bioRxiv : the preprint server for biology最新文献

{"title":"Visual experience shapes functional connectivity between occipital and non-visual networks.","authors":"Mengyu Tian, Xiang Xiao, Huiqing Hu, Rhodri Cusack, Marina Bedny","doi":"10.1101/2023.02.21.528939","DOIUrl":"10.1101/2023.02.21.528939","url":null,"abstract":"<p><p>Comparisons of visual cortex function across blind and sighted adults reveals effects of experience on human brain function. Since almost all research has been done with adults, little is known about the developmental origins of plasticity. We compared resting state functional connectivity of visual cortices of blind adults ( <i>n</i> = 30), blindfolded sighted adults ( <i>n</i> = 50) to a large cohort of sighted infants (Developing Human Connectome Project, <i>n</i> = 475). Visual cortices of sighted adults show stronger coupling with non-visual sensory-motor networks (auditory, somatosensory/motor), than with higher-cognitive prefrontal cortices (PFC). In contrast, visual cortices of blind adults show stronger coupling with higher-cognitive PFC than with nonvisual sensory-motor networks. Are infant visual cortices functionally like those of sighted adults? Alternatively, do infants start like blind adults, with vision required to set up the sighted adult pattern? Remarkably, we find that, in infants, secondary visual cortices are more like those of blind adults: stronger coupling with PFC than with nonvisual sensory-motor networks, suggesting that visual experience establishes elements of the sighted-adult long-range connectivity. Infant primary visual cortices are in-between blind and sighted adults i.e., equal PFC and sensory-motor connectivity. The lateralization of occipital-to-frontal connectivity in infants resembles the sighted adults, consistent with reorganization by blindness. These results reveal instructive effects of vision and reorganizing effects of blindness on functional connectivity.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10142513","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":"Lithium Restores Inhibitory Function and Neuronal Excitability through GSK-3β Inhibition in a Bipolar Disorder-Associated <i>Ank3</i> Variant Mouse Model.","authors":"René N Caballero-Florán, Kendall P Dean, Andrew D Nelson, Lia Min, Paul M Jenkins","doi":"10.1101/2023.10.26.564203","DOIUrl":"10.1101/2023.10.26.564203","url":null,"abstract":"<p><p>Bipolar disorder (BD) is a prevalent psychiatric condition characterized by mood dysregulation, psychosocial impairment, and an increased risk of suicide. The gene <i>ANK3</i> has been identified as a risk locus for BD through multiple genome-wide association studies (GWAS). However, the mechanisms by which <i>ANK3</i> variants influence BD pathophysiology and treatment response remain unclear. <i>ANK3</i> encodes ankyrin-G, a protein that organizes the axon initial segment (AIS) and nodes of Ranvier by scaffolding ion channels and cell adhesion molecules to the cytoskeleton. Recent studies show that ankyrin-G interacts with the GABA_A receptor-associated protein (GABARAP) to stabilize inhibitory synapses, potentially linking <i>ANK3</i> variants to inhibitory (GABAergic) signaling deficits associated with BD. We previously demonstrated that the BD-associated variant, <i>ANK3</i> p.W1989R, disrupts the ankyrin-G/GABARAP interaction, resulting in inhibitory deficits and cortical pyramidal neuron hyperexcitability in mice. In this study, we investigate how lithium, a common BD therapeutic, modulates neuronal excitability in this model. Our findings show that chronic lithium treatment selectively enhances presynaptic GABAergic neurotransmission, reduces neuronal hyperexcitability, and partially rescues AIS length, without altering the density of GABAergic synapses. We also show that the selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor Tideglusib recapitulates the enhancement of presynaptic GABAergic signaling. These findings shed new light on how <i>ANK3</i> variants may contribute to inhibitory deficits in BD and demonstrate that lithium treatment is able to restore these deficits, likely through GSK-3β inhibition. Furthermore, these findings highlight GSK-3β inhibition as a promising therapeutic strategy for treating BD and other neurological disorders affected by GABAergic dysfunction.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10634991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92157709","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":"Multi-omic identification of key transcriptional regulatory programs during endurance exercise training in rats.","authors":"Gregory R Smith, Bingqing Zhao, Malene E Lindholm, Archana Raja, Mark Viggars, Hanna Pincas, Nicole R Gay, Yifei Sun, Yongchao Ge, Venugopalan D Nair, James A Sanford, Mary Anne S Amper, Mital Vasoya, Kevin S Smith, Stephen Montgomery, Elena Zaslavsky, Sue C Bodine, Karyn A Esser, Martin J Walsh, Michael P Snyder, Stuart C Sealfon","doi":"10.1101/2023.01.10.523450","DOIUrl":"10.1101/2023.01.10.523450","url":null,"abstract":"<p><p>Transcription factors (TFs) play a key role in regulating gene expression. We conducted an integrated analysis of chromatin accessibility, DNA methylation, mRNA expression, protein abundance and phosphorylation across eight tissues in fifty rats of equally represented sexes following endurance exercise training (EET) to identify coordinated epigenomic and transcriptional changes and determine key TFs involved. We uncovered tissue-specific EET associated changes and TF motif enrichment across differentially expressed genes (DEGs), accessible regions (DARs), and methylated regions (DMRs). We discovered distinct routes of EET-induced regulation through either epigenomic alterations providing better access for TFs to affect target genes, or via changes in TF expression or activity enabling target gene responses. We identified TF motifs enriched among correlated epigenomic and transcriptomic alterations, DEGs correlated with exercise-related phenotypic and cell type composition changes, and EET-induced activity changes of TFs whose target genes are enriched for DEGs. This analysis elucidates the unique gene regulatory mechanisms mediating diverse transcriptional responses to EET across tissues.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/79/bf/nihpp-2023.01.10.523450v1.PMC9882056.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10698707","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":"Spatiotemporal mapping of the contractile and adhesive forces sculpting early <i>C. elegans</i> embryos.","authors":"Kazunori Yamamoto, Sacha Ichbiah, Matthieu Perez, Joana Borrego-Pinto, Fabrice Delbary, Nate Goehring, Hervé Turlier, Guillaume Charras","doi":"10.1101/2023.03.07.531437","DOIUrl":"10.1101/2023.03.07.531437","url":null,"abstract":"<p><p>Embryo shape is determined by individual cell mechanics, intercellular interaction strength, and geometrical constraints. Models based on surface tensions at cell interfaces can predict 3D static cellular arrangements within aggregates. However, predicting the dynamics of such arrangements is challenging due to difficulties in measuring temporal changes in tensions. Here, we characterise the spatiotemporal changes in cellular tensions shaping the early nematode embryo using AFM, live microscopy, and tension inference. Using excoriated embryos, we validate a hybrid inference pipeline that calibrates relative inferred tensions temporally using cortical myosin enrichment and absolute tensions using AFM measurements. Applied to embryos within their native shell, we infer a spatiotemporal map of absolute tensions, revealing that ABa, ABp, and EMS compaction is driven by increased tension at free surfaces, while P₂'s initial exclusion is due to high tension at intercellular contacts. We uncover a direct and non-affine contribution of cadherins to cell-cell contact tension, comparable to cadherins' indirect contribution via actomyosin regulation.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89062248","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":"Computation-guided redesign of promoter specificity of a bacterial RNA polymerase.","authors":"Xiangyang Liu, Anthony T Meger, Thomas Gillis, Jonah O'Mara Schwartz, Balendra Sah, Robert Landick, Srivatsan Raman","doi":"10.1101/2022.11.29.518332","DOIUrl":"10.1101/2022.11.29.518332","url":null,"abstract":"<p><p>The ability to regulate genetic circuits and metabolic pathways is central to cellular control. The existing toolkit is predominantly comprised of local transcription regulators that are unsuitable for exerting control at a global genome-wide scale. Bacterial sigma factors are ideal global regulators as together they direct the RNA polymerase to thousands of transcription sites. Here, we redesigned the promoter specificity of the <i>E. coli</i> housekeeping sigma factor, sigma-70, toward five orthogonal promoter targets not recognized by the native sigma-70. These orthogonal sigma-70 factors were developed by screening a pooled library of computationally designed variants of the -35 DNA recognition helix, each tailored to a specific target promoter. In the redesigned sigma factors new target-specific interactions facilitate new promoter recognition. Activity of the top performing redesigned sigma-70s varied across the promoter targets and ranged from 17% to 77% of native sigma-70 on its canonical active promoter. These orthogonal sigma factors represent a new suite of regulators for global transcriptional control.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12262734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84622366","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":"Incorporation of collagen into <i>Pseudomonas aeruginosa, Staphylococcus aureus</i>, and <i>Burkholderia pseudomallei</i> biofilms enhances their elasticity and resistance against phagocytic clearance.","authors":"Xuening Zhou, Ashlee McGovern, Marilyn J Wells, Deepesh B Verma, Hailey Currie, Afsana Mimi Raka, Jiachun Shen, Katherine A Brown, Rae Robertson-Anderson, Vernita D Gordon","doi":"10.1101/2023.10.25.564018","DOIUrl":"10.1101/2023.10.25.564018","url":null,"abstract":"<p><p>Biofilms are communities of microbes embedded in a matrix of extracellular polymeric substances (EPS) and other components such as proteins. Matrix components can be produced by the microorganisms themselves but can also originate from the environment and then be incorporated into the biofilm. For example, we and our collaborators have recently shown that collagen, a host-produced protein that is abundant in many different infection sites, can be taken up into the matrices of <i>Pseudomonas aeruginosa</i> biofilms, altering biofilm mechanics. In an infection, the biofilm matrix protects bacteria from clearance by the immune system, and some of that protection likely arises from the mechanical properties of the biofilm. <i>P. aeruginosa, Staphylococcus aureus</i>, and <i>Burkholderia pseudomallei</i> are human pathogens notable for forming biofilms <i>in vitro</i> and <i>in vivo</i> in tissues rich in collagen such as lung and skin. Here, we show that the incorporation of Type I collagen into <i>P. aeruginosa, S. aureus</i>, and <i>B. pseudomallei</i> biofilms significantly enhances biofilm elasticity and hinders phagocytosis of biofilm bacteria by human neutrophils. Additionally, enzymatic degradation of collagen using collagenase reverses these effects, increasing biofilm susceptibility to neutrophils. Our findings suggest that host materials play significant roles in stabilizing biofilms and may present promising targets for therapeutic interventions.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10634824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92157703","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":"Widespread epistasis shapes RNA Polymerase II active site function and evolution.","authors":"Bingbing Duan, Chenxi Qiu, Sing-Hoi Sze, Craig Kaplan","doi":"10.1101/2023.02.27.530048","DOIUrl":"10.1101/2023.02.27.530048","url":null,"abstract":"<p><p>Multi-subunit RNA Polymerases (msRNAPs) are responsible for transcription in all kingdoms of life. These enzymes rely on dynamic, highly conserved active site domains such as the so-called \"trigger loop\" (TL) to accomplish steps in the transcription cycle. Mutations in the RNA polymerase II (Pol II) TL confer a spectrum of biochemical and genetic phenotypes that suggest two main classes, which decrease or increase catalysis or other nucleotide addition cycle (NAC) events. The Pol II active site relies on networks of residue interactions to function, and mutations likely perturb these networks in ways that may alter mechanisms. We have undertaken a structural genetics approach to reveal residue interactions within and surrounding the Pol II TL - determining its \"interaction landscape\" - by deep mutational scanning in <i>Saccharomyces cerevisiae</i> Pol II. This analysis reveals connections between TL residues and surrounding domains, demonstrating that TL function is tightly coupled to its specific enzyme context.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5e/78/nihpp-2023.02.27.530048v2.PMC10002619.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9307975","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":"Brain-wide arousal signals are segregated from movement planning in the superior colliculus.","authors":"Richard Johnston, Matthew A Smith","doi":"10.1101/2024.04.26.591284","DOIUrl":"10.1101/2024.04.26.591284","url":null,"abstract":"<p><p>The superior colliculus (SC) is traditionally considered a brain region that functions as an interface between processing visual inputs and generating eye movement outputs. Although its role as a primary reflex center is thought to be conserved across vertebrate species, evidence suggests that the SC has evolved to support higher-order cognitive functions including spatial attention. When it comes to oculomotor areas such as the SC, it is critical that high precision fixation and eye movements are maintained even in the presence of signals related to ongoing changes in cognition and brain state, both of which have the potential to interfere with eye position encoding and movement generation. In this study, we recorded spiking responses of neuronal populations in the SC while monkeys performed a memory-guided saccade task and found that the activity of some of the neurons fluctuated over tens of minutes. By leveraging the statistical power afforded by high-dimensional neuronal recordings, we were able to identify a low-dimensional pattern of activity that was correlated with the subjects' arousal levels. Importantly, we found that the spiking responses of deep-layer SC neurons were less correlated with this brain-wide arousal signal, and that neural activity associated with changes in pupil size and saccade tuning did not overlap in population activity space with movement initiation signals. Taken together, these findings provide a framework for understanding how signals related to cognition and arousal can be embedded in the population activity of oculomotor structures without compromising the fidelity of the motor output.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11092505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923800","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":"Inferring Neural Communication Dynamics from Field Potentials Using Graph Diffusion Autoregression.","authors":"Felix Schwock, Julien Bloch, Karam Khateeb, Jasmine Zhou, Les Atlas, Azadeh Yazdan-Shahmorad","doi":"10.1101/2024.02.26.582177","DOIUrl":"10.1101/2024.02.26.582177","url":null,"abstract":"<p><p>Estimating dynamic network communication is attracting increased attention, spurred by rapid advancements in multi-site neural recording technologies and efforts to better understand cognitive processes. Yet, traditional methods, which infer communication from statistical dependencies among distributed neural recordings, face core limitations: they do not incorporate possible mechanisms of neural communication, neglect spatial information from the recording setup, and yield predominantly static estimates that cannot capture rapid changes in the brain. To address these issues, we introduce the graph diffusion autoregressive model. Designed for distributed field potential recordings, our model combines vector autoregression with a network communication process to produce a high-resolution communication signal. We successfully validated the model on simulated neural activity and recordings from subdural and intracortical micro-electrode arrays placed in macaque sensorimotor cortex demonstrating its ability to describe rapid communication dynamics induced by optogenetic stimulation, changes in resting state communication, and neural correlates of behavior during a reach task.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10925120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140095205","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":"Protein functional site annotation using local structure embeddings.","authors":"Alexander Derry, Alp Tartici, Russ B Altman","doi":"10.1101/2023.10.13.562298","DOIUrl":"10.1101/2023.10.13.562298","url":null,"abstract":"<p><p>The rapid expansion of protein sequence and structure databases has resulted in a significant number of proteins with ambiguous or unknown function. While advances in machine learning techniques hold great potential to fill this annotation gap, current methods for function prediction are unable to associate global function reliably to the specific residues responsible for that function. We address this issue by introducing PARSE (Protein Annotation by Residue-Specific Enrichment), a knowledge-based method which combines pre-trained embeddings of local structural environments with traditional statistical techniques to simultaneously predict function and provide residue-level annotations. For the task of predicting the catalytic function of enzymes, PARSE achieves comparable or superior global performance to state-of-the-art machine learning methods (F1 score > 85%) while simultaneously annotating the specific residues involved in each function with much greater precision. Since it does not require supervised training, our method can make one-shot predictions for very rare functions and is not limited to a particular type of functional label (e.g. Enzyme Commission numbers or Gene Ontology codes). Finally, we leverage the AlphaFold Structure Database to perform functional annotation at a proteome scale. By applying PARSE to the dark proteome-predicted structures which cannot be classified into known structural families-we predict several novel bacterial metalloproteases. Each of these proteins shares a strongly conserved catalytic site despite highly divergent sequences and global folds, illustrating the value of local structure representations for new function discovery.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71415625","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}