Ethan P. Shealy, Tonia S. Schwartz, Robert M. Cox, Aaron M. Reedy, Benjamin B. Parrott
Sex differences in life span are widespread across animal taxa, but their causes remain unresolved. Alterations to the epigenome are hypothesized to contribute to vertebrate aging, and DNA methylation–based aging clocks allow for quantitative estimation of biological aging trajectories. Here, we investigate the influence of age, sex, and their interaction on genome-wide DNA methylation patterns in the brown anole (Anolis sagrei), a lizard with pronounced female-biased survival and longevity. We develop a series of age predictor models and find that, contrary to our predictions, rates of epigenetic aging were not slower in female lizards. However, methylation states at loci acquiring age-associated changes appear to be more “youthful” in young females, suggesting that female DNA methylomes are preemptively fortified in early life in opposition to the direction of age-related drift. Collectively, our findings provide insights into epigenetic aging in reptiles and suggest that early-life epigenetic profiles may be more informative than rates of change for predicting sex biases in longevity.
{"title":"DNA methylation–based age prediction and sex-specific epigenetic aging in a lizard with female-biased longevity","authors":"Ethan P. Shealy, Tonia S. Schwartz, Robert M. Cox, Aaron M. Reedy, Benjamin B. Parrott","doi":"","DOIUrl":"","url":null,"abstract":"<div >Sex differences in life span are widespread across animal taxa, but their causes remain unresolved. Alterations to the epigenome are hypothesized to contribute to vertebrate aging, and DNA methylation–based aging clocks allow for quantitative estimation of biological aging trajectories. Here, we investigate the influence of age, sex, and their interaction on genome-wide DNA methylation patterns in the brown anole (<i>Anolis sagrei</i>), a lizard with pronounced female-biased survival and longevity. We develop a series of age predictor models and find that, contrary to our predictions, rates of epigenetic aging were not slower in female lizards. However, methylation states at loci acquiring age-associated changes appear to be more “youthful” in young females, suggesting that female DNA methylomes are preemptively fortified in early life in opposition to the direction of age-related drift. Collectively, our findings provide insights into epigenetic aging in reptiles and suggest that early-life epigenetic profiles may be more informative than rates of change for predicting sex biases in longevity.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 5","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq3589","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yangjunjie Xu-Yang, Charlotte Skonieczny, Sophie Ayrault, Jean-Sébastien Barbier, Rémi Bizeul, Octave Bryskere, Pierre-Alexis Chaboche, Thomas G Chalaux, José A Corcho-Alvarado, Anthony Foucher, Alice Karsenti, Maxime Leblanc, Germán Orizaola, Amélie Plautre, Stefan Röllin, Nirina Taraconat, Nicolas Tenaud, Ana Elisa Valdés, François Dulac, Olivier Evrard
The Reggane region, where the first French atmospheric nuclear tests were conducted in the 1960s in Southern Algeria, is located in one of the most active dust source regions responsible for recurrent massive Saharan dust events reaching Western Europe and affecting air quality. After a major outbreak in March 2022, a citizen participative science campaign was launched to study the radioactivity born by the dust. One hundred ten deposit samples were collected from six countries in Western Europe with 53 demonstrated as scientifically representative. Geochemical and mineralogical sample analyses combined with satellite observations and back trajectory calculations confirmed an origin from South Algeria, including the Reggane site. Plutonium isotopic signatures, a unique nuclear bomb fingerprint, remained in the range of the global fallout signatures largely dominated by US and former USSR nuclear tests, significantly different from French fallout signatures. Radioactive contamination detected in all samples did not, however, present a risk to public health in terms of radioactivity exposure.
{"title":"Radioactive contamination transported to Western Europe with Saharan dust.","authors":"Yangjunjie Xu-Yang, Charlotte Skonieczny, Sophie Ayrault, Jean-Sébastien Barbier, Rémi Bizeul, Octave Bryskere, Pierre-Alexis Chaboche, Thomas G Chalaux, José A Corcho-Alvarado, Anthony Foucher, Alice Karsenti, Maxime Leblanc, Germán Orizaola, Amélie Plautre, Stefan Röllin, Nirina Taraconat, Nicolas Tenaud, Ana Elisa Valdés, François Dulac, Olivier Evrard","doi":"10.1126/sciadv.adr9192","DOIUrl":"10.1126/sciadv.adr9192","url":null,"abstract":"<p><p>The Reggane region, where the first French atmospheric nuclear tests were conducted in the 1960s in Southern Algeria, is located in one of the most active dust source regions responsible for recurrent massive Saharan dust events reaching Western Europe and affecting air quality. After a major outbreak in March 2022, a citizen participative science campaign was launched to study the radioactivity born by the dust. One hundred ten deposit samples were collected from six countries in Western Europe with 53 demonstrated as scientifically representative. Geochemical and mineralogical sample analyses combined with satellite observations and back trajectory calculations confirmed an origin from South Algeria, including the Reggane site. Plutonium isotopic signatures, a unique nuclear bomb fingerprint, remained in the range of the global fallout signatures largely dominated by US and former USSR nuclear tests, significantly different from French fallout signatures. Radioactive contamination detected in all samples did not, however, present a risk to public health in terms of radioactivity exposure.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 5","pages":"eadr9192"},"PeriodicalIF":11.7,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143071335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jonathan L Richardson, Elizabeth P McCoy, Nicholas Parlavecchio, Ryan Szykowny, Eli Beech-Brown, Jan A Buijs, Jacqueline Buckley, Robert M Corrigan, Federico Costa, Ray DeLaney, Rachel Denny, Leah Helms, Wade Lee, Maureen H Murray, Claudia Riegel, Fabio N Souza, John Ulrich, Adena Why, Yasushi Kiyokawa
Urban rats are commensal pests that thrive in cities by exploiting the resources accompanying large human populations. Identifying long-term trends in rat numbers and how they are shaped by environmental changes is critical for understanding their ecology, and projecting future vulnerabilities and mitigation needs. Here, we use public complaint and inspection data from 16 cities around the world to estimate trends in rat populations. Eleven of 16 cities (69%) had significant increasing trends in rat numbers, including Washington D.C., New York, and Amsterdam. Just three cities experienced declines. Cities experiencing greater temperature increases over time saw larger increases in rats. Cities with more dense human populations and more urbanization also saw larger increases in rats. Warming temperatures and more people living in cities may be expanding the seasonal activity periods and food availability for urban rats. Cities will have to integrate the biological impacts of these variables into future management strategies.
{"title":"Increasing rat numbers in cities are linked to climate warming, urbanization, and human population.","authors":"Jonathan L Richardson, Elizabeth P McCoy, Nicholas Parlavecchio, Ryan Szykowny, Eli Beech-Brown, Jan A Buijs, Jacqueline Buckley, Robert M Corrigan, Federico Costa, Ray DeLaney, Rachel Denny, Leah Helms, Wade Lee, Maureen H Murray, Claudia Riegel, Fabio N Souza, John Ulrich, Adena Why, Yasushi Kiyokawa","doi":"10.1126/sciadv.ads6782","DOIUrl":"10.1126/sciadv.ads6782","url":null,"abstract":"<p><p>Urban rats are commensal pests that thrive in cities by exploiting the resources accompanying large human populations. Identifying long-term trends in rat numbers and how they are shaped by environmental changes is critical for understanding their ecology, and projecting future vulnerabilities and mitigation needs. Here, we use public complaint and inspection data from 16 cities around the world to estimate trends in rat populations. Eleven of 16 cities (69%) had significant increasing trends in rat numbers, including Washington D.C., New York, and Amsterdam. Just three cities experienced declines. Cities experiencing greater temperature increases over time saw larger increases in rats. Cities with more dense human populations and more urbanization also saw larger increases in rats. Warming temperatures and more people living in cities may be expanding the seasonal activity periods and food availability for urban rats. Cities will have to integrate the biological impacts of these variables into future management strategies.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 5","pages":"eads6782"},"PeriodicalIF":11.7,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143071318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Charul Jani, Neha Jain, Amanda K. Marsh, Pooja Uchil, Triet Doan, Meggie Hudspith, Owen T. Glover, Zach R. Baskir, Julie Boucau, David E. Root, Nicole N. van der Wel, John G. Doench, Amy K. Barczak
Mycobacterium tuberculosis (Mtb) has evolved to be exquisitely adapted to survive within host macrophages. The capacity to damage the phagosomal membrane has emerged as central to Mtb virulence. While Mtb factors driving membrane damage have been described, host factors that maintain phagosomal integrity or repair Mtb-induced damage to contain the pathogen remain largely unknown. We used a genome-wide CRISPR screen to identify host factors required to repair Mtb-damaged phagosomal membranes. Vacuolar protein sorting–associated protein 18 (VPS18), a member of the HOPS and CORVET trafficking complexes, was among the top hits. VPS18 colocalized with Mtb in macrophages beginning shortly after infection, and VPS18-knockout macrophages demonstrated increased damage of Mtb-containing phagosomes without impaired autophagy. Mtb grew more robustly in VPS18-knockout cells, and the first-line antituberculosis antibiotic pyrazinamide was less effective. Our results identify VPS18 as required for phagosomal membrane integrity in Mtb-infected cells and suggest that modulating phagosome integrity may hold promise for improving the efficacy of antibiotic treatment for TB.
{"title":"VPS18 contributes to phagosome membrane integrity in Mycobacterium tuberculosis–infected macrophages","authors":"Charul Jani, Neha Jain, Amanda K. Marsh, Pooja Uchil, Triet Doan, Meggie Hudspith, Owen T. Glover, Zach R. Baskir, Julie Boucau, David E. Root, Nicole N. van der Wel, John G. Doench, Amy K. Barczak","doi":"","DOIUrl":"","url":null,"abstract":"<div ><i>Mycobacterium tuberculosis</i> (Mtb) has evolved to be exquisitely adapted to survive within host macrophages. The capacity to damage the phagosomal membrane has emerged as central to Mtb virulence. While Mtb factors driving membrane damage have been described, host factors that maintain phagosomal integrity or repair Mtb-induced damage to contain the pathogen remain largely unknown. We used a genome-wide CRISPR screen to identify host factors required to repair Mtb-damaged phagosomal membranes. Vacuolar protein sorting–associated protein 18 (VPS18), a member of the HOPS and CORVET trafficking complexes, was among the top hits. VPS18 colocalized with Mtb in macrophages beginning shortly after infection, and <i>VPS18</i>-knockout macrophages demonstrated increased damage of Mtb-containing phagosomes without impaired autophagy. Mtb grew more robustly in <i>VPS18</i>-knockout cells, and the first-line antituberculosis antibiotic pyrazinamide was less effective. Our results identify VPS18 as required for phagosomal membrane integrity in Mtb-infected cells and suggest that modulating phagosome integrity may hold promise for improving the efficacy of antibiotic treatment for TB.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 5","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adr6166","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Francesca Palermo, Nicole Marrocco, Letizia Dacomo, Elena Grisafi, Viviana Moresi, Alessia Sanna, Lorenzo Massimi, Marianna Musella, Laura Maugeri, Inna Bukreeva, Fabio Fiordaliso, Alessandro Corbelli, Olga Junemann, Marina Eckermann, Peter Cloetens, Timm Weitkamp, Giuseppe Gigli, Nicole Kerlero de Rosbo, Claudia Balducci, Alessia Cedola
Alzheimer’s disease (AD), a debilitating neurodegenerative disorder, remains one of the foremost public health challenges affecting more than 30 million people worldwide with the etiology still largely enigmatic. The intricate gut-brain axis, serving as a vital communication network between the gut and the brain, appears to wield influence in the progression of AD. Our study showcases the remarkable precision of x-ray phase-contrast tomography (XPCT) in conducting an advanced three-dimensional examination of gut cellular composition and structure. The exploitation of micro- and nano-XPCT on various AD mouse models unveiled relevant alterations in villi and crypts, cellular transformations in Paneth and goblet cells, along with the detection of telocytes, neurons, erythrocytes, and mucus secretion by goblet cells within the gut cavity. The observed gut structural variations may elucidate the transition from dysbiosis to neurodegeneration and cognitive decline. Leveraging XPCT could prove pivotal in early detection and prognosis of the disease.
{"title":"Investigating gut alterations in Alzheimer’s disease: In-depth analysis with micro- and nano-3D X-ray phase contrast tomography","authors":"Francesca Palermo, Nicole Marrocco, Letizia Dacomo, Elena Grisafi, Viviana Moresi, Alessia Sanna, Lorenzo Massimi, Marianna Musella, Laura Maugeri, Inna Bukreeva, Fabio Fiordaliso, Alessandro Corbelli, Olga Junemann, Marina Eckermann, Peter Cloetens, Timm Weitkamp, Giuseppe Gigli, Nicole Kerlero de Rosbo, Claudia Balducci, Alessia Cedola","doi":"","DOIUrl":"","url":null,"abstract":"<div >Alzheimer’s disease (AD), a debilitating neurodegenerative disorder, remains one of the foremost public health challenges affecting more than 30 million people worldwide with the etiology still largely enigmatic. The intricate gut-brain axis, serving as a vital communication network between the gut and the brain, appears to wield influence in the progression of AD. Our study showcases the remarkable precision of x-ray phase-contrast tomography (XPCT) in conducting an advanced three-dimensional examination of gut cellular composition and structure. The exploitation of micro- and nano-XPCT on various AD mouse models unveiled relevant alterations in villi and crypts, cellular transformations in Paneth and goblet cells, along with the detection of telocytes, neurons, erythrocytes, and mucus secretion by goblet cells within the gut cavity. The observed gut structural variations may elucidate the transition from dysbiosis to neurodegeneration and cognitive decline. Leveraging XPCT could prove pivotal in early detection and prognosis of the disease.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 5","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adr8511","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Breakthroughs in high-throughput sequencing and microscopic imaging technologies have revealed that chromatin structures vary considerably between cells of the same type. However, a thorough characterization of this heterogeneity remains elusive due to the labor-intensive and time-consuming nature of these experiments. To address these challenges, we introduce ChromoGen, a generative model based on state-of-the-art artificial intelligence techniques that efficiently predicts three-dimensional, single-cell chromatin conformations de novo with both region and cell type specificity. These generated conformations accurately reproduce experimental results at both the single-cell and population levels. Moreover, ChromoGen successfully transfers to cell types excluded from the training data using just DNA sequence and widely available DNase-seq data, thus providing access to chromatin structures in myriad cell types. These achievements come at a remarkably low computational cost. Therefore, ChromoGen enables the systematic investigation of single-cell chromatin organization, its heterogeneity, and its relationship to sequencing data, all while remaining economical.
{"title":"ChromoGen: Diffusion model predicts single-cell chromatin conformations.","authors":"Greg Schuette, Zhuohan Lao, Bin Zhang","doi":"10.1126/sciadv.adr8265","DOIUrl":"10.1126/sciadv.adr8265","url":null,"abstract":"<p><p>Breakthroughs in high-throughput sequencing and microscopic imaging technologies have revealed that chromatin structures vary considerably between cells of the same type. However, a thorough characterization of this heterogeneity remains elusive due to the labor-intensive and time-consuming nature of these experiments. To address these challenges, we introduce ChromoGen, a generative model based on state-of-the-art artificial intelligence techniques that efficiently predicts three-dimensional, single-cell chromatin conformations de novo with both region and cell type specificity. These generated conformations accurately reproduce experimental results at both the single-cell and population levels. Moreover, ChromoGen successfully transfers to cell types excluded from the training data using just DNA sequence and widely available DNase-seq data, thus providing access to chromatin structures in myriad cell types. These achievements come at a remarkably low computational cost. Therefore, ChromoGen enables the systematic investigation of single-cell chromatin organization, its heterogeneity, and its relationship to sequencing data, all while remaining economical.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 5","pages":"eadr8265"},"PeriodicalIF":11.7,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143071309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Danish Khan, Alastair J A Price, Bing Huang, Maximilian L Ach, O Anatole von Lilienfeld
Exact exchange contributions significantly affect electronic states, influencing covalent bond formation and breaking. Hybrid density functional approximations, which average exact exchange admixtures empirically, have achieved success but fall short of high-level quantum chemistry accuracy due to delocalization errors. We propose adaptive hybrid functionals, generating optimal exact exchange admixture ratios on the fly using data-efficient quantum machine learning models with negligible overhead. The adaptive Perdew-Burke-Ernzerhof hybrid density functional (aPBE0) improves energetics, electron densities, and HOMO-LUMO gaps in QM9, QM7b, and GMTKN55 benchmark datasets. A model uncertainty-based constraint reduces the method smoothly to PBE0 in extrapolative regimes, ensuring general applicability with limited training. By tuning exact exchange fractions for different spin states, aPBE0 effectively addresses the spin gap problem in open-shell systems such as carbenes. We also present a revised QM9 (revQM9) dataset with more accurate quantum properties, including stronger covalent binding, larger bandgaps, more localized electron densities, and larger dipole moments.
{"title":"Adapting hybrid density functionals with machine learning.","authors":"Danish Khan, Alastair J A Price, Bing Huang, Maximilian L Ach, O Anatole von Lilienfeld","doi":"10.1126/sciadv.adt7769","DOIUrl":"10.1126/sciadv.adt7769","url":null,"abstract":"<p><p>Exact exchange contributions significantly affect electronic states, influencing covalent bond formation and breaking. Hybrid density functional approximations, which average exact exchange admixtures empirically, have achieved success but fall short of high-level quantum chemistry accuracy due to delocalization errors. We propose adaptive hybrid functionals, generating optimal exact exchange admixture ratios on the fly using data-efficient quantum machine learning models with negligible overhead. The adaptive Perdew-Burke-Ernzerhof hybrid density functional (aPBE0) improves energetics, electron densities, and HOMO-LUMO gaps in QM9, QM7b, and GMTKN55 benchmark datasets. A model uncertainty-based constraint reduces the method smoothly to PBE0 in extrapolative regimes, ensuring general applicability with limited training. By tuning exact exchange fractions for different spin states, aPBE0 effectively addresses the spin gap problem in open-shell systems such as carbenes. We also present a revised QM9 (revQM9) dataset with more accurate quantum properties, including stronger covalent binding, larger bandgaps, more localized electron densities, and larger dipole moments.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 5","pages":"eadt7769"},"PeriodicalIF":11.7,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143071299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ben Stocks, Julia Prats Quesada, Anthony M Mozzicato, Carolina Jacob, Simone Jensen, Kirstin A MacGregor, Jens Bangsbo, Juleen R Zierath, Morten Hostrup, Atul S Deshmukh
The skeletal muscle interstitial space is the extracellular region around myofibers and mediates cross-talk between resident cell types. We applied a proteomic workflow to characterize the human skeletal muscle interstitial fluid proteome at rest and in response to exercise. Following exhaustive exercise, markers of skeletal muscle damage accumulate in the interstitial space followed by the appearance of immune cell-derived proteins. Among the proteins up-regulated after exercise, we identified cathelicidin-related antimicrobial peptide (CAMP) as a bioactive molecule regulating muscle fiber development. Treatment with the bioactive peptide derivative of CAMP (LL-37) resulted in the growth of larger C2C12 skeletal muscle myotubes. Phosphoproteomics revealed that LL-37 activated pathways central to muscle growth and proliferation, including phosphatidylinositol 3-kinase, AKT serine/threonine kinase 1, mitogen-activated protein kinases, and mammalian target of rapamycin. Our findings provide a proof of concept that the interstitial fluid proteome is quantifiable via microdialysis sampling in vivo. These data highlight the importance of cellular communication in the adaptive response to exercise.
{"title":"Temporal dynamics of the interstitial fluid proteome in human skeletal muscle following exhaustive exercise.","authors":"Ben Stocks, Julia Prats Quesada, Anthony M Mozzicato, Carolina Jacob, Simone Jensen, Kirstin A MacGregor, Jens Bangsbo, Juleen R Zierath, Morten Hostrup, Atul S Deshmukh","doi":"10.1126/sciadv.adp8608","DOIUrl":"10.1126/sciadv.adp8608","url":null,"abstract":"<p><p>The skeletal muscle interstitial space is the extracellular region around myofibers and mediates cross-talk between resident cell types. We applied a proteomic workflow to characterize the human skeletal muscle interstitial fluid proteome at rest and in response to exercise. Following exhaustive exercise, markers of skeletal muscle damage accumulate in the interstitial space followed by the appearance of immune cell-derived proteins. Among the proteins up-regulated after exercise, we identified cathelicidin-related antimicrobial peptide (CAMP) as a bioactive molecule regulating muscle fiber development. Treatment with the bioactive peptide derivative of CAMP (LL-37) resulted in the growth of larger C2C12 skeletal muscle myotubes. Phosphoproteomics revealed that LL-37 activated pathways central to muscle growth and proliferation, including phosphatidylinositol 3-kinase, AKT serine/threonine kinase 1, mitogen-activated protein kinases, and mammalian target of rapamycin. Our findings provide a proof of concept that the interstitial fluid proteome is quantifiable via microdialysis sampling in vivo. These data highlight the importance of cellular communication in the adaptive response to exercise.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 5","pages":"eadp8608"},"PeriodicalIF":11.7,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jongwook Cho, Sangkyu Lee, Yeon Hee Kook, Jiyoung Park, Won Do Heo, C. Justin Lee, Hyoung-Ihl Kim
Stroke is caused by disruption of cerebral blood flow, leading to neuronal death and dysfunction in the interconnected areas, which results in a wide range of severe symptoms depending on the specific brain regions affected. While previous studies have primarily focused on direct modulation of neuronal activity for post-stroke treatment, accumulating evidence suggests that astrocytes may play a critical role in post-stroke progression and could serve as a potential therapeutic target for recovery. In this study, we investigate the effects of selective modulation of astrocytic calcium signals on chronic stroke using OptoSTIM1, an optogenetic tool that activates endogenous calcium channels. In contrast to channelrhodopsin-2 (ChR2), OptoSTIM1 robustly elevates astrocytic calcium levels, sustaining the increase for over 10 min upon a single activation. The calcium elevation in astrocytes in the ipsilesional sensory-parietal cortex leads to remarkable recovery from post-stroke impairment. Thus, manipulating intracellular calcium levels in astrocytes holds promise as a potential therapeutic strategy for improving recovery following a stroke.
{"title":"Optogenetic calcium modulation in astrocytes enhances post-stroke recovery in chronic capsular infarct","authors":"Jongwook Cho, Sangkyu Lee, Yeon Hee Kook, Jiyoung Park, Won Do Heo, C. Justin Lee, Hyoung-Ihl Kim","doi":"","DOIUrl":"","url":null,"abstract":"<div >Stroke is caused by disruption of cerebral blood flow, leading to neuronal death and dysfunction in the interconnected areas, which results in a wide range of severe symptoms depending on the specific brain regions affected. While previous studies have primarily focused on direct modulation of neuronal activity for post-stroke treatment, accumulating evidence suggests that astrocytes may play a critical role in post-stroke progression and could serve as a potential therapeutic target for recovery. In this study, we investigate the effects of selective modulation of astrocytic calcium signals on chronic stroke using OptoSTIM1, an optogenetic tool that activates endogenous calcium channels. In contrast to channelrhodopsin-2 (ChR2), OptoSTIM1 robustly elevates astrocytic calcium levels, sustaining the increase for over 10 min upon a single activation. The calcium elevation in astrocytes in the ipsilesional sensory-parietal cortex leads to remarkable recovery from post-stroke impairment. Thus, manipulating intracellular calcium levels in astrocytes holds promise as a potential therapeutic strategy for improving recovery following a stroke.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 5","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adn7577","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Philippe N. Azimzadeh, George M. Birchenough, Nathaniel C. Gualbuerto, Jerome S. Pinkner, Kevin O. Tamadonfar, Wandy Beatty, Thomas J. Hannan, Karen W. Dodson, Enid C. Ibarra, Seonyoung Kim, Henry L. Schreiber 4th, James W. Janetka, Andrew L. Kau, Ashlee M. Earl, Mark J. Miller, Gunnar C. Hansson, Scott J. Hultgren
Urinary tract infections (UTIs) are highly recurrent and frequently caused by Uropathogenic Escherichia coli (UPEC) strains that can be found in patient intestines. Seeding of the urinary tract from this intestinal reservoir likely contributes to UTI recurrence (rUTI) rates. Thus, understanding the factors that promote UPEC intestinal colonization is of critical importance to designing therapeutics to reduce rUTI incidence. Although E. coli is found in high abundance in large intestine mucus, little is known about how it is able to maintain residence in this continuously secreted hydrogel. We discovered that the FimH adhesin of type 1 pili (T1P) bound throughout the secreted mucus layers of the colon and to epithelial cells in mouse and human samples. Disruption of T1P led to reduced association with colon mucus. Notably, this mutant up-regulated flagellar production and infiltrated the protective inner mucus layer of the colon. This could explain how UPEC resists being washed off by the continuously secreted mucus layers of the colon.
{"title":"Mechanisms of uropathogenic E. coli mucosal association in the gastrointestinal tract","authors":"Philippe N. Azimzadeh, George M. Birchenough, Nathaniel C. Gualbuerto, Jerome S. Pinkner, Kevin O. Tamadonfar, Wandy Beatty, Thomas J. Hannan, Karen W. Dodson, Enid C. Ibarra, Seonyoung Kim, Henry L. Schreiber 4th, James W. Janetka, Andrew L. Kau, Ashlee M. Earl, Mark J. Miller, Gunnar C. Hansson, Scott J. Hultgren","doi":"","DOIUrl":"","url":null,"abstract":"<div >Urinary tract infections (UTIs) are highly recurrent and frequently caused by Uropathogenic <i>Escherichia coli</i> (UPEC) strains that can be found in patient intestines. Seeding of the urinary tract from this intestinal reservoir likely contributes to UTI recurrence (rUTI) rates. Thus, understanding the factors that promote UPEC intestinal colonization is of critical importance to designing therapeutics to reduce rUTI incidence. Although <i>E. coli</i> is found in high abundance in large intestine mucus, little is known about how it is able to maintain residence in this continuously secreted hydrogel. We discovered that the FimH adhesin of type 1 pili (T1P) bound throughout the secreted mucus layers of the colon and to epithelial cells in mouse and human samples. Disruption of T1P led to reduced association with colon mucus. Notably, this mutant up-regulated flagellar production and infiltrated the protective inner mucus layer of the colon. This could explain how UPEC resists being washed off by the continuously secreted mucus layers of the colon.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 5","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp7066","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}