Tingting Wang, Liyan Zhu, Emily Guo, Chunxiang Wu, Florian Schueder, Maria Lara-Tejero, Jorge E. Galán
Type III secretion systems (T3SS) are critical virulence machines in many Gram-negative bacteria, enabling hierarchical secretion of translocases followed by effectors. In the Salmonella enterica serovar Typhimurium SPI-1 T3SS, the regulatory protein InvE (SctW) enforces this order. Here, we show that InvE assembles into tetramers and higher-order oligomers and that oligomerization is essential for function. A 2.4 Å cryo-electron microscopy (cryo-EM) structure reveals a tetramer built as a dimer of antiparallel dimers. Photocrosslinking maps one set of residues to the interdimer seams in this tetramer, while crosslinks from additional sites suggest lateral docking between dimers in alternative registries in vivo. Blue-native electrophoresis and SEC–MALS detect native high-molecular-weight species consistent with such assemblies. DNA-PAINT superresolution microscopy confirms the presence of higher-order InvE oligomers in vivo. Charge-reversal mutations that disrupt oligomerization collapse InvE to monomers and abolish secretion, effector translocation, invasion, and virulence. Together, these data define an oligomerization-based switch in which InvE reuses the dimeric face to form higher-order contacts that govern the transition from translocase to effector secretion.
{"title":"Oligomeric assembly of the gatekeeper InvE orchestrates hierarchical type III protein secretion in Salmonella Typhimurium","authors":"Tingting Wang, Liyan Zhu, Emily Guo, Chunxiang Wu, Florian Schueder, Maria Lara-Tejero, Jorge E. Galán","doi":"10.1073/pnas.2530441123","DOIUrl":"https://doi.org/10.1073/pnas.2530441123","url":null,"abstract":"Type III secretion systems (T3SS) are critical virulence machines in many Gram-negative bacteria, enabling hierarchical secretion of translocases followed by effectors. In the <jats:italic toggle=\"yes\"> <jats:italic toggle=\"yes\">Salmonella enterica</jats:italic> </jats:italic> serovar Typhimurium SPI-1 T3SS, the regulatory protein InvE (SctW) enforces this order. Here, we show that InvE assembles into tetramers and higher-order oligomers and that oligomerization is essential for function. A 2.4 Å cryo-electron microscopy (cryo-EM) structure reveals a tetramer built as a dimer of antiparallel dimers. Photocrosslinking maps one set of residues to the interdimer seams in this tetramer, while crosslinks from additional sites suggest lateral docking between dimers in alternative registries in vivo. Blue-native electrophoresis and SEC–MALS detect native high-molecular-weight species consistent with such assemblies. DNA-PAINT superresolution microscopy confirms the presence of higher-order InvE oligomers in vivo. Charge-reversal mutations that disrupt oligomerization collapse InvE to monomers and abolish secretion, effector translocation, invasion, and virulence. Together, these data define an oligomerization-based switch in which InvE reuses the dimeric face to form higher-order contacts that govern the transition from translocase to effector secretion.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"67 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048211","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}
Jennifer M. Sun, Euna Kim, Heidi M. Pickard, Bjarni Mikkelsen, Katrin S. Hoydal, Halla W. Reinert, Colin P. Thackray, Elsie M. Sunderland
The ocean is thought to be the terminal sink for per- and polyfluoroalkyl substances (PFAS), persistent organofluorine chemicals used widely in modern commerce for decades. Industry and stewardship programs phased out the most abundantly produced legacy PFAS in the early 2000s due to toxicity concerns. However, they have since been replaced by shorter carbon chain and “novel” chemistries, and past work hypothesized likely increases in these replacement PFAS that were not previously quantifiable. To address this gap, we measured bulk extractable organofluorine (EOF) in archived liver and muscle tissues from pelagic Subarctic pilot whales over the last several decades. Results show EOF concentrations peaked in 2011 and declined by over 60% by 2023. Among a broad suite of targeted and suspect PFAS measured using high-resolution mass spectrometry, only one was consistently increasing through 2023. Tissue concentrations of four main legacy PFAS that accounted for over 75% of EOF were all decreasing by 2023. The timing of peak concentrations depended primarily on whether they were transported to the subarctic by ocean circulation or atmospheric deposition, with the latter declining much faster. Oceanic transport and bioaccumulation modeling suggests that decadal-scale lags between production and food web bioaccumulation are primarily driven by marine transport processes. Large declines in tissue concentrations in this study reinforce the effectiveness of phase-outs in chemical production. However, other work showing stable or increasing EOF in human serum suggests many emerging PFAS with more neutral physicochemical properties may be preferentially accumulating in terrestrial and nearshore environments compared to legacy PFAS.
{"title":"Large declines in organofluorine contamination indicated by subarctic marine mammal tissues","authors":"Jennifer M. Sun, Euna Kim, Heidi M. Pickard, Bjarni Mikkelsen, Katrin S. Hoydal, Halla W. Reinert, Colin P. Thackray, Elsie M. Sunderland","doi":"10.1073/pnas.2524513123","DOIUrl":"https://doi.org/10.1073/pnas.2524513123","url":null,"abstract":"The ocean is thought to be the terminal sink for per- and polyfluoroalkyl substances (PFAS), persistent organofluorine chemicals used widely in modern commerce for decades. Industry and stewardship programs phased out the most abundantly produced legacy PFAS in the early 2000s due to toxicity concerns. However, they have since been replaced by shorter carbon chain and “novel” chemistries, and past work hypothesized likely increases in these replacement PFAS that were not previously quantifiable. To address this gap, we measured bulk extractable organofluorine (EOF) in archived liver and muscle tissues from pelagic Subarctic pilot whales over the last several decades. Results show EOF concentrations peaked in 2011 and declined by over 60% by 2023. Among a broad suite of targeted and suspect PFAS measured using high-resolution mass spectrometry, only one was consistently increasing through 2023. Tissue concentrations of four main legacy PFAS that accounted for over 75% of EOF were all decreasing by 2023. The timing of peak concentrations depended primarily on whether they were transported to the subarctic by ocean circulation or atmospheric deposition, with the latter declining much faster. Oceanic transport and bioaccumulation modeling suggests that decadal-scale lags between production and food web bioaccumulation are primarily driven by marine transport processes. Large declines in tissue concentrations in this study reinforce the effectiveness of phase-outs in chemical production. However, other work showing stable or increasing EOF in human serum suggests many emerging PFAS with more neutral physicochemical properties may be preferentially accumulating in terrestrial and nearshore environments compared to legacy PFAS.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"51 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048213","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}
Zhou Sha, Anthony M. Pedley, Timothy D. Iles, Shaoqing Zhang, Jack R. Staub, Ruobo Zhou, Stephen J. Benkovic
The spatial coordination between cellular organelles and metabolic enzyme assemblies represents a fundamental mechanism for maintaining metabolic efficiency under stress. While previous work has shown that membrane-bound organelles regulate metabolic activities and that membrane-less condensates conduct metabolic reactions, the coordination between these two organizations remains unaddressed. By using a combination of proximity labeling, superresolution fluorescence microscopy, and metabolite analyses using isotopic tracing, we investigated the relationships between these metabolic hotspots. Here, we show that nutrient deficiency elongates mitochondria and transforms the ER from a tubular to sheet-like morphology, coinciding with increased mitochondrial respiration and inosine 5′-monophosphate levels. These structural changes promote the colocalization of purinosomes with these organelles, enhancing metabolic channeling. Disruption of ER sheet formation via MTM1 knockout destabilizes purinosomes, impairs substrate channeling, and reduces intracellular purine nucleotide pools without altering enzyme expression. Our findings reveal that organelle morphology and interorganelle contacts dynamically regulate the assembly and function of metabolic condensates, providing a structural basis for coordinated metabolic control in response to nutrient availability.
{"title":"Coordination of cell organelles to promote metabolon formation","authors":"Zhou Sha, Anthony M. Pedley, Timothy D. Iles, Shaoqing Zhang, Jack R. Staub, Ruobo Zhou, Stephen J. Benkovic","doi":"10.1073/pnas.2532504123","DOIUrl":"https://doi.org/10.1073/pnas.2532504123","url":null,"abstract":"The spatial coordination between cellular organelles and metabolic enzyme assemblies represents a fundamental mechanism for maintaining metabolic efficiency under stress. While previous work has shown that membrane-bound organelles regulate metabolic activities and that membrane-less condensates conduct metabolic reactions, the coordination between these two organizations remains unaddressed. By using a combination of proximity labeling, superresolution fluorescence microscopy, and metabolite analyses using isotopic tracing, we investigated the relationships between these metabolic hotspots. Here, we show that nutrient deficiency elongates mitochondria and transforms the ER from a tubular to sheet-like morphology, coinciding with increased mitochondrial respiration and inosine 5′-monophosphate levels. These structural changes promote the colocalization of purinosomes with these organelles, enhancing metabolic channeling. Disruption of ER sheet formation via MTM1 knockout destabilizes purinosomes, impairs substrate channeling, and reduces intracellular purine nucleotide pools without altering enzyme expression. Our findings reveal that organelle morphology and interorganelle contacts dynamically regulate the assembly and function of metabolic condensates, providing a structural basis for coordinated metabolic control in response to nutrient availability.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"85 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048243","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}
Shivani T. Shivani, Brynn E. LeMasters, Thirupathi Ravula, Harrison J. Esterly, Nikhil Maroli, Kacie L. Rich, Caitlyn R. Fields, Sidney S. Dicke, Owen A. Warmuth, Donald S. Stapleton, Mark P. Keller, Alan D. Attie, Alexei A. Kananenka, Katherine A. Henzler-Wildman, Chad M. Rienstra, Martin T. Zanni
Amyloid oligomers of the human islet amyloid polypeptide (hIAPP) are a likely cytotoxic species driving β-cell death in type 2 diabetes, but their transient nature has precluded atomic-level structural characterization. We obtained a high-resolution structure of a physiologically relevant hIAPP oligomer. Using 2D IR spectroscopy, we identified three substitutions that slowed aggregation sufficiently for comprehensive 2D/3D NMR analysis while retaining the key wild-type structural features and cytotoxicity. The structural model reveals a dimeric assembly with N-terminal helices and a kink that facilitates an intermolecular β-sheet. The β-sheet spans the famous FGAILS portion of the sequence, helping to explain species-specific diabetes susceptibility and the origin of early-onset familial mutations. The integrated 2D IR/NMR strategy provides a unique approach to obtaining high-resolution structures of amyloid oligomers.
{"title":"A structural model of toxic amyloid oligomers involved in type 2 diabetes","authors":"Shivani T. Shivani, Brynn E. LeMasters, Thirupathi Ravula, Harrison J. Esterly, Nikhil Maroli, Kacie L. Rich, Caitlyn R. Fields, Sidney S. Dicke, Owen A. Warmuth, Donald S. Stapleton, Mark P. Keller, Alan D. Attie, Alexei A. Kananenka, Katherine A. Henzler-Wildman, Chad M. Rienstra, Martin T. Zanni","doi":"10.1073/pnas.2528103123","DOIUrl":"https://doi.org/10.1073/pnas.2528103123","url":null,"abstract":"Amyloid oligomers of the human islet amyloid polypeptide (hIAPP) are a likely cytotoxic species driving β-cell death in type 2 diabetes, but their transient nature has precluded atomic-level structural characterization. We obtained a high-resolution structure of a physiologically relevant hIAPP oligomer. Using 2D IR spectroscopy, we identified three substitutions that slowed aggregation sufficiently for comprehensive 2D/3D NMR analysis while retaining the key wild-type structural features and cytotoxicity. The structural model reveals a dimeric assembly with N-terminal helices and a kink that facilitates an intermolecular β-sheet. The β-sheet spans the famous FGAILS portion of the sequence, helping to explain species-specific diabetes susceptibility and the origin of early-onset familial mutations. The integrated 2D IR/NMR strategy provides a unique approach to obtaining high-resolution structures of amyloid oligomers.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"41 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048241","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}
Shaowen Jiang, Jahanara Freedman, Madhav Mantri, Viviana Maymi, Scott A. Leddon, Peter Schweitzer, Subash Bhandari, Chase Holdener, Ioannis Ntekas, Christopher Vollmers, Andrew I. Flyak, Deborah J. Fowell, Brian D. Rudd, Iwijn De Vlaminck
The spatial organization of adaptive immune cells within lymph nodes is critical for understanding immune responses during infection and disease. Here, we introduce AIR-SPACE, an integrative approach that combines high-resolution spatial transcriptomics with paired, high-fidelity long-read sequencing of T and B cell receptors. This method enables the simultaneous analysis of cellular transcriptomes and adaptive immune receptor (AIR) repertoires within their native spatial context. We applied AIR-SPACE to mouse popliteal lymph nodes at five distinct time points after Vaccinia virus footpad infection and constructed a comprehensive map of the developing adaptive immune response. Our analysis revealed heterogeneous activation niches, characterized by Interferon-gamma (IFN-γ) production, during the early stages of infection. At later stages, we delineated subanatomical structures within the germinal center (GC) and observed evidence that antibody-producing plasma cells differentiate and exit the GC through the dark zone. Furthermore, by combining clonotype data with spatial lineage tracing, we demonstrate that B cell clones are shared among multiple GCs within the same lymph node, reinforcing the concept of a dynamic, interconnected network of GCs. Overall, our study demonstrates how AIR-SPACE can be used to gain insight into the spatial dynamics of infection responses within lymphoid organs.
{"title":"A temporal and spatial atlas of adaptive immune responses in the lymph node following viral infection","authors":"Shaowen Jiang, Jahanara Freedman, Madhav Mantri, Viviana Maymi, Scott A. Leddon, Peter Schweitzer, Subash Bhandari, Chase Holdener, Ioannis Ntekas, Christopher Vollmers, Andrew I. Flyak, Deborah J. Fowell, Brian D. Rudd, Iwijn De Vlaminck","doi":"10.1073/pnas.2504742123","DOIUrl":"https://doi.org/10.1073/pnas.2504742123","url":null,"abstract":"The spatial organization of adaptive immune cells within lymph nodes is critical for understanding immune responses during infection and disease. Here, we introduce AIR-SPACE, an integrative approach that combines high-resolution spatial transcriptomics with paired, high-fidelity long-read sequencing of T and B cell receptors. This method enables the simultaneous analysis of cellular transcriptomes and adaptive immune receptor (AIR) repertoires within their native spatial context. We applied AIR-SPACE to mouse popliteal lymph nodes at five distinct time points after Vaccinia virus footpad infection and constructed a comprehensive map of the developing adaptive immune response. Our analysis revealed heterogeneous activation niches, characterized by Interferon-gamma (IFN-γ) production, during the early stages of infection. At later stages, we delineated subanatomical structures within the germinal center (GC) and observed evidence that antibody-producing plasma cells differentiate and exit the GC through the dark zone. Furthermore, by combining clonotype data with spatial lineage tracing, we demonstrate that B cell clones are shared among multiple GCs within the same lymph node, reinforcing the concept of a dynamic, interconnected network of GCs. Overall, our study demonstrates how AIR-SPACE can be used to gain insight into the spatial dynamics of infection responses within lymphoid organs.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"3 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048216","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}
Peng-Jun Zhang, Rui-Chen Li, Ye-Hua Li, Hong-Jian Wan, Da-Wei Xue, Bao-Li Qiu, Ted C. J. Turlings
Whiteflies pose a major threat to crops worldwide, primarily because they transmit begomoviruses with which they have evolved intricate mutualistic relationships. The mutualisms are known to exacerbate whitefly invasions and drive widespread plant virus pandemics. Yet, certain plant genotypes are able to resist both the whiteflies and the viruses and a good understanding of the underlying mechanisms could help to develop more resistant varieties. Here, we show that the viruliferous whitefly Bemisia tabaci induces an early and strong release of the sesquiterpene β-caryophyllene in cultivated tomato plants. This volatile functions as an airborne signal that primes neighboring conspecifics for enhanced resistance to begomoviruses, including Tomato yellow leaf curl virus and Papaya leaf curl China virus. These results challenge the view that whitefly-induced volatile emissions primarily benefit the insect vector, suggesting instead that the plant prioritizes antiviral defense over antiherbivore resistance. β-Caryophyllene exposure was also found to enhance the emission of β-Caryophyllene, methyl salicylate and β-myrcene upon whitefly attack, increasing plant attractiveness to the parasitoid Encarsia formosa . Using a β-caryophyllene overproducing transgenic tomato line and synthetic β-caryophyllene dispensers, we confirmed that β-caryophyllene exposure primes antipathogen defenses in tomato plants and confers improved plant fitness under sustained infestation by viruliferous whiteflies. Importantly, this defense priming is genotype-specific and limited to certain tomato cultivars, suggesting that β-caryophyllene-mediated resistance can be harnessed through selective breeding. Our findings reveal a volatile-based mechanism by which tomato plants may counteract the virus–vector mutualism, offering promising avenues for integrated pest and disease management.
{"title":"Airborne β-caryophyllene disrupts virus–vector mutualism by priming tomato defenses","authors":"Peng-Jun Zhang, Rui-Chen Li, Ye-Hua Li, Hong-Jian Wan, Da-Wei Xue, Bao-Li Qiu, Ted C. J. Turlings","doi":"10.1073/pnas.2520719123","DOIUrl":"https://doi.org/10.1073/pnas.2520719123","url":null,"abstract":"Whiteflies pose a major threat to crops worldwide, primarily because they transmit begomoviruses with which they have evolved intricate mutualistic relationships. The mutualisms are known to exacerbate whitefly invasions and drive widespread plant virus pandemics. Yet, certain plant genotypes are able to resist both the whiteflies and the viruses and a good understanding of the underlying mechanisms could help to develop more resistant varieties. Here, we show that the viruliferous whitefly <jats:italic toggle=\"yes\">Bemisia tabaci</jats:italic> induces an early and strong release of the sesquiterpene β-caryophyllene in cultivated tomato plants. This volatile functions as an airborne signal that primes neighboring conspecifics for enhanced resistance to begomoviruses, including Tomato yellow leaf curl virus and Papaya leaf curl China virus. These results challenge the view that whitefly-induced volatile emissions primarily benefit the insect vector, suggesting instead that the plant prioritizes antiviral defense over antiherbivore resistance. β-Caryophyllene exposure was also found to enhance the emission of β-Caryophyllene, methyl salicylate and β-myrcene upon whitefly attack, increasing plant attractiveness to the parasitoid <jats:italic toggle=\"yes\">Encarsia formosa</jats:italic> . Using a β-caryophyllene overproducing transgenic tomato line and synthetic β-caryophyllene dispensers, we confirmed that β-caryophyllene exposure primes antipathogen defenses in tomato plants and confers improved plant fitness under sustained infestation by viruliferous whiteflies. Importantly, this defense priming is genotype-specific and limited to certain tomato cultivars, suggesting that β-caryophyllene-mediated resistance can be harnessed through selective breeding. Our findings reveal a volatile-based mechanism by which tomato plants may counteract the virus–vector mutualism, offering promising avenues for integrated pest and disease management.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"100 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048217","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}
Xin Sun, Lanhui Peng, Takumi Tsutaya, Qigao Jiangzuo, Yoshikazu Hasegawa, Yuxin Hou, Yu Han, Yan Zhuang, Jazmin Ramos Madrigal, Alberto J. Taurozzi, Meaghan Mackie, Gaudry Trochė, Jesper V. Olsen, Enrico Cappellini, Stephen J. O’Brien, M. Thomas P. Gilbert, Nobuyuki Yamaguchi, Shu-Jin Luo
Lions and tigers, as dominant apex predators, likely became competitors when lions expanded from Africa into Eurasia approximately one million years ago (Ma), forming a lion–tiger transition belt from the Middle East through Central Asia to the Russian Far East. At the easternmost edge of this zone, the Japanese Archipelago has long been considered a Late Pleistocene tiger refugium, supported by large felid subfossils traditionally attributed to tigers ( Panthera tigris ), though their taxonomic identity remained unresolved. To clarify the origin, evolutionary history, and biogeography of Japan’s Pleistocene felids, we analyzed 26 ancient specimens previously assumed to be tigers. Using mitochondrial and nuclear genome hybridization capture and sequencing, paleoproteomics, Bayesian molecular dating, and radiocarbon dating, we found that all ancient Japanese “tiger” remains yielding molecular data were, unexpectedly, cave lions ( Panthera spelaea ). One specimen from Yamaguchi Prefecture, western Japan, was radiocarbon dated to 36,000-34,891 cal. BP. These cave lions likely dispersed to the Japanese Archipelago between ~72.7 and 37.5 thousand years ago (ka), when a land bridge connected northern Japan to the mainland during the Last Glacial Period. Our findings challenge the long-held view that tigers once took refuge in Japan, showing instead that cave lions were widespread in northeast Asia during this period and were the Panthera lineage that colonized Japan, reaching even its southwestern regions despite habitats previously thought to favor tigers.
{"title":"The Japanese Archipelago sheltered cave lions, not tigers, during the Late Pleistocene","authors":"Xin Sun, Lanhui Peng, Takumi Tsutaya, Qigao Jiangzuo, Yoshikazu Hasegawa, Yuxin Hou, Yu Han, Yan Zhuang, Jazmin Ramos Madrigal, Alberto J. Taurozzi, Meaghan Mackie, Gaudry Trochė, Jesper V. Olsen, Enrico Cappellini, Stephen J. O’Brien, M. Thomas P. Gilbert, Nobuyuki Yamaguchi, Shu-Jin Luo","doi":"10.1073/pnas.2523901123","DOIUrl":"https://doi.org/10.1073/pnas.2523901123","url":null,"abstract":"Lions and tigers, as dominant apex predators, likely became competitors when lions expanded from Africa into Eurasia approximately one million years ago (Ma), forming a lion–tiger transition belt from the Middle East through Central Asia to the Russian Far East. At the easternmost edge of this zone, the Japanese Archipelago has long been considered a Late Pleistocene tiger refugium, supported by large felid subfossils traditionally attributed to tigers ( <jats:italic toggle=\"yes\">Panthera tigris</jats:italic> ), though their taxonomic identity remained unresolved. To clarify the origin, evolutionary history, and biogeography of Japan’s Pleistocene felids, we analyzed 26 ancient specimens previously assumed to be tigers. Using mitochondrial and nuclear genome hybridization capture and sequencing, paleoproteomics, Bayesian molecular dating, and radiocarbon dating, we found that all ancient Japanese “tiger” remains yielding molecular data were, unexpectedly, cave lions ( <jats:italic toggle=\"yes\">Panthera spelaea</jats:italic> ). One specimen from Yamaguchi Prefecture, western Japan, was radiocarbon dated to 36,000-34,891 cal. BP. These cave lions likely dispersed to the Japanese Archipelago between ~72.7 and 37.5 thousand years ago (ka), when a land bridge connected northern Japan to the mainland during the Last Glacial Period. Our findings challenge the long-held view that tigers once took refuge in Japan, showing instead that cave lions were widespread in northeast Asia during this period and were the <jats:italic toggle=\"yes\">Panthera</jats:italic> lineage that colonized Japan, reaching even its southwestern regions despite habitats previously thought to favor tigers.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"395 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048237","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}
Young Mie Kim, Ross Dahlke, Hyebin Song, Richard Heinrich
In light of continued foreign interference in the US presidential elections, where undisclosed digital voter suppression advertising has been deployed, this study addresses the questions of who is exposed to these ads and whether and how such exposure influences voter turnout. Using a sample that resembles the US voting-age population, the study directly measures each individual’s ad exposure through a user-level real-time ad tracking tool, which is merged with the same individual’s survey responses to identify voter suppression content and its targeting patterns. By further matching individual-level exposure to voter suppression ads with the same individual’s verified voter turnout records, the study estimates the effects of voter suppression on actual turnout. The study findings from the 2016 US Presidential Election reveal clear geo-racial targeting patterns in voter suppression: non-Whites residing in the racial minority counties of battleground states were exposed to substantially more voter suppression ads than their counterparts. Moreover, exposure to voter suppression ads was associated with decreases in voter turnout at the population level, albeit small. The sharpest declines were observed among non-Whites residing in minority counties of battleground states, suggesting that the intensified turnout suppression among the targeted segments of the electorate may have played a role in shaping turnout.
{"title":"Targeted digital voter suppression efforts likely decrease voter turnout","authors":"Young Mie Kim, Ross Dahlke, Hyebin Song, Richard Heinrich","doi":"10.1073/pnas.2519944123","DOIUrl":"https://doi.org/10.1073/pnas.2519944123","url":null,"abstract":"In light of continued foreign interference in the US presidential elections, where undisclosed digital voter suppression advertising has been deployed, this study addresses the questions of who is exposed to these ads and whether and how such exposure influences voter turnout. Using a sample that resembles the US voting-age population, the study directly measures each individual’s ad exposure through a user-level real-time ad tracking tool, which is merged with the same individual’s survey responses to identify voter suppression content and its targeting patterns. By further matching individual-level exposure to voter suppression ads with the same individual’s verified voter turnout records, the study estimates the effects of voter suppression on actual turnout. The study findings from the 2016 US Presidential Election reveal clear geo-racial targeting patterns in voter suppression: non-Whites residing in the racial minority counties of battleground states were exposed to substantially more voter suppression ads than their counterparts. Moreover, exposure to voter suppression ads was associated with decreases in voter turnout at the population level, albeit small. The sharpest declines were observed among non-Whites residing in minority counties of battleground states, suggesting that the intensified turnout suppression among the targeted segments of the electorate may have played a role in shaping turnout.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"53 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048238","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}
Subcellular proteomics maps protein localization within restricted domains of a cell, complementing high-resolution imaging by expanding the number of proteins that can be profiled at once. Achieving this at depth from subcellular inputs remains challenging. Here, we advance microprobe capillary electrophoresis–mass spectrometry (CE–MS) with trapped ion mobility spectrometry and data-independent acquisition (diaPASEF) to quantify more than a thousand proteins from opposite poles of an asymmetrically dividing embryonic blastomere in live Xenopus laevis embryos. From ~200 pg of HeLa digest—approximately 80% of a cell—the technology identified 1,035 proteins with high reproducibility in quantification (coefficient of variation <15% across technical triplicates). With microprobe sampling in vivo, we quantified 808–1,022 proteins from opposite poles of the dorsal–animal (D1) blastomere before division, and we traced how these spatial distributions are retained or remodeled in the descendant D1.1 (neural-fated) and D1.2 (epidermal-destined) cells. To decouple subcellular distributions from dorsal–ventral axis cues, we perturbed patterning by ultraviolet ventralization. These results establish microprobe CE–MS for deep subcellular proteomics in intact embryos and reveal spatially distinct protein distributions during early fate specification. These spatial proteome differences appear consistent with early lineage tendencies yet precede and likely bias, rather than fix, later fate decisions that depend on gastrula-stage inductive signals.
{"title":"Subcellular mass spectrometry reveals proteome remodeling in an asymmetrically dividing (frog) embryonic stem cell","authors":"Bowen Shen, Leena R. Pade, Fei Zhou, Peter Nemes","doi":"10.1073/pnas.2518372123","DOIUrl":"https://doi.org/10.1073/pnas.2518372123","url":null,"abstract":"Subcellular proteomics maps protein localization within restricted domains of a cell, complementing high-resolution imaging by expanding the number of proteins that can be profiled at once. Achieving this at depth from subcellular inputs remains challenging. Here, we advance microprobe capillary electrophoresis–mass spectrometry (CE–MS) with trapped ion mobility spectrometry and data-independent acquisition (diaPASEF) to quantify more than a thousand proteins from opposite poles of an asymmetrically dividing embryonic blastomere in live <jats:italic toggle=\"yes\">Xenopus laevis</jats:italic> embryos. From ~200 pg of HeLa digest—approximately 80% of a cell—the technology identified 1,035 proteins with high reproducibility in quantification (coefficient of variation <15% across technical triplicates). With microprobe sampling in vivo, we quantified 808–1,022 proteins from opposite poles of the dorsal–animal (D1) blastomere before division, and we traced how these spatial distributions are retained or remodeled in the descendant D1.1 (neural-fated) and D1.2 (epidermal-destined) cells. To decouple subcellular distributions from dorsal–ventral axis cues, we perturbed patterning by ultraviolet ventralization. These results establish microprobe CE–MS for deep subcellular proteomics in intact embryos and reveal spatially distinct protein distributions during early fate specification. These spatial proteome differences appear consistent with early lineage tendencies yet precede and likely bias, rather than fix, later fate decisions that depend on gastrula-stage inductive signals.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"220 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048240","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}
Brynn E. LeMasters, Caitlyn R. Fields, Justin P. Lomont, Farzaneh Chalyavi, Kacie L. Rich, Donald S. Stapleton, Sidney S. Dicke, Mark P. Keller, Alan D. Attie, Martin T. Zanni
Some mammals develop amyloid plaques and type 2 diabetes, much like humans, depending on the sequence of their islet amyloid polypeptide (IAPP). In humans, IAPP forms a toxic oligomer with a parallel β-sheet across residues 23 FGAIL 28 S. Using two-dimensional infrared spectroscopy, we monitor the structure of IAPP from seven different mammals, five of which are from species that can develop type 2 diabetes (ferret, raccoon, cat, baboon, and human) and three from those that do not (hamster, rat, and pig). G24 is isotope labeled to monitor for the presence of the oligomeric β-sheet previously found in human IAPP. For the species that develop type 2 diabetes, their IAPP is cytotoxic, and a β-sheet at G24 is observed during the lag phase prior to fibril formation. In contrast, the species that do not develop type 2 diabetes have nontoxic IAPP, and their IAPP does not form this β-sheet structure. Pig IAPP forms oligomers, but with a different structure that is nontoxic. Thus, an oligomer with a parallel β-sheet at G24 that resembles that of the known human IAPP oligomer correlates with cytotoxicity and propensity for type 2 diabetes. These results indicate that the sequence within the 20 to 29 region of human islet amyloid polypeptide (hIAPP), long known to correlate with type 2 diabetes in mammals, determines the structure and toxicity of an oligomer, supporting the oligomer hypothesis for type 2 diabetes and providing an explanation other than plaque formation for why some mammals develop insulin deficiency in late-stage type 2 diabetes, and others do not.
{"title":"Mammals that can develop type 2 diabetes have a similarly structured β-sheet amyloid oligomer","authors":"Brynn E. LeMasters, Caitlyn R. Fields, Justin P. Lomont, Farzaneh Chalyavi, Kacie L. Rich, Donald S. Stapleton, Sidney S. Dicke, Mark P. Keller, Alan D. Attie, Martin T. Zanni","doi":"10.1073/pnas.2530570123","DOIUrl":"https://doi.org/10.1073/pnas.2530570123","url":null,"abstract":"Some mammals develop amyloid plaques and type 2 diabetes, much like humans, depending on the sequence of their islet amyloid polypeptide (IAPP). In humans, IAPP forms a toxic oligomer with a parallel β-sheet across residues <jats:sup>23</jats:sup> FGAIL <jats:sup>28</jats:sup> S. Using two-dimensional infrared spectroscopy, we monitor the structure of IAPP from seven different mammals, five of which are from species that can develop type 2 diabetes (ferret, raccoon, cat, baboon, and human) and three from those that do not (hamster, rat, and pig). G24 is isotope labeled to monitor for the presence of the oligomeric β-sheet previously found in human IAPP. For the species that develop type 2 diabetes, their IAPP is cytotoxic, and a β-sheet at G24 is observed during the lag phase prior to fibril formation. In contrast, the species that do not develop type 2 diabetes have nontoxic IAPP, and their IAPP does not form this β-sheet structure. Pig IAPP forms oligomers, but with a different structure that is nontoxic. Thus, an oligomer with a parallel β-sheet at G24 that resembles that of the known human IAPP oligomer correlates with cytotoxicity and propensity for type 2 diabetes. These results indicate that the sequence within the 20 to 29 region of human islet amyloid polypeptide (hIAPP), long known to correlate with type 2 diabetes in mammals, determines the structure and toxicity of an oligomer, supporting the oligomer hypothesis for type 2 diabetes and providing an explanation other than plaque formation for why some mammals develop insulin deficiency in late-stage type 2 diabetes, and others do not.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"53 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048210","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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