PLoS Biology最新文献

{"title":"A histidine-mediated supramolecular mechanism links temperature and pH activation of the sperm channel CatSper.","authors":"Billy Zhao, Shweta Bhagwat, Juan Ferreira, Kiersten M Ruff, Dilip K Swain, Rohit V Pappu, Celia M Santi, Ziao Fu, Polina V Lishko","doi":"10.1371/journal.pbio.3003776","DOIUrl":"10.1371/journal.pbio.3003776","url":null,"abstract":"<p><p>The cation channel of sperm, CatSper, is a sperm-specific calcium channel essential for male fertility across metazoans. CatSper is activated by intracellular alkalinization, membrane depolarization, and elevated temperature, which together ensure maximal current generation. However, the structural mechanisms by which these physiological stimuli jointly regulate channel activation remain poorly understood, in part because CatSper is an unusually complex ~15-subunit assembly organized in zigzag supramolecular arrays along the sperm flagellum. Here, we combine comparative genomics across 47 species with AlphaFold3-based modeling and evolutionary sequence-structure analyses to investigate a mechanism underlying temperature and pH sensitivity of CatSper. Phylogenetic analysis shows that N-terminal length and histidine enrichment of the pore-forming subunit CatSper1 strongly correlate with species-specific fertilization temperatures, suggesting evolutionary adaptation of temperature and pH sensitivity. Structural modeling further revealed conserved surface-exposed histidine clusters that form predicted contact interfaces between adjacent CatSper assemblies, with this contact interface positioned near the dominant voltage-sensing module. Functional validation using electrophysiology and calcium imaging in mouse sperm shows that capacitation-associated partial removal of the CatSper1 N-terminus selectively impairs temperature-dependent activation. Together, these findings support a model in which temperature-dependent histidine deprotonation functionally couples neighboring CatSper complexes within the supramolecular assembly, thereby promoting synchronized channel activation.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 10","pages":"e3003776"},"PeriodicalIF":7.2,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13674862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The histone methyltransferase complex subunit RBBP5 serves as a central epigenetic regulator of proteostasis dynamics.","authors":"Syeda Kubra, Michelle Sun, William Dion, Yu Bian, Ahmet Catak, Hannah Luong, Haokun Wang, Yinghong Pan, Jia-Jun Liu, Aishwarya Ponna, Lijun Liu, Ian Sipula, Jian-Hua Luo, Michael J Jurczak, Silvia Liu, Bokai Zhu","doi":"10.1371/journal.pbio.3004048","DOIUrl":"10.1371/journal.pbio.3004048","url":null,"abstract":"<p><p>Proteostasis is essential for cellular health, with its disruption contributing to aging, neurodegeneration, and metabolic disorders. While the upstream proteotoxic stress-sensing and protein-folding mechanisms in the ER and cytosol are well studied, the transcriptional regulation of proteostasis remains incompletely understood, particularly concerning the temporal epigenome dynamics, chromatin landscapes, and co-regulatory networks underlying dynamic proteostasis control. Traditionally, proteotoxic stress responses were viewed as acute reactions to noxious stimuli, but recent evidence shows that many proteostasis genes exhibit ~12-hour ultradian rhythms under physiological conditions, driven by an XBP1s-dependent oscillator independent of the canonical circadian clock and cell cycle. By mapping the chromatin landscape of the murine 12-hour oscillator, we identified RBBP5-an essential subunit of the COMPASS complex responsible for H3K4 trimethylation-as a pivotal epigenetic regulator of proteostasis dynamics. In contrast, histone acetyltransferases and H3K9 acetylation were dispensable for dynamic proteostasis gene expression. RBBP5 is not only indispensable for the 12-hour oscillator but also essential for the transcriptional regulation of diverse proteotoxic stresses response, by coactivating XBP1s and promoting H3K4me3 deposition at the promoters of proteostasis genes. As a result, loss of RBBP5 sensitizes cells to proteotoxic stress in part due to impaired autophagy. Proximity labeling of H3K4me3 further uncovered a dynamic chromatin-associated proteomic architecture, including components of COMPASS, the Integrator complex and SWI/SNF remodelers, that constitutes the transcriptional response to proteotoxic stress. Together, these findings establish RBBP5 as a central regulator of proteostasis dynamics, essential for maintaining cellular resilience.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 10","pages":"e3004048"},"PeriodicalIF":7.2,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13667922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149138962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct millisecond-scale click-train patterns evoke discriminable behavioral and neural responses in humans and rats.","authors":"Yuying Zhai, Peirun Song, Ana Belén Lao-Rodríguez, Xinyu Du, Haoxuan Xu, Hangting Ye, Xuehui Bao, Ishrat Mehmood, Nayaab Shahir Pandit, Cheng Chang, Zhouyou Dai, Zhiyi Tu, Pei Chen, Tingting Zhang, Lingling Zhang, Xuan Zhao, David Pérez-González, Manuel S Malmierca, Xiongjie Yu","doi":"10.1371/journal.pbio.3004046","DOIUrl":"10.1371/journal.pbio.3004046","url":null,"abstract":"<p><p>Natural sounds are shaped by both spectral content and temporal patterning. Here we ask whether click trains with the same mean inter-click interval, but different millisecond-scale temporal patterns evoke distinct behavioral and neural responses. Human listeners discriminated several such click-train patterns, and human EEG revealed context-dependent deviance-related responses. Awake rats showed analogous cortical response differences at the ECoG level. Along the IC-MGB-A1 pathway, unit recordings revealed weak oddball/context sensitivity in IC, intermediate sensitivity in MGB, and stronger stimulus-specific adaptation in A1. Reversible inactivation of the auditory cortex reduced MGB sensitivity, indicating a contribution of corticothalamic feedback. Further A1 layer analyses showed stronger effects in supragranular than deep cortical layers. Together, these results show that distinct click-train temporal patterns are differentially represented across the auditory system, with stronger sensitivity emerging in higher auditory structures.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 10","pages":"e3004046"},"PeriodicalIF":7.2,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149139003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Type III effectors of symbiotic Rhizobia include diverse predicted transcriptional and post-transcriptional modulators.","authors":"Albin Teulet, Sebastian Schornack","doi":"10.1371/journal.pbio.3004038","DOIUrl":"10.1371/journal.pbio.3004038","url":null,"abstract":"<p><p>Rhizobia are soil bacteria that establish nitrogen-fixing symbioses with legumes. While many rhizobia use a Type III Secretion System to deliver \"Nodulation Outer Protein\" (Nop) effectors, some uniquely use these proteins to initiate nodule organogenesis, bypassing classical signalling. The molecular functions of these effectors remain largely unknown due to extreme sequence divergence. Using AlphaFold2-mediated structural proteomics, we identified a modular architecture in rhizobial effectors composed of 22 distinct structural units. We reveal that many Nop effectors are cryptic transcriptional or post-transcriptional regulators, harbouring unrecognised nucleic acid-binding modules and RNA-dependent RNA polymerase domains. Crucially, these modules are conserved in specific plant pathogens, such as gall-inducing Pantoea, where our predicted structural units align with experimentally validated DNA-binding domains. Furthermore, we discovered the BPN (B3 and PUA-like nucleic acid binding) domain as a structural mimic of plant B3-domain transcription factors, pointing to a direct mechanism for hijacking legume development. Our findings strongly suggest that rhizobia employ a modular domain-fusion strategy to act as direct genetic modulators, uncovering a conserved mechanism used by both symbionts and pathogens to hijack host developmental programmes.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 10","pages":"e3004038"},"PeriodicalIF":7.2,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13667924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149138978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Better antibodies, better science.","authors":"Johan Duchêne","doi":"10.1371/journal.pbio.3004001","DOIUrl":"10.1371/journal.pbio.3004001","url":null,"abstract":"<p><p>Poorly validated antibodies generate misleading results and waste research resources. Two new studies in PLOS Biology quantify the ethical costs of this issue, examine why unvalidated antibodies are still used, and identify solutions to reduce their use.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 10","pages":"e3004001"},"PeriodicalIF":7.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13645081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inadequate antibody validation places substantial numbers of animal and human tissue samples at risk of waste.","authors":"Michael Biddle, Jemma Cooper, Katherine Blades, Dominic Ruddy, Eva M Krockow, Harvinder Virk","doi":"10.1371/journal.pbio.3003984","DOIUrl":"10.1371/journal.pbio.3003984","url":null,"abstract":"<p><p>Lack of antibody validation by researchers frequently misdirects biomedical research, yet the ethical consequences-particularly avoidable use of animal and human biological materials-remain unquantified. Using focus groups (n = 12), surveys (n = 107), and systematic analysis of 785 publications, we examined how researchers select and validate antibodies, and quantified the downstream ethical costs. Antibody selection is substantially influenced by social factors such as previous laboratory use and peer recommendations, while systematic evaluation of performance characteristics remains limited. From a dataset of 614 antibodies subjected to rigorous characterisation using knockout controls, 97 (15.8%) failed across all tested applications; we systematically searched for publications linked to these antibodies. Within the 760 publications (those where validation status could be confirmed), only 120 (15.8%) presented any validation evidence-despite 72.0% of surveyed researchers reporting having used at least one recommended validation method. The remaining 640 papers reported a minimum of 8,064 animal samples and 4,424 human tissue samples used with antibodies of demonstrated poor performance and without evidence of fitness for the specific experimental purpose; we describe these as samples at risk of waste. Reserving the term waste for samples used with reagents since withdrawn from sale, and therefore irreproducible, conservative extrapolation gives lower-bound, order-of-magnitude estimates of millions of animal and human tissue samples consumed globally. Researchers identified time, cost, and lack of supervisor support as primary barriers, whilst strongly supporting open data sharing, dedicated validation funding, and publisher requirements as solutions. These findings provide a first quantification of the ethical costs of inadequate antibody validation and highlight the need for coordinated stakeholder interventions to reduce avoidable biological sample waste in biomedical research.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 10","pages":"e3003984"},"PeriodicalIF":7.2,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149117234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A binding-activated CRISPR/dCas13X imaging system enables precise RNA tracking in plants.","authors":"Jiayu Zhang, Yiran Tao, Yun Zhao, Miaomiao Lei, Yucheng Shen, Qicong Li, Chenxu Liu, Jiuyuan Bai","doi":"10.1371/journal.pbio.3004043","DOIUrl":"10.1371/journal.pbio.3004043","url":null,"abstract":"<p><p>Visualizing the spatiotemporal dynamics of native RNA molecules with single-transcript-level sensitivity in living plant cells remains a formidable challenge due to the high background noise caused by the unique cellular architecture of plants. Here, using transiently transformed Nicotiana benthamiana cells and stable Arabidopsis thaliana lines, we present a high-signal-to-noise RNA imaging platform that couples CRISPR-dCas13X with a binding-associated fluorescence stabilization strategy. We identified a novel plant-specific degron that selectively targets unbound probes for proteasomal degradation while preserving target-associated signal in a manner consistent with binding-dependent protection, enabling high-fidelity detection of endogenous mRNA puncta with minimal perturbation. Leveraging this platform, we characterized dynamics of FT mRNA trafficking in living plant cells, including plasmodesmata-targeting, cell-to-cell trafficking, and long-distance movement. Loss-of-function analysis further identified the established RNA-binding protein GRP7 as a factor that contributes to efficient FT mRNA transport. This work establishes a useful toolkit for investigating plant RNA biology and provides mechanistic insight into the systemic transport of florigenic signals.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 10","pages":"e3004043"},"PeriodicalIF":7.2,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13667925/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149117214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Actionable solutions to address antibody validation failures.","authors":"Katherine Blades, Michael Biddle, Robert Froud, Eva M Krockow, Harvinder Virk","doi":"10.1371/journal.pbio.3003981","DOIUrl":"10.1371/journal.pbio.3003981","url":null,"abstract":"<p><p>The experimental use of antibodies that have not been validated for context-specific use frequently misdirects biomedical research. Experimental results that derive from the use of inadequately validated antibodies are estimated to waste over $1 billion annually in the United States alone and to consume millions of animal and human biological samples in experiments whose conclusions may be unreliable. Community validation frameworks, reporting standards, and independent characterisation initiatives have made important progress, and multi-stakeholder coordination efforts are emerging. However, the research community lacks a formally developed, consensus-based action plan that specifies what each stakeholder group should do, by when, and with what priority. We conducted a modified Delphi study with international experts representing academic researchers, scientific publishers, research funders, antibody manufacturers, and institutional research leaders to develop actionable recommendations for improving antibody validation, selection, and reporting practices. Thirty-two participants rated 33 proposed actions on effectiveness and feasibility using 9-point scales, with consensus assessed using the RAND/UCLA Appropriateness Method. Over two rounds, the panel achieved consensus on 15 items as both effective and feasible for implementation by 2030. These spanned institutional actions (training in antibody validation, integration into research integrity frameworks, support for local expertise networks), funder actions (dedicated validation budgets, grant application requirements, endorsement of community reporting standards), publisher actions (complete antibody reporting packages, clear validation standards), manufacturer actions (assignment of unique identifiers at source), and cross-stakeholder coordination (a shared roadmap for improvement). An additional 15 items were rated as effective but with uncertain feasibility, reflecting a consistent pattern in which the panel agreed on the value of proposed interventions but expressed reservations about realistic implementation timelines. One item was rejected by the panel with concerns around effectiveness and feasibility. Participants described four interconnected barriers to progress: diffuse ownership of the problem across stakeholders; market dynamics that inadequately reward antibody quality; difficulty justifying investment when returns are distributed across the research system; and coordination challenges among actors with different incentive structures. These barriers are addressable through coordinated action, and the findings complement existing technical and data-sharing initiatives by providing the structured, expert-informed policy framework to help translate awareness of the problem into concrete practice and policy changes.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 10","pages":"e3003981"},"PeriodicalIF":7.2,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149117265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Moral and perceptual conflict processing are implemented by distinct brain activation and functional connectivity patterns.","authors":"Ruida Zhu, Marcus Grueschow, Marius Moisa, Chao Liu, Christian C Ruff","doi":"10.1371/journal.pbio.3004025","DOIUrl":"https://doi.org/10.1371/journal.pbio.3004025","url":null,"abstract":"<p><p>While humans resemble other primates in terms of motor and perceptual abilities, our behavior is uniquely characterized by morality-the ability to choose our actions based on specific ethical values. The evolutionary origins and neurobiological basis of moral behavior are debated intensely, with opposing proposals about whether moral decisions rely on domain-general decision-making neural circuitry (neural common currency hypothesis) or on unique neural processes that were shaped by evolutionary pressures associated with life in groups (social brain hypothesis). Here we examine the potential overlap between moral and perceptual decision-making, by combining functional magnetic resonance imaging with computational modeling of behavior in a novel task requiring human participants to make alternating moral and perceptual choices on identical stimuli. At the algorithmic level, we found that moral and perceptual choices were well fit by the same sequential sampling model, which allowed us to quantify and directly compare conflicts between the choice alternatives for both types of decision-making. At the implementational level, moral and perceptual choice conflicts were represented by distinct neural activity patterns; in fact, neural signals in some brain areas (e.g., temporoparietal junction) encoded the strength of the two types of conflict in opposite directions. Our findings suggest that while similar computational decision mechanisms underlie both moral and perceptual choices, their neural implementation is fundamentally different, supporting the social brain hypothesis.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 10","pages":"e3004025"},"PeriodicalIF":7.2,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149117242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uracil-driven ROS signaling and larval TrpA1-B neuron activation are required for priming the adult Drosophila gustatory response to bacteria.","authors":"Romane Milleville, Gérard Manière, Martine Berthelot-Grosjean, Olivier Lamotte, Yaël Grosjean, Julien Royet, Cyril Léopold Kurz","doi":"10.1371/journal.pbio.3004042","DOIUrl":"10.1371/journal.pbio.3004042","url":null,"abstract":"<p><p>Animals perceive their immediate environment through their sensory systems. While these systems rely on well-defined neuronal circuits and receptor proteins encoded by the genome, they can also be modulated by internal physiological conditions or exogenous factors. We have previously shown that the presence of certain pathogenic bacteria in the larval gut can alter the specificity of bacterial peptidoglycan recognition in the adults that emerge from these larvae. However, the nature of the bacterial signal and the host cells and molecules involved in receiving and transducing this signal remained unknown. Our results identify uracil as the bacterial metabolite responsible for this priming and demonstrate that the effect is mediated by Duox-dependent production of reactive oxygen species (ROS) in the larval gut. We further show that specific expression of TrpA1 isoforms in a Gr66a-expressing neuron of the larval terminal organ is required for the adult response. Together, these findings reveal uracil as the bacterial cue and the Duo/ROS signaling and TrpA1/Gr66a modules as key mediators linking larval gut microbial signals and host integration to subsequent sensory system modulation in the adult.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 10","pages":"e3004042"},"PeriodicalIF":7.2,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149116792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}