bioRxiv : the preprint server for biology最新文献

Learning neural dynamics through instructive signals. 通过指导性信号学习神经动力学。

bioRxiv : the preprint server for biology Pub Date : 2025-10-13 DOI: 10.1101/2025.08.30.673300

Rich Pang, Juncal Arbelaiz, Jonathan W Pillow

{"title":"Learning neural dynamics through instructive signals.","authors":"Rich Pang, Juncal Arbelaiz, Jonathan W Pillow","doi":"10.1101/2025.08.30.673300","DOIUrl":"10.1101/2025.08.30.673300","url":null,"abstract":"Rapid learning is essential for flexible behavior, but its basis in the brain remains unknown. Here we introduce the PRISM plasticity rule, a unifying mechanistic model of three well-established, fast-acting synaptic plasticity rules---in hippocampus, cerebellum and mushroom body---which relies exclusively on pre-synaptic activity and an \"instructive signal\" from another brain area. Using a multi-region network model we show that guiding PRISM plasticity with instructive signals enables the network to quickly learn extremely flexible nonlinear dynamics underlying behaviorally relevant computations, as well as to emulate unknown external system dynamics from real-time error signals, which we demonstrate with comprehensive simulations supported by exact mathematical theory. Thus, PRISM plasticity guided by instructive signals is well-suited to rapidly learn general-purpose neural computations---in contrast to canonical Hebbian rules. Finally, we show how including this plasticity rule in artificial learning algorithms can solve long-range temporal credit assignment, a long-standing challenge in machine learning.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12424665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dental aging offers new insights to the first epigenetic clock for common dolphins ( Delphinus delphis ). 牙齿老化为普通海豚（Delphinus delphis）的第一个表观遗传时钟提供了新的见解。

bioRxiv : the preprint server for biology Pub Date : 2025-10-13 DOI: 10.1101/2025.07.20.665818

Eva-Maria F Hanninger, Katharina J Peters, Livia Gerber, Ashley Barratclough, Emma L Betty, Emily I Palmer, Steve Horvath, Karen A Stockin

{"title":"Dental aging offers new insights to the first epigenetic clock for common dolphins ( Delphinus delphis ).","authors":"Eva-Maria F Hanninger, Katharina J Peters, Livia Gerber, Ashley Barratclough, Emma L Betty, Emily I Palmer, Steve Horvath, Karen A Stockin","doi":"10.1101/2025.07.20.665818","DOIUrl":"10.1101/2025.07.20.665818","url":null,"abstract":"Determining exact age in wild odontocetes is essential for understanding population dynamics, survival, and reproduction, yet remains logistically challenging. While epigenetic aging is emerging as a valuable approach, only nine species-specific clocks currently exist. Most have been calibrated using captive known-age animals or well-studied wild populations. Only two previous studies have used dental ages from stranded or bycaught individuals. This is due to concerns that dental age inaccuracies, especially in older animals, may affect epigenetic clock performance. To explore this, we developed the first species-specific epigenetic clock for common dolphins ( Delphinus delphis ), analysing DNA methylation at 37,492 cytosine-phosphate-guanine sites in skin samples from stranded and bycaught dolphins with estimated dental ages. Elastic net models with Leave-One-Out Cross-Validation were applied to three subsets: the ' relaxed ' subset (all individuals; n = 75, median absolute error (MAE) = 2.02, r = 0.81, R 2 = 0.66), the ' strict ' subset (excluding individuals with minimum dental age estimates only; n = 73, MAE = 2.29, r = 0.81, R 2 = 0.66), and the ' restricted ' subset (excluding outliers with prediction errors > 6 years; n = 63, MAE = 1.80, r = 0.91, R 2 = 0.82) to compare performance. Our models consistently underestimated the age of dolphins >16 years, even when minimum dental ages were applied, suggesting absolute errors between dental and epigenetic estimates unlikely reflect dental aging error. Additionally, post-mortem decomposition condition code (DCC 1 to 3) did not affect age prediction, signalling promise for future epigenetic clocks calibrated with strandings and bycaught individuals.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144802188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cortical microtubules act as a template to organize nano-scale patterning of exocytosis. 皮质微管是组织纳米级外吞模式的模板。

bioRxiv : the preprint server for biology Pub Date : 2025-10-12 DOI: 10.1101/2024.12.01.626273

Jelmer Lindeboom, Ryan Gutierrez, Viktor Kirik, David W Ehrhardt

{"title":"Cortical microtubules act as a template to organize nano-scale patterning of exocytosis.","authors":"Jelmer Lindeboom, Ryan Gutierrez, Viktor Kirik, David W Ehrhardt","doi":"10.1101/2024.12.01.626273","DOIUrl":"10.1101/2024.12.01.626273","url":null,"abstract":"The microtubule cytoskeleton plays an important role in targeting and organizing exocytosis, enabling cellular morphogenesis, motility and polarized transport. In centrosomal systems, this occurs primarily through directed transport along polarized microtubule tracks to plus ends, but how non-centrosomal microtubule arrays organize exocytosis remains poorly understood. Here, we investigate this question in plant cells, which completely lack centrosomes and form planar cortical microtubule arrays. We identify the exocytotic protein KEULE, an essential SEC/MUNC, as a dynamic marker for exocytosis that forms clusters associated with and is required for discrete exocytotic events in growing Arabidopsis cells. Live cell imaging revealed that these clusters have stereotyped patterns of protein accumulation and loss, suggesting distinct phases in the assembly and function of exocytotic protein complexes. Super-resolution image analysis and Bayesian inference for distance distributions revealed that exocytotic events are not randomly distributed but are significantly enriched in ~180 nm wide linear domains flanking cortical microtubules, while being under-represented in adjacent ~520 nm domains. Thus, cortical microtubule arrays act as two-dimensional spatial templates for exocytosis, representing a fundamentally different organizational modality from centrosomal arrays that may be conserved across non-centrosomal arrays.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11642816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Endothelial type I interferon signaling modulates the vascular response to ischemic brain injury. 内皮I型干扰素信号调节血管对缺血性脑损伤的反应。

bioRxiv : the preprint server for biology Pub Date : 2025-10-12 DOI: 10.1101/2025.09.09.675258

Mary Claire Tuohy, Ping-Chang Kuo, Adrian Chelminski, Eti Muharremi, Claudia DeSantis, Aomeng Cui, Alicia Russo, Danny Jamoul, Elizabeth Hillman, John F Crary, Jui-Hung Jimmy Yen, Dritan Agalliu

{"title":"Endothelial type I interferon signaling modulates the vascular response to ischemic brain injury.","authors":"Mary Claire Tuohy, Ping-Chang Kuo, Adrian Chelminski, Eti Muharremi, Claudia DeSantis, Aomeng Cui, Alicia Russo, Danny Jamoul, Elizabeth Hillman, John F Crary, Jui-Hung Jimmy Yen, Dritan Agalliu","doi":"10.1101/2025.09.09.675258","DOIUrl":"10.1101/2025.09.09.675258","url":null,"abstract":"Vascular normalization [stabilization of aberrant angiogenesis and restoration of blood-brain barrier (BBB)] is critical for reducing long-term secondary sequelae after ischemic stroke. How immune and developmental signaling pathways coordinate these processes is poorly understood. Here we identify a unique brain endothelial cell (BEC) type one interferon (IFN1) signature in human and mouse ischemic stroke tissue. By leveraging two clinically-relevant murine ischemic stroke models, single-cell transcriptomics, and BBB functional assays, we find that deletion of endothelial IFN1 receptor (Ifnar1) exacerbates post-stroke BBB disruption and expands a BEC population expressing angiogenic and immature BBB markers. Conversely, IFN-beta administration after stroke reduces acute BBB disruption. Activation of IFN1 signaling in BECs in vitro reduces vascular endothelial growth factor (VEGF) signaling to promote junctional stabilization, enhance barrier properties, and suppress angiogenic features. Thus, endogenous endothelial IFN1 signaling modulates BBB dysfunction and angiogenesis to promote vascular normalization after ischemic brain injury.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12458465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145152915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A personalized multi-platform assessment of somatic mosaicism in the human frontal cortex. 人类额叶皮质体细胞嵌合体的个性化多平台评估。

bioRxiv : the preprint server for biology Pub Date : 2025-10-11 DOI: 10.1101/2024.12.18.629274

Weichen Zhou, Camille Mumm, Yanming Gan, Jessica A Switzenberg, Jinhao Wang, Paulo De Oliveira, Kunal Kathuria, Steven J Losh, Brandt Bessell, Torrin L McDonald, Michael J McConnell, Alan P Boyle, Ryan E Mills

{"title":"A personalized multi-platform assessment of somatic mosaicism in the human frontal cortex.","authors":"Weichen Zhou, Camille Mumm, Yanming Gan, Jessica A Switzenberg, Jinhao Wang, Paulo De Oliveira, Kunal Kathuria, Steven J Losh, Brandt Bessell, Torrin L McDonald, Michael J McConnell, Alan P Boyle, Ryan E Mills","doi":"10.1101/2024.12.18.629274","DOIUrl":"10.1101/2024.12.18.629274","url":null,"abstract":"Somatic mutations in individual cells create genomic mosaicism, influencing genetic disorders and cancers. While clonal mutations in cancers are well-studied, rarer somatic variants in normal tissues remain poorly characterized. This study systematically evaluates detection methods using a personalized donor-specific assembly (DSA) from a neurotypical individual's dorsolateral prefrontal cortex assessed with Oxford Nanopore, NovaSeq, linked-read sequencing, Cas9-targeted long-read sequencing (TEnCATS), and single-neuron MALBAC amplification. The haplotype-resolved DSA improved cross-platform analysis, dramatically increasing phasing rates. Germline SNVs, structural variations (SVs), and transposable elements (TEs) were recalled with 99.4%-99.7% accuracy in bulk tissue, and phased haplotype analysis reduced false positives by 15.4%-75.1% for putative somatic candidates. Long-read single-neuron sequencing detected nine somatic SV candidates, demonstrating enhanced sensitivity for rare variants, while TEnCATS identified eight low-frequency somatic TE candidates. These findings highlight advanced methodologies for precise somatic variant detection, critical for understanding mosaicism's role in health and disease.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11702624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142985923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Oxytocin neurons in the anterior and posterior paraventricular nucleus have distinct behavioral functions and electrophysiological profiles. 脑室旁核前后侧的催产素神经元具有不同的行为功能和电生理特征。

bioRxiv : the preprint server for biology Pub Date : 2025-10-11 DOI: 10.1101/2025.08.03.668226

Audrey N Chrisman, Chiho Sugimoto, Hanna Butler-Struben, Vanessa A Minie, Daniela Anderson, Andrew L Eagle, Natalia Duque-Wilckens, Ashley Ramos, Yasmine I Lewis, Sinéad C Archdeacon, Alfred J Robison, Brian C Trainor

{"title":"Oxytocin neurons in the anterior and posterior paraventricular nucleus have distinct behavioral functions and electrophysiological profiles.","authors":"Audrey N Chrisman, Chiho Sugimoto, Hanna Butler-Struben, Vanessa A Minie, Daniela Anderson, Andrew L Eagle, Natalia Duque-Wilckens, Ashley Ramos, Yasmine I Lewis, Sinéad C Archdeacon, Alfred J Robison, Brian C Trainor","doi":"10.1101/2025.08.03.668226","DOIUrl":"10.1101/2025.08.03.668226","url":null,"abstract":"Oxytocin is a neuropeptide that can either promote or inhibit affiliative social behaviors. Recent evidence suggests that these diverse effects are mediated by distinct oxytocin receptor-expressing neuron. An outstanding question is whether these behavioral effects are also driven by distinct or overlapping populations of oxytocin-producing neurons. The paraventricular nucleus (PVN) of the hypothalamus is a major source of oxytocin and sends projections to the mesolimbic dopamine system and the extended amygdala. Previous work found that social defeat increased oxytocin neuron activity in the anterior PVN (aPVN) but not posterior PVN (pPVN). We reduced oxytocin synthesis with antisense morpholino oligonucleotides in either anterior or posterior PVN in California mice (Peromyscus californicus), a strong model system for studying effects of social stress on brain function and behavior. Antisense morpholinos in aPVN had no effect on behavior in unstressed females but increased social approach and reduced social vigilance in females exposed to social defeat stress. In pPVN, antisense morpholinos reduced social approach in unstressed male and female California mice. We then used OxtCre mice to compare electrophysiological profiles of oxytocin in aPVN and pPVN with a population of oxytocin neurons in the bed nucleus of the stria terminalis (BNST). Oxytocin neurons in aPVN and BNST oxytocin neurons had higher post-synaptic potentials and responded more strongly to current injections versus oxytocin neurons in pPVN. These findings shed light onto functional and physiological heterogeneity of PVN oxytocin neurons. Our results suggest that context dependent effects of oxytocin are mediated by different populations of oxytocin neurons.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12324468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144791534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cul5Wsb2 uses BCL2 proteins as co-receptors to target Bim for degradation. Cul5 Wsb2利用BCL2蛋白作为共受体靶向Bim降解。

bioRxiv : the preprint server for biology Pub Date : 2025-10-11 DOI: 10.1101/2025.08.14.670414

Wilhelm Vaysse-Zinkhofer, Enya Alcindor, Nicholas Garaffo, David P Toczyski

引用次数: 0

Validation and Optimization of Breeding Strategy for miR-141/200c Knockout Mice to Eliminate Off-Target Gene Silencing using FLPo Deleter mice. 重新定义生成条件miR-141/200c miRNA簇敲除小鼠的策略，以消除混杂的新卡带。

bioRxiv : the preprint server for biology Pub Date : 2025-10-11 DOI: 10.1101/2025.09.02.673774

Rashmi Srivastava, Sanjeev Kumar Yadav, Mary-Katherine Cormier, Siu-Pok Yee, Katie Lowther, Rajkumar Verma

{"title":"Validation and Optimization of Breeding Strategy for miR-141/200c Knockout Mice to Eliminate Off-Target Gene Silencing using FLPo Deleter mice.","authors":"Rashmi Srivastava, Sanjeev Kumar Yadav, Mary-Katherine Cormier, Siu-Pok Yee, Katie Lowther, Rajkumar Verma","doi":"10.1101/2025.09.02.673774","DOIUrl":"10.1101/2025.09.02.673774","url":null,"abstract":"MicroRNAs (miRNAs) of the miR-200 family specifically miR-141 and miR-200c regulate neurogenesis, differentiation, and epithelial mesenchymal transitions in development and several diseases including cancer and stroke. The STOCK Mirc13tm1Mtm /Mmjax mouse line, which targets the miR-141/200c cluster, was originally generated and described by Park et al. 2012 as a conditional knockout-first allele requiring a two-step breeding strategy: FLP recombination to excise lacZ/neo cassettes followed by Cre recombination to delete the floxed miRNA cluster (1). However, subsequent studies either bypassed this step and reported knockouts based on direct crosses with Cre mouse lines, leaving residual lacZ/neo sequences that may silence upstream elements or introduce transcriptional artifacts or rare studies used less efficient FLPe Deleter mice. Here, we present a detailed and refined strategy to conditional miR-141/200c knockouts mice using FLPo Deleter mice to efficiently eliminate lacZ/neo cassettes. Our approach not only confirmed complete deletion of miR-141 and miR-200c in various organs such olfactory bulbs and lungs where these miRNAs are robustly expressed using various approach such as genotyping qPCR validation and in situ hybridization but showed that without the use of FLPo deleter mice deletion of miR-141/200c cluster may also lead to loss of several close proximity physiologically important genes such as ptpn6, phb2, atn1 and eno1 . By restoring a clean floxed allele using FLPo deleter mice prior to Cre deletion, we establish a reliable and interpretable mouse model for dissecting the roles of the miR-141/200c cluster miRNA in various disease models.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12424681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Innate detection of Salmonella replication triggers caspase-8-dependent apoptosis via TLR-driven TNF signaling and NLRC4-mediated sensing of the SPI-2 Type III secretion system. 先天检测沙门氏菌复制可通过tlr驱动的TNF信号和nlrc4介导的SPI-2 III型分泌系统感知触发caspase-8依赖性细胞凋亡。

bioRxiv : the preprint server for biology Pub Date : 2025-10-11 DOI: 10.1101/2025.09.10.675376

Beatrice I Herrmann, Maxime Zamba-Campero, Reyna Garcia Sillas, Winslow W Yost, Lance W Peterson, Justin L Roncaioli, Shelley C Rankin, Dieter M Schifferli, Kodi Ravichandran, Igor E Brodsky

{"title":"Innate detection of Salmonella replication triggers caspase-8-dependent apoptosis via TLR-driven TNF signaling and NLRC4-mediated sensing of the SPI-2 Type III secretion system.","authors":"Beatrice I Herrmann, Maxime Zamba-Campero, Reyna Garcia Sillas, Winslow W Yost, Lance W Peterson, Justin L Roncaioli, Shelley C Rankin, Dieter M Schifferli, Kodi Ravichandran, Igor E Brodsky","doi":"10.1101/2025.09.10.675376","DOIUrl":"10.1101/2025.09.10.675376","url":null,"abstract":"Salmonella enterica comprises over 2500 serovars that are responsible for over 90 million annual infections and 100,000 deaths worldwide. Despite this diversity, our understanding of innate immune responses to Salmonella is based on extensive study of a few serovars, primarily Typhimurium, including strains that cannot replicate within primary murine macrophages. Non-replicating Salmonella trigger caspase-1 and -11-dependent pyroptosis. Whether the innate immune system distinguishes between replicating and non-replicating intracellular Salmonella is poorly defined. Here we demonstrate that replicating Salmonella enterica induce a distinct pathway of TNF- and caspase-8-driven apoptosis via host TLR4 and Salmonella Pathogenicity Island-2 activity. This pathway is independent of gasdermin D and involves the apoptotic pore protein Pannexin-1. Combined loss of Pannexin-1 and gasdermin D resulted in defective control of systemic Salmonella, indicating that these pathways function together to promote anti-Salmonella host defense. Altogether, our findings uncover a previously unappreciated pathway by which macrophages sense intracellular replicating bacteria.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Methionine matters: a common mechanism of viral inhibition of host defense identified via AI-assisted molecular dynamics. 蛋氨酸问题：通过人工智能辅助分子动力学鉴定的病毒抑制宿主防御的共同机制。

bioRxiv : the preprint server for biology Pub Date : 2025-10-08 DOI: 10.1101/2025.09.19.677134

Skye J Bixler, Gregory A Babbitt, Liv K Casperson, Maureen C Ferran

{"title":"Methionine matters: a common mechanism of viral inhibition of host defense identified via AI-assisted molecular dynamics.","authors":"Skye J Bixler, Gregory A Babbitt, Liv K Casperson, Maureen C Ferran","doi":"10.1101/2025.09.19.677134","DOIUrl":"10.1101/2025.09.19.677134","url":null,"abstract":"Diverse groups of viruses infecting higher eukaryotes inhibit mRNA export via physical blockage of the Rae1-Nup98 complex within the host cell's nucleopore. This is thought to most often involve the critical placement of hydrophilic flanked single methionine residues along polypeptide extensions that reach into the nucleopore. However, it is unknown how this presumably conserved mechanism might function across diverse viral taxa. Here we employ a comparative molecular dynamics (MD) approach comparing motions of wild-type and mutant viral proteins in Rae-Nup98 bound vs. unbound states. Our comparisons of MD simulations are enhanced by kernel-based denoising allowing the isolation of non-random functional dynamics from random thermal noise. We demonstrate that despite large structural differences, three evolutionarily distinct viral systems (i.e. VSV M protein, SARS-CoV2 ORF 6, and KSHV ORF 10) share nearly identical single methionine-dependent functional dynamics related to the host cell inhibition of nuclear transport. This finding strongly supports a convergently-evolved common functional mechanism across viruses involving specific structural placement of non-polar residues like methionine and potentially providing a common therapeutic target for broad spectrum anti-viral treatment.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12458179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145152847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0