain-containing genes that mediate the parasite’s manipulation of host escape behaviour by inducing reactive oxygen species in the host central nervous system. We further uncover an evolutionary scenario in which neofunctionalization and specialization gave rise to the novel role of RhoGAP domain in avoiding superparasitism, with an ancestral origin prior to the divergence between Leptopilina specialist and generalist species. Our study suggests that superparasitism avoidance is adaptive for a parasite and adds to our understanding of how the molecular manipulation of host behaviour has evolved in this system. Introduction How competition shapes the communities of animals and plants has been one of the central topics in ecology and evolution for decades 1 , 2 , 3 , 4 , 5 . Under limited resources, intraspecific competition limits the increase in population size and potentially lowers genetic diversity due to genetic drift; hence, the population is more likely to become extinct when exposed to new environments 4 , 6 , 7 . On the other hand, competition induces natural selection that might enable rapid adaptation to novel conditions and niche expansion for the populations at longer timescales 5 , 8 , 9 . Intraspecific competition is widespread and particularly important in communities of parasitoid wasps and other parasites, whose development closely relies on the condition of hosts 10 . Furthermore, the offspring of parasitic wasps are typically confined to the host that was parasitized, so the strategies of the ovipositing female therefore largely determine her reproductive outputs; her strategy is therefore under strong natural selection. 11 . Superparasitism, i.e. two or more eggs being laid into a single host by one or more parasitoid females, and superparasitism avoidance are among the most fundamental intraspecific competition behaviours of solitary wasps 12 , 13 , 14 . However, issues regarding their evolutionary consequences and fitness costs have long been debated 12 , 15 , 16 , 17 . In most conditions, parasitoid females refuse to lay additional eggs into already parasitized hosts (superparasitism avoidance), since superparasitism would introduce intense competition between wasps in a narrow niche 12 , 18 . Superparasitism seriously lowers the reproductive efficiency of parasitoids by affecting the body size or weight of parasitoid offspring, extending the developmental time of wasp progeny, and increasing premature mortality of both developing hosts and parasitoids 19 , 20 , 21 , 22 , 23 . Despite being considered disadvantageous, female parasitoids superparasitize on some occasions. This paradoxical decision was first interpreted as being the consequence of ‘errors’ on the part of the egg-laying females but was later re-interpreted as an adaptive decision when females have no better solution, i.e. when the overall environmental quality is low 12 , 24 , 25 . Furthermore, recent studies discovered an inheritable filamentous virus (FV) that can manipulate superparasitism in wasps, suggesting that superparasitism is likely to be manipulated by symbionts as an adaptive strategy for virus transmission 13 , 26 , 27 . Despite long being of interest and the topic of debate, the detailed mechanism underlying superparasitism avoidance remains largely underexplored, which limits further addressing its enigmatic ecological context. Drosophila parasitoids have been widely utilised as both experimental and theoretical models to study the mechanisms underpinning the host response to parasite infection 28 , 29 , 30 , 31 , 32 , 33 , 34 . In this study, we use the solitary endoparasitoid Leptopilina boulardi (Lb) as the study system to characterise the molecular basis underlying the avoidance of parasitoid superparasitism. We find that Lb avoids superparasitism by manipulating the host escape behaviour via inducing reactive oxygen species in the host central nervous system. By tracing the evolutionary scenario of this mechanism, we find that the neofunctionalization and expression specialisation gave rise to the novel role of an ancient RhoGAP domain which allows parasitoids to manipulating the host behaviour. Results Parasitisation of Lb induces host escape behaviour Solitary parasitoids usually lay a single egg inside the host per each oviposition. Even when multiple ovipositions occur, at most one of the laid offsprings can successfully develop into the adult and emerge from a single host (if survived) 10 , 11 , 12 . Thus, behavioural qualification of “superparasitism” in solitary parasitoids is unambiguous, i.e., the appearance of more than one egg in a single host. This strictly exclusive pattern makes this type of parasitoids as an ideal model to study superparasitism. Lb is a classic solitary parasitoid of Drosophila that mainly attacks 2nd instar larvae of D. melanogaster , and adult wasps emerge when hosts are at the pupal stage 28 . The Lb line in this study was checked to verify the absence of LbFV infection ('Methods'), and its parasitisation strategy was observed under different parasite to host ratios. When fly larvae were exposed to 3-day-old Lb females with a parasite to host ratio of 1:10 in standard fly food bottles, we found that most larvae contained a single (parasitoid) egg after 60 min, while the prevalence of hosts with two or more eggs increased substantially thereafter to become almost universal by 240 min (Fig. 1a ). Similarly, the parasitized Drosophila hosts generally had only one Lb egg during the early phase of parasitism, but two or more eggs per host were often observed when wasps were present for a long time when there was a 1:20 parasite:host ratio (Fig. 1b ). These results confirm that Lb usually has a tendency to avoid superparasitism when there are sufficient<|im_end|> <|im_start|>assistant Parasitic wasps are natural enemies for effective control over the population of pests in nature. Hence, they are extensively used as green agents of pest control in agriculture and forestry. There are a diversity of parasitic wasps, which have assorted parasitic habits. In general, parasitism can be divided into three types: solitary parasitism, gregarious parasitism and synparasitism. Superparasitism—two or more eggs being laid into a single host by one or more parasitoid females—usually leads to intraspecific or interspecific competition, which is thus a waste of parasitic resource. Superparasitism avoidance has captured immense attention among biologists both at home and abroad, but the underlying mechanism remains obscure. The team led by Prof. Chen Xuexin and Prof. Huang Jianhua from the Zhejiang University College of Agriculture and Biotechnology worked in partnership with the team led by researcher Zhan Shuai from the CAS Center for Excellence in Molecular Plant Sciences to conduct research into how parasitic wasps manipulate their host behavior to avoid intraspecific competition. Their research findings were published in an article titled "Neofunctionalization of an ancient domain allows parasites to avoid intraspecific competition by manipulating host behavior" in the journal Nature Communications on September 16. Leptopilina genus has some important parasitoid wasps of soft fruit pests, including some Drosophila species. Researchers discovered that two closely related species of Leptopilina—L. boulardi and L. heterotoma—are characterized by superparasitism avoidance. Therefore, these two parasitic systems are the ideal model for exploring the avoidance of intraspecific competition among parasitoid wasps. They first found that Leptopilina parasitism is often accompanied by the host escape response. By comparing escaped and non-escaped hosts, they detected noticeable superparasitism among non-escaped, i.e. they often had multiple parasitic eggs in their bodies, suggesting that host escape is a strategy that helps parasitoid wasps avoid intraspecific competition. It was further found that all escaped hosts had eggs laid and venom protein injected by the parasitoid wasps. By combining multi-omics data, researchers characterized a small set of RhoGAP genes (termed as Escape-related genes with a GtPase Activating Protein domain—EsGAP) that mediate the parasite's manipulation of host escape by inducing reactive oxygen species in the host central nervous system. Functional studies revealed that this family of proteins can cause elevated levels of reactive oxygen species (ROS) in the central nervous system of the host larvae, thereby leading to the host escape behavior. The study finally traced the origin and evolution of such EsGAP genes and found that the RhoGAP structural domain, which is pervasive in eukaryotes, has evolved in a large number of independent replication events, and one of its branches is recruited and eventually specialized into a venom gland-specific expression gene by Leptopilina, fulfilling a new function in regulating host behavior. "We have identified a parasitic strategy of Leptopilina in regulating host behavior, thus avoiding intraspecific competition and elucidating the involvement of EsGAP in manipulating host escape behavior at the molecular level," said Prof. Chen. "We have also proposed a new theory regarding how avoidance of superparasitism and intraspecific competition promotes population differentiation and host expansion among parasitoid wasps. These research findings contribute to a perspicacious understanding of the molecular mechanism of superparasitism avoidance in parasitoid wasps and provide a theoretical basis for enhancing the potential effect of parasitoid wasps in biological control." <|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 Around 5% of the population is affected by a rare genetic disease, yet most endure years of uncertainty before receiving a genetic test. A common feature of genetic diseases is the presence of multiple rare phenotypes that often span organ systems. Here, we use diagnostic billing information from longitudinal clinical data in the electronic health records (EHRs) of 2,286 patients who received a chromosomal microarray test, and 9,144 matched controls, to build a model to predict who should receive a genetic test. The model achieved high prediction accuracies in a held-out test sample (area under the receiver operating characteristic curve (AUROC), 0.97; area under the precision–recall curve (AUPRC), 0.92), in an independent hospital system (AUROC, 0.95; AUPRC, 0.62), and in an independent set of 172,265 patients in which cases were broadly defined as having an interaction with a genetics provider (AUROC, 0.9; AUPRC, 0.63). Patients carrying a putative pathogenic copy number variant were also accurately identified by the model. Compared with current approaches for genetic test determination, our model could identify more patients for testing while also increasing the proportion of those tested who have a genetic disease. We demonstrate that phenotypic patterns representative of a wide range of genetic diseases can be captured from EHRs to systematize decision-making for genetic testing, with the potential to speed up diagnosis, improve care and reduce costs. Main Rare diseases, of which the majority are genetic, affect 3.5–6.2% of the world’s population 1 , 2 . Many genetic diseases have yet to be discovered or characterized, leaving those patients to endure particularly long and challenging diagnostic odysseys 2 , 3 . Even for the thousands of genetic diseases that have already been described 4 , 5 , heterogenous clinical symptoms may complicate identification of the underlying cause, thereby delaying diagnosis and the opportunity for medical benefits. Genetic testing represents a standard means to diagnose a patient with a genetic disease. However, current approaches that determine which patients receive a genetic test are inconsistent and inequitable 6 . There are numerous conditions for which genetic testing is recommended, yet the vast majority of patients still do not receive a genetic test 7 , 8 . Developing a systematized way to identify patients who are likely to have a rare genetic disease could guide genetic testing decision-making to improve diagnostic outcomes, reduce the healthcare costs and the burden on patients, and enable opportunities for improved care. The identification of genetic diseases has typically been through clinical ascertainment of shared syndromic features 9 , 10 . However, there exists variable expressivity and penetrance such that two patients with the same underlying genetic variant may not present similarly, or may not present with all or many of the features of the well-characterized genetic disease 11 . For example, a large deletion on chromosome 22 causes 22q11.2 deletion syndrome, which includes both velocardiofacial syndrome and DiGeorge syndrome, which were historically believed to be different syndromes due to their differing clinical presentations. Additionally, patients may carry multiple contributing genetic factors leading to a phenotypic presentation that deviates from those previously defined and challenges a clear diagnosis 12 , 13 . Longitudinal clinical data stored in the electronic health record (EHR) have enabled approaches to identify patients at risk for numerous conditions 14 . In particular, recent work has shown that specific genetic diseases can be identified by looking for patients carrying many of the expected symptoms 15 , 16 . Although each genetic disease may present with a recognizable phenotypic profile, across the majority of genetic diseases there exists a recurring pattern of multiple phenotypes that are often rare and affect multiple organ systems. We propose that this constellation of rare and diverse phenotypes is a hallmark signature of patients with a genetic disease and can be captured from data in the EHR. Here, we test this hypothesis by building a machine learning-based prediction model to identify patients who have a clinical profile representative of receiving a genetic test for a suspected genetic disease. Specifically, we trained and tested our model on 2,286 patients who received a chromosomal microarray (CMA) test and 9,144 demographically matched controls using only diagnostic billing information from the EHR. We show highly accurate performance in our held-out testing sample, as well as in an external validation sample from another institution, and in an independent set of more than 170,000 hospital patients. We further validate the ability of this model to identify patients with genetic disease from among patients with putative pathogenic copy number variants (CNVs) and those carrying a diverse array of genetic diseases including many not present in our training data. Overall, our approach establishes the potential to identify patients with genetic disease from EHR data and presents a systemized way to improve the consistency and equity of genetic testing. Results Demographic and phenotype description of the CMA sample The primary case population consisted of 2,286 patients who received a CMA test. We matched each patient in the CMA group to four controls based exactly on age, sex, race, number of unique years in which they visited Vanderbilt University Medical Center (VUMC), and the closest available match on medical record length in days (maximum difference, 365 days). The vast majority (95%) of the recipients of the CMA test were less than 20 years old (mean age, 8.1 years), and most were male (61.3%) and white (75.6%, Table 1 ). Twenty-four per cent of patients ( n = 550) had an abnormal result, including 250 with at least one gain and 257 with at least one loss. Of these 550 patients, 37% (201 of 550) had a potential diagnosis included in the report. Although the reported genomic coordinates were most often unique, several known recurrent syndromes were seen more frequently, such as DiGeorge syndrome, Charcot-Marie-Tooth syndrome and 16p11.2 deletion syndrome. Table 1 Demographic and hospital utilization information for genetic testing and hospital population datasets Full size table We tested the difference in the frequency of phecodes (that is, an organization of EHR-based diagnostic", "role": "user" }, { "content": "Patients who, perhaps unbeknownst to their health care providers, are in need of genetic testing for rare undiagnosed diseases can be identified en masse based on routine information in electronic health records (EHRs), a research team reported today in the journal Nature Medicine. Findings from the Vanderbilt University Medical Center study suggest that, among the patients of any sizeable health care system, there are hundreds or thousands with undiagnosed rare diseases of the sort where a genetic test could lead to a diagnosis. \"Patients with rare genetic diseases often face years of diagnostic odyssey before getting a genetic test, if they get one at all. Our work could contribute to a more systematic and timely approach, alerting providers of patients that might benefit from a genetic test,\" said the leader of the study, geneticist Douglas Ruderfer, Ph.D., associate professor of Medicine at VUMC. It's estimated that more than 70% of rare diseases are genetic in origin. According to authors of the study, rare genetic diseases may look quite different from one patient to the next and may go undiagnosed even when well characterized in the medical literature. Using routine EHR data to directly identify patients with specific genetic diseases is, for now, quite challenging: according to the study authors, the current state of knowledge about disease-causing genetic variation is too wanting, and the genetic resolution of current clinical tests is too low. Given this state of affairs, the team developed their predictive model to instead detect patients who fit historical criteria for testing in the eyes of clinicians. To begin, the team developed a range of competing predictive algorithms. For training data, they used EHRs of patients for whom clinicians had ordered a type of genetic test called chromosomal microarray (1,818 cases), and similar patients whose records showed no history of genetic testing (7,326 matched controls). Across the training and test sets, the average age of the patients represented was 8. \"We were really aiming to build a model that captured and automated clinical suspicion of a genetic disease,\" said Theodore Morley, a staff data scientist who worked closely with Ruderfer on the study. With all traces of genetic testing removed from a test set of 2,286 records, a machine learning algorithm emerged as the best performer, correctly classifying 87% of cases and 96% of controls. Also showing high accuracy were independent validation efforts at Boston's Massachusetts General Hospital and again at VUMC, with far greater numbers of longstanding patients, cases now defined by evidence in the EHR of interaction with a genetics provider. Importantly, the algorithm also performed well in identifying patients who received genetic tests other than chromosomal microarray. The study supports the hypothesis that, within any EHR population, patients who are to be suspected of having rare genetic diseases are distinguishable via computation thanks to the presence of multiple rare signs and symptoms—phenotypes, in the language of the study—that are subject to documentation in the EHR. The team's predictive algorithms used EHR diagnosis codes exclusively (the same codes that drive health care billing), amalgamated for prediction purposes into so-called phenotype codes. \"After extensive validation demonstrated high predictive performance, we were really interested in assessing how an implementation of our model might compare to the current status quo for who receives a test, and what the results of those tests are,\" Ruderfer said. From a set of 6,445 deidentified EHRs corresponding to genotyped patient specimens from BioVU, Vanderbilt's DNA biobank, the algorithm proved accurate in picking out individuals with pathogenic copy number variations, a type of genetic abnormality. In collating this and other findings from the study, the authors estimate there are more than 2,000 patients at VUMC who have an unrecognized, potentially diagnostic copy number variation that could be identified with a genetic test. Among close observers of the study is Josh Peterson, MD, MPH, director of VUMC's Center for Precision Medicine (where Ruderfer is an affiliated faculty member). \"The team's predictive model was shown to handily outperform current clinical performance, identifying patients who need testing more quickly and in greater numbers. Crucially, the model also proved portable to another health system. This paper's findings align very well with the push at VUMC to use data science to improve diagnosis of genomic syndromes,\" Peterson 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 Around 5% of the population is affected by a rare genetic disease, yet most endure years of uncertainty before receiving a genetic test. A common feature of genetic diseases is the presence of multiple rare phenotypes that often span organ systems. Here, we use diagnostic billing information from longitudinal clinical data in the electronic health records (EHRs) of 2,286 patients who received a chromosomal microarray test, and 9,144 matched controls, to build a model to predict who should receive a genetic test. The model achieved high prediction accuracies in a held-out test sample (area under the receiver operating characteristic curve (AUROC), 0.97; area under the precision–recall curve (AUPRC), 0.92), in an independent hospital system (AUROC, 0.95; AUPRC, 0.62), and in an independent set of 172,265 patients in which cases were broadly defined as having an interaction with a genetics provider (AUROC, 0.9; AUPRC, 0.63). Patients carrying a putative pathogenic copy number variant were also accurately identified by the model. Compared with current approaches for genetic test determination, our model could identify more patients for testing while also increasing the proportion of those tested who have a genetic disease. We demonstrate that phenotypic patterns representative of a wide range of genetic diseases can be captured from EHRs to systematize decision-making for genetic testing, with the potential to speed up diagnosis, improve care and reduce costs. Main Rare diseases, of which the majority are genetic, affect 3.5–6.2% of the world’s population 1 , 2 . Many genetic diseases have yet to be discovered or characterized, leaving those patients to endure particularly long and challenging diagnostic odysseys 2 , 3 . Even for the thousands of genetic diseases that have already been described 4 , 5 , heterogenous clinical symptoms may complicate identification of the underlying cause, thereby delaying diagnosis and the opportunity for medical benefits. Genetic testing represents a standard means to diagnose a patient with a genetic disease. However, current approaches that determine which patients receive a genetic test are inconsistent and inequitable 6 . There are numerous conditions for which genetic testing is recommended, yet the vast majority of patients still do not receive a genetic test 7 , 8 . Developing a systematized way to identify patients who are likely to have a rare genetic disease could guide genetic testing decision-making to improve diagnostic outcomes, reduce the healthcare costs and the burden on patients, and enable opportunities for improved care. The identification of genetic diseases has typically been through clinical ascertainment of shared syndromic features 9 , 10 . However, there exists variable expressivity and penetrance such that two patients with the same underlying genetic variant may not present similarly, or may not present with all or many of the features of the well-characterized genetic disease 11 . For example, a large deletion on chromosome 22 causes 22q11.2 deletion syndrome, which includes both velocardiofacial syndrome and DiGeorge syndrome, which were historically believed to be different syndromes due to their differing clinical presentations. Additionally, patients may carry multiple contributing genetic factors leading to a phenotypic presentation that deviates from those previously defined and challenges a clear diagnosis 12 , 13 . Longitudinal clinical data stored in the electronic health record (EHR) have enabled approaches to identify patients at risk for numerous conditions 14 . In particular, recent work has shown that specific genetic diseases can be identified by looking for patients carrying many of the expected symptoms 15 , 16 . Although each genetic disease may present with a recognizable phenotypic profile, across the majority of genetic diseases there exists a recurring pattern of multiple phenotypes that are often rare and affect multiple organ systems. We propose that this constellation of rare and diverse phenotypes is a hallmark signature of patients with a genetic disease and can be captured from data in the EHR. Here, we test this hypothesis by building a machine learning-based prediction model to identify patients who have a clinical profile representative of receiving a genetic test for a suspected genetic disease. Specifically, we trained and tested our model on 2,286 patients who received a chromosomal microarray (CMA) test and 9,144 demographically matched controls using only diagnostic billing information from the EHR. We show highly accurate performance in our held-out testing sample, as well as in an external validation sample from another institution, and in an independent set of more than 170,000 hospital patients. We further validate the ability of this model to identify patients with genetic disease from among patients with putative pathogenic copy number variants (CNVs) and those carrying a diverse array of genetic diseases including many not present in our training data. Overall, our approach establishes the potential to identify patients with genetic disease from EHR data and presents a systemized way to improve the consistency and equity of genetic testing. Results Demographic and phenotype description of the CMA sample The primary case population consisted of 2,286 patients who received a CMA test. We matched each patient in the CMA group to four controls based exactly on age, sex, race, number of unique years in which they visited Vanderbilt University Medical Center (VUMC), and the closest available match on medical record length in days (maximum difference, 365 days). The vast majority (95%) of the recipients of the CMA test were less than 20 years old (mean age, 8.1 years), and most were male (61.3%) and white (75.6%, Table 1 ). Twenty-four per cent of patients ( n = 550) had an abnormal result, including 250 with at least one gain and 257 with at least one loss. Of these 550 patients, 37% (201 of 550) had a potential diagnosis included in the report. Although the reported genomic coordinates were most often unique, several known recurrent syndromes were seen more frequently, such as DiGeorge syndrome, Charcot-Marie-Tooth syndrome and 16p11.2 deletion syndrome. Table 1 Demographic and hospital utilization information for genetic testing and hospital population datasets Full size table We tested the difference in the frequency of phecodes (that is, an organization of EHR-based diagnostic<|im_end|> <|im_start|>assistant Patients who, perhaps unbeknownst to their health care providers, are in need of genetic testing for rare undiagnosed diseases can be identified en masse based on routine information in electronic health records (EHRs), a research team reported today in the journal Nature Medicine. Findings from the Vanderbilt University Medical Center study suggest that, among the patients of any sizeable health care system, there are hundreds or thousands with undiagnosed rare diseases of the sort where a genetic test could lead to a diagnosis. "Patients with rare genetic diseases often face years of diagnostic odyssey before getting a genetic test, if they get one at all. Our work could contribute to a more systematic and timely approach, alerting providers of patients that might benefit from a genetic test," said the leader of the study, geneticist Douglas Ruderfer, Ph.D., associate professor of Medicine at VUMC. It's estimated that more than 70% of rare diseases are genetic in origin. According to authors of the study, rare genetic diseases may look quite different from one patient to the next and may go undiagnosed even when well characterized in the medical literature. Using routine EHR data to directly identify patients with specific genetic diseases is, for now, quite challenging: according to the study authors, the current state of knowledge about disease-causing genetic variation is too wanting, and the genetic resolution of current clinical tests is too low. Given this state of affairs, the team developed their predictive model to instead detect patients who fit historical criteria for testing in the eyes of clinicians. To begin, the team developed a range of competing predictive algorithms. For training data, they used EHRs of patients for whom clinicians had ordered a type of genetic test called chromosomal microarray (1,818 cases), and similar patients whose records showed no history of genetic testing (7,326 matched controls). Across the training and test sets, the average age of the patients represented was 8. "We were really aiming to build a model that captured and automated clinical suspicion of a genetic disease," said Theodore Morley, a staff data scientist who worked closely with Ruderfer on the study. With all traces of genetic testing removed from a test set of 2,286 records, a machine learning algorithm emerged as the best performer, correctly classifying 87% of cases and 96% of controls. Also showing high accuracy were independent validation efforts at Boston's Massachusetts General Hospital and again at VUMC, with far greater numbers of longstanding patients, cases now defined by evidence in the EHR of interaction with a genetics provider. Importantly, the algorithm also performed well in identifying patients who received genetic tests other than chromosomal microarray. The study supports the hypothesis that, within any EHR population, patients who are to be suspected of having rare genetic diseases are distinguishable via computation thanks to the presence of multiple rare signs and symptoms—phenotypes, in the language of the study—that are subject to documentation in the EHR. The team's predictive algorithms used EHR diagnosis codes exclusively (the same codes that drive health care billing), amalgamated for prediction purposes into so-called phenotype codes. "After extensive validation demonstrated high predictive performance, we were really interested in assessing how an implementation of our model might compare to the current status quo for who receives a test, and what the results of those tests are," Ruderfer said. From a set of 6,445 deidentified EHRs corresponding to genotyped patient specimens from BioVU, Vanderbilt's DNA biobank, the algorithm proved accurate in picking out individuals with pathogenic copy number variations, a type of genetic abnormality. In collating this and other findings from the study, the authors estimate there are more than 2,000 patients at VUMC who have an unrecognized, potentially diagnostic copy number variation that could be identified with a genetic test. Among close observers of the study is Josh Peterson, MD, MPH, director of VUMC's Center for Precision Medicine (where Ruderfer is an affiliated faculty member). "The team's predictive model was shown to handily outperform current clinical performance, identifying patients who need testing more quickly and in greater numbers. Crucially, the model also proved portable to another health system. This paper's findings align very well with the push at VUMC to use data science to improve diagnosis of genomic syndromes," Peterson 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 Out-of-hospital cardiac arrest is a leading cause of death worldwide. Rapid diagnosis and initiation of cardiopulmonary resuscitation (CPR) is the cornerstone of therapy for victims of cardiac arrest. Yet a significant fraction of cardiac arrest victims have no chance of survival because they experience an unwitnessed event, often in the privacy of their own homes. An under-appreciated diagnostic element of cardiac arrest is the presence of agonal breathing, an audible biomarker and brainstem reflex that arises in the setting of severe hypoxia. Here, we demonstrate that a support vector machine (SVM) can classify agonal breathing instances in real-time within a bedroom environment. Using real-world labeled 9-1-1 audio of cardiac arrests, we train the SVM to accurately classify agonal breathing instances. We obtain an area under the curve (AUC) of 0.9993 ± 0.0003 and an operating point with an overall sensitivity and specificity of 97.24% (95% CI: 96.86–97.61%) and 99.51% (95% CI: 99.35–99.67%). We achieve a false positive rate between 0 and 0.14% over 82 h (117,985 audio segments) of polysomnographic sleep lab data that includes snoring, hypopnea, central, and obstructive sleep apnea events. We also evaluate our classifier in home sleep environments: the false positive rate was 0–0.22% over 164 h (236,666 audio segments) of sleep data collected across 35 different bedroom environments. We prototype our proof-of-concept contactless system using commodity smart devices (Amazon Echo and Apple iPhone) and demonstrate its effectiveness in identifying cardiac arrest-associated agonal breathing instances played over the air. Introduction Out-of-hospital cardiac arrest (OHCA) is a leading cause of death worldwide 1 and in North America accounts for nearly 300,000 deaths annually. 2 A relatively under-appreciated diagnostic element of cardiac arrest is the presence of a distinctive type of disordered breathing: agonal breathing. 3 , 4 Agonal breathing, which arises from a brainstem reflex in the setting of severe hypoxia, 5 , 6 appears to be evident in approximately half of cardiac arrest cases reported to 9-1-1. Agonal breathing indicates a relatively short duration from arrest and has been associated with higher survival rates. 7 , 8 , 9 Sometimes reported as “gasping” breaths, agonal respirations may hold potential as an audible diagnostic biomarker, particularly in unwitnessed cardiac arrests that occur in a private residence, the location of 2/3 of all OHCAs. 10 , 11 The widespread adoption of smartphones and smart speakers (projected to be in 75% of US households by 2020 12 ) presents a unique opportunity to identify this audible biomarker and connect unwitnessed cardiac arrest victims to Emergency Medical Services (EMS) or others who can administer cardiopulmonary resuscitation (CPR). In this study, we hypothesized that existing commodity devices (e.g., smartphones and smart speakers) could be used to accurately identify OHCA-associated agonal breathing instances in a domestic setting. As initial proof-of-concept, we focus on a relatively controlled environment, the bedroom, which is the location of the majority of OHCA events that occur within a private residence. 11 , 13 A key challenge to algorithm development for this purpose is accessing real-world data on agonal breathing; agonal breathing events are relatively uncommon, lack gold-standard measurements and cannot be reproduced in a lab because of their emergent nature. To overcome this challenge, we leverage a unique data source, 9-1-1 audio of confirmed cardiac arrest cases, which can include agonal breathing instances captured during the call. As our negative dataset, we use ambient household noise and audio from polysomnographic sleep studies, which include data that share similar audio characteristics to agonal breathing such as snoring and obstructive apnea events. Using real-world audio of agonal instances from OHCA events, we evaluate (1) whether a support vector machine (SVM) can be trained to detect OHCA-associated agonal breathing instances in a bedroom and sleep setting and (2) whether the SVM can be deployed and accurately classify agonal breathing audio in real-time using existing commodity smartphones and smart speakers. Results Concept Our agonal breathing detection pipeline (Fig. 1a ) captures audio samples from a smart speaker and smartphone and outputs the probability of agonal breathing in real-time on each 2.5 s audio segment. We use Google’s VGGish model 14 as a feature extractor to transform the raw audio waveforms into embeddings which are passed into an SVM. Each segment is transformed from the time-domain into a log-mel spectrogram, 15 and is further compressed into a feature embedding using principal component analysis. These embeddings are then passed into an SVM with a radial basis function kernel that can distinguish between agonal breathing instances (positive data) and non-agonal instances (negative data). An agonal-breathing frequency filter is then applied to the classifier’s probability outputs to reduce the false positive rate of the overall system. For comparison, Fig. 1b, c shows example audio waveforms and spectrograms for agonal breathing as well as snoring and apnea events, which can sound similar to but are physiologically different from agonal breathing. Fig. 1 Using a smart speaker to detect agonal breathing. a Agonal breathing detection pipeline. b Audio waveform and c spectrogram of agonal breathing, hypopnea, central apnea, and obstructive apnea Full size image Datasets Our agonal breathing recordings are sourced from 9-1-1 emergency calls from 2009 to 2017, provided by Public Health-Seattle & King County, Division of Emergency Medical Services. The dataset included 162 calls (19 h) that had clear recordings of agonal breathing (Fig. 2a ). For each occurrence, we extract 2.5 s worth of audio from the start of each agonal breath. We extracted a total of 236 clips of agonal breathing instances. Given the relatively small size of our agonal breathing dataset, we augment the number of agonal breathing instances with label preserving transformations, a common technique applied to sparse datasets. 16 , 17 We augment the data by playing the recordings over the air over distances of 1, 3, and 6 m, in the presence of interference from indoor and outdoor sounds with different volumes and when a noise cancellation filter is applied. The recordings were captured on different devices, namely an Amazon Alexa, an iPhone 5s and a Samsung Galaxy", "role": "user" }, { "content": "Almost 500,000 Americans die each year from cardiac arrest, when the heart suddenly stops beating. People experiencing cardiac arrest will suddenly become unresponsive and either stop breathing or gasp for air, a sign known as agonal breathing. Immediate CPR can double or triple someone's chance of survival, but that requires a bystander to be present. Cardiac arrests often occur outside of the hospital and in the privacy of someone's home. Recent research suggests that one of the most common locations for an out-of-hospital cardiac arrest is in a patient's bedroom, where no one is likely around or awake to respond and provide care. Researchers at the University of Washington have developed a new tool to monitor people for cardiac arrest while they're asleep without touching them. A new skill for a smart speaker— like Google Home and Amazon Alexa—or smartphone lets the device detect the gasping sound of agonal breathing and call for help. On average, the proof-of-concept tool, which was developed using real agonal breathing instances captured from 911 calls, detected agonal breathing events 97% of the time from up to 20 feet (or 6 meters) away. The findings are published June 19 in npj Digital Medicine. \"A lot of people have smart speakers in their homes, and these devices have amazing capabilities that we can take advantage of,\" said co-corresponding author Shyam Gollakota, an associate professor in the UW's Paul G. Allen School of Computer Science & Engineering. \"We envision a contactless system that works by continuously and passively monitoring the bedroom for an agonal breathing event, and alerts anyone nearby to come provide CPR. And then if there's no response, the device can automatically call 911.\" Agonal breathing is present for about 50% of people who experience cardiac arrests, according to 911 call data, and patients who take agonal breaths often have a better chance of surviving. \"This kind of breathing happens when a patient experiences really low oxygen levels,\" said co-corresponding author Dr. Jacob Sunshine, an assistant professor of anesthesiology and pain medicine at the UW School of Medicine. \"It's sort of a guttural gasping noise, and its uniqueness makes it a good audio biomarker to use to identify if someone is experiencing a cardiac arrest.\" The researchers gathered sounds of agonal breathing from real 911 calls to Seattle's Emergency Medical Services. Because cardiac arrest patients are often unconscious, bystanders recorded the agonal breathing sounds by putting their phones up to the patient's mouth so that the dispatcher could determine whether the patient needed immediate CPR. The team collected 162 calls between 2009 and 2017 and extracted 2.5 seconds of audio at the start of each agonal breath to come up with a total of 236 clips. The team captured the recordings on different smart devices—an Amazon Alexa, an iPhone 5s and a Samsung Galaxy S4—and used various machine learning techniques to boost the dataset to 7,316 positive clips. \"We played these examples at different distances to simulate what it would sound like if it the patient was at different places in the bedroom,\" said first author Justin Chan, a doctoral student in the Allen School. \"We also added different interfering sounds such as sounds of cats and dogs, cars honking, air conditioning, things that you might normally hear in a home.\" For the negative dataset, the team used 83 hours of audio data collected during sleep studies, yielding 7,305 sound samples. These clips contained typical sounds that people make in their sleep, such as snoring or obstructive sleep apnea. From these datasets, the team used machine learning to create a tool that could detect agonal breathing 97% of the time when the smart device was placed up to 6 meters away from a speaker generating the sounds. Next the team tested the algorithm to make sure that it wouldn't accidentally classify a different type of breathing, like snoring, as agonal breathing. \"We don't want to alert either emergency services or loved ones unnecessarily, so it's important that we reduce our false positive rate,\" Chan said. For the sleep lab data, the algorithm incorrectly categorized a breathing sound as agonal breathing 0.14% of the time. The false positive rate was about 0.22% for separate audio clips, in which volunteers had recorded themselves while sleeping in their own homes. But when the team had the tool classify something as agonal breathing only when it detected two distinct events at least 10 seconds apart, the false positive rate fell to 0% for both tests. The team envisions this algorithm could function like an app, or a skill for Alexa that runs passively on a smart speaker or smartphone while people sleep. \"This could run locally on the processors contained in the Alexa. It's running in real time, so you don't need to store anything or send anything to the cloud,\" Gollakota said. \"Right now, this is a good proof of concept using the 911 calls in the Seattle metropolitan area,\" he said. \"But we need to get access to more 911 calls related to cardiac arrest so that we can improve the accuracy of the algorithm further and ensure that it generalizes across a larger population.\" The researchers plan to commercialize this technology through a UW spinout, Sound Life Sciences, Inc. \"Cardiac arrests are a very common way for people to die, and right now many of them can go unwitnessed,\" Sunshine said. \"Part of what makes this technology so compelling is that it could help us catch more patients in time for them to be treated.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Out-of-hospital cardiac arrest is a leading cause of death worldwide. Rapid diagnosis and initiation of cardiopulmonary resuscitation (CPR) is the cornerstone of therapy for victims of cardiac arrest. Yet a significant fraction of cardiac arrest victims have no chance of survival because they experience an unwitnessed event, often in the privacy of their own homes. An under-appreciated diagnostic element of cardiac arrest is the presence of agonal breathing, an audible biomarker and brainstem reflex that arises in the setting of severe hypoxia. Here, we demonstrate that a support vector machine (SVM) can classify agonal breathing instances in real-time within a bedroom environment. Using real-world labeled 9-1-1 audio of cardiac arrests, we train the SVM to accurately classify agonal breathing instances. We obtain an area under the curve (AUC) of 0.9993 ± 0.0003 and an operating point with an overall sensitivity and specificity of 97.24% (95% CI: 96.86–97.61%) and 99.51% (95% CI: 99.35–99.67%). We achieve a false positive rate between 0 and 0.14% over 82 h (117,985 audio segments) of polysomnographic sleep lab data that includes snoring, hypopnea, central, and obstructive sleep apnea events. We also evaluate our classifier in home sleep environments: the false positive rate was 0–0.22% over 164 h (236,666 audio segments) of sleep data collected across 35 different bedroom environments. We prototype our proof-of-concept contactless system using commodity smart devices (Amazon Echo and Apple iPhone) and demonstrate its effectiveness in identifying cardiac arrest-associated agonal breathing instances played over the air. Introduction Out-of-hospital cardiac arrest (OHCA) is a leading cause of death worldwide 1 and in North America accounts for nearly 300,000 deaths annually. 2 A relatively under-appreciated diagnostic element of cardiac arrest is the presence of a distinctive type of disordered breathing: agonal breathing. 3 , 4 Agonal breathing, which arises from a brainstem reflex in the setting of severe hypoxia, 5 , 6 appears to be evident in approximately half of cardiac arrest cases reported to 9-1-1. Agonal breathing indicates a relatively short duration from arrest and has been associated with higher survival rates. 7 , 8 , 9 Sometimes reported as “gasping” breaths, agonal respirations may hold potential as an audible diagnostic biomarker, particularly in unwitnessed cardiac arrests that occur in a private residence, the location of 2/3 of all OHCAs. 10 , 11 The widespread adoption of smartphones and smart speakers (projected to be in 75% of US households by 2020 12 ) presents a unique opportunity to identify this audible biomarker and connect unwitnessed cardiac arrest victims to Emergency Medical Services (EMS) or others who can administer cardiopulmonary resuscitation (CPR). In this study, we hypothesized that existing commodity devices (e.g., smartphones and smart speakers) could be used to accurately identify OHCA-associated agonal breathing instances in a domestic setting. As initial proof-of-concept, we focus on a relatively controlled environment, the bedroom, which is the location of the majority of OHCA events that occur within a private residence. 11 , 13 A key challenge to algorithm development for this purpose is accessing real-world data on agonal breathing; agonal breathing events are relatively uncommon, lack gold-standard measurements and cannot be reproduced in a lab because of their emergent nature. To overcome this challenge, we leverage a unique data source, 9-1-1 audio of confirmed cardiac arrest cases, which can include agonal breathing instances captured during the call. As our negative dataset, we use ambient household noise and audio from polysomnographic sleep studies, which include data that share similar audio characteristics to agonal breathing such as snoring and obstructive apnea events. Using real-world audio of agonal instances from OHCA events, we evaluate (1) whether a support vector machine (SVM) can be trained to detect OHCA-associated agonal breathing instances in a bedroom and sleep setting and (2) whether the SVM can be deployed and accurately classify agonal breathing audio in real-time using existing commodity smartphones and smart speakers. Results Concept Our agonal breathing detection pipeline (Fig. 1a ) captures audio samples from a smart speaker and smartphone and outputs the probability of agonal breathing in real-time on each 2.5 s audio segment. We use Google’s VGGish model 14 as a feature extractor to transform the raw audio waveforms into embeddings which are passed into an SVM. Each segment is transformed from the time-domain into a log-mel spectrogram, 15 and is further compressed into a feature embedding using principal component analysis. These embeddings are then passed into an SVM with a radial basis function kernel that can distinguish between agonal breathing instances (positive data) and non-agonal instances (negative data). An agonal-breathing frequency filter is then applied to the classifier’s probability outputs to reduce the false positive rate of the overall system. For comparison, Fig. 1b, c shows example audio waveforms and spectrograms for agonal breathing as well as snoring and apnea events, which can sound similar to but are physiologically different from agonal breathing. Fig. 1 Using a smart speaker to detect agonal breathing. a Agonal breathing detection pipeline. b Audio waveform and c spectrogram of agonal breathing, hypopnea, central apnea, and obstructive apnea Full size image Datasets Our agonal breathing recordings are sourced from 9-1-1 emergency calls from 2009 to 2017, provided by Public Health-Seattle & King County, Division of Emergency Medical Services. The dataset included 162 calls (19 h) that had clear recordings of agonal breathing (Fig. 2a ). For each occurrence, we extract 2.5 s worth of audio from the start of each agonal breath. We extracted a total of 236 clips of agonal breathing instances. Given the relatively small size of our agonal breathing dataset, we augment the number of agonal breathing instances with label preserving transformations, a common technique applied to sparse datasets. 16 , 17 We augment the data by playing the recordings over the air over distances of 1, 3, and 6 m, in the presence of interference from indoor and outdoor sounds with different volumes and when a noise cancellation filter is applied. The recordings were captured on different devices, namely an Amazon Alexa, an iPhone 5s and a Samsung Galaxy<|im_end|> <|im_start|>assistant Almost 500,000 Americans die each year from cardiac arrest, when the heart suddenly stops beating. People experiencing cardiac arrest will suddenly become unresponsive and either stop breathing or gasp for air, a sign known as agonal breathing. Immediate CPR can double or triple someone's chance of survival, but that requires a bystander to be present. Cardiac arrests often occur outside of the hospital and in the privacy of someone's home. Recent research suggests that one of the most common locations for an out-of-hospital cardiac arrest is in a patient's bedroom, where no one is likely around or awake to respond and provide care. Researchers at the University of Washington have developed a new tool to monitor people for cardiac arrest while they're asleep without touching them. A new skill for a smart speaker— like Google Home and Amazon Alexa—or smartphone lets the device detect the gasping sound of agonal breathing and call for help. On average, the proof-of-concept tool, which was developed using real agonal breathing instances captured from 911 calls, detected agonal breathing events 97% of the time from up to 20 feet (or 6 meters) away. The findings are published June 19 in npj Digital Medicine. "A lot of people have smart speakers in their homes, and these devices have amazing capabilities that we can take advantage of," said co-corresponding author Shyam Gollakota, an associate professor in the UW's Paul G. Allen School of Computer Science & Engineering. "We envision a contactless system that works by continuously and passively monitoring the bedroom for an agonal breathing event, and alerts anyone nearby to come provide CPR. And then if there's no response, the device can automatically call 911." Agonal breathing is present for about 50% of people who experience cardiac arrests, according to 911 call data, and patients who take agonal breaths often have a better chance of surviving. "This kind of breathing happens when a patient experiences really low oxygen levels," said co-corresponding author Dr. Jacob Sunshine, an assistant professor of anesthesiology and pain medicine at the UW School of Medicine. "It's sort of a guttural gasping noise, and its uniqueness makes it a good audio biomarker to use to identify if someone is experiencing a cardiac arrest." The researchers gathered sounds of agonal breathing from real 911 calls to Seattle's Emergency Medical Services. Because cardiac arrest patients are often unconscious, bystanders recorded the agonal breathing sounds by putting their phones up to the patient's mouth so that the dispatcher could determine whether the patient needed immediate CPR. The team collected 162 calls between 2009 and 2017 and extracted 2.5 seconds of audio at the start of each agonal breath to come up with a total of 236 clips. The team captured the recordings on different smart devices—an Amazon Alexa, an iPhone 5s and a Samsung Galaxy S4—and used various machine learning techniques to boost the dataset to 7,316 positive clips. "We played these examples at different distances to simulate what it would sound like if it the patient was at different places in the bedroom," said first author Justin Chan, a doctoral student in the Allen School. "We also added different interfering sounds such as sounds of cats and dogs, cars honking, air conditioning, things that you might normally hear in a home." For the negative dataset, the team used 83 hours of audio data collected during sleep studies, yielding 7,305 sound samples. These clips contained typical sounds that people make in their sleep, such as snoring or obstructive sleep apnea. From these datasets, the team used machine learning to create a tool that could detect agonal breathing 97% of the time when the smart device was placed up to 6 meters away from a speaker generating the sounds. Next the team tested the algorithm to make sure that it wouldn't accidentally classify a different type of breathing, like snoring, as agonal breathing. "We don't want to alert either emergency services or loved ones unnecessarily, so it's important that we reduce our false positive rate," Chan said. For the sleep lab data, the algorithm incorrectly categorized a breathing sound as agonal breathing 0.14% of the time. The false positive rate was about 0.22% for separate audio clips, in which volunteers had recorded themselves while sleeping in their own homes. But when the team had the tool classify something as agonal breathing only when it detected two distinct events at least 10 seconds apart, the false positive rate fell to 0% for both tests. The team envisions this algorithm could function like an app, or a skill for Alexa that runs passively on a smart speaker or smartphone while people sleep. "This could run locally on the processors contained in the Alexa. It's running in real time, so you don't need to store anything or send anything to the cloud," Gollakota said. "Right now, this is a good proof of concept using the 911 calls in the Seattle metropolitan area," he said. "But we need to get access to more 911 calls related to cardiac arrest so that we can improve the accuracy of the algorithm further and ensure that it generalizes across a larger population." The researchers plan to commercialize this technology through a UW spinout, Sound Life Sciences, Inc. "Cardiac arrests are a very common way for people to die, and right now many of them can go unwitnessed," Sunshine said. "Part of what makes this technology so compelling is that it could help us catch more patients in time for them to be treated." <|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 rational design of heterogeneous catalysts relies on the efficient survey of mechanisms by density functional theory (DFT). However, massive reaction networks cannot be sampled effectively as they grow exponentially with the size of reactants. Here we present a statistical principal component analysis and regression applied to the DFT thermochemical data of 71 C \${}_{1}\$ –C \${}_{2}\$ species on 12 close-packed metal surfaces. Adsorption is controlled by covalent ( \$d\$ -band center) and ionic terms (reduction potential), modulated by conjugation and conformational contributions. All formation energies can be reproduced from only three key intermediates (predictors) calculated with DFT. The results agree with accurate experimental measurements having error bars comparable to those of DFT. The procedure can be extended to single-atom and near-surface alloys reducing the number of explicit DFT calculation needed by a factor of 20, thus paving the way for a rapid and accurate survey of whole reaction networks on multimetallic surfaces. Introduction Heterogeneous catalysis holds the key to solving fundamental sustainability issues by introducing renewable compounds as a source of chemicals and energy vectors 1 , 2 , 3 . The rational search for new catalysts benefits from the extensive use of density functional theory (DFT) and kinetic models derived from it 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 . This procedure requires sampling the reaction network that links reactants, intermediates, and products through transition states. For large molecules, such as those involved in biomass valorization processes, the number of intermediates and transition states grow exponentially with the molecular size, rendering the computational screening of new catalysts impractical. For instance, the decomposition of a medium size C \${}_{5}\$ –C \${}_{6}\$ sugar alcohols encompasses more than \$1{0}^{4}\$ species and \$1{0}^{5}\$ transition states in its reaction network 11 . The positive aspect is that kinetic barriers are linked to the formation energies of different intermediates 4 , 12 . Thus, the screening may be reduced to obtain the thermodynamics for the adsorbed species and couple them with linear-scaling relationships and microkinetic models to simulate operation conditions. The upgrade of biomass-derived molecules is often done by metals and alloys 1 , 13 , and lately attention has been drawn to the versatile properties of single-atom alloys (SAAs) and near-surface alloys (NSAs) 9 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 . The number of combinations is again unlimited and some have shown an almost continuum of adsorption strengths 21 . To this end, new thermochemical models based on statistical learning may allow a rapid survey of the energies of adsorbed species for faster screening 8 , 18 , 23 , 24 , 25 , 26 , 27 . The pioneering work by Benson established the basis for thermochemical scaling relationships of gas-phase molecules already in the 60s 28 . In this formulation, the formation energy for a hydrocarbon or oxygenated molecule is obtained as the sum of the energies stored on C–C, C–O, C–H, and O–H bonds, considering also the contribution from rings, unsaturations, and radicals 28 . Despite its simplicity, Benson’s model has an impressive accuracy for small molecules such as hydrocarbons, alcohols, and ethers, the formation energy of which is predicted with errors lower than 0.05 eV 29 . When molecules adsorb on metal surfaces, the interaction has covalent, ionic, and dispersion contributions. The most studied term is the covalency appearing from the coupling of the metal \$sp\$ - and \$d\$ -states with the adsorbate. The \$sp\$ part depends on the species but it is rather constant along the metals. The second one gives the metal-to-metal variability and comes from the \$d\$ -band center and filling 30 , 31 . As a consequence, the adsorption energy of a molecular fragment AH \${}_{x}\$ is a linear function of that of its heteroatom, A, and the slope accounts for the valence of AH \${}_{x}\$ 32 . Further linear dependencies have been identified for heteroatoms belonging to the same group in the periodic table, i.e., P* scales with N* 33 . In addition, the accuracy of the above models can be improved by using site-specific adsorption rules 22 , 32 and the dependence on the local coordination of the adsorption sites 22 , 34 , 35 . In the particular case of very small nanoparticles, the activity modulation is linearly dependent with the local electrostatic potential 36 . These adsorption energy models have been extended to multifunctionalized molecules by combining the heteroatom scalings and the Benson model 28 , 37 , 38 . The combination can be centered either on individual bond energies 37 or on the coordination environment of each heteroatom 38 . Attempts to generalize simplified thermochemical models to other materials are less frequent, but for perovskites and transition metal oxides 39 , 40 , 41 , electronic parameters such as the occupancy of e \${}_{g}\$ orbitals and the covalency for the oxygen-transition metal bond were deemed descriptors for their catalytic activity. Still, the reactivity on metals has provided the largest amount of DFT data and benchmarks on the thermochemistry demonstrate the robustness of the results 42 . Thus, large FAIR databases 43 open alternative paths to rationally design heterogeneous catalysts 10 , by improving existing thermochemical models and generating new ones through statistical learning. For instance, the formation energies of large molecules in gas phase can be retrieved from neural networks with an accuracy comparable to DFT, 0.04 eV MAE 44 , thus beyond Benson’s model 29 . An alternative approach is to predict the formation energy of few reactivity descriptors from geometric and electronic features, such as atomic radius, local electronegativity, ionic potential, and the coordination of the active site 9 , 18 , 22 , 45 . Particularly, a recent SISSO study considers features from the adsorbate, the metal, and the adsorption site 45 , providing excellent predictions with one DFT evaluation for each metal. However, the method does not belong to the explanatory class of machine-learning techniques", "role": "user" }, { "content": "Researchers from ICIQ's López group present a new method that allows for the rational design of heterogeneous catalysts. After applying principal component analysis and regression (PCA) to the adsorption energies of 71 different C1 and C2 species on 12 close-packed (transition) metal surfaces, the scientists elucidated for the first time an interpretable model in heterogeneous catalysis. The team's new method, published in Nature Communications, will facilitate the discovery of heterogeneous catalysts able to transform the non-edible fraction of biomass into valuable chemical products. The procedure reduces the number of calculations by a factor of 20 while retaining error bars comparable to density functional theory (DFT). As simple as possible, but not simpler Biomass molecules are big. With complex molecular structures, there are many reaction sites to be considered when biomass interacts with a catalyst. A relatively small molecule, such as a C6, could present a reaction network of about 500,000 reactions—making it too time and resource-demanding to study using current models. In contrast, by studying C1 and C2 species the scientists now can extrapolate the behavior to bigger molecules commonly found in biomass. The researchers from the López group applied PCA, a simple and unsupervised Machine Learning technique, to reduce the dimensionality of the problem. After analyzing the formation energies of 71 adsorbates on 12 close-packed metal surfaces, the researchers obtained a two-term linear expression that allows for the rapid and accurate survey of whole reaction networks on metallic surfaces while drastically slashing the number of DFT calculations needed. The simplicity of the resulting model has allowed the ICIQ researchers to go one step beyond the state of the art and interpret the results—a first in heterogeneous catalysis. From black to green Interpreting the results of machine learning tools yield can be a challenge. Luckily, the ICIQ scientists have been able to open the box and interpret in physical terms the parameters of the equation. \"If you know what each of the terms in the equation means, you can go further and expand your model,\" explains Rodrigo García-Muelas, first author of the paper. \"The equation's first term describes bond covalency while the second one is related to the bond's ionicity.\" The mathematical sequence used to find the models is publicly available to other researchers to reproduce the results. The new model applies to a wide range of scenarios and allows the prediction of how a system will react and what it will yield by just knowing the characteristics of the bonds. Machine learning approaches applied to catalysis are expanding our understanding of the inner workings of molecules bringing closer the transformation of biomass into biofuels, thus providing a greener alternative to fossil fuels. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users 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 rational design of heterogeneous catalysts relies on the efficient survey of mechanisms by density functional theory (DFT). However, massive reaction networks cannot be sampled effectively as they grow exponentially with the size of reactants. Here we present a statistical principal component analysis and regression applied to the DFT thermochemical data of 71 C ${}_{1}$ –C ${}_{2}$ species on 12 close-packed metal surfaces. Adsorption is controlled by covalent ( $d$ -band center) and ionic terms (reduction potential), modulated by conjugation and conformational contributions. All formation energies can be reproduced from only three key intermediates (predictors) calculated with DFT. The results agree with accurate experimental measurements having error bars comparable to those of DFT. The procedure can be extended to single-atom and near-surface alloys reducing the number of explicit DFT calculation needed by a factor of 20, thus paving the way for a rapid and accurate survey of whole reaction networks on multimetallic surfaces. Introduction Heterogeneous catalysis holds the key to solving fundamental sustainability issues by introducing renewable compounds as a source of chemicals and energy vectors 1 , 2 , 3 . The rational search for new catalysts benefits from the extensive use of density functional theory (DFT) and kinetic models derived from it 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 . This procedure requires sampling the reaction network that links reactants, intermediates, and products through transition states. For large molecules, such as those involved in biomass valorization processes, the number of intermediates and transition states grow exponentially with the molecular size, rendering the computational screening of new catalysts impractical. For instance, the decomposition of a medium size C ${}_{5}$ –C ${}_{6}$ sugar alcohols encompasses more than $1{0}^{4}$ species and $1{0}^{5}$ transition states in its reaction network 11 . The positive aspect is that kinetic barriers are linked to the formation energies of different intermediates 4 , 12 . Thus, the screening may be reduced to obtain the thermodynamics for the adsorbed species and couple them with linear-scaling relationships and microkinetic models to simulate operation conditions. The upgrade of biomass-derived molecules is often done by metals and alloys 1 , 13 , and lately attention has been drawn to the versatile properties of single-atom alloys (SAAs) and near-surface alloys (NSAs) 9 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 . The number of combinations is again unlimited and some have shown an almost continuum of adsorption strengths 21 . To this end, new thermochemical models based on statistical learning may allow a rapid survey of the energies of adsorbed species for faster screening 8 , 18 , 23 , 24 , 25 , 26 , 27 . The pioneering work by Benson established the basis for thermochemical scaling relationships of gas-phase molecules already in the 60s 28 . In this formulation, the formation energy for a hydrocarbon or oxygenated molecule is obtained as the sum of the energies stored on C–C, C–O, C–H, and O–H bonds, considering also the contribution from rings, unsaturations, and radicals 28 . Despite its simplicity, Benson’s model has an impressive accuracy for small molecules such as hydrocarbons, alcohols, and ethers, the formation energy of which is predicted with errors lower than 0.05 eV 29 . When molecules adsorb on metal surfaces, the interaction has covalent, ionic, and dispersion contributions. The most studied term is the covalency appearing from the coupling of the metal $sp$ - and $d$ -states with the adsorbate. The $sp$ part depends on the species but it is rather constant along the metals. The second one gives the metal-to-metal variability and comes from the $d$ -band center and filling 30 , 31 . As a consequence, the adsorption energy of a molecular fragment AH ${}_{x}$ is a linear function of that of its heteroatom, A, and the slope accounts for the valence of AH ${}_{x}$ 32 . Further linear dependencies have been identified for heteroatoms belonging to the same group in the periodic table, i.e., P* scales with N* 33 . In addition, the accuracy of the above models can be improved by using site-specific adsorption rules 22 , 32 and the dependence on the local coordination of the adsorption sites 22 , 34 , 35 . In the particular case of very small nanoparticles, the activity modulation is linearly dependent with the local electrostatic potential 36 . These adsorption energy models have been extended to multifunctionalized molecules by combining the heteroatom scalings and the Benson model 28 , 37 , 38 . The combination can be centered either on individual bond energies 37 or on the coordination environment of each heteroatom 38 . Attempts to generalize simplified thermochemical models to other materials are less frequent, but for perovskites and transition metal oxides 39 , 40 , 41 , electronic parameters such as the occupancy of e ${}_{g}$ orbitals and the covalency for the oxygen-transition metal bond were deemed descriptors for their catalytic activity. Still, the reactivity on metals has provided the largest amount of DFT data and benchmarks on the thermochemistry demonstrate the robustness of the results 42 . Thus, large FAIR databases 43 open alternative paths to rationally design heterogeneous catalysts 10 , by improving existing thermochemical models and generating new ones through statistical learning. For instance, the formation energies of large molecules in gas phase can be retrieved from neural networks with an accuracy comparable to DFT, 0.04 eV MAE 44 , thus beyond Benson’s model 29 . An alternative approach is to predict the formation energy of few reactivity descriptors from geometric and electronic features, such as atomic radius, local electronegativity, ionic potential, and the coordination of the active site 9 , 18 , 22 , 45 . Particularly, a recent SISSO study considers features from the adsorbate, the metal, and the adsorption site 45 , providing excellent predictions with one DFT evaluation for each metal. However, the method does not belong to the explanatory class of machine-learning techniques<|im_end|> <|im_start|>assistant Researchers from ICIQ's López group present a new method that allows for the rational design of heterogeneous catalysts. After applying principal component analysis and regression (PCA) to the adsorption energies of 71 different C1 and C2 species on 12 close-packed (transition) metal surfaces, the scientists elucidated for the first time an interpretable model in heterogeneous catalysis. The team's new method, published in Nature Communications, will facilitate the discovery of heterogeneous catalysts able to transform the non-edible fraction of biomass into valuable chemical products. The procedure reduces the number of calculations by a factor of 20 while retaining error bars comparable to density functional theory (DFT). As simple as possible, but not simpler Biomass molecules are big. With complex molecular structures, there are many reaction sites to be considered when biomass interacts with a catalyst. A relatively small molecule, such as a C6, could present a reaction network of about 500,000 reactions—making it too time and resource-demanding to study using current models. In contrast, by studying C1 and C2 species the scientists now can extrapolate the behavior to bigger molecules commonly found in biomass. The researchers from the López group applied PCA, a simple and unsupervised Machine Learning technique, to reduce the dimensionality of the problem. After analyzing the formation energies of 71 adsorbates on 12 close-packed metal surfaces, the researchers obtained a two-term linear expression that allows for the rapid and accurate survey of whole reaction networks on metallic surfaces while drastically slashing the number of DFT calculations needed. The simplicity of the resulting model has allowed the ICIQ researchers to go one step beyond the state of the art and interpret the results—a first in heterogeneous catalysis. From black to green Interpreting the results of machine learning tools yield can be a challenge. Luckily, the ICIQ scientists have been able to open the box and interpret in physical terms the parameters of the equation. "If you know what each of the terms in the equation means, you can go further and expand your model," explains Rodrigo García-Muelas, first author of the paper. "The equation's first term describes bond covalency while the second one is related to the bond's ionicity." The mathematical sequence used to find the models is publicly available to other researchers to reproduce the results. The new model applies to a wide range of scenarios and allows the prediction of how a system will react and what it will yield by just knowing the characteristics of the bonds. Machine learning approaches applied to catalysis are expanding our understanding of the inner workings of molecules bringing closer the transformation of biomass into biofuels, thus providing a greener alternative to fossil fuels. <|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 Extant species have wildly different numbers of chromosomes, even among taxa with relatively similar genome sizes (for example, insects) 1 , 2 . This is likely to reflect accidents of genome history, such as telomere–telomere fusions and genome duplication events 3 , 4 , 5 . Humans have 23 pairs of chromosomes, whereas other apes have 24. One human chromosome is a fusion product of the ancestral state 6 . This raises the question: how well can species tolerate a change in chromosome numbers without substantial changes to genome content? Many tools are used in chromosome engineering in Saccharomyces cerevisiae 7 , 8 , 9 , 10 , but CRISPR–Cas9-mediated genome editing facilitates the most aggressive engineering strategies. Here we successfully fused yeast chromosomes using CRISPR–Cas9, generating a near-isogenic series of strains with progressively fewer chromosomes ranging from sixteen to two. A strain carrying only two chromosomes of about six megabases each exhibited modest transcriptomic changes and grew without major defects. When we crossed a sixteen-chromosome strain with strains with fewer chromosomes, we noted two trends. As the number of chromosomes dropped below sixteen, spore viability decreased markedly, reaching less than 10% for twelve chromosomes. As the number of chromosomes decreased further, yeast sporulation was arrested: a cross between a sixteen-chromosome strain and an eight-chromosome strain showed greatly reduced full tetrad formation and less than 1% sporulation, from which no viable spores could be recovered. However, homotypic crosses between pairs of strains with eight, four or two chromosomes produced excellent sporulation and spore viability. These results indicate that eight chromosome–chromosome fusion events suffice to isolate strains reproductively. Overall, budding yeast tolerates a reduction in chromosome number unexpectedly well, providing a striking example of the robustness of genomes to change. Main Chromosome engineering in S. cerevisiae is driven by technological advances 7 , 8 , 9 , 10 . A haploid yeast strain with 33 chromosomes has been generated by splitting natural chromosomes into smaller chromosomes 7 . On the other hand, the two largest S. cerevisiae chromosomes, IV and XII, were fused by homologous recombination 8 , producing yeast with a 3.2-Mb compound chromosome that grew well. Further fusions (chromosomes VII–V–XV–IV) generated a 4.3-Mb compound chromosome with the longest yeast chromosome arm engineered previously (3.7 Mb), and a haploid chromosome number of n = 12, with no observed effect on fitness 9 . CRISPR–Cas9 expression in S. cerevisiae 10 permits efficient engineering without selection. We used this to push the lower limit of chromosome numbers in S. cerevisiae by fusing chromosomes, producing a series of strains with progressively fewer chromosomes without affecting gene content. At least three potential biological obstacles might hinder engineering of karyotype. First, studies of the field bean Vicia faba have suggested that the length limit to chromosome arms is half the average spindle axis at telophase for normal development 11 . Longer arms might yield incomplete sister chromatid separation, lagging chromosomes and micronucleus formation, impairing fertility and development. Second, as centromeres are deleted, excess kinetochore proteins may cause problems. Finally, mitotic mechanics may be affected—centromeric force may not suffice to pull very long chromosomes poleward. The latter is a particular concern for S. cerevisiae , in which point centromeres are bound by single microtubules; most organisms with larger chromosomes have regional centromeres bound by multiple microtubules 12 . Karyotype engineering in S. cerevisiae , therefore, investigates whether point centromeres can segregate large chromosomes. We devised specific paths to evaluate minimization of the number of chromosomes ( n ). We first fused all small chromosomes to maximize the number of chromosomes fused before hitting a potential chromosome arm length limit. Specifically, we fused chromosomes IX, III and I, then V and VIII, and finally II and VI to generate an n = 12 strain (Fig. 1 ). We developed a CRISPR–Cas9-based strategy to fuse any two chromosomes while largely preserving isogenicity (Fig. 2a , Extended Data Fig. 1a and Extended Data Table 1 ; see Methods ). Pulsed field gel electrophoresis, used for karyotyping S. cerevisiae , confirmed the presence of progressively fewer and larger chromosomes (Fig. 2b ) with all chromosomes shorter than 600 kb merged in the n = 12 strain. Fig. 1: Fusion chromosome paths and strategy. This diagram shows how we fused chromosomes together from the wild type ( n = 16) to n = 12, n = 8, n = 4 and finally n = 2. The 16 chromosomes are coloured uniquely and arranged by number. A ruler indicates the distance from the centromere. The centromeres of n = 4 and n = 2 are aligned to the 0 position. Please note that the length of the rDNA array, whose position is indicated with an asterisk, is omitted. Red lettering indicates the chromosome that has an active centromere in the compound chromosome. All the chromosomes are oriented from left to right (bottom to top in the figure) in the fusion chromosomes. For more details see Extended Data Fig. 1b . Full size image Fig. 2: Construction and characterization of fusion chromosomes. a , A schematic showing a CRISPR–Cas9 based method to fuse any two chromosomes together. CEN3 and CEN1, centromeres of chromosomes III and I, respectively. b , Pulsed-field gel electrophoresis with a standard protocol for Saccharomyces cerevisiae . c , Pulsed-field gel electrophoresis with Hansenula wingei (also known as Wickerhamomyces canadensis ) chromosomal DNA as a marker. d , Pulsed-field gel electrophoresis with S. pombe ( S.p .) chromosomal DNA as a marker. S.c ., S. cerevisiae. n = 3 strain is yJL381; n = 3′ strain is yJL410. Full size image Given that 3.2-Mb and 4.3-Mb compound acrocentric chromosomes have been engineered previously 8 , 9 , we next produced a strain with four long chromosomes, each about 3 Mb long (for simplicity, the length of the rDNA array is omitted from lengths reported herein; Fig. 1 ). The serial disappearance of chromosomes confirmed that sequential fusion events occurred as planned (Fig. 2c ). The n = 4 strain", "role": "user" }, { "content": "Baker's yeast survive and grow after a drastic reorganization, not of their genes, but of the chromosome superstructures that house, protect and control access to their DNA code, a study just published in Nature finds. Led by NYU School of Medicine, a research team fused together chromosomes in stages until the 6,000 genes in a species of one-celled fungus, Saccharomyces cerevisiae, were contained in two massive chromosomes instead of the naturally occurring 16 in each cell nucleus. The researchers also found that members of this yeast species could no longer make viable reproductive cells if the difference became too great between the numbers of chromosomes inherited from each of their \"parents.\" Engineering such \"reproductive isolation\" between yeast strains would be a must to achieve certain hoped-for, future applications of yeast—like recycling agricultural waste to make fuel, or fighting starvation by supplementing livestock feed, say the study authors. Such endeavors would require the creation of strains that could be released into the field, but that were incapable of mating with naturally occurring yeast to alter ecosystems. Further in the future, a better understanding of how chromosomes are copied and apportioned in sex cells—spores in yeast; eggs and sperm in humans—may suggest ways to counter errors that cause too short, too long, missing or extra chromosomes to be passed down in human cells. Such events are a main cause of miscarriages and mental retardation, including Down's syndrome, in which an embryo receives an extra copy of the 21st human chromosome. Yeast chromosomes are similar enough to human ones to make good models for study. \"We found that yeast can tolerate drastic changes in chromosome number without disrupting the action of the genes in them, more evidence of their robustness as an engineering platform,\" says senior study author Jef Boeke, Ph.D., director of the Institute for Systems Genetics at NYU Langone Health. \"Beyond applications, this work sheds light on the wild trajectory of accidental chromosome duplications and fusions across evolution that has left one ant species with a single pair of chromosomes, humans with 23 pairs, and one species of butterfly with 220. We are learning how one species becomes two.\" Sixteen into Two The study results concern chromosomes, large protein bundles that, upon receiving the right signals, unwind to expose for reading by the cellular machinery just the bits of DNA instructions needed for the jobs at hand in each cell type. All chromosomes unwind when it is time to copy the entire genetic code before cell division, where one cell becomes two. Such divisions either create more genetically identical cells during growth (mitosis), or further divide a parental cell's chromosomes in rounds (meiosis) that yield sex cells, which can then combine with other sex cells to create new organisms. As cells get ready to divide such that each resulting cell gets its proper share of DNA, the newly copied chromosomes are connected by special DNA sets called centromeres, creating pairs with four chromosome \"arms.\" Each arm is capped by DNA sets called telomeres which protect against enzymes that would otherwise damage the exposed tips. The current study authors used the famous CRISPR-Cas9 gene editing technology to cut 14 centromeres and 28 telomeres out of the complete set of yeast chromosomes (the genome). Without these telomeres or centromeres in place, the remaining DNA chains fused in steps until only two remained, each containing roughly half the genetic material for the S. cerevisiae species. Interestingly, the team was unable to generate a living strain of yeast with just one chromosome pair housing all of its genes. The authors say this may be because the two large chromosomes operating in the new strain had arms that, at about 5.9 million DNA molecular letters (bases) each, approached the maximum length limit. Longer than that and an arm is likely to have its end clipped off as a cell divides. Remarkably, the researchers found that yeast with chromosomes that are up to four times the maximum size of those seen in nature survived, divided and multiplied (grew) via mitosis at roughly the same rates as natural strains. However, when the team took the offspring from crosses of yeast strains with different chromosome numbers, and then induced the offspring of the crosses to make sex cells via meiosis, the ability to produce viable spores dropped in this next generation as the difference grew between the chromosome numbers of their parents. The team surmises that this is because chromosomes within such sex cells no longer lined up so that the DNA could be divided properly during cell division, leaving some with lethal DNA dosage abnormalities. Experiments showed that a difference in chromosome number of eight, say after eight fusions, was enough to keep an engineered strain from interbreeding with its ancestral species, achieving the reproductive isolation so important to envisioned applications. When two members of a species can no longer interbreed, they can no longer mix DNA and accumulate different genetic changes over time. This begins the process of their becoming different species, says Boeke. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Extant species have wildly different numbers of chromosomes, even among taxa with relatively similar genome sizes (for example, insects) 1 , 2 . This is likely to reflect accidents of genome history, such as telomere–telomere fusions and genome duplication events 3 , 4 , 5 . Humans have 23 pairs of chromosomes, whereas other apes have 24. One human chromosome is a fusion product of the ancestral state 6 . This raises the question: how well can species tolerate a change in chromosome numbers without substantial changes to genome content? Many tools are used in chromosome engineering in Saccharomyces cerevisiae 7 , 8 , 9 , 10 , but CRISPR–Cas9-mediated genome editing facilitates the most aggressive engineering strategies. Here we successfully fused yeast chromosomes using CRISPR–Cas9, generating a near-isogenic series of strains with progressively fewer chromosomes ranging from sixteen to two. A strain carrying only two chromosomes of about six megabases each exhibited modest transcriptomic changes and grew without major defects. When we crossed a sixteen-chromosome strain with strains with fewer chromosomes, we noted two trends. As the number of chromosomes dropped below sixteen, spore viability decreased markedly, reaching less than 10% for twelve chromosomes. As the number of chromosomes decreased further, yeast sporulation was arrested: a cross between a sixteen-chromosome strain and an eight-chromosome strain showed greatly reduced full tetrad formation and less than 1% sporulation, from which no viable spores could be recovered. However, homotypic crosses between pairs of strains with eight, four or two chromosomes produced excellent sporulation and spore viability. These results indicate that eight chromosome–chromosome fusion events suffice to isolate strains reproductively. Overall, budding yeast tolerates a reduction in chromosome number unexpectedly well, providing a striking example of the robustness of genomes to change. Main Chromosome engineering in S. cerevisiae is driven by technological advances 7 , 8 , 9 , 10 . A haploid yeast strain with 33 chromosomes has been generated by splitting natural chromosomes into smaller chromosomes 7 . On the other hand, the two largest S. cerevisiae chromosomes, IV and XII, were fused by homologous recombination 8 , producing yeast with a 3.2-Mb compound chromosome that grew well. Further fusions (chromosomes VII–V–XV–IV) generated a 4.3-Mb compound chromosome with the longest yeast chromosome arm engineered previously (3.7 Mb), and a haploid chromosome number of n = 12, with no observed effect on fitness 9 . CRISPR–Cas9 expression in S. cerevisiae 10 permits efficient engineering without selection. We used this to push the lower limit of chromosome numbers in S. cerevisiae by fusing chromosomes, producing a series of strains with progressively fewer chromosomes without affecting gene content. At least three potential biological obstacles might hinder engineering of karyotype. First, studies of the field bean Vicia faba have suggested that the length limit to chromosome arms is half the average spindle axis at telophase for normal development 11 . Longer arms might yield incomplete sister chromatid separation, lagging chromosomes and micronucleus formation, impairing fertility and development. Second, as centromeres are deleted, excess kinetochore proteins may cause problems. Finally, mitotic mechanics may be affected—centromeric force may not suffice to pull very long chromosomes poleward. The latter is a particular concern for S. cerevisiae , in which point centromeres are bound by single microtubules; most organisms with larger chromosomes have regional centromeres bound by multiple microtubules 12 . Karyotype engineering in S. cerevisiae , therefore, investigates whether point centromeres can segregate large chromosomes. We devised specific paths to evaluate minimization of the number of chromosomes ( n ). We first fused all small chromosomes to maximize the number of chromosomes fused before hitting a potential chromosome arm length limit. Specifically, we fused chromosomes IX, III and I, then V and VIII, and finally II and VI to generate an n = 12 strain (Fig. 1 ). We developed a CRISPR–Cas9-based strategy to fuse any two chromosomes while largely preserving isogenicity (Fig. 2a , Extended Data Fig. 1a and Extended Data Table 1 ; see Methods ). Pulsed field gel electrophoresis, used for karyotyping S. cerevisiae , confirmed the presence of progressively fewer and larger chromosomes (Fig. 2b ) with all chromosomes shorter than 600 kb merged in the n = 12 strain. Fig. 1: Fusion chromosome paths and strategy. This diagram shows how we fused chromosomes together from the wild type ( n = 16) to n = 12, n = 8, n = 4 and finally n = 2. The 16 chromosomes are coloured uniquely and arranged by number. A ruler indicates the distance from the centromere. The centromeres of n = 4 and n = 2 are aligned to the 0 position. Please note that the length of the rDNA array, whose position is indicated with an asterisk, is omitted. Red lettering indicates the chromosome that has an active centromere in the compound chromosome. All the chromosomes are oriented from left to right (bottom to top in the figure) in the fusion chromosomes. For more details see Extended Data Fig. 1b . Full size image Fig. 2: Construction and characterization of fusion chromosomes. a , A schematic showing a CRISPR–Cas9 based method to fuse any two chromosomes together. CEN3 and CEN1, centromeres of chromosomes III and I, respectively. b , Pulsed-field gel electrophoresis with a standard protocol for Saccharomyces cerevisiae . c , Pulsed-field gel electrophoresis with Hansenula wingei (also known as Wickerhamomyces canadensis ) chromosomal DNA as a marker. d , Pulsed-field gel electrophoresis with S. pombe ( S.p .) chromosomal DNA as a marker. S.c ., S. cerevisiae. n = 3 strain is yJL381; n = 3′ strain is yJL410. Full size image Given that 3.2-Mb and 4.3-Mb compound acrocentric chromosomes have been engineered previously 8 , 9 , we next produced a strain with four long chromosomes, each about 3 Mb long (for simplicity, the length of the rDNA array is omitted from lengths reported herein; Fig. 1 ). The serial disappearance of chromosomes confirmed that sequential fusion events occurred as planned (Fig. 2c ). The n = 4 strain<|im_end|> <|im_start|>assistant Baker's yeast survive and grow after a drastic reorganization, not of their genes, but of the chromosome superstructures that house, protect and control access to their DNA code, a study just published in Nature finds. Led by NYU School of Medicine, a research team fused together chromosomes in stages until the 6,000 genes in a species of one-celled fungus, Saccharomyces cerevisiae, were contained in two massive chromosomes instead of the naturally occurring 16 in each cell nucleus. The researchers also found that members of this yeast species could no longer make viable reproductive cells if the difference became too great between the numbers of chromosomes inherited from each of their "parents." Engineering such "reproductive isolation" between yeast strains would be a must to achieve certain hoped-for, future applications of yeast—like recycling agricultural waste to make fuel, or fighting starvation by supplementing livestock feed, say the study authors. Such endeavors would require the creation of strains that could be released into the field, but that were incapable of mating with naturally occurring yeast to alter ecosystems. Further in the future, a better understanding of how chromosomes are copied and apportioned in sex cells—spores in yeast; eggs and sperm in humans—may suggest ways to counter errors that cause too short, too long, missing or extra chromosomes to be passed down in human cells. Such events are a main cause of miscarriages and mental retardation, including Down's syndrome, in which an embryo receives an extra copy of the 21st human chromosome. Yeast chromosomes are similar enough to human ones to make good models for study. "We found that yeast can tolerate drastic changes in chromosome number without disrupting the action of the genes in them, more evidence of their robustness as an engineering platform," says senior study author Jef Boeke, Ph.D., director of the Institute for Systems Genetics at NYU Langone Health. "Beyond applications, this work sheds light on the wild trajectory of accidental chromosome duplications and fusions across evolution that has left one ant species with a single pair of chromosomes, humans with 23 pairs, and one species of butterfly with 220. We are learning how one species becomes two." Sixteen into Two The study results concern chromosomes, large protein bundles that, upon receiving the right signals, unwind to expose for reading by the cellular machinery just the bits of DNA instructions needed for the jobs at hand in each cell type. All chromosomes unwind when it is time to copy the entire genetic code before cell division, where one cell becomes two. Such divisions either create more genetically identical cells during growth (mitosis), or further divide a parental cell's chromosomes in rounds (meiosis) that yield sex cells, which can then combine with other sex cells to create new organisms. As cells get ready to divide such that each resulting cell gets its proper share of DNA, the newly copied chromosomes are connected by special DNA sets called centromeres, creating pairs with four chromosome "arms." Each arm is capped by DNA sets called telomeres which protect against enzymes that would otherwise damage the exposed tips. The current study authors used the famous CRISPR-Cas9 gene editing technology to cut 14 centromeres and 28 telomeres out of the complete set of yeast chromosomes (the genome). Without these telomeres or centromeres in place, the remaining DNA chains fused in steps until only two remained, each containing roughly half the genetic material for the S. cerevisiae species. Interestingly, the team was unable to generate a living strain of yeast with just one chromosome pair housing all of its genes. The authors say this may be because the two large chromosomes operating in the new strain had arms that, at about 5.9 million DNA molecular letters (bases) each, approached the maximum length limit. Longer than that and an arm is likely to have its end clipped off as a cell divides. Remarkably, the researchers found that yeast with chromosomes that are up to four times the maximum size of those seen in nature survived, divided and multiplied (grew) via mitosis at roughly the same rates as natural strains. However, when the team took the offspring from crosses of yeast strains with different chromosome numbers, and then induced the offspring of the crosses to make sex cells via meiosis, the ability to produce viable spores dropped in this next generation as the difference grew between the chromosome numbers of their parents. The team surmises that this is because chromosomes within such sex cells no longer lined up so that the DNA could be divided properly during cell division, leaving some with lethal DNA dosage abnormalities. Experiments showed that a difference in chromosome number of eight, say after eight fusions, was enough to keep an engineered strain from interbreeding with its ancestral species, achieving the reproductive isolation so important to envisioned applications. When two members of a species can no longer interbreed, they can no longer mix DNA and accumulate different genetic changes over time. This begins the process of their becoming different species, says Boeke. <|im_end|>

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19677, 18316, 4135, 22761, 4692, 285, 449, 264, 5410, 11766, 369, 23916, 1799, 5650, 1634, 28091, 2749, 73078, 662, 272, 1174, 393, 14630, 291, 19677, 18316, 4135, 22761, 4692, 285, 449, 58253, 5724, 289, 18177, 72, 320, 19171, 3967, 439, 468, 5327, 5721, 5650, 1634, 649, 329, 87778, 883, 22083, 96108, 15922, 439, 264, 11381, 13, 294, 1174, 393, 14630, 291, 19677, 18316, 4135, 22761, 4692, 285, 449, 328, 13, 30584, 1395, 320, 328, 558, 662, 8, 22083, 96108, 15922, 439, 264, 11381, 13, 328, 522, 119604, 328, 13, 28091, 2749, 73078, 13, 308, 284, 220, 18, 26800, 374, 379, 41, 43, 19162, 26, 308, 284, 220, 18, 39615, 26800, 374, 379, 41, 43, 14487, 13, 8797, 1404, 2217, 16644, 430, 220, 18, 13, 17, 5364, 65, 323, 220, 19, 13, 18, 5364, 65, 24549, 1645, 299, 1189, 2265, 83181, 617, 1027, 46036, 8767, 220, 23, 1174, 220, 24, 1174, 584, 1828, 9124, 264, 26800, 449, 3116, 1317, 83181, 11, 1855, 922, 220, 18, 51365, 1317, 320, 2000, 40075, 11, 279, 3160, 315, 279, 436, 56420, 1358, 374, 40542, 505, 29416, 5068, 36881, 26, 23966, 13, 220, 16, 7609, 578, 6275, 52979, 315, 83181, 11007, 430, 52100, 37608, 4455, 10222, 439, 13205, 320, 30035, 13, 220, 17, 66, 7609, 578, 308, 284, 220, 19, 26800, 128257, 198, 128256, 78191, 198, 33, 4506, 596, 41580, 18167, 323, 3139, 1306, 264, 60883, 312, 24844, 11, 539, 315, 872, 21389, 11, 719, 315, 279, 51815, 2307, 47194, 430, 3838, 11, 6144, 323, 2585, 2680, 311, 872, 15922, 2082, 11, 264, 4007, 1120, 4756, 304, 22037, 14035, 13, 32755, 555, 12551, 52, 6150, 315, 19152, 11, 264, 3495, 2128, 75754, 3871, 83181, 304, 18094, 3156, 279, 220, 21, 11, 931, 21389, 304, 264, 9606, 315, 832, 1824, 15556, 79902, 11, 23916, 1799, 5650, 1634, 28091, 2749, 73078, 11, 1051, 13282, 304, 1403, 11191, 83181, 4619, 315, 279, 18182, 31965, 220, 845, 304, 1855, 2849, 62607, 13, 578, 12074, 1101, 1766, 430, 3697, 315, 420, 41580, 9606, 1436, 912, 5129, 1304, 31528, 42889, 7917, 422, 279, 6811, 6244, 2288, 2294, 1990, 279, 5219, 315, 83181, 28088, 505, 1855, 315, 872, 330, 26534, 1210, 17005, 1778, 330, 265, 34370, 31398, 1, 1990, 41580, 42400, 1053, 387, 264, 2011, 311, 11322, 3738, 26253, 15548, 11, 3938, 8522, 315, 41580, 2345, 4908, 34978, 29149, 12571, 311, 1304, 10633, 11, 477, 11039, 78245, 555, 22822, 287, 51876, 5510, 11, 2019, 279, 4007, 12283, 13, 15483, 79645, 1053, 1397, 279, 9886, 315, 42400, 430, 1436, 387, 6004, 1139, 279, 2115, 11, 719, 430, 1051, 58271, 315, 73219, 449, 18182, 31965, 41580, 311, 11857, 61951, 13, 15903, 304, 279, 3938, 11, 264, 2731, 8830, 315, 1268, 83181, 527, 22523, 323, 1469, 15750, 291, 304, 1877, 7917, 2345, 2203, 4692, 304, 41580, 26, 19335, 323, 40699, 304, 12966, 2345, 18864, 4284, 5627, 311, 5663, 6103, 430, 5353, 2288, 2875, 11, 2288, 1317, 11, 7554, 477, 5066, 83181, 311, 387, 5946, 1523, 304, 3823, 7917, 13, 15483, 4455, 527, 264, 1925, 5353, 315, 80662, 38132, 323, 10723, 77072, 367, 11, 2737, 6419, 596, 28439, 11, 304, 902, 459, 87701, 21879, 459, 5066, 3048, 315, 279, 220, 1691, 267, 3823, 51815, 13, 32269, 561, 83181, 527, 4528, 3403, 311, 3823, 6305, 311, 1304, 1695, 4211, 369, 4007, 13, 330, 1687, 1766, 430, 41580, 649, 50134, 60883, 4442, 304, 51815, 1396, 2085, 87843, 279, 1957, 315, 279, 21389, 304, 1124, 11, 810, 6029, 315, 872, 22514, 2136, 439, 459, 15009, 5452, 1359, 2795, 10195, 4007, 3229, 622, 830, 2577, 68, 441, 11, 2405, 920, 2637, 7690, 315, 279, 10181, 369, 15264, 84386, 520, 12551, 52, 23272, 606, 6401, 13, 330, 56441, 8522, 11, 420, 990, 77039, 3177, 389, 279, 8545, 35782, 315, 50016, 51815, 27444, 811, 323, 282, 36807, 4028, 15740, 430, 706, 2163, 832, 3276, 9606, 449, 264, 3254, 6857, 315, 83181, 11, 12966, 449, 220, 1419, 13840, 11, 323, 832, 9606, 315, 56269, 449, 220, 8610, 13, 1226, 527, 6975, 1268, 832, 9606, 9221, 1403, 1210, 19198, 15247, 1139, 9220, 578, 4007, 3135, 4747, 83181, 11, 3544, 13128, 49707, 430, 11, 5304, 12588, 279, 1314, 17738, 11, 82610, 311, 29241, 369, 5403, 555, 279, 35693, 26953, 1120, 279, 9660, 315, 15922, 11470, 4460, 369, 279, 7032, 520, 1450, 304, 1855, 2849, 955, 13, 2052, 83181, 82610, 994, 433, 374, 892, 311, 3048, 279, 4553, 19465, 2082, 1603, 2849, 13096, 11, 1405, 832, 2849, 9221, 1403, 13, 15483, 37601, 3060, 1893, 810, 52033, 20086, 7917, 2391, 6650, 320, 1800, 10934, 705, 477, 4726, 22497, 264, 46679, 2849, 596, 83181, 304, 20101, 320, 2727, 91260, 8, 430, 7692, 1877, 7917, 11, 902, 649, 1243, 16343, 449, 1023, 1877, 7917, 311, 1893, 502, 44304, 13, 1666, 7917, 636, 5644, 311, 22497, 1778, 430, 1855, 13239, 2849, 5334, 1202, 6300, 4430, 315, 15922, 11, 279, 13945, 22523, 83181, 527, 8599, 555, 3361, 15922, 7437, 2663, 2960, 442, 13213, 11, 6968, 13840, 449, 3116, 51815, 330, 16293, 1210, 9062, 6916, 374, 61246, 555, 15922, 7437, 2663, 19227, 316, 13213, 902, 6144, 2403, 56067, 430, 1053, 6062, 5674, 279, 15246, 10631, 13, 578, 1510, 4007, 12283, 1511, 279, 11495, 12904, 1669, 6616, 7813, 300, 24, 15207, 16039, 5557, 311, 4018, 220, 975, 2960, 442, 13213, 323, 220, 1591, 19227, 316, 13213, 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7969, 439, 5933, 42400, 13, 4452, 11, 994, 279, 2128, 3952, 279, 46471, 505, 50535, 315, 41580, 42400, 449, 2204, 51815, 5219, 11, 323, 1243, 36572, 279, 46471, 315, 279, 50535, 311, 1304, 1877, 7917, 4669, 757, 91260, 11, 279, 5845, 311, 8356, 31528, 993, 4692, 12504, 304, 420, 1828, 9659, 439, 279, 6811, 14264, 1990, 279, 51815, 5219, 315, 872, 6699, 13, 578, 2128, 1765, 76, 5014, 430, 420, 374, 1606, 83181, 2949, 1778, 1877, 7917, 912, 5129, 32393, 709, 779, 430, 279, 15922, 1436, 387, 18255, 10489, 2391, 2849, 13096, 11, 9564, 1063, 449, 45089, 15922, 47040, 75815, 13, 1398, 50732, 8710, 430, 264, 6811, 304, 51815, 1396, 315, 8223, 11, 2019, 1306, 8223, 282, 36807, 11, 574, 3403, 311, 2567, 459, 46036, 26800, 505, 958, 21152, 16490, 449, 1202, 78771, 9606, 11, 32145, 279, 42889, 31398, 779, 3062, 311, 74389, 8522, 13, 3277, 1403, 3697, 315, 264, 9606, 649, 912, 5129, 958, 21152, 291, 11, 814, 649, 912, 5129, 6651, 15922, 323, 47376, 2204, 19465, 4442, 927, 892, 13, 1115, 12302, 279, 1920, 315, 872, 10671, 2204, 9606, 11, 2795, 2577, 68, 441, 13, 220, 128257, 198 ]

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