bioRxiv : the preprint server for biology最新文献

{"title":"BLTP3A is associated with membranes of the late endocytic pathway and is an effector of CASM.","authors":"Michael G Hanna, Hely O Rodriguez Cruz, Kenshiro Fujise, Yumei Wu, C Shan Xu, Song Pang, Li Zhuoning, Mara Monetti, Pietro De Camilli","doi":"10.1101/2024.09.28.615015","DOIUrl":"10.1101/2024.09.28.615015","url":null,"abstract":"<p><p>Recent studies have identified a family of rod-shaped proteins thought to mediate lipid transfer at intracellular membrane contacts by a bridge-like mechanism. We show one such protein, bridge-like lipid transfer protein 3A (BLTP3A)/UHRF1BP1 binds VAMP7 vesicles via its C-terminal region and anchors them to lysosomes via its chorein domain containing N-terminal region to Rab7. Upon lysosome damage, BLTP3A-positive vesicles rapidly (within minutes) dissociate from lysosomes. Lysosome damage is known to activate the CASM (Conjugation of ATG8 to Single Membranes) pathway leading to lipidation and recruitment to lysosomes of mammalian ATG8 (mATG8) proteins. We find that this process drives the reassociation of BLTP3A with damaged lysosomes via an interaction of its LIR motif with mATG8 which coincides with a dissociation from the vesicles. Our findings reveal that BLTP3A is an effector of CASM, potentially as part of a mechanism to help repair or minimize lysosome damage.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142396669","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 magnitude-independent neural code for linguistic information during sentence production.","authors":"Adam M Morgan, Orrin Devinsky, Werner Doyle, Patricia Dugan, Daniel Friedman, Adeen Flinker","doi":"10.1101/2024.06.20.599931","DOIUrl":"10.1101/2024.06.20.599931","url":null,"abstract":"<p><p>Humans are the only species with the ability to convey an unbounded number of novel thoughts by combining words into sentences. This process is guided by complex semantic and abstract syntactic representations. Despite their centrality to human cognition, the neural mechanisms underlying these systems remain obscured by inherent limitations of non-invasive brain measures and a near total focus on comprehension paradigms. Here, we address these limitations with high-resolution neurosurgical recordings (electrocorticography) and a controlled sentence production experiment. We uncover distinct cortical networks encoding word-level, semantic, and syntactic information. These networks are broadly distributed across traditional language areas, but with focal sensitivity to syntactic structure in middle and inferior frontal gyri. In contrast to previous findings from comprehension studies, these networks are largely non-overlapping, each specialized for just one of the three linguistic constructs we investigate. Most strikingly, our data reveal an unexpected property of higher-order linguistic information: it is encoded independent of neural activity levels. We propose that this \"magnitude-independent coding\" scheme represents a novel mechanism for encoding information, reserved for higher-order cognition more broadly.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474469","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":"Caveolin assemblies displace one bilayer leaflet to organize and bend membranes.","authors":"Milka Doktorova, Sebastian Daum, Tyler R Reagle, Hannah I Cannon, Jan Ebenhan, Sarah Neudorf, Bing Han, Satyan Sharma, Peter Kasson, Kandice Levental, Kirsten Bacia, Anne K Kenworthy, Ilya Levental","doi":"10.1101/2024.08.28.610209","DOIUrl":"10.1101/2024.08.28.610209","url":null,"abstract":"<p><p>Caveolin is a monotopic integral membrane protein, widely expressed in metazoa and responsible for constructing enigmatic membrane invaginations known as caveolae. Recently, the high-resolution structure of a purified human caveolin assembly, the CAV1-8S complex, revealed a unique organization of 11 protomers arranged in a tightly packed, radially symmetric spiral disc. One face and the outer rim of this disc are hydrophobic, suggesting that the complex incorporates into membranes by displacing hundreds of lipids from one leaflet. The feasibility of this unique molecular architecture and its biophysical and functional consequences are currently unknown. Using Langmuir film balance measurements, we find that CAV1-8S is highly surface active, intercalating into lipid monolayers of various compositions. CAV1-8S can also incorporate into pre-formed bilayers, but only upon removal of phospholipids from the outer-facing leaflet. Atomistic and coarse-grained simulations of biomimetic bilayers support this 'leaflet replacement' model and also reveal that CAV1-8S accumulates 40-70 cholesterol molecules into a disordered monolayer between the complex and its distal lipid leaflet. We find that CAV1-8S preferentially associates with positively curved membrane surfaces due to its influence on the conformations of distal leaflet lipids, and that these effects laterally sort lipids. Large-scale simulations of multiple caveolin assemblies confirmed their association with large, positively curved membrane morphologies consistent with the shape of caveolae. Further, association with curved membranes regulates the exposure of caveolin residues implicated in protein-protein interactions. Altogether, the unique structure of CAV1-8S imparts unusual modes of membrane interaction with implications for membrane organization, morphology, and physiology.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11383982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142305831","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":"Actomyosin forces trigger a conformational change in desmoplakin within desmosomes.","authors":"Yinchen Dong, Ahmed Elgerbi, Bin Xie, John S Choy, Sanjeevi Sivasankar","doi":"10.1101/2024.11.19.624364","DOIUrl":"10.1101/2024.11.19.624364","url":null,"abstract":"<p><p>Desmosomes are essential cell-cell adhesion organelles that enable tension-prone tissue, like the skin and heart, to withstand mechanical stress. Desmosomal anomalies are associated with numerous epidermal disorders and cardiomyopathies. Despite their critical role in maintaining tissue resilience, an understanding of how desmosomes sense and respond to mechanical stimuli is lacking. Here, we use a combination of super-resolution imaging, FRET-based tension sensors, atomistic computer simulations, and biochemical assays to demonstrate that actomyosin forces induce a conformational change in desmoplakin, a critical cytoplasmic desmosomal protein. We show that in human breast cancer MCF7 cells, actomyosin contractility reorients keratin intermediate filaments and directs force to desmoplakin along the keratin filament backbone. These forces induce a conformational change in the N-terminal plakin domain of desmoplakin, converting this domain from a folded (closed) to an extended (open) conformation. Our findings establish that desmoplakin is mechanosensitive and responds to changes in cellular load by undergoing a force-induced conformational change.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142742101","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 computational approach to understanding effort-based decision-making in depression.","authors":"Vincent Valton, Anahit Mkrtchian, Madeleine Moses-Payne, Alan Gray, Karel Kieslich, Samantha VanUrk, Veronika Samborska, Don Chamith Halahakoon, Sanjay G Manohar, Peter Dayan, Masud Husain, Jonathan P Roiser","doi":"10.1101/2024.06.17.599286","DOIUrl":"10.1101/2024.06.17.599286","url":null,"abstract":"<p><strong>Objective: </strong>Motivational dysfunction is a core feature of depression, and can have debilitating effects on everyday function. However, it is unclear which disrupted cognitive processes underlie impaired motivation, and whether impairments persist following remission. Decision-making concerning exerting effort to obtain rewards offers a promising framework for understanding motivation, especially when examined with computational tools which can offer precise quantification of latent processes.</p><p><strong>Methods: </strong>Effort-based decision-making was assessed using the Apple Gathering Task, in which participants decide whether to exert effort via a grip-force device to obtain varying levels of reward; effort levels were individually calibrated and varied parametrically. We present a comprehensive computational analysis of decision-making, initially validating our model in healthy volunteers (N=67), before applying it in a case-control study including current (N=41) and remitted (N=46) unmedicated depressed individuals, and healthy volunteers with (N=36) and without (N=57) a family history of depression.</p><p><strong>Results: </strong>Four fundamental computational mechanisms that drive patterns of effort-based decisions, which replicated across samples, were identified: overall bias to accept effort challenges; reward sensitivity; and linear and quadratic effort sensitivity. Traditional model-agnostic analyses showed that both depressed groups showed lower willingness to exert effort. In contrast with previous findings, computational analysis revealed that this difference was primarily driven by lower effort acceptance bias, but not altered effort or reward sensitivity.</p><p><strong>Conclusions: </strong>This work provides insight into the computational mechanisms underlying motivational dysfunction in depression. Lower willingness to exert effort could represent a trait-like factor contributing to symptoms, and might represent a fruitful target for treatment and prevention.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383242","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":"Intrinsic dynamic shapes responses to external stimulation in the human brain.","authors":"Maximilian Nentwich, Marcin Leszczynski, Charles E Schroeder, Stephan Bickel, Lucas C Parra","doi":"10.1101/2024.08.05.606665","DOIUrl":"10.1101/2024.08.05.606665","url":null,"abstract":"<p><p>Sensory stimulation of the brain reverberates in its recurrent neural networks. However, current computational models of brain activity do not separate immediate sensory responses from this intrinsic dynamic. We apply a vector-autoregressive model with external input (VARX), combining the concepts of 'functional connectivity' and 'encoding models', to intracranial recordings in humans. This model captures the extrinsic effect of the stimulus and separates that from the intrinsic effect of the recurrent brain dynamic. We find that the intrinsic dynamic enhances and prolongs the neural responses to scene cuts, eye movements, and sounds. Failing to account for these extrinsic inputs, leads to spurious recurrent connections that govern the intrinsic dynamic. We also find that the recurrent connectivity during rest is reduced during movie watching. The model shows that an external stimulus can reduce intrinsic noise. It also shows that sensory areas have mostly outward, whereas higher-order brain areas mostly incoming connections. We conclude that the response to an external audiovisual stimulus can largely be attributed to the intrinsic dynamic of the brain, already observed during rest.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11507726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142515998","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":"On variability in local field potentials.","authors":"Mohsen Parto-Dezfouli, Elizabeth L Johnson, Eleni Psarou, Conrado Arturo Bosman, B Suresh Krishna, Pascal Fries","doi":"10.1101/2025.03.27.645661","DOIUrl":"https://doi.org/10.1101/2025.03.27.645661","url":null,"abstract":"<p><p>Neuronal coding and decoding would be compromised if neuronal responses were highly variable. Intriguingly, neuronal spike counts (SCs) show a reduction in across-trial variance (ATV) in response to sensory stimulation, when SC variance is normalized by SC mean, that is, when using the Fano factor ¹ . Inspired by this seminal finding, ATV has also been studied in electroencephalography (EEG) signals, revealing effects of various stimulus and cognitive factors as well as disease states. Here, we empirically show that outside of evoked potentials, the ATV of the EEG or local field potential (LFP) is very highly correlated to the intra-trial variance (ITV), which corresponds to the well-known power metric. We propose that the LFP power, rather than the raw LFP signal, should be considered with regard to putative changes of its variability. We quantify LFP power variability as the standard deviation of the logarithm of the power ratio between an active and a baseline condition, normalized by the mean of that log(power ratio), that is the coefficient of variation (CV) of the log(power ratio). This CV(log(power ratio)) is reduced for gamma and alpha power when they are enhanced by stimulation, and it is enhanced for alpha power when it is reduced by stimulation. This suggests a potential inverse relation between changes in band-limited power and the corresponding CV. We propose that the CV(log(power ratio)) is a useful metric that can be computed for numerous existing and future LFP, EEG or MEG datasets, which will provide insights into those signals' frequency-specific variability and how they might be used for neuronal coding and decoding.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805408","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":"An Open-Source Deep Learning-Based GUI Toolbox For Automated Auditory Brainstem Response Analyses (ABRA).","authors":"Abhijeeth Erra, Jeffrey Chen, Cayla Miller, Elena Chrysostomou, Shannon Barret, Yasmin M Kassim, Rick Adam Friedman, Amanda Lauer, Federico Ceriani, Walter Marcotti, Cody Carroll, Uri Manor","doi":"10.1101/2024.06.20.599815","DOIUrl":"10.1101/2024.06.20.599815","url":null,"abstract":"<p><p>Hearing loss is a pervasive global health challenge with profound impacts on communication, cognitive function, and quality of life. Recent studies have established age-related hearing loss as a significant risk factor for dementia, highlighting the importance of hearing loss research. Auditory brainstem responses (ABRs), which are electrophysiological recordings of synchronized neural activity from the auditory nerve and brainstem, serve as in vivo readouts for sensory hair cell, synaptic integrity, hearing sensitivity, and other key features of auditory pathway functionality, making them highly valuable for both basic neuroscience research and clinical diagnostics. Despite their utility, traditional ABR analyses rely heavily on subjective manual interpretation, leading to considerable variability and limiting reproducibility across studies. Here, we introduce Auditory Brainstem Response Analyzer (ABRA), a novel open-source graphical user interface powered by deep learning, which automates and standardizes ABR waveform analysis. ABRA employs convolutional neural networks trained on diverse datasets collected from multiple experimental settings, achieving rapid and unbiased extraction of key ABR metrics, including peak amplitude, latency, and auditory threshold estimates. We demonstrate that ABRA's deep learning models provide performance comparable to expert human annotators while dramatically reducing analysis time and enhancing reproducibility across datasets from different laboratories. By bridging hearing research, sensory neuroscience, and advanced computational techniques, ABRA facilitates broader interdisciplinary insights into auditory function. An online version of the tool is available for use at no cost at https://abra.ucsd.edu.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474430","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-cell analysis of the epigenome and 3D chromatin architecture in the human retina.","authors":"Ying Yuan, Pooja Biswas, Nathan Zemke, Kelsey Dang, Yue Wu, Matteo D Antonio, Yang Xie, Qian Yang, Keyi Dong, Pik Ki Lau, Daofeng Li, Chad Seng, Weronika Bartosik, Justin Buchanan, Lin Lin, Ryan Lancione, Kangli Wang, Seoyeon Lee, Zane Gibbs, Joseph Ecker, Kelly Frazer, Ting Wang, Sebastian Preissl, Allen Wang, Radha Ayyagari, Bing Ren","doi":"10.1101/2024.12.28.630634","DOIUrl":"10.1101/2024.12.28.630634","url":null,"abstract":"<p><p>Most genetic risk variants linked to ocular diseases are non-protein coding and presumably contribute to disease through dysregulation of gene expression, however, deeper understanding of their mechanisms of action has been impeded by an incomplete annotation of the transcriptional regulatory elements across different retinal cell types. To address this knowledge gap, we carried out single-cell multiomics assays to investigate gene expression, chromatin accessibility, DNA methylome and 3D chromatin architecture in human retina, macula, and etinal pigment epithelium (RPE)/choroid. We identified 420,824 unique candidate regulatory elements and characterized their chromatin states in 23 sub-classes of retinal cells. Comparative analysis of chromatin landscapes between human and mouse retina cells further revealed both evolutionarily conserved and divergent retinal gene-regulatory programs. Leveraging the rapid advancements in deep-learning techniques, we developed sequence-based predictors to interpret non-coding risk variants of retina diseases. Our study establishes retina-wide, single-cell transcriptome, epigenome, and 3D genome atlases, and provides a resource for studying the gene regulatory programs of the human retina and relevant diseases.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11703273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961150","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":"Hierarchical glycolytic pathways control the carbohydrate utilization regulator in human gut Bacteroides.","authors":"Seth G Kabonick, Kamalesh Verma, Jennifer L Modesto, Victoria H Pearce, Kailyn M Winokur, Eduardo A Groisman, Guy E Townsend","doi":"10.1101/2024.11.13.623061","DOIUrl":"10.1101/2024.11.13.623061","url":null,"abstract":"<p><p>Human dietary choices control the gut microbiome. Industrialized populations consume abundant glucose and fructose, resulting in microbe-dependent intestinal disorders. Simple sugars inhibit the carbohydrate utilization regulator (Cur), a transcription factor in the prominent gut bacterial phylum, Bacteroidetes. Cur encodes products necessary for carbohydrate utilization, host immunomodulation, and intestinal colonization. Here, we demonstrate how simple sugars decrease Cur activity in the mammalian gut. Our findings in two Bacteroides species show that ATP-dependent fructose-1,6-bisphosphate (FBP) synthesis is necessary for glucose or fructose to inhibit Cur, but dispensable for growth because of an essential pyrophosphate (PPi)-dependent enzyme. Furthermore, we show that ATP-dependent FBP synthesis is required to regulate Cur in the gut but does not contribute to fitness when cur is absent, indicating PPi is sufficient to drive glycolysis in these bacteria. Our findings reveal how sugar-rich diets inhibit Cur, thereby disrupting Bacteroides fitness and diminishing products that are beneficial to the host.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142742072","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}