bioRxiv : the preprint server for biology最新文献

{"title":"Comparative analyses of disease-linked missense mutations in the RNA exosome modeled in budding yeast reveal distinct functional consequences in translation.","authors":"Maria C Sterrett, Lauryn A Cureton, Lauren N Cohen, Ambro van Hoof, Sohail Khoshnevis, Milo B Fasken, Anita H Corbett, Homa Ghalei","doi":"10.1101/2023.10.18.562946","DOIUrl":"10.1101/2023.10.18.562946","url":null,"abstract":"<p><p>The RNA exosome is a multi-subunit, evolutionarily conserved ribonuclease complex that is essential for processing, decay and surveillance of many cellular RNAs. Missense mutations in genes encoding the structural subunits of the RNA exosome complex cause a diverse range of diseases, collectively known as RNA exosomopathies, often involving neurological and developmental defects. The varied symptoms suggest that different mutations lead to distinct in vivo consequences. To investigate these functional consequences and distinguish whether they are unique to each RNA exosomopathy mutation, we generated a collection of in vivo models by introducing pathogenic missense mutations in orthologous S. cerevisiae genes. Comparative RNA-seq analysis assessing broad transcriptomic changes in each mutant model revealed that three yeast mutant models, <i>rrp4-G226D</i> , <i>rrp40-W195R</i> and <i>rrp46-L191H</i> , which model mutations in the genes encoding <i>EXOSC2</i> , <i>EXOSC3</i> and <i>EXOSC5</i> , respectively, had the largest transcriptomic differences. While some transcriptomic changes, particularly in transcripts related to ribosome biogenesis, were shared among mutant models, each mutation also induced unique transcriptomic changes. Thus, our data suggests that while there are some shared consequences, there are also distinct differences in RNA exosome function by each variant. Assessment of ribosome biogenesis and translation defects in the three models revealed distinct differences in polysome profiles. Collectively, our results provide the first comparative analyses of RNA exosomopathy mutant models and suggest that different RNA exosome gene mutations result in in vivo consequences that are both unique and shared across each variant, providing further insight into the biology underlying each distinct pathology.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71415513","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":"Dynamically shifting from compositional to conjunctive brain representations supports cognitive task learning.","authors":"Ravi D Mill, Michael W Cole","doi":"10.1101/2023.06.27.546751","DOIUrl":"10.1101/2023.06.27.546751","url":null,"abstract":"<p><p>During cognitive task learning, neural representations must be rapidly constructed for novel task performance, then optimized for robust practiced task performance. How the geometry of neural representations changes to enable this transition from novel to practiced performance remains unknown. We hypothesized that practice involves a shift from compositional representations (task-general activity patterns that can be flexibly reused across tasks) to conjunctive representations (task-specific activity patterns specialized for the current task). Functional MRI during learning of multiple complex tasks substantiated this dynamic shift from compositional to conjunctive representations, which was associated with reduced cross-task interference (via pattern separation) and behavioral improvement. Further, we found that conjunctions originated in subcortex (hippocampus and cerebellum) and slowly spread to cortex, extending multiple memory systems theories to encompass cognitive task learning. The strengthening of conjunctive representations hence serves as a computational signature of learning, reflecting cortical-subcortical dynamics that optimize task representations in the human brain.</p><p><strong>Highlights: </strong>Learning shifts multi-task representations from compositional to conjunctive formatsCortical conjunctions uniquely associate with improved behavior and pattern separationThese conjunctions strengthen over separated learning events and index switch costsSubcortical regions are critical for cross-region binding of task rule information.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10327096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9865751","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":"Mechanistic Basis for Enhanced Strigolactone Sensitivity in KAI2 Triple Mutant.","authors":"Briana L Sobecks, Jiming Chen, Tanner J Dean, Diwakar Shukla","doi":"10.1101/2023.01.18.524622","DOIUrl":"10.1101/2023.01.18.524622","url":null,"abstract":"<p><p><i>Striga hermonthica</i> is a parasitic weed that destroys billions of dollars' worth of staple crops every year. Its rapid proliferation stems from an enhanced ability to me-tabolize strigolactones (SLs), plant hormones that direct root branching and shoot growth. <i>Striga's</i> SL receptor, <i>Sh</i> HTL7, bears more similarity to the staple crop kar-rikin receptor KAI2 than to SL receptor D14, though KAI2 variants in plants like <i>Arabidopsis thaliana</i> show minimal SL sensitivity. Recently, studies have indicated that a small number of point mutations to HTL7 residues can confer SL sensitivity to <i>At</i> KAI2. Here, we analyze both wild-type <i>At</i> KAI2 and SL-sensitive mutant Var64 through all-atom, long-timescale molecular dynamics simulations to determine the ef-fects of these mutations on receptor function at a molecular level. We demonstrate that the mutations stabilize SL binding by about 2 kcal/mol. They also result in a doubling of the average pocket volume, and eliminate the dependence of binding on certain pocket conformational arrangements. While the probability of certain non-binding SL-receptor interactions increases in the mutant compared with the wild-type, the rate of binding also increases by a factor of ten. All these changes account for the increased SL sensitivity in mutant KAI2, and suggest mechanisms for increasing functionality of host crop SL receptors.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9a/6f/nihpp-2023.01.18.524622v1.PMC9882355.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10657155","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":"Image-based identification and isolation of micronucleated cells to dissect cellular consequences.","authors":"Lucian DiPeso, Sriram Pendyala, Heather Z Huang, Douglas M Fowler, Emily M Hatch","doi":"10.1101/2023.05.04.539483","DOIUrl":"10.1101/2023.05.04.539483","url":null,"abstract":"<p><p>Recent advances in isolating cells based on visual phenotypes have transformed our ability to identify the mechanisms and consequences of complex traits. Micronucleus (MN) formation is a frequent outcome of genome instability, triggers extensive changes in genome structure and signaling coincident with MN rupture, and is almost exclusively defined by visual analysis. Automated MN detection in microscopy images has proved challenging, limiting discovery of the mechanisms and consequences of MN. In this study we describe two new MN segmentation modules: a rapid model for classifying micronucleated cells and their rupture status (VCS MN), and a robust model for accurate MN segmentation (MNFinder) from a broad range of cell lines. As proof-of-concept, we define the transcriptome of non-transformed human cells with intact or ruptured MN after chromosome missegregation by combining VCS MN with photoactivation-based cell isolation and RNASeq. Surprisingly, we find that neither MN formation nor rupture triggers a strong unique transcriptional response. Instead, transcriptional changes appear correlated with small increases in aneuploidy in these cell classes. Our MN segmentation modules overcome a significant challenge with reproducible MN quantification, and, joined with visual cell sorting, enable the application of powerful functional genomics assays to a wide-range of questions in MN biology.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10187275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9610318","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":"Glucose-stimulated KIF5B-driven microtubule sliding organizes microtubule networks in pancreatic β cells.","authors":"Kai M Bracey, Margret Fye, Alisa Cario, Kung-Hsien Ho, Pi'illani Noguchi, Guoqiang Gu, Irina Kaverina","doi":"10.1101/2023.06.25.546468","DOIUrl":"10.1101/2023.06.25.546468","url":null,"abstract":"<p><p>In pancreatic islet β cells, molecular motors use cytoskeletal polymers microtubules as tracks for intracellular transport of insulin secretory granules. β-cell microtubule network has a complex architecture and is non-directional, which provide insulin granules at the cell periphery for rapid secretion response, yet to avoid over-secretion and subsequent hypoglycemia. We have previously characterized a peripheral sub-membrane microtubule array, which is critical for withdrawal of excessive insulin granules from the secretion sites. Microtubules in β cells originate at the Golgi in the cell interior, and how the peripheral array is formed is unknown. Using real-time imaging and photo-kinetics approaches in clonal mouse pancreatic β cells MIN6, we now demonstrate that kinesin KIF5B, a motor protein with a capacity to transport microtubules as cargos, slides existing microtubules to the cell periphery and aligns them to each other along the plasma membrane. Moreover, like many physiological β-cell features, microtubule sliding is facilitated by a high glucose stimulus. These new data, together with our previous report that in high glucose sub-membrane MT array is destabilized to allow for robust secretion, indicate that MT sliding is another integral part of glucose-triggered microtubule remodeling, likely replacing destabilized peripheral microtubules to prevent their loss over time and β-cell malfunction.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ae/fa/nihpp-2023.06.25.546468v1.PMC10327020.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10168225","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":"How Occam's razor guides human decision-making.","authors":"Eugenio Piasini, Shuze Liu, Pratik Chaudhari, Vijay Balasubramanian, Joshua I Gold","doi":"10.1101/2023.01.10.523479","DOIUrl":"10.1101/2023.01.10.523479","url":null,"abstract":"<p><p>Occam's razor is the principle that, all else being equal, simpler explanations should be preferred over more complex ones. This principle is thought to guide human decision-making, but the nature of this guidance is not known. Here we used preregistered behavioral experiments to show that people tend to prefer the simpler of two alternative explanations for uncertain data. These preferences match predictions of formal theories of model selection that penalize excessive flexibility. These penalties emerge when considering not just the best explanation but the integral over all possible, relevant explanations. We further show that these simplicity preferences persist in humans, but not in certain artificial neural networks, even when they are maladaptive. Our results imply that principled notions of statistical model selection, including integrating over possible, latent causes to avoid overfitting to noisy observations, may play a central role in human decision-making.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9882019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10790279","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":"The distinct roles of MSH2 and MLH1 in basal-like breast cancer and immune modulation.","authors":"Tanzia Islam Tithi, Jiao Mo, Nicholas Borcherding, Sung Jo, Heather R Kates, Edward Cho, Kailey E Cash, Masayoshi Honda, Lei Wang, Kawther K Ahmed, Kalyanee Shirlekar, Li Chen, Katherine Gibson-Corley, Ronald Weigel, Maria Spies, Ryan Kolb, Weizhou Zhang","doi":"10.1101/2023.07.20.549745","DOIUrl":"10.1101/2023.07.20.549745","url":null,"abstract":"<p><p>The mismatch repair (MMR) pathway is known as a tumor suppressive pathway and genes involved in MMR are commonly mutated in hereditary colorectal or other cancer types. However, the function of MMR genes/proteins in breast cancer progression and metastasis are largely undefined. We found that MSH2, but not MLH1, is highly enriched in basal-like breast cancer (BLBC) and that its protein expression is inversely correlated with overall survival time (OS). <i>MSH2</i> expression is frequently elevated due to genomic amplification or gain-of-expression in BLBC, which results in increased MSH2 protein to pair with MSH6 (collectively referred to as MutSα). Genetic deletion of <i>MSH2</i> or <i>MLH1</i> results in a contrasting phenotype in metastasis, with <i>MSH2</i> -deletion leading to reduced metastasis and <i>MLH1</i> -deletion to enhanced liver or lung metastasis. Mechanistically, MSH2 - but not MLH1 - binds to the promoter region of interferon α receptor 1 ( <i>IFNAR1</i> ) and suppresses its expression in BLBC. Deletion of MSH2 initiates a chain of immune reactions via the upregulation of IFNAR1 expression and the activation of type 1 interferon signaling, which explains a highly immune active tumor microenvironment in tumors with MSH2-deficiency. Our study supports the contrasting functions of MSH2 and MLH1 in BLBC progression and metastasis due to the differential regulation of IFNAR1 expression, which challenges the paradigm of the MMR pathway as a universal tumor suppressive mechanism.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/86/bd/nihpp-2023.07.20.549745v2.PMC10515760.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41142416","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 Latent Activated Olfactory Stem Cell State Revealed by Single-Cell Transcriptomic and Epigenomic Profiling.","authors":"Koen Van den Berge, Dana Bakalar, Hsin-Jung Chou, Divya Kunda, Davide Risso, Kelly Street, Elizabeth Purdom, Sandrine Dudoit, John Ngai, Whitney Heavner","doi":"10.1101/2023.10.26.564041","DOIUrl":"10.1101/2023.10.26.564041","url":null,"abstract":"<p><p>The olfactory epithelium is one of the few regions of the nervous system that sustains neurogenesis throughout life. Its experimental accessibility makes it especially tractable for studying molecular mechanisms that drive neural regeneration in response to injury. In this study, we used single-cell sequencing to identify the transcriptional cascades and epigenetic processes involved in determining olfactory epithelial stem cell fate during injury-induced regeneration. By combining gene expression and accessible chromatin profiles of individual lineage-traced olfactory stem cells, we identified transcriptional heterogeneity among activated stem cells at a stage when cell fates are being specified. We further identified a subset of resting cells that appears poised for activation, characterized by accessible chromatin around wound response and lineage-specific genes prior to their later expression in response to injury. Together these results provide evidence for a latent activated stem cell state, in which a subset of quiescent olfactory epithelial stem cells are epigenetically primed to support injury-induced regeneration.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10634988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92157588","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":"Precise Spatial Tuning of Visually Driven Alpha Oscillations in Human Visual Cortex.","authors":"Kenichi Yuasa, Iris I A Groen, Giovanni Piantoni, Stephanie Montenegro, Adeen Flinker, Sasha Devore, Orrin Devinsky, Werner Doyle, Patricia Dugan, Daniel Friedman, Nick Ramsey, Natalia Petridou, Jonathan Winawer","doi":"10.1101/2023.02.11.528137","DOIUrl":"10.1101/2023.02.11.528137","url":null,"abstract":"<p><p>Neuronal oscillations at about 10 Hz, called alpha oscillations, are often thought to arise from synchronous activity across occipital cortex, reflecting general cognitive states such as arousal and alertness. However, there is also evidence that modulation of alpha oscillations in visual cortex can be spatially specific. Here, we used intracranial electrodes in human patients to measure alpha oscillations in response to visual stimuli whose location varied systematically across the visual field. We separated the alpha oscillatory power from broadband power changes. The variation in alpha oscillatory power with stimulus position was then fit by a population receptive field (pRF) model. We find that the alpha pRFs have similar center locations to pRFs estimated from broadband power (70-180 Hz) but are several times larger. The results demonstrate that alpha suppression in human visual cortex can be precisely tuned. Finally, we show how the pattern of alpha responses can explain several features of exogenous visual attention.</p><p><strong>Significance statement: </strong>The alpha oscillation is the largest electrical signal generated by the human brain. An important question in systems neuroscience is the degree to which this oscillation reflects system-wide states and behaviors such as arousal, alertness, and attention, versus much more specific functions in the routing and processing of information. We examined alpha oscillations at high spatial precision in human patients with intracranial electrodes implanted over visual cortex. We discovered a surprisingly high spatial specificity of visually driven alpha oscillations, which we quantified with receptive field models. We further use our discoveries about properties of the alpha response to show a link between these oscillations and the spread of visual attention.Grant support: NIH R01 MH111417 (Petridou, Winawer, Ramsey, Devinsky); JSPS Overseas Research Fellowship (Yuasa)The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9979988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9788874","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":"Transcriptome Complexity Disentangled: A Regulatory Molecules Approach.","authors":"Amir Asiaee, Zachary B Abrams, Heather H Pua, Kevin R Coombes","doi":"10.1101/2023.04.17.537241","DOIUrl":"10.1101/2023.04.17.537241","url":null,"abstract":"<p><p>Transcription factors (TFs) and microRNAs (miRNAs) are fundamental regulators of gene expression, cell state, and biological processes. This study investigated whether a small subset of TFs and miRNAs could accurately predict genome-wide gene expression. We analyzed 8895 samples across 31 cancer types from The Cancer Genome Atlas and identified 28 miRNA and 28 TF clusters using unsupervised learning. Medoids of these clusters could differentiate tissues of origin with 92.8% accuracy, demonstrating their biological relevance. We developed Tissue-Agnostic and Tissue-Aware models to predict 20,000 gene expressions using the 56 selected medoid miRNAs and TFs. The Tissue- Aware model attained an <i>R</i> ² of 0.70 by incorporating tissue-specific information. Despite measuring only 1/400th of the transcriptome, the prediction accuracy was comparable to that achieved by the 1000 landmark genes. This suggests the transcriptome has an intrinsically low-dimensional structure that can be captured by a few regulatory molecules. Our approach could enable cheaper transcriptome assays and analysis of low-quality samples. It also provides insights into genes that are heavily regulated by miRNAs/TFs versus alternative mechanisms. However, model transportability was impacted by dataset discrepancies, especially in miRNA distribution. Overall, this study demonstrates the potential of a biology-guided approach for robust transcriptome representation.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/07/ad/nihpp-2023.04.17.537241v2.PMC10153180.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9435398","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}