bioRxiv : the preprint server for biology最新文献

{"title":"Working memory readout varies with frontal theta rhythms.","authors":"Hio-Been Han, Scott L Brincat, Timothy J Buschman, Earl K Miller","doi":"10.1101/2025.03.27.645781","DOIUrl":"https://doi.org/10.1101/2025.03.27.645781","url":null,"abstract":"<p><p>Increasing evidence suggests that attention varies rhythmically, phase-locked to ongoing cortical oscillations. Here, we report that the phase of theta oscillations (3-6 Hz) in the frontal eye field (FEF) is associated with temporal and spatial variation of the read-out of information from working memory (WM). Non-human primates were briefly shown a sample array of colored squares. A short time later, they viewed a test array and were rewarded for identifying which square changed color (the target). Better performance (accuracy and reaction time) varied systematically with the phase of local field potential (LFP) theta at the time of test array onset as well as the target's location. This is consistent with theta \"scanning\" across the FEF and thus visual space from top to bottom. Theta was coupled, on opposing phases, to both spiking and beta (12-20 Hz). These results could be explained by a wave of activity that moves across the FEF, modulating the readout of information from WM.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805548","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":"Contrastive Learning Enables Epitope Overlap Predictions for Targeted Antibody Discovery.","authors":"Clinton M Holt, Alexis K Janke, Parastoo B Amlashi, Toma M Marinov, Ivelin S Georgiev","doi":"10.1101/2025.02.25.640114","DOIUrl":"10.1101/2025.02.25.640114","url":null,"abstract":"<p><p>Computational epitope prediction remains an unmet need for therapeutic antibody development. We present three complementary approaches for predicting epitope relationships from antibody amino acid sequences. First, we analyze ~18 million antibody pairs targeting ~250 protein families and establish that a threshold of >70% CDRH3 sequence identity among antibodies sharing both heavy and light chain V-genes reliably predicts overlapping-epitope antibody pairs. Next, we develop a supervised contrastive fine-tuning framework for antibody large language models which results in embeddings that better correlate with epitope information than those from pre-trained models. Applying this contrastive learning approach to SARS-CoV-2 receptor binding domain antibodies, we achieve 82.7% balanced accuracy in distinguishing same-epitope versus different-epitope antibody pairs and demonstrate the ability to predict relative levels of structural overlap from learning on functional epitope bins (Spearman ρ = 0.25). Finally, we create AbLang-PDB, a generalized model for predicting overlapping-epitope antibodies for a broad range of protein families. AbLang-PDB achieves five-fold improvement in average precision for predicting overlapping-epitope antibody pairs compared to sequence-based methods, and effectively predicts the amount of epitope overlap among overlapping-epitope pairs (ρ = 0.81). In an antibody discovery campaign searching for overlapping-epitope antibodies to the HIV-1 broadly neutralizing antibody 8ANC195, 70% of computationally selected candidates demonstrated HIV-1 specificity, with 50% showing competitive binding with 8ANC195. Together, the computational models presented here provide powerful tools for epitope-targeted antibody discovery, while demonstrating the efficacy of contrastive learning for improving epitope-representation.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589379","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":"Force transmission through the inner kinetochore is enhanced by centromeric DNA sequences.","authors":"Elise Miedlar, Grace E Hamilton, Samuel R Witus, Sara J Gonske, Michael Riffle, Alex Zelter, Rachel E Klevit, Charles L Asbury, Yoana N Dimitrova, Trisha N Davis","doi":"10.1101/2024.11.13.623448","DOIUrl":"10.1101/2024.11.13.623448","url":null,"abstract":"<p><p>Previously, we reconstituted a minimal functional kinetochore from recombinant <i>S. cerevisiae</i> proteins that was capable of transmitting force from dynamic microtubules to nucleosomes containing the centromere-specific histone variant Cse4 (Hamilton et al. 2020). This work revealed two paths of force transmission through the inner kinetochore: through Mif2 and through the Okp1/Ame1 complex (OA). Here, using a chimeric DNA sequence that contains crucial centromere-determining elements of the budding yeast point centromere, we demonstrate that the presence of centromeric DNA sequences in Cse4-containing nucleosomes significantly strengthens OA-mediated linkages. Our findings indicate that centromeric sequences are important for the transmission of microtubule-based forces to the chromosome.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601294/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142742112","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 Commander-independent function of COMMD3 in endosomal trafficking.","authors":"Galen T Squiers, Chun Wan, James Gorder, Harrison Puscher, Jingshi Shen","doi":"10.1101/2024.12.12.628173","DOIUrl":"10.1101/2024.12.12.628173","url":null,"abstract":"<p><p>Endosomal recycling is a branch of intracellular membrane trafficking that retrieves endocytosed cargo proteins from early and late endosomes to prevent their degradation in lysosomes. A key player in endosomal recycling is the Commander complex, a 16-subunit protein assembly that cooperates with other endosomal factors to recruit cargo proteins and facilitate the formation of tubulo-vesicular carriers. While the crucial role of Commander in endosomal recycling is well established, its molecular mechanism remains poorly understood. Here, we genetically dissected the Commander complex using unbiased genetic screens and comparative targeted mutations. Unexpectedly, our findings revealed a Commander-independent function for COMMD3, a subunit of the Commander complex, in endosomal recycling. COMMD3 regulates a subset of cargo proteins independently of the other Commander subunits. The Commander-independent function of COMMD3 is mediated by its N-terminal domain (NTD), which binds and stabilizes ADP-ribosylation factor 1 (ARF1), a small GTPase regulating endosomal recycling. Mutations disrupting the COMMD3-ARF1 interaction diminish ARF1 expression and impair COMMD3-dependent cargo recycling. These data provide direct evidence that Commander subunits can function outside the holo-complex and raise the intriguing possibility that components of other membrane trafficking complexes may also possess functions beyond their respective complexes.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11702528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961114","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 miniature CRISPR-Cas10 enzyme confers immunity by an inverse signaling pathway.","authors":"Erin E Doherty, Benjamin A Adler, Peter H Yoon, Kendall Hsieh, Kenneth Loi, Emily G Armbuster, Arushi Lahiri, Cydni S Bolling, Xander E Wilcox, Amogha Akkati, Anthony T Iavarone, Joe Pogliano, Jennifer A Doudna","doi":"10.1101/2025.03.28.646030","DOIUrl":"https://doi.org/10.1101/2025.03.28.646030","url":null,"abstract":"<p><p>Microbial and viral co-evolution has created immunity mechanisms involving oligonucleotide signaling that share mechanistic features with human anti-viral systems ¹ . In these pathways, including CBASS and type III CRISPR systems in bacteria and cGAS-STING in humans, oligonucleotide synthesis occurs upon detection of virus or foreign genetic material in the cell, triggering the antiviral response ^2-4 . In a surprising inversion of this process, we show here that the CRISPR-related enzyme mCpol synthesizes cyclic oligonucleotides constitutively as part of an active mechanism that maintains cell health. Cell-based experiments demonstrated that the absence or loss of mCpol-produced cyclic oligonucleotides triggers cell death, preventing spread of viruses that attempt immune evasion by depleting host cyclic nucleotides. Structural and mechanistic investigation revealed mCpol to be a di-adenylate cyclase whose product, c-di-AMP, prevents toxic oligomerization of the effector protein 2TMβ. Analysis of cells by fluorescence microscopy showed that lack of mCpol allows 2TMβ-mediated cell death due to inner membrane collapse. These findings unveil a powerful new defense strategy against virus-mediated immune suppression, expanding our understanding of oligonucleotides in cell health and disease. These results raise the possibility of similar protective roles for cyclic oligonucleotides in other organisms including humans.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805271","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":"Combining a rhesus cytomegalovirus/SIV vaccine with neutralizing antibody to protect against SIV challenge in rhesus macaques.","authors":"Jessica Coppola, Mara Parren, Raiza Bastidas, Karen Saye-Francisco, Jacqueline Malvin, Joseph G Jardine, Roxanne M Gilbride, Sohita Ojha, Shana Feltham, David Morrow, Aaron Barber-Axthelm, Rachele Bochart, Randy Fast, Kelli Oswald, Rebecca Shoemaker, Jeffrey D Lifson, Louis J Picker, Dennis R Burton, Scott G Hansen","doi":"10.1101/2025.03.20.644395","DOIUrl":"https://doi.org/10.1101/2025.03.20.644395","url":null,"abstract":"<p><p>A vaccine is widely regarded as necessary for the control of the HIV pandemic and eventual eradication of AIDS. Neutralizing antibodies and MHC-E-restricted CD8+ T cells have both been shown capable of vaccine protection against the simian counterpart of HIV, SIV, in rhesus macaques. Here we provide preliminary evidence that combining these orthogonal antiviral mechanisms can provide increased protection against SIV challenge such that replication arrest observed following vaccination with a rhesus cytomegalovirus (RhCMV/SIV)-based vaccine was enhanced in the presence of passively administered incompletely protective levels of neutralizing antibody. The report invites studies involving larger cohorts of macaques and alternate routes of providing neutralizing antibody.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805378","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":"Landscape and regulation of new protein translation in the early C. elegans embryo.","authors":"Yash Shukla, Vighnesh Ghatpande, Cindy F Hu, Daniel J Dickinson, Can Cenik","doi":"10.1101/2024.12.13.628416","DOIUrl":"10.1101/2024.12.13.628416","url":null,"abstract":"<p><p>Translation of maternal mRNAs is crucial for early embryonic development. In C. elegans, cell fates become determined from the first division without new transcription, making this organism ideal for studying post-transcriptional regulation of lineage specification. Using low-input ribosome profiling combined with RNA sequencing on precisely staged embryos, we measured protein translation during the first four cell cycles of C. elegans development. We uncovered stage-specific patterns of developmentally coordinated translational regulation. We found that mRNA localization correlates with translational efficiency, though initial translational repression in germline precursors occurs prior to P-granule association. The RNA-binding protein OMA-1 emerged as a key regulator of translational efficiency in a stage-specific manner. These findings illuminate how post-transcriptional mechanisms shape the embryonic proteome to direct cell differentiation, with implications for understanding similar regulation across species where maternal factors guide early development.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11741243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018633","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":"Mutations that prevent phosphorylation of the BMP4 prodomain impair proteolytic maturation of homodimers leading to lethality in mice.","authors":"Hyung-Seok Kim, Mary L Sanchez, Joshua Silva, Heidi L Schubert, Rebecca Dennis, Christopher P Hill, Jan L Christian","doi":"10.1101/2024.10.08.617306","DOIUrl":"10.1101/2024.10.08.617306","url":null,"abstract":"<p><p>Bone morphogenetic protein4 (BMP4) plays numerous roles during embryogenesis and can signal either alone as a homodimer, or together with BMP7 as a more active heterodimer. BMPs are generated as inactive precursor proteins that dimerize and are cleaved to generate the bioactive ligand and inactive prodomain fragments. In humans, heterozygous mutations within the prodomain of BMP4 are associated with birth defects. We studied the effect of two of these mutations (p.S91C and p.E93G), which disrupt a conserved FAM20C phosphorylation motif, on ligand activity. We compared the activity of ligands generated from BMP4, BMP4S91C or BMP4E93G in Xenopus embryos and found that these mutations reduce the activity of BMP4 homodimers but not BMP4/7 heterodimers. We generated Bmp4S91C and Bmp4E93G knock-in mice and found that Bmp4S91C/S91C mice die by E11.5 and display reduced BMP activity in multiple tissues including the heart. Most Bmp4E93G/E93G mice die before weaning and Bmp4-/E93G mutants die prenatally with reduced or absent eyes, heart and ventral body wall closure defects. Mouse embryonic fibroblasts (MEFs) isolated from Bmp4S91C and Bmp4E93G embryos show accumulation of BMP4 precursor protein, reduced levels of cleaved BMP ligand and reduced BMP activity relative to MEFs from wild type littermates. Because Bmp7 is not expressed in MEFs, the accumulation of unprocessed BMP4 precursor protein in mice carrying these mutations most likely reflects an inability to cleave BMP4 homodimers, leading to reduced levels of ligand and BMP activity in vivo. Our results suggest that phosphorylation of the BMP4 prodomain is required for proteolytic activation of BMP4 homodimers, but not heterodimers.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142485498","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":"Cognitive reserve linked to network-specific brain-ventricle coupling.","authors":"Fulvia Francesca Campo, Elvira Brattico, Vânia Miguel, Vicente Magalhaes, Salvatore Nigro, Benedetta Tafuri, Giancarlo Logroscino, Joana Cabral","doi":"10.1101/2025.01.04.631289","DOIUrl":"10.1101/2025.01.04.631289","url":null,"abstract":"<p><p>Despite showing significant impact in cognitive preservation, the relationship between brain activity captured with functional Magnetic Resonance Imaging (fMRI) in gray matter and ventricular cerebrospinal fluid dynamics remains poorly understood. We analyzed 599 fMRI scans from 163 elderly participants at rest with varying degrees of cognitive impairment employing a unified phase coupling analysis that breaks from convention by incorporating both tissue and ventricular signal fluctuations. This whole-brain approach identified distinct brain-ventricle coupling modes that differentiate between cognitive status groups and correlate with specific cognitive abilities. Beyond the previously reported anti-phase coupling between global brain signals and ventricles-which we confirm occurs more frequently in cognitively normal controls-our analysis method uncovered additional coupling modes where signals in specific brain networks temporarily align with ventricle signals. At the cortical level, these modes reveal patterns corresponding to known resting-state networks: one overlapping with the Default Mode Network occurs significantly less frequently in Alzheimer's Disease patients, while another revealing the Frontoparietal Network correlates positively with memory scores. Our findings demonstrate that different brain-ventricle coupling modes correlate with specific cognitive domains, with particular modes predicting memory, executive function, and visuospatial abilities. The coupling between signals in brain ventricles and established resting-state networks challenges our current understanding of functional network formation, suggesting an integral link with brain fluid motion. This reconceptualization of brain dynamics through the lens of fluid-tissue interactions establishes a fundamental physical basis for cognitive preservation, suggesting that therapeutic interventions targeting these interactions may prove more effective than approaches focused solely on cellular or molecular mechanisms.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974359","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":"MPAC: a computational framework for inferring pathway activities from multi-omic data.","authors":"Peng Liu, David Page, Paul Ahlquist, Irene M Ong, Anthony Gitter","doi":"10.1101/2024.06.15.599113","DOIUrl":"10.1101/2024.06.15.599113","url":null,"abstract":"<p><p>Fully capturing cellular state requires examining genomic, epigenomic, transcriptomic, proteomic, and other assays for a biological sample and comprehensive computational modeling to reason with the complex and sometimes conflicting measurements. Modeling these so-called multi-omic data is especially beneficial in disease analysis, where observations across omic data types may reveal unexpected patient groupings and inform clinical outcomes and treatments. We present Multi-omic Pathway Analysis of Cells (MPAC), a computational framework that interprets multi-omic data through prior knowledge from biological pathways. MPAC uses network relationships encoded in pathways using a factor graph to infer consensus activity levels for proteins and associated pathway entities from multi-omic data, runs permutation testing to eliminate spurious activity predictions, and groups biological samples by pathway activities to prioritize proteins with potential clinical relevance. Using DNA copy number alteration and RNA-seq data from head and neck squamous cell carcinoma patients from The Cancer Genome Atlas as an example, we demonstrate that MPAC predicts a patient subgroup related to immune responses not identified by analysis with either input omic data type alone. Key proteins identified via this subgroup have pathway activities related to clinical outcome as well as immune cell compositions. Our MPAC R package, available at https://bioconductor.org/packages/MPAC, enables similar multi-omic analyses on new datasets.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474583","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}