Proceedings of the National Academy of Sciences of the United States of America最新文献

{"title":"SETDB1 ensures the continuity of embryonic to adult neural stem cells through metabolic alterations in the dentate gyrus.","authors":"Yunyun Huang,Yue Zhu,Yueyan Zhu,Yan Jiang,Yunli Xie","doi":"10.1073/pnas.2424315122","DOIUrl":"https://doi.org/10.1073/pnas.2424315122","url":null,"abstract":"Embryonic neural progenitors give rise to adult neural stem cells (aNSCs), which share transcriptomic similarities with astrocytes while sustaining neurogenesis in the adult brain. How embryonic neural progenitors transit into aNSCs while preventing astrocyte fate to maintain the aNSC pool remains unclear. Here, we found that the Setdb1-mediated metabolic state is essential for the transition from embryonic neural progenitors to aNSCs. Loss of the histone methyltransferase SETDB1 during dentate gyrus development leads to increased astrocyte production at the expense of aNSCs and ultimately constraining neurogenesis. Single-cell RNA sequencing reveals a specific metabolic alteration following Setdb1 loss, notably implicating the cytochrome c oxidase, subunit 6b2 (Cox6b2)-a component of the mitochondrial complex-as a key target of SETDB1. COX6B2 modulates oxidative phosphorylation (OXPHOS) to control aNSC fate over astrocyte differentiation. Elevated Cox6b2 levels promote astrocyte fate during dentate gyrus development. Thus, our findings reveal a mechanism underlying the continuity of neural progenitors to generate aNSC enabling the production of new neurons in the adult brain, highlighting the potential therapeutic strategies for transforming astrocytes into neurons via aNSCs.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"110 1","pages":"e2424315122"},"PeriodicalIF":11.1,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693340","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}

{"title":"Norms emerge through iterated learning.","authors":"Scott Partington, Rachana Kamtekar, Shaun Nichols","doi":"10.1073/pnas.2504178122","DOIUrl":"https://doi.org/10.1073/pnas.2504178122","url":null,"abstract":"<p><p>Injunctive norms are universal: Every culture has rules that specify what actions are forbidden, obligatory, or permitted. Where do all of these norms come from? In this paper, we identify a mechanism of cultural transmission that can explain the emergence of injunctive norms. In particular, we develop an <i>iterated learning</i> account that shows how weak biases in pedagogy and inference can drive norm emergence through cultural transmission. Using transmission chain studies, we confirm the core predictions of the iterated learning account. In five studies (<i>N</i> = 3,688), an initial generation of participants learn about an action that is merely <i>inadvisable</i> and teach a new generation of participants about that action. After this learning process repeats iteratively, participants in later generations reliably judge that the action is <i>impermissible</i> and subject to punishment. We find this <i>inadvisable</i>-to-<i>impermissible</i> effect is elicited across a wide range of initial conditions. Overall, then, our results support the idea that iterated learning can drive the emergence of injunctive norms across a wide range of contexts.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 29","pages":"e2504178122"},"PeriodicalIF":9.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664044","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}

{"title":"N<i>-</i>acetyltransferases required for iron uptake and aminoglycoside resistance promote virulence lipid production in <i>Mycobacterium marinum</i>.","authors":"Bradley S Jones, Vikram Pareek, Daniel D Hu, Simon D Weaver, Camille Syska, Grace Galfano, Matthew M Champion, Patricia A Champion","doi":"10.1073/pnas.2502577122","DOIUrl":"10.1073/pnas.2502577122","url":null,"abstract":"<p><p>Phagosomal lysis is essential for mycobacterial infection of macrophages. Acetylation is a protein modification mediated enzymatically by N-acetyltransferases (NATs) that impacts bacterial pathogenesis and physiology. To identify NATs required for lytic activity, we leveraged <i>Mycobacterium marinum,</i> a nontubercular pathogen and a model for <i>Mycobacterium tuberculosis. M. marinum</i> hemolysis is a proxy for phagolytic activity. We generated <i>M. marinum</i> strains with deletions in conserved NAT genes and screened for hemolytic activity. Several conserved lysine acetyltransferases (KATs) contributed to hemolysis, which is mediated by the ESX-1 secretion system and by the virulence lipid phthiocerol dimycocerosate (PDIM). Using thin-layer chromatography, we found that MbtK, a conserved acyl-transferase required for mycobactin siderophore synthesis and virulence, was required for PDIM and phenolic glycolipid (PGL) production. Exogenous addition of sodium propionate or Mycobactin J restored PDIM/PGL production in the Δ<i>mbtK</i> strain. The Δ<i>mbtK M. marinum</i> strain was attenuated in macrophage and <i>Galleria mellonella</i> infection models. Constitutive expression of either <i>eis</i> or <i>papA5,</i> which encode a KAT required for aminoglycoside resistance and a PDIM/PGL biosynthetic enzyme, rescued PDIM/PGL production, and virulence of the ∆<i>mbtK</i> strain. Eis N-terminally acetylated PapA5 in vitro, providing a plausible mechanism for restored lipid production. Overall, our study establishes connections between the MbtK and Eis NATs, and between iron uptake and PDIM and PGL synthesis in <i>M. marinum</i>. Our findings underscore the multifunctional nature of mycobacterial NATs and their connection to key virulence pathways.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 29","pages":"e2502577122"},"PeriodicalIF":9.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664043","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}

{"title":"Cell-type-informed genotyping of mosaic focal epilepsies reveals cell-autonomous and non-cell-autonomous disease-associated transcriptional programs.","authors":"Sara Bizzotto, Maya Talukdar, Edward A Stronge, Rosita B Ramirez, Yingxi Yang, August Yue Huang, Qiwen Hu, Yingping Hou, Norma K Hylton, Benjamin Finander, Ashton Tillett, Zinan Zhou, Brian H Chhouk, Alissa M D'Gama, Edward Yang, Timothy E Green, David C Reutens, Saul A Mullen, Ingrid E Scheffer, Michael S Hildebrand, Russell J Buono, Ingmar Blümcke, Annapurna H Poduri, Sattar Khoshkhoo, Christopher A Walsh","doi":"10.1073/pnas.2509622122","DOIUrl":"https://doi.org/10.1073/pnas.2509622122","url":null,"abstract":"<p><p>While it is widely accepted that somatic variants that activate the PI3K-mTOR pathway are a major cause of drug-resistant focal epilepsy, typically associated with focal cortical dysplasia (FCD) type 2, understanding the mechanism of epileptogenesis requires identifying genotype-associated changes at the single-cell level, which is technically challenging with existing methods. Here, we performed single-nucleus RNA-sequencing (snRNA-seq) of 18 FCD type 2 samples removed surgically for treatment of drug-resistant epilepsy, and 17 non-FCD control samples, and analyzed additional published data comprising >400,000 single nuclei. We also performed simultaneous single-nucleus genotyping and gene expression analysis using two independent approaches: 1) a method that we called genotyping of transcriptomes enhanced with nanopore sequencing (GO-TEN) that combines targeted cDNA long-read sequencing with snRNA-seq, 2) ResolveOME snRNA-seq and DNA genotyping. snRNA-seq showed similar cell identities and proportions between cases and controls, suggesting that mosaic pathogenic variants in PI3K-mTOR pathway genes in FCD exert their effect by disrupting transcription in conserved cell types. GO-TEN and ResolveOME analyses confirmed that pathogenic variant-carrying cells have well-differentiated neuronal or glial identities, with enrichment of variants in cells of the neuroectodermal lineage, pointing to cortical neural progenitors as possible loci of somatic mutation. Within FCD type 2 lesions, we identified upregulation of PI3K-mTOR signaling and related pathways in variant-carrying neurons, downregulation of these pathways in non-variant-carrying neurons, as well as associated changes in microglial activation, cellular metabolism, synaptic homeostasis, and neuronal connectivity, all potentially contributing to epileptogenesis. These genotype-specific changes in mosaic lesions highlight potential disease mechanisms and therapeutic targets.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 29","pages":"e2509622122"},"PeriodicalIF":9.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144660012","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}

{"title":"Structures of <i>Chaetomium thermophilum</i> TOM complexes with bound preproteins.","authors":"Ahmed-Noor A Agip, Pamela Ornelas, Tzu-Jing Yang, Ermanno Uboldi, Sabine Häder, Melanie A McDowell, Werner Kühlbrandt","doi":"10.1073/pnas.2507279122","DOIUrl":"https://doi.org/10.1073/pnas.2507279122","url":null,"abstract":"<p><p>Mitochondria import most of their proteins from the cytoplasm through the TOM complex. Preproteins containing targeting signals are recognized by the TOM receptor subunits and translocated by Tom40 across the outer mitochondrial membrane. We present four structures of the preprotein-bound and preprotein-free TOM core and holo complexes from the thermophilic fungus <i>Chaetomium thermophilum</i>, obtained by single-particle electron cryomicroscopy. Our structures reveal the symmetric arrangement of two copies of the Tom20 receptor subunit in the TOM holo complex. Several different conformations of Tom20 within the TOM holo complex highlight the dynamic nature of the receptor. The structure of preprotein-bound Tom20 provides insight into the early stages of protein translocation.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 29","pages":"e2507279122"},"PeriodicalIF":9.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144660014","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}

{"title":"Threonine phosphorylation of STAT1 safeguards gut epithelial integrity and restricts interferon-mediated cytotoxicity.","authors":"Hozaifa Metwally,Maha M Elbrashy,Hisako Kayama,Kazuki Okuyama,Ichiro Taniuchi,Kiyoshi Takeda,Tadamitsu Kishimoto","doi":"10.1073/pnas.2511957122","DOIUrl":"https://doi.org/10.1073/pnas.2511957122","url":null,"abstract":"Barrier tissues such as the intestine are constantly challenged by environmental stressors and must adapt to maintain integrity and prevent excessive inflammation. Although traditionally viewed as a proinflammatory effector of interferon (IFN) signaling, STAT1 is shown here to play a protective role in intestinal epithelial cells (IEC) by promoting resilience to damage and restraining IFN-induced cytotoxicity. We identify phosphorylation of threonine 748 (Thr748) on STAT1 as an evolutionarily selected adaptation-highly conserved between humans and mice-that reciprocally regulates IEC integrity and IFN responsiveness. Mice expressing a phospho-deficient T748A Stat1 mutant exhibit severe colitis-induced tissue damage comparable to Stat1-deficient littermates, underscoring the critical role of Thr748 phosphorylation in mediating Stat1-driven protection during intestinal inflammation. Bone marrow transfer experiments further demonstrate that this protective effect is nonhematopoietic. Integrated genomic and transcriptomic analyses reveal that Thr748 phosphorylation modulates STAT1 DNA binding, directly activates the Itgb4 promoter, and enhances integrin β4 expression in IEC following inflammation. In intestinal organoid models, gain- and loss-of-function experiments demonstrate that Thr748 phosphorylation drives integrin β4 expression and epithelial resilience independently of IFN-induced Tyrosine 701 (Tyr701) phosphorylation. In contrast, IFN stimulation via Tyr701 induces Zbp1-a cytotoxic nucleic acid sensor-while repressing integrin β4, resulting in epithelial injury that is mitigated by Thr748 phosphorylation. Together, these findings reveal a modular architecture of STAT1 signaling in which Thr748 phosphorylation functions as a molecular rheostat that safeguards epithelial integrity while tempering IFN-driven cytotoxic responses.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"52 1","pages":"e2511957122"},"PeriodicalIF":11.1,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684051","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}

{"title":"TMEM63A, associated with hypomyelinating leukodystrophies, is an evolutionarily conserved regulator of myelination","authors":"Julia Halford, Amanda J. Senatore, Sage Berryman, Antonio Muñoz, Destinee Semidey, Ryan A. Doan, Adam M. Coombs, Brandon Noimany, Katie Emberley, Ben Emery, Kelly R. Monk, Swetha E. Murthy","doi":"10.1073/pnas.2507354122","DOIUrl":"https://doi.org/10.1073/pnas.2507354122","url":null,"abstract":"Infantile hypomyelinating leukodystrophy 19 (HLD19) is a rare genetic disorder where patients exhibit reduced myelin in central nervous system (CNS) white matter tracts and present with varied neurological symptoms. The causative gene <jats:italic toggle=\"yes\">TMEM63A</jats:italic> encodes a mechanosensitive ion channel whose role in myelination is largely unexplored. Our study shows that TMEM63A is a major regulator of oligodendrocyte (OL)-dependent myelination in the CNS. In mouse and zebrafish, <jats:italic toggle=\"yes\">Tmem63a</jats:italic> inactivation led to early deficits in myelination, recapitulating the HLD19 phenotype. OL-specific conditional mouse knockouts of <jats:italic toggle=\"yes\">Tmem63a</jats:italic> exhibited transient reductions in myelin, indicating that TMEM63A regulates myelination cell-autonomously. We show that TMEM63A is present at the plasma membrane and on lysosomes and modulates myelin production in the presence of mechanical cues. Intriguingly, HLD19-associated <jats:italic toggle=\"yes\">TMEM63A</jats:italic> variants from patients blocked trafficking to cell membrane. Together, our results reveal an ancient role for TMEM63A in fundamental aspects of myelination in vivo and highlight two exciting models for the development of treatments for devastating hypomyelinating leukodystrophies.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"32 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144685174","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}

{"title":"In This Issue.","authors":"","doi":"10.1073/iti2925122","DOIUrl":"https://doi.org/10.1073/iti2925122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 29","pages":"eiti2925122"},"PeriodicalIF":9.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691337","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}

{"title":"A quantitative figure of merit for battery SEI films and their use as functional solid-state electrolytes","authors":"Bo Liu, Dingyi Zhao, Katelyn Lyle, Xintong Yuan, Po-Hung Chen, Xinyue Zhang, Jin Koo Kim, Tian-Yu Wang, Haoyang Wu, Chongzhen Wang, Jiayi Yu, Keyue Liang, Jung Tae Kim, Kaiyan Liang, Yuzhang Li","doi":"10.1073/pnas.2425556122","DOIUrl":"https://doi.org/10.1073/pnas.2425556122","url":null,"abstract":"As a key passivation film that governs battery operation, the solid electrolyte interphase (SEI) has long been credited for enabling high-performance batteries or blamed for their eventual death. However, qualitative descriptions of the SEI often found in the literature (e.g., “conductive,” “passivating”) highlight our incomplete understanding of this layer, where even the most basic properties foundational to SEI function remain difficult to measure. Here, we quantify SEI conductivities and SEI transference numbers using a separator-free Cu|SEI|Li architecture that treats the SEI as a functional solid-state electrolyte (SSE). We find that while any SEI property alone (e.g., electronic conductivity) is weakly correlated (R <jats:sup>2</jats:sup> &lt; 0.67) with battery performance (e.g., Coulombic efficiency), a strong correlation (R <jats:sup>2</jats:sup> &gt; 0.99) can be achieved by defining the “SEI <jats:italic toggle=\"yes\">cT</jats:italic> number” as a product between the SEI transference number ( <jats:italic toggle=\"yes\">T</jats:italic> ) and the ratio of SEI conductivities ( <jats:italic toggle=\"yes\">c</jats:italic> ). Analogous to the thermoelectric figure of merit (i.e., <jats:italic toggle=\"yes\">zT</jats:italic> ), SEI <jats:italic toggle=\"yes\">cT</jats:italic> quantitatively benchmarks the holistic impact of SEI properties on battery performance and underscores the pitfalls of citing such properties in isolation. Perhaps most strikingly, we demonstrate that Li metal deposition and stripping at room temperature is possible in our separator-free Cu|SEI|Li cell, confirming that the SEI can function precisely as an SSE. Together, these results enrich our understanding of the SEI, not just as a passivation layer but as a functional structure that can potentially have important implications for solid-state batteries.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"47 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144685162","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}

{"title":"Sharks and rays have the oldest vertebrate sex chromosome with unique sex determination mechanisms","authors":"Taiki Niwa, Yoshinobu Uno, Yuta Ohishi, Mitsutaka Kadota, Naotaka Aburatani, Itsuki Kiyatake, Daiki Katooka, Michikazu Yorozu, Nobutaka Tsuzuki, Atsushi Toyoda, Wataru Takagi, Masaru Nakamura, Shigehiro Kuraku","doi":"10.1073/pnas.2513676122","DOIUrl":"https://doi.org/10.1073/pnas.2513676122","url":null,"abstract":"Sex determination has been investigated across vertebrate lineages to reveal the stepwise evolution of sex chromosomes and the diversity of responsible molecular mechanisms. However, these studies rarely include cartilaginous fishes, which diverged from the other vertebrates 450 Mya, hindering the comprehensive view of vertebrate sex determination. Here, we produced chromosome-scale genome assemblies of egg-laying shark species and comparatively investigated genome sequences and transcriptome profiles across diverse cartilaginous fishes. Sex chromosome identification, supported by cytogenetic experiments, elucidated the homology of X chromosomes between sharks and rays as well as an extensively degenerated Y chromosome harboring no detectable male-specific genes. Orthologs of documented sex-determining genes were identified, but not on these sex chromosomes. Transcriptomic analyses combined with histology of embryonic gonads revealed female-biased expression of X-linked genes—including those implicated in the TGF-β and IGF signaling pathways—attributed to incomplete dosage compensation. Our findings indicate that sharks and rays share the oldest sex chromosomes among vertebrates that originated around 300 Mya and the dosage-dependent sex determination mechanism composed of distinct molecules from other vertebrates. This study highlights the antiquity of sex chromosomes and the uniqueness of sex determination mechanisms in sharks and rays, which advances our understanding of evolutionary plasticity in vertebrate sex determination.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"143 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144685173","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}