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

{"title":"In mice, a population of male germ cells show characteristics of nonapoptotic cell death during G0 arrest.","authors":"Kara Stark, Talia Hatkevich, Edward A Miao, Tomokazu Souma, Blanche Capel","doi":"10.1073/pnas.2533604123","DOIUrl":"https://doi.org/10.1073/pnas.2533604123","url":null,"abstract":"<p><p>In mammals, a small population of spermatogonial stem cells (SSCs) is established shortly after birth. These cells self-renew and produce sperm for the male's reproductive lifespan, passing the genome on to the next generation. Establishment of a population of SSCs with high genomic integrity is essential. SSCs are derived from a much larger precursor population of male germ cells (MGCs) that differentiate during fetal life. During the last third of gestation, MGCs undergo a prolonged period of G0 cell cycle arrest during which they sustain high levels of transcription and acquire epigenetic programming for SSC fate. Although these differentiation steps can cause cellular and genomic damage, it has been unclear whether selection for germ cell quality occurs during G0 arrest since no classic markers of cell death have been detected. In this study, we used a mouse model to characterize a population of MGCs that begin to accumulate markers of cell death, such as AnnexinV (AnV) and propidium iodide (PI), at E16.5. The AnV- and PI-positive MGC population is characterized by low expression of the RNA-binding protein, Dead End 1, and exhibits dsDNA breaks and mitochondrial dysfunction. Interestingly, we do not see evidence of an active cell death cascade until the time of birth, when phosphorylation of MLKL, a hallmark of necroptotic cell death, occurs. Based on these findings, we propose that variable cellular health is an important basis for selection of SSC precursors.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2533604123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171104","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":"Competing presynaptic protein assemblies coordinate basal neurotransmission with homeostatic plasticity.","authors":"Wen-Chieh Hsieh, Tae Hee Han, Rosario Vicidomini, Peter Nguyen, Mihaela Serpe","doi":"10.1073/pnas.2604255123","DOIUrl":"https://doi.org/10.1073/pnas.2604255123","url":null,"abstract":"<p><p>Neural circuits establish a stable basal level of synaptic transmission that is maintained throughout life. When synaptic activity is perturbed, homeostatic mechanisms restore this set point, but how neurons reconcile long-term stability and rapid compensatory plasticity remains unclear. Here, we identify two competing presynaptic multimolecular complexes that control steady-state transmission and homeostatic potentiation and define the molecular switch that enables transitions between these functional states. At <i>Drosophila</i> neuromuscular junction, the transmembrane protein PlexinB (PlexB) and the auxiliary subunit Neto-α regulate both basal synaptic function and homeostatic plasticity. PlexB association with presynaptic KaiR1D/Neto-α receptor complexes modulates channel properties and fine-tunes neurotransmitter release, whereas PlexB signaling with Semaphorin2b (Sema2b) and Neto-α drives homeostatic potentiation. KaiR1D and Sema2b/PlexB compete for a limited pool of presynaptic Neto-α. Motor neurons switch from steady-state transmission to homeostatic potentiation by exchanging KaiR1D/Neto-α/PlexB complexes for Neto-α/PlexB/Sema2b. Critically, Neto-α must dissociate from KaiR1D-containing complexes to initiate the homeostatic response. Variants of Neto-α or KaiR1D that fail to dissociate support normal basal neurotransmission but abolish homeostatic plasticity. These findings demonstrate that dynamic reorganization of competing presynaptic protein assemblies enables neurons to preserve stable baseline transmission while mounting robust compensatory responses to perturbations. Given the widespread roles of presynaptic receptors and Semaphorin/Plexin signaling in synaptic regulation, this mechanism may represent a conserved strategy for balancing stability and plasticity in neural circuits.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2604255123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171628","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":"Shedding light on left hippocampal mGlu5 in Alzheimer's disease.","authors":"Charleine Zussy, Magalie Mathias, Mathieu Vitalis, Tristan Moujellil-Legagneur, Fanny Malhaire, Geoffrey Canet, Catherine Desrumaux, Sylvie Claeysen, Xavier Gómez-Santacana, Cyril Goudet, Amadeu Llebaria, Laurent Givalois","doi":"10.1073/pnas.2535413123","DOIUrl":"https://doi.org/10.1073/pnas.2535413123","url":null,"abstract":"<p><p>Metabotropic glutamate receptor 5 (mGlu5) is essential for synaptic plasticity and memory, making it a potential therapeutic target in Alzheimer's disease (AD). While hemispheric asymmetries in hippocampal function have been observed in AD patients, the lateralized contribution of mGlu5 signaling to cognitive decline remains unclear. Here, we show a physiological left-right asymmetry in hippocampal mGlu5 expression in wild-type mice, with higher levels in the left hemisphere, consistent with previous reports. This physiological asymmetry is lost in two distinct mouse models of AD, the J20 and 5xFAD mice, revealing a hemisphere-specific disruption of hippocampal mGlu5 regulation. Using the light-controllable negative allosteric modulator Alloswitch-1, we show that selective inhibition of left, but not right, hippocampal mGlu5 restores working and short-term memory in AD mice. This finding indicates that altered mGlu5 expression does not simply reflect receptor loss, but rather a dysregulated signaling state that remains functionally relevant and pharmacologically targetable. Left-specific modulation also normalizes pathological downstream signaling, including aberrant Pyk2 and GSK-3β activation and tau hyperphosphorylation, across both hemispheres, indicating a widespread impact of hemisphere-selective intervention. These findings establish a functional lateralization of hippocampal mGlu5 signaling and identify the left hippocampus as a critical site for mGlu5-dependent memory dysfunction in AD. They also highlight the therapeutic potential of region-specific photopharmacology for precise intervention in early AD pathology, providing a strategy for spatially targeted modulation of pathological synaptic signaling in neurodegenerative disease.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2535413123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170267","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":"Insights from coproduced scenarios toward urban sustainability transformations.","authors":"David M Iwaniec, Nancy B Grimm, Marta Berbés Blázquez, Elizabeth M Cook, Tischa A Muñoz-Erickson","doi":"10.1073/pnas.2537819123","DOIUrl":"https://doi.org/10.1073/pnas.2537819123","url":null,"abstract":"<p><p>Urban sustainability transformations call for fundamental shifts in how cities are organized, developed, and governed. Yet we need a better understanding of the diversity of visions and pathways that can enable transformative change. We address this gap through an analysis of 60 coproduced positive scenario visions and pathways developed using the Sustainable Future Scenario process, across nine US and Latin American cities participating in the Urban Resilience to Extremes Sustainability Research Network. We engaged diverse urban stakeholders-including government, nonprofit, and private decision-makers, community leaders, residents, and academic collaborators-in more than 20 coproduction workshops to explore alternative urban futures of sustainability and resilience. We examined how the coproduced scenarios represent five domains of transformative change (nature-human relationships, economic transformation, governance, social and environmental justice, and infrastructure futures) and four theories of transformative change (structural/institutional, agency/power, goals of the system, and worldviews/values). Most pathways combined multiple theories of change operating across multiple domains, revealing urban transformations as entangled rather than singular interventions. Some strategies were common across cities-car-free regions, decentralized infrastructure, community-based governance, expanded fundamental rights-yet were pursued with different transformative aims, demonstrating how a strategy's transformative intent depends on the theories of change behind it. These findings position coproduced scenarios as more than a normative or planning tool and offer an analytical approach for surfacing the possibility space of urban transformation.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2537819123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207590","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":"Physical origins of speed control in swimming fishes.","authors":"Jung-Hee Seo, Ji Zhou, Ashley N Peterson, Matthew J McHenry, Valentina Di Santo, Rajat Mittal","doi":"10.1073/pnas.2616348123","DOIUrl":"https://doi.org/10.1073/pnas.2616348123","url":null,"abstract":"<p><p>The linear relationship between tail-beat frequency and swimming speed in fish, first described by Bainbridge in 1958, has since been confirmed in species as disparate as eels and tuna. Dimensional scaling has explained why linearity should emerge at high Reynolds numbers, but the frequency-speed relationship itself has remained empirical, with no physical framework describing its behavior across swimming regimes, and no account of what sets the two quantities that define it: the distance covered per tail beat and the frequency below which forward motion supposedly ceases. Here, we derive a relationship from a balance of fin thrust, generated by a leading-edge vortex, and drag due to the boundary layer on the body. This framework yields an explicit expression for speed in terms of midline kinematics and body morphology. This formulation shows that the maximum stride length is set by the undulatory wavelength and the tail-beat phase offset, rather than by the conventional scaling metric of body length, and that no minimum frequency is required for forward motion. The model reproduces kinematic measurements from freely swimming glass catfish, published simulations, and Bainbridge's original data. Without recalibration, it predicts the results of independent simulations spanning wide variations in wavelength, phase offset, and morphology to within ten percent. Linear scaling is thus one asymptotic limit of a more general propulsive relationship linking morphology and body-wave kinematics to swimming speed in fishes and bioinspired vehicles, where the body waveform, rather than the actuation frequency, emerges as the variable that sets performance.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2616348123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207702","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":"The basins of attraction of soft-sphere packings are not fractal.","authors":"Praharsh Suryadevara, Mathias Casiulis, Stefano Martiniani","doi":"10.1073/pnas.2604040123","DOIUrl":"https://doi.org/10.1073/pnas.2604040123","url":null,"abstract":"<p><p>The energy landscape picture is a central tool to study many-body systems. In particular, the energy landscapes of glass-forming liquids, jammed packings, constraint satisfaction problems, or neural networks contain a plethora of minima corresponding to competing states. Due to their complexity, these landscapes resist analytical treatment and must be studied numerically. We focus on jammed soft spheres, a paradigmatic model of glasses and granulars, to expose the limitations of standard numerical methods in resolving the true structure of energy landscapes. We show that the C-language Variable-coefficients ordinary differential equation solver is the one with the best time-for-error trade-off for this problem, outperforming commonly used steepest-descent solvers by several orders of magnitude. Using this numerical approach, we provide unequivocal evidence that optimizers widely used in computational studies destroy all semblance of the true landscape geometry, even in moderately low dimensions. Employing a range of geometric indicators, both low- and high-dimensional, we show that earlier claims on the fractality of basins of attraction of minima originated from the use of inadequate mapping strategies. In reality, the basins of attraction of soft-sphere packings are smooth structures with well-defined length scales, a result that likely extends to a much broader family of problems.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2604040123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207746","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":"Convergent genome streamlining accompanies independent miniaturization in the world's smallest fishes.","authors":"Hiranya Sudasinghe, Michael Matschiner, Ralf Britz, Kevin W Conway, Heok Hui Tan, Walter Salzburger, Catherine L Peichel, Lukas Rüber","doi":"10.1073/pnas.2614605123","DOIUrl":"https://doi.org/10.1073/pnas.2614605123","url":null,"abstract":"<p><p>Miniaturization, the reduction of adult body size to an extreme degree, has evolved repeatedly across vertebrates. Yet its genomic underpinnings remain poorly understood. Cypriniformes, the most species-rich order of freshwater fishes, contains multiple miniaturized lineages that have evolved via contrasting developmental processes. Proportioned dwarfs are tiny-bodied but otherwise morphologically similar to larger relatives, while progenetic miniatures exhibit developmental truncation and retain larval-like anatomical features into adulthood. Using a new time-calibrated phylogeny of 309 cypriniform species and comparative genomic analyses of 33 high-quality genome assemblies, we investigated the evolutionary history and genomic correlates of miniaturization across this order. Ancestral state reconstruction revealed multiple independent origins of both miniature types, with reversals to the nonminiature state rarely recovered and miniature origins nonrandomly distributed across the phylogeny. The origins of the two types of miniatures differed in their timing. Progenetic miniatures arose predominantly in the Eocene whereas proportioned dwarfs arose mainly within the Miocene period. Genome size variation across Cypriniformes has been overwhelmingly driven by polyploidy. However, progenetic miniatures showed a directionally consistent, though nonsignificant, trend toward genome size reduction. Comparative genomic analyses revealed that all three independently evolved progenetic miniature lineages share convergent signatures of repeat loss alongside genome-wide intron shortening, patterns absent in proportioned dwarfs. Our study provides the broadest evidence to date that progenetic miniaturization, despite independent origins, is underpinned by predictable structural genomic changes, revealing a fundamental link between developmental truncation and genome architecture in vertebrates.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2614605123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184005","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":"Understanding consciousness (biological and artificial) as a society of self-schemas.","authors":"Michael S A Graziano","doi":"10.1073/pnas.2628598123","DOIUrl":"https://doi.org/10.1073/pnas.2628598123","url":null,"abstract":"<p><p>This article argues that human cognition is more than the performance of functions such as memory, decision-making, and attention. The brain also builds schematic models of those cognitive functions and uses those models to monitor, predict, and partially control them. When you introspect, your understanding of who you are and what is happening inside of you is derived from those schematic, sometimes inaccurate, but generally useful models, rather than from the actual cognitive functions that are represented by those models. The proposal expands the previously proposed attention schema theory to a more general schema theory, in which the mind as we know it introspectively is a society of interacting self-schemas. The article focuses on five self-schemas including the attention schema (which is proposed to give us our intuitions about a conscious mind that takes possession of items in a vivid manner), a decision schema (which generates simplified, sometimes confabulated accounts of the decision-making process and gives us our intuitive understanding of agency and will), emotion schemas (which create complex interpretations of the physiological state of the body and provide us with our understanding of emotional experience), the body schema (which provides our understanding of who we are as physical beings), and personas (which give us our understanding of our emotional, social, and moral character, and act as a framework to guide our behavior). The article includes a discussion of how consciousness in a machine requires a similar suite of self-schemas used for similar functional purposes and may already be partially present.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2628598123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147805","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":"GTP orchestrates CTP synthase via an allosteric effector-cycling mechanism.","authors":"Chen-Jun Guo, Yu-Fen Wu, Shu-Ying Guo, Jia-Li Lu, Liang Xu, You Fu, Xian Zhou, Jiale Zhong, Zherong Zhang, Ji-Long Liu","doi":"10.1073/pnas.2620272123","DOIUrl":"https://doi.org/10.1073/pnas.2620272123","url":null,"abstract":"<p><p>Cytidine triphosphate (CTP), a fundamental building block of RNA, plays vital roles in diverse biological processes. CTP synthase (CTPS) is the only known enzyme for de novo synthesis of CTP. Efficient CTPS catalysis requires guanosine triphosphate (GTP) in a dose-dependent, nonconsumptive manner; however, the precise mechanism by which GTP drives CTP formation remains unclear. Here, we integrate a series of cryo-EM structures of <i>Drosophila melanogaster</i> CTPS captured from actively catalyzing samples with biochemical and mutagenesis analyses, yielding 34 distinct CTPS states at resolutions up to 2.0 Å. We find that GTP binds to and dissociates from CTPS once per catalytic cycle, thereby enabling the production of a single CTP molecule. Initial GTP engagement requires formation of 4-phosphoryl-UTP in the AL domain, whereas full stabilization of GTP binding is promoted by occupancy of the GAT active site. Together, these two checkpoints couple GTP recruitment and stabilization to catalytic progress in the two domains, enabling the coordinated synthesis of one CTP molecule per GTP binding-dissociation cycle. Moreover, the GTP-recognition site is highly conserved across the three domains of life. These findings establish a comprehensive mechanistic framework for efficient CTPS catalysis and define \"effector-cycling\"-in which GTP undergoes obligatory binding and dissociation during each catalytic cycle to regulate an intermediate step in a multistep catalytic process-as a distinct mode of allosteric regulation.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2620272123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148798","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":"Coordinated transformations of the labyrinth and occiput during the dinosaur-bird transition.","authors":"Guillermo Navalón, Serjoscha W Evers, Emma Hughes, Alexander Bjarnason, Luis M Chiappe, Stig A Walsh, James M Neenan, Elsa Panciroli, Daniel J Field, Roger B J Benson","doi":"10.1073/pnas.2612503123","DOIUrl":"https://doi.org/10.1073/pnas.2612503123","url":null,"abstract":"<p><p>Evolutionary shape changes of the vertebrate semicircular canals (SCCs) are often ascribed to evolutionary transitions in locomotion, including the origin of flight during the dinosaur-bird transition. However, the potential for transformations of braincase architecture to influence SCC shape independent of sensory-functional adaptation has generally been overlooked. We evaluate the influence of both factors using a large dataset of 146 living and recently extinct crown birds, including taxa representing ~24 independent evolutionary losses of flight, together with Mesozoic stem avialans, nonavialan dinosaurs, and pterosaurs. Among crown birds, evolutionary changes in locomotor capabilities, including the total loss of flight, have only weak effects on SCC shape, contrasting with large effects from changes in braincase geometry. Notably, rotation of the occiput toward a ventral orientation is associated with important changes to SCC shape that match those observed during the dinosaur-bird transition. This suggests that evolutionary transformations of SCC shape during the Mesozoic origin of avian flight resulted from evolutionary changes in the orientation of the craniocervical joint, and not from tuning of SCC sensory function. These findings illuminate the importance of integrated morphological changes to the head-neck system during bird origins and challenge the long-standing assumption that SCC morphology enables confident inferences of the locomotor capabilities of extinct vertebrates.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 42","pages":"e2612503123"},"PeriodicalIF":9.5,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164921","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}