bioRxiv : the preprint server for biology最新文献

{"title":"Spatial Attention Weakly Modulates Visual Responses in the Lateral Geniculate Nucleus.","authors":"Henry J Alitto, Jeffrey S Johnson, W Martin Usrey","doi":"10.1101/2025.05.16.652890","DOIUrl":"10.1101/2025.05.16.652890","url":null,"abstract":"<p><p>Visual responses in the cerebral cortex are strongly influenced by shifts in spatial attention. This modulation of visual processing includes changes in firing rate, decreased response variability, and decreased interneuronal correlations; all of which are thought to underlie enhanced visual perception near the center of attention at the cost of visual perception at other locations. Visual information from the retina is relayed to primary visual cortex via neurons in the lateral geniculate nucleus (LGN) of the dorsal thalamus. Although early studies describe an enhancement of LGN activity with spatial attention, more recent work has cast doubt on this view. Given its strategic position as the gateway to the cortex, an understanding of the effects of attention on visual processing in the LGN is important. We therefore performed experiments to reexamine the influence of covert spatial attention on the spiking activity of single units in the macaque LGN and applied a broad set of analyses and functional metrics to assess possible effects. Our results reveal a statistically significant effect of spatial attention in the LGN: firing rates were slightly higher and more reliable when monkeys directed attention towards the receptive fields of recorded neurons compared to when attention was directed to different retinotopic locations. However, effects were much smaller than previously reported (∼1% vs ∼4%) and further analyses suggest that effects are weak and inconsistent. Thus, while spatial attention does exert an influence in the LGN, its effects are weak and may have limited impact on downstream processing.</p><p><strong>Significance statement: </strong>The lateral geniculate nucleus (LGN) is a critical relay in the visual system, shaping the flow of sensory information from the eye to the brain. Although higher-order brain regions show strong modulation by attention, it remains unclear whether the LGN is similarly affected. By directly recording LGN activity in monkeys performing a covert attention task, we found that spatial attention produces only weak and inconsistent modulation of visual responses. These findings suggest that the LGN largely operates independently of spatial attention, highlighting a potential boundary between early sensory processing and cognitive control.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236664","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}

{"title":"Oncogenic virus hijacks SOX18 pioneer function to enhance viral persistence.","authors":"Krista Tuohinto, Matthew S Graus, Peyton Staab, Ville Tiusanen, Fei Liangru, Susav Pradhan, Yew Yan Wong, Simon Weissmann, Jieqiong Lou, Elizabeth Hinde, Justin Wong, Quintin Lee, Alexey Terskikh, Martin Alvarez-Kuglen, Tara Karnezis, Thomas Günther, Adam Grundhoff, Biswajyoti Sahu, Mathias Francoís, Päivi M Ojala","doi":"10.1101/2025.06.28.662102","DOIUrl":"10.1101/2025.06.28.662102","url":null,"abstract":"<p><p>Kaposi's sarcoma herpesvirus (KSHV) establishes lifelong oncogenic infection in lymphatic endothelial cells (LECs) by ensuring episomal maintenance of its genome via the viral protein LANA. Efficient viral genome maintenance typically involves host DNA replication and episome tethering, but the extent of cell-type-specific regulation remains unclear. Here, we identify that KSHV hijacks the pioneering function of the endothelial-specific transcription factor SOX18 to facilitate persistence of viral episomes. Upon infection, LANA co-opts SOX18 to recruit the SWI/SNF chromatin-remodeling complex via its ATPase subunit BRG1, enhancing chromatin accessibility and enabling efficient viral genome persistence. Disruption of SOX18 or BRG1-genetically or pharmacologically-leads to reduced episome load and attenuated hallmarks of virus infection. This work highlights how viruses can harness lineage-specific transcriptional regulators to establish persistent nuclear retention of their episome into the host genome.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593548","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}

{"title":"Lineage recording in monoclonal gastruloids reveals heritable modes of early development.","authors":"Samuel G Regalado, Chengxiang Qiu, Sanjay Kottapalli, Beth K Martin, Wei Chen, Hanna Liao, Haedong Kim, Xiaoyi Li, Jean-Benoît Lalanne, Nobuhiko Hamazaki, Silvia Domcke, Junhong Choi, Jay Shendure","doi":"10.1101/2025.05.23.655664","DOIUrl":"10.1101/2025.05.23.655664","url":null,"abstract":"<p><p>Mammalian stem cells possess a remarkable capacity for self-organization, a property that underlies increasingly sophisticated <i>in vitro</i> models of early development. However, even under carefully controlled conditions, stem cell-derived models exhibit substantial \"inter-individual\" heterogeneity. Focusing on gastruloids, a powerful model of the early posterior embryo ¹ , we sought to investigate the origins of this heterogeneity. To this end, we developed a scalable protocol for generating gastruloids that are monoclonal, <i>i.e.</i> derived from a single mouse embryonic stem cell (mESC). Single cell transcriptional profiling of monoclonal gastruloids revealed extensive inter-individual heterogeneity, with some hardly progressing, others resembling conventional gastruloids but biased towards mesodermal or neural lineages, and yet others bearing cell types rare or absent from conventional polyclonal gastruloids. To investigate this further, we leveraged DNA Typewriter ² to record the cell lineage relationships among the mESCs from which monoclonal gastruloids originate. Early in the expansion of \"founder\" mESCsーprior to induction of the resulting aggregates to form gastruloidsーwe observe clear examples of fate bias or fate restriction, <i>i.e.</i> sister clades that exhibit markedly different cell type compositions. In a separate experiment with DNA Typewriter, we reconstructed a monophyletic \"tree of trees\", composed of ∼50,000 cells derived from ∼100 gastruloids, all descended from a single \"founder of founders\" stem cell. From these data, we find that founder mESCs that are more closely related are more likely to give rise to monoclonal gastruloids with similar cell type compositions. Our results suggest that fluctuations in the intrinsic states of mESCs are heritable, and shape their descendants' fates across many cell divisions. Our study also showcases how DNA Typewriter can be used to reconstruct high-resolution, monophyletic cell lineage trees in stem cell models of early development.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236517","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}

{"title":"PIWIL2 downregulation in colon cancer promotes transposon activity and pro-tumorigenic phenotypes.","authors":"Alyssa Risner, Joyce Nair-Menon, Abhinav Cheedipudi, Joe R Delaney, Vamsi Gangaraju, Antonis Kourtidis","doi":"10.1101/2025.05.20.655197","DOIUrl":"10.1101/2025.05.20.655197","url":null,"abstract":"<p><p>Reactivation of transposable elements (TEs) in somatic tissues, particularly of LINE-1, is associated with disease by causing gene mutations and DNA damage. Previous work has shown that the PIWI pathway is crucial for TE suppression in the germline. However, the status and function of this pathway is not well characterized in differentiated somatic cells and there is lack of consensus on the role of the pathway in somatic tumorigenesis. To shed light on this conundrum, we examined the PIWI pathway in colon cancer through combining bioinformatic analyses and cell-based assays. Shifted Weighted Annotation Network (SWAN) analysis revealed that the pathway experiences significant allelic losses in colon cancer and that PIWIL2, the main catalytic component of the pathway responsible for TE silencing, experiences the highest percent deletions. PIWIL2 is downregulated in colon tumors of advanced stage, nodal metastasis, and in certain subtypes, correlating with poor survival, while it is also downregulated in ulcerative colitis, an inflammatory bowel disease that predisposes to colon cancer. PIWIL2 depletion in colon epithelial Caco2 cells leads to increased anchorage-independent growth, loss of transposon-targeting - non-canonical - piRNAs, increased LINE-1 levels and activity, and in DNA damage, altogether highlighting a tumor-suppressing role of PIWIL2 in the colon.</p><p><strong>Summary statement: </strong>This study investigates the PIWI-piRNA pathway in colon cancer using a nuanced bioinformatic and cell-based approach, linking the downregulation of PIWIL2 to disease progression, transposable element activation and DNA damage.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236616","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}

{"title":"Single-Nucleus Transcriptomics Reveals How Cell Type Shapes the Circadian Transcriptome of the Arabidopsis Leaf.","authors":"Alveena Zulfiqar, Zachary A Myers, Ananda Menon, Kathleen Greenham","doi":"10.1101/2025.06.12.659411","DOIUrl":"10.1101/2025.06.12.659411","url":null,"abstract":"<p><p>Circadian regulation enables plants to coordinate cellular processes with daily environmental cycles, yet the dynamics and hierarchy of the clock across cell types remains poorly understood. To characterize circadian regulation across cell types in the mature <i>Arabidopsis thaliana</i> leaf, we performed a 24 hour single nucleus RNA-sequencing circadian time course. We captured ∼30,000 nuclei across seven circadian time points, recovering all major leaf cell types. We identified over 7,400 genes with cluster-resolved circadian regulation, and used coexpression analysis to define five major temporal expression clades shared across all cell types. We leveraged these assignments to identify genes with cell-type-specific temporal shifts in expression. Single cell gene regulatory networks were generated for each cluster through GENIE3, identifying many shared and unique transcription factor target interactions across clusters. A close examination of core clock component targets identified complex light and hormone signaling associated networks, capturing both broad cross-cell type regulation and cell-type-specific target regulation. Our results demonstrate the extent to which circadian transcriptional regulation is present in the mature Arabidopsis leaf, and highlight the immense complexity in cell-type-specific regulation.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12262343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645003","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}

{"title":"Rapid, open-source, and automated quantification of the head twitch response in C57BL/6J mice using DeepLabCut and Simple Behavioral Analysis.","authors":"Alexander D Maitland, Nicholas R Gonzalez, Donna Walther, Francisco Pereira, Michael H Baumann, Grant C Glatfelter","doi":"10.1101/2025.04.28.650242","DOIUrl":"10.1101/2025.04.28.650242","url":null,"abstract":"<p><p>Serotonergic psychedelics induce the head twitch response (HTR) in mice, an index of serotonin (5-HT) 2A receptor (5-HT _2A ) agonism and a behavioral proxy for psychedelic effects in humans. Existing methods for detecting HTRs include time-consuming visual scoring, magnetometer-based approaches, and analysis of videos using semi-automated commercial software. Here, we present a new automated approach for quantifying HTRs from experimental videos using the open-source machine learning-based toolkits, DeepLabCut (DLC) and Simple Behavioral Analysis (SimBA). Pose estimation DLC models were trained to predict X,Y coordinates of 13 body parts of C57BL/6J mice using historical experimental videos of HTRs induced by various psychedelic drugs. Next, a non-overlapping set of historical experimental videos was analyzed and used to train SimBA random forest behavioral classifiers to predict the presence of the HTR. The DLC+SimBA approach was then validated using a separate subset of visually scored videos. DLC+SimBA model performance was assessed at different video resolutions (50%, 25%, 12.5%) and frame rates (120, 60, 30 frames per second or fps). Our results indicate that HTRs can be quantified accurately at 50% resolution and 120 fps (precision = 95.45, recall = 95.56, F ₁ = 95.51) or at lower frame rates and resolutions (i.e., 50% resolution and 60 fps). The best performing DLC+SimBA model combination was deployed to evaluate the effects of bufotenine, a tryptamine derivative with uncharacterized potency and efficacy in the HTR paradigm. Interestingly, bufotenine only induced elevated HTRs (ED ₅₀ = 0.99 mg/kg, max counts = 24) when serotonin 1A receptors (5-HT _1A ) were pharmacologically blocked and activity at other sites of action may also impact its pharmacological effects (e.g., serotonin transporter). HTR counts for a subset of 21 videos from bufotenine experiments were strongly correlated for DLC+SimBA vs. visual scoring and semi-automated software detection methods ( <i>r</i> = 0.98 and 0.99). Finally, the DLC+SimBA approach displayed high accuracy when compared to visual scoring of HTRs for three serotonergic psychedelic drugs with variable HTR frequencies ( <i>r</i> = 0.99 vs. mean visual scores from 3 blinded raters). In summary, the DLC+SimBA approach represents a modular, noninvasive, and open-source method of HTR detection from experimental videos with accuracy comparable to magnetometer-based approaches and greater speed than visual scoring.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12190173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500118","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}

{"title":"Dynamic convergence of neurodevelopmental disorder risk genes across neurodevelopment.","authors":"Meilin Fernandez Garcia, Kayla Retallick-Townsley, April Pruitt, Elizabeth Davidson, Novin Balafkan, Jonathan Warrell, Tzu-Chieh Huang, Alfred Kibowen, Zhiyuan Chu, Yi Dai, Sarah E Fitzpatrick, Ran Meng, Annabel Sen, Sophie Cohen, Olivia Livoti, Suha Khan, Charlotte Becker, Andre Luiz Teles E Silva, Jenny Liu, Grace Dossou, Jen Cheung, Susanna Liu, Sadaf Ghorbani, P J Michael Deans, Marisa DeCiucis, Prashant Emani, Huanyao Gao, Hongying Shen, Mark Gerstein, Zuoheng Wang, Laura M Huckins, Ellen J Hoffman, Kristen Brennand","doi":"10.1101/2024.08.23.609190","DOIUrl":"10.1101/2024.08.23.609190","url":null,"abstract":"<p><p>Over three hundred and seventy-three risk genes, broadly enriched for roles in neuronal communication and gene expression regulation, underlie risk for autism spectrum disorder (ASD) and developmental delay (DD). Functional genomic studies of subsets of these genes consistently indicate a convergent role in neurogenesis, but how these diverse risk genes converge on a smaller number of biological pathways in mature neurons is unclear. To uncover shared downstream impacts between neurodevelopmental disorder (NDD) risk genes, here we apply a pooled CRISPR approach to contrast the transcriptomic impacts of targeting 29 NDD loss-of-function genes across human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells, glutamatergic neurons, and GABAergic neurons. Points of convergence vary between the cell types of the brain and are greatest in mature glutamatergic neurons, where they broadly target not just synaptic and epigenetic, but unexpectedly, mitochondrial biology. The strongest convergent networks occur between NDD genes with common co-expression patterns in the post-mortem brain, biological annotations, and clinical associations, suggesting that convergence may one-day inform patient stratification and treatment. Towards this, ten out of eleven drugs tested that were predicted to reverse convergent signatures in human cells and/or arousal and sensory processing behaviors in zebrafish ameliorated at least one behavioral phenotype <i>in vivo</i> . Altogether, robust convergence in post-mitotic neurons represents a clinically actionable therapeutic window.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127966","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}

{"title":"Barcoded monoclonal embryoids are a potential solution to confounding bottlenecks in mosaic organoid screens.","authors":"Samuel G Regalado, Chengxiang Qiu, Jean-Benoît Lalanne, Beth K Martin, Madeleine Duran, Cole Trapnell, Aidan Keith, Silvia Domcke, Jay Shendure","doi":"10.1101/2025.05.23.655669","DOIUrl":"10.1101/2025.05.23.655669","url":null,"abstract":"<p><p>Genetic screens in organoids hold tremendous promise for accelerating discoveries at the intersection of genomics and developmental biology. Embryoid bodies (EBs) are self-organizing multicellular structures that recapitulate aspects of early mammalian embryogenesis. We set out to perform a CRISPR screen perturbing all transcription factors (TFs) in murine EBs. Specifically, a library of TF-targeting guide RNAs (gRNAs) was used to generate mouse embryonic stem cells (mESCs) bearing single TF knockouts. Aggregates of these mESCs were induced to form mouse EBs, such that each resulting EB was 'mosaic' with respect to the TF perturbations represented among its constituent cells. Upon performing single cell RNA-seq (scRNA-seq) on cells derived from mosaic EBs, we found many TF perturbations exhibiting large and seemingly significant effects on the likelihood that individual cells would adopt certain fates, suggesting roles for these TFs in lineage specification. However, to our surprise, these results were not reproducible across biological replicates. Upon further investigation, we discovered cellular bottlenecks during EB differentiation that dramatically reduce clonal complexity, curtailing statistical power and confounding interpretation of mosaic screens. Towards addressing this challenge, we developed a scalable protocol in which each individual EB is monoclonally derived from a single mESC and genetically barcoded. In a proof-of-concept experiment, we show how these monoclonal EBs enable us to better quantify the consequences of TF perturbations as well as 'inter-individual' heterogeneity across EBs harboring the same genetic perturbation. Looking forward, monoclonal EBs and EB-derived organoids may be powerful tools not only for genetic screens, but also for modeling Mendelian disorders, as their underlying genetic lesions are overwhelmingly constitutional ( <i>i.e.</i> present in all somatic cells), yet give rise to phenotypes with incomplete penetrance and variable expressivity.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236478","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}

{"title":"A mathematical framework for human neutrophil state transitions inferred from single-cell RNA sequence data.","authors":"Gustaf Wigerblad, Jonathan Carruthers, Sumanta Ray, Thomas Finnie, Grant Lythe, Carmen Molina-París, Saumyadipta Pyne, Mariana J Kaplan","doi":"10.1101/2025.06.27.662068","DOIUrl":"10.1101/2025.06.27.662068","url":null,"abstract":"<p><p>Neutrophils, the most abundant immune cells in the human circulation, play a central role in the innate immune system. While neutrophil heterogeneity is a topic of increasing research interest, few efforts have been made to model the dynamics of neutrophil population subsets. We develop a mathematical model to describe the dynamics that characterizes the states and transitions involved in the maturation of human neutrophils. We use single-cell gene expression data to identify five clusters of healthy human neutrophils, and pseudo-time analysis to inform model structure. We find that precursor neutrophils transition into immature neutrophils, which then either transition to an interferon-responsive state or continue to mature through two further states. The key model parameters are the transition rates (the inverse of a transition rate is the mean waiting time in one state before transitioning to another). In this framework, the transition from the precursor to immature state (mean time less than an hour) is more rapid than subsequent transitions (mean times more than 12 hours). Approximately a quarter of neutrophils are estimated to follow the interferon-responsive path; the remainder continue along the standard maturation pathway. We use Bayesian inference to describe the variation, between individuals, in the fraction of cells within each cluster.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593437","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}

{"title":"Learning Biophysical Dynamics with Protein Language Models.","authors":"Chao Hou, Haiqing Zhao, Yufeng Shen","doi":"10.1101/2024.10.11.617911","DOIUrl":"10.1101/2024.10.11.617911","url":null,"abstract":"<p><p>Structural dynamics are fundamental to protein functions and mutation effects. Current protein deep learning models are predominantly trained on sequence and/or static structure data, which often fail to capture the dynamic nature of proteins. To address this, we introduce SeqDance and ESMDance, two protein language models trained on dynamic biophysical properties derived from molecular dynamics simulations and normal mode analyses of over 64,000 proteins. SeqDance, trained from scratch, learns both local dynamic interactions and global conformational properties for ordered and disordered proteins. SeqDance predicted dynamic property changes reflect mutation effect on protein folding stability. ESMDance, built upon ESM2 outputs, substantially outperforms ESM2 in zero-shot prediction of mutation effects for designed and viral proteins which lack evolutionary information. Together, SeqDance and ESMDance offer a new framework for integrating protein dynamics into language models, enabling more generalizable predictions of protein behavior and mutation effects.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11507661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142516120","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}