Pub Date : 2024-09-17Epub Date: 2024-09-05DOI: 10.1073/pnas.2409775121
Jamie K Reaser, Jonathan E Kolby
{"title":"Wildlife trade data capture: National policy is foundational to science.","authors":"Jamie K Reaser, Jonathan E Kolby","doi":"10.1073/pnas.2409775121","DOIUrl":"https://doi.org/10.1073/pnas.2409775121","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17Epub Date: 2024-09-05DOI: 10.1073/pnas.2409263121
Sara A Goeking, Christopher W Woodall, Renate Bush, Linda S Heath
{"title":"Collaboration can preserve the integrity of gold standard carbon data from forest inventories.","authors":"Sara A Goeking, Christopher W Woodall, Renate Bush, Linda S Heath","doi":"10.1073/pnas.2409263121","DOIUrl":"https://doi.org/10.1073/pnas.2409263121","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
New data sources and AI methods for extracting information are increasingly abundant and relevant to decision-making across societal applications. A notable example is street view imagery, available in over 100 countries, and purported to inform built environment interventions (e.g., adding sidewalks) for community health outcomes. However, biases can arise when decision-making does not account for data robustness or relies on spurious correlations. To investigate this risk, we analyzed 2.02 million Google Street View (GSV) images alongside health, demographic, and socioeconomic data from New York City. Findings demonstrate robustness challenges; built environment characteristics inferred from GSV labels at the intracity level often do not align with ground truth. Moreover, as average individual-level behavior of physical inactivity significantly mediates the impact of built environment features by census tract, intervention on features measured by GSV would be misestimated without proper model specification and consideration of this mediation mechanism. Using a causal framework accounting for these mediators, we determined that intervening by improving 10% of samples in the two lowest tertiles of physical inactivity would lead to a 4.17 (95% CI 3.84–4.55) or 17.2 (95% CI 14.4–21.3) times greater decrease in the prevalence of obesity or diabetes, respectively, compared to the same proportional intervention on the number of crosswalks by census tract. This study highlights critical issues of robustness and model specification in using emergent data sources, showing the data may not measure what is intended, and ignoring mediators can result in biased intervention effect estimates.
{"title":"Utilizing big data without domain knowledge impacts public health decision-making","authors":"Miao Zhang, Salman Rahman, Vishwali Mhasawade, Rumi Chunara","doi":"10.1073/pnas.2402387121","DOIUrl":"https://doi.org/10.1073/pnas.2402387121","url":null,"abstract":"New data sources and AI methods for extracting information are increasingly abundant and relevant to decision-making across societal applications. A notable example is street view imagery, available in over 100 countries, and purported to inform built environment interventions (e.g., adding sidewalks) for community health outcomes. However, biases can arise when decision-making does not account for data robustness or relies on spurious correlations. To investigate this risk, we analyzed 2.02 million Google Street View (GSV) images alongside health, demographic, and socioeconomic data from New York City. Findings demonstrate robustness challenges; built environment characteristics inferred from GSV labels at the intracity level often do not align with ground truth. Moreover, as average individual-level behavior of physical inactivity significantly mediates the impact of built environment features by census tract, intervention on features measured by GSV would be misestimated without proper model specification and consideration of this mediation mechanism. Using a causal framework accounting for these mediators, we determined that intervening by improving 10% of samples in the two lowest tertiles of physical inactivity would lead to a 4.17 (95% CI 3.84–4.55) or 17.2 (95% CI 14.4–21.3) times greater decrease in the prevalence of obesity or diabetes, respectively, compared to the same proportional intervention on the number of crosswalks by census tract. This study highlights critical issues of robustness and model specification in using emergent data sources, showing the data may not measure what is intended, and ignoring mediators can result in biased intervention effect estimates.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Julien Oury, Begona Gamallo-Lana, Leah Santana, Christophe Steyaert, Dana L. E. Vergoossen, Adam C. Mar, Bernhardt Vankerckhoven, Karen Silence, Roeland Vanhauwaert, Maartje G. Huijbers, Steven J. Burden
Myasthenia gravis (MG) is a chronic and severe disease of the skeletal neuromuscular junction (NMJ) in which the effects of neurotransmitters are attenuated, leading to muscle weakness. In the most common forms of autoimmune MG, antibodies attack components of the postsynaptic membrane, including the acetylcholine receptor (AChR) or muscle-specific kinase (MuSK). MuSK, a master regulator of NMJ development, associates with the low-density lipoprotein-related receptor 4 (Lrp4) to form the signaling receptor for neuronal Agrin, a nerve-derived synaptic organizer. Pathogenic antibodies to MuSK interfere with binding between MuSK and Lrp4, inhibiting the differentiation and maintenance of the NMJ. MuSK MG can be debilitating and refractory to treatments that are effective for AChR MG. We show here that recombinant antibodies, derived from MuSK MG patients, cause severe neuromuscular disease in mice. The disease can be prevented by a MuSK agonist antibody, presented either prophylactically or after disease onset. These findings suggest a therapeutic alternative to generalized immunosuppression for treating MuSK MG by selectively and directly targeting the disease mechanism.
{"title":"Agonist antibody to MuSK protects mice from MuSK myasthenia gravis","authors":"Julien Oury, Begona Gamallo-Lana, Leah Santana, Christophe Steyaert, Dana L. E. Vergoossen, Adam C. Mar, Bernhardt Vankerckhoven, Karen Silence, Roeland Vanhauwaert, Maartje G. Huijbers, Steven J. Burden","doi":"10.1073/pnas.2408324121","DOIUrl":"https://doi.org/10.1073/pnas.2408324121","url":null,"abstract":"Myasthenia gravis (MG) is a chronic and severe disease of the skeletal neuromuscular junction (NMJ) in which the effects of neurotransmitters are attenuated, leading to muscle weakness. In the most common forms of autoimmune MG, antibodies attack components of the postsynaptic membrane, including the acetylcholine receptor (AChR) or muscle-specific kinase (MuSK). MuSK, a master regulator of NMJ development, associates with the low-density lipoprotein-related receptor 4 (Lrp4) to form the signaling receptor for neuronal Agrin, a nerve-derived synaptic organizer. Pathogenic antibodies to MuSK interfere with binding between MuSK and Lrp4, inhibiting the differentiation and maintenance of the NMJ. MuSK MG can be debilitating and refractory to treatments that are effective for AChR MG. We show here that recombinant antibodies, derived from MuSK MG patients, cause severe neuromuscular disease in mice. The disease can be prevented by a MuSK agonist antibody, presented either prophylactically or after disease onset. These findings suggest a therapeutic alternative to generalized immunosuppression for treating MuSK MG by selectively and directly targeting the disease mechanism.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rémi Tuffet, Gabriel Carvalho, Anne-Sophie Godeux, Fanny Mazzamurro, Eduardo P. C. Rocha, Maria-Halima Laaberki, Samuel Venner, Xavier Charpentier
The opportunistic pathogen Acinetobacter baumannii , carries variants of A. baumannii resistance islands (AbaR)-type genomic islands conferring multidrug resistance. Their pervasiveness in the species has remained enigmatic. The dissemination of AbaRs is intricately linked to their horizontal transfer via natural transformation, a process through which bacteria can import and recombine exogenous DNA, effecting allelic recombination, genetic acquisition, and deletion. In experimental populations of the closely related pathogenic Acinetobacter nosocomialis , we quantified the rates at which these natural transformation events occur between individuals. When integrated into a model of population dynamics, they lead to the swift removal of AbaRs from the population, contrasting with the high prevalence of AbaRs in genomes. Yet, genomic analyses show that nearly all AbaRs specifically disrupt comM , a gene encoding a helicase critical for natural transformation. We found that such disruption impedes gene acquisition, and deletion, while moderately impacting acquisition of single nucleotide polymorphism. A mathematical evolutionary model demonstrates that AbaRs inserted into comM gain a selective advantage over AbaRs inserted in sites that do not inhibit or completely inhibit transformation, in line with the genomic observations. The persistence of AbaRs can be ascribed to their integration into a specific gene, diminishing the likelihood of their removal from the bacterial genome. This integration preserves the acquisition and elimination of alleles, enabling the host bacterium—and thus its AbaR—to adapt to unpredictable environments and persist over the long term. This work underscores how manipulation of natural transformation by mobile genetic elements can drive the prevalence of multidrug resistance.
{"title":"Manipulation of natural transformation by AbaR-type islands promotes fixation of antibiotic resistance in Acinetobacter baumannii","authors":"Rémi Tuffet, Gabriel Carvalho, Anne-Sophie Godeux, Fanny Mazzamurro, Eduardo P. C. Rocha, Maria-Halima Laaberki, Samuel Venner, Xavier Charpentier","doi":"10.1073/pnas.2409843121","DOIUrl":"https://doi.org/10.1073/pnas.2409843121","url":null,"abstract":"The opportunistic pathogen <jats:italic>Acinetobacter baumannii</jats:italic> , carries variants of <jats:italic>A. baumannii</jats:italic> resistance islands (AbaR)-type genomic islands conferring multidrug resistance. Their pervasiveness in the species has remained enigmatic. The dissemination of AbaRs is intricately linked to their horizontal transfer via natural transformation, a process through which bacteria can import and recombine exogenous DNA, effecting allelic recombination, genetic acquisition, and deletion. In experimental populations of the closely related pathogenic <jats:italic>Acinetobacter nosocomialis</jats:italic> , we quantified the rates at which these natural transformation events occur between individuals. When integrated into a model of population dynamics, they lead to the swift removal of AbaRs from the population, contrasting with the high prevalence of AbaRs in genomes. Yet, genomic analyses show that nearly all AbaRs specifically disrupt <jats:italic>comM</jats:italic> , a gene encoding a helicase critical for natural transformation. We found that such disruption impedes gene acquisition, and deletion, while moderately impacting acquisition of single nucleotide polymorphism. A mathematical evolutionary model demonstrates that AbaRs inserted into <jats:italic>comM</jats:italic> gain a selective advantage over AbaRs inserted in sites that do not inhibit or completely inhibit transformation, in line with the genomic observations. The persistence of AbaRs can be ascribed to their integration into a specific gene, diminishing the likelihood of their removal from the bacterial genome. This integration preserves the acquisition and elimination of alleles, enabling the host bacterium—and thus its AbaR—to adapt to unpredictable environments and persist over the long term. This work underscores how manipulation of natural transformation by mobile genetic elements can drive the prevalence of multidrug resistance.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Peter Rodriguez, Vrinda Kalia, Cristina Fenollar-Ferrer, Chelsea L. Gibson, Zayna Gichi, Andre Rajoo, Carson D. Matier, Aidan T. Pezacki, Tong Xiao, Lucia Carvelli, Christopher J. Chang, Gary W. Miller, Andy V. Khamoui, Jana Boerner, Randy D. Blakely
Cuprous copper [Cu(I)] is an essential cofactor for enzymes that support many fundamental cellular functions including mitochondrial respiration and suppression of oxidative stress. Neurons are particularly reliant on mitochondrial production of ATP, with many neurodegenerative diseases, including Parkinson’s disease, associated with diminished mitochondrial function. The gene MBLAC1 encodes a ribonuclease that targets pre-mRNA of replication-dependent histones, proteins recently found in yeast to reduce Cu(II) to Cu(I), and when mutated disrupt ATP production, elevates oxidative stress, and severely impacts cell growth. Whether this process supports neuronal and/or systemic physiology in higher eukaryotes is unknown. Previously, we identified swip-10 , the putative Caenorhabditis elegans ortholog of MBLAC1 , establishing a role for glial swip-10 in limiting dopamine (DA) neuron excitability and sustaining DA neuron viability. Here, we provide evidence from computational modeling that SWIP-10 protein structure mirrors that of MBLAC1 and locates a loss of function coding mutation at a site expected to disrupt histone RNA hydrolysis. Moreover, we find through genetic, biochemical, and pharmacological studies that deletion of swip-10 in worms negatively impacts systemic Cu(I) levels, leading to deficits in mitochondrial respiration and ATP production, increased oxidative stress, and neurodegeneration. These phenotypes can be offset in swip-10 mutants by the Cu(I) enhancing molecule elesclomol and through glial expression of wildtype swip-10 . Together, these studies reveal a glial-expressed pathway that supports systemic mitochondrial function and neuronal health via regulation of Cu(I) homeostasis, a mechanism that may lend itself to therapeutic strategies to treat devastating neurodegenerative diseases.
{"title":"Glial swip-10 controls systemic mitochondrial function, oxidative stress, and neuronal viability via copper ion homeostasis","authors":"Peter Rodriguez, Vrinda Kalia, Cristina Fenollar-Ferrer, Chelsea L. Gibson, Zayna Gichi, Andre Rajoo, Carson D. Matier, Aidan T. Pezacki, Tong Xiao, Lucia Carvelli, Christopher J. Chang, Gary W. Miller, Andy V. Khamoui, Jana Boerner, Randy D. Blakely","doi":"10.1073/pnas.2320611121","DOIUrl":"https://doi.org/10.1073/pnas.2320611121","url":null,"abstract":"Cuprous copper [Cu(I)] is an essential cofactor for enzymes that support many fundamental cellular functions including mitochondrial respiration and suppression of oxidative stress. Neurons are particularly reliant on mitochondrial production of ATP, with many neurodegenerative diseases, including Parkinson’s disease, associated with diminished mitochondrial function. The gene <jats:italic>MBLAC1</jats:italic> encodes a ribonuclease that targets pre-mRNA of replication-dependent histones, proteins recently found in yeast to reduce Cu(II) to Cu(I), and when mutated disrupt ATP production, elevates oxidative stress, and severely impacts cell growth. Whether this process supports neuronal and/or systemic physiology in higher eukaryotes is unknown. Previously, we identified <jats:italic>swip-10</jats:italic> , the putative <jats:italic>Caenorhabditis elegans</jats:italic> ortholog of <jats:italic>MBLAC1</jats:italic> , establishing a role for glial <jats:italic>swip-10</jats:italic> in limiting dopamine (DA) neuron excitability and sustaining DA neuron viability. Here, we provide evidence from computational modeling that SWIP-10 protein structure mirrors that of MBLAC1 and locates a loss of function coding mutation at a site expected to disrupt histone RNA hydrolysis. Moreover, we find through genetic, biochemical, and pharmacological studies that deletion of <jats:italic>swip-10</jats:italic> in worms negatively impacts systemic Cu(I) levels, leading to deficits in mitochondrial respiration and ATP production, increased oxidative stress, and neurodegeneration. These phenotypes can be offset in <jats:italic>swip-10</jats:italic> mutants by the Cu(I) enhancing molecule elesclomol and through glial expression of wildtype <jats:italic>swip-10</jats:italic> . Together, these studies reveal a glial-expressed pathway that supports systemic mitochondrial function and neuronal health via regulation of Cu(I) homeostasis, a mechanism that may lend itself to therapeutic strategies to treat devastating neurodegenerative diseases.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Duane S. Juang, Wren E. Wightman, Gabriel L. Lozano, Terry D. Juang, Layla J. Barkal, Jiaquan Yu, Manuel F. Garavito, Amanda Hurley, Ophelia S. Venturelli, Jo Handelsman, David J. Beebe
Multispecies microbial communities drive most ecosystems on Earth. Chemical and biological interactions within these communities can affect the survival of individual members and the entire community. However, the prohibitively high number of possible interactions within a microbial community has made the characterization of factors that influence community development challenging. Here, we report a Microbial Community Interaction (µCI) device to advance the systematic study of chemical and biological interactions within a microbial community. The µCI creates a combinatorial landscape made up of an array of triangular wells interconnected with circular wells, which each contains either a different chemical or microbial strain, generating chemical gradients and revealing biological interactions. Bacillus cereus UW85 containing green fluorescent protein provided the “target” readout in the triangular wells, and antibiotics or microorganisms in adjacent circular wells are designated the “variables.” The µCI device revealed that gentamicin and vancomycin are antagonistic to each other in inhibiting the target B. cereus UW85, displaying weaker inhibitory activity when used in combination than alone. We identified three-member communities constructed with isolates from the plant rhizosphere that increased or decreased the growth of B. cereus . The µCI device enables both strain-level and community-level insight. The scalable geometric design of the µCI device enables experiments with high combinatorial efficiency, thereby providing a simple, scalable platform for systematic interrogation of three-factor interactions that influence microorganisms in solitary or community life.
{"title":"Microbial community interactions on a chip","authors":"Duane S. Juang, Wren E. Wightman, Gabriel L. Lozano, Terry D. Juang, Layla J. Barkal, Jiaquan Yu, Manuel F. Garavito, Amanda Hurley, Ophelia S. Venturelli, Jo Handelsman, David J. Beebe","doi":"10.1073/pnas.2403510121","DOIUrl":"https://doi.org/10.1073/pnas.2403510121","url":null,"abstract":"Multispecies microbial communities drive most ecosystems on Earth. Chemical and biological interactions within these communities can affect the survival of individual members and the entire community. However, the prohibitively high number of possible interactions within a microbial community has made the characterization of factors that influence community development challenging. Here, we report a Microbial Community Interaction (µCI) device to advance the systematic study of chemical and biological interactions within a microbial community. The µCI creates a combinatorial landscape made up of an array of triangular wells interconnected with circular wells, which each contains either a different chemical or microbial strain, generating chemical gradients and revealing biological interactions. <jats:italic>Bacillus cereus</jats:italic> UW85 containing green fluorescent protein provided the “target” readout in the triangular wells, and antibiotics or microorganisms in adjacent circular wells are designated the “variables.” The µCI device revealed that gentamicin and vancomycin are antagonistic to each other in inhibiting the target <jats:italic>B. cereus</jats:italic> UW85, displaying weaker inhibitory activity when used in combination than alone. We identified three-member communities constructed with isolates from the plant rhizosphere that increased or decreased the growth of <jats:italic>B. cereus</jats:italic> . The µCI device enables both strain-level and community-level insight. The scalable geometric design of the µCI device enables experiments with high combinatorial efficiency, thereby providing a simple, scalable platform for systematic interrogation of three-factor interactions that influence microorganisms in solitary or community life.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Edward D. B. Lopatto, Jerome S. Pinkner, Denise A. Sanick, Robert F. Potter, Lily X. Liu, Jesús Bazán Villicaña, Kevin O. Tamadonfar, Yijun Ye, Maxwell I. Zimmerman, Nathaniel C. Gualberto, Karen W. Dodson, James W. Janetka, David A. Hunstad, Scott J. Hultgren
Klebsiella pneumoniae is an important pathogen causing difficult-to-treat urinary tract infections (UTIs). Over 1.5 million women per year suffer from recurrent UTI, reducing quality of life and causing substantial morbidity and mortality, especially in the hospital setting. Uropathogenic E. coli (UPEC) is the most prevalent cause of UTI. Like UPEC, K. pneumoniae relies on type 1 pili, tipped with the mannose-binding adhesin FimH, to cause cystitis. However, K. pneumoniae FimH is a poor binder of mannose, despite a mannose-binding pocket identical to UPEC FimH. FimH is composed of two domains that are in an equilibrium between tense (low-affinity) and relaxed (high-affinity) conformations. Substantial interdomain interactions in the tense conformation yield a low-affinity, deformed mannose-binding pocket, while domain–domain interactions are broken in the relaxed state, resulting in a high-affinity binding pocket. Using crystallography, we identified the structural basis by which domain–domain interactions direct the conformational equilibrium of K. pneumoniae FimH, which is strongly shifted toward the low-affinity tense state. Removal of the pilin domain restores mannose binding to the lectin domain, thus showing that poor mannose binding by K. pneumoniae FimH is not an inherent feature of the mannose-binding pocket. Phylogenetic analyses of K. pneumoniae genomes found that FimH sequences are highly conserved. However, we surveyed a collection of K. pneumoniae isolates from patients with long-term indwelling catheters and identified isolates that possessed relaxed higher-binding FimH variants, which increased K. pneumoniae fitness in bladder infection models, suggesting that long-term residence within the urinary tract may select for higher-binding FimH variants.
{"title":"Conformational ensembles in Klebsiella pneumoniae FimH impact uropathogenesis","authors":"Edward D. B. Lopatto, Jerome S. Pinkner, Denise A. Sanick, Robert F. Potter, Lily X. Liu, Jesús Bazán Villicaña, Kevin O. Tamadonfar, Yijun Ye, Maxwell I. Zimmerman, Nathaniel C. Gualberto, Karen W. Dodson, James W. Janetka, David A. Hunstad, Scott J. Hultgren","doi":"10.1073/pnas.2409655121","DOIUrl":"https://doi.org/10.1073/pnas.2409655121","url":null,"abstract":"<jats:italic>Klebsiella pneumoniae</jats:italic> is an important pathogen causing difficult-to-treat urinary tract infections (UTIs). Over 1.5 million women per year suffer from recurrent UTI, reducing quality of life and causing substantial morbidity and mortality, especially in the hospital setting. Uropathogenic <jats:italic>E. coli</jats:italic> (UPEC) is the most prevalent cause of UTI. Like UPEC, <jats:italic>K. pneumoniae</jats:italic> relies on type 1 pili, tipped with the mannose-binding adhesin FimH, to cause cystitis. However, <jats:italic>K. pneumoniae</jats:italic> FimH is a poor binder of mannose, despite a mannose-binding pocket identical to UPEC FimH. FimH is composed of two domains that are in an equilibrium between tense (low-affinity) and relaxed (high-affinity) conformations. Substantial interdomain interactions in the tense conformation yield a low-affinity, deformed mannose-binding pocket, while domain–domain interactions are broken in the relaxed state, resulting in a high-affinity binding pocket. Using crystallography, we identified the structural basis by which domain–domain interactions direct the conformational equilibrium of <jats:italic>K. pneumoniae</jats:italic> FimH, which is strongly shifted toward the low-affinity tense state. Removal of the pilin domain restores mannose binding to the lectin domain, thus showing that poor mannose binding by <jats:italic>K. pneumoniae</jats:italic> FimH is not an inherent feature of the mannose-binding pocket. Phylogenetic analyses of <jats:italic>K. pneumoniae</jats:italic> genomes found that FimH sequences are highly conserved. However, we surveyed a collection of <jats:italic>K. pneumoniae</jats:italic> isolates from patients with long-term indwelling catheters and identified isolates that possessed relaxed higher-binding FimH variants, which increased <jats:italic>K. pneumoniae</jats:italic> fitness in bladder infection models, suggesting that long-term residence within the urinary tract may select for higher-binding FimH variants.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17Epub Date: 2024-08-28DOI: 10.1073/pnas.2413204121
Susan Strome, J Richard McIntosh
{"title":"William B. Wood: Pioneering scientist and educator (1938 to 2024).","authors":"Susan Strome, J Richard McIntosh","doi":"10.1073/pnas.2413204121","DOIUrl":"10.1073/pnas.2413204121","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Blood platelets are produced by megakaryocytes (MKs), their parent cells, which are in the bone marrow. Once mature, MK pierces through the sinusoid vessel, and the initial protrusion further elongates as proplatelet or buds to release platelets. The mechanisms controlling the decision to initiate proplatelet and platelet formation are unknown. Here, we show that the mechanical properties of the microenvironment prevent proplatelet and platelet release in the marrow stroma while allowing this process in the bloodstream. Loss of marrow confinement following myelosuppression led to inappropriate proplatelet and platelet release into the extravascular space. We further used an inert viscoelastic hydrogel to evaluate the impact of compressive stress. Transcriptional analysis showed that culture in three-dimensional gel induced upregulation of genes related to the Rho-GTPase pathway. We found higher Rho-GTPase activation, myosin light chain phosphorylation and F-actin under mechanical constraints while proplatelet formation was inhibited. The use of latrunculin-A to decrease F-actin promoted microtubule-dependent budding and proplatelet extension inside the gel. Additionally, ex vivo exposure of intact bone marrow to latrunculin-A triggered proplatelet extensions in the interstitial space. In vivo, this confinement-mediated high intracellular tension is responsible for the formation of the peripheral zone, a unique actin-rich structure. Cytoskeleton reorganization induces the disappearance of the peripheral zone upon reaching a liquid milieu to facilitate proplatelet and platelet formation. Hence, our data provide insight into the mechanisms preventing ectopic platelet release in the marrow stroma. Identifying such pathways is especially important for understanding pathologies altering marrow mechanics such as chemotherapy or myelofibrosis.
{"title":"Mechanical confinement prevents ectopic platelet release.","authors":"Ines Guinard, Noémie Brassard-Jollive, Laurie Ruch, Josiane Weber, Anita Eckly, Julie Boscher, Catherine Léon","doi":"10.1073/pnas.2407829121","DOIUrl":"https://doi.org/10.1073/pnas.2407829121","url":null,"abstract":"<p><p>Blood platelets are produced by megakaryocytes (MKs), their parent cells, which are in the bone marrow. Once mature, MK pierces through the sinusoid vessel, and the initial protrusion further elongates as proplatelet or buds to release platelets. The mechanisms controlling the decision to initiate proplatelet and platelet formation are unknown. Here, we show that the mechanical properties of the microenvironment prevent proplatelet and platelet release in the marrow stroma while allowing this process in the bloodstream. Loss of marrow confinement following myelosuppression led to inappropriate proplatelet and platelet release into the extravascular space. We further used an inert viscoelastic hydrogel to evaluate the impact of compressive stress. Transcriptional analysis showed that culture in three-dimensional gel induced upregulation of genes related to the Rho-GTPase pathway. We found higher Rho-GTPase activation, myosin light chain phosphorylation and F-actin under mechanical constraints while proplatelet formation was inhibited. The use of latrunculin-A to decrease F-actin promoted microtubule-dependent budding and proplatelet extension inside the gel. Additionally, ex vivo exposure of intact bone marrow to latrunculin-A triggered proplatelet extensions in the interstitial space. In vivo, this confinement-mediated high intracellular tension is responsible for the formation of the peripheral zone, a unique actin-rich structure. Cytoskeleton reorganization induces the disappearance of the peripheral zone upon reaching a liquid milieu to facilitate proplatelet and platelet formation. Hence, our data provide insight into the mechanisms preventing ectopic platelet release in the marrow stroma. Identifying such pathways is especially important for understanding pathologies altering marrow mechanics such as chemotherapy or myelofibrosis.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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