bioRxiv : the preprint server for biology最新文献

{"title":"Inflammasomes primarily restrict cytosolic <i>Salmonella</i> replication within human macrophages.","authors":"Marisa S Egan, Emily A O'Rourke, Shrawan Kumar Mageswaran, Biao Zuo, Inna Martynyuk, Tabitha Demissie, Emma N Hunter, Antonia R Bass, Yi-Wei Chang, Igor E Brodsky, Sunny Shin","doi":"10.1101/2023.07.17.549348","DOIUrl":"10.1101/2023.07.17.549348","url":null,"abstract":"<p><p><i>Salmonella enterica</i> serovar Typhimurium is a facultative intracellular pathogen that utilizes its type III secretion systems (T3SSs) to inject virulence factors into host cells and colonize the host. In turn, a subset of cytosolic immune receptors respond to T3SS ligands by forming multimeric signaling complexes called inflammasomes, which activate caspases that induce interleukin-1 (IL-1) family cytokine release and an inflammatory form of cell death called pyroptosis. Human macrophages mount a multifaceted inflammasome response to <i>Salmonella</i> infection that ultimately restricts intracellular bacterial replication. However, how inflammasomes restrict <i>Salmonella</i> replication remains unknown. We find that caspase-1 is essential for mediating inflammasome responses to <i>Salmonella</i> and restricting bacterial replication within human macrophages, with caspase-4 contributing as well. We also demonstrate that the downstream pore-forming protein gasdermin D (GSDMD) and Ninjurin-1 (NINJ1), a mediator of terminal cell lysis, play a role in controlling <i>Salmonella</i> replication in human macrophages. Notably, in the absence of inflammasome responses, we observed hyperreplication of <i>Salmonella</i> within the cytosol of infected cells as well as increased bacterial replication within vacuoles, suggesting that inflammasomes control <i>Salmonella</i> replication primarily within the cytosol and also within vacuoles. These findings reveal that inflammatory caspases and pyroptotic factors mediate inflammasome responses that restrict the subcellular localization of intracellular <i>Salmonella</i> replication within human macrophages.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e9/ac/nihpp-2023.07.17.549348v1.PMC10370064.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9986540","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":"Sparse Annotation is Sufficient for Bootstrapping Dense Segmentation.","authors":"Vijay Venu Thiyagarajan, Arlo Sheridan, Kristen M Harris, Uri Manor","doi":"10.1101/2024.06.14.599135","DOIUrl":"10.1101/2024.06.14.599135","url":null,"abstract":"<p><p>Producing dense 3D reconstructions from biological imaging data is a challenging instance segmentation task that requires significant ground-truth training data for effective and accurate deep learning-based models. Generating training data requires intense human effort to annotate each instance of an object across serial section images. Our focus is on the especially complicated brain neuropil, comprising an extensive interdigitation of dendritic, axonal, and glial processes visualized through serial section electron microscopy. We developed a novel deep learning-based method to generate dense 3D segmentations rapidly from sparse 2D annotations of a few objects on single sections. Models trained on the rapidly generated segmentations achieved similar accuracy as those trained on expert dense ground-truth annotations. Human time to generate annotations was reduced by three orders of magnitude and could be produced by non-expert annotators. This capability will democratize generation of training data for large image volumes needed to achieve brain circuits and measures of circuit strengths.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11195258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141447700","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":"Macrophage-specific lipid nanoparticle therapy blocks the lung's mechanosensitive immunity due to macrophage-epithelial interactions.","authors":"Liberty Mthunzi, Mohammad N Islam, Galina A Gusarova, Sunita Bhattacharya, Brian Karolewski, Jahar Bhattacharya","doi":"10.1101/2023.05.24.541735","DOIUrl":"10.1101/2023.05.24.541735","url":null,"abstract":"<p><p>The lung's mechanosensitive immune response, which occurs when pulmonary alveoli are overstretched, is a major impediment to ventilation therapy for hypoxemic respiratory failure. The cause is not known. We tested the hypothesis that alveolar stretch causes stretch of alveolar macrophages (AMs), leading to the immune response. In lungs viewed by optical imaging, sessile AMs expressed gap junctional protein connexin-43 (Cx43), and they communicated with the alveolar epithelium through gap junctions. Alveolar hyperinflation increased Ca²⁺ in the AMs but did not stretch the AMs. The Ca²⁺ response, and concomitant TNFα secretion by AMs were blocked in mice with AM-specific deletion of Cx43. The AM responses, as also lung injury due to mechanical ventilation at high tidal volume, were inhibited by AM-specific delivery of lipid nanoparticles containing Xestospongin C, which blocked the induced Ca²⁺ increases. We conclude, Cx43- and Ca²⁺-dependent AM-epithelial interactions determine the lung's mechanosensitive immunity, providing a basis for therapy for ventilator-induced lung injury.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/93/5f/nihpp-2023.05.24.541735v1.PMC10245918.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9991436","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":"ATR promotes mTORC1 activity via <i>de novo</i> cholesterol synthesis.","authors":"Naveen Kumar Tangudu, Alexandra N Grumet, Richard Fang, Raquel Buj, Aidan R Cole, Apoorva Uboveja, Amandine Amalric, Baixue Yang, Zhentai Huang, Cassandra Happe, Mai Sun, Stacy L Gelhaus, Matthew L MacDonald, Nadine Hempel, Nathaniel W Snyder, Katarzyna M Kedziora, Alexander J Valvezan, Katherine M Aird","doi":"10.1101/2023.10.27.564195","DOIUrl":"10.1101/2023.10.27.564195","url":null,"abstract":"<p><p>DNA damage and cellular metabolism exhibit a complex interplay characterized by bidirectional feedback mechanisms. Key mediators of the DNA damage response and cellular metabolic regulation include Ataxia Telangiectasia and Rad3-related protein (ATR) and the mechanistic Target of Rapamycin Complex 1 (mTORC1), respectively. Previous studies have established ATR as a regulatory upstream factor of mTORC1 during replication stress; however, the precise mechanisms by which mTORC1 is activated in this context remain poorly defined. Additionally, the activity of this signaling axis in unperturbed cells has not been extensively investigated. Here, we demonstrate that ATR promotes mTORC1 activity across various cellular models under basal conditions. This effect is particularly enhanced in cells following the loss of p16, which we have previously associated with hyperactivation of mTORC1 signaling and here found have increased ATR activity. Mechanistically, we found that ATR promotes <i>de novo</i> cholesterol synthesis and mTORC1 activation through the upregulation of lanosterol synthase (LSS), independently of both CHK1 and the TSC complex. Furthermore, the attenuation of mTORC1 activity resulting from ATR inhibition was rescued by supplementation with lanosterol or cholesterol in multiple cellular contexts. This restoration corresponded with enhanced localization of mTOR to the lysosome. Collectively, our findings demonstrate a novel connection linking ATR and mTORC1 signaling through the modulation of cholesterol metabolism.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10634888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92157626","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":"Leveraging a new data resource to define the response of <i>C. neoformans</i> to environmental signals: How host-like signals drive gene expression and capsule expansion in <i>Cryptococcus neoformans</i>.","authors":"Yu Sung Kang, Jeffery Jung, Holly Brown, Chase Mateusiak, Tamara L Doering, Michael R Brent","doi":"10.1101/2023.04.19.537239","DOIUrl":"10.1101/2023.04.19.537239","url":null,"abstract":"<p><p><i>Cryptococcus neoformans</i> is an opportunistic fungal pathogen with a polysaccharide capsule that becomes greatly enlarged in the mammalian host and during <i>in vitro</i> growth under host-like conditions. To understand how individual environmental signals affect capsule size and gene expression, we grew cells in all combinations of five signals implicated in capsule size and systematically measured cell and capsule sizes. We also sampled these cultures over time and performed RNA-Seq in quadruplicate, yielding 881 RNA-Seq samples. Analysis of the resulting data sets showed that capsule induction in tissue culture medium, typically used to represent host-like conditions, requires the presence of either CO₂ or exogenous cyclic AMP (cAMP). Surprisingly, adding either of these pushes overall gene expression in the opposite direction from tissue culture media alone, even though both are required for capsule development. Another unexpected finding was that rich medium blocks capsule growth completely. Statistical analysis further revealed many genes whose expression is associated with capsule thickness; deletion of one of these significantly reduced capsule size. Beyond illuminating capsule induction, our massive, uniformly collected dataset will be a significant resource for the research community.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/94/3f/nihpp-2023.04.19.537239v1.PMC10153387.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9467037","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 in the Bone Morphogenetic Protein signaling pathway sensitize zebrafish and humans to ethanol-induced jaw malformations.","authors":"John R Klem, Tae-Hwi Schwantes-An, Marco Abreu, Michael Suttie, Raeden Gray, Hieu Vo, Grace Conley, Tatiana M Foroud, Leah Wetherill, C Ben Lovely","doi":"10.1101/2023.06.28.546932","DOIUrl":"10.1101/2023.06.28.546932","url":null,"abstract":"<p><p>Fetal Alcohol Spectrum Disorders (FASD) describe ethanol-induced developmental defects including craniofacial malformations. While ethanol-sensitive genetic mutations contribute to facial malformations, the impacted cellular mechanisms remain unknown. Bmp signaling is a key regulator of epithelial morphogenesis driving facial development, providing a possible ethanol-sensitive mechanism. We found that zebrafish mutants for Bmp signaling components are ethanol-sensitive and affect anterior pharyngeal endoderm shape and gene expression, indicating ethanol-induced malformations of the anterior pharyngeal endoderm cause facial malformations. Integrating FASD patient data, we provide the first evidence that variants in the human Bmp receptor gene <i>BMPR1B</i> associate with ethanol-related differences in jaw volume. Our results show that ethanol exposure disrupts proper morphogenesis of, and tissue interactions between, facial epithelia that mirror overall viscerocranial shape changes and are predictive for Bmp-ethanol associations in human jaw development. Our data provide a mechanistic paradigm linking ethanol to disrupted epithelial cell behaviors that underlie facial defects in FASD.</p><p><strong>Summary statement: </strong>In this study, we apply a unique combination of zebrafish-based approaches and human genetic and facial dysmorphology analyses to resolve the cellular mechanisms driven by the ethanol-sensitive Bmp pathway.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10327032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9813588","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":"FORMATION OF MALIGNANT, METASTATIC SMALL CELL LUNG CANCERS THROUGH OVERPRODUCTION OF cMYC PROTEIN IN TP53 AND RB1 DEPLETED PULMONARY NEUROENDOCRINE CELLS DERIVED FROM HUMAN EMBRYONIC STEM CELLS.","authors":"Huanhuan Joyce Chen, Eric E Gardner, Yajas Shah, Kui Zhang, Abhimanyu Thakur, Chen Zhang, Olivier Elemento, Harold Varmus","doi":"10.1101/2023.10.06.561244","DOIUrl":"10.1101/2023.10.06.561244","url":null,"abstract":"<p><p>We recently described our initial efforts to develop a model for small cell lung cancer (SCLC) derived from human embryonic stem cells (hESCs) that were differentiated to form pulmonary neuroendocrine cells (PNECs), a putative cell of origin for neuroendocrine-positive SCLC. Although reduced expression of the tumor suppressor genes <i>TP53</i> and <i>RB1</i> allowed the induced PNECs to form subcutaneous growths in immune-deficient mice, the tumors did not display the aggressive characteristics of SCLC seen in human patients. Here we report that the additional, doxycycline-regulated expression of a transgene encoding wild-type or mutant cMYC protein promotes rapid growth, invasion, and metastasis of these hESC-derived cells after injection into the renal capsule. Similar to others, we find that the addition of cMYC encourages the formation of the SCLC-N subtype, marked by high levels of <i>NEUROD1</i> RNA. Using paired primary and metastatic samples for RNA sequencing, we observe that the subtype of SCLC does not change upon metastatic spread and that production of NEUROD1 is maintained. We also describe histological features of these malignant, SCLC-like tumors derived from hESCs and discuss potential uses of this model in efforts to control and better understand this recalcitrant neoplasm.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5f/d3/nihpp-2023.10.06.561244v1.PMC10592623.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49694525","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 transcriptionally active lipid vesicle encloses the injected <i>Chimalliviridae</i> genome in early infection.","authors":"Emily G Armbruster, Phoolwanti Rani, Jina Lee, Niklas Klusch, Joshua Hutchings, Lizbeth Y Hoffman, Hannah Buschkaemper, Eray Enustun, Benjamin A Adler, Koe Inlow, Arica R VanderWal, Madelynn Y Hoffman, Daksh Daksh, Ann Aindow, Amar Deep, Zaida K Rodriguez, Chase J Morgan, Majid Ghassemian, Thomas G Laughlin, Emeric Charles, Brady F Cress, David F Savage, Jennifer A Doudna, Kit Pogliano, Kevin D Corbett, Elizabeth Villa, Joe Pogliano","doi":"10.1101/2023.09.20.558163","DOIUrl":"10.1101/2023.09.20.558163","url":null,"abstract":"<p><p>Many eukaryotic viruses require membrane-bound compartments for replication, but no such organelles are known to be formed by prokaryotic viruses^1-3. Bacteriophages of the <i>Chimalliviridae</i> family sequester their genomes within a phage-generated organelle, the phage nucleus, which is enclosed by a lattice of the viral protein ChmA^4-10. Previously, we observed lipid membrane-bound vesicles in cells infected by <i>Chimalliviridae</i>, but due to the paucity of genetics tools for these viruses it was unknown if these vesicles represented unproductive, abortive infections or a <i>bona fide</i> stage in the phage life cycle. Using the recently-developed dRfxCas13d-based knockdown system CRISPRi-ART¹¹ in combination with fluorescence microscopy and cryo-electron tomography, we show that inhibiting phage nucleus formation arrests infections at an early stage in which the injected phage genome is enclosed within a membrane-bound early phage infection (EPI) vesicle. We demonstrate that early phage genes are transcribed by the virion-associated RNA polymerase from the genome within the compartment, making the EPI vesicle the first known example of a lipid membrane-bound organelle that separates transcription from translation in prokaryotes. Further, we show that the phage nucleus is essential for the phage life cycle, with genome replication only beginning after the injected DNA is transferred from the EPI vesicle to the newly assembled phage nucleus. Our results show that <i>Chimalliviridae</i> require two sophisticated subcellular compartments of distinct compositions and functions that facilitate successive stages of the viral life cycle.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/be/81/nihpp-2023.09.20.558163v1.PMC10541120.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41143585","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 gene expression signature of electrical stimulation in the human brain.","authors":"Snehajyoti Chatterjee, Yann Vanrobaeys, Annie I Gleason, Brian J Park, Shane A Heiney, Ariane E Rhone, Kirill V Nourski, Lucy Langmack, Budhaditya Basu, Utsav Mukherjee, Christopher K Kovach, Zsuzsanna Kocsis, Yukiko Kikuchi, Yaneri A Ayala, Christopher I Petkov, Marco M Hefti, Ethan Bahl, Jacob J Michaelson, Hiroto Kawasaki, Hiroyuki Oya, Matthew A Howard, Thomas Nickl-Jockschat, Li-Chun Lin, Ted Abel","doi":"10.1101/2023.09.21.558812","DOIUrl":"10.1101/2023.09.21.558812","url":null,"abstract":"<p><p>Direct electrical stimulation has been used for decades as a gold standard clinical tool to map cognitive function in neurosurgery patients^1-8. However, the molecular impact of electrical stimulation in the human brain is unknown. Here, using state-of-the-art transcriptomic and epigenomic sequencing techniques, we define the molecular changes in bulk tissue and at the single-cell level in the human cerebral cortex following direct electrical stimulation of the anterior temporal lobe in patients undergoing neurosurgery. Direct electrical stimulation surprisingly had a robust and consistent impact on the expression of genes related to microglia-specific cytokine activity, an effect that was replicated in mice. Using a newly developed deep learning computational tool, we further demonstrate cell type-specific molecular activation, which underscores the effects of electrical stimulation on gene expression in microglia. Taken together, this work challenges the notion that the immediate impact of electrical stimulation commonly used in the clinic has a primary effect on neuronal gene expression and reveals that microglia robustly respond to electrical stimulation, thus enabling these non-neuronal cells to sculpt and shape the activity of neuronal circuits in the human brain.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/cf/61/nihpp-2023.09.21.558812v1.PMC10542502.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41179661","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":"Multimodal subspace independent vector analysis effectively captures the latent relationships between brain structure and function.","authors":"Xinhui Li, Peter Kochunov, Tulay Adali, Rogers F Silva, Vince D Calhoun","doi":"10.1101/2023.09.17.558092","DOIUrl":"10.1101/2023.09.17.558092","url":null,"abstract":"<p><p>A key challenge in neuroscience is to understand the structural and functional relationships of the brain from high-dimensional, multimodal neuroimaging data. While conventional multivariate approaches often simplify statistical assumptions and estimate one-dimensional independent sources shared across modalities, the relationships between true latent sources are likely more complex - statistical dependence may exist within and between modalities, and span one or more dimensions. Here we present Multimodal Subspace Independent Vector Analysis (MSIVA), a methodology to capture both joint and unique vector sources from multiple data modalities by defining both cross-modal and unimodal subspaces with variable dimensions. In particular, MSIVA enables flexible estimation of varying-size independent subspaces within modalities and their one-to-one linkage to corresponding subspaces across modalities. As we demonstrate, a main benefit of MSIVA is the ability to capture subject-level variability at the voxel level within independent subspaces, contrasting with the rigidity of traditional methods that share the same independent components across subjects. We compared MSIVA to a unimodal initialization baseline and a multimodal initialization baseline, and evaluated all three approaches with five candidate subspace structures on both synthetic and neuroimaging datasets. We show that MSIVA successfully identified the ground-truth subspace structures in multiple synthetic datasets, while the multimodal baseline failed to detect high-dimensional subspaces. We then demonstrate that MSIVA better detected the latent subspace structure in two large multimodal neuroimaging datasets including structural MRI (sMRI) and functional MRI (fMRI), compared with the unimodal baseline. From subsequent subspace-specific canonical correlation analysis, brain-phenotype prediction, and voxelwise brain-age delta analysis, our findings suggest that the estimated sources from MSIVA with optimal subspace structure are strongly associated with various phenotype variables, including age, sex, schizophrenia, lifestyle factors, and cognitive functions. Further, we identified modality- and group-specific brain regions related to multiple phenotype measures such as age (e.g., cerebellum, precentral gyrus, and cingulate gyrus in sMRI; occipital lobe and superior frontal gyrus in fMRI), sex (e.g., cerebellum in sMRI, frontal lobe in fMRI, and precuneus in both sMRI and fMRI), schizophrenia (e.g., cerebellum, temporal pole, and frontal operculum cortex in sMRI; occipital pole, lingual gyrus, and precuneus in fMRI), shedding light on phenotypic and neuropsychiatric biomarkers of linked brain structure and function.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10516023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41174660","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}